tbuckley/cabot-search huggingface dataset:
Local Delivery of OncoVEXmGM-CSF Generates Systemic Antitumor Immune Responses Enhanced by Cytotoxic T-Lymphocyte–Associated Protein Blockade
Authors: Achim K. Moesta, Keegan Cooke, Julia Piasecki, Petia Mitchell, James B. Rottman, Karen Fitzgerald, Jinghui Zhan, Becky Yang, Tiep Le, Brian Belmontes, Oluwatayo F. Ikotun, Kim Merriam, Charles Glaus, Kenneth Ganley, David H. Cordover, Andrea M. Boden, Rafael Ponce, Courtney Beers, Pedro J. Beltran
Journal: Clinical Cancer Research (2017)

Purpose: Talimogene laherparepvec, a new oncolytic immunotherapy, has been recently approved for the treatment of melanoma. Using a murine version of the virus, we characterized local and systemic antitumor immune responses driving efficacy in murine syngeneic models.Experimental Design: The activity of talimogene laherparepvec was characterized against melanoma cell lines using an in vitro viability assay. Efficacy of OncoVEXmGM-CSF (talimogene laherparepvec with the mouse granulocyte-macrophage colony-stimulating factor transgene) alone or in combination with checkpoint blockade was characterized in A20 and CT-26 contralateral murine tumor models. CD8+ depletion, adoptive T-cell transfers, and Enzyme-Linked ImmunoSpot assays were used to study the mechanism of action (MOA) of systemic immune responses.Results: Treatment with OncoVEXmGM-CSF cured all injected A20 tumors and half of contralateral tumors. Viral presence was limited to injected tumors and was not responsible for systemic efficacy. A significant increase in T cells (CD3+/CD8+) was observed in injected and contralateral tumors at 168 hours. Ex vivo analyses showed these cytotoxic T lymphocytes were tumor-specific. Increased neutrophils, monocytes, and chemokines were observed in injected tumors only. Importantly, depletion of CD8+ T cells abolished all systemic efficacy and significantly decreased local efficacy. In addition, immune cell transfer from OncoVEXmGM-CSF-cured mice significantly protected from tumor challenge. Finally, combination of OncoVEXmGM-CSF and checkpoint blockade resulted in increased tumor-specific CD8+ anti-AH1 T cells and systemic efficacy.Conclusions: The data support a dual MOA for OncoVEXmGM-CSF that involves direct oncolysis of injected tumors and activation of a CD8+-dependent systemic response that clears injected and contralateral tumors when combined with checkpoint inhibition. Clin Cancer Res; 23(20); 6190-202. ©2017 AACR.
Phase I study of neoadjuvant chemoradiation (CRT) plus sorafenib (S) for high-risk extremity soft tissue sarcomas (STS).
Authors: Janelle Marie Meyer, Kelly Shea Perlewitz, James B. Hayden, Arthur Hung, Yee-Cheen Doung, Atiya Mansoor, Brooke Beckett, Megan L. Holtorf, William J. Woodward, Eve T. Rodler, Robin Lewis Jones, Wei Huang, Christopher W. Ryan
Journal: Journal of Clinical Oncology (2012)

10011^ Background: We previously reported a regimen of epirubicin/ifosfamide (E/I) and hypofractionated radiation (RT) followed by surgery and postoperative E/I. We hypothesize that S + CRT is safe and augments activity through anti-angiogenic mechanisms. We performed dynamic contrast-enhanced MRI using shutter speed pharmacokinetic analysis (SSM DCE-MRI) to assess preoperative therapy effect. Methods: Subjects with &gt;5 cm, grade 2-3 extremity STS were treated in cohorts of escalating S dose using a 3+3 design based on dose-limiting toxicity (DLT) during the first 8 weeks. Daily S was initiated 14 days prior to E/I (E 30 mg/m 2 /day days 1-3 and I 2.5 g/m 2 /day days 1-3 every 21 days for 3 pre- and 3 postoperative cycles). 28 Gy preoperative RT was administered in 8 fractions during cycle 2 (E omitted). Primary objective was to determine maximum tolerated dose (MTD). DCE-MRI was performed at baseline, after 2 weeks S, and prior to surgery. Results: 16 subjects were enrolled. Histologies included pleomorphic (5), synovial (5), liposarcoma (3), other (3). All were extremity (12 lower, 4 upper) tumors. Median tumor size was 11.7 cm. The MTD of S was 400 mg daily (see table). Most common grade 3/4 adverse events among all dose levels were neutropenia (94%), anemia (75%), hypophosphatemia (69%), thrombocytopenia (56%), neutropenic fever/infection (50%), and hypokalemia (31%). 38% developed wound complications requiring surgical intervention including amputation in 1 subject. 44% had &gt;95% histologic necrosis at surgery. No subjects have recurred with median follow-up of 15 (6-27) months. 8 subjects underwent DCE-MRI. Changes in SSM DCE-MRI biomarkers after 2 weeks S correlated with histologic response (R 2 =0.71). Conclusions: The addition of S to CRT is feasible with promising activity that warrants further investigation. Rate of wound complications is similar to other reports of preoperative radiation. SSM DCE-MRI detected changes in tumor perfusion after only 2 weeks of S and may prove useful to assess early drug effect in STS. [Table: see text]
APOBEC3A and APOBEC3B Activities Render Cancer Cells Susceptible to ATR Inhibition
Authors: Rémi Buisson, Michael S. Lawrence, Cyril H. Benes, Lee Zou
Journal: Cancer Research (2017)

