tbuckley/cabot-search huggingface dataset:
Gonadal germinal testicular tumors (GGTT): The Henry Moore´s latest series
Authors: E. J. Rivarola, C. García Gerardi, D. Santillan, G. Martín Reinas, M. Abal, J. C. Calarame, E. Gil Deza, E. Morgenfeld, F. G. Gercovich
Journal: Journal of Clinical Oncology (2008)

16132 Background: Testicular cancer represents only 1% of all oncological diagnoses in men. It is, however, of peculiar importance, given that it is the most frequent solid tumor found in teenagers and young adults (age range: 15 to 35 years) andhas a high rate of cure. Objective: The aim of this study is to present and analyze the cohort of patients with a confirmed diagnosis of GGTT treated at our Institution. Material and Methods: Our institute’s database, which covers the past 10 years, was analyzed, and the patients diagnosed with GGTT were selected. Patients who had “extra-gonadal” tumors, were excluded from the present series. The patients were categorized in two different groups: “seminomatous” (S) and “non-seminomatous” (NS). The classification of the cases in risk groups was made following the International Consensus of the Collaborative Group. The risk groups were low, medium and high, based on two variables: the level of blood markers and site of metastasis. The treatment followed the guidelines of the NCCN. Results: The number of evaluable patients was 265. The main characteristics of the population are outlined in table 1: Conclusion: The GGTT are the most curable neoplasias amongst solid tumors. In our cohort we have found that the primary therapeutical objective (curability) has been reached, and correlates with the results that have been obtained by other prestigious international institutions. While this illness might not be frequent, it is very important considering the age range that encompasses. Table 1:Characteristics of the population Age (years) Seminomatous (n=116) Non-Seminomatous (n=149) Mean 40 yo Mean 35 yo Risk Groups Low 113 (97%) Medium 3 High 0 Low 133 (89%) Medium 12 High 4 Chemotherapy First line 30 Second line 9 First line 103 Second line 16 Radiotherapy Yes 79 (68%) Yes 4 (3%) Follow up (months) Median 22 m Median 22 m Status Alive NED 106 (91%) Alive NED 130 (87%) No significant financial relationships to disclose.
Human agricultural economy is, and likely always was, largely based on kinship – Why?
Authors: Hannes Rusch, Eckart Voland
Journal: Behavioral and Brain Sciences (2016)

Abstract We question the sequence of evolutionary transitions leading to ultrasociality in humans proposed by Gowdy &amp; Krall. Evidence indicates that families are, and likely always have been, the primary productive units in human agricultural economies, suggesting that genetic relatedness is key to understanding when the suppression of individual autonomy to the benefit of subsistence groups, that is, extended families, evolved.
2013 Late-Breaking Basic Science Abstracts
Authors: Pearl Quijada, Jonathan Cubillo, Claudio Staub, Mark Sussman, San Diego, Rajinikanth Gogiraju, Julia Steinbrecher, Stephan Lehnart, Matthias Dobbelstein, Katrin Schaefer, Yingfeng Tu, Lin Wan, Dongliang Zhao, Lihong Bu, Baozhong Shen, Michael Katz, Elizabeth Brandon-Warner, Anthony Fargnoli, Richard Williams, Rachel Kaplan, Tracy Walling, Roger Hajjar, Laura Schrum, Charles Bridges, None Brandon-Warner, Moshi Song, Yun Chen, Stephan Frank, Luca Scorrano, Gerald Dorn, Esperanza Pascual, Xianming Lin, Anna Pfenniger, Indra Lübkemeier, Klaus Willecke, Eli Rothenberg, Mario Delmar, D Lobb, None Logdon, None Doviak, None O'neill, Martin Dichgans, Rainer Malik, Inke König, Jonathan Rosand, Robert Clarke, Solveig Gretarsdottir, Braxton Mitchell, Jeanette Erdmann, Sekar Kathiresan, Ruth Mcpherson, Cathie Sudlow, Muredach Reilly, John Thompson, Pankaj Sharma, John Chambers, Hugh Watkins, Peter Rothwell, Robert Roberts, Hugh Markus, Nilesh Samani, Martin Farrall, Heribert Schunkert
Journal: Circulation Research (2013)

