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Sökning: WFRF:(Georgii Hemming P)

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1.
  • Tzortzatos, G., et al. (författare)
  • The gynecological surveillance of women with Lynch Syndrome in Sweden
  • 2015
  • Ingår i: Gynecologic Oncology. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0090-8258 .- 1095-6859. ; 138:3, s. 717-722
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective. Women with Lynch syndrome (LS) have up to a 60% lifetime risk of endometrial cancer (EC) and up to a 24% risk of ovarian cancer (OC). Gynecological surveillance is recommended, but the benefit and how it should be performed remain unclear. The purpose of this study was to assess diagnostic modalities for gynecological screening of LS patients in Sweden and clinical outcome. Methods. A retrospective nationwide study of 170 women with molecularly confirmed LS. Data including gynecological LS screening history, biopsy results (if any), genetic records, number of screening visits, results from screening including transvaginal ultrasound (TVUS), endometrial biopsy (EB), blood test for tumor marker cancer antigen (CA) 125, prophylactic surgery including age at procedure, and setting from which screening data were obtained from medical records. Results. A total of 117 women were eligible for gynecological screening and of these, 86 patients attended screening visits. Of these, 41 underwent prophylactic hysterectomy and/or bilateral salpingo-oophorectomy. Two patients (4.9%) were diagnosed with EC and two (4.9%) with precancerous lesions in conjunction with prophylactic surgery. Total incidence of gynecological cancer in the surveillance group (45 women) was 20% EC, 4% OC. Five patients had endometrial cancer or complex hyperplasia with atypia (n = 2) detected by endometrial biopsy. Four additional cases were detected due to interval bleeding. Both cases of ovarian cancer were detected by transvaginal ultrasound in patients with ovarian cysts under surveillance. The youngest woman with endometrial cancer was diagnosed at 35 years of age, before she was aware of her diagnosis of Lynch syndrome. Conclusions. Gynecological surveillance of women with Lynch syndrome may lead to earlier detection of precancerous lesions, which might have some impact on the morbidity from endometrial cancer although further studies are needed to prove this. Prophylactic hysterectomy with or without bilateral salpingo-oophorectomy reduces the cancer incidence. A practical approach to surveillance in Lynch syndrome women would be to offer annual surveillance beginning at age 30 years including probably both TVUS and EB in order to increase diagnostic yield with prospective data registry for follow-up studies. Prophylactic surgery could be performed at a suitable age after childbearing to obtain a balance between reducing the risk of cancer and minimizing long-term complications from premature menopause.
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  • Caramuta, S., et al. (författare)
  • Role of microRNAs and microRNA machinery in the pathogenesis of diffuse large B-cell lymphoma
  • 2013
  • Ingår i: Blood Cancer Journal. - 2044-5385 .- 2044-5385. ; 3, s. e152-
  • Tidskriftsartikel (refereegranskat)abstract
    • Deregulation of microRNA (miRNA) expression has been documented in diffuse large B-cell lymphoma (DLBCL). However, the impact of miRNAs and their machinery in DLBCL is not fully determined. Here, we assessed the role of miRNA expression and their processing genes in DLBCL development. Using microarray and RT-qPCR approaches, we quantified global miRNAs and core components of miRNA-processing genes expression in 75 DLBCLs (56 de novo and 19 transformed) and 10 lymph nodes (LN). Differential miRNA signatures were identified between DLBCLs and LNs, or between the de novo and transformed DLBCLs. We also identified subsets of miRNAs associated with germinal center B-cell phenotype, BCL6 and IRF4 expression, and clinical staging. In addition, we showed a significant over-expression of TARBP2 in de novo DLBCLs as compared with LNs, and decreased expression of DROSHA, DICER, TARBP2 and PACT in transformed as compared with de novo cases. Interestingly, cases with high TARBP2 and DROSHA expression had a poorer chemotherapy response. We further showed that TARBP2 can regulate miRNA-processing efficiency in DLBCLs, and its expression inhibition decreases cell growth and increases apoptosis in DLBCL cell lines. Our findings provide new insights for the understanding of miRNAs and its machinery in DLBCL.
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  • Lindstrand, Anna, et al. (författare)
  • From cytogenetics to cytogenomics : whole-genome sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability
  • 2019
  • Ingår i: ; 11:1
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundSince different types of genetic variants, from single nucleotide variants (SNVs) to large chromosomal rearrangements, underlie intellectual disability, we evaluated the use of whole-genome sequencing (WGS) rather than chromosomal microarray analysis (CMA) as a first-line genetic diagnostic test.MethodsWe analyzed three cohorts with short-read WGS: (i) a retrospective cohort with validated copy number variants (CNVs) (cohort 1, n=68), (ii) individuals referred for monogenic multi-gene panels (cohort 2, n=156), and (iii) 100 prospective, consecutive cases referred to our center for CMA (cohort 3). Bioinformatic tools developed include FindSV, SVDB, Rhocall, Rhoviz, and vcf2cytosure.ResultsFirst, we validated our structural variant (SV)-calling pipeline on cohort 1, consisting of three trisomies and 79 deletions and duplications with a median size of 850kb (min 500bp, max 155Mb). All variants were detected. Second, we utilized the same pipeline in cohort 2 and analyzed with monogenic WGS panels, increasing the diagnostic yield to 8%. Next, cohort 3 was analyzed by both CMA and WGS. The WGS data was processed for large (>10kb) SVs genome-wide and for exonic SVs and SNVs in a panel of 887 genes linked to intellectual disability as well as genes matched to patient-specific Human Phenotype Ontology (HPO) phenotypes. This yielded a total of 25 pathogenic variants (SNVs or SVs), of which 12 were detected by CMA as well. We also applied short tandem repeat (STR) expansion detection and discovered one pathologic expansion in ATXN7. Finally, a case of Prader-Willi syndrome with uniparental disomy (UPD) was validated in the WGS data.Important positional information was obtained in all cohorts. Remarkably, 7% of the analyzed cases harbored complex structural variants, as exemplified by a ring chromosome and two duplications found to be an insertional translocation and part of a cryptic unbalanced translocation, respectively.ConclusionThe overall diagnostic rate of 27% was more than doubled compared to clinical microarray (12%). Using WGS, we detected a wide range of SVs with high accuracy. Since the WGS data also allowed for analysis of SNVs, UPD, and STRs, it represents a powerful comprehensive genetic test in a clinical diagnostic laboratory setting.
