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Find video protocols related to scientific articles indexed in Pubmed.
New foe treated with old guns ¿ supportive role of steroids in the treatment of acute severe hepatitis E.
BMC Gastroenterol
PUBLISHED: 05-15-2014
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BackgroundAutochthonous hepatitis E has been observed with growing incidence in industrialized countries. Hepatitis E virus infection causes an acute hepatitis with spontaneous resolution in the majority of cases. However, in individual cases, hepatitis E may lead to life-threatening acute liver failure. In this report, we describe a case of acute liver injury caused by an autochthonous hepatitis E that resolved under steroid treatment. To our knowledge, this is the first case report describing supportive steroid monotherapy for acute liver injury due to hepatitis E.Case presentationA 63-year-old Caucasian male presented with acute liver injury of unknown origin. After excluding the most prevalent causes of acute liver injury, liver histology revealed signs of immune-mediated toxic or drug-induced liver injury. Therefore, immunosuppressive treatment with prednisolone was started. After initialization of steroid treatment, polymerase chain reaction analyses of peripheral blood and liver tissue revealed an acute hepatitis E virus infection (genotype 3). Under sustained steroid treatment, acute liver injury improved and hepatitis E infection resolved.ConclusionSteroid treatment might be an option to prevent progress of life-threatening liver failure and liver transplantation in patients with hepatitis E-induced acute liver injury and high-grade inflammation.
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Cyclin D1 gene amplification is highly homogeneous in breast cancer.
Breast Cancer
PUBLISHED: 05-09-2014
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Cyclin D1 (CCND1) gene amplification is a molecular key alteration in breast cancer and was suggested to predict resistance to antihormonal therapy. As tissue heterogeneity may affect diagnostic accuracy of predictive biomarkers, CCND1 genetic heterogeneity was assessed in this study. A novel tissue microarray (TMA) platform was manufactured for this purpose.
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Clinical significance of different types of p53 gene alteration in surgically treated prostate cancer.
Int. J. Cancer
PUBLISHED: 04-26-2014
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Despite a multitude of p53 immunohistochemistry (IHC) studies, data on the combined effect of nuclear p53 protein accumulation and TP53 genomic inactivation are lacking for prostate cancer. A tissue microarray including 11,152 prostate cancer samples was analyzed by p53 IHC and fluorescence in situ hybridization. Nuclear p53 accumulation was found in 10.1% of patients including 1.4% with high-level and 8.7% with low-level immunostaining. TP53 sequencing revealed that 17 of 22 (77%) cases with high-level p53 immunostaining, but only 3% (1 of 31) low-level p53 cases carried putative dominant-negative mutations. TP53 deletions occurred in 14.8% of cancers. Both deletions and protein accumulation were linked to unfavorable tumor phenotype and prostate specific antigen (PSA) recurrence (p<0.0001 each). The combination of both methods revealed subgroups with remarkable differences in their clinical course. Tumors with either TP53 deletion (14%) or low-level p53 positivity (8.7%) had identical risks of PSA recurrence, which were markedly higher than in cancers without p53 alterations (p<0.0001). Tumors with both p53 deletion and low-level p53 positivity (1.5%) had a worse prognosis than patients with only one of these alterations (p<0.0001). Tumors with strong p53 immunostaining or homozygous inactivation through deletion of one allele and disrupting translocation involving the second allele had the worst outcome, independent from clinical and pathological parameters. These data demonstrate a differential clinical impact of various TP53 alterations in prostate cancer. Strong p53 immunostaining-most likely accompanying dominant negative or oncogenic p53 mutation-has independent prognostic relevance and may thus represent a clinical useful molecular feature of prostate cancer.
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Frequency of TERT promoter mutations in primary tumors of the liver.
Virchows Arch.
