tbuckley/cabot-search huggingface dataset:
Systematic review and meta-analysis of the effects of football heading
Authors: Anthony P Kontos, Rock Braithwaite, Sara P D Chrisman, Jamie McAllister-Deitrick, Larissa Symington, Valerie L Reeves, Michael W Collins
Journal: British Journal of Sports Medicine (2016)

Aim/objective The objective of this study was to provide a meta-analysis examining the effects of football heading. Design Meta-analytical review on football heading effects on neurocognitive performance, cognition and symptom reports. Data sources Combinations of the key terms were entered into the following electronic database search engines: Cochrane Libraries, PyscARTICLE, PyscINFO, PubMed, ProQuest, SPORTDiscus and Web of Science on 7 July 2016. Eligibility criteria for selecting studies The following inclusion criteria were used to determine eligibility for studies: (1) the study examined and reported on soccer athletes; (2) the population's age, sex and sport position was described; (3) cognitive function, symptoms, balance or other outcomes were quantitatively measured; (4) football heading exposure was quantitatively measured between at least two groups and (5) the study was written in the English language after December 1979. Results The literature search process identified 467 unique studies. After applying exclusion criteria, 28 studies remained. Included studies had a total of 2288 participants (female participants =933, male participants =1355), aged 13–70 years. The overall results of random effects modelling of football heading were found to be inconclusive across all outcomes, groups and time points. No moderating variables related to methodological, sample or study characteristics were supported in the analysis; age was a potential moderating variable. Summary/conclusions We provide the first meta-analytical review of football heading effects aggregated from multiple studies and extended findings from a recent systematic review of the effects of football heading. Our analysis indicates no overall effect for heading a football on adverse outcomes.
Secondary Myelodysplastic Syndrome.(sMDS) Presentation and Evolution.
Authors: Laura Kornblihtt, Alicia Enrico, Jorge Milone, Maria Virginia Prates, Carolina B Belli, Jorge Arbelbide, Diana Lafalce, Diana Penchasky, Dorotea Fantl, Maria Marta Rivas, Maria Cabrejo, Maria Caicedo
Journal: Blood (2009)
Abstract 3762: The landscape of therapeutic targetable fusions
Authors: Kosuke Yoshihara, Qianghu Wang, Wandaliz Torres-Garcia, Siyuan Zheng, Rahulsimham Vegesna, Hoon Kim, Roel GW Verhaak
Journal: Cancer Research (2015)

Abstract Gene fusions are an important class of cancer-contributing somatic alteration, and have an important significance as a tumor-initiating event and as a molecular therapeutic target for specific tumors. We analyzed RNA sequencing, DNA copy number and gene mutation data from 4,366 primary tumor samples to comprehensively detect fusion events in 13 tumor types. To reduce the number of false-positive predictions, we developed strict quality criteria on the basis of gene homology, transcript allele fraction (TAF), and partner gene variety. In addition, we used fusions detected in RNAseq data from 364 normal tissue samples to extract tumor-specific fusions. In total, 7,887 fusion transcripts with high confidence were detected across 13 tumor types. Our fusion prediction was validated by supporting evidence for a genomic rearrangement for 78 of 79 fusions in 48 glioma samples where whole genome sequencing data was available. Fusion transcript frequency was positively correlated with the levels of genomic instability in cancers, whereas tumor samples harboring fusions contained statistically significantly fewer driver gene mutations. We identified 221 fusion transcripts involving a tumor suppressor gene and these were wildtype in majority (98.2%), suggesting the fusion has a disruptive effect and a role in tumorigenesis. We identified at least one in-frame protein kinase fusion in 324 of 4,366 samples (7.4%). Potentially therapeutic targetable kinase fusions such as ALK, ROS, RET, NTRK, and FGFR gene families were detected in thyroid carcinoma (8.7%), glioblastoma (4.4%), bladder carcinoma (3.3%), lung squamous cell carcinoma (2.3%), lung adenocarcinoma (1.6%), lower grade glioma (1.5%), and head and neck cancer (1.0%), suggesting a potential for application of kinase inhibitors for multiple tumor types. In-frame fusion transcripts involving histone methyltransferase or histone demethylase genes, which may also be considered as therapeutic targets, were detected in 111 samples (2.5%). In summary, the landscape of transcript fusions detected across a large number of tumor samples revealed fusion events with clinical relevance that have not been previously recognized. Our findings support the concept of basket clinical trials where patients are matched with experimental therapies based on their genomic profile rather than the tissue where the tumor originated. Citation Format: Kosuke Yoshihara, Qianghu Wang, Wandaliz Torres-Garcia, Siyuan Zheng, Rahulsimham Vegesna, Hoon Kim, Roel GW Verhaak. The landscape of therapeutic targetable fusions. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3762. doi:10.1158/1538-7445.AM2015-3762
<i>Alox5</i> Blockade Eradicates <i>JAK2V617F</i>-Induced Polycythemia Vera in Mice
Authors: Yaoyu Chen, Yi Shan, Min Lu, Ngoc DeSouza, Zhiru Guo, Ronald Hoffman, Aibin Liang, Shaoguang Li
Journal: Cancer Research (2016)

