liu.seSearch for publications in DiVA
Change search
Refine search result
45678910 301 - 350 of 582
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 301.
    Kotti, Angeliki
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Department of Medical and Health Sciences.
    Holmqvist, Annica
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Albertsson, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Survival benefit of statins in older patients with rectal cancer: A Swedish population-based cohort study2019In: Journal of Geriatric Oncology, ISSN 1879-4068, E-ISSN 1879-4076Article in journal (Refereed)
    Abstract [en]

    Objectives

    Increasing evidence suggests that statins may have antitumor effects but their rolein rectal cancer appears inconclusive. The aim of this study was to investigate whether statins may have an impact on survival of older and younger patients with rectal cancer.

    Materials and Methods

    This study included 238 patients ≥70 years and 227 patients <70 years old, from the Southeast Health Care Region of Sweden, who were diagnosed with rectal adenocarcinoma between 2004 and 2013.

    Results

    In the older group (n = 238), statin use at the time of diagnosis was related to better cancer-specific survival (CSS) and overall survival (OS), compared to non-use (CSS: Hazard Ratio (HR), 0.37; 95% CI, 0.19–0.72; P = .003; OS: HR, 0.62; 95% CI, 0.39–0.96; P = .032). In the older group with stages I-III disease (n = 199), statin use was associated with better disease-free survival (DFS) compared to non use (HR, 0.18; 95% CI, 0.06–0.59; P = .005). The improvement of CSS, OS and DFS remained significant after adjusting for potential confounders. In the older group with stage III disease, statin users had better CSS and DFS compared to non-users (log rank P = .043; log-rank P = .028, respectively). In the older group with short course radiotherapy, statin use was related to better CSS (log-rank P = .032). No such association was present in the younger group.

    Conclusion

    Statin use was related to improved survival in older patients with rectal cancer.

    This observation is important given the low cost and safety of statins as a drug.

  • 302.
    Krauss, Tobias
    et al.
    Univ Freiburg, Germany.
    Ferrara, Alfonso Massimiliano
    IRCCS, Italy.
    Links, Thera P.
    Univ Groningen, Netherlands.
    Wellner, Ulrich
    Univ Lubeck, Germany.
    Bancoss, Irina
    Mayo Clin, MN USA.
    Kvachenyuk, Andrey
    NAMS Ukraine, Ukraine.
    Gomez de las Heras, Karim Villar
    Serv Salud Castilla La Mancha SESCAM, Spain.
    Yukina, Marina Y.
    Endocrinol Res Ctr, Russia.
    Petrov, Roman
    Bakhrushin Bros Moscow City Hosp, Russia.
    Bullivant, Garrett
    Univ Hlth Network, Canada.
    von Duecker, Laura
    Albert Ludwigs Univ, Germany.
    Jadhav, Swati
    King Edward Mem Hosp, India.
    Ploeckinger, Ursula
    Charite Univ Med Berlin, Germany.
    Welin, Staffan
    Uppsala Univ Hosp, Sweden.
    Schalin-Jantti, Camilla
    Univ Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Pfeifer, Marija
    Univ Med Ctr, Slovenia.
    Ngeow, Joanne
    Nanyang Technol Univ, Singapore; Nanyang Technol Univ, Singapore.
    Hasse-Lazar, Kornelia
    MSC Mem Inst, Poland.
    Sanso, Gabriela
    Hosp Ninos Dr Ricardo Gutierrez, Argentina.
    Qi, Xiaoping
    Wenzhou Med Univ, Peoples R China.
    Ugurlu, M. Umit
    Marmara Univ, Turkey.
    Diaz, Rene E.
    Hosp Salvador, Chile.
    Wohllk, Nelson
    Univ Chile, Chile.
    Peczkowska, Mariola
    Inst Cardiol, Poland.
    Aberle, Jens
    Univ Med Ctr Hamburg Eppendorf, Germany.
    Lourenco Jr, Delmar M.
    Univ Sao Paulo, Brazil; Univ Sao Paulo, Brazil.
    Pereira, Maria A. A.
    Univ Sao Paulo, Brazil.
    Fragoso, Maria C. B. V
    Univ Sao Paulo, Brazil; Univ Sao Paulo, Brazil.
    Hoff, Ana O.
    Univ Sao Paulo, Brazil; Univ Sao Paulo, Brazil.
    Almeida, Madson Q.
    Univ Sao Paulo, Brazil; Univ Sao Paulo, Brazil.
    Violante, Alice H. D.
    Univ Fed Rio de Janeiro, Brazil.
    Ouidute, Ana R. P.
    Fed Univ Ceara UFC, Brazil.
    Zhang, Zhewei
    Zhejiang Univ, Peoples R China.
    Recasens, Monica
    Hosp Univ Girona, Spain.
    Robles Diaz, Luis
    Hosp Univ 12 Octubre, Spain.
    Kunavisarut, Tada
    Mahidol Univ, Thailand.
    Wannachalee, Taweesak
    Mahidol Univ, Thailand.
    Sirinvaravong, Sirinart
    Mahidol Univ, Thailand.
    Jonasch, Eric
    Univ Texas MD Anderson Canc Ctr, TX 77030 USA.
    Grozinsky-Glasberg, Simona
    Hadassah Hebrew Univ, Israel.
    Fraenkel, Merav
    Hadassah Hebrew Univ, Israel.
    Beltsevich, Dmitry
    Endocrinol Res Ctr, Russia.
    Egorov, Viacheslav I
    Bakhrushin Bros Moscow City Hosp, Russia.
    Bausch, Dirk
    Univ Lubeck, Germany.
    Schott, Matthias
    Heinrich Heine Univ, Germany.
    Tiling, Nikolaus
    Charite Univ Med Berlin, Germany.
    Pennelli, Gianmaria
    Univ Padua, Italy.
    Zschiedrich, Stefan
    Albert Ludwigs Univ, Germany.
    Daerr, Roland
    Albert Ludwigs Univ, Germany; Univ Freiburg, Germany.
    Ruf, Juri
    Albert Ludwigs Univ, Germany.
    Denecke, Timm
    Charite Univ Med Berlin, Germany.
    Link, Karl-Heinrich
    Asklepios Paulinen Klin, Germany.
    Zovato, Stefania
    IRCCS, Italy.
    von Dobschuetz, Ernst
    Acad Teaching Hosp Univ Hamburg, Germany.
    Yaremchuk, Svetlana
    NAMS Ukraine, Ukraine.
    Amthauer, Holger
    Charite Univ Med Berlin, Germany.
    Makay, Ozer
    Dept Gen Surg, Turkey.
    Patocs, Attila
    Semmelweis Univ, Hungary; Semmelweis Univ, Hungary.
    Walz, Martin K.
    Huyssens Fdn Clin, Germany.
    Huber, Tobias B.
    Univ Med Ctr Hamburg Eppendorf, Germany.
    Seufert, Jochen
    Univ Freiburg, Germany.
    Hellman, Per
    Uppsala Univ, Sweden.
    Ekaterina, Raymond H.
    Univ Toronto, Canada; Mt Sinai Hosp, Canada.
    Kuchinskaya, Ekaterina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Schiavi, Francesca
    IRCCS, Italy.
    Malinoc, Angelica
    Albert Ludwigs Univ, Germany.
    Reisch, Nicole
    Ludwigs Maximilians Univ Munich, Germany.
    Jarzab, Barbara
    MSC Mem Inst, Poland.
    Barontini, Marta
    Hosp Ninos Dr Ricardo Gutierrez, Argentina.
    Januszewicz, Andrzej
    Inst Cardiol, Poland.
    Shah, Nalini
    King Edward Mem Hosp, India.
    Young, William F. Jr.
    Mayo Clin, MN USA.
    Opocher, Giuseppe
    Veneto Inst Oncol IOV IRCCS, Italy.
    Eng, Charis
    Cleveland Clin, OH 44106 USA.
    Neumann, Hartmut P. H.
    Albert Ludwigs Univ, Germany.
    Bausch, Birke
    Univ Freiburg, Germany.
    Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors2018In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 25, no 9, p. 783-793Article in journal (Refereed)
    Abstract [en]

    Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P amp;lt; 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P = 0.001). All metastatic tumors were amp;gt;= 2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off amp;gt;= 2.8 cm, 44% and 91% for TVDT cut-off of amp;lt;= 24 months). In 117 of 273 patients, PanNETs amp;gt; 1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs amp;lt; 2.8 cm vs amp;gt;= 2.8 cm (94% vs 85% by 10 years; P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.

  • 303.
    Krishnan, Harini
    et al.
    SUNY Stony Brook, NY 11794 USA.
    Rayes, Julie
    Univ Birmingham, England.
    Miyashita, Tomoyuki
    Natl Canc Ctr, Japan; Univ Tokyo, Japan.
    Ishii, Genichiro
    Natl Canc Ctr, Japan; Univ Tokyo, Japan.
    Retzbach, Edward P.
    Rowan Univ, NJ USA.
    Sheehan, Stephanie A.
    Rowan Univ, NJ USA.
    Takemoto, Ai
    Japanese Fdn Canc Res, Japan.
    Chang, Yao-Wen
    Chang Gung Univ, Taiwan.
    Yoneda, Kazue
    Univ Occupat and Environm Hlth, Japan.
    Asai, Jun
    Kyoto Prefectural Univ Med, Japan.
    Jensen, Lasse
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Chalise, Lushun
    Nagoya Univ, Japan.
    Natsume, Atsushi
    Nagoya Univ, Japan.
    Goldberg, Gary S.
    Rowan Univ, NJ USA.
    Podoplanin: An emerging cancer biomarker and therapeutic target2018In: Cancer Science, ISSN 1347-9032, E-ISSN 1349-7006, Vol. 109, no 5, p. 1292-1299Article, review/survey (Refereed)
    Abstract [en]

    Podoplanin (PDPN) is a transmembrane receptor glycoprotein that is upregulated on transformed cells, cancer associated fibroblasts and inflammatory macrophages that contribute to cancer progression. In particular, PDPN increases tumor cell clonal capacity, epithelial mesenchymal transition, migration, invasion, metastasis and inflammation. Antibodies, CAR-T cells, biologics and synthetic compounds that target PDPN can inhibit cancer progression and septic inflammation in preclinical models. This review describes recent advances in how PDPN may be used as a biomarker and therapeutic target for many types of cancer, including glioma, squamous cell carcinoma, mesothelioma and melanoma.

  • 304.
    Kristoffersen, Laila
    et al.
    Department of Neonatology, St. Olavs University Hospital, Trondheim, Norway; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
    Støen, Ragnhild
    Department of Neonatology, St. Olavs University Hospital, Trondheim, Norway; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
    Bergseng, Håkon
    Department of Neonatology, St. Olavs University Hospital, Trondheim, Norway; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
    Follestad, Turid
    Department of Public Health and Nursing, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Vederhus, Bente
    Department of Pediatrics, Haukeland University Hospital, Bergen, Norway; Faculty of Health and Social Science, Western Norway University of Applied Sciences, Bergen, Norway.
    Adde, Lars
    Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; Clinic of Clinical Services, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
    Austeng, Dordi
    Department of Neuromedicine and Movement Science (INB), Norwegian University of Science and Technology (NTNU), Trondheim, Norway; Department of Ophthalmology, St. Olavs University Hospital, Trondheim, Norway.
    Skin-to-skin contact during eye examination did not reduce pain compared to standard care with parental support in preterm infants2019In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 108, no 8, p. 1434-1440Article in journal (Refereed)
    Abstract [en]

    AIM: We compared the pain relieving effect of skin-to-skin contact versus standard care in the incubator during screening for retinopathy of prematurity.

    METHODS: This randomised crossover study included 35 preterm infants of less than 32 weeks of gestational age admitted to St Olavs University Hospital, Trondheim, Norway, between January 2014 and June 2016. Randomisation was for skin-to-skin with one of the parents or standard care with supportive positioning by parents for the first of two consecutive eye examinations. The pain score was measured twice using the Premature Infant Pain Profile (PIPP) during and after the eye examination. The infants' movement activity was video recorded after the examination.

    RESULTS: There was no difference in mean pain scores with skin-to-skin contact versus standard care during (10.2 vs. 10.3, p = 0.91) or after (7.0 vs. 6.8, p = 0.76) the procedure. Independent of the randomisation group, PIPP scores were lower than previous comparable studies have found. Bouts of movement activity were also the same whether the examination was conducted in skin-to-skin position or in the incubator (p = 0.91).

    CONCLUSION: Skin-to-skin contact during the eye examination did not provide additional pain relief compared to standard care where the parents were already a part of the multidimensional approach.

  • 305.
    Krynitz, B.
    et al.
    Karolinska University of Labs, Sweden; Karolinska Institute, Sweden.
    Olsson, H.
    Karolinska Institute, Sweden.
    Lundh Rozell, Barbro
    Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics. Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Lindelof, B.
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Edgren, G.
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Smedby, K. E.
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Risk of basal cell carcinoma in Swedish organ transplant recipients: a population-based study2016In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 174, no 1, p. 95-103Article in journal (Refereed)
    Abstract [en]

    Background Risk of basal cell carcinoma (BCC) has been reported to be several-fold increased among organ transplant recipients (OTRs). However, due to lack of reliable BCC registration, population-based risk estimates are scarce. Objectives To characterize risk of BCC among OTRs compared with the general population, and contrast with risk of cutaneous squamous cell carcinoma (SCC). Subjects and methods OTRs transplanted during 2004-2011 were identified through national healthcare registers and linked with the nationwide Swedish BCC Register initialized in 2004. Relative risk of BCC was expressed as standardized incidence ratios (SIR) with 95% confidence intervals (CI). Results Altogether, 4023 transplanted patients developed 341 BCCs during follow-up. Compared with the general population, the relative risk of BCC was increased sixfold (SIR 6.1, 95% CI 5.4-6.9). The risk was higher in kidney and heart/lung than in liver recipients (SIRkidney 7.2, 6.3-8.3; SIRheart/lung 5.8, 4.0-8.2; SIRliver 2.6, 1.7-4.0), and risk increased with time since transplantation (P-trend &lt; 0.01). The SCC to BCC ratio was 1 : 1.7 and BCC developed earlier after transplantation than SCC. Distribution of anatomical sites and histological types did not differ substantially between OTR- and population-BCCs. Conclusions Risk of BCC was strikingly elevated in OTRs compared with the general population. Risk was higher in kidney recipients and increased with follow-up time. These findings support a tumour-promoting effect of immunosuppressive drugs in BCC development. The low SCC to BCC ratio was possibly attributed to short follow-up time.

  • 306.
    Krynitz, Britta
    et al.
    Karolinska University of Labs, Sweden; Karolinska University, Sweden.
    Lundh Rozell, Barbro
    Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics. Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Lyth, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Health and Developmental Care, Regional Cancer Center South East Sweden.
    Smedby, Karin E.
    Karolinska University Hospital, Sweden.
    Lindelof, Bernt
    Karolinska University, Sweden; Karolinska University, Sweden.
    Cutaneous malignant melanoma in the Swedish organ transplantation cohort: A study of clinicopathological characteristics and mortality2015In: The Journal of American Academy of Dermatology, ISSN 0190-9622, E-ISSN 1097-6787, Vol. 73, no 1, p. 106-U190Article in journal (Refereed)
    Abstract [en]

    Background: Risk of cutaneous melanoma is increased among organ transplant recipients (OTRs) but outcome has rarely been evaluated. Objective: We sought to assess melanoma characteristics and prognosis among OTRs versus the general population. Methods: Using Swedish health care registers, we identified melanomas in OTRs (n = 49) and in the general population (n = 22,496), given a diagnosis between 1984 and 2008 and followed up through December 31, 2012. Tumor slides of posttransplantation melanomas were reviewed. Odds ratios for comparison of histopathological characteristics and hazard ratios of melanoma-specific death were calculated. Results: Among OTRs the trunk was the most common anatomic melanoma site (50% among female vs 51% among male) and 73% (n = 36) of all melanomas were histologically associated with a melanocytic nevus, 63% (n = 31) atypical/dysplastic. Compared with population melanomas, posttransplantation melanomas were more advanced at diagnosis (Clark level III-V: odds ratio 2.2 [95% confidence interval 1.01-4.7, P = .03], clinical stages III-IV: odds ratio 4.2 [1.6-10.8, P = .003]). Risk of melanoma-specific death was increased among OTRs: adjusted hazard ratio 3.0 (1.7-5.3, P = .0002). Limitations: Only posttransplantation melanoma slides were reviewed. Conclusions: Melanomas were more advanced at diagnosis and melanoma-specific survival was poorer in OTRs than in the general population. Prophylactic excision of truncal nevi among OTRs may be advised.

