tbuckley/cabot-search huggingface dataset:
SUMO conjugation and postreplication repair pathways protect cells from DNA topoisomerase I poisons.
Authors: H. R. Jacquiau, R. C. A. M. Van Waardenburg, M-A. Bjornsti
Journal: Cancer Research (2006)

5678  Eukaryotic DNA topoisomerase I (Top1) functions in DNA replication, transcription and recombination by catalyzing changes in DNA topology. Top1 transiently cleaves one strand of duplex DNA and forms a covalent enzyme-DNA intermediate. Camptothecin (CPT) reversibly stabilizes this Top1-DNA complex, inducing S-phase dependent cell death. To define cellular processes that function in the recognition and repair of CPT-induced DNA lesions, we isolated temperature sensitive yeast mutants with increased sensitivity to Top1 poisons at 36°C. Self-poisoning top1 mutants were used in these screens, which induce distinct DNA lesions - Top1T722A acts as a CPT mimetic to inhibit DNA religation, while Top1N726H exhibits increased rates of DNA cleavage. However, despite these differences, the same hypomorphic allele of the Ubc9 SUMO conjugating enzyme, ubc9P123L, was isolated in both screens. Ubc9 is a conserved, essential enzyme that covalently attaches the ubiquitin-like protein, SUMO, to lysine residues in target proteins to alter protein activity, sub-cellular localization and/or stability. The Pro123 to Leu mutation in ubc9P123L cells reduced global protein SUMOylation at 36°C yet sufficed to maintain cell viability in the absence of genotoxic stress. In contrast, these cells were hypersensitive to Top1 poisons and to a wide range of DNA damaging agents, independent of Top1. Several lines of evidence suggest the Pro123 to Leu mutation induces specific alterations in the SUMO modification of nonessential cellular targets that dictate cellular responses to genotoxic stress. First, compensatory alterations in SUMO conjugation through deletion of the Ulp2 SUMO protease did not restore ubc9P123L cell resistance to Top1 poisons or hydroxyurea. Second, mutation of consensus SUMO sites in Top1 failed to recapitulate the pattern or extent of ubc9P123L cell sensitivity to Top1 poisons. Third, although the single mutants are viable in the absence of DNA damage, the ubc9P123L,rad6Δ and ubc9P123L,sgs1Δ double mutants were inviable at 36°C. These synthetic lethal phenotypes indicate a common essential function is abrogated by alterations in Ubc9 and either Rad6 or Sgs1. Sgs1, yeast ortholog of human BLM, genetically interacts with the Srs2 helicase, recruited by SUMO-modified PCNA to suppress inappropriate homologous recombination of replication forks. Rad6 functions to modulate PCNA activity in error-free and error-prone postreplicative repair. As PCNA activity is also regulated by Ubc9-dependent modification, these finding suggest defects in Ubc9 conjugation alter cell sensitivity to Top1 poisons through direct effects on postreplication repair. Supported by NIH grant CA111542 and ALSAC.
A Finding of Increased Risk of Nonaffective Psychosis in Refugees That Is Highly Relevant to the Current Worldwide Refugee Crisis
Authors: Kristina Sundquist
Journal: JAMA Psychiatry (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Psychiatry HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Psychiatry journal
Gastroesophageal Reflux Disease
Authors: Peter J. Kahrilas
Journal: New England Journal of Medicine (2008)

A 53-year-old man, who is otherwise healthy and has a 20-year history of occasional heartburn, reports having had worsening heartburn for the past 12 months, with daily symptoms that disturb his sleep. He reports having had no dysphagia, gastrointestinal bleeding, or weight loss and in fact has recently gained 20 lb (9 kg). What would you advise regarding his evaluation and treatment?
Epidemiological considerations in the design of tissue microarrays
Authors: Peter Gann, Margaret Wright, Vijayalakshmi Ananthanarayanan, Andre Kajdacsy-Balla
Journal: Cancer Research (2008)

