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Hamrin, E., Ernerudh, J. & Rosén, A. (2018). Immunological and Quality-of-Life Profiles in Women with Breast Cancer: Complementary versus Conventional Care. Complementary Medicine Research, 25, 391-397
Open this publication in new window or tab >>Immunological and Quality-of-Life Profiles in Women with Breast Cancer: Complementary versus Conventional Care
2018 (English)In: Complementary Medicine Research, ISSN 2504-2092, Vol. 25, p. 391-397Article in journal (Refereed) Published
Abstract [en]

Background: Previous studies showed that women with breast cancer treated in anthroposophic clinic versus conventional care had increased quality of life (QoL) parameters, fighting spirit, and anxiety coping. We have now analyzed immune and QoL factors in these 2 groups for possible differences during the first 6 months after admission, prompted by anthroposophic studies, including mistletoe extracts, showing beneficial immune system effects.

Patients and MethodsFourteen immunological variables, including leukocyte count, lymphocyte count, activated T cells (CD4+ and CD8+), NK cells, B cells, IL1β, IL6, IL10, and oxytocin, were longitudinally analyzed in both groups (n = 2 × 26). A panel of QoL parameters were analyzed using 3 different instruments. Statistical evaluation included that each patient was its own control.

Results: Cytotoxic CD8+ T cell frequency (percent of lymphocytes analyzed by flow-cytometry) significantly decreased over time in the anthroposophic group versus the conventional group (repeated measures ANOVA, p = 0.05). No major differences were observed in other immunological parameters, whereas QoL variables, anxiety decreased and physical symptoms increased/improved significantly in the anthroposophic group (p = 0.04 and p = 0.05, respectively).

Conclusion: Overall, women with breast cancer in anthroposophic or conventional therapy did not differ in their immune profiles over time, with exception of decreased cytotoxic T cells in the anthroposophic group. Improvement in physical symptoms along with less anxiety in this group may have influenced the brain-immune axis resulting in lower frequency of CD8+ T cells, a feature associated with less aggressive cancer stages. To evaluate whether this observation is associated with good or bad prognosis, further detailed analyses of memory and naïve CD8+ T cells at tumor site and in blood circulation are essential.

Abstract [de]

Hintergrund: Bisherige Studien haben gezeigt, dass die Behandlung von Brustkrebspatientinnen in anthroposophischen Kliniken gegenüber einer konventionellen Behandlung mit einer verbesserten Lebensqualität (quality of life; QoL), größerem Kampfgeist und einer besseren Angstbewältigung einhergeht. Angespornt durch anthroposophische Studien, solche mit Mistelextrakt eingeschlossen, die eine günstige Wirkung auf das Immunsystem zeigten, haben wir nun Immun- und QoL-Faktoren in diesen beiden Gruppen während der ersten 6 Monate nach Aufnahme untersucht.

Patienten und Methoden: 14 immunologische Variablen, einschließlich Leukozyten- und Lymphozytenzahl, aktivierter T-Zellen (CD4+ und CD8+), NK-Zellen, B-Zellen, IL1β, IL6, IL10 und Oxytocin, wurden in beiden Gruppen longitudinal analysiert (n = 2 × 26). Unter Zuhilfenahme von 3 verschiedenen Instrumenten wurde eine Reihe von QoL-Parametern analysiert. Die statistische Auswertung war so angelegt, dass jeder Patient als seine eigene Kontrolle diente.

Ergebnisse: Die Häufigkeit von zytotoxischen CD8+-T-Zellen (prozentualer Anteil an Lymphozyten analysiert mittels Durchflusszytometrie) nahm in der anthroposophischen gegenüber der konventionell behandelten Gruppe im Zeitverlauf signifikant ab (wiederholte ANOVA-Messungen; p = 0,05). Während für weitere immunologische Parameter keine größeren Unterschiede festgestellt wurden, verbesserten sich die QoL-Variablen; die Angst verringerte sich und die physischen Symptome verbesserten sich signifikant in der anthroposophischen Gruppe (p = 0,04 bzw. p = 0,05).