  • 307.
    Kuchenbaecker, Karoline B.
    et al.
    University of Cambridge, England.
    Ramus, Susan J.
    University of So Calif, CA USA.
    Tyrer, Jonathan
    University of Cambridge, England.
    Lee, Andrew
    University of Cambridge, England; University of So Calif, CA USA.
    Shen, Howard C.
    University of So Calif, CA USA.
    Beesley, Jonathan
    QIMR Berghofer Medical Research Institute, Australia.
    Lawrenson, Kate
    University of So Calif, CA USA.
    McGuffog, Lesley
    University of Cambridge, England.
    Healey, Sue
    QIMR Berghofer Medical Research Institute, Australia.
    Lee, Janet M.
    University of So Calif, CA USA.
    Spindler, Tassja J.
    University of So Calif, CA USA.
    Lin, Yvonne G.
    University of So Calif, CA USA.
    Pejovic, Tanja
    Oregon Health and Science University, OR 97201 USA; Knight Cancer Institute, OR USA.
    Bean, Yukie
    Oregon Health and Science University, OR 97201 USA; Knight Cancer Institute, OR USA.
    Li, Qiyuan
    Centre Funct Cancer Epigenet, MA USA.
    Coetzee, Simon
    University of Sao Paulo, Brazil; Centre Integrat Syst Biol, Brazil.
    Hazelett, Dennis
    University of So Calif, CA USA; University of So Calif, CA USA.
    Miron, Alexander
    Case Western Reserve University, OH 44106 USA.
    Southey, Melissa
    University of Melbourne, Australia.
    Beth Terry, Mary
    Columbia University, NY USA.
    Goldgar, David E.
    University of Utah, UT USA.
    Buys, Saundra S.
    University of Utah, UT USA.
    Janavicius, Ramunas
    Vilnius University Hospital Santariskiu Clin, Lithuania; State Research Institute Centre Innovat Med, Lithuania.
    Dorfling, Cecilia M.
    University of Pretoria, South Africa.
    van Rensburg, Elizabeth J.
    University of Pretoria, South Africa.
    Neuhausen, Susan L.
    City Hope National Medical Centre, CA 91010 USA.
    Chun Ding, Yuan
    City Hope National Medical Centre, CA 91010 USA.
    Hansen, Thomas V. O.
    University of Copenhagen Hospital, Denmark.
    Jonson, Lars
    University of Copenhagen Hospital, Denmark.
    Gerdes, Anne-Marie
    University of Copenhagen Hospital, Denmark.
    Ejlertsen, Bent
    University of Copenhagen Hospital, Denmark.
    Barrowdale, Daniel
    University of Cambridge, England.
    Dennis, Joe
    University of Cambridge, England; University of Cambridge, England.
    Benitez, Javier
    Spanish National Cancer Centre CNIO, Spain; CIBERER, Spain.
    Osorio, Ana
    Spanish National Cancer Centre CNIO, Spain; CIBERER, Spain.
    Jose Garcia, Maria
    Spanish National Cancer Centre CNIO, Spain; CIBERER, Spain.
    Komenaka, Ian
    Maricopa County Gen Hospital, CA USA.
    Weitzel, Jeffrey N.
    Clin Cancer Genet, CA USA.
    Ganschow, Pamela
    Cook County Health and Hospital Syst, CA USA.
    Peterlongo, Paolo
    Italian Fdn Cancer Research, Italy.
    Bernard, Loris
    Ist Europeo Oncol, Italy; Cogentech Cancer Genet Test Lab, Italy.
    Viel, Alessandra
    CRO, Italy.
    Bonanni, Bernardo
    Ist Europeo Oncol, Italy.
    Peissel, Bernard
    Italian Research Hospital, Italy.
    Manoukian, Siranoush
    Italian Research Hospital, Italy.
    Radice, Paolo
    Fdn IRCCS, Italy.
    Papi, Laura
    University of Florence, Italy.
    Ottini, Laura
    University of Roma La Sapienza, Italy.
    Fostira, Florentia
    National Centre Science Research Demokritos, Greece.
    Konstantopoulou, Irene
    National Centre Science Research Demokritos, Greece.
    Garber, Judy
    Childrens Hospital, MA 02115 USA.
    Frost, Debra
    University of Cambridge, England.
    Perkins, Jo
    University of Cambridge, England.
    Platte, Radka
    University of Cambridge, England.
    Ellis, Steve
    University of Cambridge, England.
    Godwin, Andrew K.
    University of Kansas, KS 66103 USA.
    Katharina Schmutzler, Rita
    University Hospital Cologne, Germany.
    Meindl, Alfons
    Technical University of Munich, Germany.
    Engel, Christoph
    University of Leipzig, Germany.
    Sutter, Christian
    Heidelberg University, Germany.
    Sinilnikova, Olga M.
    University of Lyon, France; Hospital Civils Lyon, France.
    Damiola, Francesca
    University of Lyon, France.
    Mazoyer, Sylvie
    University of Lyon, France.
    Stoppa-Lyonnet, Dominique
    Institute Curie, France; University of Paris 05, France.
    Claes, Kathleen
    University of Ghent, Belgium.
    De Leeneer, Kim
    University of Ghent, Belgium.
    Kirk, Judy
    Westmead Hospital, Australia; Westmead Hospital, Australia.
    Rodriguez, Gustavo C.
    NorthShore University of HealthSystem, IL USA.
    Piedmonte, Marion
    Roswell Pk Cancer Institute, NY 14263 USA.
    OMalley, David M.
    Ohio State University, OH 43210 USA.
    de la Hoya, Miguel
    Hospital Clin San Carlos, Spain.
    Caldes, Trinidad
    Hospital Clin San Carlos, Spain.
    Aittomaeki, Kristiina
    University of Helsinki, Finland.
    Nevanlinna, Heli
    University of Helsinki, Finland; University of Helsinki, Finland.
    Margriet Collee, J.
    Erasmus University, Netherlands.
    Rookus, Matti A.
    Netherlands Cancer Institute, Netherlands.
    Oosterwijk, Jan C.
    University of Groningen, Netherlands.
    Tihomirova, Laima
    Latvian Biomed Research and Study Centre, Latvia.
    Tung, Nadine
    Beth Israel Deaconess Medical Centre, MA 02215 USA.
    Hamann, Ute
    DKFZ, Germany.
    Isaccs, Claudine
    Georgetown University, DC USA.
    Tischkowitz, Marc
    McGill University, Canada.
    Imyanitov, Evgeny N.
    NN Petrov Institute Oncol, Russia.
    Caligo, Maria A.
    University of Pisa, Italy; University Hospital Pisa, Italy.
    Campbell, Ian G.
    Peter MacCallum Cancer Centre, Australia.
    Hogervorst, Frans B. L.
    Netherlands Cancer Institute, Netherlands.
    Olah, Edith
    National Institute Oncol, Hungary.
    Diez, Orland
    University Hospital Vall Hebron, Spain; University of Autonoma Barcelona, Spain.
    Blanco, Ignacio
    Catalan Institute Oncol, Spain.
    Brunet, Joan
    Catalan Institute Oncol, Spain.
    Lazaroso, Conxi
    Catalan Institute Oncol, Spain.
    Angel Pujana, Miguel
    Catalan Institute Oncol, Spain.
    Jakubowska, Anna
    Pomeranian Medical University, Poland.
    Gronwald, Jacek
    Pomeranian Medical University, Poland.
    Lubinski, Jan
    Pomeranian Medical University, Poland.
    Sukiennicki, Grzegorz
    Pomeranian Medical University, Poland.
    Barkardottir, Rosa B.
    Landspitali University Hospital, Iceland; University of Iceland, Iceland.
    Plante, Marie
    CHUQ, Canada.
    Simard, Jacques
    University of Laval, Canada.
    Soucy, Penny
    University of Laval, Canada.
    Montagna, Marco
    IRCCS, Italy.
    Tognazzo, Silvia
    IRCCS, Italy.
    Teixeira, Manuel R.
    University of Porto, Portugal; Portuguese Oncology Institute, Portugal.
    Pankratz, Vernon S.
    Mayo Clin, MN USA.
    Wang, Xianshu
    Mayo Clin, MN USA.
    Lindor, Noralane
    Mayo Clin, MN USA.
    Szabo, Csilla I.
    NHGRI, MD 20892 USA.
    Kauff, Noah
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Vijai, Joseph
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Aghajanian, Carol A.
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Pfeiler, Georg
    Medical University of Vienna, Austria.
    Berger, Andreas
    Medical University of Vienna, Austria.
    Singer, Christian F.
    Medical University of Vienna, Austria.
    Tea, Muy-Kheng
    Medical University of Vienna, Austria.
    Phelan, Catherine M.
    H Lee Moffitt Cancer Centre and Research Institute, FL USA.
    Greene, Mark H.
    NCI, MD USA.
    Mai, Phuong L.
    NCI, MD USA.
    Rennert, Gad
    Carmel Hospital, Israel.
    Marie Mulligan, Anna
    University of Toronto, Canada; University of Health Network, Canada.
    Tchatchou, Sandrine
    Mt Sinai Hospital, Canada.
    Andrulis, Irene L.
    University of Toronto, Canada; University of Toronto, Canada.
    Glendon, Gord
    Mt Sinai Hospital, Canada.
    Ewart Toland, Amanda
    Ohio State University, OH 43210 USA.
    Birk Jensen, Uffe
    Aarhus University Hospital, Denmark.
    Kruse, Torben A.
    Odense University Hospital, Denmark.
    Thomassen, Mads
    Odense University Hospital, Denmark.
    Bojesen, Anders
    Vejle Hospital, Denmark.
    Zidan, Jamal
    Rivka Ziv Medical Centre, Israel.
    Friedman, Eitan
    Sheba Medical Centre, Israel.
    Laitman, Yael
    Sheba Medical Centre, Israel.
    Soller, Maria
    University of Lund Hospital, Sweden.
    Liljegren, Annelie
    Karolinska University Hospital, Sweden.
    Arver, Brita
    Karolinska University Hospital, Sweden.
    Einbeigi, Zakaria
    Sahlgrens University Hospital, Sweden.
    Askmalm Stenmark, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Olopade, Olufunmilayo I.
    University of Chicago, IL 60637 USA.
    Nussbaum, Robert L.
    University of Calif San Francisco, CA 94143 USA.
    Rebbeck, Timothy R.
    University of Penn, PA 19104 USA.
    Nathanson, Katherine L.
    University of Penn, PA 19104 USA.
    Domchek, Susan M.
    University of Penn, PA 19104 USA.
    Lu, Karen H.
    University of Texas MD Anderson Cancer Centre, TX 77030 USA.
    Karlan, Beth Y.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Walsh, Christine
    Cedars Sinai Medical Centre, CA 90048 USA.
    Lester, Jenny
    Cedars Sinai Medical Centre, CA 90048 USA.
    Hein, Alexander
    University of Erlangen Nurnberg, Germany.
    Ekici, Arif B.
    University of Erlangen Nurnberg, Germany.
    Beckmann, Matthias W.
    University of Erlangen Nurnberg, Germany.
    Fasching, Peter A.
    University of Erlangen Nurnberg, Germany; University of Calif Los Angeles, CA 90095 USA.
    Lambrechts, Diether
    Vesalius Research Centre, Belgium; University of Leuven, Belgium.
    Van Nieuwenhuysen, Els
    University of Leuven, Belgium.
    Vergote, Ignace
    University of Leuven, Belgium.
    Lambrechts, Sandrina
    University of Leuven, Belgium.
    Dicks, Ed
    University of Cambridge, England.
    Doherty, Jennifer A.
    Geisel School Med, NH USA.
    Wicklund, Kristine G.
    Fred Hutchinson Cancer Research Centre, WA 98104 USA.
    Anne Rossing, Mary
    Fred Hutchinson Cancer Research Centre, WA 98104 USA; University of Washington, WA 98195 USA.
    Rudolph, Anja
    German Cancer Research Centre, Germany.
    Chang-Claude, Jenny
    German Cancer Research Centre, Germany.
    Wang-Gohrke, Shan
    University of Ulm, Germany.
    Eilber, Ursula
    German Cancer Research Centre, Germany.
    Moysich, Kirsten B.
    Roswell Pk Cancer Institute, NY 14263 USA.
    Odunsi, Kunle
    Roswell Pk Cancer Institute, NY 14263 USA.
    Sucheston, Lara
    Roswell Pk Cancer Institute, NY 14263 USA.
    Lele, Shashi
    Roswell Pk Cancer Institute, NY 14263 USA.
    Wilkens, Lynne R.
    University of Hawaii Cancer Centre, HI USA.
    Goodman, Marc T.
    Cedars Sinai Medical Centre, CA 90048 USA; Cedars Sinai Medical Centre, CA 90048 USA.
    Thompson, Pamela J.
    Cedars Sinai Medical Centre, CA 90048 USA; Cedars Sinai Medical Centre, CA 90048 USA.
    Shvetsov, Yurii B.
    University of Hawaii Cancer Centre, HI USA.
    Runnebaum, Ingo B.
    University of Jena, Germany.
    Duerst, Matthias
    University of Jena, Germany.
    Hillemanns, Peter
    Hannover Medical Sch, Germany.
    Doerk, Thilo
    Hannover Medical Sch, Germany.
    Antonenkova, Natalia
    Byelorussian Institute Oncology and Medical Radiol Aleksandrov, Byelarus.
    Bogdanova, Natalia
    Hannover Medical Sch, Germany.
    Leminen, Arto
    University of Helsinki, Finland; University of Helsinki, Finland.
    Pelttari, Liisa M.
    University of Helsinki, Finland; University of Helsinki, Finland.
    Butzow, Ralf
    University of Helsinki, Finland; University of Helsinki, Finland; University of Helsinki, Finland.
    Modugno, Francesmary
    University of Pittsburgh, PA USA; Magee Womens Research Institute, PA USA; University of Pittsburgh, PA USA.
    Kelley, Joseph L.
    University of Pittsburgh, PA USA.
    Edwards, Robert P.
    University of Pittsburgh, PA USA; University of Pittsburgh, PA USA.
    Ness, Roberta B.
    University of Texas Houston, TX USA.
    du Bois, Andreas
    Dr Horst Schmidt Klin Wiesbaden, Germany; Klin Essen Mitte, Germany.
    Heitz, Florian
    Dr Horst Schmidt Klin Wiesbaden, Germany; Klin Essen Mitte, Germany.
    Schwaab, Ira
    Institute Humangenetik Wiesbaden, Germany.
    Harter, Philipp
    Dr Horst Schmidt Klin Wiesbaden, Germany; Klin Essen Mitte, Germany.
    Matsuo, Keitaro
    Kyushu University, Japan.
    Hosono, Satoyo
    Aichi Cancer Centre, Japan.
    Orsulic, Sandra
    Cedars Sinai Medical Centre, CA 90048 USA.
    Jensen, Allan
    Danish Cancer Soc, Denmark.
    Kruger Kjaer, Susanne
    Danish Cancer Soc, Denmark; University of Copenhagen, Denmark.
    Hogdall, Estrid
    Danish Cancer Soc, Denmark; University of Copenhagen, Denmark.
    Nazihah Hasmad, Hanis
    Cancer Research Initiat Fdn, Malaysia.
    Adenan Noor Azmi, Mat
    University of Malaya, Malaysia.
    Teo, Soo-Hwang
    Cancer Research Initiat Fdn, Malaysia; University of Malaya, Malaysia.
    Woo, Yin-Ling
    University of Malaya, Malaysia; University of Malaya, Malaysia.
    Fridley, Brooke L.
    University of Kansas, KS 66103 USA.
    Goode, Ellen L.
    Mayo Clin, MN USA.
    Cunningham, Julie M.
    Mayo Clin, MN USA.
    Vierkant, Robert A.
    Mayo Clin, MN USA.
    Bruinsma, Fiona
    Cancer Council Victoria, Australia.
    Giles, Graham G.
    Cancer Council Victoria, Australia.
    Liang, Dong
    Texas So University, TX 77004 USA.
    Hildebrandt, Michelle A. T.
    University of Texas MD Anderson Cancer Centre, TX 77030 USA.
    Wu, Xifeng
    University of Texas MD Anderson Cancer Centre, TX 77030 USA.
    Levine, Douglas A.
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Bisogna, Maria
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Berchuck, Andrew
    Duke University, NC 27710 USA.
    Iversen, Edwin S.
    Duke University, NC USA.
    Schildkraut, Joellen M.
    Duke Cancer Institute, NC USA; Duke University, NC 27710 USA.
    Concannon, Patrick
    University of Florida, FL USA; University of Florida, FL USA.
    Palmieri Weber, Rachel
    Duke University, NC 27710 USA.
    Cramer, Daniel W.
    Harvard University, MA 02115 USA; Harvard University, MA 02115 USA.
    Terry, Kathryn L.
    Harvard University, MA 02115 USA; Harvard University, MA 02115 USA.
    Poole, Elizabeth M.
    Harvard University, MA 02115 USA; Harvard University, MA 02115 USA.
    Tworoger, Shelley S.
    Harvard University, MA 02115 USA; Harvard University, MA 02115 USA.
    Bandera, Elisa V.
    Rutgers Cancer Institute New Jersey, NJ USA.
    Orlow, Irene
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Olson, Sara H.
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Krakstad, Camilla
    University of Bergen, Norway; Haukeland Hospital, Norway.
    Salvesen, Helga B.
    University of Bergen, Norway; Haukeland Hospital, Norway.
    Tangen, Ingvild L.
    University of Bergen, Norway; Haukeland Hospital, Norway.
    Bjorge, Line
    University of Bergen, Norway; Haukeland Hospital, Norway.
    van Altena, Anne M.
    Radboud University of Nijmegen, Netherlands.
    Aben, Katja K. H.
    Centre Comprehens Canc, Netherlands; Radboud University of Nijmegen, Netherlands.
    Kiemeney, Lambertus A.
    Radboud University of Nijmegen, Netherlands; Radboud University of Nijmegen, Netherlands.
    Massuger, Leon F. A. G.
    Radboud University of Nijmegen, Netherlands.
    Kellar, Melissa
    Oregon Health and Science University, OR 97201 USA; Knight Cancer Institute, OR USA.
    Brooks-Wilson, Angela
    British Columbia Cancer Agency, Canada; Simon Fraser University, Canada.
    Kelemen, Linda E.
    Medical University of S Carolina, SC 29425 USA.
    Cook, Linda S.
    University of New Mexico, NM 87131 USA.
    Le, Nhu D.
    British Columbia Cancer Agency, Canada.
    Cybulski, Cezary
    Pomeranian Medical University, Poland.
    Yang, Hannah
    NCI, MD 20892 USA.
    Lissowska, Jolanta
    Maria Sklodowska Curie Mem Cancer Centre, Poland.
    Brinton, Louise A.
    NCI, MD 20892 USA.
    Wentzensen, Nicolas
    NCI, MD 20892 USA.
    Hogdall, Claus
    University of Copenhagen, Denmark.
    Lundvall, Lene
    University of Copenhagen, Denmark.
    Nedergaard, Lotte
    University of Copenhagen, Denmark.
    Baker, Helen
    University of Cambridge, England.
    Song, Honglin
    University of Cambridge, England.
    Eccles, Diana
    Princess Anne Hospital, England.
    McNeish, Ian
    University of Porto, Portugal; University of Glasgow, Scotland.
    Paul, James
    University of Copenhagen, Denmark.
    Carty, Karen
    University of Copenhagen, Denmark.
    Siddiqui, Nadeem
    Glasgow Royal Infirm, Scotland.
    Glasspool, Rosalind
    Beatson West Scotland, Scotland.
    Whittemore, Alice S.
    Stanford University, CA 94305 USA.
    Rothstein, Joseph H.
    Stanford University, CA 94305 USA.
    McGuire, Valerie
    Stanford University, CA 94305 USA.
    Sieh, Weiva
    Stanford University, CA 94305 USA.
    Ji, Bu-Tian
    NCI, MD 20892 USA.
    Zheng, Wei
    Vanderbilt University, TN 37212 USA.
    Shu, Xiao-Ou
    Vanderbilt University, TN 37212 USA.
    Gao, Yu-Tang
    Shanghai Cancer Institute, Peoples R China.
    Rosen, Barry
    University of Toronto, Canada; Princess Margaret Hospital, Canada.
    Risch, Harvey A.
    Yale School Public Heatlh, CT USA.
    McLaughlin, John R.
    Mt Sinai Hospital, Canada.
    Narod, Steven A.
    University of Toronto, Canada.
    Monteiro, Alvaro N.
    H Lee Moffitt Cancer Centre and Research Institute, FL USA.
    Chen, Ann
    H Lee Moffitt Cancer Centre and Research Institute, FL USA.
    Lin, Hui-Yi
    H Lee Moffitt Cancer Centre and Research Institute, FL USA.
    Permuth-Wey, Jenny
    H Lee Moffitt Cancer Centre and Research Institute, FL USA.
    Sellers, Thomas A.
    H Lee Moffitt Cancer Centre and Research Institute, FL USA.
    Tsai, Ya-Yu
    H Lee Moffitt Cancer Centre and Research Institute, FL USA.
    Chen, Zhihua
    H Lee Moffitt Cancer Centre and Research Institute, FL USA.
    Ziogas, Argyrios
    University of Calif Irvine, CA USA.
    Anton-Culver, Hoda
    University of Calif Irvine, CA USA.
    Gentry-Maharaj, Aleksandra
    UCL, England.
    Menon, Usha
    UCL, England.
    Harrington, Patricia
    University of Cambridge, England.
    Lee, Alice W.
    University of Cambridge, England; University of So Calif, CA USA.
    Wu, Anna H.
    University of So Calif, CA USA.
    Pearce, Celeste L.
    University of So Calif, CA USA.
    Coetzee, Gerry
    University of So Calif, CA USA; University of So Calif, CA USA.
    Pike, Malcolm C.
    University of So Calif, CA USA; Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Dansonka-Mieszkowska, Agnieszka
    Maria Sklodowska Curie Mem Cancer Centre, Poland.
    Timorek, Agnieszka
    Medical University of Warsaw, Poland; Brodnowski Hospital, Poland.
    Rzepecka, Iwona K.
    Maria Sklodowska Curie Mem Cancer Centre, Poland.
    Kupryjanczyk, Jolanta
    Maria Sklodowska Curie Mem Cancer Centre, Poland.
    Freedman, Matt
    Centre Funct Cancer Epigenet, MA USA.
    Noushmehr, Houtan
    University of Sao Paulo, Brazil.
    Easton, Douglas F.
    University of Cambridge, England.
    Offit, Kenneth
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Couch, Fergus J.
    Mayo Clin, MN USA; Mayo Clin, MN USA.
    Gayther, Simon
    University of So Calif, CA USA.
    Pharoah, Paul P.
    University of Cambridge, England.
    Antoniou, Antonis C.
    University of Cambridge, England.
    Chenevix-Trench, Georgia
    QIMR Berghofer Medical Research Institute, Australia.
    Identification of six new susceptibility loci for invasive epithelial ovarian cancer2015In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, no 2, p. 164-171Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P less than 5 x 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

