tbuckley/cabot-search huggingface dataset:
Statins and risk of breast cancer recurrence.
Authors: Minas Sakellakis, Anastasia Kostaki, Karolina Akinosoglou, Despina Spyropoulou, Angelos Koutras
Journal: Journal of Clinical Oncology (2016)

e13044 Background: The primary endpoint of our study was to test whether the concurrent use of a statin is related to a lower risk of recurrence and increased relapse-free survival in patients with early breast cancer. Methods: We reviewed 610 female patients with breast cancer of stage 1, 2 or 3 that had been surgically treated and received adjuvant chemotherapy in order to prevent recurrence. Results: Among patients with breast cancer, 83 patients (13,6%) were receiving a statin on a chronic basis, for other medical purposes. Overall, statin users displayed a lower risk of recurrence (HR, 0,58; 95% CI, 0,36 to 0,94; p = 0,028). This observation was particularly evident in the younger age group (HR, 0,34; 95% CI, 0,14 to 0,79; p = 0,004). A marginal association was also noted in the hormone receptor positive subgroup (HR, 0,42; 95% CI, 0,18 to 0,98; p = 0,024). Conclusions: Statins are linked to a favorable outcome in early breast cancer patients, especially in the younger age group.
Three-year Safety of Radium-223 Dichloride in Patients with Castration-resistant Prostate Cancer and Symptomatic Bone Metastases from Phase 3 Randomized Alpharadin in Symptomatic Prostate Cancer Trial
Authors: Christopher C. Parker, Robert E. Coleman, Oliver Sartor, Nicholas J. Vogelzang, David Bottomley, Daniel Heinrich, Svein I. Helle, Joe M. O'Sullivan, Sophie D. Fosså, Aleš Chodacki, Paweł Wiechno, John Logue, Mihalj Seke, Anders Widmark, Dag Clement Johannessen, Peter Hoskin, Nicholas D. James, Arne Solberg, Isabel Syndikus, Jan Kliment, Steffen Wedel, Sibylle Boehmer, Marcos Dall’Oglio, Lars Franzén, Øyvind S. Bruland, Oana Petrenciuc, Karin Staudacher, Rui Li, Sten Nilsson
Journal: European Urology (2017)

In Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial, radium-223 versus placebo prolonged overall survival with favorable safety in castration-resistant prostate cancer patients with symptomatic bone metastases. Long-term radium-223 monitoring underlies a comprehensive safety and risk/benefit assessment.To report updated ALSYMPCA safety, including long-term safety up to 3 yr after the first injection.Safety analyses from phase 3 randomized ALSYMPCA trial included patients receiving ≥1 study-drug injection (600 radium-223 and 301 placebo). Patients (405 radium-223 and 167 placebo) entered long-term safety follow-up starting 12 wk after the last study-drug injection, to 3 yr from the first injection. Forty-eight of 405 (12%) radium-223 and 12/167 (7%) placebo patients completed follow-up, with evaluations every 2 mo for 6 mo, then every 4 mo until 3 yr.All adverse events (AEs) were collected until 12 wk after the last injection; subsequently, only treatment-related AEs were collected. Additional long-term safety was assessed by development of acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), aplastic anemia, and secondary malignancies. Data analysis used descriptive statistics.During treatment to 12 wk following the last injection, 564/600 (94%) radium-223 and 292/301 (97%) placebo patients had treatment-emergent AEs (TEAEs). Myelosuppression incidence was low. Grade 3/4 hematologic TEAEs in radium-223 and placebo groups were anemia (13% vs 13%), neutropenia (2% vs 1%), and thrombocytopenia (7% vs 2%). Ninety-eight of 600 (16%) radium-223 and 68/301 (23%) placebo patients experienced grade 5 TEAEs. Long-term follow-up showed no AML, MDS, or new primary bone cancer; secondary non-treatment-related malignancies occurred in four radium-223 and three placebo patients. One radium-223 patient had aplastic anemia 16 mo after the last injection. No other cases were observed. Limitations include short (3-yr) follow-up.Final long-term safety ALSYMPCA analysis shows that radium-223 remained well tolerated, with low myelosuppression incidence and no new safety concerns.Updated Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial findings show that radium-223 remained well tolerated during treatment and up to 3 yr after each patient's first injection.
Abstract 37: Genetic Profile and Modifiers of Transient Cardiomyopathy from Tamoxifen-Induced Cardiomyocyte Expression of Mutated Estrogen Receptor-Cre Fusion Protein
Authors: Janelle Rowell, Norimichi Koitabashi, Andreas Barth, Djahida Bedja, Kathleen L Gabrielson, Shuxun Ren, Yibin Wang, David A Kass
Journal: Circulation Research (2012)

