tbuckley/cabot-search huggingface dataset:
T cells lacking HDAC11 have increased effector functions and mediate enhanced alloreactivity in a murine model
Authors: David M. Woods, Karrune V. Woan, Fengdong Cheng, Andressa L. Sodré, Dapeng Wang, Yongxia Wu, Zi Wang, Jie Chen, John Powers, Javier Pinilla-Ibarz, Yu Yu, Ya Zhang, Xuefeng Wu, Xiaoyan Zheng, Jeffrey Weber, Wayne W. Hancock, Edward Seto, Alejandro Villagra, Xue-Zhong Yu, Eduardo M. Sotomayor
Journal: Blood (2017)
<i>BRAF</i> Fusion as a Novel Mechanism of Acquired Resistance to Vemurafenib in <i>BRAF</i>V600E Mutant Melanoma
Authors: Atul Kulkarni, Husam Al-Hraishawi, Srilatha Simhadri, Kim M. Hirshfield, Suzie Chen, Sharon Pine, Chandrika Jeyamohan, Levi Sokol, Siraj Ali, Man Lung Teo, Eileen White, Lorna Rodriguez-Rodriguez, Janice M. Mehnert, Shridar Ganesan
Journal: Clinical Cancer Research (2017)

Purpose: Many patients with BRAFV600E mutant melanoma treated with BRAF inhibitors experience a rapid response, but ultimately develop resistance. Insight into the mechanism of resistance is critical for development of more effective treatment strategies.Experimental Design: Comprehensive genomic profiling of serial biopsies was performed in a patient with a BRAFV600E mutant metastatic melanoma who developed resistance to vemurafenib. An AGAP3-BRAF fusion gene, identified in the vemurafenib-resistant tumor, was expressed in BRAFV600E melanoma cell lines, and its effect on drug sensitivity was evaluated.Results: Clinical resistance to vemurafenib in a melanoma harboring a BRAFV600E mutation was associated with acquisition of an AGAP3-BRAF fusion gene. Expression of the AGAP3-BRAF fusion in BRAFV600E mutant melanoma cells induced vemurafenib resistance; however, these cells remained relatively sensitive to MEK inhibitors. The patient experienced clinical benefit following treatment with the combination of a BRAF and a MEK inhibitor. Rebiopsy of the tumor at a later time point, after BRAF and MEK inhibitors had been discontinued, showed loss of the AGAP3-BRAF fusion gene. Mixing experiments suggest that cells harboring both BRAFV600E and AGAP3-BRAF only have a fitness advantage over parental BRAFV600E cells during active treatment with a BRAF inhibitor.Conclusions: We report acquisition of a BRAF fusion as a novel mechanism of acquired resistance to vemurafenib in a patient with melanoma harboring a BRAFV600E mutation. The acquisition and regression of clones harboring this fusion during the presence and absence of a BRAF inhibitor are consistent with rapidly evolving clonal dynamics in melanoma. Clin Cancer Res; 23(18); 5631-8. ©2017 AACR.
TT Virus in Bone Marrow Transplant Recipients
Authors: Yoshinobu Kanda, Yuji Tanaka, Masahiro Kami, Toshiki Saito, Takashi Asai, Koji Izutsu, Koichiro Yuji, Seishi Ogawa, Hiroaki Honda, Kinuko Mitani, Shigeru Chiba, Yoshio Yazaki, Hisamaru Hirai
Journal: Blood (1999)
HGG-19. ETV5 EXPRESSION AND FUNCTION IN PEDIATRIC GLIOMA
Authors: Hannah Park, Rachelle Levy, Danielle Antonuk, Jessica Molina, Marina Dutra-Clarke, Aslam Abassi Akhtar, Gi Bum Kim, Xin Hu, Serguei I. Bannykh, Rowel G.W. Verhakk, Moise Danielpour, Joshua Breunig
Journal: Neuro-Oncology (2017)