  • 308.
    Kumar Jeengar, Manish
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. National Institute Pharmaceut Educ and Research Institute, India.
    Thummuri, Dinesh
    National Institute Pharmaceut Educ and Research Institute, India.
    Magnusson, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Naidu, V. G. M.
    National Institute Pharmaceut Educ and Research Institute, India; National Institute Pharmaceut Educ and Research Institute, India.
    Uppugunduri, Srinivas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Uridine Ameliorates Dextran Sulfate Sodium (DSS)-Induced Colitis in Mice2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 3924Article in journal (Refereed)
    Abstract [en]

    Uridine, one of the four components that comprise RNA, has attracted attention as a novel therapeutic modulator of inflammation. However, very little is known about its effect on intestinal inflammation. The aim of the present study was to investigate the potential protective effect of intracolonic administered uridine against DSS induced colitis in male C57BL/6 mice. Intracolonic instillation of 3 doses of uridine 1 mg/Kg (lower dose), 5 mg/Kg (medium dose), and 10 mg/Kg (higher dose) in saline was performed daily. Uridine at medium and high dose significantly reduced the severity of colitis (DAI score) and alleviated the macroscopic and microscopic signs of the disease. The levels of proinflammatory cytokines IL-6, IL-1 beta and TNF in serum as well as mRNA expression in colon were significantly reduced in the uridine treated groups. Moreover, colon tissue myloperoxidase activities, protein expression of IL-6, TNF-alpha, COX-2, P-NFkB and P-Ikk-alpha beta in the colon tissues were significantly reduced in medium and high dose groups. These findings demonstrated that local administration of uridine alleviated experimental colitis in male C57BL/6 mice accompanied by the inhibition of neutrophil infiltration and NF-kappa B signaling. Thus, Uridine may be a promising candidate for future use in the treatment of inflammatory bowel disease.

  • 309.
    Kvernby, Sofia
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Diagnostics, Medical radiation physics.
    Rönnerfalk, Mattias
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Warntjes, Marcel Jan Bertus
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV). SyntheticMR AB, Linkoping, Sweden.
    Carlhäll, Carljohan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Nylander, Eva
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Engvall, Jan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Tamas, Eva
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Thoracic and Vascular Surgery. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Ebbers, Tino
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Longitudinal Changes in Myocardial T-1 and T-2 Relaxation Times Related to Diffuse Myocardial Fibrosis in Aortic Stenosis; Before and After Aortic Valve Replacement2018In: Journal of Magnetic Resonance Imaging, ISSN 1053-1807, E-ISSN 1522-2586, Vol. 48, no 3, p. 799-807Article in journal (Refereed)
    Abstract [en]

    Background: Diffuse myocardial fibrosis is associated with adverse outcomes, although detection and quantification is challenging. Cardiac MR relaxation times mapping represents a promising imaging biomarker for diffuse myocardial fibrosis. Purpose: To investigate whether relaxation times can detect longitudinal changes in myocardial tissue composition associated with diffuse fibrosis in patients with severe aortic stenosis (AS) before and after aortic valve replacement (AVR). Study type: Prospective longitudinal study. Population/Subjects/Phantom/Specimen/Animal Model: Fifteen patients with severe AS. Field Strength/Sequence: 3T /3(3) 3(3) 5-MOLLI, T2-GraSE, and 3D-QALAS. Assessment: Patients underwent MR examinations at three timepoints: before AVR, as well as 3 and 12 months after AVR. Data from each patient was analyzed in 16 myocardial segments. Statistical Tests: The segment-wise T1 and T2 data were analyzed over time after surgery using linear mixed models for repeated measures analysis. Results: The results showed that T1 relaxation times were significantly (Pamp;lt; 0.05) shorter 3 and 12 months postoperative than preoperative and that the T2 relaxation times were significantly (Pamp;lt; 0.05) longer 3 and 12 months postoperative than preoperative for both 3D and 2D mapping methods. No significant changes were seen between 3 and 12 months postoperative for any of the methods (P50.06/0.19 for T1 with 3D-QALAS/MOLLI and P50.09/0.25 for T2 with 3DQALAS/ GraSE). Data Conclusion: We demonstrated that changes in myocardial relaxation times and thus tissue characteristics can be observed within 3 months after AVR surgery. The significant changes in relaxation times from preoperative examinations to the follow-up may be interpreted as a reduction of interstitial fibrosis in the left ventricular wall. Level of Evidence: 1 Technical Efficacy: Stage 3

  • 310.
    Lagerstedt-Robinson, Kristina
    et al.
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Rohlin, Anna
    Sahlgrens University Hospital, Sweden; University of Gothenburg, Sweden.
    Aravidis, Christos
    Uppsala University, Sweden.
    Melin, Beatrice
    Umeå University, Sweden.
    Nordling, Margareta
    Sahlgrens University Hospital, Sweden; University of Gothenburg, Sweden.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics. University of Lund Hospital, Sweden.
    Lindblom, Annika
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Nilbert, M. E. F.
    Lund University, Sweden; University of Copenhagen, Denmark.
    Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population2016In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 36, no 5, p. 2823-2835Article in journal (Refereed)
    Abstract [en]

    Lynch syndrome caused by constitutional mismatch-repair defects is one of the most common hereditary cancer syndromes with a high risk for colorectal, endometrial, ovarian and urothelial cancer. Lynch syndrome is caused by mutations in the mismatch repair (MMR) genes i.e., MLH1, MSH2, MSH6 and PMS2. After 20 years of genetic counseling and genetic testing for Lynch syndrome, we have compiled the mutation spectrum in Sweden with the aim to provide a population-based perspective on the contribution from the different MMR genes, the various types of mutations and the influence from founder mutations. Mutation data were collected on a national basis from all laboratories involved in genetic testing. Mutation analyses were performed using mainly Sanger sequencing and multiplex ligation-dependent probe amplification. A total of 201 unique disease-predisposing MMR gene mutations were identified in 369 Lynch syndrome families. These mutations affected MLH1 in 40%, MSH2 in 36%, MSH6 in 18% and PMS2 in 6% of the families. A large variety of mutations were identified with splice site mutations being the most common mutation type in MLH1 and frameshift mutations predominating in MSH2 and MSH6. Large deletions of one or several exons accounted for 21% of the mutations in MLH1 and MSH2 and 22% in PMS2, but were rare (4%) in MSH6. In 66% of the Lynch syndrome families the variants identified were private and the effect from founder mutations was limited and predominantly related to a Finnish founder mutation that accounted for 15% of the families with mutations in MLH1. In conclusion, the Swedish Lynch syndrome mutation spectrum is diverse with private MMR gene mutations in two-thirds of the families, has a significant contribution from internationally recognized mutations and a limited effect from founder mutations.

  • 311.
    Lantz, Jonas
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Gupta, Vikas
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Henriksson, Lilian
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Karlsson, Matts
    Linköping University, Department of Management and Engineering, Applied Thermodynamics and Fluid Mechanics. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Persson, Anders
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Carlhäll, Carljohan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Ebbers, Tino
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Characterization of Cardiac Flow in Heart Disease Patients by CFD and 4D Flow MRI2017In: Bulletin of the Amerian Physcial Society, American Physical Society, 2017Conference paper (Refereed)
    Abstract [en]

    In this study, cardiac blood flow was simulated using Computational Fluid Dynamics and compared to in vivo flow measurements by 4D Flow MRI. In total, nine patients with various heart diseases were studied. Geometry and heart wall motion for the simulations were obtained from clinical CT measurements, with 0.3x0.3x0.3 mm spatial resolution and 20 time frames covering one heartbeat. The CFD simulations included pulmonary veins, left atrium and ventricle, mitral and aortic valve, and ascending aorta. Mesh sizes were on the order of 6-16 million cells, depending on the size of the heart, in order to resolve both papillary muscles and trabeculae. The computed flow field agreed visually very well with 4D Flow MRI, with characteristic vortices and flow structures seen in both techniques. Regression analysis showed that peak flow rate as well as stroke volume had an excellent agreement for the two techniques. We demonstrated the feasibility, and more importantly, fidelity of cardiac flow simulations by comparing CFD results to in vivo measurements. Both qualitative and quantitative results agreed well with the 4D Flow MRI measurements. Also, the developed simulation methodology enables “what if” scenarios, such as optimization of valve replacement and other surgical procedures.

  • 312.
    Lantz, Jonas
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Gupta, Vikas
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Henriksson, Lilian
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Karlsson, Matts
    Linköping University, Department of Management and Engineering, Applied Thermodynamics and Fluid Mechanics. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Persson, Anders
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Carlhäll, Carljohan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Ebbers, Tino
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    First Results of CT-derived Cardiac 4D Blood Flow - Comparison With 4D Flow MRI2017Conference paper (Other academic)
  • 313.
    Lantz, Jonas
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Gupta, Vikas
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences.
    Henriksson, Lilian
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Karlsson, Matts
    Linköping University, Department of Management and Engineering, Applied Thermodynamics and Fluid Mechanics. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Persson, Anders
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Carlhäll, Carl-Johan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    Ebbers, Tino
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Impact of Pulmonary Venous Inflow on Cardiac Flow Simulations: Comparison with In Vivo 4D Flow MRI2019In: Annals of Biomedical Engineering, ISSN 0090-6964, E-ISSN 1573-9686, Vol. 47, no 2, p. 413-424Article in journal (Refereed)
    Abstract [en]

    Blood flow simulations are making their way into the clinic, and much attention is given to estimation of fractional flow reserve in coronary arteries. Intracardiac blood flow simulations also show promising results, and here the flow field is expected to depend on the pulmonary venous (PV) flow rates. In the absence of in vivo measurements, the distribution of the flow from the individual PVs is often unknown and typically assumed. Here, we performed intracardiac blood flow simulations based on time-resolved computed tomography on three patients, and investigated the effect of the distribution of PV flow rate on the flow field in the left atrium and ventricle. A design-of-experiment approach was used, where PV flow rates were varied in a systematic manner. In total 20 different simulations were performed per patient, and compared to in vivo 4D flow MRI measurements. Results were quantified by kinetic energy, mitral valve velocity profiles and root-mean-square errors of velocity. While large differences in atrial flow were found for varying PV inflow distributions, the effect on ventricular flow was negligible, due to a regularizing effect by mitral valve. Equal flow rate through all PVs most closely resembled in vivo measurements and is recommended in the absence of a priori knowledge.

  • 314.
    Lantz, Jonas
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Gupta, Vikas
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Henriksson, Lilian
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Karlsson, Matts
    Linköping University, Department of Management and Engineering, Applied Thermodynamics and Fluid Mechanics. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Persson, Anders
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Carlhäll, Carljohan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Ebbers, Tino
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Intracardiac Flow at 4D CT: Comparison with 4D Flow MRI2018In: Radiology, ISSN 0033-8419, E-ISSN 1527-1315, Vol. 289, no 1, p. 51-58Article in journal (Refereed)
    Abstract [en]

    Purpose

    To investigate four-dimensional (4D) flow CT for the assessment of intracardiac blood flow patterns as compared with 4D flow MRI.

    Materials and Methods

    This prospective study acquired coronary CT angiography and 4D flow MRI data between February and December 2016 in a cohort of 12 participants (age range, 36–74 years; mean age, 57 years; seven men [age range, 36–74 years; mean age, 57 years] and five women [age range, 52–73 years; mean age, 64 years]). Flow simulations based solely on CT-derived cardiac anatomy were assessed together with 4D flow MRI measurements. Flow patterns, flow rates, stroke volume, kinetic energy, and flow components were quantified for both techniques and were compared by using linear regression.

    Results

    Cardiac flow patterns obtained by using 4D flow CT were qualitatively similar to 4D flow MRI measurements, as graded by three independent observers. The Cohen κ score was used to assess intraobserver variability (0.83, 0.79, and 0.70) and a paired Wilcoxon rank-sum test showed no significant change (P > .05) between gradings. Peak flow rate and stroke volumes between 4D flow MRI measurements and 4D flow CT measurements had high correlation (r = 0.98 and r = 0.81, respectively; P < .05 for both). Integrated kinetic energy quantified at peak systole correlated well (r = 0.95, P < .05), while kinetic energy levels at early and late filling showed no correlation. Flow component analysis showed high correlation for the direct and residual components, respectively (r = 0.93, P < .05 and r = 0.87, P < .05), while the retained and delayed components showed no correlation.

    Conclusion

    Four-dimensional flow CT produced qualitatively and quantitatively similar intracardiac blood flow patterns compared with the current reference standard, four-dimensional flow MRI.

  • 315.
    Lantz, Jonas
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Henriksson, Lilian
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Persson, Anders
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Karlsson, Matts
    Linköping University, Department of Management and Engineering, Applied Thermodynamics and Fluid Mechanics. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Ebbers, Tino
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Importance Of Including Papillary Muscles And Trabeculae In Cardiac Flow Simulations2016In: Proceedings of the 2016 Summer Biomechanics, Bioengineering and Biotransport Conference, Organizing Committee for the 2016 Summer Biomechanics, Bioengineering and Biotransport , 2016Conference paper (Other academic)
  • 316.
    Lantz, Jonas
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences.
    Henriksson, Lilian
    Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Persson, Anders
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Karlsson, Matts
    Linköping University, Department of Management and Engineering, Applied Thermodynamics and Fluid Mechanics. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Ebbers, Tino
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Patient-Specific Simulation of Cardiac Blood Flow From High-Resolution Computed Tomography2016In: Journal of Biomechanical Engineering, ISSN 0148-0731, E-ISSN 1528-8951, Vol. 138, no 12Article in journal (Refereed)
    Abstract [en]

    Cardiac hemodynamics can be computed from medical imaging data, and results could potentially aid in cardiac diagnosis and treatment optimization. However, simulations are often based on simplified geometries, ignoring features such as papillary muscles and trabeculae due to their complex shape, limitations in image acquisitions, and challenges in computational modeling. This severely hampers the use of computational fluid dynamics in clinical practice. The overall aim of this study was to develop a novel numerical framework that incorporated these geometrical features. The model included the left atrium, ventricle, ascending aorta, and heart valves. The framework used image registration to obtain patient-specific wall motion, automatic remeshing to handle topological changes due to the complex trabeculae motion, and a fast interpolation routine to obtain intermediate meshes during the simulations. Velocity fields and residence time were evaluated, and they indicated that papillary muscles and trabeculae strongly interacted with the blood, which could not be observed in a simplified model. The framework resulted in a model with outstanding geometrical detail, demonstrating the feasibility as well as the importance of a framework that is capable of simulating blood flow in physiologically realistic hearts.