2185  Tissue microarrays (TMAs), which have been available to researchers for nearly 10 years, allow investigators to more rapidly evaluate large sets of tissue samples while greatly reducing the cost of reagents and the error due to variations between staining batches. TMAs can be built to address various types of research questions, and each TMA design can be conceptualized as a corresponding epidemiological study design. The two most common types of TMA in cancer research are referred to as “progression” or “outcomes” arrays. Many investigators using TMAs however, are unaware of the study design considerations implicit in planning a TMA and thus may build arrays that are less statistically efficient or are prone to bias. We have identified several major types of designs, and, using examples, discuss important issues affecting the precision or validity of the results. These design types include: cross-sectional, case-control, nested case-control, case-cohort, full cohort and clinical trial. Major issues include: patient selection, control selection (including incidence density vs. other approaches), matching, the use of replicates to reduce donor block sampling error, assignment of sample position within the array, and handling of confounding variables. Relevant statistical issues include the potential use of mixed effects models, conditional vs. unconditional logistic models, and the estimation of predictive values or absolute risk (as opposed to relative risk) from various designs. We have undertaken a systematic sampling of the recent medical literature to describe how TMA design decisions are being made, and how these decisions might affect progress in cancer research.
National point prevalence survey on healthcare-associated infections in acute care hospitals, Switzerland, 2017
Authors: Walter Zingg, Aliki Metsini, Carlo Balmelli, Dionysios Neofytos, Michael Behnke, Céline Gardiol, Andreas Widmer, Didier Pittet
Journal: Eurosurveillance (2019)

Background As a part of the national strategy on the prevention of healthcare-associated infections (HAI), a point prevalence survey (PPS) was conducted in acute care hospitals in Switzerland. Aim Our objective was to assess the burden of HAI in Swiss acute care hospitals. Methods All acute care hospitals were invited to participate in this cross-sectional survey during the second quarter of 2017. The protocol by the European Centre for Disease Prevention and Control was applied. Patients of all ages, hospitalised on the day of survey were included, except when admitted to outpatient clinics, emergency and psychiatry. Results Ninety-six acute care hospitals (79% of all hospitals ≥ 100 beds) provided data on 12,931 patients. Pooled and randomised HAI prevalences were 5.9% (95% confidence interval (CI): 5.5–6.3) and 5.4% (95% CI: 4.8–6.0), respectively. The HAI incidence was estimated at 4.5 (95% CI: 4.0–5.0). The most common type of HAI was surgical site infection (29.0%), followed by lower respiratory tract (18.2%), urinary tract (14.9%) and bloodstream (12.8%) infections. The highest prevalence was identified in intensive care (20.6%), in large hospitals &gt; 650 beds (7.8%), among elderly patients (7.4%), male patients (7.2%) and patients with an ultimately (9.3%) or rapidly (10.6%) fatal McCabe score. Discussion This is the first national PPS of Switzerland allowing direct comparison with other European countries. The HAI prevalence was at European Union average (5.9% in 2016 and 2017), but higher than in some countries neighbouring Switzerland. Based on the limited information from previous surveys, HAI appear not to decrease.
Influence of BRAF mutations and RAC1b/RAC1 mRNA expression ratio on outcome in patients with metastatic colorectal cancer (mCRC) treated with first-line chemotherapy.
Authors: Virginia Alonso-Espinaco, Maribel Marmol, Vicente Alonso, Pilar Escudero, Carlos Horndler, Javier Ortego, Rosa Gallego, Xabier Garcia-Albeniz, Pedro Jares, Miriam Cuatrecasas, Juan Jose Lozano, Antoni Castells, Joan Maurel
Journal: Journal of Clinical Oncology (2012)