PUBLISHED: 03-04-2014
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Transcriptional regulation of the TERT gene is a major cause of the cancer-specific increase in telomerase activity. Recently, frequent somatic mutations in the TERT promoter have been described in several tumor entities such as melanoma, glioblastoma, bladder cancer, and hepatocellular carcinoma. By generating a putative consensus binding site for ETS transcription factors within the TERT promoter, these mutations are predicted to increase promoter activity and TERT transcription. In order to improve the understanding of the role of TERT promoter mutation in liver tumorigenesis, the mutational status of the TERT promoter was analyzed in 78 hepatocellular carcinomas, 15 hepatocellular adenomas, and 52 intrahepatic cholangiocarciomas. The promoter region of TERT was screened for the two hotspot mutations using PCR and restriction fragment length analysis, utilizing the introduction of novel restriction sites by the somatic mutations. TERT promoter mutation was found in 37 of 78 hepatocellular carcinomas (47 %) and was restricted to the -124C>T mutation. Frequency of mutations was associated with grade of differentiation ranging from 39 % in well-differentiated tumors to 73 % in high-grade hepatocellular carcinomas. TERT promoter mutations were not found in 15 hepatocellular adenomas and 52 intrahepatic cholangiocarcinomas. These data show that TERT promoter mutation is the most frequent genetic alteration in hepatocellular carcinoma known at this time. The striking predominance of the -124C>T mutation compared with other tumor entities suggest a biological difference of the two hotspot mutations. Analysis of TERT promoter mutation might become a diagnostic tool distinguishing hepatocellular adenoma from well-differentiated hepatocellular carcinoma.
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The prognostic impact of high Nijmegen breakage syndrome (NBS1) gene expression in ERG-negative prostate cancers lacking PTEN deletion is driven by KPNA2 expression.
Int. J. Cancer
PUBLISHED: 01-16-2014
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The Nijmegen breakage syndrome (NBS1) gene was suggested as a prostate cancer susceptibility gene. This study was undertaken to determine, whether NBS1 expression is linked to clinically or molecularly relevant subgroups of prostate cancer. NBS1 expression was analyzed by immunohistochemistry on a tissue microarray containing 11,152 prostate cancer specimens. NBS1 expression was absent or only weakly detectable in benign prostate. In prostate cancers, NBS1 expression was found in 81.3% of interpretable tumors and was considered strong in 41.3% of cases. NBS1 upregulation was tightly linked to ERG-positive cancers (p<0.0001). Within ERG-negative cancers, strong NBS1 immunostaining was linked to advanced pathological tumor stage, high Gleason grade, and positive nodal status (p<0.0001 each), while high NBS1 immunostaining was only weakly associated with advanced pathological tumor stage in ERG-positive cancers (p=0.0099). A comparison with chromosomal deletions revealed a strong NBS1 upregulation in PTEN-deleted cancers, while deletions of 3p13, 5q21 and 6q15 did not affect NBS1 expression. High NBS1 expression was linked to biochemical recurrence in ERG-negative and PTEN non-deleted cancers (p<0.0001), which was largely driven by high KPNA2 karyopherin alpha 2 expression. In conclusion, our study identifies an association of NBS1 expression with surrogates of genomic instability in prostate cancer including TMPRSS2-ERG rearrangements and PTEN deletion. The prognostic impact of NBS1 expression in ERG-negative, PTEN non-deleted cancers was dependent of the expression status of its interaction partner KPNA2.
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NY-ESO-1 expression is tightly linked to TMPRSS2-ERG fusion in prostate cancer.
Prostate
PUBLISHED: 01-15-2014
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NY-ESO-1 has been suggested as therapeutic cancer vaccine in prostate cancer. This study was undertaken to explore the relationship of NY-ESO-1 with tumor phenotype, biochemical recurrence, and molecular subgroups in hormone-naive prostate cancers.
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Reduced FOXP3(+) regulatory T cells in patients with primary sclerosing cholangitis are associated with IL2RA gene polymorphisms.
J. Hepatol.
PUBLISHED: 01-08-2014
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Recently, genome wide association studies in primary sclerosing cholangitis (PSC) revealed associations with gene polymorphisms that potentially could affect the function of regulatory T cells (Treg). The aim of this study was to investigate Treg in patients with PSC and to associate their numbers with relevant gene polymorphisms.
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Glomangioma of the lung: a case report and review of the literature.
J Med Case Rep
PUBLISHED: 01-03-2014
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Glomangiomas are rare soft tissue tumors originating from the perivascular tissue. The most common localization is in the dermis of the extremities, with a few reports of respiratory tract involvement.