Schlussfolgerung: Insgesamt zeigte sich, dass es während des untersuchten Zeitraums keinen Unterschied in den Immunprofilen von Brustkrebspatientinnen mit anthroposophischer gegenüber solchen mit ausschließlich konventioneller Therapie gab. Die Verbesserung der physischen Symptome sowie die verringerte Angst in dieser Gruppe könnte die Gehirnimmunachse beeinflusst und zu einer geringeren Häufigkeit der CD8+-T-Zellen, einem Kennzeichen für weniger aggressive Tumorstadien, geführt haben. Um beurteilen zu können, ob diese Beobachtung mit einer guten oder schlechten Prognose assoziiert ist, sind weitere detaillierte Untersuchungen von Gedächtnis- und naiven CD8+-T-Zellen am Tumorort und in der Blutzirkulation unerlässlich.

Place, publisher, year, edition, pages
S. Karger, 2018
Keywords
Breast cancer treatment, Complementary medicine, Anthroposophical care, Immunology, Tumor immunity, Cytotoxic CD8 + T cells, Physical symptoms, Anxiety, Brustkrebstherapie, Komplementärmedizin, Anthroposophische Versorgung, Immunologie, Tumorimmunität, Zytotoxische CD8+-T-Zellen, Physische Symptome, Angst
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-153754 (URN)10.1159/000490049 (DOI)000456452900009 ()30145583 (PubMedID)2-s2.0-85053163476 (Scopus ID)
Funder
Swedish Cancer Society
Available from: 2019-01-08 Created: 2019-01-08 Last updated: 2019-03-06Bibliographically approved
Ingelsson, B., Söderberg, D., Strid, T., Söderberg, A., Bergh, A.-C., Loitto, V.-M., . . . Rosén, A. (2018). Lymphocytes eject interferogenic mitochondrial DNA webs in response to CpG and non-CpG oligodeoxynucleotides of class C. Proceedings of the National Academy of Sciences of the United States of America, 115(3), E478-E487
Open this publication in new window or tab >>Lymphocytes eject interferogenic mitochondrial DNA webs in response to CpG and non-CpG oligodeoxynucleotides of class C
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2018 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 3, p. E478-E487Article in journal (Refereed) Published
Abstract [en]

Circulating mitochondrial DNA (mtDNA) is receiving increasing attention as a danger-associated molecular pattern in conditions such as autoimmunity, cancer, and trauma. We report here that human lymphocytes [B cells, T cells, natural killer (NK) cells], monocytes, and neutrophils derived from healthy blood donors, as well as B cells from chronic lymphocytic leukemia patients, rapidly eject mtDNA as web filament structures upon recognition of CpG and non-CpG oligodeoxynucleotides of class C. The release was quenched by ZnCl2, independent of cell death (apoptosis, necrosis, necroptosis, autophagy), and continued in the presence of TLR9 signaling inhibitors. B-cell mtDNA webs were distinct from neutrophil extracellular traps concerning structure, reactive oxygen species (ROS) dependence, and were devoid of antibacterial proteins. mtDNA webs acted as rapid (within minutes) messengers, priming antiviral type I IFN production. In summary, our findings point at a previously unrecognized role for lymphocytes in antimicrobial defense, utilizing mtDNA webs as signals in synergy with cytokines and natural antibodies, and cast light on the interplay between mitochondria and the immune system.

Place, publisher, year, edition, pages
Washington, DC, United States: National Academy of Sciences, 2018
Keywords
CpG-C, DAMP, immune DNA sensing, lymphocyte signaling, mitochondrial DNA release
National Category
Basic Medicine Immunology in the medical area
Research subject
Economic Information Systems
Identifiers
urn:nbn:se:liu:diva-144187 (URN)10.1073/pnas.1711950115 (DOI)000423091400018 ()29295921 (PubMedID)2-s2.0-85042104216 (Scopus ID)
Funder
Swedish Cancer Society
Note

Funding agencies: Linkoping Medical Society; Linkoping University; ALF grants; Region Ostergotland, Sweden; Linkoping University Cancer; Ingrid Asp Foundation; Swedish Cancer Society

