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  • 251.
    Vikingsson, Svante
    et al.
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Carlsson, Björn
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Almer, Sven H C
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Peterson, Curt
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Monitoring of thiopurine metabolites in patients with inflammatory bowel disease-what is actually measured?2009In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 31, no 3, p. 345-50Article in journal (Refereed)
    Abstract [en]

    Azathioprine and 6-mercaptopurine are often used in the treatment of patients with inflammatory bowel disease (IBD). They are prodrugs and undergo a complex metabolism to active and inactive metabolites. Thiopurine treatment is monitored in many laboratories by measuring metabolite concentrations in erythrocytes (red blood cells). The metabolites of interest are not measured directly but as hydrolysis products, which can be produced from several metabolites. The aim of this study was to examine which metabolites are actually measured during routine monitoring. Samples from 18 patients treated with a thiopurine were analyzed by a typical routine high-performance liquid chromatography method for therapeutic drug monitoring and by a newly developed specific method measuring thioguanosine monophosphate (TGMP), thioguanosine diphosphate (TGDP), and thioguanosine triphosphate (TGTP), as well as methylthioinosine monophosphate (meTIMP), and the results were compared. 6-Thioguanine nucleotide (TGN) values detected by the routine method were 69% (range 40%-90%) of the sum of TGMP, TGDP, and TGTP measured by the specific method. TGTP and TGDP contributed 85% (range 78%-90%) and 14% (range 10%-21%) of the TGN total, respectively. Thioguanosine was not found in any patient sample. The concentration of meTIMP obtained by the routine method was 548% of the value obtained by the specific method (range 340%-718%). The difference in TGN measurements between the routine and specific methods can be explained by low hydrolysis efficiency in the routine method, although the most likely explanation for the difference in meTIMP values is that not yet identified metabolites are codetermined in the routine high-performance liquid chromatography method. Concentrations reported as TGN during therapeutic drug monitoring of thiopurine metabolites consist of TGDP and TGTP with a minor contribution of the TGMP. Concentrations reported as meTIMP or methyl mercaptopurine consist in part of meTIMP, but other not yet identified metabolites are codetermined.

  • 252.
    Vikingsson, Svante
    et al.
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Carlsson, Björn
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Peterson, Curt
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    How Should Thiopurine Treatment be Monitored? Methodological Aspects2010In: Nucleosides, Nucleotides & Nucleic Acids, ISSN 1525-7770, E-ISSN 1532-2335, Vol. 29, no 04-Jun, p. 278-283Article in journal (Refereed)
    Abstract [en]

    Monitoring of thiopurine metabolites is important due to a complex metabolism with large interindividual variation, but the suitability of currently used methods has been questioned. The drawbacks include poor reproducibility, the inability to differentiate between the different analytes, as well as the use of a nontarget matrix. Further research should be directed toward measuring thiopurine metabolites in mononuclear cells, measuring the different nucleotides specifically, as well as measuring the incorporation of thioguanine into DNA. The studies should not be limited to thioguanosine nucleotides but include methylthioinosine nucleotides as well.

  • 253.
    Wall, Najme
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Starkhammar, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Chemotherapy of soft tissue sarcoma: A clinical evaluation of treatment over ten years2003In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 42, no 1, p. 55-61Article in journal (Refereed)
    Abstract [en]

    The aim of the study was to evaluate the effect of palliative chemotherapy on soft tissue sarcomas given outside controlled trials. Therapy and response rates of 77 patients with non-resectable sarcoma treated with different regimens between 1991 and 2000 were reviewed. Thirty-six patients were treated with first-line chemotherapy comprising cyclophosphamide+vincristine+doxorubicin+dacarbazine (CYVADIC), with a response rate of 28% (median response duration 5.5 months). Etoposide and ifosfamide (IVP, or VIG, which also includes granulocyte colony-stimulating factor (G-CSF)) were used in the treatment of 18 patients. The response rate was 22% (median response duration 4.5 months), Nineteen patients were treated with doxorubicin+ifosfamide and one patient responded. Four patients received other first-line treatments. Thirty-eight patients were given second-line chemotherapy and 4 (10%) patients responded. Thirteen patients were given third-line treatment and 5 patients received fourth-line treatment, but without any response. Disease progression was the dominant reason for discontinuation of therapy. The response rate in the present study was lower than the best published results, probably due to the fact that our soft tissue sarcoma patient material was unselected. Treatment with CYVADIC yields at least as high a response rate as the more recently described doxorubicin+ifosfamide combination, but third- and fourth-line therapy is not beneficial. Clinical trials with more active drugs are needed, as are more predictive and prognostic tests and a better selection of patient groups suited for different treatment options for soft tissue sarcomas.

  • 254.
    Wallin, Åsa
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Francis, P.
    Department of Oncology, Institute of Clinical Sciences, Lund University, Lund, Sweden.
    Nilbert, N.
    Department of Oncology, Institute of Clinical Sciences, Lund University, Lund, Sweden.
    Svanvik, Joar
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Gene expression profile of colon cancer cell lines treated with SN-382010In: Chemotherapy, ISSN 0009-3157, E-ISSN 1421-9794, Vol. 56, no 1, p. 17-25Article in journal (Refereed)
    Abstract [en]

    Aim: Colorectal cancer is the third most common form of cancer in the industrialcountries. Due to advances regarding the treatments, primarily development ofimproved surgical methods, and the ability to make the earlier diagnosis, the mortalityhas remained constant during the past decades even though the incidence in fact hasincreased. To improve chemotherapy and enable personalised treatment, the need ofbiomarkers is of great significance. In this study we evaluated the gene expressionprofiles of the colon cancer cell lines treated with SN-38, the active metabolite oftopoisomerase-1 inhibitor irinotecan which leads to cell cycle arrest and apoptosis.Material and Methods: The study included three colon cancer cell lines KM12C,KM12SM and KM12l4a. The three cell lines were treated with SN-38, and sampleswere obtained after 24 and 48 hour treatments. The gene expression analyses wereperformed using oligonucleotide microarrays comprising of ~27,000 spots where theuntreated controls were compared to the SN-38 treated samples. Results: Unsupervisedclustering clearly distinguished the treated cell lines from the untreated. Supervisedanalysis identified 3974 significant genes (p=0.05) differentiating the treated samplesfrom the untreated, majority of which were downregulated after treatment. The toprankeddownregulated genes in the treated cell lines included those related to receptorand kinase activity, signal transduction, apoptosis, RNA processing, protein metabolismand transport, cell cycle and transcription. A smaller number of genes were upregulatedin the cell lines after treatment and included genes involved in apoptosis, transcription,development and differentiation. Conclusions: These results demonstrate that theexpression of the genes involved in cell proliferation and apoptosis as well as RNA,DNA and protein metabolism were affected by SN-38. The impact of certain genes oncolorectal cancer development needs to be further evaluated, however these resultscould serve as a basis for further studies in order to find targets for irinotecan treatment.

  • 255.
    Wallin, Åsa
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Svanvik, Joar
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Holmlund, Birgitta
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Ferreud, Lillianne
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Anticancer effect of SN-38 on colon cancer cell lines with different metastatic potential2008In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 19, no 6, p. 1493-1498Article in journal (Refereed)
    Abstract [en]

    SN-38 is an active metabolite of the topoisomerase I inhibitor irinotecan. The mechanism behind its antitumor effect in colorectal cancer is not fully understood. In this study, we examined the response of colon cancer cell lines with different metastatic potential to SN-38. The parental human colon cancer cell line KM12C and its two highly metastatic derivatives KM12SM and KM12L4a were cultivated in 5% CO2 at 37°C for 24 h and then exposed to SN-38 (2.5 µg/ml) at 37°C for 4, 24 and 48 h, respectively. The cell cycle was measured by flow cytometry, apoptotic activity was determined by flow cytometry and immunocytochemistry and the expression of topoisomerase I, Bax and survivin proteins were examined by Western blot. The exposure of the cells to SN-38 induced S-phase and G2 arrest (P<0.0001) and the KM12L4a cells had the highest response in a time-dependent manner (P<0.0001). The rates of apoptosis in the KM12SM (P=0.001) and KM12L4a cell lines (P=0.01) were increased time-dependently, though there was no such change in the KM12C cells. The expression of topoisomerase I protein was decreased in each cell line tested and the expression of Bax protein was increased, especially in KM12L4a. In conclusion, the effect of SN-38 on the colon cancer cell lines was mediated via conducting S-phase and G2 arrest and apoptosis. This effect was found in the cell lines with higher metastatic potentials, indicating that SN-38 can be used to treat advanced colon cancers.

  • 256.
    Waltersson, MA
    et al.
    Karolinska University Hospital.
    Karlsson, E
    Karolinska University Hospital.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Fornander, T
    Karolinska University Hospital.
    Skoog, L
    Karolinska University Hospital.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    miR-206 Expression Is Downregulated in Cyclin D1 Amplified Breast Tumours. in CANCER RESEARCH, vol 69, issue 24, pp 579S-579S2009In: CANCER RESEARCH, 2009, Vol. 69, no 24, p. 579S-579SConference paper (Refereed)
    Abstract [en]

    n/a

  • 257.
    Wang, Chaojie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Stratmann, Johannes
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Zhou, Zong-Guang
    Sichuan University.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Suppression of microRNA-31 increases sensitivity to 5-FU at an early stage, and affects cell migration and invasion in HCT-116 colon cancer cells2010In: BMC CANCER, ISSN 1471-2407, Vol. 10, no 616Article in journal (Refereed)
    Abstract [en]

    Background: MicroRNAs (miRNAs) are endogenously expressed noncoding RNAs with important biological and pathological functions. Although several studies have shown that microRNA-31 (miR-31) is obviously up-regulated in colorectal cancer (CRC), there is no study on the functional roles of miR-31 in CRC. Methods: Anti-miR (TM) miRNA 31 inhibitor (anti-miR-31) is a sequence-specific and chemically modified oligonucleotide to specifically target and knockdown miR-31 molecule. The effect of anti-miR-31 transfection was investigated by real-time PCR. HCT-116(p53+/+) and HCT-116(p53-/-)colon cancer cells were treated by anti-miR-31 with or without 5-fluorouracil (5-FU), cell proliferation was determined by MTT assay; apoptosis was detected by DAPI staining; cell cycle was evaluated by flow cytometry; colony formation, migration and invasion assays were performed to investigate the effect of suppression of miR-31 on the cell lines. Results: Real-time PCR results showed that anti-miR-31 was efficiently introduced into the cells and reduced miR-31 levels to 44.1% in HCT-116(p53+/+) and 67.8% in HCT-116p(53-/-)cell line (p = 0.042 and 0.046). MTT results showed that anti-miR-31 alone had no effect on the proliferation of HCT-116(p53+/+) or HCT-116(p53-/-). However, when combined with 5-FU, anti-miR-31 inhibited the proliferation of the two cell lines as early as 24 h after exposure to 5-FU (p = 0.038 and 0.044). Suppression of miR-31 caused a reduction of the migratory cells by nearly 50% compared with the negative control in both HCT-116(p53+/+) and HCT-116(p53-/-)(p = 0.040 and 0.001). The invasive ability of the cells were increased by 8-fold in HCT-116(p53+/+) and 2-fold in HCT-116(p53-/-)(p = 0.045 and 0.009). Suppression of miR-31 had no effect on cell cycle and colony formation (p andgt; 0.05). Conclusions: Suppression of miR-31 increases sensitivity to 5-FU at an early stage, and affects cell migration and invasion in HCT-116 colon cancer cells.