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High mitochondria content is associated with prostate cancer disease progression.
Mol. Cancer
PUBLISHED: 08-27-2013
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Mitochondria are suggested to be important organelles for cancer initiation and promotion. This study was designed to evaluate the prognostic value of MTC02, a marker for mitochondrial content, in prostate cancer.
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?III-Tubulin Overexpression Is an Independent Predictor of Prostate Cancer Progression Tightly Linked to ERG Fusion Status and PTEN Deletion.
Am. J. Pathol.
PUBLISHED: 06-17-2013
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Evidence suggests that class III ?-tubulin (?III-tubulin) may represent a prognostic and predictive molecular marker in prostate cancer. ?III-Tubulin expression was determined by IHC in 8179 prostate cancer specimens in a TMA format. Results were compared with tumor phenotype, biochemical recurrence, electroretinographic (ERG) status, and deletions on PTEN, 3p13, 5q21, and 6q15. ?III-Tubulin expression was detectable in 25.6% of 8179 interpretable cancers. High ?III-tubulin expression was strongly associated with both TMPRSS2:ERG rearrangement and ERG expression (P < 0.0001 each). High ?III-tubulin expression was tightly linked to high Gleason grade, advanced pT stage, and early prostate-specific antigen (PSA) recurrence in all cancers (P < 0.0001 each), but also in the subgroups of ERG-negative and ERG-positive cancers. When all tumors were analyzed, the prognostic role of ?III-tubulin expression was independent of Gleason grade, pT stage, pN stage, surgical margin status, and preoperative PSA. Independent prognostic value became even more evident if the analysis was limited to preoperatively available features, such as biopsy specimen Gleason grade, preoperative PSA, cT stage, and ?III-tubulin expression (P < 0.0001 each). ?III-Tubulin expression was associated with PTEN (P < 0.0001) when all tumors were analyzed, but also in the subgroups of ERG-negative and ERG-positive cancers. ?III-Tubulin expression is an independent prognostic parameter. The significant associations with key genomic alterations of prostate cancer, such as TMPRSS2:ERG fusions and PTEN deletions, suggest interactions with several pivotal pathways involved in prostate cancer.
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Lymphatic invasion predicts survival in patients with early node-negative non-small cell lung cancer.
J. Thorac. Cardiovasc. Surg.
PUBLISHED: 04-14-2013
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The aim of this study was to assess the influence of lymphatic and vascular invasion on overall survival in patients with surgically resected non-small cell lung cancer (NSCLC) without lymph node and distant metastases.
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Increased T helper type 17 response to pathogen stimulation in patients with primary sclerosing cholangitis.
Hepatology
PUBLISHED: 04-04-2013
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T helper (Th)17 cells are important for host defense against bacteria and fungi, but are also involved in the pathogenesis of autoimmune diseases. In primary sclerosing cholangitis (PSC), bile fluid is frequently colonized with pathogens and its strong association with inflammatory bowel disease suggests the contribution of pathogen responses to disease pathogenesis. Interleukin (IL)-17A, the signature cytokine of Th17 cells, was recently described to promote inflammation and fibrosis within the liver. Therefore, we investigated Th17 immune response to pathogens in patients with PSC. Bile fluid was obtained by endoscopic retrograde cholangiography, and bacterial and fungal species grew in the majority of samples. In addition, bacterial RNA was stained in liver sections using 16sRNA fluorescence in situ hybridization and was detected in the portal tracts in 12 of 13 tested PSC patients. Bacteria grown from patients bile fluid were then used to stimulate peripheral blood mononuclear cells (PBMCs) and to assess their Th17 response. Compared to healthy controls or primary biliary cirrhosis patients, PBMCs from PSC patients manifested significantly higher frequencies of Th17 and Th1/Th17 cells after pathogen stimulation. The highest frequencies of Th17 cells were detected after stimulation with Candida albicans, a pathogen that has been linked to disease progression. Immunohistochemically, IL-17A-expressing lymphocytes were detected within the periductal areas of PSC patients. Th17 induction was also noted after stimulation of Toll-like receptor 5 or 7, but not of other pattern recognition receptors tested, pointing to signaling pathways potentially involved in Th17 induction in PSC. Conclusion: We demonstrate an increased Th17 response to microbial stimulation in patients with PSC. These data should prompt further studies investigating the link between pathogen responses, inflammation, and fibrosis in patients with PSC.