  • 317.
    Larsson, A.
    et al.
    Lund University, Sweden.
    Tynngård, Nahreen
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Kander, T.
    Lund University, Sweden; Skåne University Hospital Lund, Sweden.
    Bonnevier, J.
    Lund University, Sweden; Skåne University Hospital Lund, Sweden.
    Schott, U.
    Lund University, Sweden; Skåne University Hospital Lund, Sweden.
    Comparison of point-of-care hemostatic assays, routine coagulation tests, and outcome scores in critically ill patients2015In: Journal of critical care, ISSN 0883-9441, E-ISSN 1557-8615, Vol. 30, no 5, p. 1032-1038Article in journal (Refereed)
    Abstract [en]

    Purpose: The purposes of the study are to compare point-of-care (POC) hemostatic devices in critically ill patients with routine laboratory tests and intensive care unit (ICU) outcome scoring assessments and to describe the time course of these variables in relation to mortality rate. Materials and methods: Patients admitted to the ICU with a prognosis of more than 3 days of stay were included. The POC devices, Multiplate platelet aggregometry, rotational thromboelastometry, and ReoRox viscoelastic tests, were used. All variables were compared between survivors and nonsurvivors. Point-of-care results were compared to prothrombin time, activated partial thromboplastin time, platelet count, fibrinogen concentration, and Sequential Organ Failure Assessment score and Simplified Acute Physiology Score 3. Results: Blood was sampled on days 0 to 1, 2 to 3, and 4 to 10 from 114 patients with mixed diagnoses during 237 sampling events. Nonsurvivors showed POC and laboratory signs of hypocoagulation and decreased fibrinolysis over time compared to survivors. ReoRox detected differences between survivors and nonsurvivors better than ROTEM and Multiplate. Conclusions: All POC and routine laboratory tests showed a hypocoagulative response in nonsurvivors compared to survivors. ReoRox was better than ROTEM and Multiplate at detecting differences between surviving and nonsurviving ICU patients. However, Simplified Acute Physiology Score 3 showed the best association to mortality outcome.

  • 318.
    Lash, Gendie E.
    et al.
    Newcastle University, England.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Decidual cytokines and pregnancy complications: focus on spontaneous miscarriage2015In: Journal of Reproductive Immunology, ISSN 0165-0378, E-ISSN 1872-7603, Vol. 108, p. 83-89Article in journal (Refereed)
    Abstract [en]

    The establishment of pregnancy requires the co-ordinated implantation of the embryo into the receptive decidua, placentation, trophoblast invasion of the maternal decidua and myometrium in addition to remodelling of the uterine spiral arteries. Failure of any of these steps can lead to a range of pregnancy complications, including miscarriage, pre-eclampsia, fetal growth restriction, placenta accreta and pre-term birth. Cytokines are small multifunctional proteins often derived from leucocytes and have primarily been described through their immunomodulatory actions. The maternal-fetal interface is considered to be immunosuppressed to allow development of the semi-allogeneic placental fetal unit. However, cytokine profiles of the decidua and different decidual cell types suggest that the in vivo situation might be more complex. Data suggest that decidual-derived cytokines not only play roles in immunosuppression, but also in other aspects of the establishment of pregnancy, including the regulation of trophoblast invasion and spiral artery remodelling. This review focuses on the potential role of decidua-derived cytokines in the aetiology of unexplained spontaneous miscarriage. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

  • 319.
    Lawrenson, Kate
    et al.
    University of Southern Calif, CA 90033 USA; Cedars Sinai Medical Centre, CA 90048 USA.
    Kar, Siddhartha
    University of Cambridge, England.
    McCue, Karen
    QIMR Berghofer Medical Research Institute, Australia.
    Kuchenbaeker, Karoline
    University of Cambridge, England.
    Michailidou, Kyriaki
    University of Cambridge, England.
    Tyrer, Jonathan
    University of Cambridge, England.
    Beesley, Jonathan
    QIMR Berghofer Medical Research Institute, Australia.
    Ramus, Susan J.
    University of Southern Calif, CA 90033 USA.
    Li, Qiyuan
    Xiamen University, Peoples R China; Dana Farber Cancer Institute, MA 02215 USA.
    Delgado, Melissa K.
    University of Southern Calif, CA 90033 USA.
    Lee, Janet M.
    University of Southern Calif, CA 90033 USA.
    Aittomaki, Kristiina
    University of Helsinki, Finland.
    Andrulis, Irene L.
    Mt Sinai Hospital, Canada; University of Toronto, Canada.
    Anton-Culver, Hoda
    University of Calif Irvine, CA 92697 USA.
    Arndt, Volker
    German Cancer Research Centre, Germany.
    Arun, Banu K.
    University of Texas MD Anderson Cancer Centre, TX 77030 USA.
    Arver, Brita
    Karolinska University Hospital, Sweden.
    Bandera, Elisa V.
    Rutgers Cancer Institute New Jersey, NJ 08903 USA.
    Barile, Monica
    Ist Europeo Oncol, Italy.
    Barkardottir, Rosa B.
    University of Iceland, Iceland; University of Iceland, Iceland.
    Barrowdale, Daniel
    University of Cambridge, England.
    Beckmann, Matthias W.
    University of Erlangen Nurnberg, Germany.
    Benitez, Javier
    Spanish National Cancer Research Centre, Spain; Centre Invest Red Enfermedades Raras, Spain.
    Berchuck, Andrew
    Duke University, NC 27710 USA.
    Bisogna, Maria
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Bjorge, Line
    Haukeland Hospital, Norway; University of Bergen, Norway.
    Blomqvist, Carl
    University of Helsinki, Finland.
    Blot, William
    Vanderbilt University, TN 37203 USA; Int Epidemiol Institute, MD 20850 USA.
    Bogdanova, Natalia
    Hannover Medical Sch, Germany.
    Bojesen, Anders
    Vejle Hospital, Denmark; Seoul National University, South Korea; Lunenfeld Tanenbaum Research Institute Mt Sinai Hospital, Canada.
    Bojesen, Stig E.
    University of Copenhagen, Denmark; Copenhagen University Hospital, Denmark; Copenhagen University Hospital, Denmark.
    Bolla, Manjeet K.
    University of Cambridge, England.
    Bonanni, Bernardo
    Ist Europeo Oncol, Italy.
    Borresen-Dale, Anne-Lise
    Oslo University Hospital, Norway; University of Oslo, Norway.
    Brauch, Hiltrud
    Dr Margarete Fischer Bosch Institute Clin Pharmacol, Germany; University of Tubingen, Germany; German Cancer Research Centre, Germany.
    Brennan, Paul
    Int Agency Research Canc, France.
    Brenner, Hermann
    German Cancer Research Centre, Germany; German Cancer Research Centre, Germany; German Cancer Research Centre, Germany.
    Bruinsma, Fiona
    Cancer Council Victoria, Australia.
    Brunet, Joan
    Catalan Institute Oncol, Spain.
    Ahmad Buhari, Shaik
    National University of Health Syst, Singapore.
    Burwinkel, Barbara
    German Cancer Research Centre, Germany; Heidelberg University, Germany.
    Butzow, Ralf
    University of Helsinki, Finland.
    Buys, Saundra S.
    University of Utah, UT 84112 USA.
    Cai, Qiuyin
    Vanderbilt University, TN 37203 USA.
    Caldes, Trinidad
    IdISSC El Institute Invest Sanitaria Hospital Clin San Car, Spain.
    Campbell, Ian
    Peter MacCallum Cancer Centre, Australia.
    Canniotto, Rikki
    Roswell Pk Cancer Institute, NY 14263 USA.
    Chang-Claude, Jenny
    German Cancer Research Centre, Germany; University of Medical Centre Hamburg Eppendorf, Germany.
    Chiquette, Jocelyne
    University of Quebec, Canada.
    Choi, Ji-Yeob
    Seoul National University, South Korea.
    Claes, Kathleen B. M.
    University of Ghent, Belgium.
    Cook, Linda S.
    University of New Mexico, NM 87131 USA.
    Cox, Angela
    University of Sheffield, England.
    Cramer, Daniel W.
    Harvard University, MA 02115 USA; Brigham and Womens Hospital, MA 02115 USA; Harvard University, MA 02115 USA.
    Cross, Simon S.
    University of Sheffield, England.
    Cybulski, Cezary
    Pomeranian Medical University, Poland.
    Czene, Kamila
    Karolinska Institute, Sweden.
    Daly, Mary B.
    Fox Chase Cancer Centre, PA 19111 USA.
    Damiola, Francesca
    University of Lyon, France.
    Dansonka-Mieszkowska, Agnieszka
    Maria Sklodowska Curie Mem Cancer Centre, Poland; Institute Oncol, Poland.
    Darabi, Hatef
    Karolinska Institute, Sweden.
    Dennis, Joe
    University of Cambridge, England.
    Devilee, Peter
    Leiden University, Netherlands.
    Diez, Orland
    University Hospital Vall Hebron, Spain; University of Autonoma Barcelona, Spain.
    Doherty, Jennifer A.
    Geisel School Medical Dartmouth, NH 03755 USA.
    Domchek, Susan M.
    University of Penn, PA 19104 USA.
    Dorfling, Cecilia M.
    University of Pretoria, South Africa.
    Doerk, Thilo
    Hannover Medical Sch, Germany.
    Dumont, Martine
    University of Laval, Canada.
    Ehrencrona, Hans
    Uppsala University, Sweden; University of Lund Hospital, Sweden.
    Ejlertsen, Bent
    Copenhagen University Hospital, Denmark.
    Ellis, Steve
    University of Cambridge, England.
    Engel, Christoph
    University of Leipzig, Germany.
    Lee, Eunjung
    University of Southern Calif, CA 90033 USA.
    Gareth Evans, D.
    University of Manchester, England.
    Fasching, Peter A.
    University of Erlangen Nurnberg, Germany; University of Calif Los Angeles, CA 90095 USA.
    Feliubadalo, Lidia
    Catalan Institute Oncol, Spain.
    Figueroa, Jonine
    NCI, MD 20892 USA.
    Flesch-Janys, Dieter
    University of Medical Centre Hamburg Eppendorf, Germany; University of Medical Centre Hamburg Eppendorf, Germany.
    Fletcher, Olivia
    Institute Cancer Research, England.
    Flyger, Henrik
    Copenhagen University Hospital, Denmark.
    Foretova, Lenka
    Masaryk Mem Cancer Institute, Czech Republic; Medical Fac MU, Czech Republic.
    Fostira, Florentia
    Aghia Paraskevi Attikis, Greece.
    Foulkes, William D.
    McGill University, Canada.
    Fridley, Brooke L.
    University of Kansas, KS 66103 USA.
    Friedman, Eitan
    Chaim Sheba Medical Centre, Israel.
    Frost, Debra
    University of Cambridge, England.
    Gambino, Gaetana
    University of and University Hospital Pisa, Italy.
    Ganz, Patricia A.
    Jonsson Comprehens Cancer Centre, CA 90024 USA.
    Garber, Judy
    Dana Farber Cancer Institute, MA 02215 USA.
    Garcia-Closas, Montserrat
    NCI, MD 20892 USA; Institute Cancer Research, England.
    Gentry-Maharaj, Aleksandra
    UCL EGA Institute Womens Heatlh, England.
    Ghoussaini, Maya
    University of Cambridge, England.
    Giles, Graham G.
    Cancer Council Victoria, Australia; University of Melbourne, Australia.
    Glasspool, Rosalind
    Beatson West Scotland Cancer Centre, Scotland.
    Godwin, Andrew K.
    University of Kansas, KS 66160 USA.
    Goldberg, Mark S.
    McGill University, Canada; McGill University, Canada.
    Goldgar, David E.
    University of Utah, UT 84132 USA.
    Gonzalez-Neira, Anna
    Spanish National Cancer Research Centre, Spain.
    Goode, Ellen L.
    Mayo Clin, MN 55902 USA.
    Goodman, Marc T.
    Cedars Sinai Medical Centre, CA 90048 USA; Cedars Sinai Medical Centre, CA 90048 USA.
    Greene, Mark H.
    NCI, MD 20892 USA.
    Gronwald, Jacek
    Pomeranian Medical University, Poland.
    Guenel, Pascal
    INSERM, France; University of Paris 11, France.
    Haiman, Christopher A.
    University of Southern Calif, CA 90033 USA.
    Hall, Per
    Karolinska Institute, Sweden.
    Hallberg, Emily
    Mayo Clin, MN 55902 USA.
    Hamann, Ute
    German Cancer Research Centre, Germany.
    Hansen, Thomas V. O.
    Copenhagen University Hospital, Denmark.
    Harrington, Patricia A.
    University of Cambridge, England.
    Hartman, Mikael
    National University of Health Syst, Singapore; National University of Singapore, Singapore.
    Hassan, Norhashimah
    University of Malaya, Malaysia; Cancer Research Initiat Fdn, Malaysia.
    Healey, Sue
    QIMR Berghofer Medical Research Institute, Australia.
    Heitz, Florian
    Kliniken Essen Mitte, Germany; Dr Horst Schmidt Kliniken Wiesbaden, Germany.
    Herzog, Josef
    City Hope Clin Cancer Genet Community Research Network, CA 91010 USA.
    Hogdall, Estrid
    University of Copenhagen, Denmark; Danish Cancer Soc Research Centre, Denmark.
    Hogdall, Claus K.
    University of Copenhagen, Denmark.
    Hogervorst, Frans B. L.
    Netherlands Cancer Institute, Netherlands.
    Hollestelle, Antoinette
    Erasmus MC Cancer Institute, Netherlands.
    Hopper, John L.
    University of Melbourne, Australia.
    Hulick, Peter J.
    NorthShore University of Health Syst, IL 60201 USA.
    Huzarski, Tomasz
    Pomeranian Medical University, Poland.
    Imyanitov, Evgeny N.
    NN Petrov Institute Oncol, Russia.
    Isaacs, Claudine
    Georgetown University, DC 20057 USA.
    Ito, Hidemi
    Aichi Cancer Centre, Japan.
    Jakubowska, Anna
    Pomeranian Medical University, Poland.
    Janavicius, Ramunas
    Centre Innovat Med, Lithuania.
    Jensen, Allan
    University of Copenhagen, Denmark.
    John, Esther M.
    Cancer Prevent Institute Calif, CA 94538 USA.
    Johnson, Nichola
    Institute Cancer Research, England.
    Kabisch, Maria
    German Cancer Research Centre, Germany.
    Kang, Daehee
    Seoul National University, South Korea.
    Kapuscinski, Miroslav
    University of Melbourne, Australia.
    Karlan, Beth Y.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Khan, Sofia
    University of Helsinki, Finland.
    Kiemeney, Lambertus A.
    Radboud University of Nijmegen, Netherlands.
    Kruger Kjaer, Susanne
    Danish Cancer Soc Research Centre, Denmark; University of Copenhagen, Denmark.
    Knight, Julia A.
    Lunenfeld Tanenbaum Research Institute Mt Sinai Hospital, Canada; University of Toronto, Canada.
    Konstantopoulou, Irene
    Aghia Paraskevi Attikis, Greece.
    Kosma, Veli-Matti
    Kuopio University Hospital, Finland; University of Eastern Finland, Finland.
    Kristensen, Vessela
    Oslo University Hospital, Norway; University of Oslo, Norway; University of Oslo, Norway.
    Kupryjanczyk, Jolanta
    Maria Sklodowska Curie Mem Cancer Centre, Poland; Institute Oncol, Poland.
    Kwong, Ava
    Hong Kong Sanat and Hospital, Peoples R China; University of Hong Kong, Peoples R China.
    de la Hoya, Miguel
    IdISSC El Institute Invest Sanitaria Hospital Clin San Car, Spain.
    Laitman, Yael
    Chaim Sheba Medical Centre, Israel.
    Lambrechts, Diether
    VIB, Belgium; University of Leuven, Belgium.
    Le, Nhu
    University of Southern Calif, CA 90033 USA.
    De Leeneer, Kim
    University of Ghent, Belgium.
    Lester, Jenny
    Cedars Sinai Medical Centre, CA 90048 USA.
    Levine, Douglas A.
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Li, Jingmei
    Karolinska Institute, Sweden.
    Lindblom, Annika
    Karolinska Institute, Sweden.
    Long, Jirong
    Vanderbilt University, TN 37203 USA.
    Lophatananon, Artitaya
    University of Warwick, England.
    Loud, Jennifer T.
    NCI, MD 20892 USA.
    Lu, Karen
    University of Texas MD Anderson Cancer Centre, TX 77030 USA.
    Lubinski, Jan
    Pomeranian Medical University, Poland.
    Mannermaa, Arto
    Kuopio University Hospital, Finland; Kuopio University Hospital, Finland; University of Eastern Finland, Finland.
    Manoukian, Siranoush
    Ist Nazl Tumori, Italy.
    Le Marchand, Loic
    University of Hawaii, HI 96813 USA.
    Margolin, Sara
    Karolinska Institute, Sweden.
    Marme, Frederik
    Heidelberg University, Germany; Heidelberg University, Germany.
    Massuger, Leon F. A. G.
    Radboud University of Nijmegen, Netherlands.
    Matsuo, Keitaro
    Kyushu University, Japan.
    Mazoyer, Sylvie
    University of Lyon, France.
    McGuffog, Lesley
    University of Cambridge, England.
    McLean, Catriona
    Alfred Hospital, Australia.
    McNeish, Iain
    University of Glasgow, Scotland.
    Meindl, Alfons
    Technical University of Munich, Germany.
    Menon, Usha
    UCL EGA Institute Womens Heatlh, England.
    Mensenkamp, Arjen R.
    Radboud University of Nijmegen, Netherlands.
    Milne, Roger L.
    Cancer Council Victoria, Australia; University of Melbourne, Australia.
    Montagna, Marco
    IRCCS, Italy.
    Moysich, Kirsten B.
    Roswell Pk Cancer Institute, NY 14263 USA.
    Muir, Kenneth
    University of Warwick, England; University of Manchester, England.
    Mulligan, Anna Marie
    University of Health Network, Canada; University of Toronto, Canada.
    Nathanson, Katherine L.
    University of Penn, PA 19104 USA.
    Ness, Roberta B.
    University of Texas Houston, TX 77030 USA.
    Neuhausen, Susan L.
    Beckman Research Institute City Hope, CA 91010 USA.
    Nevanlinna, Heli
    University of Helsinki, Finland; University of Helsinki, Finland.
    Nord, Silje
    University of Oslo, Norway.
    Nussbaum, Robert L.
    University of Calif San Francisco, CA 94143 USA.
    Odunsi, Kunle
    Roswell Pk Cancer Institute, NY 14263 USA.
    Offit, Kenneth
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Olah, Edith
    National Institute Oncol, Hungary.
    Olopade, Olufunmilayo I.
    University of Chicago, IL 60637 USA.
    Olson, Janet E.
    Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
    Olswold, Curtis
    Mayo Clin, MN 55902 USA.
    OMalley, David
    Ohio State University, OH 43210 USA; James Graham Brown Cancer Centre, OH 43210 USA.
    Orlow, Irene
    Mem Sloan Kettering Cancer Centre, NY 10017 USA.
    Orr, Nick
    Institute Cancer Research, England.
    Osorio, Ana
    University of Copenhagen, Denmark; Spanish National Cancer Centre CNIO, Spain; Biomed Network Rare Disease CIBERER, Spain.
    Kyung Park, Sue
    Seoul National University, South Korea; Seoul National University, South Korea; Seoul National University, South Korea.
    Pearce, Celeste L.
    University of Southern Calif, CA 90033 USA.
    Pejovic, Tanja
    Oregon Health and Science University, OR 97239 USA; Oregon Health and Science University, OR 97239 USA.
    Peterlongo, Paolo
    FIRC Italian Fdn Cancer Research, Italy.
    Pfeiler, Georg
    Medical University of Vienna, Austria.
    Phelan, Catherine M.
    H Lee Moffitt Cancer Centre and Research Institute, FL 33606 USA.
    Poole, Elizabeth M.
    Harvard University, MA 02115 USA; Brigham and Womens Hospital, MA 02115 USA; Harvard University, MA 02115 USA.
    Pylkas, Katri
    Centre NordLab, Finland; University of Oulu, Finland.
    Radice, Paolo
    Ist Nazl Tumori, Italy.
    Rantala, Johanna
    Karolinska University Hospital, Sweden.
    Usman Rashid, Muhammad
    German Cancer Research Centre, Germany; Shaukat Khanum Mem Cancer Hospital and Research Centre SKMCH and RC, Pakistan.
    Rennert, Gad
    Clalit National Israeli Cancer Control Centre, Israel; Carmel Hospital, Israel.
    Rhenius, Valerie
    University of Cambridge, England.
    Rhiem, Kerstin
    University Hospital Cologne, Germany; University Hospital Cologne, Germany.
    Risch, Harvey A.
    Yale University, CT 06510 USA.
    Rodriguez, Gus
    NorthShore University of HealthSyst, IL 60201 USA.
    Anne Rossing, Mary
    Fred Hutchinson Cancer Research Centre, WA 98109 USA; University of Washington, WA 98109 USA.
    Rudolph, Anja
    German Cancer Research Centre, Germany.
    Salvesen, Helga B.
    Haukeland Hospital, Norway; University of Bergen, Norway.
    Sangrajrang, Suleeporn
    National Cancer Institute, Thailand.
    Sawyer, Elinor J.
    Kings Coll London, England.
    Schildkraut, Joellen M.
    Duke University, NC 27710 USA; Duke Cancer Institute, NC 27710 USA.
    Schmidt, Marjanka K.
    Netherlands Cancer Institute, Netherlands.
    Schmutzler, Rita K.
    University Hospital Cologne, Germany; University Hospital Cologne, Germany; University Hospital Cologne, Germany; University Hospital Cologne, Germany.
    Sellers, Thomas A.
    H Lee Moffitt Cancer Centre and Research Institute, FL 33606 USA.
    Seynaeve, Caroline
    Erasmus MC Cancer Institute, Netherlands.
    Shah, Mitul
    University of Cambridge, England.
    Shen, Chen-Yang
    Academic Sinica, Taiwan; China Medical University, Taiwan.
    Shu, Xiao-Ou
    Vanderbilt University, TN 37203 USA.
    Sieh, Weiva
    Stanford University, CA 94305 USA.
    Singer, Christian F.
    Medical University of Vienna, Austria.
    Sinilnikova, Olga M.
    Centre Leon Berard, France; University of Lyon 1, France.
    Slager, Susan
    Mayo Clin, MN 55902 USA.
    Song, Honglin
    University of Cambridge, England.
    Soucy, Penny
    University of Laval, Canada.
    Southey, Melissa C.
    University of Melbourne, Australia.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics. University of Lund Hospital, Sweden.
    Stoppa-Lyonnet, Dominique
    Institute Curie, France; Institute Curie, France; Sorbonne Paris Cite, France.
    Sutter, Christian
    University of Heidelberg Hospital, Germany.
    Swerdlow, Anthony
    Institute Cancer Research, England; Institute Cancer Research, England.
    Tchatchou, Sandrine
    Mt Sinai Hospital, Canada.
    Teixeira, Manuel R.
    Portuguese Oncology Institute, Portugal; University of Porto, Portugal.
    Teo, Soo H.
    University of Malaya, Malaysia; Cancer Research Initiat Fdn, Malaysia.
    Terry, Kathryn L.
    Harvard University, MA 02115 USA; Brigham and Womens Hospital, MA 02115 USA; Harvard University, MA 02115 USA.
    Beth Terry, Mary
    Columbia University, NY 10027 USA.
    Thomassen, Mads
    Odense University Hospital, Denmark.
    Grazia Tibiletti, Maria
    University of Insubria, Italy.
    Tihomirova, Laima
    Latvian Biomed Research and Study Centre, Latvia.
    Tognazzo, Silvia
    IRCCS, Italy.
    Ewart Toland, Amanda
    Vanderbilt University, TN 37203 USA; IdISSC El Institute Invest Sanitaria Hospital Clin San Car, Spain; Ohio State University, OH 43210 USA.
    Tomlinson, Ian
    University of Oxford, England; University of Oxford, England.
    Torres, Diana
    German Cancer Research Centre, Germany; Pontificia University of Javeriana, Colombia.
    Truong, Therese
    INSERM, France; University of Paris 11, France.
    Tseng, Chiu-chen
    University of Southern Calif, CA 90033 USA.
    Tung, Nadine
    Beth Israel Deaconess Medical Centre, MA 02215 USA.
    Tworoger, Shelley S.
    Harvard University, MA 02115 USA; Brigham and Womens Hospital, MA 02115 USA; Harvard University, MA 02115 USA.
    Vachon, Celine
    Mayo Clin, MN 55902 USA.
    van den Ouweland, Ans M. W.
    Erasmus University, Netherlands.
    van Doorn, Helena C.
    Erasmus MC Cancer Institute, Netherlands.
    van Rensburg, Elizabeth J.
    University of Pretoria, South Africa.
    Vant Veer, Laura J.
    Netherlands Cancer Institute, Netherlands.
    Vanderstichele, Adriaan
    University Hospital Leuven, Belgium.
    Vergote, Ignace
    University Hospital Leuven, Belgium.
    Vijai, Joseph
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Wang, Qin
    University of Cambridge, England.
    Wang-Gohrke, Shan
    University Hospital Ulm, Germany.
    Weitzel, Jeffrey N.
    City Hope Clin Cancer Genet Community Research Network, CA 91010 USA.
    Wentzensen, Nicolas
    NCI, MD 20892 USA.
    Whittemore, Alice S.
    Stanford University, CA 94305 USA.
    Wildiers, Hans
    University Hospital Leuven, Belgium.
    Winqvist, Robert
    Centre NordLab, Finland; University of Oulu, Finland.
    Wu, Anna H.
    University of Southern Calif, CA 90033 USA.
    Yannoukakos, Drakoulis
    National Centre Science Research Demokritos, Greece.
    Yoon, Sook-Yee
    Sime Darby Medical Centre, Malaysia; University of Malaya, Malaysia.
    Yu, Jyh-Cherng
    National Def Medical Centre, Taiwan.
    Zheng, Wei
    Vanderbilt University, TN 37203 USA.
    Zheng, Ying
    Shanghai Centre Disease Control and Prevent, Peoples R China.
    Kum Khanna, Kum
    QIMR Berghofer Medical Research Institute, Australia.
    Simard, Jacques
    University of Laval, Canada.
    Monteiro, Alvaro N.
    H Lee Moffitt Cancer Centre and Research Institute, FL 33612 USA.
    French, Juliet D.
    QIMR Berghofer Medical Research Institute, Australia.
    Couch, Fergus J.
    Mayo Clin, MN 55902 USA; Mayo Clin, MN 55905 USA.
    Freedman, Matthew L.
    Dana Farber Cancer Institute, MA 02215 USA.
    Easton, Douglas F.
    University of Cambridge, England; University of Cambridge, England.
    Dunning, Alison M.
    University of Cambridge, England.
    Pharoah, Paul D.
    University of Cambridge, England.
    Edwards, Stacey L.
    QIMR Berghofer Medical Research Institute, Australia.
    Chenevix-Trench, Georgia
    QIMR Berghofer Medical Research Institute, Australia.
    Antoniou, Antonis C.
    University of Cambridge, England.
    Gayther, Simon A.
    University of Southern Calif, CA 90033 USA; Cedars Sinai Medical Centre, CA 90048 USA.
    Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 12675Article in journal (Refereed)
    Abstract [en]