Pediatric gliomas, a type of brain tumor which arises from uncontrolled growth of glial cells, are the most common type of CNS tumor in children. As the list of putative driver mutations in glioma grows, we are just beginning to elucidate the combined effects of unhinged signaling pathways on the transformation of CNS cells. While the oncogenic role of ETV5 in various cancers is well-established, its role in high-grade pediatric gliomas has yet to be elucidated. We have created a mosaic, autochthonous, glioma model that captures the first hours and days of gliomagenesis in more resolution than conventional mouse models of cancer. Our various models of pediatric glioma have indicated a fundamental role for Etv5 in tumor cells. We show that ETV5 is highly expressed in our glioma models and primary pediatric glioma cells. We are currently pursuing an omics approach to identifying the mechanisms regulating ETV5 in high-grade glioma. Additionally, we are employing a novel single-site conditional system to identify ETV5 genomic targets in patient tumors and to explore the results of ETV5 manipulation on cell fate. Taken together, we provide evidence that Etv5 is necessary for tumor initiation and regulates the exuberant gliogenesis observed in these tumors.
Oral Glucocorticoid–Sparing Effect of Benralizumab in Severe Asthma
Authors: Parameswaran Nair, Sally Wenzel, Klaus F. Rabe, Arnaud Bourdin, Njira L. Lugogo, Piotr Kuna, Peter Barker, Stephanie Sproule, Sandhia Ponnarambil, Mitchell Goldman
Journal: New England Journal of Medicine (2017)

Many patients with severe asthma rely on oral glucocorticoids to manage their disease. We investigated whether benralizumab, a monoclonal antibody directed against the alpha subunit of the interleukin-5 receptor that significantly reduces the incidence of asthma exacerbations, was also effective as an oral glucocorticoid-sparing therapy in patients relying on oral glucocorticoids to manage severe asthma associated with eosinophilia.In a 28-week randomized, controlled trial, we assessed the effects of benralizumab (at a dose of 30 mg administered subcutaneously either every 4 weeks or every 8 weeks [with the first three doses administered every 4 weeks]) versus placebo on the reduction in the oral glucocorticoid dose while asthma control was maintained in adult patients with severe asthma. The primary end point was the percentage change in the oral glucocorticoid dose from baseline to week 28. Annual asthma exacerbation rates, lung function, symptoms, and safety were assessed.Of 369 patients enrolled, 220 underwent randomization and started receiving benralizumab or placebo. The two benralizumab dosing regimens significantly reduced the median final oral glucocorticoid doses from baseline by 75%, as compared with a reduction of 25% in the oral glucocorticoid doses in the placebo group (P<0.001 for both comparisons). The odds of a reduction in the oral glucocorticoid dose were more than 4 times as high with benralizumab as with placebo. Among the secondary outcomes, benralizumab administered every 4 weeks resulted in an annual exacerbation rate that was 55% lower than the rate with placebo (marginal rate, 0.83 vs. 1.83, P=0.003), and benralizumab administered every 8 weeks resulted in an annual exacerbation rate that was 70% lower than the rate with placebo (marginal rate, 0.54 vs. 1.83, P<0.001). At 28 weeks, there was no significant effect of either benralizumab regimen on the forced expiratory volume in 1 second (FEV1), as compared with placebo. The effects on various measures of asthma symptoms were mixed, with some showing significant changes in favor of benralizumab and others not showing significant changes. Frequencies of adverse events were similar between each benralizumab group and the placebo group.Benralizumab showed significant, clinically relevant benefits, as compared with placebo, on oral glucocorticoid use and exacerbation rates. These effects occurred without a sustained effect on the FEV1. (Funded by AstraZeneca; ZONDA ClinicalTrials.gov number, NCT02075255 .).
Amelanotic melanoma in oculocutaneous albinism: a genetic, dermoscopic and reflectance confocal microscopy study
Authors: S. Ribero, C. Carrera, G. Tell-Marti, C. Pastorino, C. Badenas, A. Garcia, J. Malvehy, S. Puig
Journal: British Journal of Dermatology (2017)