Myeloproliferative neoplasms such as polycythemia vera (PV), which are associated with the JAK mutation V617F, remain incurable despite progress in the use of JAK2 inhibitors for treatment of some of these diseases. In this study, we employed mice that undergo JAK2V617F-induced PV as a tool to explore new candidate targets for therapy. Our investigations focused on the lipid metabolic enzyme arachidonate 5-lipoxygenase (Alox5), which we found to be strongly upregulated by JAK2V617F in hematopoietic cells in vitro and in vivo Notably, genetic deletion of Alox5 or its inhibition in mice with a bioactive small-molecule inhibitor was sufficient to attenuate PV development. This therapeutic effect was associated with induction of a blockade in cell-cycle progression and also with apoptosis in PV cells. Genetic loss exerted an inhibitory effect on PV-initiating cells. Similarly, Alox5 inhibition was sufficient to suppress colony formation in human JAK2V617F-expressing CD34+ cells. Mechanistic investigations showed that Alox5 inhibition reduced AKT activation and decreased β-catenin expression in JAK2V617F-expressing cells. Together, our results define Alox5 as a key genetic effector of JAK2V617F in driving PV, and they identify this enzyme as a candidate therapeutic target to treat this refractory myeloproliferative neoplasm. Cancer Res; 77(1); 164-74. ©2016 AACR.
PTU-024 Alcoholism and alcoholic liver disease: a British Society of Gastroenterology survey of public knowledge and attitudes
Authors: S Gill, R Gardner, T Smith, C J Hawkey
Journal: Gut (2010)

<h3>Introduction</h3> Alcohol consumption and alcoholic liver disease are rising steeply in the UK. Because this is seen as a major health hazard by the British Society of Gastroenterology, and society at large, we conducted a survey of knowledge and attitudes in an age, sex and regionally balanced sample) of the UK population. <h3>Methods</h3> A 10-question 80-response survey of knowledge of and attitudes to alcohol and obesity across the UK conducted through the polling organisation, YouGov yielded 1956 complete responses. <h3>Results</h3> Twenty two per cent of respondents did not drink alcohol and 23% always stayed within recommended limits compared to 52% who exceeded them (21% doing so often and/or by great amount). Among those exceeding the limits 39% objected to health advice and 33% regarded their drinking as moderate. Binge drinking with friends was reported by 17% (36% of 18/24 years, with 11% drinking to help confidence with opposite sex). Drinking to calm nerves was cited as a reason by 15% and depression by 8%. 13% thought limits were too low and 15% that their body could handle excess alcohol. Only one third would seek help from their GP vs 20% for counselling (30% in London) and 21% for Alcoholics Anonymous. Twenty three per cent blamed social isolation for alcohol excess in UK and 49% thought consumption would continue to rise in UK for 10 years. Banning advertising aimed at young people was supported by 62%, with 23% supporting minimum unit pricing. <h3>Conclusion</h3> This large, balanced study shows that alcoholism is prevalent across the UK and people are resistant to receiving health advice about it. New approaches to communication are needed. However, a majority would support restrictions on advertising.
The Absolute Monocyte and Lymphocyte Counts at Diagnosis Predict Survival and Identify High-Risk Patients In Diffuse Large-B-Cell Lymphoma
Authors: Ryan A. Wilcox, Kay Ristow, Thomas M. Habermann, David James Inwards, Ivana Micallef, Patrick B Johnston, Joseph Colgan, Grzegorz S. Nowakowski, Thomas E. Witzig, Stephen M. Ansell, Svetomir Markovic, Luis Porrata
Journal: Blood (2010)
ITI with a VWF-Stabilised FVIII Concentrate in Haemophilia A Patients with Inhibitors and a Poor Prognosis for ITI Success: Progress Report on octanate® in the Observational ObsITI Study,
Authors: Carmen Escuriola-Ettingshausen, Vladimir Vdovin, Nadezhda Zozulya, Olga Plyushch, Wolfhart Kreuz, Bruce A. Schwartz
Journal: Blood (2011)
Abstract 2318: Genetic and functional diversity of propagating cells in glioblastoma
Authors: Sara Grazia Maria Piccirillo, Sue Colman, Nicola E. Potter, Frederik W. van Delft, Suzanne Lillis, Maria-Jose Carnicer, Lyndal Kearney, Colin Watts, Mel Greaves
Journal: Cancer Research (2015)