  • 258.
    Wang, Chao-Jie
    et al.
    Sichuan University, Institute Digest Surg, Department Colorectal Surg, W China Hospital, Chengdu 610064, Peoples R China Sichuan University, State Key Lab Biotherapy, W China Hospital, Chengdu 610064, Peoples R China .
    Zhou, Zong-Guang
    Sichuan University, Institute Digest Surg, Department Colorectal Surg, W China Hospital, Chengdu 610064, Peoples R China Sichuan University, State Key Lab Biotherapy, W China Hospital, Chengdu 610064, Peoples R China .
    Holmqvist, Annica
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Zhang, Hong
    University Skovde, Div Biomed, Sch Life Science, Skovde, Sweden .
    Li, Yuan
    Sichuan University, Institute Digest Surg, Department Colorectal Surg, W China Hospital, Chengdu 610064, Peoples R China Sichuan University, State Key Lab Biotherapy, W China Hospital, Chengdu 610064, Peoples R China .
    Adell, Gunnar
    Karolinska University Hospital, Department Oncol, Stockholm, Sweden .
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Survivin Expression Quantified by Image Pro-plus Compared With Visual Assessment2009In: APPLIED IMMUNOHISTOCHEMISTRY and MOLECULAR MORPHOLOGY, ISSN 1062-3345, Vol. 17, no 6, p. 530-535Article in journal (Refereed)
    Abstract [en]

    Over the past decades, immunohistochemistry has gained significance and already taken a crucial position in diagnosis of diseases and prognosis of patients. However, manual interpretation of immunohistochemistry and reproducibility of the scoring systems can be highly Subjective. In the article, the immunohistochemical staining of survivin in 98 rectal cancers was analyzed by using Image Pro-Plus (IPP) [3 parameters: density mean, area sum, and integrated optical density (IOD)] and the results were compared with visual assessment (2 parameters: intensity and percentage). The correlations between the 2 methods were examined, significant correlations were observed between density mean and staining intensity (Spearman correlation coefficient, r(s) = 0.806, P andlt; 0.001) IOD and staining intensity (r(s) = 0.9147 P andlt; 0.001) area sum and staining percentage (r(s) = 0.883, P andlt; 0.001), IOD and staining percentage (r(s) = 0.884, P andlt; 0.001). There was no significant difference between survivin expression and clinicopathologic variables (P andgt; 0.05) by visual assessment. However, by IPP analysis, both the density mean and IOD were higher in better-differentiated cancers than in worse differentiated ones (P = 0.02 and 0.03). There was a substantial agreement between the 2 methods. Density mean and IOD of IPP were representative parameters to assess the immunostaining quantification, and increased sensitivity in scoring and provided a more reliable and reproducible analysis of protein expression, especially, more information of the protein expression in relation to clinicopathologic variables can be provided by IPP analysis.

  • 259.
    Wang, Chao-Jie
    et al.
    Sichuan University.
    Zhou, Zong-Guang
    Sichuan University.
    Wang, Ling
    Sichuan University.
    Yang, Lie
    Sichuan University.
    Zhou, Bin
    Sichuan University.
    Gu, Jun
    Sichuan University.
    Chen, Hong-Ying
    Sichuan University.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Clinicopathological significance of microRNA-31, -143 and -145 expression in colorectal cancer2009In: Disease Markers, ISSN 0278-0240, E-ISSN 1875-8630, Vol. 26, no 1, p. 27-34Article in journal (Refereed)
    Abstract [en]

    We are just beginning to understand how microRNAs (miRNAs) are involved in tumor-related processes in humans. Applying real-time RT-PCR, we investigated the miR-31, miR-143 and miR-145 expression in 98 primary CRC specimens, along with the corresponding normal mucosa specimens, and analyze the relationship of their expression with clinicopathological features. Our results showed the miR-31 expression was up-regulated in CRC compared to normal mucosa (p = 0.001). Furthermore, miR-31 expression was positively related to advanced TNM stage (p = 0.026) and deeper invasion of tumors (p = 0.024). MiR-145 was down-regulated in both colon (p = 0.001) and rectal (p = 0.012) cancer. MiR-143 was only down-regulated in colon cancer (p = 0.023) but not in rectal cancer (p = 0.351). There was no relationship of miR-143 and miR-145 expression with other clinicopathological features (p > 0.05), except that the miR-145 expression was related to cancer site (p = 0.03). In conclusion, the miR-31 overexpression may be involved in the development and progression of CRC. The miR-143 and miR-145 may play a certain role in the development of colon and/or rectal cancers but not in progression of the disease.

  • 260.
    Wang, Da-Wei
    et al.
    University Skovde.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Adell, Gunnar
    Karolinska University Hospital.
    Mahmoudi, Salah
    Karolinska Institute.
    Farnebo, Marianne
    Karolinska Institute.
    Zhang, Hong
    University of Skovde.
    Wrap53 is an independent prognostic factor in rectal cancer - a study on Swedish rectal cancer trial in INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, vol 26, issue , pp S9-S92010In: INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, Spandidos Publications , 2010, Vol. 26, p. S9-S9Conference paper (Refereed)
    Abstract [en]

    n/a

  • 261.
    Wang, Ming-Wei
    et al.
    Hebei Med Univ, Hosp 1, Dept Neurol, Shijiazhuang, Hebei, Peoples R China.
    Gu, Ping
    Hebei Med Univ, Hosp 1, Dept Neurol, Shijiazhuang, Hebei, Peoples R China.
    Zhang, Zhi-Yong
    Tangshan Gongren Hosp, Dept Pathol, Tangshan, Hebei, Peoples R China.
    Zhu, Zhen-Long
    Hebei Med Univ, Hosp 1, Dept Pathol, Shijiazhuang, Hebei, Peoples R China.
    Geng, Yuan
    Hebei Med Univ, Hosp 1, Dept Neurol, Shijiazhuang, Hebei, Peoples R China.
    Kayed, Hany
    Univ Heidelberg, Univ Hosp Mannheim, Inst Clin Radiol and Nucl Med, Heidelberg, Germany.
    Zentgraf, Hanswalter
    German Canc Res Ctr, D-6900 Heidelberg, Germany.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    FXYD3 Expression in Gliomas and its Clinicopathological Significance2009In: Oncology Research, ISSN 0965-0407, E-ISSN 1555-3906, Vol. 18, no 4, p. 133-139Article in journal (Refereed)
    Abstract [en]

    FXYD3, interacting with Na+/K+-ATPase, is considered a cell surface regulator modulating the function of ion pumps and ion channels. The FXYD3 gene was originally cloned from murine mammary tumors and then from human breast tumors. However, no study of FXYD3 has been carried out in gliomas; therefore, we examined FXYD3 expression in gliomas and its clinicopathological significance. FXYD3 expression was immunohistochemically examined in 71 primary gliomas, along with 37 matched adjacent normal brain samples and 8 recurred gliomas. The frequency of strong FXYD3 expression was higher in the primary tumors in either unmatched (p = 0.046) or matched cases (p = 0.02), compared to normal brain tissue. FXYD3 expression was significantly more increased in females than males (p = 0.01), and in multiple site gliomas than single sites (p = 0.02). There was no difference of FXYD3 expression regarding age, tumor location, size, histological type, and tumor grade (p greater than 0.05). The results suggest that FXYD3 expression may be involved in glioma development, especially in multiple gliomas and female patients.

  • 262. Wang, Ming-Wei
    et al.
    Gu, Ping
    Zhang, Zhi-Yong
    Zhu, Zhen-Long
    Li, Yan-Min
    Zhao, Hui-Xin
    Sun, Xiao-Feng
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Expression of PINCH protein in gliomas and its clinicopathological significance2007In: Oncology, ISSN 0890-9091, Vol. 72, no 5-6, p. 343-346Article in journal (Refereed)
    Abstract [en]

    Objectives: Particularly interesting new cysteine-histidine-rich protein (PINCH), as a LIM domain adapter protein, functions in the integrin and growth factor signal transduction pathway, and is upregulated in tumor-associated stroma in several types of cancers. However, no study of PINCH has been carried out in gliomas, therefore we examined PINCH expression in gliomas and its clinicopathological significance. Methods: PINCH expression was immunohistochemically examined in 82 gliomas, along with 26 matched adjacent normal brain samples and 10 recurred gliomas. Results: PINCH was strongly expressed in the primary (35%, p = 0.0001) or recurred tumors (40%, p = 0.004) and weak in normal brain tissue. PINCH expression was significantly increased in high-grade gliomas (55 vs. 24%, high- vs. low-grade gliomas, p = 0.004). There was no association of PINCH expression with gender, age, tumor number, size, histological type and tumor location (p > 0.05). Conclusions: PINCH expression may be involved in glioma development and differentiation. Copyright © 2008 S. Karger AG.

  • 263.
    Wang, Mo-Jin
    et al.
    Sichuan University.
    Zhou, Zong-Guang
    Sichuan University.
    Wang, Ling
    Sichuan University.
    Yu, Yong-Yang
    Sichuan University.
    Zhang, Peng
    Sichuan University.
    Zhang, Yi
    Sichuan University.
    Cui, Chang-Fu
    Sichuan University.
    Yang, Lie
    Sichuan University.
    Li, Yuan
    Sichuan University.
    Zhou, Bin
    Sichuan University.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    The Ile646Val (2073A > G) Polymorphism in the Kinase-Binding Domain of A-Kinase Anchoring Protein 10 and the Risk of Colorectal Cancer2009In: ONCOLOGY, ISSN 0030-2414, Vol. 76, no 3, p. 199-204Article in journal (Refereed)
    Abstract [en]

    Objective: The purpose of this study is to investigate whether the Ile646Val (2073A>G) polymorphism in the kinase-binding domain of A-kinase anchoring protein 10 (AKAP10) is related to the risk of colorectal cancer (CRC), clinicopathological variables and the environmental factors for the development of CRC. Methods: Applying TaqMan allelic discrimination, we investigated AKAP10 Ile646Val (2073A>G) polymorphism in 288 Chinese CRC patients and 281 healthy controls. Results: Logistic regression analysis revealed a significant association of AKAP10 Ile646Val (2073A>G) polymorphism with increased CRC risk (adjusted OR = 1.44, 95% CI 1.01-2.07, p = 0.02). Stratification analysis showed that the increased risk associated with the variant genotypes (GG+AG) was more evident in male subjects (adjusted OR = 1.48, 95% CI 0.94-2.34, p = 0.03). Compared with the AA genotype, the adjusted OR for the variant genotypes was 1.81 (95% CI 1.08 - 3.05, p = 0.01) among young subjects (age ! 57 years). Among individuals who did not smoke or who smoked lightly, there was a significantly increased risk with the variant genotypes (adjusted OR = 1.66, 95% CI 1.08 - 2.56, p = 0.02). We did not observe a relationship between the AKAP10 polymorphism and other clinicopathological and environmental factors. Conclusions: Our data suggested that the AKAP10 2073A>G variation is associated with an increased risk of CRC in the Chinese population.