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5.
  • Strömberg, Thomas, et al. (författare)
  • Picropodophyllin inhibits proliferation and survival of diffuse large B-cell lymphoma cells
  • 2015
  • Ingår i: Medical Oncology. - 1357-0560 .- 1559-131X. ; 32:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults. Although chemotherapy in combination with anti-CD20 antibodies results in a cure rate of 60-70 %, novel treatment approaches are warranted for the remaining patients. The insulin-like growth factor-1 receptor (IGF-1R) and its principal ligands IGF-1 and IGF-2 have been suggested to play pivotal roles in different cancers. However, in DLBCL the importance of this system is less well understood. To assess whether interference with IGF-1R-mediated signaling may represent a therapeutic option for this malignancy, we used a panel of eight DLBCL cell lines together with primary tumor cells derived from lymph nodes in four DLBCL patients. The cells were treated with the cyclolignan picropodophyllin (PPP), a small molecule compound initially described to selectively inhibit the IGF-1R. PPP dose-dependently inhibited proliferation/survival in all cell lines and primary cell preparations. In parallel experiments, the IGF-1R inhibitor NVP-AEW541 and the microtubule-destabilizing compounds podophyllotoxin (PPT) and colchicine were demonstrated to also inhibit growth of the cell lines. Linear regression analysis showed that the responses of the cell lines to PPP correlated with their responses to the microtubule inhibitors PPT and colchicine, but not with the response to NVP-AEW541 or the expression level of surface IGF-1R. Analysis of cell cycle phase distribution revealed that treatment with PPP for only 1 h induced a clear accumulation of cells in the G2/M-phase with a corresponding depletion of the G0/G1-phase. Interestingly, these cell cycle effects could be closely mimicked by using PPT or colchicine. Treatment with PPP led to increased apoptotic cell death in the SU-DHL-6 and U-2932 cell lines, whereas the DB and U-2940 did not undergo apoptosis. However, the DB cells were still killed by PPP, suggesting another mode of cell death for this cell line. The U-2940 cells responded to PPP mainly by inhibition of proliferation. Pretreatment of U-2932 or U-2940 cell lines with PPP at biologically active concentrations did not prevent ligand-induced phosphorylation of IGF-1R at Tyr1131/1136 or its downstream targets AKT and ERK1/2. In contrast, the IGF-1R inhibitor NVP-AEW541 clearly inhibited phosphorylation of IGF-1R and AKT, while ERK1/2 phosphorylation was less affected. Taken together, the inhibitory effects of PPP in DLBCL cells together with its low toxicity in vivo makes it a promising drug candidate in the treatment of this disease. However, we suggest that the primary target of PPP in these cells is not related to inhibition of IGF-1R phosphorylation.
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  • Akyürek, L M, et al. (författare)
  • Tolerance induction ameliorates allograft vasculopathy in rat aortic transplants. Influence of Fas-mediated apoptosis.
  • 1998
  • Ingår i: The Journal of clinical investigation. - 0021-9738. ; 101:12, s. 2889-99
  • Tidskriftsartikel (refereegranskat)abstract
    • Based on successful induction of donor-specific unresponsiveness by alloantigenic stimulation in several animal models of acute rejection, we hypothesized that similar immune manipulations would also inhibit the evolution of chronic rejection and transplant vasculopathy. To induce immune tolerance, DA rats received a PVG heart allograft and were immunosuppressed with cyclosporine for 30 d. At day 100 the animals were challenged with a PVG aortic allograft after either 1 or 18 h of cold ischemia. 8 wk after the aortic transplantation, the grafts were investigated for morphological changes, infiltrating cells, apoptosis, and Fas-Fas ligand expression. Control allografts showed advanced transplant arteriosclerosis, whereas tolerance-induced aortic allografts displayed reduced neointimal formation, less medial atrophy, fewer apoptotic cells, and fewer Fas- and FasL-expressing cells. Prolonged ischemic storage time did not profoundly alter the morphological changes of the allografts. Fas expression was found in T cells, macrophages, vascular smooth muscle cells, and endothelial cells, whereas FasL was expressed mainly by T cells and macrophages. FasL mRNA expression was evident throughout the entire allograft wall. In conclusion, induction of allospecific tolerance can effectively prevent transplant arteriosclerosis. Cold ischemia damage does not abrogate the beneficial effect of tolerance, but creates a separate identity of mainly endothelial lesions. Furthermore, Fas-mediated apoptosis appears to be involved in the pathological lesions seen in chronic rejection.
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  • Chalk, AM, et al. (författare)
  • siRNAdb: a database of siRNA sequences
  • 2005
  • Ingår i: Nucleic acids research. - 1362-4962. ; 33:Database issue, s. D131-D134
  • Tidskriftsartikel (refereegranskat)
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