Abstract Glioblastoma (GBM) is a lethal malignancy whose clinical intransigence has been linked to extensive intraclonal genetic and phenotypic diversity and the common emergence of therapeutic resistance. This interpretation embodies the implicit assumption that cancer stem cells or tumor-propagating cells are themselves genetically and functionally diverse. To test this, we screened primary GBM tumors by SNP array to identify copy number alterations (a minimum of three) that could be visualized in single cells by multicolor fluorescence in situ hybridization. Interrogation of neurosphere-derived cells (from four patients) and cells derived from secondary transplants of these same cells in NOD-SCID mice allowed us to infer the clonal and phylogenetic architectures. Whole-exome sequencing and single-cell genetic analysis in one case revealed a more complex clonal structure.This proof-of-principle experiment revealed that subclones in each GBM had variable regenerative or stem cell activity, and highlighted genetic alterations associated with more competitive propagating activity in vivo. Citation Format: Sara Grazia Maria Piccirillo, Sue Colman, Nicola E. Potter, Frederik W. van Delft, Suzanne Lillis, Maria-Jose Carnicer, Lyndal Kearney, Colin Watts, Mel Greaves. Genetic and functional diversity of propagating cells in glioblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2318. doi:10.1158/1538-7445.AM2015-2318
Presurgical docetaxel (Doc) and androgen deprivation therapy (ADT) in lymph node-positive prostate cancer (PCa).
Authors: L. C. Pagliaro, A. J. Zurita, J. C. Araujo, J. F. Ward, J. W. Davis, C. A. Pettaway, S. Tu, J. Kim, P. Dieringer, C. Logothetis, L. L. Pisters
Journal: Journal of Clinical Oncology (2011)

4619 Background: For men newly diagnosed with PCa and lymph node (LN) metastasis, surgical control of the primary site is rarely considered. We conducted a phase II study of neoadjuvant Doc chemotherapy and 1 year of ADT followed by radical prostatectomy (RP) in those patients (pts). Methods: Eligible pts had histologic proof of PCa and evidence of LN metastasis (TxN1M0 or TxNxM1a) on imaging (LN size ≥2 cm) or a positive LN biopsy, or LN metastasis suspected for any of the following: stage T3 (and Gleason score ≥7), stage T4 (any Gleason score), or serum prostate specific antigen (PSA) concentration ≥25 ng/mL plus Gleason score ≥8. ADT was allowed up to 6 months before entry, but pts with bone or visceral involvement were excluded. Pts received Doc 35 mg/m2 IV on days 1, 8, 15, and 22 of a 6-week cycle for 3 cycles, and ADT for 1 year from the date of enrollment. At that time, pts with PSA <1 ng/mL and no clinical progression were offered RP and pelvic LN dissection. Postoperatively, ADT was discontinued and PSA was measured every 3 months. The primary objective was to define the rate of biochemical progression (PSA ≥1) 1 year after surgery without additional therapy; a 50% rate would indicate efficacy. Time to treatment failure (TTF) was estimated by Kaplan-Meier analysis. Results: We enrolled 40 pts (28 [70%] with confirmed and 12 [30%] with suspected LN metastasis), but 4 pts (10%) were not evaluable. Among the remaining 36, 4 (11.1%) progressed on treatment and 4 more did not achieve PSA <1. Of 28 (77.8%) with PSA <1 after neoadjuvant therapy, 26 (72.2%) completed surgery. Of those, 13 (50%; 7 with confirmed and 6 with suspected LN metastasis) had no progression 1 year postoperatively. Twenty-nine of 36 pts (81%) failed, with a median TTF of 22.3 months (95% CI: 19.1–27.2 months). Treatment was well tolerated, and no treatment-related deaths occurred. Two pts (7.7%) had no residual tumor in the prostate and LNs. Conclusions: A neoadjuvant chemohormonal plus RP strategy was feasible in selected PCa pts presenting with LN metastasis or at high risk for LN involvement, and half of the operated pts (36.1% of the total) were progression-free 1 year post-surgery.
382. Correction of Autophagic Dysregulation in Pompe Disease Following Gene Therapy
Authors: Angela L. McCall, Sylvia G. Stankov, Darin J. Falk, Barry J. Byrne
Journal: Molecular Therapy (2016)