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MALDI imaging on large-scale tissue microarrays identifies molecular features associated with tumour phenotype in oesophageal cancer.
Histopathology
PUBLISHED: 03-04-2013
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Matrix-assisted laser desorption/ionisation mass spectrometry imaging (MALDI-MSI) and tissue microarray (TMA) technologies were jointly utilized to search for molecular features associated with clinicopathological parameters in oesophageal cancer.
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A novel flexible cryoprobe for EUS-guided pancreatic biopsies.
Gastrointest. Endosc.
PUBLISHED: 02-27-2013
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EUS-guided FNA (EUS-FNA) is an established technique for the cytologic diagnosis of pancreatic disease. Attempts to obtain adequate histologic specimens have yielded variable and mostly insufficient results.
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Effect of isoflavone soy protein supplementation on endometrial thickness, hyperplasia, and endometrial cancer risk in postmenopausal women: a randomized controlled trial.
Menopause
PUBLISHED: 02-21-2013
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This study aims to determine whether long-term isoflavone soy protein (ISP) supplementation affects endometrial thickness and rates of endometrial hyperplasia and cancer in postmenopausal women.
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Infiltration of peritumoural but tumour-free parenchyma with IgG4-positive plasma cells in hilar cholangiocarcinoma and pancreatic adenocarcinoma.
Dig Liver Dis
PUBLISHED: 02-18-2013
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Recently, new guidelines for diagnosing IgG4-associated cholangitis have been published devaluing the diagnostic significance of IgG4-positive plasma cells and steroid trials. We sought to evaluate the utility of IgG4-positive plasma cells in discriminating IgG4-associated cholangitis from hilar cholangiocarcinoma and autoimmune pancreatitis from pancreatic adenocarcinoma under conditions when malignancy is likely to be missed.
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Subsquamous Extension of Intestinal Metaplasia Is Detected in 98% of Cases of Neoplastic Barretts Esophagus.
Clin. Gastroenterol. Hepatol.
PUBLISHED: 01-03-2013
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Subsquamous intestinal metaplasia (SSIM) has been observed after endotherapy in patients with neoplastic Barretts esophagus (BE). However, it is not clear whether SSIM occurs in untreated patients. Incompletely eradicated SSIM could provide a source of recurrent disease. We assessed its prevalence in a large cohort of patients who had not received endoscopic therapy.
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In vitro maturation (IVM) of murine and human germinal vesicle (GV)-stage oocytes by coculture with immortalized human fallopian tube epithelial cells.
Fertil. Steril.
PUBLISHED: 05-13-2011
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To improve the maturation rate of murine and human germinal vesicle (GV) oocytes using human tubal epithelial cells (hTECs).
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Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells.
Hepatology
PUBLISHED: 03-29-2011
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There is increasing evidence that the physical environment is a critical mediator of tumor behavior. Hepatocellular carcinoma (HCC) develops within an altered biomechanical environment, and increasing matrix stiffness is a strong predictor of HCC development. The aim of this study was to establish whether changes in matrix stiffness, which are characteristic of inflammation and fibrosis, regulate HCC cell proliferation and chemotherapeutic response. Using an in vitro system of "mechanically tunable" matrix-coated polyacrylamide gels, matrix stiffness was modeled across a pathophysiologically relevant range, corresponding to values encountered in normal and fibrotic livers. Increasing matrix stiffness was found to promote HCC cell proliferation. The proliferative index (assessed by Ki67 staining) of Huh7 and HepG2 cells was 2.7-fold and 12.2-fold higher, respectively, when the cells were cultured on stiff (12 kPa) versus soft (1 kPa) supports. This was associated with stiffness-dependent regulation of basal and hepatocyte growth factor-stimulated mitogenic signaling through extracellular signal-regulated kinase, protein kinase B (PKB/Akt), and signal transducer and activator of transcription 3. ?1-Integrin and focal adhesion kinase were found to modulate stiffness-dependent HCC cell proliferation. Following treatment with cisplatin, we observed reduced apoptosis in HCC cells cultured on stiff versus soft (physiological) supports. Interestingly, however, surviving cells from soft supports had significantly higher clonogenic capacity than surviving cells from a stiff microenvironment. This was associated with enhanced expression of cancer stem cell markers, including clusters of differentiation 44 (CD44), CD133, c-kit, cysteine-X-cysteine receptor 4, octamer-4 (CXCR4), and NANOG. Conclusion: Increasing matrix stiffness promotes proliferation and chemotherapeutic resistance, whereas a soft environment induces reversible cellular dormancy and stem cell characteristics in HCC. This has implications for both the treatment of primary HCC and the prevention of tumor outgrowth from disseminated tumor cells. (HEPATOLOGY 2011;).