Dual stem cell transplantation of c-kit positive cardiac progenitor cells (CPCs) and mesenchymal stem cells (MSCs) after infarction support modest improvements in cardiac function, however there are currently no reports substantiating a single stem cell type supporting both direct and indirect mechanisms of myocardial repair.Therefore we created a CardioChimera, a stem/progenitor cell formed by fusion between CPCs and MSCs, resulting in a unique progeny superior to either individual precursor.CardioChimeras were purified after cell fusion with Hemagglutinating virus of Japan and expanded clonally based on dual expression of fluorescent proteins mCherry and eGFP from CPCs and MSCs respectively.CardioChimeras are mono-nucleated, have comparable growth kinetics to parental CPCs and MSCs and display increased cellular size unrelated to cell cycle arrest and/or senescence.CardioChimeras have increased expression of cardiomyogenic lineage markers cardiac troponin T (2.5-fold), smooth muscle 22 (9.3-fold), and CD31 (10.7-fold) concomitantly associated with decreased c-kit protein expression (50%) relative to parent CPCs.Lineage commitment of CardioChimeras is bolstered by dexamethasone treatment measured by mRNA levels of cardiogenic genes and increases in active mitochondria (2.2-fold) after labeling with MitoTracker.Induction of apoptosis is blunted in cardiomyocytes co-cultured with CardioChimeras compared to co-culturing with CPCs and MSCs alone, or combination of non-fused parent cells.Cardio-Chimeras enhance cardiomyocyte growth similar to parent MSCs owing to an increased propensity to secrete pro-growth factors.Collectively, CardioChimeras represent an adaptable cell therapy combining the beneficial properties of CPCs to undergo cardiac specific commitment as well as MSCs that foster an improved microenvironment with protective paracrine secretion.Clinically, CardioChimeras merge the application of distinct cell types into a single entity for increased engraftment, mitigation of inflammation and blunting the progression of heart failure by promoting myocardial regeneration.
A 27-Gene NGS Panel in Primary Myelofibrosis Identifies ASXL1, CBL, RUNX1 and SRSF2 Mutations As Being Unfavorable and Absence of Any Non-Driver Mutation As Being Favorable to Survival
Authors: Ayalew Tefferi, Terra L. Lasho, Christy Finke, Yoseph Elala, Daniela Barraco, Naseema Gangat, Curtis A. Hanson, Rhett P. Ketterling, Animesh Pardanani
Journal: Blood (2015)
NHS unveils service to help GPs with burnout
Authors: Gareth Iacobucci
Journal: BMJ (2016)

GPs in England who experience stress and burnout will be able to access a new, free confidential support service from January 2017.

The NHS GP Health Service, funded by NHS England at a cost of £19.5m (€22.1m; $24.7) over the next five years, will offer services such as general psychiatric assessment and treatment, support for addiction related health problems, and one to one and group psychotherapy sessions.

The service will be available across England and will be provided by the Hurley Clinic Partnership, run by the former chair of the Royal College of General Practitioners, Clare Gerada, which currently provides the NHS Practitioner Health Programme …
Treatment of Children and Adolescents With Metastatic Medulloblastoma and Prognostic Relevance of Clinical and Biologic Parameters
Authors: André O. von Bueren, Rolf-Dieter Kortmann, Katja von Hoff, Carsten Friedrich, Martin Mynarek, Klaus Müller, Tobias Goschzik, Anja zur Mühlen, Nicolas Gerber, Monika Warmuth-Metz, Niels Soerensen, Frank Deinlein, Martin Benesch, Isabella Zwiener, Robert Kwiecien, Andreas Faldum, Udo Bode, Gudrun Fleischhack, Volker Hovestadt, Marcel Kool, David Jones, Paul Northcott, Joachim Kuehl, Stefan Pfister, Torsten Pietsch, Stefan Rutkowski
Journal: Journal of Clinical Oncology (2016)