    A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10−20), ER-negative BC (P=1.1 × 10−13), BRCA1-associated BC (P=7.7 × 10−16) and triple negative BC (P-diff=2 × 10−5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10−3) and ABHD8 (P<2 × 10−3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.

  • 320.
    Lennikov, Anton
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Laboratory of Biomedical Cell Technologies, School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia.
    Mirabelli, Pierfrancesco
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Mukwaya, Anthony
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Schaupper, Mira
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Thangavelu, Muthukumar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Lachota, Mieszko
    Department of Immunology, Medical University of Warsaw, Warsaw, Poland.
    Ali, Zaheer
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Jensen, Lasse
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Selective IKK2 inhibitor IMD0354 disrupts NF-kappa B signaling to suppress corneal inflammation and angiogenesis2018In: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 21, no 2, p. 267-285Article in journal (Refereed)
    Abstract [en]

    Corneal neovascularization is a sight-threatening condition caused by angiogenesis in the normally avascular cornea. Neovascularization of the cornea is often associated with an inflammatory response, thus targeting VEGF-A alone yields only a limited efficacy. The NF-kappa B signaling pathway plays important roles in inflammation and angiogenesis. Here, we study consequences of the inhibition of NF-kappa B activation through selective blockade of the IKK complex I kappa B kinase beta (IKK2) using the compound IMD0354, focusing on the effects of inflammation and pathological angiogenesis in the cornea. In vitro, IMD0354 treatment diminished HUVEC migration and tube formation without an increase in cell death and arrested rat aortic ring sprouting. In HUVEC, the IMD0354 treatment caused a dose-dependent reduction in VEGF-A expression, suppressed TNF alpha-stimulated expression of chemokines CCL2 and CXCL5, and diminished actin filament fibers and cell filopodia formation. In developing zebrafish embryos, IMD0354 treatment reduced expression of Vegf-a and disrupted retinal angiogenesis. In inflammation-induced angiogenesis in the rat cornea, systemic selective IKK2 inhibition decreased inflammatory cell invasion, suppressed CCL2, CXCL5, Cxcr2, and TNF-alpha expression and exhibited anti-angiogenic effects such as reduced limbal vessel dilation, reduced VEGF-A expression and reduced angiogenic sprouting, without noticeable toxic effect. In summary, targeting NF-kappa B by selective IKK2 inhibition dampened the inflammatory and angiogenic responses in vivo by modulating the endothelial cell expression profile and motility, thus indicating an important role of NF-kappa B signaling in the development of pathologic corneal neovascularization.

  • 321.
    Lewander, Per
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Dahle, Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Larsson, B.
    Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Circulating cartilage oligomeric matrix protein in juvenile idiopathic arthritis2017In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 46, no 3, p. 194-197Article in journal (Refereed)
    Abstract [en]

    Objectives: Raised serum cartilage oligomeric matrix protein (sCOMP) has been reported to predict erosive disease in early rheumatoid arthritis (RA). In juvenile idiopathic arthritis (JIA), subnormal sCOMP levels have been associated with ongoing inflammation and growth retardation. In this study we aimed to assess sCOMP, C-reactive protein (CRP), and insulin-like growth factor (IGF)-1 in children/adolescents with JIA and in referents.Method: We enrolled 52 JIA patients at planned outpatient visits and 54 inpatients with ongoing infection (infection referents). A total of 120 referents testing negative for immunoglobulin (Ig)E-mediated allergy (IgE referents) served as controls. All serum samples were analysed for COMP, IGF-1, and CRP.Results: The average sCOMP level was highest among the IgE referents and lowest among the infection referents. In the JIA patients, the level of sCOMP was not associated with the level of CRP or with clinical signs of disease activity.Conclusions: The results of this study do not support routine clinical analysis of sCOMP levels in patients with JIA.

  • 322.
    Lidayova, Kristina
    et al.
    Uppsala University, Sweden.
    Frimmel, Hans
    Uppsala University, Sweden.
    Wang, Chunliang
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). KTH Royal Institute Technology, Sweden.
    Bengtsson, Ewert
    Uppsala University, Sweden.
    Smedby, Örjan
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV). KTH Royal Institute Technology, Sweden.
    Fast vascular skeleton extraction algorithm2016In: Pattern Recognition Letters, ISSN 0167-8655, E-ISSN 1872-7344, Vol. 76, p. 67-75Article in journal (Refereed)
    Abstract [en]

    Vascular diseases are a common cause of death, particularly in developed countries. Computerized image analysis tools play a potentially important role in diagnosing and quantifying vascular pathologies. Given the size and complexity of modern angiographic data acquisition, fast, automatic and accurate vascular segmentation is a challenging task. In this paper we introduce a fully automatic high-speed vascular skeleton extraction algorithm that is intended as a first step in a complete vascular tree segmentation program. The method takes a 3D unprocessed Computed Tomography Angiography (CTA) scan as input and produces a graph in which the nodes are centrally located artery voxels and the edges represent connections between them. The algorithm works in two passes where the first pass is designed to extract the skeleton of large arteries and the second pass focuses on smaller vascular structures. Each pass consists of three main steps. The first step sets proper parameters automatically using Gaussian curve fitting. In the second step different filters are applied to detect voxels nodes - that are part of arteries. In the last step the nodes are connected in order to obtain a continuous centerline tree for the entire vasculature. Structures found, that do not belong to the arteries, are removed in a final anatomy-based analysis. The proposed method is computationally efficient with an average execution time of 29 s and has been tested on a set of CTA scans of the lower limbs achieving an average overlap rate of 97% and an average detection rate of 71%. (C) 2015 Elsevier B.V. All rights reserved.

  • 323.
    Liest, Lisbeth
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Omran, Ahmed Shaker
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Mikiver, Rasmus
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Business support and Development, Regional Cancer Center.
    Rosenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Uppugunduri, Srinivas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    RMI and ROMA are equally effective in discriminating between benign and malignant gynecological tumors: A prospective population-based study2019In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 98, no 1, p. 24-33Article in journal (Refereed)
    Abstract [en]

    Introduction Our primary objective was to test the hypothesis that human epididymal protein 4 (HE4) and risk of ovarian malignancy index outperform the CA 125 and risk of malignancy index tests in categorizing a pelvic mass into high or low risk of malignancy in a Swedish population. Furthermore, cut-off values needed to be defined for HE4 and ROMA in premenopausal and postmenopausal women prior to their introduction to clinical practice. A third objective was to investigate the correlation between HE4 levels in serum and urine. Material and methods Women with a pelvic mass scheduled for surgery were recruited from nine hospitals in south-east Sweden. Preoperative blood samples were taken for analyzing CA125 and HE4 as well as urine samples for analyzing HE4. Results We enrolled a total of 901 women, of whom 784 were evaluable. In the premenopausal and postmenopausal groups, no significant differences were found for sensitivity, positive and negative predictive value, either for RMI vs ROMA or for CA125 vs HE4 using a fixed specificity of 75%. Cut-off values indicating malignancy were established for HE4 and ROMA in premenopausal and postmenopausal women. We found no correlation between HE4 concentration in serum and urine. Conclusions We could not confirm that ROMA had diagnostic superiority over RMI in categorizing women with a pelvic mass into low-risk or high-risk groups for malignancy in a Swedish population. We have defined cut-off values for HE4 and ROMA. The lack of correlation between serum and urine HE4 obviates the introduction of urine HE4 analysis in clinical diagnostics.