  • 264.
    Wang, Yong
    et al.
    Sichuan University.
    Li, Yuan
    Sichuan University.
    Zhang, Wen-Yan
    Sichuan University.
    Xia, Qing-Jie
    Sichuan University.
    Li, Hong-Guang
    Sichuan University.
    Wang, Rong
    Sichuan University.
    Yang, Lie
    Sichuan University.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Zhou, Zong-Guang
    Sichuan University.
    mRNA expression of minichromosome maintenance 2 in colonic adenoma and adenocarcinoma2009In: EUROPEAN JOURNAL OF CANCER PREVENTION, ISSN 0959-8278, Vol. 18, no 1, p. 40-45Article in journal (Refereed)
    Abstract [en]

    As proliferation is essential for Progression from normal cells to tumor, certain markers specific to proliferating cells may permit detection of premalignant lesions. Here, we aimed to evaluate the possible value of a proliferation marker, minichromosome maintenance 2 (MCM2), in the early diagnosis of colorectal cancer, by analyzing the difference in MCM2 expression among normal mucosa, adenoma, and adenocarcinoma, and investigating the relationship of MCM2 expression in adenomas with clinicopathologic variables. Using immunohistochemistry and real-time reverse transcription-PCR, we observed that the expression of MCM2 protein was present on basal third to half of colonic crypts in normal mucosa, whereas throughout the epithelium in adenomas and adenocarcinomas, the expression of MCM2 mRNA in adenocarcinomas was significantly higher than in adenomas (P=0.001), whereas the difference between adenoma and normal mucosa was not significant (P=0.184); we also found that the expression of MCM2 mRNA tended to be increased in the adenomas with high-grade dysplasia, or in older patients, respectively, compared with those with low-grade dysplasia, and younger patients. These results suggested the potential value of MCM2 in early diagnosis of colorectal cancer.

  • 265.
    Wegman Palmebäck, Pia
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Elingarami, Sauli
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Carstensen, John
    Linköping University, Department of Medical and Health Sciences, Health and Society. Linköping University, Faculty of Arts and Sciences.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Wingren, Sten
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal breast cancer patients2007In: Breast Cancer Research, ISSN 1465-5411, Vol. 9, no 1, p. R7-Article in journal (Refereed)
    Abstract [en]

    Introduction

    Tamoxifen therapy reduces the risk of recurrence and prolongs the survival of oestrogen-receptor-positive patients with breast cancer. Even if most patients benefit from tamoxifen, many breast tumours either fail to respond or become resistant. Because tamoxifen is extensively metabolised by polymorphic enzymes, one proposed mechanism underlying the resistance is altered metabolism. In the present study we investigated the prognostic and/or predictive value of functional polymorphisms in cytochrome P450 3A5 CYP3A5 (*3), CYP2D6 (*4), sulphotransferase 1A1 (SULT1A1; *2) and UDP-glucuronosyltransferase 2B15 (UGT2B15; *2) in tamoxifen-treated patients with breast cancer.

    Methods

    In all, 677 tamoxifen-treated postmenopausal patients with breast cancer, of whom 238 were randomised to either 2 or 5 years of tamoxifen, were genotyped by using PCR with restriction fragment length polymorphism or PCR with denaturing high-performance liquid chromatography.

    Results

    The prognostic evaluation performed in the total population revealed a significantly better disease-free survival in patients homozygous for CYP2D6*4. For CYP3A5, SULT1A1 and UGT2B15 no prognostic significance was observed. In the randomised group we found that for CYP3A5, homozygous carriers of the *3 allele tended to have an increased risk of recurrence when treated for 2 years with tamoxifen, although this was not statistically significant (hazard ratio (HR) = 2.84, 95% confidence interval (CI) = 0.68 to 11.99, P = 0.15). In the group randomised to 5 years' tamoxifen the survival pattern shifted towards a significantly improved recurrence-free survival (RFS) among CYP3A5*3-homozygous patients (HR = 0.20, 95% CI = 0.07 to 0.55, P = 0.002). No reliable differences could be seen between treatment duration and the genotypes of CYP2D6, SULT1A1 or UGT2B15. The significantly improved RFS with prolonged tamoxifen treatment in CYP3A5*3 homozygotes was also seen in a multivariate Cox model (HR = 0.13, CI = 0.02 to 0.86, P = 0.03), whereas no differences could be seen for CYP2D6, SULT1A1 and UGT2B15.

    Conclusion

    The metabolism of tamoxifen is complex and the mechanisms responsible for the resistance are unlikely to be explained by a single polymorphism; instead it is a combination of several mechanisms. However, the present data suggest that genetic variation in CYP3A5 may predict response to tamoxifen therapy.

  • 266.
    Wegman, Pia
    et al.
    University Orebro, Sch Hlth and Med Science, Department Clin Med, S-70185 Orebro, Sweden .
    Gothlin Eremo, Anna
    University Orebro, Sch Hlth and Med Science, Department Clin Med, S-70185 Orebro, Sweden .
    Lindlof, Angelica
    Skovde University, Sch Life Science, Syst Biol Research Centre, S-54145 Skovde, Sweden .
    Karlsson, Mats
    Orebro University Hospital, Sch Hlth and Med Science, Department Pathol, S-70185 Orebro, Sweden .
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Wingren, Sten
    University Orebro, Sch Hlth and Med Science, Department Clin Med, S-70185 Orebro, Sweden .
    Expression of the forkhead transcription factor FOXL2 correlates with good prognosis in breast cancer patients treated with tamoxifen2011In: INTERNATIONAL JOURNAL OF ONCOLOGY, ISSN 1019-6439, Vol. 38, no 4, p. 1145-1151Article in journal (Refereed)
    Abstract [en]

    Aromatase is an important enzyme in the local synthesis of oestrogens and its expression has been shown to be increased in breast cancer through the activation of multiple promoters. However, the mechanisms behind this are not yet fully understood. A novel candidate in this context is the transcription factor forkhead box L2 (FOXL2), which has been recognised to be co-expressed with aromatase and transcriptionally active promoter 11 in developing goat and chicken ovaries. We propose that FOXL2 could be involved in the increased expression of aromatase in breast cancer. We examined FOXL2 and its relation to aromatase in 132 postmenopausal breast cancer patients by immunohistochemistry. Using in silico analysis, we further searched for FOXL2 binding-elements in the aromatase gene promoters. The results demonstrate that FOXL2 is expressed in breast cancer and influences clinical outcome with improved recurrence-free survival in cases with nuclear expression. In a multivariate Cox model, nuclear FOXL2 was a significant prognostic factor in ER-positive patients treated with tamoxifen (HR=0.18, 95% confidence interval (CI)=0.04-0.81, P=0.03). Tumours expressing nuclear FOXL2 were also more likely positive for stromal and/or cytoplasmic aromatase (P=0.03 and P=0.008, respectively). In silico analyses revealed binding elements of FOXL2 in promoters 1.3, 11 and 17 of the aromatase gene of which promoter 1.7 was most significant. In conclusion, this is the first study to report that FOXL2 is expressed in breast cancer and correlates with aromatase as well as with clinical outcome. The results further strengthen a possible binding of FOXL2 to aromatase promoter 1.7. Nevertheless, whether FOXL2 is a direct activator of aromatase requires further investigation.

  • 267.
    Wennerstrand, Patricia
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Mårtensson, Lars-Göran
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Dametto, P
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Hennig, Janosch
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Skoglund, Karin
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Peterson, Curt
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Different mechanisms behind low enzyme activity in vivo of two different variants of Thiopurine S-methyltransferase, TPMT2010In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 277, no Suppl. 1, p. 257-258Article in journal (Other academic)
    Abstract [en]

    In treatment of acute lymphoblastic leukemia and inflammatorybowel disease (IBD) thiopurines such as azathioprine and 6-mercaptopurineare used. All of these drugs are prodrugs and are, inthe cell, converted to 6-thioguanines (6-TGNs) and incorporatedinto DNA or inhibiting purine synthesis. A key enzyme for thisregulation is the cytosolic enzyme thiopurine S-methyltransferase(TPMT). This enzyme degrades azathioprine and 6-mercaptopurineto methylmercapto-purine and thereby reduces the bioavailabilityof the 6-TGNs incorporated into DNA. TPMT is apolymorphic enzyme with at least 29 different allelic variantsknown today and is one of the more classical examples of pharmacogeneticswhere the TPMT enzyme activity of the allelic variantsis directly correlated to the clinical dosages of the thiopurines, with a 10–15 fold dosage reduction for an allelic variantwith low TPMT enzyme activity. Even though TPMT is awell studied protein. Many studies have been performed in yeast‘‘suspensions’’ and not on pure protein solutions. It has beenspeculated and in a few cases shown that the reason for the lowactivity for most of the allelic variants is mainly due to the lowstability and/or tendency to aggregate. The mutations in thisstudy TPMT *2 (A80P) and TPMT * 5 (L49S) are both situatedat a distance far from the active site, however the enzyme activitiesare severely affected at 37°C. Preliminary results, using a repertoireof techniques such as CD, fluorescence and limitedproteolysis experiments suggest two different mechanisms for thelow enzyme activity at a temperature corresponding to in vivo conditions.

  • 268.
    Widegren, Emma
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Önnesjö, Sofia
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Arbman, Gunnar
    Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Kayed, Hany
    Univ Heidelberg, Inst Clin Radiol and Nucl Med, Univ Hosp Mannheim, Heidelberg, Germany.
    Zentgraf, Hanswalter
    German Canc Res Ctr, D-6900 Heidelberg, Germany.
    Kleeff, Joerg
    Tech Univ Munich, Dept Surg, Munich, Germany.
    Zhang, Hong
    Univ Skovde, Sch Life Sci, Skovde, Sweden.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Expression of FXYD3 Protein in Relation to Biological and Clinicopathological Variables in Colorectal Cancers2009In: Chemotherapy, ISSN 0009-3157, E-ISSN 1421-9794, Vol. 55, no 6, p. 407-413Article in journal (Refereed)
    Abstract [en]

    Background: FXYD3 is up-/down-regulated in different types of cancers. We examined FXYD3 expression in colorectal cancers and its relationship to biological and clinicopathological variables. Patients and Methods: Expression of FXYD3 protein was immunohistochemically examined in distant normal mucosa (n = 34), adjacent normal mucosa (n = 72), primary tumour (n = 150) and lymph node metastasis (n = 35) from colorectal cancer patients. Results: FXYD3 was highly expressed in primary tumour compared to adjacent normal mucosa (p = 0.02). FXYD3 was or tended to be positively related to the expression of ras (p = 0.02), p53 (p = 0.06), legumain (p = 0.02) and proliferating cell nuclear antigen (p = 0.03). Moreover, there was a higher frequency of strong FXYD3 expression in Dukes A-C tumours than in D tumours (p = 0.04). The strong FXYD3 expression tended to predict worse survival in the patients with Dukes A + B tumour (p = 0.07), while there was no such tendency in the patients with Dukes C + D tumour (p = 0.94). The tumours located in the colon had a higher degree of FXYD3 expression than the tumours located in the rectum (p = 0.05). Conclusion: The FXYD3 was associated with certain biological variables and may be involved in the development of the relative earlier stages of colorectal cancers.