Pompe Disease (PD) is a fatal metabolic disorder caused by mutations in the GAA gene leading to a deficiency in acid alpha-glucosidase (GAA) and affects 1 in 40,000 births. Clinically, this lysosomal storage disorder presents with cardiomegaly and skeletal muscle weakness, leading to cardiorespiratory failure. GAA is responsible for the breakdown of glycogen in the lysosome, an important energy source for striated muscle and neurons. Currently, the only approved treatment for PD is enzyme replacement therapy (ERT). While ERT has increased patient survival, there are several limitations including treatment cost and the inability of the enzyme to cross the blood-brain barrier and breakdown lysosomal glycogen deposition within the central nervous system. ERT therapy is dependent upon receptor-mediated endocytosis of the exogenous enzyme; much of which remains in amphisomes resulting in insufficiently trafficking of GAA to the lysosome. These issues illustrate the need for an alternative treatment. We propose that endogenous production of GAA enzyme mediated by adeno-associated virus (AAV)-delivery of the GAA gene will improve targeting of GAA to the lysosome and reduce the overall dysregulation of vesicular systems. In this study, we performed intravenous delivery of AAV9-DES-coGAA to 12-week old Gaa−/− animals at three doses (1×1011 vg/kg, 1×1013 vg/kg, and 1×1014vg/kg) and compared to AAV9-CMV-GFP (1×1013 vg/kg) and vehicle-control groups. Previous research has revealed that cellular dysregulation due to lysosomal storage of glycogen is amassed by twelve-weeks of age prior to onset of the physiological phenotype of PD in the Gaa−/− murine model. One month after AAV or sham injection, cardiac and skeletal muscles were harvested for biochemical and histological analyses. GAA activity assays demonstrate that therapeutic levels of enzyme activity are not attained with doses 1×1011 vg/kg and 1×1013 vg/kg, but were when a dose of 1×1014 vg/kg is administered. Western Blot analysis of autophagy-associated proteins, such as Beclin, LAMP1, LC3-I, and LC3-II show a decrease in protein levels following gene therapy indicating an improvement in autophagic regulation. Hematoxalin & Eosin staining of tibialis anterior and gastrocnemius muscle sections show an inverse relationship between level of vacuolarization of muscle fibers and dose of AAV9-DES-coGAA vector. Additionally, preliminary data suggest increased endocytosis of AAVs without reaching the therapeutic threshold may activate autophagy. Further analysis by RT-qPCR and immunofluorescence will elucidate the mechanism by which treatment modifies autophagic flux.
P189 Oxygen use is becoming more conservative on intensive care units in the uk
Authors: BR O’Driscoll, P Dark, M Wijesinghe, D McAuley
Journal: Thorax (2016)