Available from: 2018-01-09 Created: 2018-01-09 Last updated: 2018-09-07Bibliographically approved
Russo, M., Milito, A., Spagnuolo, C., Carbone, V., Rosén, A., Minasi, P., . . . Russo, G. L. (2017). CK2 and PI3K are direct molecular targets of quercetin in chronic lymphocytic leukaemia.. OncoTarget, 8(26), 42571-42587
Open this publication in new window or tab >>CK2 and PI3K are direct molecular targets of quercetin in chronic lymphocytic leukaemia.
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 26, p. 42571-42587Article in journal (Refereed) Published
Abstract [en]

Despite the encouraging results of the innovative therapeutic treatments, complete remission is uncommon in patients affected by chronic lymphocytic leukaemia, which remains an essentially incurable disease. Recently, clinical trials based on BH3-mimetic drugs showed positive outcomes in subjects with poor prognostic features. However, resistance to treatments occurs in a significant number of patients. We previously reported that the multi-kinase inhibitor quercetin, a natural flavonol, restores sensitivity to ABT-737, a BH3-mimetic compound, in both leukemic cell lines and B-cells isolated from patients. To identify the molecular target of quercetin, we employed a new cell line, HG3, obtained by immortalization of B-cells from a chronic lymphocytic leukaemia patient at the later stage of disease. We confirmed that quercetin in association with ABT-737 synergistically enhances apoptosis in HG3 (combination index < 1 for all fractions affected). We also reported that the cellular uptake of quercetin is extremely rapid, with an intracellular concentration of about 38.5 ng/106 cells, after treatment with 25 μM for 5 min. We demonstrated that the activity of protein kinase CK2, which positively triggers PI3K/Akt pathway by inactivating PTEN phosphatase, is inhibited by quercetin immediately after its addition to HG3 cells (0-2 min). PI3K activity was also inhibited by quercetin within 60 min from the treatment. The combined inhibition of CK2 and PI3K kinase activities by quercetin restored ABT-737 sensitivity and increased lethality in human leukemia cells.

Place, publisher, year, edition, pages
Impact Journals LLC, 2017
Keywords
Mcl-1, PI3K, chronic lymphocytic leukaemia, protein kinase CK2, quercetin
National Category
Hematology
Identifiers
urn:nbn:se:liu:diva-137339 (URN)10.18632/oncotarget.17246 (DOI)000405493400068 ()28489572 (PubMedID)
Note

Funding agencies: C.I.S.I.A. project Innovazione e Sviluppo del Mezzogiorno - Conoscenze Integrate per Sostenibilita ed Innovazione del Made in Italy Agroalimentare - Legge from the Italian Ministry of Economy and Finance [191/2009]; BenTeN project (Wellness from biotechno

Available from: 2017-05-13 Created: 2017-05-13 Last updated: 2017-11-29Bibliographically approved
El-Schich, Z., Abdullah, M., Shinde, S., Dizeyi, N., Rosén, A., Sellergren, B. & Gjörloff Wingren, A. (2016). Different expression levels of glycans on leukemic cells-a novel screening method with molecularly imprinted polymers (MIP) targeting sialic acid.. Tumor Biology, 37(10), 13763-13768
Open this publication in new window or tab >>Different expression levels of glycans on leukemic cells-a novel screening method with molecularly imprinted polymers (MIP) targeting sialic acid.
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2016 (English)In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 37, no 10, p. 13763-13768Article in journal (Refereed) Published
Abstract [en]

Sialic acid (SA) is normally expressed on the cell membranes and is located at the terminal position of the sugar chains. SA plays an important role for regulation of the innate immunity, function as markers of the cells and can be recognized by a variety of receptors. Interestingly, the level of SA expression is increased on metastatic cancer cells. The availability of specific antibodies against SA is limited and, therefore, biomarker tools for detection of SA are lacking. We have recently presented a novel method for specific fluorescence labeling of SA molecular imprinted polymers (MIP). Here, we have performed an extended screening of SA expression by using SA-MIP and included four different chronic lymphocytic leukemia (CLL) cell lines, conveniently analyzed by flow cytometry and fluorescence microscopy. SA expression was detected in four cell lines at different levels, and the SA expression were verified with lectin-FITC. These results show that SA-MIP can be used as a plastic antibody for detection of SA using both flow cytometry and fluorescence microscopy. We suggest that SA-MIP can be used for screening of different tumor cells of various stages, including CLL cells.

