tbuckley/cabot-search huggingface dataset:
Abstract 3312: Transcriptional regulation of chemokine receptor 4 (CXCR4) by nuclear respiratory factor 1 (NRF1) controls estrogen-induced malignant transformation of breast epithelial cells to breast cancer stem cells
Authors: Jayanta Kumar Das, Deodutta Roy
Journal: Cancer Research (2016)

Abstract Chemokine receptor 4 (CXCR4) is involved in the maintenance normal stem cells and metastasis of cancer stem cells. NRF1 is one of the major transcription factor that controls transcription of CXCR4. The functional regulation of transcription of NRF1 target genes has not been explored in breast cancer. In this study, we have investigated whether transcriptional regulation of CXCR4 by NRF1 regulates estrogen-induced malignant transformation of breast epithelial cells to breast cancer stem cells (CSCs). We have previously shown that NRF1 may be involved in 17 β-estradiol (E2) induced malignant transformation of breast epithelial cells, however, the mechanism of transcriptional regulation of the NRF1 target genes remains unknown. In this study we showed that NRF1 and E2 jointly contributed in reprogramming of breast epithelial cells to CSCs. Levels of breast cancer stem cell markers (CD44+CD24+ALDH1+CD133+) were significantly increased by E2 treatment in NRF1 overexpressing cells compared to cells transfected with vector receiving E2. E2-induced increases of spheroid formation, cell survival and growth of cancer stem cells were modulated by functional gain or loss of NRF1. For morphological details we used a holographic microscope (HoloMonitor M4), we observed that E2 generated breast cancer stem cells with CD44+CD24+ALDH1+CD133+ markers produced large live spheroids in NRF1 overexpressing cells compared to cells transfected with vector receiving E2. Overexpression of NRF1 promoted the transition of E2-treated breast epithelial MCF-10A cells to mesenchymal stem cell-like phenotype. The ChIP qPCR, RT-qPCR, Western blotting and immunofluorescence microscopic assays showed that NRF1 mediated transcriptional changes of its target genes CXCR4, BNIP3, and DJ-1 correlated with malignant phenotypic changes. The suppression of NRF-1 activity induced growth arrest and apoptosis, and reduced stemness, growth and tumorigenic property of cancer stem cells. In summary, our findings for the first time showed that transcriptional regulation of CXCR4 by NRF1 may contribute in the induction of a pre-malignant phenotype by estrogen presumably by promoting generation of breast cancer stem cells. These data suggest NRF1 as an emerging potential target for therapeutic intervention against breast cancer. Citation Format: Jayanta Kumar Das, Deodutta Roy. Transcriptional regulation of chemokine receptor 4 (CXCR4) by nuclear respiratory factor 1 (NRF1) controls estrogen-induced malignant transformation of breast epithelial cells to breast cancer stem cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3312.
Dose-dense and less dose-intense Total Therapy 5 for gene expression profiling-defined high-risk multiple myeloma
Authors: Y Jethava, A Mitchell, M Zangari, S Waheed, C Schinke, S Thanendrarajan, J Sawyer, D Alapat, E Tian, C Stein, R Khan, C J Heuck, N Petty, D Avery, D Steward, R Smith, C Bailey, J Epstein, S Yaccoby, A Hoering, J Crowley, G Morgan, B Barlogie, F van Rhee
Journal: Blood Cancer Journal (2016)

Abstract Multiple myeloma (MM) is a heterogeneous disease with high-risk patients progressing rapidly despite treatment. Various definitions of high-risk MM are used and we reported that gene expression profile (GEP)-defined high risk was a major predictor of relapse. In spite of our best efforts, the majority of GEP70 high-risk patients relapse and we have noted higher relapse rates during drug-free intervals. This prompted us to explore the concept of less intense drug dosing with shorter intervals between courses with the aim of preventing inter-course relapse. Here we report the outcome of the Total Therapy 5 trial, where this concept was tested. This regimen effectively reduced early mortality and relapse but failed to improve progression-free survival and overall survival due to relapse early during maintenance.
Abstract 4038: Developmentof a murine tumor immunophenotyping platform to support drug discovery anddevelopment in immuno-oncology
Authors: Brian Belmontes, Stephanie Matyas, Sarah O’Brien, Hong Tan, Kenneth Ganley, Kimberly Merriam, Jim Rottman, Jackson Egen, Pedro Beltran, Gordon Moody
Journal: Cancer Research (2016)