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Adhesion molecule L1 is down-regulated in malignant peripheral nerve sheath tumors versus benign neurofibromatosis type 1-associated tumors.
Oral Surg Oral Med Oral Pathol Oral Radiol
PUBLISHED: 01-06-2011
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Type 1 neurofibromatosis (NF-1), also known as von Recklinghausen disease, is caused by a disorder of a single gene on chromosome 17 that usually restrains cell division. A sequence that is frequently associated with NF-1 is tumor progression from neurofibromas to malignant peripheral nerve sheath tumors (MPNSTs). The aim of this study was to determine the expression of the neural L1 cell adhesion molecule in dermal-diffuse neurofibromas, plexiform neurofibromas, and MPNSTs of NF-1. We retrospectively analyzed surgically resected primary tumors, including 20 dermal neurofibromas, 23 plexiform neurofibromas, and 17 MPNSTs, by immunohistochemistry in paraffin sections of NF-1 tumors with the use of the L1-specific monoclonal antibody UJ127, which does not cross-react with other members of the L1 family. Immunostainings for CD34 and S100 were included to distinguish and allocate L1-expressing Schwann cells and perineural (specialized) fibroblasts. Our data showed that L1 is highly expressed in all benign NF-1 tumors and in some but not all MPNSTs. Furthermore, we demonstrated a correlation between L1 expression and differentiation grade of MPNSTs. There was a significant trend toward lower or nondetectable expression in the poorly differentiated MPNSTs, in contrast to all other tumor entities so far investigated, in which L1 expression correlated positive with malignancy, except for juvenile but not adult-derived neuroblastomas. Future studies are warranted to elucidate the molecular basis of the varying effects of the degree of L1 expression, receptor, and signal transduction mechanisms in different tumors.
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Robotic myomectomy: a review of indications and techniques.
Rev Obstet Gynecol
PUBLISHED: 12-22-2010
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The primary surgical techniques used in myomectomy are open surgery, laparoscopic surgery, and, recently, robot-assisted ("robotic") surgery. The optimal surgical treatment of myomas is still a subject of debate because of the limitations of minimally invasive techniques and the disadvantages of laparotomy. In this article, the authors discuss the technique and the application of robotic myomectomy in the treatment of uterine fibroids.
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Y-box-binding protein-1 is a potential novel tumour marker for neuroblastoma.
Anticancer Res.
PUBLISHED: 06-10-2010
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The Y-box-binding protein-1 (YB-1) is a member of a family of DNA-binding proteins and an oncogenic transcription factor that is highly expressed in cancers of the breast, lung and prostate. To date, no data are available on its role in neuroblastoma. The aim of the present study was to evaluate the YB-1 expression in neuroblastoma.
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L1 is highly expressed in tumors of the nervous system: a study of over 8000 human tissues.
J. Surg. Res.
PUBLISHED: 03-06-2010
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L1 cell adhesion molecule (CD171) has been detected in different malignant tumors and is associated with unfavorable outcome. It thus represents a target for tumor diagnosis and therapy. In this study, we assessed L1 expression in more than 8000 normal human tissues and different types of tumors, both malignant and non-malignant, and neural and non-neural.
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Evaluation of a formal mentoring program in an obstetrics and gynecology residency training program: resident feedback and suggestions.
J Grad Med Educ
PUBLISHED: 09-01-2009
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A formal mentoring program for residents was introduced at our Department of Obstetrics and Gynecology in 2004. The objective of this study was to assess residents attitudes toward and suggestions for the mentoring program.