The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like APOBEC3A and APOBEC3B have emerged as key mutation drivers in cancer. Here, we show that APOBEC3A and APOBEC3B activities impose a unique type of replication stress by inducing abasic sites at replication forks. In contrast to cells under other types of replication stress, APOBEC3A-expressing cells were selectively sensitive to ATR inhibitors (ATRi), but not to a variety of DNA replication inhibitors and DNA-damaging drugs. In proliferating cells, APOBEC3A modestly elicited ATR but not ATM. ATR inhibition in APOBEC3A-expressing cells resulted in a surge of abasic sites at replication forks, revealing an ATR-mediated negative feedback loop during replication. The surge of abasic sites upon ATR inhibition associated with increased accumulation of single-stranded DNA, a substrate of APOBEC3A, triggering an APOBEC3A-driven feed-forward loop that ultimately drove cells into replication catastrophe. In a panel of cancer cell lines, ATRi selectively induced replication catastrophe in those harboring high APOBEC3A and/or APOBEC3B activities, showing that APOBEC3A and APOBEC3B activities conferred susceptibility to ATRi. Our results define an APOBEC-driven replication stress in cancer cells that may offer an opportunity for ATR-targeted therapy. Cancer Res; 77(17); 4567-78. ©2017 AACR.
GP who certified taxi drivers without examining them gets 12 month suspension
Authors: Clare Dyer
Journal: BMJ (2017)

A GP has been suspended for 12 months after an undercover reporter for the Sun newspaper secretly recorded him selling a medical certification for taxi drivers without conducting a medical examination.

Ashraful Haque Mirza, 42, of south London, admitted to a Manchester hearing of the Medical Practitioners Tribunal Service that he had recorded a blood pressure reading and vision readings despite not performing the necessary tests during a 2 minute consultation.

Mirza also admitted signing a statement in the form attesting that he had seen the patient’s full medical records, when in fact he had not. He admitted that he had been …
Fatal and non-fatal injury outcomes: results from a purposively sampled census of seven rural subdistricts in Bangladesh
Authors: Olakunle Alonge, Priyanka Agrawal, Abu Talab, Qazi S Rahman, AKM Fazlur Rahman, Shams El Arifeen, Adnan A Hyder
Journal: The Lancet Global Health (2017)

90% of the global burden of injuries is borne by low-income and middle-income countries (LMICs). However, details of the injury burden in LMICs are less clear because of the scarcity of data and population-based studies. The Saving of Lives from Drowning project, implemented in rural Bangladesh, did a census on 1·2 million people to fill this gap. This Article describes the epidemiology of fatal and non-fatal injuries from the study.In this study, we used data from the baseline census conducted as part of the Saving of Lives from Drowning (SoLiD) project. The census was implemented in 51 unions from seven purposively sampled rural subdistricts of Bangladesh between June and November, 2013. Sociodemographic, injury mortality, and morbidity information were collected for the whole population in the study area. We analysed the data for descriptive measures of fatal and non-fatal injury outcomes. Age and gender distribution, socioeconomic characteristics, and injury characteristics such as external cause, intent, location, and body part affected were reported for all injury outcomes.The census covered a population of 1 169 593 from 270 387 households and 451 villages. The overall injury mortality rate was 38 deaths per 100 000 population per year, and 104 703 people sustained major non-fatal injuries over a 6-month recall period. Drowning was the leading external cause of injury death for all ages, and falls caused the most number of non-fatal injuries. Fatal injury rates were highest in children aged 1-4 years. Non-fatal injury rates were also highest in children aged 1-4 years and those aged 65 years and older. Males had more fatal and non-fatal injuries than females across all external causes except for burns. Suicide was the leading cause of injury deaths in individuals aged 15-24 years, and more than 50% of the suicides occurred in females. The home environment was the most common location for most injuries.The burden of fatal and non-fatal injuries in rural Bangladesh is substantial, accounting for 44 050 deaths and 21 million people suffering major events annually. Targeted approaches addressing drowning in children (especially those aged 1-4 years), falls among the elderly, and suicide among young female adults are urgently needed to reduce injury deaths and morbidity in Bangladesh.Bloomberg Philanthropies.
Unmasking hidden disease: exercise pulmonary haemodynamics in systemic sclerosis
Authors: Robin Condliffe
Journal: European Respiratory Journal (2017)