  • 269.
    Wilking, N.
    et al.
    Department of Oncology, Karolinska Institutet, Stockholm, Sweden, Radiumhemmet Karolinska Hospital, Stockholm, Sweden.
    Lidbrink, E.
    Radiumhemmet, Karolinska Institutet and University Hospital, Solna, S-171 76 Stockholm, Sweden.
    Wiklund, T.
    Roche OY, Espoo, Finland, Department of Oncology, University Hospital, Helsinki, Finland.
    Erikstein, B.
    Southern Norway Regional Health Authority, Skien, Norway, The Norwegian Radiumhospital, Oslo, Norway.
    Lindman, H.
    Department of Oncology, Akademiska Hospital, Uppsala, Sweden.
    Malmstrom, P.
    Malmström, P., Department of Oncology, University Hospital, Lund, Sweden.
    Kellokumpu-Lehtinen, P.
    Department of Oncology, Tampere University, University Hospital, Tampere, Finland.
    Bengtsson, N.-O.
    Department of Oncology, University Hospital, Umeå, Sweden.
    Söderlund, G.
    Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Anker, G.
    Department of Oncology, Haukeland University Hospital, Bergen, Norway, Department of Oncology, Haukeland Hospital, Bergen, Norway.
    Wist, E.
    Department of Oncology, Ullevål University Hospital and Faculty of Medicine, University of Oslo, Oslo, Norway, Department of Oncology, Regional Hospital, Tromsø, Norway.
    Ottosson, S.
    Department of Oncology, NÄL, Trollhättan, Sweden.
    Salminen, E.
    Department of Oncology, Turku University Hospital, Turku, Finland.
    Ljungman, P.
    Haematology Centre, Karolinska University Hospital, Stockholm, Sweden, Department of Hematology, Huddinge Hospital, Stockholm, Sweden.
    Holte, H.
    Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway, Hematology Section, The Norwegian Radiumhospital, Oslo, Norway.
    Nilsson, J.
    Trial Form Support AB, Stockholm, Sweden.
    Blomqvist, C.
    Department of Oncology, University Hospital, Helsinki, Finland.
    Bergh, J.
    Department of Oncology, Karolinska Institutet, Stockholm, Sweden, Radiumhemmet, Karolinska Institutet and University Hospital, Solna, S-171 76 Stockholm, Sweden, Radiumhemmet Karolinska Hospital, Stockholm, Sweden.
    Hoglund, M.
    Höglund, M., Department of Hematology, University Hospital, Uppsala, Sweden.
    Bengtsson, M.
    Department of Clinical Immunology, University Hospital, Uppsala, Sweden.
    Gruber, A.
    Department of Hematology, Karolinska Hospital, Stockholm, Sweden.
    Fornander, T.
    Department of Oncology, Södersjukhuset,, Stockholm, Sweden.
    Petterson-Skold, D.
    Petterson-Sköld, D., Department of Oncology, Danderyd Hospital, Stockholm, Sweden.
    Lofvenberg, E.
    Löfvenberg, E., Department of Hematology, University Hospital, Umeå, Sweden.
    Villman, K.
    Department of Oncology, Örebro Hospital, Örebro, Sweden.
    Karlsson, Katarina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Nursing Science.
    Hultborn, R.
    Department of Oncology, Sahlgrenska Hospital, Göteborg, Sweden.
    Ottoson, S.
    Department of Oncology, Sahlgrenska Hospital, Göteborg, Sweden.
    Mattson, J.
    Department of Surgery, Sahlgrenska Hospital, Göteborg, Sweden.
    Jansson, S.
    Department of Surgery, Sahlgrenska Hospital, Göteborg, Sweden.
    Braide, I.
    Department of Hematology, Sahlgrenska Hospital, Göteborg, Sweden.
    Carlsson, G.
    Department of Oncology, Östra Hospital, Göteborg, Sweden.
    Rodjer, S.
    Rödjer, S., Department of Hematology, Östra Hospital, Göteborg, Sweden.
    Sallerfors, B.
    Department of Hematology, University Hospital, Lund, Sweden.
    Ahlgren, J.
    Department of Oncology, Gävle Hospital, Gävle, Sweden.
    Gawelin, A.
    Department of Oncology, Gävle Hospital, Gävle, Sweden.
    Solderberg, M.
    Sölderberg, M., Department of Oncology, Karlstad Hospital, Karlstad, Sweden.
    Hansen, J.
    Department of Oncology, Västerås Hospital, Västerås, Sweden.
    Stenstam, B.
    Department of Oncology, Mälarsjukhuset, Eskilstuna, Sweden.
    Svensson, J.-H.
    Mälarsjukhuset Eskilstuna of Oncology, Borås Hospital, Borås, Sweden.
    Norberg, B.
    Department of Oncology, Ryhov Hospital, Jönköping, Sweden.
    Kvalheim, G.
    Department of Medicine, The Norwegian Radiumhospital, Oslo, Norway.
    Sommer, H.H.
    Department of Oncology, Ullevål Hospital, Oslo, Norway.
    Tangen, J.M.
    Department of Hematology, Ullevål Hospital, Oslo, Norway.
    Lundgren, S.
    Department of Oncology, Regional Hospital, Trondheim, Norway.
    Remes, K.
    Department of Internal Medicine, University Hospital, Turku, Finland.
    Lehtinen, M.
    Department of Clinical Chemistry, Division of Hematology, University Hospital, Tampere, Finland.
    Koivinen, E.
    Department of Clinical Chemistry, Division of Hematology, University Hospital, Tampere, Finland.
    Turpeenniemi-Hujanen, T.
    Department of Oncology, Oulu University Hospital, Oulu, Finland.
    Kuittinen, O.
    Department of Oncology, Oulu University Hospital, Oulu, Finland.
    Voutilainen, L.
    Department of Oncology, Kuopio University Hospital, Kuopio, Finland.
    Mirza, M.R.
    Department of Oncology, University Hospital, Odense, Denmark.
    Rose, C.
    Department of Oncology, University Hospital, Odense, Denmark.
    Long-term follow-up of the SBG 9401 study comparing tailored FEC-based therapy versus marrow-supported high-dose therapy2007In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 18, no 4, p. 694-700Article in journal (Refereed)
    Abstract [en]

    Background: The purpose was to investigate adjuvant marrow-supportive high-dose chemotherapy compared with an equitoxicity-tailored comparator arm. Patients and methods: Five hundred and twenty-five women below theage of 60 years with operated high-risk primary breast cancer were randomised to nine cycles of granulocyte colony-stimulating factor supported and individually tailored FEC (5-fluorouracil, epirubicin, cyclophosphamide), (n = 251) or standard FEC followed by marrow-supported high-dose therapy with CTCb (cyclophosphamide, thiotepa, carboplatin) therapy (n = 274), followed by locoregional radiotherapy and tamoxifen for 5 years. Results: There were 104 breast cancer relapses in the tailored FEC group versus 139 in the CTCb group (double triangular method by Whitehead, P = 0.046), with a median follow-up of all included patients of 60.8 months. The event-free survival demonstrated 121 and 150 events in the tailored FEC- and CTCb group, respectively [P = 0.074, hazard ratio (HR) 0.804, 95% confidence interval (CI) 0.633-1.022]. Ten patients in the tailored FEC regimen developed acute myeloid leukaemia (AML)/myelodysplasia (MDS). One hundred deaths occurred in the tailored FEC group and 121 in the CTCb group (P = 0.287, HR 0.866, 95% CI 0.665-1.129). Conclusion: The update of this study shows an improved outcome linked to the tailored FEC treatment in relation to breast cancer relapse, but also an increased incidence of AML/MDS. © 2007 Oxford University Press.

  • 270. Wolfraim, Larence A
    et al.
    Walz, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    James, Zakiya
    Fernandez, Tania
    Letterio, John J
    p21Cip1 and p27Kip1 act in synergy to alter the sensitivy of naive T cells to TGF-beta-mediated G1 arrest through modulation of IL-2 responsiveness2004In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 173, p. 3093-3102Article in journal (Refereed)
  • 271. Wolfraim, Lawrence A
    et al.
    Fernandez, Tania M
    Mamura, Mizuko
    Fuller, Walter L
    Kumar, Rajesh
    Cole, Diane E
    Byfield, Stacey
    Felici, Angelina
    Flanders, Kathleen C
    Walz, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Roberts, Anita B
    Aplan, Peter D
    Balis, Frank M
    Letterio, John J
    Loss of Smad3 in acute T-cell lymphoblastic leukemia2004In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 351, no 6, p. 552-559Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The receptors for transforming growth factor β (TGF-β) and their signaling intermediates make up an important tumor-suppressor pathway. The role of one of these intermediates - Smad3 - in the pathogenesis of lymphoid neoplasia is unknown. METHODS: We measured Smad3 messenger RNA (mRNA) and protein in leukemia cells obtained at diagnosis from 19 children with acute leukemia, including 10 with T-cell acute lymphoblastic leukemia (ALL), 7 with pre-B-cell ALL, and 2 with acute nonlymphoblastic leukemia (ANLL). All nine exons of the SMAD3 gene (MADH3) were sequenced. Mice in which one or both alleles of Smad3 were inactivated were used to evaluate the role of Smad3 in the response of normal T cells to TGF-β and in the susceptibility to spontaneous leukemogenesis in mice in which both alleles of the tumor suppressor p27Kip1 were deleted. RESULTS: Smad3 protein was absent in T-cell ALL but present in pre-B-cell ALL and ANLL. No mutations were found in the MADH3 gene in T-cell ALL, and Smad3 mRNA was present in T-cell ALL and normal T cells at similar levels. In mice, the loss of one allele for Smad3 impairs the inhibitory effect of TGF-β on the proliferation of normal T cells and works in tandem with the homozygous inactivation of p27Kip1 to promote T-cell leukemogenesis. CONCLUSIONS: Loss of Smad3 protein is a specific feature of pediatric T-cell ALL. A reduction in Smad3 expression and the loss of p27Kip1 work synergistically to promote T-cell leukemogenesis in mice.