3553 Background: Metastatic colorectal cancer (mCRC) patients (pts), with BRAF tumor mutation (V600E) present poor overall survival (OS). RAC1b, a RAC1 spliced variant, is overexpressed in CRC, and impairs apoptosis by activation of nuclear-factor-KB. Because RAC1b and BRAF (V600E) are significantly associated in CRC (Matos et al, 2008), we evaluated if RAC1b/RAC1 mRNA expression ratio (RNA ER) was an independent prognostic factor in mCRC. Methods: We analyzed tumor samples from 186 mCRC pts, treated in first-line therapy with FOLFOX or CAPOX in three Spanish hospitals. We examined BRAF (V600E) mutational status by allelic discrimination, RAC1b/RAC1 expression ratio by mRNA RT-PCR (quantitative real time polymerase chain reaction) and mismatch repair (MMR) deficiency by microsatellite instability (MSI) analysis. We assessed whether these biomarkers were independently predictive of response rate (RR), progression free survival (PFS) or OS. Results: 88% of samples were informative for BRAF, 75% for MMR status and 85% for RAC1b/RAC1 (RNA ER). BRAF (V600E) was found in 7%, MSI-H in 5% and high &gt;0.9-fold RAC1b/RAC1 (RNA ER) in 20% of pts. Five of 11 pts (46%) with BRAF mutation had high RAC1b/RAC1 (RNA ER) compared with 25/144 (18%) without BRAF mutation (p=0.036). All pts with BRAF mutation were MMR and none of the MSI-H pts, showed high RAC1b/RAC1 (RNA ER). Patients with low RAC1b/RAC1 (RNA ER) and BRAF WT had higher response rate (68% vs 43%; p=0.035). Response rate were not different according BRAF mutation (64% WT vs 63% mutant) (p=NS). The multivariate regression analysis identified ECOG PS (HR: 4.2 (CI 1.4-12.7) as a significant variable for PFS and LDH levels (HR: 2.26 (CI 1.3-3.8), PS (HR: 3.85 (CI 1.5-9.8) and high RAC1b/RAC1 (RNA ER) (HR: 2.6 (CI 1.1-5.9) for OS in WT BRAF pts. Conclusions: High RAC1b/RAC1 (RNA ER) constitutes a marker of poor OS and a potential marker of acquired chemo-resistance in WT BRAF mCRC pts treated with first-line oxaliplatin-based therapy.
Phase I/Ib Study of Pembrolizumab Plus Vorinostat in Advanced/Metastatic Non–Small Cell Lung Cancer
Authors: Jhanelle E. Gray, Andreas Saltos, Tawee Tanvetyanon, Eric B. Haura, Ben Creelan, Scott J. Antonia, Michael Shafique, Hong Zheng, Wenjie Dai, James J. Saller, Zhihua Chen, Nishan Tchekmedyian, Kristen Goas, Ram Thapa, Theresa A. Boyle, Dung-Tsa Chen, Amer A. Beg
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Histone deacetylase inhibitors (HDACi) enhance tumor immunogenicity through several mechanisms and may improve response to immune checkpoint inhibitors (ICIs). In a phase I/Ib trial, we tested the oral HDACi vorinostat combined with the programmed cell death protein 1 inhibitor pembrolizumab in advanced/metastatic non–small cell lung cancer. Patients and Methods: Patients received intravenous pembrolizumab (200 mg every 3 weeks) plus oral vorinostat (200 or 400 mg/day). Primary endpoint was safety/tolerability. Secondary endpoints included response rate, progression-free survival, disease control rate (DCR), and overall survival. Tumor gene expression changes, T-cell density, and myeloid cell levels were studied in serial tissue specimens. Results: Thirty-three patients were treated (13 in phase I, 20 in phase Ib). In phase I, both ICI-naïve and ICI-pretreated patients were enrolled to determine dose-limiting toxicities (DLT). No DLTs were observed, and the recommended phase I dose was pembrolizumab 200 mg and vorinostat 400 mg. Any-grade adverse events were mainly fatigue (33%) and nausea/vomiting (27%). Of six ICI-naïve and 24 ICI-pretreated patients evaluable for response, four (13%) had partial response [two confirmed, one unconfirmed with subsequent prolonged stable disease (SD), one unconfirmed with subsequent progressive disease (PD)], 16 (53%) had SD, and 10 (33%) had PD for a DCR of 67%. In the ICI-pretreated cohort, three patients (one confirmed, two unconfirmed) had partial response and 10 had SD. Pretreatment CD8+ T-cell presence in tumor stromal regions was associated with treatment benefit. Conclusions: Pembrolizumab plus vorinostat was well tolerated and demonstrated preliminary antitumor activity despite progression on prior ICI treatment.
Cryptic activation of an Irf8 enhancer governs cDC1 fate specification
Authors: Vivek Durai, Prachi Bagadia, Jeffrey M. Granja, Ansuman T. Satpathy, Devesha H. Kulkarni, Jesse T. Davidson, Renee Wu, Swapneel J. Patel, Arifumi Iwata, Tian-Tian Liu, Xiao Huang, Carlos G. Briseño, Gary E. Grajales-Reyes, Miriam Wöhner, Hiromi Tagoh, Barbara L. Kee, Rodney D. Newberry, Meinrad Busslinger, Howard Y. Chang, Theresa L. Murphy, Kenneth M. Murphy
Journal: Nature Immunology (2019)
Indoor bacterial microbiota and development of asthma by 10.5 years of age
Authors: Anne M. Karvonen, Pirkka V. Kirjavainen, Martin Täubel, Balamuralikrishna Jayaprakash, Rachel I. Adams, Joanne E. Sordillo, Diane R. Gold, Anne Hyvärinen, Sami Remes, Erika von Mutius, Juha Pekkanen
Journal: Journal of Allergy and Clinical Immunology (2019)
Requirement of caveolin polarity for endothelial cell spreading and migration.
Authors: Andrew Beardsley, Kai Fang, Heather Mertz, Vince Castranova, Jun Liu
Journal: Cancer Research (2004)