Purpose To assess an intensified treatment in the context of clinical and biologic risk factors in metastatic medulloblastoma. Patients and Methods Patients (4 to 21 years old, diagnosed between 2001 and 2007) received induction chemotherapy, dose-escalated hyperfractionated craniospinal radiotherapy, and maintenance chemotherapy. Subgroup status and other biologic parameters were assessed. Results In 123 eligible patients (median age, 8.2 years old; median follow-up, 5.38 years), 5-year event-free survival (EFS) and overall survival (OS) were 62% (95% CI, 52 to 72) and 74% (95% CI, 66 to 82), respectively. OS was superior compared with the precedent HIT '91 trial. The 5-year EFS and OS were both 89% (95% CI, 67 to 100) for desmoplastic/nodular (n = 11), 61% (95% CI, 51 to 71) and 75% (95% CI, 65 to 85) for classic (n = 107), and 20% (95% CI, 0 to 55) and 40% (95% CI, 0 to 83) for large-cell/anaplastic (n = 5) medulloblastoma ( P < .001 for EFS; P = .001 for OS). Histology (hazard ratio, 0.19 for desmoplastic/nodular and 45.97 for large-cell/anaplastic medulloblastoma) and nonresponse to the first chemotherapy cycle (hazard ratio, 1.97) were independent risk factors (EFS). Among 81 (66%) patients with tumor material, 5-year EFS and OS differed between low-risk (wingless [WNT], n = 4; both 100%), high-risk ( MYCC/ MYCN amplification; n = 5, both 20%), and intermediate-risk patients (neither; n = 72, 63% and 73%, respectively). Survival rates were different between molecular subgroups (WNT, n = 4; sonic hedgehog [SHH; n = 4]; group 4 [n = 41]; group 3 with [n = 3] or without [n = 17] MYCC/MYCN amplification; P < .001). All cases showed p53 immuno-negativity. There was no association between patients with nonresponding tumors to induction chemotherapy and WNT ( P = .143) or MYCC/MYCN status ( P = .075), histologic subtype ( P = .814), or molecular subtype ( P = .383), as assessed by Fisher's exact test. Conclusion This regimen was feasible and conferred overall favorable survival. Our data confirm the relevance of subgroup status and biologic parameters (WNT/ MYCC/ MYCN status) in a homogeneous prospective trial population, and show that metastatic group 3 patients do not uniformly have poor outcomes. Biologic subgroup, MYCC/ MYCN status, response to induction chemotherapy, and histologic subtype may serve for improved treatment stratification.
‘Don't let kids play football’: a killer idea
Authors: James MacDonald, Gregory D Myer
Journal: British Journal of Sports Medicine (2016)

Recent calls to ban or curb youth tackle football, rugby and other contact sports markedly underplay an essential point: it is generally more dangerous for youth to be sedentary than to risk injury playing a contact sport. And for many kids, sports are the only thing that will get them away from smartphones and off the couch.

Please hear us out. As experts in paediatrics, sports medicine and injury biomechanics, we understand that brain injury caused by blows to the head in sports is a serious medical issue for athletes of all ages. But the answer is not shutting down youth sports programmes, as some well-intentioned advocates suggest. We are convinced this would have unintended consequences and ultimately do more harm than good.

We also must recognise the limitations of current science. If concussions seem to be on the rise,1 it is possible that caregivers are doing a better job than ever identifying them when they happen. Also, more kids, especially girls, are playing all sports than they were decades ago. Moreover, the highly publicised brain damage known as chronic traumatic encephalopathy (CTE), discovered in a targeted sample of …
Phase I safety and pharmacokinetic/pharmacodynamic results of the histone deacetylase inhibitor vorinostat in combination with bevacizumab in patients with kidney cancer
Authors: H. J. Hammers, H. Verheul, B. Wilky, B. Salumbides, J. Holleran, M. J. Egorin, M. Lodge, R. L. Wahl, J. A. Zwiebel, M. A. Carducci, R. Pili
Journal: Journal of Clinical Oncology (2008)