Abstract Recent clinical data highlights the importance of immune cell localization, phenotype, and gene signature as it correlates to a productive anti-tumor response. Preclinically, multiple syngeneic mouse models have been used to study the effects of immunomodulation and define anti-tumor responses to transplanted “self” tumors. However, while the literature describes distinct aspects of many of these models, there is no comprehensive dataset comparing and contrasting their tumor-immune microenvironments across models. These data are critical for better understanding the role that various immune populations play in the anti-tumor response and interpreting observed changes in tumor clearance following treatment with immunomodulatory agents. We have therefore established a platform that 1) quantitates the types of immune cells within murine tumor models, and 2) describes the location of these cells within the tumor. In parallel to the immunophenotyping efforts we have benchmarked tumor models based on their response to antibodies against T cell checkpoint pathways. We sought to use this immunophenotyping platform to identify specific immune modulation that occurs in syngeneic tumors post depletion of macrophages via CSF1R blockade. Tumor-associated macrophages (TAMs) are believed to help promote tumor survival through suppression of the adaptive immune response and the secretion of growth factors that promote tumor growth and angiogenesis. Therefore depletion of TAMs should lead to T-cell recruitment and bolster the antitumor T-cell response. Here we show that treatment of CT-26 and RENCA syngeneic tumors with a CSF1R antagonist leads to depletion of MHCII+ and F4/80+ expressing cells. Future experiments will seek to understand if CSF1R blockade improves the response to T-cell checkpoint immunotherapies. In summary, the development of a murine tumor immunophenotyping platform has allowed insight and evaluation of immune cells in the tumor microenvironment that can ultimately be leveraged to understand the synergistic effects of immunotherapeutics. Citation Format: Brian Belmontes, Stephanie Matyas, Sarah O’Brien, Hong Tan, Kenneth Ganley, Kimberly Merriam, Jim Rottman, Jackson Egen, Pedro Beltran, Gordon Moody. Developmentof a murine tumor immunophenotyping platform to support drug discovery anddevelopment in immuno-oncology. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4038.
Effects on Health Outcomes of a Mediterranean Diet With No Restriction on Fat Intake
Authors: Hanna E. Bloomfield, Eva Koeller, Nancy Greer, Roderick MacDonald, Robert Kane, Timothy J. Wilt
Journal: Annals of Internal Medicine (2016)

Mediterranean diets may be healthier than typical Western diets.To summarize the literature comparing a Mediterranean diet with unrestricted fat intake with other diets regarding their effects on health outcomes in adults.Ovid MEDLINE, CINAHL, and the Cochrane Library from 1990 through April 2016.Controlled trials of 100 or more persons followed for at least 1 year for mortality, cardiovascular, hypertension, diabetes, and adherence outcomes, as well as cohort studies for cancer outcomes.Data extracted by 1 investigator was verified by another. Two reviewers assessed risk of bias and strength of evidence.Two primary prevention trials found no difference in all-cause mortality between diet groups. One large primary prevention trial found that a Mediterranean diet resulted in a lower incidence of major cardiovascular events (hazard ratio [HR], 0.71 [95% CI, 0.56 to 0.90]), breast cancer (HR, 0.43 [CI, 0.21 to 0.88]), and diabetes (HR, 0.70 [CI, 0.54 to 0.92]). Pooled analyses of primary prevention cohort studies showed that compared with the lowest quantile, the highest quantile of adherence to a Mediterranean diet was associated with a reduction in total cancer mortality (risk ratio [RR], 0.86 [CI, 0.82 to 0.91]; 13 studies) and in the incidence of total (RR, 0.96 [CI, 0.95 to 0.97]; 3 studies) and colorectal (RR, 0.91 [CI, 0.84 to 0.98; 9 studies]) cancer. Of 3 secondary prevention studies reporting cardiovascular outcomes, 1 found a lower risk for recurrent myocardial infarction and cardiovascular death with the Mediterranean diet. There was inconsistent, minimal, or no evidence pertaining to any other outcome, including adherence, hypertension, cognitive function, kidney disease, rheumatoid arthritis, and quality of life.Few trials; medium risk-of-bias ratings for many studies; low or insufficient strength of evidence for outcomes; heterogeneous diet definitions and components.Limited evidence suggests that a Mediterranean diet with no restriction on fat intake may reduce the incidence of cardiovascular events, breast cancer, and type 2 diabetes mellitus but may not affect all-cause mortality.Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Quality Enhancement Research Initiative. (PROSPERO: CRD42015020262).
PTU-071 Improved outcomes following covered TIPSS in patients admitted to intensive care following a variceal bleed: a single centre study: Abstract PTU-071 Figure 1
Authors: C Corbett, D Tripathi, N Murphy, S Olliff, K Mangat
Journal: Gut (2012)