The Myh6-MerCreMer (MCM) transgenic mouse is used to conditionally augment or reduce targeted gene expression in cardiomyocytes in vivo. Studies report transient cardiomyopathy upon tamoxifen exposure in the MCM mouse itself; however, this varies among investigators despite their using seemingly similar protocols and mouse strain. To better understand this model and apparent variable response, we studied the transcriptome-function relationship during the initial days of tamoxifen therapy, and tested if a genetic background involving gene deletion for nicotinamide nucleotide transhydrogenase (Nnt) found in C57BL/6J (common strain in MCM studies) influences the severity of transient cardiac dysfunction. MCM +/- mice (pure C57BL/6J, all Nnt -/- ) received intra-peritoneal injections of tamoxifen (40 mg/kg/day for 5 days). LV function remained normal until Day 2 after tamoxifen, yet qtPCR and microarray analysis in MCM +/- mice revealed markedly reduced expression of metabolic and calcium handling genes ( Pgc1a, Pgc1b, Plb, Atp2a2 ) and upregulation of sarcomere protein skeletal isoforms by Day 2. This transcriptome subsequently evolved to one typical of cardiomyopathy (initial highlighted metabolic/Ca 2+ genes remaining low) that correlated with LV dysfunction. Purchased MCM +/+ mice (sv129xC57BL/6J) were Nnt heterozygotes. After 7-10 days following tamoxifen dosing, offspring lacking Nnt developed worse cardiodepression than those with at least one Nnt allele. The MCM mouse exhibits marked changes in transcription profile 2 days after tamoxifen suggesting potential causal mechanisms for subsequent cardiomyopathy. The severity of dysfunction is influenced by background genetics in part related to Nnt.
A rash localised around the eyes
Authors: Mitsuhito Ota
Journal: BMJ (2017)

A 26 year old woman presented with a sudden rash on the face (fig 1⇓). The previous day, she had had severe vomiting, diarrhoea, and fever, and had been diagnosed with acute viral gastroenteritis. The rash was localised around the eyes. What is the cause of rash?



Fig 1  Localised peri-orbital pinpoint rash



The diagnosis is facial purpura caused by emesis. The cause is rupture of capillaries in the upper dermis resulting from elevated intravascular pressure during vomiting.

### Discussion

Purpura is caused by extravasation of …
Effect of matrix metalloproteinase-2 on CD8+ T cell and NK cell responses.
Authors: Anne Gallois, Emmanuelle Godefroy, Olivier Manches, Nina Bhardwaj
Journal: Journal of Clinical Oncology (2012)

e21081 Background: Matrix metalloproteinase 2 (MMP-2) cleaves many components of the extracellular matrix and is over-expressed in several cancers including melanoma. High levels of MMP-2 expressed by tumors are associated with later tumor stages, increased dissemination and poorer survival/prognosis. We recently identified a pathway whereby MMP-2 functions as a human endogenous “conditioner” that skews CD4 + T cells towards a detrimental/inefficient T H 2 phenotype through OX40L expression and inhibition of IL-12p70 production. We unraveled the underlying mechanism: MMP-2 degrades the type I IFN receptor (IFNAR1), thereby preventing STAT1 phosphorylation necessary for IL-12 production. Here, we described IFNAR1 as a novel MMP-2 substrate. This finding opens the way to characterize a possible new immunosuppressive effect of MMP-2 on other IFNAR1 + immune cells such as NK cells and CD8 + T cells. Methods: CD8 + T cells and NK cells were purified from PBMCs and incubated with MMP-2 overnight. IFNAR1 expression was assessed by FACS and Western Blot. Granzyme B, TNF alpha and IFN gamma expression was determined by intracellular staining of memory T cells. NK cells cytotoxicity was measured by Lamp-1 expression after 4h of coculture with K562 cells. Results: We first found that IFNAR1 is expressed by NK and CD8 + T cells and confirmed that MMP-2 degraded it. Memory CD8 + T cells significantly down-regulate granzyme B expression in the presence of MMP-2. Furthermore, memory CD8 + T cells pre-incubated with MMP-2 were significantly impaired with respect to IFN-gamma and TNF-alpha production. Finally, our data suggest that NK cells’ cytotoxicity might also be affected by MMP-2 through modulation of Granzyme B production. Conclusions: Our data strongly suggest that MMP-2 regulates memory CD8 + T cells not only by down regulating cytolytic activity through inhibition of granzyme B, but also by inhibiting cytokine production such as IFN-gamma and TNF-alpha. Elucidating the underlying mechanisms of MMP-2-dependent immune regulation should lead to the development of innovative immune therapies bypassing tumor escape to treat cancer patients.
Does Obstructive Sleep Apnea Treatment Reduce Cardiovascular Risk?
Authors: Daniel J. Gottlieb
Journal: JAMA (2017)