Although pulmonary arterial hypertension (PAH) is a rare condition in the general population, it is not uncommon in systemic sclerosis (SSc), with a prevalence of 9% [1]. Furthermore, survival in patients with PAH associated with SSc (SSc-PAH) is worse than in those with idiopathic PAH, even when accounting for their older age [2–4]. As a result, patients with SSc are the main "at-risk" patient group who undergo widespread screening for the presence of PAH. Patients identified with SSc-PAH as a result of screening appear to have less severe disease and better survival than those who are diagnosed following symptomatic presentation [5]. If PAH results from progressive loss of the pulmonary arterial bed, and over 50% of this vasculature needs to be obstructed before pulmonary hypertension (PH; as defined by a resting mean pulmonary arterial pressure (mPAP) ≥25 mmHg) develops, then there is a good rationale for the use of exercise to unmask hidden pulmonary vascular disease. Measuring pulmonary pressures on exercise in patients with systemic sclerosis may unmask pulmonary vascular disease <http://ow.ly/EVZ330cyLNd>
Burnout among doctors
Authors: Jane B Lemaire, Jean E Wallace
Journal: BMJ (2017)

Thank you for your interest in spreading the word about The BMJ.NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address. Username * Your Email * Send To * You are going to email the following Burnout among doctors Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Treatment of metastatic renal cell carcinomawith constant-rate floxuridine infusion plus recombinant alpha 2b-interferon
Authors: Alfredo Falcone, C. Cianci, E. Pfanner, S. Ricci, M. Lencioni, I. Brunetti, Pc Giulianotti, L. Vannucci, Franco Mosca, Pf Conte
Journal: Annals of Oncology (1996)
Abstract 372: Regulation of Ski and Scleraxis in the Infarcted Rat Heart
Authors: Krista L Filomeno, Sunil G Rattan, Sheri Bage, Matthew Zeglinski, Michael P Czubryt, Ian M Dixon
Journal: Circulation Research (2015)

Introduction: Coronary heart disease is causal to myocardial infarction (MI) and cardiac fibrosis. Upon ischemic myocardial injury, resident cardiac fibroblasts phenoconvert to myofibroblasts and synthesize large amounts of fibrillar collagens to produce scar tissue. Although the myofibroblast numbers are reduced in the infarct scar following the completion of wound healing, a sub-population of cells persist in the wounded area, leading to maladaptive chronic remodeling of the scar area and eventually the non-infarcted myocardium. Ski has been identified as a repressor of the TGF-β1 signaling pathway, attenuating the myofibroblast phenotype and its functional properties. Scleraxis has been implicated in canonical TGF-β1 signaling to promote collagen1α2 expression. We investigated how Ski and Scleraxis contribute to physiological and pathological wound healing in vivo. Methods: The study was carried out using 64 male Sprague-Dawley rats. The left anterior descending (LAD) coronary artery was ligated to induce a myocardial infarction. Control (sham) operated animals underwent surgery without ligation of the LAD artery. Animals were sacrificed at 2, 4, and 8 weeks post-MI and tissue collected for Western blot and qPCR studies. Results: Scleraxis mRNA expression remained at baseline at 2 and 8 weeks post-MI, but was significantly increased 4 weeks post-MI. Scleraxis protein expression was down-regulated within the scar area of infarcted hearts when compared to control samples 2 and 4 weeks post-MI. Ski mRNA expression was up-regulated within the scar area of infarcted hearts 2, 4 and 8 weeks after infarction. Conclusions: Scleraxis protein is down-regulated in myofibroblasts of the infarct scar in the chronic stages of myocardial infarction, corresponding to the maturation of the scar. At these stages of wound healing, we have previously published that Ski is up-regulated in the cytosol of these same cells. We suggest reciprocal feedback in the expression of these two proteins exists in myofibroblasts in the infarct scar. We hope to learn more about the Ski/Scleraxis feedback loop in pathological wound healing to identify novel therapeutic targets.
Determination of the maximum tolerated dose (MTD) of the CNS penetrant tyrosine kinase inhibitor (TKI) tesevatinib administered in combination with trastuzumab in HER2+ patients with metastatic breast cancer (BC).
Authors: Nancy U. Lin, Rachel A. Freedman, Kathy Miller, Komal L. Jhaveri, David A. Eiznhamer, Mark S. Berger, Erika Paige Hamilton
Journal: Journal of Clinical Oncology (2016)