Herein we describe the usefulness of a successful combination of dermoscopy and in vivo RCM for the early diagnosis of 3 AM in 2 OCA patients OCA is a group of rare autosomal recessive disorders of pigmentation. It consists in the absence or reduction of melanin in the skin, hair, and eyes due to a partial or total deficit in the activity of tyrosinase(TYR)1 or other related genes2,3. Those patients are at higher risk of non melanoma skin cancer, while still debated is their increased risk of melanoma, in particular amelanotic4. They usually lack in clinical and dermoscopic pattern, what makes them challenging to be diagnosed, especially at early stage.

This article is protected by copyright. All rights reserved.
Maternal and Fetal Outcomes of Anticoagulation in Pregnant Women With Mechanical Heart Valves
Authors: Zachary L. Steinberg, Clara P. Dominguez-Islas, Catherine M. Otto, Karen K. Stout, Eric V. Krieger
Journal: Journal of the American College of Cardiology (2017)

Anticoagulation for mechanical heart valves during pregnancy is essential to prevent thromboembolic events. Each regimen has drawbacks with regard to maternal or fetal risk.This meta-analysis sought to estimate and compare the risk of adverse maternal and fetal outcomes in pregnant women with mechanical heart valves who received different methods of anticoagulation.Studies were identified using a Medline search including all publications up to June 5, 2016. Study inclusion required reporting of maternal death, thromboembolism, and valve failure, and/or fetal spontaneous abortion, death, and congenital defects in pregnant women treated with any of the following: 1) a vitamin K antagonist (VKA) throughout pregnancy; 2) low-molecular-weight heparin (LMWH) throughout pregnancy; 3) LMWH for the first trimester, followed by a VKA (LMWH and VKA); or 4) unfractionated heparin for the first trimester, followed by a VKA (UFH and VKA).A total of 800 pregnancies from 18 publications were included. Composite maternal risk was lowest with VKA (5%), compared with LMWH (16%; ratio of averaged risk [RAR]: 3.2; 95% confidence interval [CI]: 1.5 to 7.5), LMWH and VKA (16%; RAR: 3.1; 95% CI: 1.2 to 7.5), or UFH and VKA (16%; RAR: 3.1; 95% CI: 1.5 to 7.1). Composite fetal risk was lowest with LMWH (13%; RAR: 0.3; 95% CI: 0.1 to 0.8), compared with VKA (39%), LMWH and VKA (23%), or UFH and VKA (34%). No significant difference in fetal risk was observed between women taking ≤5 mg daily warfarin and those with an LMWH regimen (RAR: 0.9; 95% CI: 0.3 to 2.4).VKA treatment was associated with the lowest risk of adverse maternal outcomes, whereas the use of LMWH throughout pregnancy was associated with the lowest risk of adverse fetal outcomes. Fetal risk was similar between women taking ≤5 mg warfarin daily and women treated with LMWH.
THE WOMEN'S INJURY SURVEILLANCE EXTENSION FOR AUSTRALIAN FOOTBALL (FOOTYWISE)
Authors: Lauren Fortington, Alex Donaldson, Caroline Finch
Journal: British Journal of Sports Medicine (2017)