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Aurora kinase inhibitor PHA-739358 suppresses growth of hepatocellular carcinoma in vitro and in a xenograft mouse model.
Neoplasia
PUBLISHED: 04-20-2009
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Patients with advanced stages of hepatocellular carcinoma (HCC) face a poor prognosis. Although encouraging clinical results have been obtained with multikinase inhibitor sorafenib, the development of improved therapeutic strategies for HCC remains an urgent goal. Aurora kinases are key regulators of the cell cycle, and their uncontrolled expression promotes aneuploidy and tumor development. In tissue microarray analyses, we detected aurora-A kinase expression in all of the examined 93 human HCC samples, whereas aurora-B kinase expression levels significantly correlated with the proliferation index of HCCs. In addition, two human HCC cell lines (Huh-7 and HepG2) were tested positive for aurora-A and -B and revealed Ser10 phosphorylation of histone H3, indicating an increased aurora-B kinase activity. The antiproliferative features of a novel aurora kinase inhibitor, PHA-739358, currently under investigation in phase 2 clinical trials for other solid tumors, were examined in vitro and in vivo. At concentrations exceeding 50 nM, PHA-739358 completely suppressed tumor cell proliferation in cell culture experiments and strongly decreased histone H3 phosphorylation. Cell cycle inhibition and endoreduplication were observed at 50 nM, whereas higher concentrations led to a complete G(2)/M-phase arrest. In vivo, administration of PHA-739358 resulted in significant tumor growth inhibition at a well-tolerated dose. In combination with sorafenib, additive effects were observed. Remarkably, when tumors restarted to grow under sorafenib monotherapy, subsequent treatment with PHA-739358 induced tumor shrinkage by up to 81%. Thus, targeting aurora kinases with PHA-739358 is a promising therapeutic strategy administered alone or in combination with sorafenib for patients with advanced stages of HCC.
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Perivascular epitheloid cell tumour (PEComa) of the retroperitoneum - a rare tumor with uncertain malignant behaviour: a case report.
J Med Case Rep
PUBLISHED: 02-16-2009
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Perivascular epitheloid cell tumours are rare mesenchymal neoplasms characterized by a proliferation of perivascular cells with an epitheloid phenotype and expression of myomelanocytic markers.
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Gonadotropin-releasing hormone antagonist use is associated with increased pregnancy rates in ovulation induction-intrauterine insemination to in vitro fertilization conversions, independent of age and estradiol level on the day of human chorionic gonadot
Fertil. Steril.
PUBLISHED: 01-17-2009
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To determine whether the use of GnRH antagonist in cycles converted from ovulation induction-IUI to IVF affects cycle outcome and pregnancy rates.
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Egg banking in the United States: current status of commercially available cryopreserved oocytes.
Fertil. Steril.
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To estimate the current availability of donor cryopreserved oocytes and to describe the emerging phenomenon of commercial egg banks (CEBs) in the United States.
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Infliximab as a rescue treatment in difficult-to-treat autoimmune hepatitis.
J. Hepatol.
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Autoimmune hepatitis is a chronic inflammatory liver disease that leads to liver cirrhosis and corresponding complications, if left untreated. Current standard treatment with azathioprine and prednisolone induces remission in the vast majority of patients. However, for those patients not responding to standard treatment or not tolerating these drugs, few alternatives can be used and their effectiveness might be limited. We sought to analyze the safety and efficacy of off-label treatment with infliximab in a cohort of eleven patients with difficult-to-treat autoimmune hepatitis.
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Intratumoral heterogeneity of KRAS mutation is rare in non-small-cell lung cancer.
Exp. Mol. Pathol.
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Several lines of evidence indicate that mutational activation of KRAS is an early event in the carcinogenesis of non-small cell lung cancer (NSCLC). Nonetheless, previous studies report high frequencies of divergent KRAS mutational status between primary NSCLC and corresponding metastases. This suggests heterogeneity of the primary tumor in respect to its KRAS status. We therefore aimed to examine the frequency and the extent of such intratumoral heterogeneity.