Place, publisher, year, edition, pages
Springer, 2016
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-130588 (URN)10.1007/s13277-016-5280-y (DOI)000387538700076 ()27476172 (PubMedID)
Note

Funding agencies: Malmö University; Cancer Foundation at Malmo University Hospital; Swedish Knowledge Foundation

Available from: 2016-08-17 Created: 2016-08-17 Last updated: 2018-01-10Bibliographically approved
Alehagen, U., Johansson, P., Björnstedt, M., Rosén, A., Post, C. & Aaseth, J. (2016). Relatively high mortality risk in elderly Swedish subjects with low selenium status. European Journal of Clinical Nutrition, 70(1), 91-96
Open this publication in new window or tab >>Relatively high mortality risk in elderly Swedish subjects with low selenium status
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2016 (English)In: European Journal of Clinical Nutrition, ISSN 0954-3007, E-ISSN 1476-5640, Vol. 70, no 1, p. 91-96Article in journal (Refereed) Published
Abstract [en]

Background/Objectives: 

The daily dietary intake of selenium (Se), an essential trace element, is still low in Sweden in spite of decades of nutritional information campaigns and the effect of this on the public health is presently not well known. The objective of this study was to determine the serum Se levels in an elderly Swedish population and to analyze whether a low Se status had any influence on mortality.

Subjects/Methods: 

Six-hundred sixty-eight (n=668) elderly participants were invited from a municipality and evaluated in an observational study. Individuals were followed for 6.8 years and Se levels were re-evaluated in 98 individuals after 48 months. Clinical examination of all individuals included functional classification, echocardiography, electrocardiogram and serum Se measurement. All mortality was registered and endpoints of mortality were assessed by Kaplan–Meier plots, and Cox proportional hazard ratios adjusted for potential confounding factors were calculated.

Results: 

The mean serum Se level of the study population (n=668) was 67.1 μg/l, corresponding to relatively low Se intake. After adjustment for male gender, smoking, ischemic heart disease, diabetes, chronic obstructive pulmonary disease and impaired heart function, persons with serum Se in the lowest quartile had 43% (95% confidence interval (CI): 1.02–2.00) and 56% (95% CI: 1.03–2.36) increased risk for all-cause and cardiovascular mortality, respectively. The result was not driven by inflammatory effects on Se concentration in serum.

Conclusion: 

The mean serum Se concentration in an elderly Swedish population was 67.1 μg/l, which is below the physiological saturation level for several selenoprotein enzymes. This result may suggest the value of modest Se supplementation in order to improve the health of the Swedish population.

Place, publisher, year, edition, pages
Nature Publishing Group, 2016
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:liu:diva-120772 (URN)10.1038/ejcn.2015.92 (DOI)000369434800015 ()26105108 (PubMedID)
Note

Funding agencies: County Council of Ostergotland; University of Linkoping; Cancer-och Allergifonden

Available from: 2015-08-24 Created: 2015-08-24 Last updated: 2017-09-22Bibliographically approved
Quentmeier, H., Pommerenke, C., Ammerpohl, O., Geffers, R., Hauer, V., MacLeod, R. A., . . . Drexler, H. G. (2016). Subclones in B-lymphoma cell lines: isogenic models for the studyof gene regulation. OncoTarget, 7(39), 63456-63465
Open this publication in new window or tab >>Subclones in B-lymphoma cell lines: isogenic models for the studyof gene regulation
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 39, p. 63456-63465Article in journal (Refereed) Published
Abstract [en]