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Increased IFNγ+ T Cells Are Responsible for the Clinical Responses of Low-Dose DNA-Demethylating Agent Decitabine Antitumor Therapy
Authors: Xiang Li, Yan Zhang, Meixia Chen, Qian Mei, Yang Liu, Kaichao Feng, Hejin Jia, Liang Dong, Lu Shi, Lin Liu, Jing Nie, Weidong Han
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Low-dose DNA-demethylating agent decitabine therapy is effective in a subgroup of cancer patients. It remains largely elusive for the biomarker to predict therapeutic response and the underlying antitumor mechanisms, especially the impact on host antitumor immunity. Experimental Design: The influence of low-dose decitabine on T cells was detected both in vitro and in vivo. Moreover, a test cohort and a validation cohort of advanced solid tumor patients with low-dose decitabine-based treatment were involved. The activation, proliferation, polarization, and cytolysis capacity of CD3+ T cells were analyzed by FACS and CCK8 assay. Kaplan–Meier and Cox proportional hazard regression analysis were performed to investigate the prognostic value of enhanced T-cell activity following decitabine epigenetic therapy. Results: Low-dose decitabine therapy enhanced the activation and proliferation of human IFNγ+ T cells, promoted Th1 polarization and activity of cytotoxic T cells both in vivo and in vitro, which in turn inhibited cancer progression and augmented the clinical effects of patients. In clinical trials, increased IFNγ+ T cells and increased T-cell cytotoxicity predicted improved therapeutic responses and survival in the test cohort and validation cohort. Conclusions: We find that low-dose decitabine therapy promotes antitumor T-cell responses by promoting T-cell proliferation and the increased IFNγ+ T cells may act as a potential prognostic biomarker for the response to decitabine-based antitumor therapy. Clin Cancer Res; 23(20); 6031–43. ©2017 AACR.
Silencing Of Circular RNA-ZNF609 Ameliorates Vascular Endothelial Dysfunction
Authors: Chang Liu, Mu-Di Yao, Chao-Peng Li, Kun Shan, Hong Yang, Jia-Jian Wang, Ban Liu, Xiu-Miao Li, Jin Yao, Qin Jiang, Biao Yan
Journal: Theranostics (2017)

Vascular dysfunction is a hallmark of ischemic, cancer, and inflammatory diseases, contributing to disease progression. Circular RNAs (circRNAs) are endogenous non-coding RNAs, which have been reported to be abnormally expressed in many human diseases. In this study, we used retinal vasculature to determine the role of circular RNA in vascular dysfunction. We revealed that cZNF609 was significantly up-regulated upon high glucose and hypoxia stress in vivo and in vitro. cZNF609 silencing decreased retinal vessel loss and suppressed pathological angiogenesis in vivo. cZNF609 silencing increased endothelial cell migration and tube formation, and protected endothelial cell against oxidative stress and hypoxia stress in vitro. By contrast, transgenic overexpression of cZNF609 showed an opposite effects. cZNF609 acted as an endogenous miR-615-5p sponge to sequester and inhibit miR-615-5p activity, which led to increased MEF2A expression. MEF2A overexpression could rescue cZNF609 silencing-mediated effects on endothelial cell migration, tube formation, and apoptosis. Moreover, dysregulated cZNF609 expression was detected in the clinical samples of the patients with diabetes, hypertension, and coronary artery disease. Intervention of cZNF609 expression is promising therapy for vascular dysfunction.
A point‐based prediction model for cardiovascular risk in orthotopic liver transplantation: The CAR‐OLT score
Authors: Lisa B. VanWagner, Hongyan Ning, Maureen Whitsett, Josh Levitsky, Sarah Uttal, John T. Wilkins, Michael M. Abecassis, Daniela P. Ladner, Anton I. Skaro, Donald M. Lloyd‐Jones
Journal: Hepatology (2017)