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Synchronous bronchioloalveolar and squamous cell lung cancer with different 18F-FDG avidity on PET/CT.
Clin Nucl Med
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We report a case of synchronous multiple primary lung cancer diagnosed by 18F-FDG PET/CT. A 78-year-old man underwent staging FDG PET/CT that demonstrated intense tracer uptake in the primary, and a second lesion with low uptake. Histopathologic evaluation revealed synchronous squamous cell and bronchioloalveolar carcinoma, representing 2 distinct primaries. FDG PET/CT may identify and diagnose synchronous multiple primary lung cancer on the basis of different morphologic and metabolic features of distinct tumor entities. Moreover, pulmonary lesions with low FDG avidity may still represent malignant disease, even in the context of biopsy-proven FDG-avid lung cancer.
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Rare oncogenic mutations of predictive markers for targeted therapy in triple-negative breast cancer.
Breast Cancer Res. Treat.
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Women with triple-negative breast cancer (TNBC) do not benefit from endocrine therapy or trastuzumab. Chemotherapy is the only systemic therapy currently available. To reduce the elevated risk of disease progression in these patients, better treatment options are needed, which are less toxic and more targeted to this patient population. We performed a comprehensive analysis of potential targetable genetic aberrations affecting the receptor tyrosine kinase/RAS/MAPK pathway, which are observed at higher frequencies in adenocarcinomas of other organs. Sixty-five individual TNBCs were studied by sequence analysis for HER2 (exon 18-23), EGFR (exon 18-21), KRAS (exon 2), and BRAF (exon 15) mutations. In addition, a tissue microarray was constructed to screen for EGFR gene copy gain and EML4-ALK fusion by FISH. Triple-negative status was confirmed by immunohistochemistry and FISH on tissue microarray sections. EGFR and CK5/6 immunohistochemical analyses were performed for identification of the basal-like phenotype. In addition, mutation analysis of TP53 (exon 5-8) was included. Sequence analysis revealed HER2 gene mutation in only one patient (heterozygous missense mutation in exon 19: p.L755S). No mutations were found in EGFR, KRAS, and BRAF. High polysomy of EGFR was detected in 5 of the 62 informative cases by FISH. True EGFR gene amplification accompanied by strong membranous EGFR protein expression was observed in only one case. No rearrangement of the ALK gene was detected. Basal-like phenotype was identified in 38 of the 65 TNBCs (58.5 %). TP53 gene mutation was found in 36/63 (57.1 %) tumors. We conclude that targetable genetic aberrations in the receptor tyrosine kinase/RAS/MAPK pathway occur rarely in TNBC.
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FOXP3+ regulatory T cells in autoimmune hepatitis are fully functional and not reduced in frequency.
J. Hepatol.
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The pathogenesis of autoimmune hepatitis (AIH) is not understood, but it was suggested that AIH may be related to a numerical or functional impairment of CD4+CD25+FOXP3+ regulatory T cells (Treg), which are important mediators of immune tolerance to self-antigens. However, the role of Treg in AIH is not clear, since earlier studies reporting Treg impairment had used only CD25 as marker that cannot unambiguously distinguish Treg from activated effector T cells.
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Sharpin contributes to TNF? dependent NF?B activation and anti-apoptotic signalling in hepatocytes.
PLoS ONE
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TNF? stimulates both pro- and anti-apoptotic signalling in hepatocytes. Anti-apoptotic signalling depends on a cascade of ubiquitylation steps leading to NF?B activation. Using Sharpin-deficient mice, we show that the ubiquitin binding protein Sharpin interacts with Hoip, an E3 ligase which generates linear ubiquitin chains. Sharpin-deficiency sensitized hepatocytes to induction of apoptosis by TNF? even in the absence of transcriptional inhibition. TNF? induced activation of NF?B was strongly reduced in hepatocytes from Sharpin-deficient mice, due to reduced and delayed phosphorylation and degradation of I?B?. Injection of TNF?-inducing lipopolysaccharides led to strongly exacerbated liver damage and premature death in Sharpin-deficient mice. Our findings point to an essential role of Sharpin in linear ubiquitin chain formation, NF?B activation, and protection of the liver against inflammatory damaging signals.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.