16094 Background: Class II histone deacetylase (HDAC) inhibitors have antiangiogenesis and antitumor effect in combination with anti vascular endothelial factor (VEGF) agents in preclinical models. The objective of this Phase I study was to determine the safety, tolerability, and pharmacokinetic (PK)/pharmacodynamic (PD) profiles of the HDAC inhibitor vorinostat in combination with bevacizumab. Methods: Patients with stage IV clear cell renal cell carcinoma, performance status 0–2 and good organ function were eligible. Up to two prior treatment regimens were allowed. Treatment consisted of vorinostat 200 mg orally twice daily × 2 weeks, and bevacizumab 15 mg/kg intravenously every 3 weeks. PK concentrations of vorinostat were determined by LC/MS/MS. Western Blot analysis on peripheral-blood mononuclear cells (PBMCs) and platelet-rich plasma were performed to evaluate target inhibition. Results: A total of 8 male patients was enrolled, 7 patients were evaluable; prior nephrectomy = 8; prior systemic therapy (receptor tyrosine kinase inhibitors) = 7; one patient (out of 7) in dose level 1 experienced DLT with grade 4 thrombocytopenia. Other grade 3 toxicities that were not DLTs included anorexia, fatigue, hemothorax, and pulmonary embolism. The best responses in the 7 evaluable patients included stable disease. One patient with mixed response had stable disease for >18 months. Two other patients had stable disease for 5 and 6 months. Vorinostat mean Cmax concentration (Day1) and T1/2 were 1.264±0.629 μM and 1.5 h, respectively, which is consistent with prior reports for vorinostat. PBMCs analysis showed transient but consistent protein acetylation post-therapy. Platelet but not plasma derived free VEGF was reduced by treatment. Tumor metabolism and blood flow modulation was observed in two patients by PET scan. Conclusions: Combination of vorinostat and bevacizumab is reasonably well tolerated. 200 mg PO BID is the Phase II recommended dose for vorinostat in combination with bevacizumab 15 mg/ Kg every 21 days. Tumor response and PD data suggest activity for this combination strategy. The phase II study is underway. Supported by NCI U01-CA-70095; 1R21CA121590; N01-CO-124001. No significant financial relationships to disclose.
Variation in vitamin D deficiency among tuberculosis patients by ethnic group and geographical region of birth: evidence from a diverse south London population
Authors: Adam Pilarski, Nicole Penn, Sharenja Ratnakumar, Richard D. Barker, Heather J. Milburn
Journal: European Respiratory Journal (2016)

Numerous studies have demonstrated an important association of vitamin D deficiency with tuberculosis (TB) [1, 2]. Vitamin D is important for immune function and an appropriate host response to Mycobacterium tuberculosis [3, 4]; 25-hydroxyvitamin D (25(OH)D) is the primary circulating form of vitamin D and is used to measure deficiency. Ethnicity & some geographical regions of birth strongly associated with risk of vitamin D deficiency in TB patients <http://ow.ly/MiXR302uUPh> The authors would like to thank Frank Post (GU Medicine, King's College Hospital, London, UK), Jessie Randhawa (Respiratory Medicine, Guy's and St Thomas' NHS Foundation Trust, London UK) and Vanessa Kahr (Respiratory Medicine, King's College Hospital, London, UK) for their support in the early stages of the project. This report was a retrospective analysis of routine data, in which no personal identifiers were retained, and collected as part of clinical service provision. H.J. Milburn and R.D. Barker conceived the study. N. Penn, A. Pilarski, S. Ratnakumar and R.D. Barker collected the data. N. Penn carried out the statistical analysis. With guidance from H.J. Milburn, N. Penn and A. Pilarski wrote the initial manuscript. A. Pilarski revised the manuscript with guidance from H.J. Milburn. All authors contributed to the completed manuscript.
From Skeleton to Cytoskeleton
Authors: Chi Yung Yuen, Siu Ling Wong, Chi Wai Lau, Suk-Ying Tsang, Aimin Xu, Zhiming Zhu, Chi Fai Ng, Xiaoqiang Yao, Siu Kai Kong, Hung Kay Lee, Yu Huang
Journal: Circulation Research (2012)