Cardiovascular disease (CVD) complications are important causes of morbidity and mortality after orthotopic liver transplantation (OLT). There is currently no preoperative risk‐assessment tool that allows physicians to estimate the risk for CVD events following OLT. We sought to develop a point‐based prediction model (risk score) for CVD complications after OLT, the Cardiovascular Risk in Orthotopic Liver Transplantation risk score, among a cohort of 1,024 consecutive patients aged 18‐75 years who underwent first OLT in a tertiary‐care teaching hospital (2002‐2011). The main outcome measures were major 1‐year CVD complications, defined as death from a CVD cause or hospitalization for a major CVD event (myocardial infarction, revascularization, heart failure, atrial fibrillation, cardiac arrest, pulmonary embolism, and/or stroke). The bootstrap method yielded bias‐corrected 95% confidence intervals for the regression coefficients of the final model. Among 1,024 first OLT recipients, major CVD complications occurred in 329 (32.1%). Variables selected for inclusion in the model (using model optimization strategies) included preoperative recipient age, sex, race, employment status, education status, history of hepatocellular carcinoma, diabetes, heart failure, atrial fibrillation, pulmonary or systemic hypertension, and respiratory failure. The discriminative performance of the point‐based score (C statistic = 0.78, bias‐corrected C statistic = 0.77) was superior to other published risk models for postoperative CVD morbidity and mortality, and it had appropriate calibration (Hosmer‐Lemeshow P = 0.33). Conclusion: The point‐based risk score can identify patients at risk for CVD complications after OLT surgery (available at www.carolt.us); this score may be useful for identification of candidates for further risk stratification or other management strategies to improve CVD outcomes after OLT. (H epatology 2017;66:1968–1979)
Budget Impact Analysis of Treating Chemotherapy Patients with Health Care Provider-Administered Tbo-Filgrastim, Filgrastim-Sndz, and Filgrastim in the United States
Authors: Holly Trautman, Erika Szabo, Francesco Lo-Coco, Elizabeth James, Susan Gabriel, Jifang Zhou, Ashutosh Pathak, Boxiong Tang
Journal: Blood (2016)
Case 21-2017
Authors: John O. Schorge, Andrea L. Russo, Michael F. Greene, Melissa A. Woythaler, Esther Oliva
Journal: New England Journal of Medicine (2017)

A 28-year-old pregnant woman with Rh isoimmunization and endocervical carcinoma was seen in the maternal–fetal outpatient clinic at 34.1 weeks of gestation. Management decisions were made.
Inhibition of autophagy limits vertical transmission of Zika virus in pregnant mice
Authors: Bin Cao, Lindsay A. Parnell, Michael S. Diamond, Indira U. Mysorekar
Journal: The Journal of Experimental Medicine (2017)

Zika virus (ZIKV) infection during pregnancy leads to devastating fetal outcomes, including intrauterine growth restriction and microcephaly. Greater understanding of mechanisms underlying ZIKV maternal-fetal transmission is needed to develop new therapeutic interventions. Here, we define an important role for the autophagy pathway in ZIKV vertical transmission. ZIKV infection induced autophagic activity in human trophoblasts and pharmacological inhibition limited ZIKV infectivity. Furthermore, deficiency in an essential autophagy gene, Atg16l1, in mice limited ZIKV vertical transmission and placental and fetal damage and overall improved placental and fetal outcomes. This protection was due to a placental trophoblast cell-autonomous effect of autophagic activity, not to alterations in systemic maternal ZIKV infection. Finally, an autophagy inhibitor, hydroxychloroquine, approved for use in pregnant women, attenuated placental and fetal ZIKV infection and ameliorated adverse placental and fetal outcomes. Our study reveals new insights into the mechanism of ZIKV vertical transmission and suggests that an autophagy-based therapeutic warrants possible evaluation in humans to diminish the risks of ZIKV maternal-fetal transmission.
Abstract #1741: Combination treatment strategy of an IGF-1R kinase inhibitor, OSI-906, in models of progressive disease following initial response to EGFR tyrosine kinase inhibitor therapy
Authors: Eric Brown, Stacia Silva, Caroline Pirritt, Julie Wolf, David Epstein, Robert Wild, Maryland Rosenfeld-Franklin
Journal: Cancer Research (2009)