Genetic heterogeneity though common in tumors has been rarely documented in celllines. To examine how often B-lymphoma cell lines are comprised of subclones, weperformed immunoglobulin (IG) heavy chain hypermutation analysis. Revealing thatsubclones are not rare in B-cell lymphoma cell lines, 6/49 IG hypermutated cell lines(12%) consisted of subclones with individual IG mutations. Subclones were alsoidentified in 2/284 leukemia/lymphoma cell lines exhibiting bimodal CD markerexpression. We successfully isolated 10 subclones from four cell lines (HG3, SUDHL-5, TMD-8, U-2932). Whole exome sequencing was performed to molecularlycharacterize these subclones. We describe in detail the clonal structure of cell lineHG3, derived from chronic lymphocytic leukemia. HG3 consists of three subcloneseach bearing clone-specific aberrations, gene expression and DNA methylationpatterns. While donor patient leukemic cells were CD5+, two of three HG3 subcloneshad independently lost this marker. CD5 on HG3 cells was regulated byepigenetic/transcriptional mechanisms rather than by alternative splicing as reportedhitherto. In conclusion, we show that the presence of subclones in cell lines carryingindividual mutations and characterized by sets of differentially expressed genes is notuncommon. We show also that these subclones can be useful isogenic models forregulatory and functional studies.

Place, publisher, year, edition, pages
Impact Journals, LLC, 2016
Keywords
CD5, cell lines, CLL, clonal evolution, subclones
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-130591 (URN)10.18632/oncotarget.11524 (DOI)000387167800050 ()
Available from: 2016-08-17 Created: 2016-08-17 Last updated: 2018-01-10Bibliographically approved
Wang, L. Q., Wong, K. Y., Rosén, A. & Chim, C. S. (2015). Epigenetic silencing of tumor suppressor miR-3151 contributes to Chinese chronic lymphocytic leukemia by constitutive activation of MADD/ERK and PIK3R2/AKT signaling pathways. OncoTarget, 6(42), 44422-44436
Open this publication in new window or tab >>Epigenetic silencing of tumor suppressor miR-3151 contributes to Chinese chronic lymphocytic leukemia by constitutive activation of MADD/ERK and PIK3R2/AKT signaling pathways
2015 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, no 42, p. 44422-44436Article in journal (Refereed) Published
Abstract [en]

We hypothesize that miR-3151, localized to a GWAS-identified chronic lymphocytic leukemia (CLL) risk locus (8q22.3), is a tumor suppressor miRNA silenced by promoter DNA methylation in CLL. The promoter of miR-3151 was methylated in 5/7 (71%) CLL cell lines, 30/98 (31%) diagnostic primary samples, but not normal controls. Methylation of miR-3151 correlated inversely with expression. Treatment with 5-Aza-2'-deoxycytidine led to promoter demethylation and miR-3151 re-expression. Luciferase assay confirmed MAP-kinase activating death domain (MADD) and phosphoinositide-3-kinase, regulatory subunit 2 (PIK3R2) as direct targets of miR-3151. Moreover, restoration of miR-3151 resulted in inhibition of cellular proliferation and enhanced apoptosis, repression of MADD and PIK3R2, downregulation of MEK/ERK and PI3K/AKT signaling, and repression of MCL1. Lastly, miR-3151 methylation was significantly associated with methylation of miR-203 and miR-34b/c in primary CLL samples. Therefore, this study showed that miR-3151 is a tumor suppressive miRNA frequently hypermethylated and hence silenced in CLL. miR-3151 silencing by DNA methylation protected CLL cells from apoptosis through over-expression of its direct targets MADD and PIK3R2, hence constitutive activation of MEK/ERK and PI3K/AKT signaling respectively, and consequently over-expression of MCL1.