3248  Angiogenesis, the development of new blood vessels from pre-existing capillaries, is required in many physiological and pathological conditions, such as embryonic development, wound healing, tissue regeneration and tumor growth. The mechanisms underlying the pathogenesis of neovascularization are not yet fully understood, but involve endothelial cell migration, proliferation and differentiation. A clear understanding of how endothelial cells sense chemoattractants, organize signaling asymmetry and make a directional movement is of pivotal importance in the biology of normal cells as well as tumor angiogenesis. To investigate polarized cellular activity in migrating cells, human endothelial cells were incubated in Dunn chamber to allow migration towards VEGF. Immunofluorescent staining with specific antibody against caveolin-1 revealed that caveolin-1 was concentrated to the rear of moving cells. Similarly, monolayer denudation to induce cell random walk resulted in translocation of caveolin-1 to the cell rear, suggesting that migration-induced caveolin-1 polarity was a common feature both of chemotaxis and chemokenesis. Dual immunofluorescent labelings showed that, during cell spreading, nascent focal contacts as detected either by FAK or integrin β1 staining appeared along the circular lamellipodium. In contrast, caveolin-1 was located compactly in the cell center excluded from the leading edge. When cells were migrating, focal contacts appeared now at one or sometimes two polarized lamellipodia, whereas, caveolin-1 signals appeared either at the rear of most cells or two edges of cell body. Notably, wherever caveolin-1 was polarized, there was a conspicuous absence of both dashed focal contacts and lamellipod extension. Transmission electron microscopy showed that like their marker, caveolin-1, caveolae were located at cell center during cell spreading or at the cell rear during cell migration. Importantly, loss of caveolin-1 polarity by transient over-expression of caveolin-1 prevented lamellipod extension. Taken together, our results suggest a potential role of caveolae and caveolin polarity in cell migration. Supported in part by grants from the American Heart Association and NIH RR 16440.
miR-221 Targets QKI to Enhance the Tumorigenic Capacity of Human Colorectal Cancer Stem Cells
Authors: Junko Mukohyama, Taichi Isobe, Qingjiang Hu, Takanori Hayashi, Takashi Watanabe, Masao Maeda, Hisano Yanagi, Xin Qian, Kimihiro Yamashita, Hironobu Minami, Koshi Mimori, Debashis Sahoo, Yoshihiro Kakeji, Akira Suzuki, Piero Dalerba, Yohei Shimono
Journal: Cancer Research (2019)

miRNAs are key players in the integrated regulation of cellular processes and shape many of the functional properties that define the "cancer stem cell" (CSC) phenotype. Little is known, however, about miRNAs that regulate such properties in human colorectal carcinoma. In this study, we compared the expression levels of 754 miRNAs between paired samples of EpCAM+/CD44+ cancer cells (enriched in CSCs) and EpCAM+/CD44neg cancer cells (with CSC depletion) sorted in parallel from human primary colorectal carcinomas and identified miR-221 as the miRNA that displayed the highest level of preferential expression in EpCAM+/CD44+ cancer cells. High levels of miR-221 expression were associated with Lgr5+ cells in mouse colon crypts and reduced survival in patients with colorectal carcinoma. Constitutive overexpression of miR-221 enhanced organoid-forming capacity of both conventional colorectal carcinoma cell lines and patient-derived xenografts (PDX) in vitro. Importantly, constitutive downregulation of miR-221 suppressed organoid-forming capacity in vitro and substantially reduced the tumorigenic capacity of CSC populations from PDX lines in vivo. Finally, the most abundant splicing isoform of the human Quaking (QKI) gene, QKI-5, was identified as a functional target of miR-221; overexpression of miR-221-reduced QKI-5 protein levels in human colorectal carcinoma cells. As expected, overexpression of QKI-5 suppressed organoid-forming capacity in vitro and tumorigenic capacity of colorectal carcinoma PDX cells in vivo. Our study reveals a mechanistic link between miR-221 and QKI and highlights their key role in regulating CSC properties in human colorectal cancer. SIGNIFICANCE: These findings uncover molecular mechanisms underlying the maintenance of cancer stem cell properties in colon cancer.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/20/5151/F1.large.jpg.
Supression of tumorigenicity and induction of neuronal differentiation in embryonic stem cells transplanted in the adult mouse retina by folate antagonist methotrexate
Authors: Akira Hara, Masayuki Niwa, Hitomi Aoki, Takahiro Kunisada, Tetsuya Yamamoto, Osamu Kozawa, Yasuhiro Yamada, Hideki Mori
Journal: Cancer Research (2007)