<h3>Introduction</h3> Variceal bleeding occurs in a third of patients with cirrhosis and varices, and accounts for 10% of all GI bleeding in the UK. The 6-week mortality of 20% is greater than that for myocardial infarction. Recent evidence suggests that early covered TIPSS can improve outcomes after variceal bleed in certain patients. <h3>Methods</h3> This is a retrospective study of patients with a history of variceal bleeding admitted to intensive care unit over a 3-year period. Patients without no active bleeding or stigmata of variceal haemorrhage were excluded. Multiple factors surrounding the admission and therapy were analysed. All TIPSS procedures were performed using PTFE covered stents during the admission. <h3>Results</h3> 41 patients met inclusion criteria. 56% had alcoholic liver disease, 39% and 45% had Child C and B disease respectively. Mean age was 53.7 years, and median follow-up 466 days. The mean MELD was 14.4. 18% were shocked on admission, and 83% required invasive ventilation. 91% of admissions underwent endoscopy within 24 h of admission. All patients had broad spectrum antibiotics and terlipressin during the admission. The principal endoscopic therapy was variceal band ligation (44%), with 41% undergoing balloon tamponade as 1<sup>st</sup> intervention. 86% had active bleeding at index endoscopy, with 72% having balloon tamponade placed at some point. Indication for TIPSS was salvage therapy (60%), following re-bleeding (15%) and secondary prophylaxis (25%). Overall there was 34% inpatient admission mortality. The TIPSS group (n=19) had lower mortality than the non TIPSS group (n=22) at 6 weeks (11% vs 45% p&lt;0.05) that persisted throughout follow-up (36% vs 54%, p&lt;0.05). Multivariate analysis revealed a MELD≥18 and SOFA ≥11as significant predictors of mortality (p&lt;0.05). Baseline characteristics were well matched between these groups. Fewer patient in the TIPSS group reached the composite end point of rebleeding after 5 days or failure to control initial bleeding (12% vs 45%, p=0.02). <h3>Conclusion</h3> This study shows that patients with recent severe variceal bleeding admitted to intensive care have significantly better outcomes following covered TIPSS insertion. These findings need to be validated in randomised controlled trials. <h3>Competing interests</h3> None declared.
Signaling by Met and related receptor tyrosine kinases in urothelial carcinoma of the bladder.
Authors: Donald P. Bottaro, Young H. Lee, Cara E. Wright, Tiffany K. Wong, Piyush K. Agarwal, Andrea Borghese Apolo
Journal: Journal of Clinical Oncology (2015)