Keywords
DNA methylation; chronic lymphocytic leukemia; miR-3151; microRNA; tumor suppressor
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-122624 (URN)10.18632/oncotarget.6251 (DOI)26517243 (PubMedID)
Available from: 2015-11-12 Created: 2015-11-12 Last updated: 2018-01-10
Wang, L., Kwong, Y., Wong, K., Kho, C., Jin, D., Tse, E., . . . Chim, C. (2014). Epigenetic inactivation of mir-34b/c in addition to mir-34a and DAPK1 in chronic lymphocytic leukemia. Journal of Translational Medicine, 12(52)
Open this publication in new window or tab >>Epigenetic inactivation of mir-34b/c in addition to mir-34a and DAPK1 in chronic lymphocytic leukemia
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2014 (English)In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 12, no 52Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

TP53 mutation/deletion is uncommon in chronic lymphocytic leukemia (CLL). We postulated that components of TP53-centered tumor suppressor network, miR-34b/c, in addition to DAPK1 and miR-34a might be inactivated by DNA hypermethylation. Moreover, we tested if miR-34b/c methylation might correlate with miR-203 or miR-124-1 methylation in CLL.

METHODS:

miR-34b/c, miR-34a and DAPK1 methylation was studied in 11 normal controls, 7 CLL cell lines, and 78 diagnostic CLL samples by methylation-specific polymerase chain reaction. MEC-1 cells were treated with 5-Aza-2'-deoxycytidine for reversal of methylation-associated miRNA silencing. Tumor suppressor properties of miR-34b were demonstrated by over-expression of precursor miR-34b in MEC-1 cells.

RESULTS:

miR-34b/c promoter was unmethylated in normal controls, but completely methylated in 4 CLL cell lines. miR-34b/c expression inversely correlated with miR-34b/c methylation. Different MSP statuses of miR-34b/c, including complete methylation and complete unmethylation, were verified by quantitative bisulfite pyrosequencing. 5-Aza-2'-deoxycytidine treatment resulted in promoter demethylation and miR-34b re-expression in MEC1 cells. Moreover, over-expression of miR-34b resulted in inhibition of cellular proliferation and increased cell death. In primary CLL samples, miR-34a, miR-34b/c and DAPK1 methylation was detected in 2.6%, 17.9% and 34.6% of patients at diagnosis respectively. Furthermore, 39.7%, 3.8% and 2.6% patients had methylation of one, two or all three genes respectively. Overall, 46.2% patients had methylation of at least one of these three genes. Besides, miR-34b/c methylation was associated with methylation of miR-34a (P = 0.03) and miR-203 (P = 0.012) in CLL.

CONCLUSIONS:

Taken together, miR-34b/c is a tumor suppressor miRNA frequently methylated, and hence silenced in CLL. Together with DAPK1 methylation, miR-34b/c methylation is implicated in the disruption of the TP53-centered tumor suppressor network. Moreover, the association of miRNA methylation warrants further study.

Place, publisher, year, edition, pages
BioMed Central, 2014
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-104694 (URN)10.1186/1479-5876-12-52 (DOI)000335533000002 ()24559316 (PubMedID)
Available from: 2014-02-24 Created: 2014-02-24 Last updated: 2017-12-05Bibliographically approved
Gustafsson, H., Hallbeck, M., Norell, M., Lindgren, M., Engström, M., Rosén, A. & Zachrisson, H. (2014). Fe(III) distribution varies substantially within and between atherosclerotic plaques. Magnetic Resonance in Medicine, 2(71), 885-892
Open this publication in new window or tab >>Fe(III) distribution varies substantially within and between atherosclerotic plaques
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2014 (English)In: Magnetic Resonance in Medicine, ISSN 0740-3194, E-ISSN 1522-2594, Vol. 2, no 71, p. 885-892Article in journal (Refereed) Published
Abstract [en]

PURPOSE:

Vulnerable atherosclerotic plaques are structurally weak and prone to rupture, presumably due to local oxidative stress. Redox active iron is linked to oxidative stress and the aim of this study was to investigate the distribution of Fe(III) in carotid plaques and its relation to vulnerability for rupture.

METHODS:

Atherosclerotic plaques from 10 patients (three asymptomatic and seven symptomatic) were investigated. Plaque vulnerability was classified using ultrasound and immunohistochemistry and correlated to Fe(III) measured by electron paramagnetic resonance spectroscopy.