  • 324.
    Lill, Christina M.
    et al.
    University of Lubeck, Germany; Max Planck Institute Molecular Genet, Germany.
    Rengmark, Aina
    Oslo University Hospital, Norway.
    Pihlstrom, Lasse
    Oslo University Hospital, Norway.
    Fogh, Isabella
    Kings Coll London, England.
    Shatunov, Aleksey
    Kings Coll London, England.
    Sleiman, Patrick M.
    Childrens Hospital Philadelphia, PA 19104 USA; Childrens Hospital Philadelphia, PA 19104 USA; University of Penn, PA 19104 USA; University of Turin, Italy.
    Wang, Li-San
    University of Penn, PA 19104 USA; University of Turin, Italy.
    Liu, Tian
    Max Planck Institute Human Dev, Germany.
    Lassen, Christina F.
    Danish Cancer Soc, Denmark.
    Meissner, Esther
    Max Planck Institute Molecular Genet, Germany.
    Alexopoulos, Panos
    Technical University of Munich, Germany.
    Calvo, Andrea
    University of Turin, Italy.
    Chio, Adriano
    University of Turin, Italy; Neurosci Institute Turin, Italy.
    Dizdar (Dizdar Segrell), Nil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
    Faltraco, Frank
    Goethe University of Frankfurt, Germany.
    Forsgren, Lars
    Umeå University, Sweden.
    Kirchheiner, Julia
    University of Ulm, Germany.
    Kurz, Alexander
    Technical University of Munich, Germany.
    Larsen, Jan P.
    Stavanger University Hospital, Norway.
    Liebsch, Maria
    Max Planck Institute Molecular Genet, Germany.
    Linder, Jan
    Umeå University, Sweden.
    Morrison, Karen E.
    University of Birmingham, England; University Hospital Birmingham, England.
    Nissbrandt, Hans
    University of Gothenburg, Sweden.
    Otto, Markus
    University of Ulm, Germany.
    Pahnke, Jens
    University of Oslo, Norway; Oslo University Hospital, Norway; University of Lubeck, Germany.
    Partch, Amanda
    University of Penn, PA 19104 USA.
    Restagno, Gabriella
    Azienda Osped Citta Salute and Science, Italy.
    Rujescu, Dan
    University of Halle Wittenberg, Germany.
    Schnack, Cathrin
    University of Ulm, Germany.
    Shaw, Christopher E.
    Kings Coll London, England.
    Shaw, Pamela J.
    University of Sheffield, England.
    Tumani, Hayrettin
    University of Ulm, Germany.
    Tysnes, Ole-Bjorn
    Haukeland Hospital, Norway; University of Bergen, Norway.
    Valladares, Otto
    University of Penn, PA 19104 USA.
    Silani, Vincenzo
    IRCCS Ist Auxol Italiano, Italy; University of Milan, Italy.
    van den Berg, Leonard H.
    University of Medical Centre Utrecht, Netherlands.
    van Rheenen, Wouter
    University of Medical Centre Utrecht, Netherlands.
    Veldink, Jan H.
    University of Medical Centre Utrecht, Netherlands.
    Lindenberger, Ulman
    Max Planck Institute Human Dev, Germany.
    Steinhagen-Thiessen, Elisabeth
    Charite, Germany.
    Teipel, Stefan
    German Centre Neurodegenerat Disease DZNE, Germany; University of Rostock, Germany.
    Perneczky, Robert
    Technical University of Munich, Germany; University of London Imperial Coll Science Technology and Med, England; West London Mental Health Trust, England.
    Hakonarson, Hakon
    Childrens Hospital Philadelphia, PA 19104 USA; Childrens Hospital Philadelphia, PA 19104 USA; University of Penn, PA 19104 USA.
    Hampel, Harald
    AXA Research Fund, France; University of Sorbonne, France.
    von Arnim, Christine A. F.
    University of Ulm, Germany.
    Olsen, Jorgen H.
    Danish Cancer Soc, Denmark.
    Van Deerlin, Vivianna M.
    University of Penn, PA 19104 USA; University of Turin, Italy.
    Al-Chalabi, Ammar
    Kings Coll London, England.
    Toft, Mathias
    Oslo University Hospital, Norway.
    Ritz, Beate
    ICM, France.
    Bertram, Lars
    Max Planck Institute Molecular Genet, Germany; University of Calif Los Angeles, CA USA.
    The role of TREM2 R47H as a risk factor for Alzheimers disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinsons disease2015In: Alzheimer's & Dementia, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 11, no 12, p. 1407-1416Article in journal (Refereed)
    Abstract [en]

    A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimers disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinsons disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta-analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Ab42) and total-tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 x 10(-25)). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR 5 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR 5 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF-total-tau (P = .0110) but not Ab42 suggesting that TREM2s role in AD may involve tau dysfunction. (C) 2015 The Alzheimers Association. Published by Elsevier Inc. All rights reserved.

  • 325.
    Lilledahl, Magnus B.
    et al.
    Norwegian University of Science and Technoogy, Norway.
    Gustafsson, Håkan
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Diagnostics, Department of Biomedical Engineering.
    Gunnar Ellingsen, Pal
    Norwegian University of Science and Technoogy, Norway.
    Zachrisson, Helene
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Stenhjem Hagen, Vegard
    Norwegian University of Science and Technoogy, Norway.
    Kildemo, Morten
    Norwegian University of Science and Technoogy, Norway.
    Lindgren, Mikael
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology. Norwegian University of Science and Technoogy, Norway.
    Combined imaging of oxidative stress and microscopic structure reveals new features in human atherosclerotic plaques2015In: Journal of Biomedical Optics, ISSN 1083-3668, E-ISSN 1560-2281, Vol. 20, no 2, p. 020503-Article in journal (Refereed)
    Abstract [en]

    Human atherosclerotic samples collected by carotid endarterectomy were investigated using electronic paramagnetic resonance imaging (EPRI) for visualization of reactive oxygen species, and nonlinear optical microscopy (NLOM) to study structural features. Regions of strong EPRI signal, indicating a higher concentration of reactive oxygen species and increased inflammation, were found to colocalize with regions dense in cholesterol crystals as revealed by NLOM.

  • 326.
    Lindahl, Gabriel
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Rzepecka, Anna
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Dabrosin, Charlotta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Increased Extracellular Osteopontin Levels in Normal Human Breast Tissue at High Risk of Developing Cancer and Its Association With Inflammatory Biomarkers in situ2019In: Frontiers in Oncology, ISSN 2234-943X, E-ISSN 2234-943X, Vol. 9, article id 746Article in journal (Refereed)
    Abstract [en]

    Mammographic breast density is a strong independent risk factor for breast cancer (BC), but the molecular mechanisms behind this risk is yet undetermined and prevention strategies for these women are lacking. The anti-estrogen tamoxifen may reduce the risk of BC but this treatment is associated with severe side effects. Thus, other means for BC prevention, such as diet interventions, need to be developed. Osteopontin (OPN) is a major mediator of inflammation which is key in carcinogenesis. OPN may be cleaved by proteases in the tissue and cleaved OPN may in turn induce an inflammatory cascade in the extracellular microenvironment. We aimed to determine if extracellular OPN was altered in BC and in normal breast tissue with different densities and if tamoxifen or a diet of flaxseed could modify OPN levels. The study comprised 103 women; 13 diagnosed with BC, 42 healthy post-menopausal women with different breast densities at their mammography screen, and 34 post-menopausal women who added 25 g of ground flaxseed/day or were treated with tamoxifen 20 mg/day and were investigated before and after 6 weeks of exposure. Additionally, 10 premenopausal women who added flaxseed for one menstrual cycle and four who were investigated in two unexposed consecutive luteal phases of the menstrual cycle. Microdialysis was used to sample extracellular proteins in vivo in breast tissue and proteins were quantified using a multiplex proximity extension assay. We found that, similar to BC, extracellular in vivo OPN levels were significantly increased in dense breast tissue. Additionally, significant correlations were found between OPN and chemokine (C-X-C motif) ligand (CXCL)-1, -8, -9, -10, and - 11, interleukin-6, vascular endothelial growth factor, matrix metalloproteinase (MMP)-1, - 2, -3, 7, and -12 and urokinase-type plasminogen activator whereas no correlations were found with MMP-9, chemokine (C-C motif) ligand (CCL)-2, and -5. Estradiol did not affect OPN levels in breast tissue. None of the interventions altered OPN levels. The pro-tumorigenic protein OPN may indeed be a molecular target for BC prevention in women with increased breast density but other means than tamoxifen or flaxseed i.e., more potent anti-inflammatory approaches, need to be evaluated for this purpose.

  • 327.
    Lindahl, Tomas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Arbring, Kerstin
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine and Geriatrics.
    Wallstedt, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Rånby, Mats
    Zafena AB, Borensberg, Sweden.
    A novel prothrombin time method to measure all non-vitamin K-dependent oral anticoagulants (NOACs)2017In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 3, p. 171-176Article in journal (Refereed)
    Abstract [en]

    Background: There is a clinical need for point-of-care (POC) methods for non-vitamin K-dependent oral anticoagulants (NOACs). We modified a routine POC procedure: Zafena’s Simple Simon™ PT-INR, a room-temperature, wet-chemistry prothrombin time method of the Owren-type.

    Methods: To either increase or decrease NOAC interference, two assay variants were devised by replacing the standard 10 µL end-to-end capillary used to add the citrated plasma sample to 200 µL of prothrombin time (PT) reagent by either a 20 µL or a 5 µL capillary. All assay variants were calibrated to show correct PT results in plasma samples from healthy and warfarin-treated persons.

    Results: For plasmas spiked with dabigatran, apixaban, or rivaroxaban, the 20 µL variant showed markedly higher PT results than the 5 µL. The effects were even more pronounced at room temperature than at +37 °C. In plasmas from patients treated with NOACs (n = 30 for each) there was a strong correlation between the PT results and the concentration of NOACs as determined by the central hospital laboratory. For the 20 µL variant the PT response of linear correlation coefficient averaged 0.90. The PT range was INR 1.1–2.1 for dabigatran and apixaban, and INR 1.1–5.0 for rivaroxaban. Using an INR ratio between the 20 µL and 5 µL variants (PTr20/5) made the NOAC assay more robust and independent of the patient sample INR value in the absence of NOAC. Detection limits were 80 µg/L for apixaban, 60 µg/L for dabigatran, and 20 µg/L for rivaroxaban.

    Conclusions: A wet-chemistry POC PT procedure was modified to measure the concentrations of three NOACs using a single reagent.

  • 328.
    Lindahl, Tomas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Faxälv, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Stable solution2015Patent (Other (popular science, discussion, etc.))
  • 329.
    Lindahl, Tomas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Macwan, Ankit
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ramström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Protease-activated receptor 4 is more important than protease-activated receptor 1 for the thrombin-induced procoagulant effect on platelets in JOURNAL OF THROMBOSIS AND HAEMOSTASIS, vol 14, issue 8, pp 1639-16412016In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 14, no 8, p. 1639-1641Article in journal (Other academic)
    Abstract [en]

    n/a

  • 330.
    Lindahl, Tomas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Ramström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Boknäs, Niklas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Faxälv, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Caveats in studies of the physiological role of polyphosphates in coagulation2016In: Biochemical Society Transactions, ISSN 0300-5127, E-ISSN 1470-8752, Vol. 44, p. 35-39Article, review/survey (Refereed)
    Abstract [en]

    Platelet-derived polyphosphates (polyP), stored in dense granule and released upon platelet activation, have been claimed to enhance thrombin activation of coagulation factor XI (FXI) and to activate FXII directly. The latter claim is controversial and principal results leading to these conclusions are probably influenced by methodological problems. It is important to consider that low-grade contact activation is initiated by all surfaces and is greatly amplified by the presence of phospholipids simulating the procoagulant membranes of activated platelets. Thus, proper use of inhibitors of the contact pathway and a careful choice of materials for plates and tubes is important to avoid artefacts. The use of phosphatases used to degrade polyP has an important drawback as it also degrades the secondary activators ADP and ATP, which are released from activated platelets. In addition, the use of positively charged inhibitors, such as polymyxin B, to inhibit polyP in platelet-rich plasma and blood is problematic, as polymyxin B also slows coagulation in the absence of polyP. In conclusion we hope awareness of the above caveats may improve research on the physiological roles of polyP in coagulation. © 2016 Authors; published by Portland Press Limited.

  • 331.
    Lindau, Robert
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Bhai Mehta, Ratnesh
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Lash, G. E.
    Guangzhou Women and Childrens Med Ctr, Peoples R China.
    Papapavlou, Georgia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Boij, Roland
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Cty Hosp Ryhov, Sweden.
    Berg, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Svensson Arvelund, Judit
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Interleukin-34 is present at the fetal-maternal interface and induces immunoregulatory macrophages of a decidual phenotype in vitro2018In: Human Reproduction, ISSN 0268-1161, E-ISSN 1460-2350, Vol. 33, no 4, p. 588-599Article in journal (Refereed)
    Abstract [en]

    STUDY QUESTION: Is the newly discovered cytokine interleukin (IL)-34 expressed at the human fetal-maternal interface in order to influence polarization of monocytes into macrophages of a decidual immunoregulatory phenotype? SUMMARY ANSWER: IL-34 was found to be present at the fetal-maternal interface, in both fetal placenta and maternal decidua, and it was able to polarize monocytes into macrophages of a decidual phenotype. WHAT IS KNOWN ALREADY: IL-34 was shown to bind to the same receptor as macrophage-colony stimulating factor (M-CSF), which has an important immunomodulatory role at the fetal-maternal interface, for example by polarizing decidual macrophages to an M2-like regulatory phenotype. IL-34 is known to regulate macrophage subsets, such as microglia and Langerhans cells, but its presence at the fetal-maternal interface is unknown. STUDY DESIGN, SIZE, DURATION: The presence of IL-34 at the fetal-maternal interface was evaluated by immunohistochemistry (IHC) and ELISA in placental and decidual tissues as well as in isolated trophoblast cells and decidual stromal cells obtained from first trimester elective surgical terminations of pregnancy (n = 49). IL-34 expression was also assessed in third trimester placental biopsies from women with (n = 21) or without (n = 15) pre-eclampsia. The effect of IL-34 on macrophage polarization was evaluated in an in vitro model of blood monocytes obtained from healthy volunteers (n = 14). In this model, granulocyte macrophage-colony stimulating factor (GM-CSF) serves as a growth factor for M1-like polarization, and M-CSF as a growth factor for M2-like polarization. PARTICIPANTS/MATERIALS, SETTING, METHODS: First trimester placental and decidual tissues were obtained from elective pregnancy terminations. Placental biopsies were obtained from women with pre-eclampsia and matched controls in the delivery ward. Polarization of macrophages in vitro was determined by flow-cytometric phenotyping and secretion of cytokines and chemokines in cell-free supernatants by multiplex bead assay. MAIN RESULTS AND THE ROLE OF CHANCE: Our study shows that IL-34 is produced at the fetal-maternal interface by both placental cyto-and syncytiotrophoblasts and decidual stromal cells. We also show that IL-34, in vitro, is able to polarize blood monocytes into macrophages with a phenotype (CD14(high)CD163(+)CD209(+)) and cytokine secretion pattern similar to that of decidual macrophages. The IL-34-induced phenotype was similar, but not identical to the phenotype induced by M-CSF, and both IL-34-and M-CSF-induced macrophages were significantly different (P amp;lt; 0.05-0.0001 depending on marker) from GM-CSF-polarized M1-like macrophages. Our findings suggest that IL-34 is involved in the establishment of the tolerant milieu found at the fetal-maternal interface by skewing polarization of macrophages into a regulatory phenotype. LIMITATIONS, REASONS FOR CAUTION: Although it is clear that IL-34 is present at the fetal-maternal interface and polarizes macrophages in vitro, its precise role in vivo remains to be established. WIDER IMPLICATIONS OF THE FINDINGS: The recently discovered cytokine IL-34 is present at the fetal-maternal interface and has immunomodulatory properties with regard to induction of decidual macrophages, which are important for a healthy pregnancy. Knowledge of growth factors related to macrophage polarization can potentially be translated to treatment of pregnancy complications involving dysregulation of this process. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by grants from the Medical Research Council (Grant K2013-61X-22310-01-04), the Research Council of South-East Sweden (FORSS), and the County Council of Ostergotland, Sweden. No author has any conflicts of interest to declare.

  • 332.
    Lindström, Annelie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Midtbö, Kristine Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Arnesson, Lars-Gunnar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Garvin, Stina
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Shabo, Ivan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping. Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Fusion between M2-macrophages and cancer cells results in a subpopulation of radioresistant cells with enhanced DNA-repair capacity2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 31, p. 51370-51386Article in journal (Refereed)
    Abstract [en]

    Cell fusion is a natural biological process in normal development and tissue regeneration. Fusion between cancer cells and macrophages results in hybrids that acquire genetic and phenotypic characteristics from both maternal cells. There is a growing body of in vitro and in vivo data indicating that this process also occurs in solid tumors and may play a significant role in tumor progression. However, investigations of the response of macrophage: cancer cell hybrids to radiotherapy have been lacking. In this study, macrophage: MCF-7 hybrids were generated by spontaneous in vitro cell fusion. After irradiation, both hybrids and their maternal MCF-7 cells were treated with 0 Gy, 2.5 Gy and 5 Gy.-radiation and examined by clonogenic survival and comet assays at three time points (0 h, 24 h, and 48 h). Compared to maternal MCF-7 cells, the hybrids showed increased survival fraction and plating efficiency (colony formation ability) after radiation. The hybrids developed less DNA-damage, expressed significantly lower residual DNA-damage, and after higher radiation dose showed less heterogeneity in DNA-damage compared to their maternal MCF-7 cells. To our knowledge this is the first study that demonstrates that macrophage: cancer cell fusion generates a subpopulation of radioresistant cells with enhanced DNA-repair capacity. These findings provide new insight into how the cell fusion process may contribute to clonal expansion and tumor heterogeneity. Furthermore, our results provide support for cell fusion as a mechanism behind the development of radioresistance and tumor recurrence.