  • 272.
    Xu, Bing
    et al.
    Department of General Surgery West China Hospital, Sichuan University, Chengdu, China.
    Zhou, Zong-Guang
    Department of General Surgery West China Hospital, Sichuan University, Chengdu, China.
    Li, Yuan
    Department of General Surgery West China Hospital, Sichuan University, Chengdu, China.
    Wang, Ling
    Department of General Surgery West China Hospital, Sichuan University, Chengdu, China.
    Yang, Lie
    Department of General Surgery West China Hospital, Sichuan University, Chengdu, China.
    Zhou, Bin
    Department of General Surgery West China Hospital, Sichuan University, Chengdu, China.
    Liu, Hai-Li
    Department of General Surgery West China Hospital, Sichuan University, Chengdu, China.
    Song, Jun-Min
    Department of General Surgery West China Hospital, Sichuan University, Chengdu, China.
    Zeng, Yu-Jian
    Department of General Surgery West China Hospital, Sichuan University, Chengdu, China.
    Wang, Rong
    Department of General Surgery West China Hospital, Sichuan University, Chengdu, China.
    Sun, Xiao-Feng
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Clinicopathological significance of caspase-8 and caspase-10 expression in rectal cancer2008In: Oncology, ISSN 0890-9091, Vol. 74, no 3-4, p. 229-236Article in journal (Refereed)
    Abstract [en]

    Objectives: To investigate the expression of caspase-8 and -10 in rectal adenoma, adenocarcinoma and the corresponding normal mucosa tissue, and to clarify the relationship between their expression and clinicopathological parameters of rectal cancer. Methods: The expression of caspase-8 and -10 was determined by real-time RT-PCR and immunohistochemistry in 36 rectal adenomas, 93 rectal cancers and 93 corresponding normal rectal mucosa samples. Results: Compared with normal mucosa, the mRNA expression of caspase-8 was higher in adenomas (p = 0.003), while that of caspase-10 was lower in adenomas (p = 0.035) and cancers (p = 0.001). Immunohistochemical results showed caspase-8 up-regulation in adenomas (p = 0.014), and caspase-10 down-regulation in adenomas (p = 0.034) and cancers (p < 0.001) compared with normal mucosa samples. Cancers with poor differentiation had lower caspase-10 mRNA and protein levels than those with better differentiation (p = 0.041 and p = 0.046, respectively). The protein expression of caspase-8 and -10 was in accordance with the mRNA expression (p = 0.043 and p = 0.018, respectively). Conclusions: Caspase-8 expression was up-regulated in rectal adenomas. Caspase-10 expression was down-regulated in both rectal adenomas and cancers, and was further related to differentiation. Caspase-8 and -10 may be involved in the pathogenesis of rectal cancer. Copyright © 2008 S. Karger AG.

  • 273.
    Yang, Lie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Olsson, Birgit
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Pfeifer, Daniella
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Jönsson, J-I
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Zhou, Z-G
    Sichuan University.
    Jiang, X
    Sichuan University.
    Fredriksson, Bengt-Arne
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Zhang, H
    University of Skovde.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Knockdown of peroxisome proliferator-activated receptor-beta induces less differentiation and enhances cell-fibronectin adhesion of colon cancer cells2010In: ONCOGENE, ISSN 0950-9232, Vol. 29, no 4, p. 516-526Article in journal (Refereed)
    Abstract [en]

    The role of peroxisome proliferator-activated receptor-beta/delta (PPAR-beta/delta) in the pathogenesis of colon cancer remains highly controversial. This study specifically silenced the PPAR-beta expression in three colon cancer cell lines with different metastatic potentials. Although PPAR-beta knockdown resulted in more malignant morphological changes, bigger colony sizes and lower carcinoembryonic antigen (CEA) secretion, and enhanced the cell-fibronectin adhesion, cell invasion and migration were unaffected. These effects were stronger in poorly metastatic cell lines compared with highly metastatic ones. Simultaneously, PPAR-beta knockdown decreased the mRNAs encoding adipocyte differentiation-related protein and liver fatty acid binding protein, and increased the mRNA of ILK, whereas the mRNAs encoding integrin-beta 1 and angiopoietin-like 4 were unchanged. Using immunohistochemistry, we determined that the intensity of PPAR-beta expression was stronger in rectal cancers with better differentiation than in those with poor differentiation, and was stronger in early-stage tumors than in advanced ones. Together, these findings consistently indicate that PPAR-beta may facilitate differentiation and inhibit the cell-fibronectin adhesion of colon cancer, having a role as an inhibitor in the carcinogenesis and progression of colorectal cancer. Interestingly, PPAR-beta seems to have a more important role in poorly metastatic cells than in highly metastatic ones.

  • 274.
    Yngman Uhlin, Pia
    et al.
    Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences.
    Fernström, Anders
    Linköping University, Department of Medical and Health Sciences, Nephrology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    Börjeson, Sussanne
    Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Edéll-Gustafsson, Ulla
    Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences.
    Evaluation of an individual sleep intervention programme in people undergoing peritoneal dialysis treatment2012In: Journal of Clinical Nursing, ISSN 0962-1067, E-ISSN 1365-2702, Vol. 21, no 23-24, p. 3402-3417Article in journal (Refereed)
    Abstract [en]

    Objective: This study aimed at evaluate effects of a individually designed nonpharmacological intervention on sleep, activity and fatigue in peritoneal dialysis (PD) by use of both actigraphy registration and self-assessed questionnaires.

    Design: A prospective multiple baseline single-case experimental design.

    Methods: Two women and seven men with sleep problems, 48-77 years, treated with PD participated in a 17-week study. Two interventions were separately implemented. First, a pressure relieving mattress and second, a four week individual sleep hygiene and sleep scheduling intervention. The two interventions were evaluated both objectively by actigraphy and subjectively by questionnaires.

    Results: Totally 315 sleep-wake cycles from nine individuals were evaluated. Of the nine measured outcome variables i.e. sleep onset latency, nocturnal sleep duration, numbers and duration of napping, movement and fragmentation index (MFI), number of steps, metabolic equivalent unit (METs), sleep efficiency and fatigue, three patients improved clinically significantly in five or more of the outcomes. The other six patients also showed improvements but to a lesser degree. Physical activity advice was the intervention that yielded most sleep improvements.

    Conclusions: This study shows that patients on peritoneal dialysis treatment have a wide variety of sleep problems and that an individual sleep hygiene and sleep scheduling program can be applied with clinically significant improvements even in this heterogeneous and frail patient group. The intervention should be easy to use in daily clinical routines.

  • 275.
    Yngman Uhlin, Pia
    et al.
    Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences.
    Johansson, Anna
    Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences.
    Fernström, Anders
    Linköping University, Department of Medicine and Care, Nephrology. Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Nephrology UHL.
    Börjeson, Sussanne
    Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Edéll-Gustafsson, Ulla
    Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences.
    Fragmented sleep: An unrevealed problem in peritoneal dialysis patients2011In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 45, no 3, p. 206-215Article in journal (Refereed)
    Abstract [en]

    Objective. The aim of this study was to describe the sleep--wake cycle, sleep quality, fatigue and Health Related Quality of Life (HRQoL) measured with questionnaires, actigraphy and a sleep diary during a one-week period in patients undergoing peritoneal dialysis (PD) treatment at home. A further aim was to explore differences compared with patients with coronary artery disease (CAD) and individuals from the general population. Material and methods. In this study one-week actigraphy registration, four questionnaires (Uppsala Sleep Inventory, SF-36, FACIT-fatigue, International Restless Legs Study Groups form) and a sleep diary were used. Results. Data from 68 participants and 470 nights were collected. PD patients (n == 28) had more fragmented sleep (p andlt; 0.001) and worse sleep efficiency (SE%) (p andlt; 0.0001) than the CAD (n == 22) and the population (n == 18) groups. Pruritus (57%), restless legs (46%) and fatigue (89%) were prevalent in PD patients. Pruritus correlated with fragmented sleep (r == --0.45, p == 0.01) and SE (r == --0.49, p == 0.01). In HRQoL, the physical component score was decreased in the PD and CAD groups (p andlt; 0.01) compared to the population group. Conclusions. To the authors knowledge this study is the first to demonstrate that PD patients have deteriorated sleep, with serious fragmentation measured by a one-week actigraphy registration. Further, PD patients exhibit worse sleep quality than CAD patients and individuals in the population. Evaluation of sleep in clinical practice is highly recommended since PD patients are vulnerable individuals with extended self-care responsibilities and at risk for comorbidity secondary to insufficient sleep. Future research on whether PD patients sleep problems and fatigue can be improved by an individual non-pharmacological intervention programme is required.

  • 276. Zackrisson, Anna-Lena
    et al.
    Malmström, Henric
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Peterson, Curt
    No evidence that amifostine influences the plasma pharmacokinetics of topotecan in ovarian cancer patients2002In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 58, no 2, p. 103-108Article in journal (Refereed)
    Abstract [en]

    Objective: This aim of this study was to compare the pharmacokinetics of topotecan in the presence and absence of preceding amifostine to reduce the risk of side effects in patients with advanced ovarian cancer. Methods: Ten patients with advanced ovarian cancer received topotecan, 1.5 mg/m2 for 5 days, as second-line therapy in an open phase-II study after previous platinum-containing first-line therapy. Patients were randomised to receive intravenous (IV) amifostine at a daily dose of 300 mg/m2 prior to topotecan in the first cycle and topotecan alone in the second cycle or vice versa. Thereafter all patients were given amifostine and topotecan for additional four cycles. Topotecan was given as a 30-min IV infusion. On day 1 of the first and second treatment cycles, venous blood samples were collected up to 24 h after the start of topotecan infusion. Plasma concentrations of total topotecan and its active lactone form were determined using high-performance liquid chromatography. Results: There was a rapid decline in total topotecan plasma concentrations after the end of the infusion followed by a slower decay. The initial decline was even faster for the lactone form. The inter-individual variability was pronounced and the area under the plasma concentration-time curve from time zero to infinity (AUC0-8) of the total topotecan plasma concentration ranged from 182 nmol/l h to 725 nmol/l h for topotecan alone and from 188 nmol/l h to 574 nmol/l h for topotecan and amifostine. The geometric mean of AUC0-8 values were 326 nmol/l h and 297 nmol/l h, respectively (P=0.41). In the cycles when the patients received topotecan alone, the plasma AUC of the lactone averaged 40% of the AUC of the total concentration compared with 39% in the cycles when topotecan was given after amifostine. The peak plasma concentration (Cmax) of the lactone averaged 72% of the Cmax of the total topotecan concentration in the topotecan-only group. The corresponding figure after topotecan and amifostine was 80% (P=0.11). A large intra-individual pharmacokinetic of topotecan between cycles 1 and 2 was also observed. Conclusion: Amifostine, 300 mg/m2, does not significantly affect the pharmacokinetics of topotecan and there are pronounced intra- and inter-individual variabilities in the topotecan pharmacokinetics.

  • 277.
    Zhang, Hong
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Ahmadi, Ahmad
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Arbman, G
    Zdolsek, J
    Carstensen, J
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Nordenskjöld, Bo
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Söderkvist, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Sun, Xiao-Feng
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology.
    Glutathione S-transferase T1 and M1 genotypes in normal mucosa, transitional mucosa and colorectal adenocarcinom.1999In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 84, p. 135-138Article in journal (Refereed)
  • 278.
    Zhang, Hong
    et al.
    Linköping University, Department of Biomedicine and Surgery, Division of dermatology and venereology. Linköping University, Faculty of Health Sciences.
    Nordenskjöld, Bo
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Dufmats, Monika
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Sun, Xiao-Feng
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    K-ras mutations in colorectal adenocarcinomas and neighbouring transitional mucosa.1998In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 34, no 13, p. 2053-2057Article in journal (Refereed)
    Abstract [en]

    The K-ras gene in codons 12 and 13 was investigated using allele-specific polymerase chain reaction in matched normal mucosa (n = 106), transitional mucosa (n = 69) and tumours (n = 149) from 149 patients with colorectal adenocarcinomas. K-ras mutations in codon 12 were detected in 41/149 (28%) of tumours and 4/69 (6%) of transitional mucosa samples, but not in the normal mucosa. Further, mutation rates were increased in younger patients (P = 0.001) and in mucinous carcinomas (50%) compared with well differentiated (17%), moderately differentiated (26%) or poorly differentiated (24%) tumours. Our findings indicate that mucinous carcinoma may represent a distinct genetic entity.