<h3>Background</h3> There is controversy about the optimal level of oxygenation for patients in intensive care units (ICU) and several recent publications have raised the possibility of harm from hyperoxaemia amongst ICU patients.<sup>1</sup> Most recent ICU publications have reported that hyperoxaemia is common. The aim of this project was to audit blood gas data at two hospitals to determine if there is evidence of changing practice in recent years. <h3>Methods</h3> We audited all available ICU blood gas datasets for Hospital A for 2005 (n = 16,734), 2010 (n = 12,714) and 2015 (n = 17,292) and data from Hospital B from 2012–2013 (n = 11,006) and for 2015 (n = 22,223). <h3>Results</h3> At Hospital A, the percent of ICU blood gas samples with hyperoxaemia (SaO<sub>2</sub> &gt; 98%) fell from 57.4% in 2005 to 45.1% in 2010 and 29.0% in 2015. Mean SaO<sub>2</sub> fell from 97% in 2005 to 96% in 2015. The mean PaO<sub>2</sub> also fell from 15.1 KpA in 2005 to 13.5 in 2015 (The reference range for PaO2 is 12.0 to 15.0 kPa). Samples from hospital B did not span such a wide time range but they demonstrated a similar fall in the proportion of hyperoxaemic samples from 42.7% in 2012–2013 to 29.7% in 2015 which was very similar to the data for Hospital A in 2010 and 2015 (45.1% and 29.0%). <h3>Conclusions</h3> There is evidence from two hospitals that the use of oxygen in Intensive Care Units has become more conservative in recent years, possibly as a result of recent publications which have identified poor outcomes in association with hyperoxaemia. A wider survey will be undertaken to determine if this trend is taking place in Intensive Care Units throughout the UK. <h3>Reference</h3> Helmerhorst<i>et al</i>. <i>Crit Care Med</i> 2015;<b>43</b>:1508–19.
69. TNFR Costimulatory Domains Impair Expansion of CD5 CAR T Cells Due to Enhanced Fas-Mediated Apoptosis
Authors: Maksim Mamonkin, Sandhya Sharma, Malini Mukherjee, Madhuwanti Srinivasan, Diogo Silva, Jordan S. Orange, Malcolm K. Brenner
Journal: Molecular Therapy (2016)

CD5 is expressed at high levels on most normal and malignant T cells. We previously demonstrated that T cells transduced with a CD5 CAR harboring signaling domains from CD28 and TCR zeta chain (CD28. zeta) genes produce only limited fratricide against normal CD5+ T cells and expand>10,000-fold in vitro. Although these CAR T cells also have significant anti-tumor activity against CD5+ cell lines, tonic signaling from the CAR enhances terminal differentiation during in vitro expansion. The accumulation of CCR7- effector T cells and reduced frequency of CD4+ CAR T cells limits the in vivo persistence of CAR T cells ultimately allowing resurgence of CD5+ tumor cells. Since strong PI(3)K activation from the CD28 domain likely contributes to the terminal differentiation of CAR T cells, we aimed to improve CD5 CAR T cell persistence by replacing the CD28 domain with a TNFR superfamily domain 4-1BB, which elicits weaker PI(3)K activation and preserves the central memory population. Here, we show that replacing the CD28 signaling domain with one of the TNFR-superfamily genes (4-1BB, OX40, CD27, CD30 or HVEM) allowed CD5 CAR T cells to retain the CCR7+ central memory population. Unexpectedly, however, TNFR signaling domains dramatically increased CAR T cell death and reduced proliferation, resulting in 5- to 15-fold reduction in cell expansion after 2 weeks of culture. These results correlated with a 3-fold upregulation of Fas on the T cell surface and the formation of stable immunologic synapses between CAR T cells. Disrupting a TRAF2 binding site in the 4-1BB domain prevented Fas upregulation and restored the expansion of CD5 CAR T cells, but also compromised costimulation and undermined long-term cytotoxicity. In contrast, CD28. zeta CD5 CAR T cells displayed normal Fas levels and their expansion was comparable to that of ICOS. zeta and zeta-only (first generation) CD5 CAR T cells. Limited fratricide of CD28. zeta CD5 CAR T cells was dependent on PI(3)K activity, as chemical blockade of PI(3)K resulted in dose-dependent enhancement of apoptosis (56% vs 31%) and a 3-fold reduction in CD5 CAR T cell numbers after 72h. Combining CD28 and 4-1BB domains in a third generation CD5 CAR still did not rescue T cell expansion. Therefore, we developed a regulated retroviral expression system that uses a small molecule to reversibly inhibit CAR expression, thereby preventing tonic signaling and the resulting fratricide and differentiation. Withdrawing the inhibitor restores CAR expression and the anti-tumor function of T cells, and preserves the central memory population by the time the CAR is fully expressed. Overall, these studies provide a mechanism regulating T cell fratricide and offer a means of reducing the negative effects of tonic CD5 CAR signaling.
Microparticle-Associated Tissue Factor: A Molecular Link Between Coagulation Activation, Inflammation and Disease Progression in Early-Stage Prostate Cancer?
Authors: Katja Haubold, Michael Rink, Brigitte Spath, Ali Amirkhosravi, John L. Francis, Barbara Eifrig, Carsten Bokemeyer, Florian Langer
Journal: Blood (2008)