514 Background: Brain metastases (BM) are common in patients (pts) with HER2+ BC and there is a need for a potent TKI that crosses the BBB and penetrates CNS tissues. Tesevatinib is a potent EGFR inhibitor and also inhibits HER2 and SRC while crossing the BBB in whole animal models and achieving CNS levels similar to plasma. Methods: This dose escalation study defined the MTD of tesevatinib in HER2+ BC pts when combined with trastuzumab 6 mg/kg IV every 3 weeks. A 3+3 design was utilized with tesevatinib given 150 mg, 250 mg, 300 mg, or 350 mg daily (QD). Previously reported results demonstrated the tolerability of 150 mg and 250 mg QD dosing (ASCO 2015). Here we report the results of 300 mg and 350 mg QD dosing cohorts, and the establishment of the MTD. Results: After 3 pts were treated at 300 mg QD with no DLTs, the 350 mg QD cohort was initiated. The first 2 pts in the 350 mg cohort each experienced a DLT (Grade 3 diarrhea and Grade 3 QTc prolongation). To confirm the MTD, 5 additional pts were enrolled at 300 mg QD. Two pts in the additional 300 mg QD cohort discontinued dosing prior to completing 21 days and were replaced. One pt out of a total of 8 in the 300 mg QD cohort experienced Grade 3 diarrhea. The most common AE's ( > 30%) were rash, diarrhea, decreased appetite, and nausea. AE incidence did not appear to correlate with plasma concentration of drug. One pt with brain metastases (BM) on 300 mg QD (reduced to 250 mg QD) had stable disease (SD) for 7 months and another BM patient on 350 mg QD (reduced to 300 mg QD) had SD for 6 months. Conclusions: A 300 mg daily dose of tesevatinib (in combination with trastuzumab) is the MTD in HER2+ BC patients. Two of seven patients with BM had prolonged stable disease. Clinical trial information: NCT02154529.Tesevatinib Dose # Patients Median Age (Range) DLT Events 150 4 43 (29-48) - 250 3 54 (42-55) - 300 8 50 (40-61) Gr 3 Diarrhea 350 2 60 (58-61) Gr 3 Diarrhea, Gr 3 QTc Total 17 48 (29-61)
Non-Invasive Monitoring of CNS MHC-I Molecules in Ischemic Stroke Mice
Authors: Jing Xia, Ying Zhang, Huanhuan Zhao, Jie Wang, Xueren Gao, Jinpeng Chen, Bo Fu, Yuqing Shen, Fengqin Miao, Jianqiong Zhang, Gaojun Teng
Journal: Theranostics (2017)

Ischemic stroke is one of the leading causes of morbidity and mortality worldwide.The expression of major histocompatibility complex class I (MHC-I) molecules in the central nervous system, which are silenced under normal physiological conditions, have been reported to be induced by injury stimulation.The purpose of this study was to determine whether MHC-I molecules could serve as molecular targets for the acute phase of ischemic stroke and to assess whether a high-affinity peptide specific for MHC-I molecules could be applied in the near-infrared imaging of cerebral ischemic mice.Quantitative real-time PCR and Western blotting were used to detect the expression of MHC-I molecules in two mouse models of cerebral ischemic stroke and an in vitro model of ischemia.The NetMHC 4.0 server was used to screen a high-affinity peptide specific for mouse MHC-I molecules.The Rosetta program was used to identify the specificity and affinity of the screened peptide (histocompatibility-2 binding peptide, H2BP).The results demonstrated that MHC-I molecules could serve as molecular targets for the acute phase of ischemic stroke.Cy5.5-H2BP molecular probes could be applied in the near-infrared imaging of cerebral ischemic mice.Research on the expression of MHC-I molecules in the acute phase after ischemia and MHC-I-targeted imaging may not only be helpful for understanding the mechanism of ischemic and hypoxic brain injury and repair but also has potential application value in the imaging of ischemic stroke.
Abstract P006: A Potential Role for β-Arrestins in Cardiac Regeneration
Authors: Anna M Gumpert, Mai Chen, Henriette Brinks, Karsten Peppel, Erhe Gao, Walter J Koch
Journal: Circulation Research (2011)