Erlotinib is a small molecule tyrosine kinase inhibitor (TKI) of EGFR that is approved for use in non-small cell lung cancer (NSCLC) and pancreatic cancer. While this drug is highly efficacious for many patients, their disease often progresses after a period of time on erlotinib. While it is common practice to change therapies upon disease progression, recent clinical data may support a hypothesis that patients may continue to benefit from erlotinib therapy beyond disease progression. Here we report preclinical data that support maintaining erlotinib treatment in combination with another molecular targeted agent after initial response and then progression on erlotinib, which we term treatment beyond progression (TBP). We have identified two human tumor xenograft models, NCI-H292 (NSCLC) and GEO (colon) that initially respond to erlotinib but are characterized by renewed tumor growth upon prolonged and continuous treatment with erlotinib. Characterization of the tumors that acquired resistance to erlotinib revealed elevated phosphorylation of IGF-1R and downstream signaling mediators, AKT and ERK. We employed these xenograft models to evaluate the efficacy of erlotinib maintenance therapy with and without the addition of OSI-906, a potent and selective IGF-1R inhibitor, following response and then progression on erlotinib monotherapy. We observed a benefit with either continued erlotinib treatment or switching to OSI-906 treatment compared to no further treatment. However, the combination of adding OSI-906 to erlotinib treatment was significantly better than either single agent. This data provides preclinical proof of concept for the use of OSI-906 in the TBP setting and suggests that IGF-1R pathway activation may play an important role in erlotinib drug resistance.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1741.
PTU-043 Are we turning a blind eye to obesity in the out-patient clinics?
Authors: R Logan, I Bough, L Adams, J Todd, N Reynolds, M Groome, C Mowat
Journal: Gut (2017)

Introduction  Obesity rates in the UK are rising: 65% of adults in Scotland now have a BMI ≥251. Within Gastroenterology (GI) clinics, consultations are traditionally disease-focused, and the topic of obesity may only be broached in cases of reflux and liver disease. This study explored the prevalence of obesity in GI clinics compared to national figures, and whether clinicians believed weight was a contributing factor to a patient‘s presentation.  Method  Over a 4 week period, consecutive patients over the age of 14 were approached in general GI, IBD and liver clinics across NHS Tayside. BMI was recorded and categorised per the WHO BMI classification2. Patients completed a questionnaire detailing their smoking history, alcohol consumption and weekly activity levels. These findings were then collated and compared to statistics from the 2015 Scottish Health Survey1. The attending clinician was asked whether the patient’s weight was implicated in their presenting condition.  Results  53 adult clinics in Tayside were attended (12 general GI, 19 liver, 22 IBD). 485 patients were included (median age 57, range 14–95, 41% male), comprising 80 liver, 182 IBD and 223 general GI patients. Median BMI was 26.5, with a range of 15.9%–56.7. 28% were obese (BMI ≥30), comparable with 27% of the Scottish population1. Weight was a contributory factor in 32% of obese patients, in whom the most common diagnoses were UC (19%), Crohn’s (17%), NASH (14%), reflux (6%) and alcoholic liver disease (6%). 18.5% of the 118 IBD patients screened for recent steroid use had taken oral steroids within the past three months. Such patients were more likely to have a BMI ≥25, but represented 8.3% of the total IBD cohort. 18% of the study cohort were smokers, 59% failed to meet the weekly recommendations for exercise3, and an estimated 8%–9% were consuming more than those for alcohol consumption4.  Conclusion  Obesity prevalence in GI clinics is consistent with national figures but, despite the known negative impact of obesity in GI disease, is considered incidental in most cases. Obesity should be given greater consideration within consultations, and short interventions to promote exercise and healthy weight should be studied.  References  . Scottish Government Health Directorates. The Scottish Health Survey. National Statistics; 2015.  . Body mass index - BMI; WHO Europe; 2016. http://www.euro.who.int/en/health-topics/disease-prevention/nutrition/a-healthy-lifestyle/body-mass-index-bmi  . Physical Activity and Adults; WHO; 2011. http://www.who.int/dietphysicalactivity/factsheet_adults/en/  . UK Chief Medical Officers’ Low Risk Drinking Guidelines. gov.uk; 2016.  Disclosure of Interest  None Declared