Rationale: The expression of osteocalcin is augmented in human atherosclerotic lesions. How osteocalcin triggers vascular pathogenesis and remodeling is unclear. Objective: To investigate whether osteocalcin promotes transformation of adventitial fibroblast to myofibroblasts and the molecular mechanism involved. Methods and Results: Immunohistochemistry indicated that osteocalcin was expressed in the neointima of renal arteries from diabetic patients. Western blotting and wound-healing assay showed that osteocalcin induced fibroblast transformation and migration, which were attenuated by blockers of the renin-angiotensin system and protein kinase Cδ (PKCδ), toll-like receptor 4 (TLR4) neutralizing antibody, and antagonist and inhibitors of free radical production and cyclooxygenase-2. Small interfering RNA silencing of TLR4 and PKCδ abolished fibroblast transformation. Angiotensin II level in the conditioned medium from the osteocalcin-treated fibroblasts was found elevated using enzyme immunoassay. Culturing of fibroblasts in conditioned medium collected from differentiated osteoblasts promoted fibroblast transformation. The expression of fibronectin, TLR4, and cyclooxygenase-2 is augmented in human mesenteric arteries after 5-day in vitro exposure to osteocalcin. Conclusions: Osteocalcin transforms adventitial fibroblasts to myofibroblasts through stimulating angiotensin II release and subsequent activation of PKCδ/TLR4/reactive oxygen species/cyclooxygenase-2 signaling cascade. This study reveals that the skeletal hormone osteocalcin cross-talks with vascular system and contributes to vascular remodeling.
Phase I study of cetuximab (CET) in combination with 5-fluorouracil (5-FU), cisplatin (CP), and radiotherapy (RT) in patients with locally advanced squamous cell anal carcinoma (LAAC)
Authors: L. O. Olivatto, F. Meton, M. Bezerra, A. Cardoso, C. M. Araujo, L. Castro, R. Moura, B. V. Pereira, C. G. Ferreira
Journal: Journal of Clinical Oncology (2008)

4609 Background: Although chemoradiation (CRT) is a curable approach to anal carcinoma, 50% of the patients (pts) with LAAC eventually recur. Novel therapeutic strategies are needed for this population. CET is a monoclonal antibody directed against the EGFR, which is strongly expressed in anal carcinoma. Synergy of CET with RT resulted in improved survival (vs. RT alone) in head and neck cancer. This trial evaluates the feasibility and tolerability of CET/5-FU/CP combined to RT in LAAC, with maximal tolerated dose as primary endpoint. Methods: Pts with LAAC (T3-T4 and/or N+ disease per proctoscopy and MRI) received RT 45 Gy/1.8Gy day/5wks plus boost 10 Gy (2 Gy/day) to a total dose of 55 Gy in combination with CET (400mg/m2 on d1, then 7 weekly doses of 250 mg/m2). Combination chemotherapy with 96-hour infusion of escalating-dose of 5-FU and 2-hour infusion of escalating-dose CP, both on days 1 and 29 according to the following design: starting dose level (0) 800 and 60 mg/m2/day, dose level (-1) 600 and 50 mg/m2/day, dose level (+1) 800 and 80 mg/m2/day and dose level (+2) 1000 and 80 mg/m2/day. A standard 3+3 design was used. Grade 4 hematologic toxicities, grade 4 radiation dermatitis, uncontrolled diarrhea or cumulative density of dose > 70% for all treatments were included as dose-limiting toxicities (DLTs). Results: 10 patients (2 m/8f) stages T3N0:2, T2N2:2, T3N2:1, T2N3:2, T3N3:2, T4N0:1 have been enrolled. All pts completed full dose RT within 68 days (median, [50–98]). As on dose level 0 one DLT (grade 4 neutropenic fever) occurred, it was extended to 7 pts. No further DLT was observed on levels +1. Toxicities are displayed in the table. To date, out of 09 pts evaluable for pathological response, 07 achieved pCR (78%). Conclusions: CRT with 5-FU/CP plus CET seems feasible without unexpected toxicities with provocative preliminary efficacy in LAAC. The recommended doses for phase II will be available by April 2008. Study supported by Merck KGaA. Toxicity* (n=10) Grade 2 (%) Grade 3 (%) Grade 4 (%) Fatigue 70 10 0 Nauseas 40 0 0 Mucositis 40 10 0 Diarrhea 30 60 0 Dehydration 40 0 0 Neutropenic fever 0 0 10 Radiation dermatitis 40 50 0 Acneiform rash 30 0 0 Hand and foot fissures 20 0 0 * NCI-CTC 3.0 No significant financial relationships to disclose.
Strict in vivo specificity of the Bcl11a erythroid enhancer
Authors: Elenoe C. Smith, Sidinh Luc, Donyell M. Croney, Mollie B. Woodworth, Luciano C. Greig, Yuko Fujiwara, Minh Nguyen, Falak Sher, Jeffrey D. Macklis, Daniel E. Bauer, Stuart H. Orkin
Journal: Blood (2016)
Effect of lipid nanoparticle siRNA delivery systems on silencing clusterin and progression in enzalutamide resistant prostate cancer in vivo.
Authors: Yoshiaki Yamamoto, Paulo Jc Lin, Fan Zhang, Yoshihisa Kawai, Eliana Beraldi, Jeffrey Leong, Hideyasu Matsuyama, Pieter R Cullis, Martin Edwin Gleave
Journal: Journal of Clinical Oncology (2015)