Background Female participation in Australian football (AF) has increased substantially over the last 5 years. Measures for reducing injury, whether through coaching, training or rules, are currently based on anecdotal injury experiences and research from male participants. To ensure the safety of female participants, consideration of their specific injury profile is required. Objective To provide the first understanding of injury in women's AF. Design Two approaches were used. [1] compilation of four data sources: hospital-admissions, emergency department presentations, insurance claims, club-based collection; [2] online self-report survey of the worst injury sustained in the previous season. Setting Australia-wide Patients (or Participants) Female AF participants. Interventions (or Assessment of Risk Factors) Not applicable. Main Outcome Measurements Injury frequencies, injury types. Results The survey provided information on 431 self-considered ‘worst’ injuries. Over half (55%) were lower limb injuries of which joint ligament tears/sprains (29%), muscle strains (18%) and fractures (13%) dominated. The knee (18%), hand/fingers (16%), and ankle (14%) were most common body parts injured. Concussion comprised 6% of all injuries. Upper limb injuries were featured in the hospital admissions (n=500 injuries in total) and emergency presentations (n=1879), 47% and 51% of all injuries, respectively. These were largely wrist/hand injuries (32% and 40%). Most (65%) insurance claim injuries (n=522) involved the lower limb, 27% for knee ligament damage. A high proportion of concussions (33%) were reported in the club collected data (n=49). Conclusions Three injuries of particular significance were identified (knee joint ligament injuries, concussion, and wrist/hand/finger fractures, dislocations and sprains), which differ from key injuries identified in men's football where lower limb muscle strains are most prevalent, particularly hamstring/groin strains. A comprehensive prospective injury study in women's Australian football is now needed to support a robust collection of injury data, with a focus on identifying the cause and injury rates.
Parallel attentive processing and pre-attentive guidance
Authors: Hermann J. Müller, Heinrich René Liesefeld, Rani Moran, Marius Usher
Journal: Behavioral and Brain Sciences (2017)

Abstract This commentary focuses on two related, open questions in Hulleman &amp; Olivers' (H&amp;O's) proposal: (1) the nature of the parallel attentive process that determines target presence within, and thus presumably the size of, the functional visual field, and (2) how the pre-attentive guidance mechanism must be conceived to also account for search performance in tasks that afford no reliable target-based guidance.
Abstract #2944: Molecular determinants of Docetaxel-resistance in prostate cancer cells
Authors: Nader Al Nakouzi, Catherine Gaudin, Lucile Delbruel, Fanny Tabarin, Philippe Dessen, Frédéric Commo, Christophe Massard, Marine Gross-Goupil, Karim Fizazi, Anne Chauchereau
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Background: Docetaxel is the standard treatment for metastatic castration-resistant prostate cancer (CRPC) since 2004 and overall survival benefit in CRPC has been demonstrated in docetaxel-treated patients. In spite of this benefit, a drug resistance is eventually observed in all patients, leading few therapeutic options. Therefore, it is crucial to identify predictive markers that enable to select patients who will respond to treatment. Methods: In order to investigate mechanisms of Docetaxel resistance, we derived Docetaxel-resistant variants from three human prostate cancer cell lines (LNCaP, PC3 and IGR-CaP1) by continuousexposure to Docetaxel. The generated IGR-CaP1 cells are resistant to 5nM to 200nM Docetaxel, LNCaP and PC3 cells are resistant to 5nM Docetaxel. A high-density genomic profilingby cDNA microarrays (Agilent technologies) was performed to compare sensitive and chemoresistant cell lines at different Docetaxel doses. Results: Gene expression data showsignificant differential expression of 244 genes in Docetaxel resistant IGR-CaP1 cells (Fold change>2 for each doses of Docetaxel, p value <10-10). In this signature, 119 genes are over-expressed and 125 genes are under-expressed. Quantitative RT-PCR was used to validate microarray data on an independent set of samples. Good correlation between microarray data and QRT-PCR validation was demonstrated by Spearman Test (rho =0.936, p-value = 1.413x10-9, n=20). In this signature, the multidrug resistance gene ABCB1 was upregulated (15.8 fold) and 9 SLC transporterswere differentially expressed in Docetaxel resistant cells. We also found genes implicated in cellular growth, cell proliferation, cell death, cellular movement, cell to cell signalling and Wnt/s-catenin signalling. We are currently exploringthe role of a selected gene set in Docetaxel resistance by siRNA knockdownexperiments in resistant cells. Conclusion: A high-density microarray genomic analysis comparing chemo-resistant versus sensitive prostate cell lines was used to identify a signature of genes potentially implicated in Docetaxel resistance. Ultimately our studyaims to improve selection of patients that could benefit from Docetaxel chemotherapy and may also provide the framework for formulationof novel therapies that may improve taxane therapy efficacyin men with prostate cancer. 