Development of chronic heart failure (HF) syndrome following myocardial injury (MI) is characterized by an extensive loss of myocytes due to substantial apoptosis and necrosis. As bone marrow derived stem cells (BMSCs) are capable of transdifferentiating, they also show potential for regenerating the myocardium after infarction. Stem cell mobilization, egress from the bone marrow and homing to the site of injury can be regulated by signals through G protein-coupled receptors (GPCRs). β-arrestins are known for their signalling and scaffolding functions and as downstream regulators of GPCR desensitization and endocytosis in particular. We have begun to investigate whether β-arrestins play any role in cardiac precursor cell function concentrating on the properties of BMSCs. Using knockout (KO) mice, we investigated the role β-arrestin1 (βArr1) and β-arrestin2 (βArr2) with respect to modulation of regenerative competence of BMSCs and their contribution to cardiac repair following ischemic injury. First, BM-derived cells devoid of either βArr1 or βArr2 were found to proliferate and colonize in a significantly deficient manner compared to BM cells isolated from wild-type (WT) mice. In addition, the number of c-kit positive cardiac stem cells (as a % of total BM) were significantly lower in the βArr KO mice compared to WT. We carried out BM transplant studies to begin to determine whether the βArrs may play a role in cardiac repair. In our study, WT mice were irradiated and then received BM transplants from either WT donors as a control or BM from βArr1 or βArr2 KO mice. Subsequent to BM reconstitution, mice underwent a myocardial infarction (MI) and their condition was followed. Interestingly, chimeric mice with βArr1 and βArr2 KO BM had significantly poorer outcomes than mice receiving WT BM. This included significantly decreased post-MI survival with βArr2 KO BM and both βArr chimeras had significantly lower cardiac function post-MI compared to mice receiving WT BM. Additionally, our analyses of the BM cells and very small embryonic-like stem cells (VSELs) circulating in peripheral blood (PB), indicate that βArr-KO BM and PB contain fewer and less viable cardiac stem/precursor cells compared to WT transplanted controls.
The <i> <scp>BRAF</scp> </i> and <i> <scp>NRAS</scp> </i> mutation prevalence in dermoscopic subtypes of acquired naevi reveals constitutive mitogen‐activated protein kinase pathway activation
Authors: J.M. Tan, L.N. Tom, K. Jagirdar, D. Lambie, H. Schaider, R.A. Sturm, H.P. Soyer, M.S. Stark
Journal: British Journal of Dermatology (2017)

Acquired naevi can have unique dermoscopic patterns that correspond to distinct microanatomical growth patterns. Previous studies on acquired naevi stratified according to dermoscopic pattern focused on the frequency of somatic BRAF mutations, whereas NRAS mutations remained to be elucidated.To investigate the BRAF and NRAS mutation prevalence and activation of the mitogen-activated protein kinase (MAPK) pathway in distinct dermoscopic subtypes of acquired naevi.Common mutations present in BRAF and NRAS were assessed in 40 globular, reticular and peripheral rim of globules (PG) subtypes of acquired naevi from 27 participants (19 male, 8 female; mean age 46·7 years) selected from 1261 eligible volunteers. Mutations were determined using the highly sensitive and quantitative QX200 droplet digital™ polymerase chain reaction (ddPCR) system.The BRAF V600E (c.1799T>A or c.1799_1800delTGinsA) and BRAF V600K mutations were detected in 85% (n = 34/40) of naevi. All BRAF wild-type naevi (15%; n = 6/40) harboured an NRAS codon 12/13 or 61 mutation. BRAF mutations were present in 92% (n = 12/13) of globular and 100% (n = 12/12) of PG naevi, whereas reticular naevi were 67% (n = 10/15) BRAF- and 33% (n = 5/15) NRAS-mutant (P = 0·037).We discovered that 100% of the assessed acquired naevi had either a BRAF or NRAS mutation. Using sensitive techniques capable of single-cell mutation detection, it is likely that all acquired naevi will be mutated for BRAF or NRAS. Because both of these mutations are prevalent in distinct dermoscopic naevus subsets, our study supports the role of the MAPK pathway in the development of benign melanocytic proliferations, indicating that additional genomic events besides somatic mutations in BRAF or NRAS are required for melanoma development.