e15511 Background: Interim results from a phase II clinical trial of cabozantinib, a multikinase inhibitor of Met and related receptor tyrosine kinases (RTKs) for patients with advanced UC, reveal 15% partial response and 64% stable disease. Identifying the mechanisms underlying these responses would provide a rationale for developing more selective RTK inhibitors and diagnostic and pharmacodynamic biomarkers, to improve treatment efficacy and tolerability, and further define UC at the molecular level. Methods: mRNA copy number, and where relevant, protein content and signaling functionality were assessed for 38 RTKs (primarily MET- and KDR-related), 7 secreted ligands, 11 downstream effectors and 10 transcriptional activators with known roles in cancer, in 13 UC cell lines by quantitative RT-PCR, immunoassay and functional analyses. Met protein was measured in 13 UC patient tumor samples by immunoassay. Results: 22/38 RTKs (including AXL, MET, RYK, ROR2, CSF1R, DDR1 and PTK7) were robustly expressed in UC cell lines; Met protein was present in 100% UC tumor samples obtained from patients on the cabozantinib trial. Co-expression of MST1/MST1R, GAS6/AXL and CSF1/CSFR1 occurred in 13/13, 10/13 and 8/13 UC cell lines, respectively, suggestive of autocrine signaling. 10/11 oncogenically relevant transcriptional activators (mainly SOX9/2, FOXA2 and ZEB1/2) were broadly expressed in UC cells. Dose-response studies confirmed and extended the set of known cabozantinib targets. Conclusions: Several MET- and KDR-related RTKs are functional in UC cells, including many known cabozantinib targets. Evidence of autocrine activation of the MST1R, AXL and CSF1R pathways is strongly reinforced by RNA Seq results in the bladder UC provisional TCGA dataset (357 samples), where > 2-fold expression was observed in 18% of cases combined, with significant rates of co-occurrence (Log Odds Ratio > 3, p < 0.001 for all 3 pathways). These findings improve our understanding of RTK signaling in UC, provide a route to defining the molecular basis of cabozantinib response in UC cells, and in turn, provide a path to identifying and developing biomarkers and selective RTK inhibitors with improved efficacy and tolerability.
Surgical Treatment of Temporal Lobe Epilepsy
Authors: S. Ali Nabavizadeh
Journal: JAMA Neurology (2016)

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Genome-wide association study identifies a locus at 7p15.2 associated with the development of endometriosis
Authors: J N Painter, C A Anderson, Nyholt, S Macgregor, J Lin, S H Lee, A Lambert, Z Zhao, F Roseman, Q Guo, S D Gordon, L Wallace, A K Henders, P M Visscher, P Kraft, N G Martin, A P Morris, S A Treloar, S H Kennedy, S A Missmer, G W Montgomery, K T Zondervan
Journal: Nature Genetics (2010)
Abstract 680: Diet-induced obesity promotes tumor aggressiveness in genetically engineered mouse models of endometrial hyperplasia/cancer
Authors: Leslie H. Clark, Chunxiao Zhou, Stephanie A. Montgomery, Paola A. Gehrig, Victoria Bae-Jump
Journal: Cancer Research (2016)

Abstract Objective: To determine the effect of diet-induced obesity on the development of endometrial hyperplasia and cancer in genetically engineered mouse models. Methods: The PTEN heterozygous mouse model for endometrial hyperplasia and the LKB1/p53 endometrioid endometrial cancer mouse model were used. Mice were divided into two dietary groups and fed either a high-fat diet (HFD, 60% calories from fat, obese) or a low-fat diet (LFD, 10% calories from fat, lean) beginning at 3 weeks of age until sacrifice at 32 weeks (PTEN model) and 12 weeks (LKB1/p53 model). At the time of sacrifice, mouse weight and uterine/tumor size were documented. A dedicated mouse pathologist reviewed uterine pathology. For the PTEN heterozygous mouse model, uterine pathology was determined to be simple hyperplasia (SH) if increased number of simple tubular glands were seen without atypia. Complex hyperplasia (CH) was defined as branching, papillary lumenal infoldings, or back-to-back glandular crowding with or without nuclear atypic. Results: A total of 30 PTEN mice were examined, 14 in the obese group and 16 in the lean group. The HFD-fed mice were larger than the LFD-fed mice with a mean weight of 38.1 gm compared to 29.7 gm (p&amp;lt;0.001). There was no difference in uterine weight between the obese and lean mice, 0.30 versus 0.34 gm, respectively (p = 0.76). The lean mice were more likely to develop SH, 44% (n = 7) versus 7% (n = 1) in the obese group (p = 0.04). Of the obese mice, 57% (n = 8) developed CH (± atypia) compared to 31% (n = 5) of the lean mice (p = 0.16). A total of 35 LKB1/p53 mice were examined with 21 in the obese group and 14 in the lean group. The obese LKB1/p53 mice were larger (32.8 gm) than the lean mice (24.0 gm) (p = 0.033). The majority of the LKB1/p53 mice developed endometrioid adenocarcinoma with increased tumor size in the obese group (2.1 gm) versus lean group (0.79 gm) (p = 0.04). Conclusions: Diet-induced obesity led to increased mean body weight in both mouse models. In the PTEN heterozygous mouse model, a trend towards more complex endometrial hyperplasia was found in the obese group along with a higher rate of simple hyperplasia in the lean group. Increased endometrial tumor size was seen in the obese versus lean LKB1/p53 mice, suggesting that obesity may lead to increased aggressiveness in endometrial cancer. Citation Format: Leslie H. Clark, Chunxiao Zhou, Stephanie A. Montgomery, Paola A. Gehrig, Victoria Bae-Jump. Diet-induced obesity promotes tumor aggressiveness in genetically engineered mouse models of endometrial hyperplasia/cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 680.
Abstract 8667: Carvedilol Suppresses the Structural Remodeling in the Canine Atrial Fibrillation Model via the Suppression of Periostin as a Mediator of the Extracellular Matrix Synthesis
Authors: Jun Kishihara, Shinichi Niwano, Hiroe Niwano, Yuya Aoyama, Akira Satoh, Jun Oikawa, Tohru Izumi
Journal: Circulation (2011)