  • 279.
    Zhang, Hong
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of dermatology and venereology.
    Sun, Xiao-Feng
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Synnerstad, Ingrid
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of dermatology and venereology. Östergötlands Läns Landsting, Centre for Medicine, Department of Dermatology and Venerology in Östergötland.
    Rosdahl, Inger
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of dermatology and venereology. Östergötlands Läns Landsting, Centre for Medicine, Department of Dermatology and Venerology in Östergötland.
    Importance of FAS-1377, FAS-670, and FASL-844 polymorphisms in tumor onset, progression, and pigment phenotypes of Swedish patients with melanoma: a case-control analysis.2007In: Cancer Journal, ISSN 0765-7846, E-ISSN 1292-8658, Vol. 13, no 4, p. 233-237Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Human skin melanoma at later stages usually has an extremely poor prognosis. It is of importance to search for biologic markers to identify and monitor individuals at risk for melanoma for early diagnosis and to avoid tumor progression. The FAS gene and its natural ligand (FASL) gene initiate the death signal cascade, playing a central role in the apoptotic signaling pathway and tumor growth and metastasis. PATIENTS AND METHODS: In this study, we analyzed polymorphisms in 229 patients with melanoma and 351 age- and gender-matched tumor-free individuals. Genomic DNAs were isolated from mononuclear cells in peripheral vein blood, and the polymorphisms were examined with polymerase chain reaction-restriction fragment length polymorphism techniques. Frequency in distribution of the polymorphisms was compared between the patients with melanoma and the healthy control subjects, and associations with patients' pigment phenotypes, age at diagnosis, and melanoma characteristics were analyzed. RESULTS AND CONCLUSIONS: The FAS-1377, FAS-670, and FASL-844 polymorphisms were not found to be markers of melanoma risk (P > 0.05). In patients with melanoma, frequencies of the FAS-1377, FAS-670, and FASL-844 polymorphisms were different between the patients aged <50 and > or =50 years (P < or = 0.025, P < or = 0.025, and P < or = 0.01). Moreover, the FAS-670 polymorphism correlated with tumor Breslow thickness (P < or = 0.01) and Clark level (P < or = 0.001) and was associated with tumors developing in sun-exposed locations (P < or = 0.001). FAS and FASL were not markers for melanoma risk but might be important in the development and progression of sun-induced melanoma independently of skin type.

  • 280.
    Zhang, Hong-Zhen
    et al.
    Hebei Medical University.
    Li, Xue-Hui
    Hebei Medical University.
    Zhang, Xia
    Hebei Medical University.
    Zhang, Zhi-Yong
    Tangshan Gongren Hospital.
    Meng, Ya-Li
    Hebei Medical University.
    Xu, Shu-Wen
    Hebei Medical University.
    Zheng, Yan
    Hebei Medical University.
    Zhu, Zhen-Long
    Hebei Medical University.
    Cui, Dong-Sheng
    Hebei Medical University.
    Huang, Li-Xia
    Hebei Medical University.
    Yan, Bao-Yong
    Hebei Medical University.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    PINCH Protein Expression in Normal Endometrium, Atypical Endometrial Hyperplasia and Endometrioid Endometrial Carcinoma2010In: CHEMOTHERAPY, ISSN 0009-3157, Vol. 56, no 4, p. 291-297Article in journal (Refereed)
    Abstract [en]

    Background: Particularly interesting new cysteine-histidine rich protein ( PINCH), as an adapter protein of the LIM family for signal transduction in the integrin and growth factor pathway, is upregulated in the stroma of several common types of cancers and involved in promoting tumor progression. In the present study, we examined PINCH expression in normal endometrium, atypical endometrial hyperplasia and endometrioid carcinoma, and further studied the relationships of PINCH expression with clinicopathological variables in cancer patients. Methods: PINCH expression was examined by immunohistochemistry in 23 normal endometrial samples, 18 atypical endometrial hyperplasias and 48 endometrioid endometrial carcinomas. Results: The PINCH expression in the stroma of cancer (71%) was significantly increased compared to either normal endometrium (17%, p andlt; 0.0001) or atypical hyperplasia (39%, p = 0.017), along with 9 cancers that had stronger PINCH expressions at the invasive margin of the cancers compared to the inner cancers. PINCH expression in cancer was higher in the patients with hypertension (p = 0.041) and estrogen exposure time andgt;30 years (p = 0.021). On the other hand, PINCH expression was not related to menopausal status, gravid status, blood sugar/lipid, family background of cancer, histological grade, myometrial invasion, cervical involvement, lymph nodal metastases, growth pattern, estrogen and progestogen receptors (p andgt; 0.05). Conclusion: The results suggest that PINCH seems to play a role, presently unknown, in the tumorigenesis and development of endometrial cancer that merits further study.

  • 281.
    Zhang, Jin-Ting
    et al.
    Department of Stomatology Hebei Medical University, Shijiazhuang 050031, Hebei Province, China.
    Wang, Da-Wei
    Department of Stomatology Hebei Medical University, Shijiazhuang 050031, Hebei Province, China.
    Li, Qing-Xing
    Department of Stomatology Hebei Medical University, Shijiazhuang 050031, Hebei Province, China.
    Zhu, Zhen-Long
    Department of Pathology Hebei Medical University, Shijiazhuang 050031, Hebei Province, China.
    Wang, Ming-Wei
    Central Laboratory Hebei Medical University, Shijiazhuang 050031, Hebei Province, China.
    Cui, Dong-Sheng
    Central Laboratory Hebei Medical University, Shijiazhuang 050031, Hebei Province, China.
    Yang, Yan-Hong
    Department of Pathology Hebei Medical University, Shijiazhuang 050031, Hebei Province, China.
    Gu, Yu-Xin
    Department of Stomatology Hebei Medical University, Shijiazhuang 050031, Hebei Province, China.
    Sun, Xiao-Feng
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Nuclear to cytoplasmic shift of p33ING1b protein from normal oral mucosa to oral squamous cell carcinoma in relation to clinicopathological variables2008In: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 134, no 3, p. 421-426Article in journal (Refereed)
    Abstract [en]

    Purpose: p33ING1b, as a candidate tumour suppressor gene, has been found to be expressed a proportion of oral squamous cell carcinomas (OSCCs), however, its clinicopathological significance is not studied yet. Our aim was to investigate association of p33ING1b expression with clinicopathological variables and particularly interesting new cysteine-histidine rich protein (PINCH) in OSCCs. Methods: p33ING1b expression was immumohistochemically examined in 20 normal oral mucosa specimens and 49 OSCCs. Results: Normal squamous cells showed only p33ING1b nuclear expression (no cytoplasmic expression), with a rate of 90% positive cases. While 24% of OSCCs appeared cytoplasmic expression (11 of them with weak nuclear staining) and the rest tumours (76%) were negative for p33 ING1b. Furthermore, the cases having lymph node metastasis showed a higher frequency of positive cytoplasmic expression than those without metastasis (P = 0.03). The p33ING1b cytoplasmic expression was positively related to PINCH expression (P = 0.04), the cases positive for both proteins had a high rate of the metastasis (P = 0.03). Conclusions: The transfer of p33ING1b protein from the nucleus to the cytoplasm may result in loss of normal cellular function of the protein, which might play a role in the tumourigenesis and metastasis of OSCCs. © 2007 Springer-Verlag.

  • 282. Zhang, JT
    et al.
    Li, QX
    Wang, DW
    Zhu, ZL
    Yang, YH
    Cui, DS
    Wang, MW
    Sun, Xiao-Feng
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Up-regulation of PINCH in the stroma of oral squamous cell carcinoma predicts nodal metastasis2005In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 14, no 6, p. 1519-1522Article in journal (Refereed)
    Abstract [en]

    Particularly interesting new cysteine-histidine rich protein (PINCH), an adapter protein involved in integrin and growth factor signalling, is up-regulated in the stroma of colorectal, breast, prostate, lung and skin cancer. Strong stromal immunostaining for PINCH is an independent prognostic indicator for reduced survival in colorectal cancer, suggesting that PINCH is involved in the signalling that promotes tumour progression. Since no study on PINCH has been carried out in oral squamous cell carcinoma (OSCC), this study aimed to determine PINCH expression in OSCC and its clinicopathological significance. PINCH protein expression was examined by immunohistochemistry in 20 normal oral mucosa and in 57 OSCC specimens, The frequency of strong PINCH immunostaining was higher in tumour-associated stroma of OSCC (37%) as compared to normal oral mucosa (10%) (p=0.02). Strong PINCH stromal immunostaining predicted nodal metastasis: 19/26 (73%) OSCC cases with nodal metastasis had strong PINCH immunostaining compared to 9/31 (29%) cases without nodal metastasis (p=0.02). The PINCH expression in OSCC was more intense in stroma at the invasive edge than in intratumoural stroma. In conclusion, the up-regulation of PINCH protein in stroma may be involved in promoting invasion and metastasis in OSCC.

  • 283.
    Zhang, Zhiyong
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Zhang, Hong
    University of Skovde.
    Adell, Gunnar
    Karolinska University Hospital.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Endosialin expression in relation to clinicopathological and biological variables in rectal cancers with a Swedish clinical trial of preoperative radiotherapy2011In: BMC CANCER, ISSN 1471-2407, Vol. 11, no 89Article in journal (Refereed)
    Abstract [en]

    Background: The importance of changes in tumour-associated stroma for tumour initiation and progression has been established. Endosialin is expressed in fibroblasts and pericytes of blood vessels in several types of tumours, and is involved in the progression of colorectal cancer. In order to see whether endosialin was related to radiotherapy (RT) response, and clinicopathological and biological variables, we investigated endosialin expression in rectal cancers from the patients who participated in a Swedish clinical trial of preoperative RT. Methods: Endosialin was immunohistochemically examined in normal mucosa, including distant (n = 72) and adjacent (n = 112) normal mucosa, and primary tumours (n = 135). Seventy-three of 135 patients received surgery alone and 62 received additional preoperative RT. Results: Endosialin expression in the stroma increased from normal mucosa to tumour (p andlt; 0.0001) both in RT and non-RT group. In the RT group, endosialin expression in the stroma was positively associated with expression of cyclooxygenase-2 (Cox-2) (p = 0.03), p73 (p = 0.01) and phosphates of regenerating liver (PRL) (p = 0.002). Endosialin expression in the tumour cells of both in the RT group (p = 0.01) and the non-RT group (p = 0.06) was observed more often in tumours with an infiltrative growth pattern than in tumours with an expansive growth pattern. In the RT group, endosialin expression in tumour cells was positively related to PRL expression (p = 0.02), whereas in the non-RT group, endosialin expression in tumour cells was positively related to p73 expression (p = 0.01). Conclusions: Endosialin expression may be involved in the progression of rectal cancers, and was related to Cox-2, p73 and PRL expression. However, a direct relationship between endosialin expression and RT responses in patients was not found.