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2944.
The FVF might be influenced by object-based attention
Authors: Poutasi W B Urale
Journal: Behavioral and Brain Sciences (2017)

Abstract Hulleman &amp; Olivers (H&amp;O) argue that the primary unit in search should be fixations, and in doing so posit a Functional View Field (FVF). There is evidence from the object-based visual attention literature that the FVF may not process visual information uniformly. Here I sketch how object-based attention may influence processing within the FVF as well as the shape of the FVF.
Next government must tackle GP indemnity costs, royal college says
Authors: Abi Rimmer
Journal: BMJ (2017)

The next government must tackle rising GP indemnity costs, the Royal College of General Practitioners has said.

Helen Stokes-Lampard, the college’s chair, warned that indemnity costs were spiralling and that without action they could create a crisis in general practice. Unlike hospital doctors, GPs have to purchase their own medical indemnity.

In February, the lord chancellor, Elizabeth Truss, announced a legal change that critics said could add £1bn a year to the NHS bill for compensation.1 A reduction …
Abstract P241: Calpain-1 Is Increased in Mitochondria and Contributes to Mitochondrial ROS Generation in High Glucose--Stimulated Endothelial Cells and Endothelial Dysfunction in Mouse Models of Diabetes
Authors: Qing Zhao, Futian Tang, Limei Shan, Inga Cepinskas, Gedas Cepinskas, Tianqing Peng
Journal: Circulation Research (2011)

Objectives: Elevated levels of reactive oxygen species (ROS) are the initial source of endothelial dysfunction in diabetes. Calpain has been implicated in diabetic vascular complications. The present study was to investigate the role of calpain in mitochondrial ROS generation in endothelial cells and vascular dysfunction in diabetic mice. Methods: Endothelial cells cultured from human umbilical vein (HUVEC) were stimulated with high glucose. Calpain activity and protein were determined in mitochondria of HUVEC. Intracellular and mitochondrial ROS generation as well as apoptosis were measured. Type I diabetic OVE 26 mice and type II diabetic db/db mice with calpastatin over-expression (OVE26/CAST and db/db-CAST) were generated, respectively. Type I diabetes was also induced in both wild-type and Tg-CAST mice by injection of streptozocin (STZ). The endothelium-dependent relaxation of aortic ring was measured. Results: High glucose significantly increased calpain-1 protein, calpain activity and ROS generation in mitochondria of HUVEC. Pharmacological inhibition of calpain or over-expression of calpastatin abrogated high glucose-induced intracellular ROS production, mitochondrial ROS generation and apoptosis in HUVEC. Incubation of isolated mitochondria with calpain-1 protein significantly induced its ROS generation and the membrane potential. In diabetic mice, calpain activity was induced in aortic vessels, which correlated with an increase in ROS production and protein tyrosine nitration. Over-expression of calpastatin prevented calpain activity, reduced ROS production and inhibited protein tyrosine nitration in diabetic mice. Aortic ring segments from diabetic mice exhibited a significant reduction in vascular relaxation to acetylcholine, which was reversed by over-expression of calpastatin in Tg-CAST, OVE26/CAST and db/db-CAST mice. Conclusions: This study has demonstrated a novel role of calpain in mitochondrial ROS generation, which contributes to apoptosis in endothelial cells during hyperglycemia. Thus, over-expression of calpastatin inhibits reduces ROS production and ameliorates endothelium-dependent vascular dysfunction in mouse models of diabetes.
Inhibition of c-Myc By Apto-253 As an Innovative Therapeutic Approach to Induce Cell Cycle Arrest and Apoptosis in Acute Myeloid Leukemia
Authors: Hongying Zhang, Andrea Local, Khalid Benbatoul, Peter Folger, Susan Sheng, Luis Esquivies, Jeff Lightfoot, Avanish Vellanki, William G. Rice
Journal: Blood (2016)
Recognizing the Nocebo Benefits Patient Care, But Demands Greater Cultural Competency in the Clinic
Authors: Antoinette P. Joseph, Paul H. Mason, Narelle Warren, Isaac Atley
Journal: The American Journal of Bioethics (2017)