RESULTS:

Large intra-plaque Fe(III) variations were found. Plaques from symptomatic patients had a higher Fe(III) concentration as compared with asymptomatic plaques (0.36 ± 0.21 vs. 0.06 ± 0.04 nmol Fe(III)/mg tissue, P < 0.05, in sections adjoining narrowest part of the plaques). All but one plaque from symptomatic patients showed signs of cap rupture. No plaque from asymptomatic patients showed signs of cap rupture. There was a significant increase in cap macrophages in plaques from symptomatic patients compared with asymptomatic patients (31 ± 11% vs. 2.3 ± 2.3%, P < 0.01).

CONCLUSION:

Fe(III) distribution varies substantially within atherosclerotic plaques. Plaques from symptomatic patients had significantly higher concentrations of Fe(III), signs of cap rupture and increased cap macrophage activity.

Place, publisher, year, edition, pages
United States: John Wiley & Sons, 2014
Keywords
atherosclerosis; oxidative stress; reactive oxygen species; iron; electron paramagnetic resonance
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-98001 (URN)10.1002/mrm.24687 (DOI)000330769700047 ()23447110 (PubMedID)
Available from: 2013-09-24 Created: 2013-09-24 Last updated: 2017-12-06
Bergh, A.-C., Evaldsson, C., Pedersen, L. B., Geisler, C., Stamatopoulos, K., Rosenquist, R. & Rosén, A. (2014). Silenced B-cell receptor response to autoantigen in a poor-prognostic subset of chronic lymphocytic leukemia. Haematologica, 99(11), 1722-1730
Open this publication in new window or tab >>Silenced B-cell receptor response to autoantigen in a poor-prognostic subset of chronic lymphocytic leukemia
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2014 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, no 11, p. 1722-1730Article in journal (Refereed) Published
Abstract [en]

Chronic lymphocytic leukemia B-cells express auto/xeno-antigen-reactive antibodies that bind to self-epitopes and resemble natural IgM antibodies in their repertoire. One of the antigenic structures recognized is oxidation-induced malonedialdehyde present on low-density lipoprotein, apoptotic blebs, and on certain microbes. The poor-prognostic stereotyped subset #1 (Clan I IGHV genes-IGKV1(D)-39) express IgM B-cell receptors that bind oxidized low-density lipoprotein. In this study, we have used for the first time this authentic cognate antigen, since it is more faithful to B-cell physiology than anti-IgM, for analysis of downstream B-cell receptor-signal transduction events. Multivalent oxidized low-density lipoprotein showed specific binding to subset #1 IgM/IgD B-cell receptors, whereas native low-density lipoprotein did not. The antigen-binding induced prompt receptor-clustering, followed by internalization. However, the receptor-signal transduction was silenced, revealing no Ca2+ mobilization or cell-cycle entry, while phosphorylated extracellular-regulated kinase1/2 basal levels were high and could not be elevated further by oxidized low-density lipoprotein. Interestingly, B-cell receptor responsiveness was recovered after 48 hours culture in the absence of antigen in half of the cases. Toll-like receptor 9-ligand was found to breach the B-cell receptor-signaling incompetence in 5 of 12 cases pointing to intra-subset heterogeneity. Altogether, this study supports B-cell receptor-unresponsiveness to cognate self-antigen on its own in poor-prognostic subset #1 chronic lymphocytic leukemia indicating that these cells proliferate by other mechanisms that may override B-cell receptor-silencing brought about in a context of self-tolerance/anergy. These novel findings have implications for the understanding of chronic lymphocytic leukemia pathobiology and therapy.

Place, publisher, year, edition, pages
Ferrata Storti Foundation, 2014
Keywords
Anergy; B-cell Receptor Signaling; Chronic Lymphocytic Leukemia; Oxidized LDL; Stereotyped subsets
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-109020 (URN)10.3324/haematol.2014.106054 (DOI)000347016300013 ()25085355 (PubMedID)
Available from: 2014-07-28 Created: 2014-07-28 Last updated: 2017-12-05
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-5082-6423

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