  • 333.
    Linge, Jennifer
    et al.
    AMRA Medical AB, Linköping, Sweden.
    Whitcher, Brandon
    AMRA Medical AB, Linköping, Sweden.
    Borga, Magnus
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. AMRA Medical AB, Linköping, Sweden.
    Dahlqvist Leinhard, Olof
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Diagnostics, Medical radiation physics. AMRA Medical AB, Linköping, Sweden.
    Sub-phenotyping Metabolic Disorders Using Body Composition: An Individualized, Nonparametric Approach Utilizing Large Data Sets2019In: Obesity, ISSN 1930-7381, E-ISSN 1930-739X, Vol. 27, no 7, p. 1190-1199Article in journal (Refereed)
    Abstract [en]

    Objective: This study performed individual-centric, data-driven calculations of propensity for coronary heart disease (CHD) and type 2 diabetes (T2D), utilizing magnetic resonance imaging-acquired body composition measurements, for sub-phenotyping of obesity and nonalcoholic fatty liver disease (NAFLD).Methods: A total of 10,019 participants from the UK Biobank imaging substudy were included and analyzed for visceral and abdominal subcutaneous adipose tissue, muscle fat infiltration, and liver fat. An adaption of the k-nearest neighbors algorithm was applied to the imaging variable space to calculate individualized CHD and T2D propensity and explore metabolic sub-phenotyping within obesity and NAFLD.

    Results: The ranges of CHD and T2D propensity for the whole cohort were 1.3% to 58.0% and 0.6% to 42.0%, respectively. The diagnostic performance, area under the receiver operating characteristic curve (95% CI), using disease propensities for CHD and T2D detection was 0.75 (0.73-0.77) and 0.79 (0.77-0.81). Exploring individualized disease propensity, CHD phenotypes, T2D phenotypes, comorbid phenotypes, and metabolically healthy phenotypes were found within obesity and NAFLD.

    Conclusions: The adaptive k-nearest neighbors algorithm allowed an individual-centric assessment of each individual’s metabolic phenotype moving beyond discrete categorizations of body composition. Within obesity and NAFLD, this may help in identifying which comorbidities a patient may develop and conse- quently enable optimization of treatment.

  • 334.
    Liu, Caifeng
    et al.
    Karolinska Institute, Sweden; Shandong University, Peoples R China.
    Zhang, Yunjian
    Karolinska Institute, Sweden; Sun Yat Sen University, Peoples R China.
    Lim, Sharon
    Karolinska Institute, Sweden.
    Hosaka, Kayoko
    Karolinska Institute, Sweden.
    Yang, Yunlong
    Karolinska Institute, Sweden; Shenzhen University, Peoples R China.
    Pavlova, Tatiana
    Karolinska Institute, Sweden.
    Alkasalias, Twana
    Karolinska Institute, Sweden.
    Hartman, Johan
    Karolinska Institute, Sweden.
    Jensen, Lasse
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. Karolinska Institute, Sweden.
    Xing, Xiaoming
    Qingdao University, Peoples R China; Qingdao University, Peoples R China.
    Wang, Xinsheng
    Qingdao University, Peoples R China; Qingdao University, Peoples R China.
    Lu, Yongtian
    Shenzhen University, Peoples R China.
    Nie, Guohui
    Shenzhen University, Peoples R China.
    Cao, Yihai
    Karolinska Institute, Sweden; Shenzhen University, Peoples R China; Qingdao University, Peoples R China; Qingdao University, Peoples R China.
    A Zebrafish Model Discovers a Novel Mechanism of Stromal Fibroblast-Mediated Cancer Metastasis2017In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 23, no 16, p. 4769-4779Article in journal (Refereed)
    Abstract [en]

    Purpose: Cancer metastasis can occur at the early stage of tumor development when a primary tumor is at the microscopic size. In particular, the interaction of malignant cells with other cell types including cancer-associated fibroblasts (CAF) in promoting metastasis at the early stage of tumor development remains largely unknown. Here, we investigated the role of CAFs in facilitating the initial events of cancer metastasis when primary tumors were at microscopic sizes. Experimental Design: Multicolor-coded cancer cells and CAFs were coimplanted into the transparent zebrafish body and metastasis at a single-cell level was monitored in living animals. Healthy fibroblasts, tumor factor-educated fibroblasts, and CAFs isolated from various tumors were tested for their ability to facilitate metastasis. Results: We showed that CAFs promoted cancer cell metastasis at the very early stage during primary tumor development. When a primary tumor was at the microscopic size consisting of a few hundred cells, CAFs were able to hijack cancer cells for dissemination from the primary site. Surprisingly, a majority of metastatic cancer cells remained in tight association with CAFs in the circulation. Furthermore, stimulation of non-metastasis-promoting normal fibroblasts with TGF-B, FGF-2, HGF, and PDGF-BB led to acquisition of their metastatic capacity. Conclusions: Cancer metastasis occurs at the very early stage of tumor formation consisting of only a few hundred cells. CAFs are the key cellular determinant for metastasis. Our findings provide novel mechanistic insights on CAFs in promoting cancer metastasis and targeting CAFs for cancer therapy should be aimed at the early stage during cancer development. (C) 2017 AACR.

  • 335.
    Liu, Na
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Xi An Jiao Tong Univ, Peoples R China.
    Cui, Weiyingqi
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Jiang, Xia
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Hebei Med Univ, Peoples R China.
    Zhang, Zhiyong
    Fourth Mil Med Univ, Peoples R China.
    Gnosa, Sebastian
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Ali, Zaheer
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Jensen, Lasse
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Blockhuys, Stephanie
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Lam, Eric W-F
    Imperial Coll London, England.
    Zhao, Zengren
    Hebei Med Univ, Peoples R China.
    Ping, Jie
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Xie, Ning
    Xi An Jiao Tong Univ, Peoples R China.
    Kopsida, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Wang, Xin
    Fourth Mil Med Univ, Peoples R China.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    The Critical Role of Dysregulated RhoB Signaling Pathway in Radioresistance of Colorectal Cancer2019In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 104, no 5, p. 1153-1164Article in journal (Refereed)
    Abstract [en]

    Purpose

    To explore whether the Rho protein is involved in the radioresistance of colorectal cancer and investigate the underlying mechanisms.

    Methods and Materials

    Rho GTPase expression was measured after radiation treatment in colon cancer cells. RhoB knockout cell lines were established using the CRISPR/Cas9 system. In vitro assays and zebrafish embryos were used for analyzing radiosensitivity and invasive ability. Mass cytometry was used to detect RhoB downstream signaling factors. RhoB and Forkhead box M1 (FOXM1) expression were detected by immunohistochemistry in rectal cancer patients who participated in a radiation therapy trial.

    Results

    RhoB expression was related to radiation resistance. Complete depletion of the RhoB protein increased radiosensitivity and impaired radiation-enhanced metastatic potential in vitro and in zebrafish models. Probing signaling using mass cytometry–based single-cell analysis showed that the Akt phosphorylation level was inhibited by RhoB depletion after radiation. FOXM1 was downregulated in RhoB knockout cells, and the inhibition of FOXM1 led to lower survival rates and attenuated migration and invasion abilities of the cells after radiation. In the patients who underwent radiation therapy, RhoB overexpression was related to high FOXM1, late Tumor, Node, Metastasis stage, high distant recurrence, and poor survival independent of other clinical factors.

    Conclusions

    RhoB plays a critical role in radioresistance of colorectal cancer through Akt and FOXM1 pathways.

  • 336.
    Loizou, Louiza
    et al.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Duran, Carlos Valls
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Axelsson, Elisabet
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden; Uppsala Univ Hosp, Sweden.
    Andersson, Mats
    Univ Gothenburg, Sweden.
    Keussen, Inger
    Skane Univ Hosp, Sweden.
    Strinnholm, Jorgen
    Umea Univ, Sweden.
    Bartholomä, Wolf
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Del Chiaro, Marco
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Segersvard, Ralf
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Lundell, Lars
    Karolinska Inst, Sweden.
    Kartalis, Nikolaos
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Radiological assessment of local resectability status in patients with pancreatic cancer: Interreader agreement and reader performance in two different classification systems2018In: European Journal of Radiology, ISSN 0720-048X, E-ISSN 1872-7727, Vol. 106, p. 69-76Article in journal (Refereed)
    Abstract [en]

    Objectives: To assess the interreader agreement and reader performance in the evaluation of patients with pancreatic cancer (PC) in two classification systems of local resectability status prior to initiation of therapy, namely the National Comprehensive Cancer Network (NCCN) and Karolinska classification system (KCS). Methods: In this ethics review board-approved retrospective study, six radiologists independently evaluated pancreatic CT-examinations of 30 patients randomly selected from a tertiary referral centres multidisciplinary tumour board database. Based on well-defined criteria of tumour-vessel relationship, each patient was assigned to one of three NCCN and six KCS categories. We assessed the intraclass correlation coefficient (ICC) and compared the percentages of correct tumour classification of the six readers in both systems (Chi-square test; a P-value amp;lt; 0.05 was considered significant). The standard of reference was a consensus evaluation of CT-examinations by three readers not involved in the image analysis. Results: The ICC for NCCN and KCS was 0.82 and 0.84, respectively (very strong agreement). The percentages of correct tumour classification at NCCN and KCS were 53-83% and 30-57%, respectively, with no statistically significant differences in the overall reader comparison per classification system. In pair-wise comparison between readers for NCCN/KCS, there were statistically significant differences between reader 5 vs. readers 4 (P = 0.012) and 3 (P = 0.045)/ reader 5 vs. reader 4 (P = 0.037). Conclusion: Interreader agreement in both PC classification systems is very strong. NCCN may be advantageous in terms of reader performance compared to KCS.

  • 337.
    Lolas, Georgios
    et al.
    Athens School Med, Greece.
    Jensen, Lasse
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. Karolinska Institute, Sweden.
    Bourantas, George C.
    University of Luxembourg, Luxembourg.
    Tsikourkitoudi, Vasiliki
    Athens School Med, Greece.
    Syrigos, Konstantinos
    Athens School Med, Greece.
    Modeling Proteolytically Driven Tumor Lymphangiogenesis2016In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 936, p. 107-136Article in journal (Refereed)
    Abstract [en]

    With the exception of a limited number of sites in the body, primary tumors infrequently lead to the demise of cancer patients. Instead, mortality and a significant degree of morbidity result from the growth of secondary tumors in distant organs. Tumor survival, growth and dissemination are associated with the formation of both new blood vessels (angiogenesis) and new lymph vessels (lymphagenesis or lymphangiogenesis). Although intensive research in tumor angiogenesis has been going on for the past four decades, experimental results in tumor lymphangiogenesis began to appear only in the last 10 years. In this chapter we expand the models proposed by Friedman, Lolas and Pepper on tumor lymphangiogenesis mediated by proteolytically and un-proteolytically processed growth factors (Friedman and Lolas G, Math Models Methods Appl Sci 15(01): 95-107, 2005; Pepper and Lolas G, Selected topics in cancer modeling: genesis, evolution, immune competition, and therapy. In: The lymphatic vascular system in lymphangiogenesis invasion and metastasis a mathematical approach. Birkhauser Boston, Boston, pp 1-22, 2008). The variables represent different cell densities and growth factors concentrations, and where possible the parameters are estimated from experimental and clinical data. The results obtained from computational simulations carried out on the model equations produce dynamic heterogeneous ("anarchic") spatio-temporal solutions. More specifically, we observed coherent masses of tumor clusters migrating around and within the lymphatic network. Our findings are in line with recent experimental evidence that associate cluster formation with the minimization of cell loss favoring high local extracellular matrix proteolysis and thus protecting cancer invading cells from an immunological assault driven by the lymphatic network.

  • 338.
    Lood, Yvonne
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. National Board Forens Med, Department Forens Genet and Forens Toxicol, Artillerigatan 12, S-58758 Linkoping, Sweden.
    Aardal-Eriksson, Elisabeth
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Webe, C.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. National Board Forens Med, Department Forens Genet and Forens Toxicol, Artillerigatan 12, S-58758 Linkoping, Sweden.
    Ekman, Bertil
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Wahlberg, Jeanette
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Relationship between testosterone in serum, saliva and urine during treatment with intramuscular testosterone undecanoate in gender dysphoria and male hypogonadism2018In: Andrology, ISSN 2047-2919, E-ISSN 2047-2927, Vol. 6, no 1, p. 86-93Article in journal (Refereed)
    Abstract [en]

    Long-term testosterone replacement therapy is mainly monitored by trough levels of serum testosterone (S-T), while urinary testosterone (U-T) is used by forensic toxicology to evaluate testosterone doping. Testosterone in saliva (Sal-T) may provide additional information and simplify the sample collection. We aimed to investigate the relationships between testosterone measured in saliva, serum and urine during standard treatment with 1,000mg testosterone undecanoate (TU) every 12th week during 1year. This was an observational study. Males with primary and secondary hypogonadism (HG; n=23), subjects with gender dysphoria (GD FtM; n=15) and a healthy control group of men (n=32) were investigated. Sal-T, S-T and U-T were measured before and after TU injections. Sal-T was determined with Salimetrics((R)) enzyme immunoassay, S-T with Roche Elecsys((R)) testosterone II assay and U-T by gas chromatography-mass spectrometry. Sal-T correlated significantly with S-T and calculated free testosterone in both controls and patients (HG men and GD FtM), while Sal-T to U-T showed weaker correlations. Trough values of Sal-T after 12months were significantly higher in the GD FtM group (0.77 +/- 0.35nmol/L) compared to HG men (0.53 +/- 0.22nmol/L) and controls (0.46 +/- 0.15nmol/L), while no differences between S-T and U-T trough values were found. Markedly elevated concentrations of salivary testosterone, 7-14days after injection, were observed, especially in the GD FtM group. This study demonstrates that Sal-T might be a useful clinical tool to monitor long-term testosterone replacement therapy and might give additional information in forensic cases.

  • 339.
    Lourda, Magda
    et al.
    Karolinska Institute, Sweden.
    Olsson-Akefeldt, Selma
    Karolinska Institute, Sweden.
    Gavhed, Desiree
    Karolinska Institute, Sweden.
    Axdorph Nygell, Ulla
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Berlin, Gösta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Laurencikas, Evaldas
    Karolinska Institute, Sweden.
    von Bahr Greenwood, Tatiana
    Karolinska Institute, Sweden.
    Svensson, Mattias
    Karolinska Institute, Sweden.
    Henter, Jan-Inge
    Karolinska Institute, Sweden.
    Adsorptive depletion of blood monocytes reduces the levels of circulating interleukin-17A in Langerhans cell histiocytosis2016In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 128, no 9, p. 1302-1305Article in journal (Other academic)
    Abstract [en]

    n/a

  • 340.
    Lund, Mari L.
    et al.
    Section for Metabolic Receptology, Novo Nordisk Foundation Center for Basic Metabolite Research, Faculty of Health Sciences, University of Copenhagen, Denmark.
    Egerod, Kristoffer L.
    Section for Metabolic Receptology, Novo Nordisk Foundation Center for Basic Metabolite Research, Faculty of Health Sciences, University of Copenhagen, Denmark.
    Engelstoft, Maja S.
    Section for Metabolic Receptology, Novo Nordisk Foundation Center for Basic Metabolite Research, Faculty of Health Sciences, University of Copenhagen, Denmark.
    Dmytriyeva, Oksana
    Research Laboratory for Stereology and Neuroscience, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Laboratory of Neural Plasticity, Institute of Neuroscience, University of Copenhagen, Copenhagen, Denmark.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Patel, Bhavik A.
    School of Pharmacy and Biomolecular Sciences, University of Brighton, UK.
    Schwartz, Thue W.
    Section for Metabolic Receptology, Novo Nordisk Foundation Center for Basic Metabolite Research, Faculty of Health Sciences, University of Copenhagen, Denmark; Laboratory for Molecular Pharmacology, Department for Biomedical Research, Faculty of Health Sciences, University of Copenhagen, Denmark.
    Enterochromaffin 5-HT cells: A major target for GLP-1 and gut microbial metabolites2018In: MOLECULAR METABOLISM, ISSN 2212-8778, Vol. 11, p. 70-83Article in journal (Refereed)
    Abstract [en]

    Objectives

    5-HT storing enterochromaffin (EC) cells are believed to respond to nutrient and gut microbial components, and 5-HT receptor-expressing afferent vagal neurons have been described to be the major sensors of nutrients in the GI-tract. However, the molecular mechanism through which EC cells sense nutrients and gut microbiota is still unclear.

    Methods and results

    TPH1, the 5-HT generating enzyme, and chromogranin A, an acidic protein responsible for secretory granule storage of 5-HT, were highly enriched in FACS-purified EC cells from both small intestine and colon using a 5-HT antibody-based method. Surprisingly, EC cells from the small intestine did not express GPCRsensors for lipid and protein metabolites, such as FFAR1, GPR119, GPBAR1(TGR5), CaSR, and GPR142, in contrast to the neighboring GLP-1 storing enteroendocrine cell. However, the GLP-1 receptor was particularly highly expressed and enriched in EC cells as judged both by qPCR and by immunohistochemistryusing a receptor antibody. GLP-1 receptor agonists robustly stimulated 5-HT secretion from intestinal preparations using both HPLC and a specific amperometricmethod. Colonic EC cells expressed many different types of known and potential GPCR sensors of microbial metabolites including three receptors for SCFAs, i.e. FFAR2, OLF78, and OLF558 and receptors for aromatic acids, GPR35; secondary bile acids GPBAR1; and acyl-amides and lactate, GPR132.

    Conclusion

    Nutrient metabolites apparently do not stimulate EC cells of the small intestine directly but through a paracrine mechanism involving GLP-1 secreted from neighboring enteroendocrine cells. In contrast, colonic EC cells are able to sense a multitude of different metabolites generated by the gut microbiota as well as gut hormones, including GLP-1.