If the placebo has been undervalued in clinical practice, then the nocebo has been almost entirely ignored. Treating psychogenic effects as factors to be eliminated disregards their modulatory infl...
Margaret McCartney: The social care system has become inherently unsafe
Authors: Margaret McCartney
Journal: BMJ (2017)

Ellen Ash was an elderly woman with severe dementia, who lived in Glasgow. She died in 2013 after she was smothered and her house was set on fire. Her son, Jeffrey, went to the police the next day to confess to both.1 He was her carer and seems to have been under immense stress.

Social care is under intense pressure but also scrutiny. Over the past few months this complex case has been discussed at wide ranging, interdisciplinary meetings involving health and social care staff. In Scotland, social and health care are integrated in law. But in practice?

In the months before her death Ash was admitted to hospital for various reasons, including hypothermia, and with an area of necrotic tissue. “Neglect” and “vulnerability” were mentioned in her case notes. After her death a …
Biological tumor volume (BTV) as a predictor for local control in nasopharyngeal carcinoma (NPC).
Authors: Dora Lai Wan Kwong, Victor Lee, Ka-On Lam, Gary KW Wong, Pek lan Khong
Journal: Journal of Clinical Oncology (2015)

e17045 Background: Treatment of NPC is mainly guided by TNM stage. This study aims to evaluate if the active tumor volume delineated as BTV on PET scan is a predictor of local disease control. Methods: This is a retrospective review of all patients who had baseline PET scan performed before treatment in our center from Aug., 2010 to Mar., 2013. Patients with distant metastases at diagnosis were excluded. Total 77 patients were included. The BTV were automatically delineated by a signal to background ratio method we reported before. All patients completed radiotherapy (RT) with intensity modulated radiotherapy to at least 70Gy to primary tumor. 7 patients had RT alone and 70 patients had chemotherapy (cisplatin or carboplatin) concurrent with RT with either additional induction or adjuvant chemotherapy. Local control was assessed by endoscopy and biopsy at 10 weeks after completion of RT. Local failure include patients with persistent disease in NP after RT and those who had local relapse after initial disease remission. Results: T stage distributions of the group were 20 T1, 7 T2, 35 T3 and 15 T4. The BTV ranged from 2.68 to 147.5cc with a median of 14.4cc. BTV in general increase with T stage with mean BTV of 12.9, 13.6, 26.3 and 40.7cc respectively for T1, 2, 3 and 4 respectively. Median follow up of the group were 32.8 months. There were 2 patients with persistent loco-regional disease after RT and another 2 patients with NP relapse. Mean BTV for patients with local control were 22.4cc compared with 61.5cc among patients with local failure (t-test, p: 0.002). 4 years local control rates (LCR) according to T stage were 100% for T1 and T2, 91.3% for T3 and 50% for T4. Patients with BTV < 15cc had 4 year local control rate (LCR) of 100% vs 73.6% among those with BTV of 15cc or more (log rank test: p = 0.33). Multivariate analysis with Cox regression including T stage, BTV, SUV max, SUV mean and TLG in primary showed only BTV is predictive of LCR (p: 0.015). T stage and other factors were not significant for LCR. Conclusions: BTV is a good predictor for local control. Patients with BTV > 15cc are at risk of local failure and should be considered for radiation dose escalation.