  • 284.
    Zhang, Zhiyong
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology.
    Zhao, Zeng-Ren
    Adell, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Jarlsfelt, Ingvar
    Cui, Yong-Xing
    Kayed, Hany
    Kleeff, Jörg
    Wang, Ming-Wei
    Sun, Xiao-Feng
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Expression of MAC30 in rectal cancers with or without preoperative radiotherapy2007In: Oncology, ISSN 0890-9091, Vol. 71, no 3-4, p. 259-265Article in journal (Refereed)
    Abstract [en]

    Objective: Meningioma-associated protein (MAC30) is overexpressed in several types of cancers, but its therapeutic implication in the patients has not been studied. We examined the relationship of MAC30 with clinicopathological and biological factors in rectal cancer patients with or without radiotherapy (RT). Methods: MAC30 was immunohistochemically examined in 75 distant and 91 adjacent normal mucosa specimens, 132 primary tumours and 39 lymph node metastases from rectal cancer patients participating in a clinical trial of preoperative RT. Results: In the RT group, MAC30 was or tended to be positively correlated with infiltrated growth pattern (p = 0.02), PRL (phosphatase of regenerating liver, p = 0.01) and Ki-67 expression (p = 0.06). MAC30 at the invasive margin of the metastasis was related to poor survival (p = 0.02) in the whole group of patients. MAC30 in primary tumours was not related to recurrence and survival in the non-RT or RT group. Conclusions:MAC30 expression in metastasis was an indicator for poor survival. After RT, MAC30 seemed to be more related to aggressive morphological and biological factors, however, we did not find direct evidence that MAC30 expression was related to the outcome of patients with or without RT. Copyright © 2006 S. Karger AG.

  • 285. Zhang, Zhi-Yong
    et al.
    Zhao, Zeng-Ren
    Jiang, Li
    Li, Jia-Chen
    Gao, Yan-Min
    Cui, Dong-Sheng
    Wang, Che-Jiang
    Schneider, Jose
    Wang, Ming-Wei
    Sun, Xiao-Feng
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Nup88 expression in normal mucosa, adenoma, primary adenocarcinoma and lymph node metastasis in the colorectum2007In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 28, no 2, p. 93-99Article in journal (Refereed)
    Abstract [en]

    Objectives: It was the aim of this study to investigate Nup88 expression in normal colorectal mucosa, adenoma, adenocarcinoma and lymph node metastasis, as well as the relationship between Nup88 expression and clinicopathological features. Methods: Nup88 expression was examined by immunohistochemistry in 84 normal mucosa samples, 32 adenomas, 181 primary adenocarcinomas, and 18 lymph node metastases from colorectal tumour patients. Results: Nup88 expression was observed in normal epithelial and tumour cells. The frequency of strong Nup88 expression was increased from normal mucosa or adenoma to primary tumour and lymph node metastasis (p < 0.0001). There was no significant difference in the expression between normal mucosa and adenoma (p = 0.41). The frequency of strong Nup88 expression was higher in ulcerated tumours (40%) than in polypoid/large fungating tumours (23%, p = 0.048). The frequency of strong Nup88 expression was significantly different among tumours with good (21%), moderate (42%) and poor differentiation (48%, p = 0.01). Nup88 expression was not related to the patients' gender, age, tumour location, size, histological type, invasive depth, lymph node status and Dukes stage (p > 0.05). Conclusion: Our results suggest that Nup88 may play a role during the development, aggressiveness and differentiation of colorectal tumours. Copyright © 2007 S. Karger AG.

  • 286. Zhao, Zeng-Ren
    et al.
    Zhang, Zhi-Yong
    Cui, Dong-Sheng
    Jiang, Li
    Zhang, Hui-Jun
    Wang, Ming-Wei
    Sun, Xiao-Feng
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Particularly interesting new cysteine-histidine rich protein expression in colorectal adenocarcinomas2006In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 12, no 2, p. 298-301Article in journal (Refereed)
    Abstract [en]

    Aim: To study the relationship between particularly interesting new cysteine-histidine rich protein (PINCH) expression and clinicopathological factors in Chinese colorectal cancer patients. Methods: The expression of PINCH was examined by immumohistochemistry in 141 samples of primary colorectal adenocarcinoma and 92 normal samples of colorectal mucosa. Eighty of the cases had both primary tumour and normal mucosa from the same patients. Results: PINCH was expressed in the stroma of normal mucosa and tumours. PINCH expression in tumourassociated stroma was increased compared to normal mucosa in both unmatched cases (n = 141, X2 = 85.79, df = 3, P<0.0001) and matched cases (n = 80, X2 = 45.86, df = 3, P<0.0001). Among 135 tumours with visible invasive margin, 86 (64%) showed stronger PINCH expression at the invasive margin than in the intratumoural stroma. The frequency of PINCH strong expression in mucinous and signet-ring cell carcinomas was higher (52%) compared to non-mucinous carcinomas (29%, X2= 5.13, P= 0.02). We did not find that PINCH expression was related to patient's gender, age, tumour location, tumour size, gross status, histological type, differentiation, invasion depth, lymph node status and Dukes' stage (P>0.05). Conclusion: The expression of PINCH was upregulated in colorectal cancers, and especially at the margin of tumours, and further was related to mucinous and signet-ring cell carcinomas. The results suggest that expression of PINCH may be involved in the tumourigenesis and aggressiveness of colorectal cancers. © 2006 The WJG Press. All rights reserved.

  • 287.
    Zhao, Zeng-Ren
    et al.
    Department of General Surgery Hebei Medical University, Shijiazhuang 050031, P.R. China.
    Zhang, Zhiyong
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology .
    Zhang, Hong
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology .
    Jiang, Li
    Department of Pathology Tangshan Gongren Hospital, Tangshan 063000, P.R. China.
    Wang, Ming-Wei
    Laboratory Centre Hebei Medical University, Shijiazhuang 050031, P.R. China.
    Sun, Xiao-Feng
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Overexpression of Id-1 protein is a marker in colorectal cancer progression2008In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 19, no 2, p. 419-424Article in journal (Refereed)
    Abstract [en]

    The inhibitor of differentiation/DNA binding 1 (Id-1), a negative regulator of basic helix-loop-helix transcription factors, plays an important role in the regulation of cell proliferation and differentiation. We examined the Id-1 expression by immunohistochemistry in 9 adenomas, 79 primary colorectal adenocarcinomas matched with 40 adjacent normal mucosa specimens and its relationship with clinicopathological factors. The Id-1 expression was increased in the carcinoma compared to the adjacent normal mucosa either in the unmatched and matched samples or to the adenoma. There was no significant difference in the Id-1 expression between normal mucosa and adenoma. The Id-1 expression of carcinoma was increased from Dukes' stages A to B, to C and to D. The cases with lymph node metastasis had a higher rate of a stronger Id-1 expression than those without lymph node metastasis. In conclusion, Id-1 overexpression plays an important role in colorectal cancer progression.

  • 288.
    Zhou, X.
    et al.
    Sichuan University.
    Li, Y.
    Sichuan University.
    Ding, J.
    Sichuan University.
    Wang, L.
    Sichuan University.
    Wang, R.
    Sichuan University.
    Zhou, B.
    Sichuan University.
    Gu, J.
    Sichuan University.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Zhou, Z.
    Sichuan University.
    Down-regulation of tumor necrosis factor-associated factor 6 is associated with progression of acute pancreatitis complicating lung injury in mice2009In: Tohoku Journal of Experimental Medicine, ISSN 0040-8727, Vol. 217, no 4, p. 279-285Article in journal (Refereed)
    Abstract [en]

    Acute lung injury is one of the critical complications of acute pancreatitis (AP). Tumor necrosis factor-associated factor 6 (TRAF6) is a key adaptor that regulates various inflammatory signaling pathways, including those mediated by Toll-like receptors (TLRs). This study was performed to investigate the potential role of TRAF6 in the pathogenesis of AP and pancreatitis-associated acute lung injury using a mouse model of caerulein-induced AP (CAP). CAP was induced by intraperitoneal injection of caerulein hourly for 7 times (50 µg/kg), and control mice were treated with saline of the same volume. Typical pancreatic and lung inflammation was observed in the early stage (1 h) of CAP, as judged by morphological changes. Likewise, in CAP mice, the pancreatic myeloperoxidase activity and serum levels of interleukin-6 add interleukin-10 were significantly increased after 2 h, peaked it 4h, and then decreased by 24 h. The expression of TRAF6 was then studied by real time-PCR, immunohistochemistry, and Western blot analysis. Compared with control group, TRAF6 mRNA level was decreased in CAP group within the first 12 h, and then significantly increased after 24 h, which was in accordance with the protein level detected by Western blot analysis and immunohistochemistry. Moreover, TRAF6 protein was expressed in both pancreatic acinar cells and lung bronchial epithelial cells. In conclusion, the down-regulation of TRAF6 was associated with increased inflammatory severity in the pancreas and lung, suggesting that TRAF6 is involved in the anti-inflammatory process during AP. TRAF6 may be a potential molecular target for treating AP.

  • 289.
    Zhou, Xiang-Yu
    et al.
    Sichuan University.
    Zhou, Zong-Guang
    Sichuan University.
    Ding, Jun-Li
    Sichuan University.
    Wang, Ling
    Sichuan University.
    Wang, Rong
    Sichuan University.
    Zhou, Bing
    Sichuan University.
    Gu, Jun
    Sichuan University.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Li, Yuan
    Sichuan University.
    TRAF6 as the Key Adaptor of TLR4 Signaling Pathway Is Involved in Acute Pancreatitis2010In: PANCREAS, ISSN 0885-3177, Vol. 39, no 3, p. 359-366Article in journal (Refereed)
    Abstract [en]

    Objectives: To study the potential role of tumor necrosis factor receptor-associated factor 6 (TRAF6) as the key adaptor of the toll-like receptor 4 (TLR4) signaling pathway in acute pancreatitis (AP) in mice. Methods: Acute pancreatitis was induced by 7 intraperitoneal injections of cerulein in TLR4-deficient (TLR4-Def) and TLR4 wild-type (TLR4-WT) mice. Inflammatory severity was scored and evaluated based on pathological study. TRAF6 expression was determined by reverse transcriptase polymerase chain reaction, Western blot, and immunohistochemistry. Results: Acute pancreatitis was successfully induced in both mice strains, but the inflammatory progression was different. In TLR4-Def mice, pancreatic inflammation was blunt and mild first, then became increasingly intensive and peaked at the later stage, whereas in the TLR4-WT mice, the response was fast initiated and peaked at the early stage of AP, then alleviated gradually. TRAF6 expression in TLR4-Def mice was significantly higher than that in the TLR4-WT mice. Immunohistochemistry located TRAF6 expressed mainly in the pancreatic acinar cells. Conclusions: The TLR4-TRAF6 signaling pathway is critically involved in AP. Other signaling pathways beyond TLR4 may participate in the pancreatic inflammatory process via TRAF6. As a convergence point of the TLR4-dependent and the TLR4-independent signaling pathways, TRAF6 plays an important role in AP.