  • 341.
    Lundberg, Peter
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Forsgren, Mikael
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Nasr, Patrik
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Ignatova, Simone
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Leinhard Dahlqvist, Olof
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Dahlström, Nils
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Ekstedt, Mattias
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Kechagias, Stergios
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Kvantifiering av leversteatos: diagnostisk utvärdering av protonmagnetresonansspektroskopi jämfört med histologiska metoder2016Conference paper (Refereed)
    Abstract [sv]

    Bakgrund

    Leversteatos är den vanligaste manifestationen av leversjukdom i västvärlden. Leverbiopsi med semikvantitativ histologisk gradering är referensmetod vid gradering av leversteatos. Med protonmagnetsresonansspektroskopi (1H-MRS), en metod som föreslagits ersätta leverbiopsi för värdering av steatos, kan leverns innehåll av triglycerider mätas icke-invasivt. Triglyceridinnehåll >5,00 % används ofta som ett diagnostiskt kriterium för leversteatos vid undersökning med 1H-MRS. Syftet med studien var att jämföra 1H-MRS med semikvantitativ histologisk steatosgradering och kvantitativ histologisk steatosmätning.

    Metod

    Patienter remitterade för utredning av förhöjda leverenzymer in-kluderades i studien. Samtliga patienter genomgick klinisk undersökning, laboratorieprovtagning samt 1H-MRS direkt följd av leverbiopsi. För konventionell histologisk semikvantitativ gradering av steatos användes kriterierna utarbetade av Brunt och medarbetare. Kvantitativ mätning av fett i biopsierna utfördes genom att med hjälp av stereologisk punkträkning (SPC) mäta andelen av ytan som innehöll fettvakuoler.

    Resultat

    I studien inkluderades 94 patienter, varav 37 hade icke-alkoholor-sakad fettleversjukdom (NAFLD), 49 hade andra leversjukdomar och 8 hade normal leverbiopsi. En stark korrelation noterades mel-lan 1H-MRS och SPC (r=0,92, p<0,0001; к=0.82). Korrelationen mellan 1H-MRS och Brunts kriterier (к=0.26) samt mellan SPC och Brunts kriterier (к=0.38) var betydligt sämre. När patologens gradering (Brunts kriterier) användes som referensmetod för diag-nos av leversteatos så hade alla patienter med triglyceridinnehåll >5,00 % mätt med 1H-MRS steatos (specificitet 100 %). Emellertid hade 22 av 69 patienter med triglyceridinnehåll ≤5,00 % också le-versteatos enligt Brunts kriterier (sensitivitet 53 %). Motsvarande siffror när man använde gränsvärdet 3,02 % var sensitivitet 79 % och specificitet 100 %. Vid ytterligare reduktion av gränsvärdet för triglyceridinnehåll till 2,00 % ökade sensitiviteten till 87 % med upprätthållande av hög specificitet (94 %).

    Slutsats

    1H-MRS och SPC uppvisade en mycket hög korrelation vid kvantifiering av leversteatos. SPC borde därför föredras framför Brunts kriterier när noggrann histologisk kvantifiering av leversteatos är önskvärd. Många patienter kan ha histologisk leversteatos trots triglyceridinnehåll ≤5,00 % mätt med 1H-MRS. Gränsvärdet för diagnostisering av leversteatos med 1H-MRS bör därför reduceras.

  • 342.
    Lundberg, Peter
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Karlsson, Markus
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences.
    Forsgren, Mikael
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Dahlström, Nils
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Leinhard Dahlqvist, Olof
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Norén, Bengt
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Cedersund, Gunnar
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Ekstedt, Mattias
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Kechagias, Stergios
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Mechanistic modeling of qDCE-MRI data reveals increased bile excretion of Gd-EOB-DTPA in diffuse liver disease patients with severe fibrosis2016Conference paper (Refereed)
    Abstract [en]

    Introduction

    Over the past decades, several different non-invasive methods for staging hepatic fibrosis have been proposed. One such method is dynamic contrast enhanced MRI (DCE-MRI) using the contrast agent (CA) Gd-EOB-DTPA. Gd-EOB-DTPA is liver specific, which means that it is taken up specifically by the hepatocytes via the OATP3B1/B3 transporters and excreted into the bile via the MRP2 transporter. Several studies have shown that DCE-MRI and Gd-EOBDTPA can separate patients with advanced (F3-F4) from mild (F0-F2) hepatic fibrosis by measuring the signal intensity, where patients with advanced fibrosis have a lower signal intensity than the mild fibrosis cases.1 However, none of the studies up to date have been able to differentiate if the reduced signal intensity in the liver is because of an decreased uptake of CA or an increased excretion. Analyzing the DCE-MRI data with mechanistic mathematical modelling has the possibility of investigating such a differentiation.

    Subjects and methods

    88 patients with diffuse liver disease were examined using DCE-MRI (1.5 T Philips Achieva, two-point Dixon, TR=6.5 ms, TE=2.3/4.6 ms, FA=13) after a bolus injection of Gd-EOB-DTPA, followed by a liver biopsy. Regions of interest were placed within the liver, spleen and veins and a whole-body mechanistic pharmacokinetic model2 was fitted to the data. The fitted parameters in the model correspond to the rate of CA transport between different compartments, e.g. hepatocytes, blood plasma, and bile (Fig. 1).

    Results

    As can be seen in Fig. 2, the parameter corresponding to the transport of CA from the blood plasma to the hepatocytes, kph, is lower for patients with advanced fibrosis (p=0.01). Fig. 3 shows that the parameter corresponding to the CA excretion into the bile, khb, is higher for patients with advanced fibrosis (p<0.01).

    Discussion/Conclusion

    This work shows that the decreased signal intensity in DCE-MRI images in patients with advanced fibrosis depends on both a decreased uptake of CA in the hepatocytes and an increased excretion into the bile. Similar results have also been observed in a rat study3. In that study, rats with induced cirrhosis had a higher MRP2-activity than the healthy control rats.

    References

    1Norén et al: Eur. Radiol, 23(1), 174-181, 2013.

    2Forsgren et al: PloS One, 9(4): e95700, 2014.

    3Tsuda & Matsui: Radiol, 256(3): 767-773, 2010.

  • 343.
    Lundgren, Hanna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland.
    Martinsson, Klara
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland.
    Cederbrant, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Swetox, Karolinska Institutet, Unit of Toxicology Sciences, Södertälje, Sweden.
    Jirholt, Johan
    AstraZeneca RandD, Sweden.
    Mucs, Daniel
    Swetox, Karolinska Institutet, Unit of Toxicology Sciences, Södertälje, Sweden.
    Madeyski-Bengtson, Katja
    AstraZeneca RandD, Sweden.
    Havarinasab, Said
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    HLA-DR7 and HLA-DQ2: Transgenic mouse strains tested as a model system for ximelagatran hepatotoxicity2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 9, article id e0184744Article in journal (Refereed)
    Abstract [en]

    The oral thrombin inhibitor ximelagatran was withdrawn in the late clinical trial phase because it adversely affected the liver. In approximately 8% of treated patients, drug-induced liver injury (DILI) was expressed as transient alanine transaminase (ALT) elevations. No evidence of DILI had been revealed in the pre-clinical in vivo studies. A whole genome scan study performed on the clinical study material identified a strong genetic association between the major histocompatibility complex alleles for human leucocyte antigens (HLA) (HLA-DR7 and HLA-DQ2) and elevated ALT levels in treated patients. An immunemediated pathogenesis was suggested. Here, we evaluated whether HLA transgenic mice models could be used to investigate whether the expression of relevant HLA molecules was enough to reproduce the DILI effects in humans. In silico modelling performed in this study revealed association of both ximelagatran (pro-drug) and melagatran (active drug) to the antigen-presenting groove of the homology modelled HLA-DR7 molecule suggesting "altered repertoire" as a key initiating event driving development of DILI in humans. Transgenic mouse strains (tgms) expressing HLA of serotype HLA-DR7 (HLA-DRB1*0701, -DRA*0102), and HLA-DQ2 (HLA-DQB1*0202, -DQA1*0201) were created. These two lines were crossed with a human (h) CD4 transgenic line, generating the two tgms DR7xhCD4 and DQ2xhCD4. To investigate whether the DILI effects observed in humans could be reproduced in tgms, the mice were treated for 28 days with ximelagatran. Results revealed no signs of DILI when biomarkers for liver toxicity were measured and histopathology was evaluated. In the ximelagatran case, presence of relevant HLA-expression in a preclinical model did not fulfil the prerequisite for reproducing DILI observed in patients. Nonetheless, for the first time an HLA-transgenic mouse model has been investigated for use in HLA-associated DILI induced by a low molecular weight compound. This study shows that mimicking of genetic susceptibility, expressed as DILI-associated HLA-types in mice, is not sufficient for reproducing the complex pathogenesis leading to DILI in man.

  • 344.
    Lundin, Cecilia
    et al.
    Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden.
    Malmborg, Agota
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Slezak, Julia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Gemzell-Danielsson, Kristina
    Department of Women’s and Children’s Health, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden.
    Bixo, Marie
    Department of Clinical Science, Obstetrics and Gynaecology, Umeå University, Umeå, Sweden.
    Bengtsdotter, Hanna
    Department of Obstetrics and Gynaecology, Örebro University, Örebro, Sweden.
    Marions, Lena
    Department of Clinical Science and Education, Karolinska Institutet Södersjukhuset, Stockholm, Sweden.
    Lindh, Ingela
    Department of Obstetrics and Gynaecology, Sahlgrenska Academy at Gothenburg University; Sahlgrenska University Hospital, Gothenburg, Sweden.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Hammar, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Sundström-Poromaa, Inger
    Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden.
    Sexual function and combined oral contraceptives: a randomised, placebo-controlled trial2018In: Endocrine Connections, ISSN 2049-3614, E-ISSN 2049-3614, Vol. 7, no 11, p. 1208-1216Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The effect of combined oral contraceptives (COC) on female sexuality has long been a matter of discussion, but placebo-controlled studies are lacking. Thus, the aim of the present study was to investigate if an estradiol-containing COC influences sexual function.

    DESIGN: Investigator-initiated, randomised, double-blinded, placebo-controlled clinical trial where 202 healthy women were randomized to a combined oral contraceptive (1.5 mg estradiol and 2.5 mg nomegestrol acetate) or placebo for three treatment cycles.

    METHODS: Sexual function at baseline and during the last week of the final treatment cycle was evaluated by the McCoy Female Sexuality Questionnaire. Serum and hair testosterone levels were assessed at the same time points.

    RESULTS: Compared to placebo, COC use was associated with a small decrease in sexual interest (COC median change score: -2.0; interquartile range (IQR): -5.0-0.5 vs. placebo: -1.0; IQR: -3.0-2.0, p = 0.019), which remained following adjustment for change in self-rated depressive symptoms B = -0.80 ± 0.30, Wald = 7.08, p = 0.008. However, the proportion of women who reported a clinically relevant deterioration in sexual interest did not differ between COC or placebo users (COC 18 (22.2%) vs. placebo 16 (17.8%), p = 0.47). Change in other measured aspects of sexual function as well as total score of sexual function did not differ between the two treatments.

    CONCLUSIONS: This study suggests that use of estradiol-based combined oral contraceptives is associated with reduced sexual interest. However, the changes are minute, and probably not of clinical relevance.

  • 345.
    Lundin, Fredrik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Neurology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Tisell, Anders
    Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Leijon, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Neurology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Dahlqvist Leinhard, Olof
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Davidsson, Leif
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Grönqvist, Anders
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Medical radiation physics.
    Wikkelso, Carsten
    University of Gothenburg, Sweden .
    Lundberg, Peter
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Östergötlands Läns Landsting, Center for Diagnostics, Department of Radiology in Linköping.
    Preoperative and postoperative H-1-MR spectroscopy changes in frontal deep white matter and the thalamus in idiopathic normal pressure hydrocephalus2013In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 84, no 2, p. 188-193Article in journal (Refereed)
    Abstract [en]

    Background In a previous study we found significantly decreased N-acetyl aspartate (NAA) and total N-acetyl (tNA) groups in the thalamus of patients with idiopathic normal pressure hydrocephalus (iNPH) compared with healthy individuals (HI). No significant difference between the groups could be found in the frontal deep white matter (FDWM). less thanbrgreater than less thanbrgreater thanObjective The primary aim of this study was to investigate if these metabolites in the thalamus were normalised after shunt surgery. The secondary aim was to investigate postoperative metabolic changes in FDWM. less thanbrgreater than less thanbrgreater thanSubjects and methods Fourteen patients with iNPH, mean age 74 years, and 15 HI, also mean age 74 years, were examined. Assessment of a motor score (MOSs) was performed before and after shunt surgery. Absolute quantitative H-1-MR spectroscopy (1.5 T, volumes of interest 2.5-3 ml) was performed on the patients in the FDWM and in the thalamus, before and 3 months after shunt surgery, and also once on the HI. The following metabolites were analysed: tNA, NAA, total creatine, total choline (tCho), myo-inositol (mIns), glutamate and lactate concentrations. MRI volumetric calculations of the lateral ventricles were also performed. less thanbrgreater than less thanbrgreater thanResults At 3 months postoperatively, we found no significant changes of tNA or NAA in the thalamus. In contrast, in the FDWM, there was a significant increase of tCho (p=0.01) and a borderline significant decrease of mIns (p=0.06). 12/14 patients were shunt responders (motor function). Median reduction of the lateral ventricle was 16%. A weak correlation between MOS and ventricular reduction was seen. less thanbrgreater than less thanbrgreater thanConclusions Normalisation of thalamic tNA and NAA could not be detected postoperatively. The increased tCho and decreased mIns in the FDWM postoperatively might relate to clinical improvement.

  • 346.
    Lundqvist, Martina
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Medicine and Health Sciences.
    Carlsson, Per
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Medicine and Health Sciences.
    Sjödahl, Rune
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Levin, Lars-Åke
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Medicine and Health Sciences.
    Patient benefit of dog-assisted interventions in health care: a systematic review2017In: BMC Complementary and Alternative Medicine, ISSN 1472-6882, E-ISSN 1472-6882, Vol. 17, article id 358Article, review/survey (Refereed)
    Abstract [en]

    Background: Dogs are the most common companion animal, and therefore not surprisingly a popular choice for animal-assisted interventions. Dog-assisted interventions are increasingly used in healthcare. The aim of the review was to conduct a systematic literature review of quantitative studies on dog-assisted interventions in healthcare, with the intention of assessing the effects and cost-effectiveness of the interventions for different categories of patients. Methods: A systematic review of the scientific literature reporting results of studies in healthcare, nursing home or home care settings, was conducted. The inclusion criteria applied for this review were: quantitative studies, inclusion of at least 20 study subjects, existence of a control and performed in healthcare settings including nursing homes and home care. The electronic databases PubMed, AMED, CINAHL and Scopus were searched from their inception date through January 2017, for published articles from peer-reviewed journals with full text in English. Results: Eighteen studies that fulfilled the inclusion criteria, and were judged to be of at least moderate quality, were included in the analysis. Three of them showed no effect. Fifteen showed at least one significant positive effect but in most studied outcome measures there was no significant treatment effect. Dog-assisted therapy had the greatest potential in treatment of psychiatric disorders among both young and adult patients. Dog-assisted activities had some positive effects on health, wellbeing, depression and quality of life for patients with severe cognitive disorders. Dog-assisted support had positive effects on stress and mood. Conclusions: The overall assessment of the included studies indicates minor to moderate effects of dog-assisted therapy in psychiatric conditions, as well as for dog-assisted activities in cognitive disorders and for dog-assisted support in different types of medical interventions. However, the majority of studied outcome measures showed no significant effect.

  • 347.
    Lundström, Claes
    et al.
    Linköping University, Department of Science and Technology, Media and Information Technology. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Science & Engineering. Sectra AB.
    Thorstenson, Sten
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Waltersson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Persson, Anders
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Treanor, Darren
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. St. James University Hospital, Leeds, England.
    Summary of 2nd Nordic symposium on digital pathology2015In: Journal of Pathology Informatics, ISSN 2229-5089, E-ISSN 2153-3539, Vol. 6Article in journal (Refereed)
    Abstract [en]

    Techniques for digital pathology are envisioned to provide great benefits in clinical practice, but experiences also show that solutions must be carefully crafted. The Nordic countries are far along the path toward the use of whole-slide imaging in clinical routine. The Nordic Symposium on Digital Pathology (NDP) was created to promote knowledge exchange in this area, between stakeholders in health care, industry, and academia. This article is a summary of the NDP 2014 symposium, including conclusions from a workshop on clinical adoption of digital pathology among the 144 attendees.

  • 348.
    Lundström, Claes
    et al.
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Science and Technology, Media and Information Technology. Linköping University, Faculty of Science & Engineering.
    Waltersson, Marie
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Persson, Anders
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Treanor, Darren
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Department of Cellular Pathology, St. James University Hospital, Leeds, UK.
    Summary of third Nordic symposium on digital pathology2016In: Journal of Pathology Informatics, ISSN 2229-5089, E-ISSN 2153-3539, Vol. 7, no 12Article in journal (Other academic)
    Abstract [en]

    Cross-disciplinary and cross-sectorial collaboration is a key success factor for turning the promise of digital pathology into actual clinical benefits. The Nordic symposium on digital pathology (NDP) was created to promote knowledge exchange in this area, among stakeholders in health care, industry, and academia. This article is a summary of the third NDP symposium in Linkφping, Sweden. The Nordic experiences, including several hospitals using whole-slide imaging for substantial parts of their primary reviews, formed a fertile base for discussions among the 190 NDP attendees originating from 15 different countries. This summary also contains results from a survey on adoption and validation aspects of clinical digital pathology use.

  • 349.
    Lönndahl, Louise
    et al.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Holst, Mikael
    Astrid Lindgren Childrens Hosp, Sweden.
    Bradley, Maria
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Killasli, Hassan
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Heilborn, Johan
    Hudctr, Sweden.
    Hall, Martin A.
    Stad Läkarmottagning, Sweden.
    Theodorsson, Elvar