256 Background: Clusterin (CLU) is induced by androgen receptor (AR) pathway inhibition and its overexpression confers treatment resistance. Lipid nanoparticle (LNP) facilitates tumor uptake and intracellular processing through an enhanced permeation and retention effect (EPR), currently with multiple products undergoing clinical evaluation. Gene silencing using small interfering RNA (siRNA) is a promising approach but in vivo delivery remains a major barrier. In our study, we investigated the efficacy siRNA tumor delivery using LNP systems in enzalutamide-resistant (ENZ-R) castration-resistant prostate cancer (CRPC) model. Methods: To validate the effect of LNP siRNA tumor delivery in vivo, gene silencing of a reporter gene, luciferase (LUC), in PC3-M-luc stable cell line was treated with LNP LUC-siRNA and examined for Luc activity by the IVIS imaging system. Next, we investigated the efficacy of LNP CLU-siRNA tumor delivery and LNP CLU-siRNA sensitized AR knockdown activity in ENZ-R CRPC LNCaP in vitro and in vivo models. Results: LNP LUC-siRNA exhibited LUC silencing effects in PC-3M-luc xenograft and metastatic models. LNP CLU-siRNA suppressed PSA and decreased AKT and ERK phosphorylation in ENZ-R LNCaP cells in vitro. LNP CLU-siRNA sensitized AR antisense oligonucleotides (ASO) activity, more potently inhibiting ENZ-R cell growth rates and increased apoptosis when compared to AR-ASO monotherapy. In vivo,combinatory treatment of LNP CLU-siRNA and AR-ASO significantly suppressed tumor growth and serum PSA levels compared to LNP LUC -siRNA (control) and AR-ASO in ENZ-R LNCaP xenografts. Conclusions: The LNP CLU-siRNA systems sensitized AR knockdown resulting in inhibition of ENZ-R LNCaP cell growth, providing pre-clinical proof-of-principle as a promising AR co-targeting approach in ENZ-R CRPC.
The effect of host genetics on the gut microbiome
Authors: Marc Jan Bonder, Alexander Kurilshikov, Ettje F Tigchelaar, Zlatan Mujagic, Floris Imhann, Arnau Vich Vila, Patrick Deelen, Tommi Vatanen, Melanie Schirmer, Sanne P Smeekens, Daria V Zhernakova, Soesma A Jankipersadsing, Martin Jaeger, Marije Oosting, Maria Carmen Cenit, Ad A M Masclee, Morris A Swertz, Yang Li, Vinod Kumar, Leo Joosten, Hermie Harmsen, Rinse K Weersma, Lude Franke, Marten H Hofker, Ramnik J Xavier, Daisy Jonkers, Mihai G Netea, Cisca Wijmenga, Jingyuan Fu, Alexandra Zhernakova
Journal: Nature Genetics (2016)