  • 290. Zhou, Xiao-Lei
    et al.
    Eriksson, Ulrika
    Werelius, Barbro
    Kressner, Ulf
    Sun, Xiao-Feng
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Lindblom, Annika
    Definition of candidate low risk APC alleles in a Swedish population2004In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 110, no 4, p. 550-557Article in journal (Refereed)
    Abstract [en]

    Many families experience an apparently inherited increased risk of colorectal cancer (CRC) similar to the known syndromes familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). Besides these high-risk syndromes, approximately 10% of all CRC cases come from families with 2 affected 1st-degree relatives, and even 1st-degree relatives to a single case of CRC are at increased risk. Risk subjects from these families frequently show polyps at colonoscopy, which suggests the APC gene as a good candidate susceptibility gene for these attenuated polypotic syndromes. We used the sensitive DHPLC technique to search for possible predisposing germline mutations in the entire APC gene in 91 risk subjects from these high- and low-risk syndromes with unknown predisposing genes. Most exons were also screened for mutations in 96 normal controls and 96 colorectal cancer cases. In our study we probably have identified the most common APC variants in a Swedish population. Among 30 germline variants identified, 1 clearly pathogenic nonsense mutation and 11 putative pathogenic variants (10 missense and one 3′ UTR) were found in 20 index patients (22%). Twelve silent as well as 5 intronic variants were considered nonpathogenic. Two of the missense variants found here, E1317Q and D1822V, have previously been related to a difference in risk of colorectal cancer. One variant, 8636C>A, located within the 3′ UTR region of the APC gene, was suggested to constitute an additional low risk allele with a similar relative risk as the Jewish 11307K mutation (OR = 1.8, 9S% CI, 0.96-3.40). The question of whether all the other variants confer an increased colorectal cancer risk warrants future large association studies. © 2004 Wiley-Liss, Inc.

  • 291.
    Zhou, X.-L.
    et al.
    Department of Molecular Medicine, Karolinska Institutet, S-171 76 Stockholm, Sweden.
    Djureinovic, T.
    Department of Molecular Medicine, Karolinska Institutet, S-171 76 Stockholm, Sweden.
    Werelius, B.
    Department of Molecular Medicine, Karolinska Institutet, S-171 76 Stockholm, Sweden.
    Lindmark, G.
    Department of Surgery, Helsingsborg Hospital, S-251 87 Helsingborg, Sweden.
    Sun, Xiao-Feng
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Lindblom, A.
    Department of Molecular Medicine, Karolinska Institutet, S-171 76 Stockholm, Sweden, Department of Molecular Medicine, CMM L8:02, Karolinska Institutet, S-171 76 Stockholm, Sweden.
    Germline mutations in the MYH gene in Swedish familial and sporadic colorectal cancer2005In: Genetic Testing, ISSN 1090-6576, E-ISSN 1557-7473, Vol. 9, no 2, p. 147-151Article in journal (Refereed)
    Abstract [en]

    Biallelic germline mutations in the base excision repair gene MYH have been shown to predispose to a proportion of multiple colorectal adenomas and cancer. To evaluate the contribution of MYH mutations to non-FAP, non-HNPCC familial colorectal cancer, 84 unrelated Swedish individuals affected with colorectal cancer from such families were screened for germline mutations in the coding sequence of the gene. None of the cases was found to carry any pathogenic sequence change. We then determined the prevalence of the two most common pathogenic MYH mutations found in Caucasians, Y165C and G382D, in 450 Swedish sporadic colorectal cancer cases and 480 Swedish healthy controls. The frequency of both variants in Swedish cases and controls was similar to those previously reported. In addition, we found that previously unknown sequence variations at the position of amino acid 423 (R423Q, R423P, and R423R) appear to occur more frequently in cases than in controls (p = 0.02), a finding that warrants future studies. © Mary Ann Liebert, Inc.

  • 292.
    Zhu, Zhenlong
    et al.
    Department of Pathology, The First Hospital of Hebei Medical University, China.
    Yang, Yanhong
    Department of Pathology, The First Hospital of Hebei Medical University, China.
    Zhang, Yu
    Clinical College, Hebei Medical University, China.
    Wang, Zhengmin
    Department of Pathology, The First Hospital of Hebei Medical University, China.
    Cui, Dongsheng
    Central Laboratory, The First Hospital of Hebei Medical University, China.
    Zhang, Jinting
    Central Laboratory, The First Hospital of Hebei Medical University, China.
    Wang, Mingwei
    Central Laboratory, The First Hospital of Hebei Medical University, China.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    PINCH expression and its significance in esophageal squamous cell carcinoma2008In: Disease Markers, ISSN 0278-0240, E-ISSN 1875-8630, Vol. 25, no 2, p. 75-80Article in journal (Refereed)
    Abstract [en]

    Particularly interesting new cysteine-histidine rich protein (PINCH), as a newly discovered protein of LIM family members, may play a role in signal transduction of integrin and growth factor, and involved in the incidence and development of tumors. PINCH protein is overexpressed in tumor-associated stroma of several types of tumors. However, there is no study of the PINCH in esophageal cancer, therefore we investigated PINCH expression in esophageal squamous cell carcinomas and its clinicopathogical significance in the patients. PINCH expression was immunohistochemically examined in 20 normal esophageal samples and 64 esophageal squamous cell carcinomas. The results showed that PINCH expression in the stroma of cancers was heterogeneous, and its positive rate (56%) was higher than that of normal esophageal mucosa (5%, p<0.0001). The stronger staining was observed at the invasive edge of tumor when compared to the inner area of tumor. The rate of positive PINCH (90%) in the cases with lymph node metastasis was higher than that (41%) in the cases without metastasis (p<0.0001). PINCH expression was not correlated with patients’ gender, age, tumor location, size and differentiation (p>0.05). The results suggest that PINCH protein may be a marker of tumor associated-stroma involving tumor development, and predicting the ability of invasion and metastasis of esophageal squamous cell carcinoma.

  • 293.
    Zhu, Zhen-Long
    et al.
    Hebei Medical University.
    Zhao, Zeng-Ren
    Hebei Medical University.
    Zhang, Yu
    Hebei Medical University.
    Yang, Yan-Hong
    Hebei Medical University.
    Wang, Zheng-Min
    Hebei Medical University.
    Cui, Dong-Sheng
    Hebei Medical University.
    Wang, Ming-Wei
    Hebei Medical University.
    Kleeff, Joerg
    Technical University of Munich.
    Kayed, Hany
    University of Heidelberg.
    Yan, Bao-Yong
    Hebei Medical University.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Expression and significance of FXYD-3 protein in gastric adenocarcinoma2010In: DISEASE MARKERS, ISSN 0278-0240, Vol. 28, no 2, p. 63-69Article in journal (Refereed)
    Abstract [en]

    Objective: FXYD-3, also known as Mat-8, is a member of the FXYD protein family. It was reported that this protein can associate with and modify the transport properties of Na, K-ATPase, and may play an important role in a variety of physiological and pathological states. This protein is up-regulated in certain types of cancers (such as breast, prostate and pancreatic cancer), but down-regulated in other types of cancers (such as colon and kidney cancer). No study has been performed in gastric cancer; therefore, the aim of this project was to investigate FXYD-3 expression and its clinicopathological significance in gastric adenocarcinoma. Patients and methods: FXYD-3 protein was examined by immunohistochemistry in normal gastric mucous (n = 29) and gastric adenocarcinoma (n = 51), obtained from surgical resection of gastric cancer patients. Results: FXYD-3 protein was present in the cytoplasm of normal gastric epithelial cells or gastric cancer cells. The rate of FXYD-3 strong expression was significantly higher in cancer (51% of 51) than in normal mucosa (10% of 29, X-2=13.210, p andlt; 0.0001). FXYD-3 expressed strongly in ulcerative/infiltrating types of cancers compared to polypoid/fungating ones (X-2 = 5.765, p = 0.016). However, FXYD-3 expression was not correlated with patients gender, age, tumor size, lymph node status and histological grade (p andgt; 0.05). Conclosion: Up-regulated expression of FXYD-3 protein may be involved in tumourgenesis and invasion of gastric adenocarcinoma.

  • 294.
    Zwierzina, Heinz
    et al.
    Med University Klinik.
    Bardelli, Alberto
    Institute Canc Research and Treatment, Turin, Italy .
    Ciardiello, Fortunato
    University of Naples.
    Gariboldi, Manuela
    IRCCS Ist Nazl Tumori.
    Hakansson, Leif
    Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Lambrechts, Diether
    VRC, Belgium .
    Lind, Guro E
    Norwegian Radium Hospital.
    Loeffler-Ragg, Judith
    Med University Klin, Innsbruck, Austria .
    Schmoll, Hans
    University Clin Halle.
    Siena, Salvatore
    Osped Niguarda Ca Granda.
    Tabernero, Josep
    P Vall Hebron University Hospital.
    Van Cutsem, Eric
    University Hospital Gasthuisberg.
    Molecularly targeted therapies for colorectal cancer: Strategies for implementing translational research in clinical trials2010In: CURRENT OPINION IN MOLECULAR THERAPEUTICS, ISSN 1464-8431, Vol. 12, no 6, p. 703-711Article, review/survey (Refereed)
    Abstract [en]

    Few breakthroughs in preclinical research have translated into meaningful benefits, either in clinical terms or quality of life, for patients with advanced colorectal cancer, despite important preclinical discoveries regarding aberrant biological pathways associated with disease development and progression. The many reasons for the slow progress are diverse, ranging from the failure to codevelop biomarkers and targeted therapies, the regulatory burdens imposed on academic investigators, and the failure to collect serial tumor biopsies during clinical trials. This review discusses promising translational research that could help reduce the disparity between preclinical discovery and patient benefit, and advocate the concentration of efforts and resources on the most promising therapeutic targets in colorectal cancer, such as EGFR, VEGF and Fc gamma receptor.

  • 295.
    Åstradsson, Eva
    et al.
    Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Granath, Lena
    Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Heedman, Per-Anders
    Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Starkhammar, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Cancer patients hospitalised for palliative reasons. Symptoms and needs presented at a University Hospital2001In: Supportive Care in Cancer, ISSN 0941-4355, E-ISSN 1433-7339, Vol. 9, no 2, p. 97-102Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to identify patients in need of palliative care in 11 different care units with a total of 256 beds at Link÷ping University Hospital and to look at their overall situation with respect to assessed symptom control and quality of life. There were 46 patients fulfilling the two criteria of incurable cancer and need for palliative care, and each was assessed with the aid of a questionnaire (five oral questions on life situation) and a single visual analogue scale (VAS) about their overall quality of life (QoL). Each patient also assessed him- or herself on the Edmonton Symptom Assessment Scale (ESAS). Total ESAS scores ranged from 20 to 639 mm (median 211). Median VAS scores (100 mm = greatest symptom severity) were as follows: nausea 6 mm, pain 9 mm, anxiety 17 mm, depression 18 mm, drowsiness 35 mm, activity 38 mm, appetite 45 mm, and sensation of well-being 46 mm. The median score for QoL was 47 and correlated well with the total ESAS score. Thirty-seven patients answered the open question "What in your current situation troubles you the most?". Seven patients answered "nothing", and 10 said "the present symptoms". Twenty patients had different concerns (existential, social, and psychological). The low number of hospitalised patients found reflects a well-functioning hospital-based home-care unit. Reduced appetite, sensation of well-being and activity were dominant, while pain and nausea were less intense. The simple QoL-VAS seemed to be comparable to ESAS, which is more useful for assessing each single symptom. The non-physical dimensions need more attention in the future in order to achieve totally satisfactory palliative care.

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