1336  Transplanted embryonic stem (ES) cells can be integrated into the retinas of adult mice as well-differentiated neuronal cells. However, the undifferentiated ES cells also have a tumorigenic effect just because they have the ability for multipotential differentiation to various types of tissues. ES cells have some similarities with cancer cells, such as anchorage-independent growth, loss of contact inhibition and tumour formation. Thus, control of neoplastic potentials of transplanted ES cells is very important for the treatment of degenerative or injured retinal diseases. Mouse ES cells carrying the sequence for the green fluorescent protein (GFP) gene were transplanted into adult mouse retinas by intravitreal injections 20 h after intravitreal administration of N-methyl-D-aspartate, which induces neuro-toxicity to retinal ganglion cells. One week after the ES cell injection, folate antagonist methotrexate (MTX) was injected intravitreally. Eyes were retrieved 4 weeks after ES cell transplantation for histologic analyses. Conventional histological analysis was performed by hematoxylin and eosin staining with the use of paraffin-embedded sections. Neuronal differentiation and teratogenic potential of ES cells were demonstrated by immunohistochemistry. The proliferative activity of transplanted cells was detected by mitotic index, proliferating cell nuclear antigen index and AgNOR count. The incorporation of transplanted ES cells in MTX-treated and non-treated retinas at 4weeks after transplantation was observed in 8/16 eyes (50%) and 8/16 eyes (50%), respectively. Transplanted ES cells in MTX-treated retina showed increased neuronal differentiation and decreased expression of teratogenic markers, compared with ES cells in non-treated retina. The proliferative activity of transplanted ES cells in MTXtreated retina was lower than that in non-treated retina. Although intravitreal injection of MTX induced neuronal differentiation and reduced teratogenic and proliferative activity to the transplanted ES cells, small amount of OCT4 positive stem cells are still recognized in the MTX-treated retina. These results suggest that intravitreal injection of MTX after the retinal transplantation of ES cells is useful for the induction of the neuronal differentiation in vivo, however, long-term management of undifferentiated stem cells is needed even in the MTX-treated ES cells.
Long noncoding RNA GAS5 induces abdominal aortic aneurysm formation by promoting smooth muscle apoptosis
Authors: Xiang He, Shifei Wang, Mengsha Li, Lintao Zhong, Hao Zheng, Yili Sun, Yanxian Lai, Xiaoqiang Chen, Guoquan Wei, Xiaoyun Si, Yuan Han, Senlin Huang, Xinzhong Li, Wangjun Liao, Yulin Liao, Jianping Bin
Journal: Theranostics (2019)

Objective: Long noncoding RNAs (lncRNAs) may serve as specific targets for the treatment of abdominal aortic aneurysms (AAAs). LncRNA GAS5, functionally associated with smooth muscle cell (SMC) apoptosis and proliferation, is likely involved in AAA formation, but the exact role of GAS5 in AAA is unknown. We thus explored the contribution of GAS5 to SMC-regulated AAA formation and its underlying mechanisms. Methods: Human specimens were used to verify the diverse expression of GAS5 in normal and AAA tissues. The angiotensin II (Ang II)-induced AAA model in ApoE-/- mice and the CaCl2-induced AAA model in wild-type C57BL/6 mice were used. RNA pull-down and luciferase reporter gene assays were performed in human aortic SMCs to detect the interaction between GAS5 and its downstream targets of protein or microRNA (miR). Results: GAS5 expression was significantly upregulated in human AAA specimens and two murine AAA models compared to human normal aortas and murine sham-operated controls. GAS5 overexpression induced SMC apoptosis and repressed its proliferation, thereby promoting AAA formation in two murine AAA models. Y-box-binding protein 1 (YBX1) was identified as a direct target of GAS5 while it also formed a positive feedback loop with GAS5 to regulate the downstream target p21. Furthermore, GAS5 acted as a miR-21 sponge to release phosphatase and tensin homolog from repression, which blocked the activation and phosphorylation of Akt to inhibit proliferation and promote apoptosis in SMCs. Conclusion: The LncRNA GAS5 contributes to SMC survival during AAA formation. Thus, GAS5 might serve as a novel target against AAA.