Background: Periostin is a novel extracellular matrix (ECM) protein, secreted from cardiac fibroblasts, and is considered to be related with cardiac fibrosis and remodeling as one of the mediators of ECM synthesis. In our canine atrial fibrillation (AF) model, we have documented that the ECM synthesis was observed as the atrial structural remodeling and the AF inducibility was suppressed by carvedilol, a beta-blocker with the anti oxidative action. In this study, we evaluate the effect of carvedilol against the periostin synthesis and the development of structural remodeling in the canine AF model. Methods: AF model was produced by performing rapid atrial stimulation in 15 dogs. They were divided into 3 groups; 1) carvedilol group (n=5): 6-week pacing with carvedilol (50mg/day), 2) control group (n=5): pacing without carvedilol, and 3) non-pacing group (n=5). At the end of the protocol, atrial tissues were sampled for the evaluation of mRNA and protein expressions of periostin by the real time RT-PCR and the western blot analysis. The immuno-fluorescent staining analysis of periostin and the 8-OHdG, one of the major forms of DNA damage induced by the reactive oxygen species, were performed to evaluate the expression of periostin and oxidative stress in the atrial tissue. Results: The mRNA and protein expressions of periostin were up-regulated in the control in comparison with non-pacing group, and this up-regulation was suppressed by carvedilol (p&lt;0.05). Immuno-fluorescent staining analysis exhibited abundant accumulation of periostin within the interstitial space with the fibrosis in the control, and it was suppressed by carvedilol. In the 8-OHdG staining, enhanced oxidative stress was observed in the atrial tissue in the control, but not in the carvedilol group. Conclusion: Periostin was remarkably up-regulated within the interstitial space in the atria with the fibrosis in our canine AF model. Because this up-regulation was suppressed by carvedilol, periostin up-regulation was speculated to be mediated by the oxidative stress in the AF model.
Salmonella enteritidis en Europe occidentale 1995-98 – un rapport de surveillance d’Enter-net
Authors: I. S.T. Fisher
Journal: Eurosurveillance (1999)

Une baisse de l’incidence des infections a Salmonella enteritidis entre 1993 et 1995 a ete signalee en Europe occidentale par la base de donnees sur les salmonelles du reseau Salm-Net (predecesseur d’Enter-Net). Au cours de cette periode, le nombre d’isolats de S. enteritidis est passe de 37 647 a 31 482 (1). Cette baisse de 16% a ete rapportee par les sept laboratoires nationaux de reference dont les donnees etaient disponibles. Cependant, une augmentation rapide des declarations de ce serotype s’est produite a la mi-1997 (2). D’apres les donnees de 1995-1998 fournies par 12 pays, cette resurgence est en cours de diminution (figure).