tbuckley/cabot-search huggingface dataset:
A dose-finding study of a MUC-1 vaccine in conjunction with <i>poly-IC:LC</i> (polyinosinic-polycytidylic acid stabilized with polylysine and carboxy methylcellulose) in immunosuppressed (IS) patients (pts) with advanced prostate cancer (PCa).
Authors: A. K. Patel, L. J. Appleman, W. E. Gooding, D. Friedland, J. McKolanis, A. M. Salazar, O. J. Finn, G. S. Chatta
Journal: Journal of Clinical Oncology (2011)

2564 Background: One barrier to the efficacy of vaccines in advanced PCa may be the presence of cancer-associated IS. Poly-IC:LC (PICLC), a potent immune adjuvant, can reverse IS in other malignancies; we studied its effects in boosting the immunologic response to a MUC-1 peptide vaccine. Methods: A single arm study was conducted to determine the efficacy of PICLC. Eligible pts had advanced PCa with evidence of systemic IS, defined as low levels of IFN-γ and TNF-α production by peripheral blood mononuclear cells. On weeks 1 and 2, pts were treated with PICLC 25μg/kg, 3 days per week. On weeks 3, 5, and 7, pts were treated with injections of MUC-1 vaccine. They continued to receive PICLC twice weekly till progression. Cytokine levels were measured prior to treatment and at week 3. The primary endpoint was an increase in levels of IFN-γ and TNF-α in > 40% of pts. Cytokine levels in CD4/CD8 T-cell subsets, anti-MUC-1 IgM and IgG levels, and serial PSAs were secondary endpoints. Results: Fourteen pts with advanced PCa were enrolled, with 13 being castrate-resistant. Their ages ranged from 51 to 80 years (median 72). 12 of 14 pts (86%) had increased TNF-α production; 9 of 14 (64%) had an increase in IFN-γ; and 9 pts (64%) upregulated both cytokines. 2 of these 9 (22%) pts maintained stable PSA levels for at least 6 months following therapy. The level of response ranged from 15% to 76% for IFN-γ and 9% to 137% for TNF-α. Of the 14 pts, 2 (14%) upregulated IFN-γ in CD4 T-cells and 5 (38%) in CD8 T-cells. TNF-α upregulation was observed equally in CD4/CD8 subsets in 8 (57%) pts. IgM and IgG anti-MUC-1 antibody responses were seen in 3 (21%) pts, with these pts also demonstrating increases in both IFN-γ and TNF-α. PICLC was well tolerated with primary side-effect being mild flu-like symptoms in 10 of 14pts (71%). Conclusions: PICLC (25μg/kg) successfully reversed IS in 9 of 14 (64%) pts with advanced PCa. This, coupled with the encouraging immune and clinical responses observed in some pts, warrants further investigation of PICLC as a vaccine adjuvant in advanced PCa.
Arthroscopic surgery for knee pain: where is the shared decision making?
Authors: Samuel J Finnikin
Journal: BMJ (2016)

Evidence suggests significant overtreatment of knee pain with arthroscopy when less invasive, less expensive treatment options are equally effective.1 Not only is this potentially harmful for patients but it represents an inexcusable misuse of resources. Surely this could be solved through judicious application of shared decision making?

A brief search for patient decision aids in this area finds the …
Association between functional gastrointestinal disorders and migraine in children and adolescents: a case-control study
Authors: Julie Le Gal, Jean-Francois Michel, Victoria Elisa Rinaldi, Daniele Spiri, Raffaella Moretti, Donatella Bettati, Silvia Romanello, Paola Berlese, Rosa Lualdi, Priscilla Boizeau, Jerome Viala, Marc Bellaiche, Gian Vincenzo Zuccotti, Giovanni Crichiutti, Corinne Alberti, Luigi Titomanlio
Journal: The Lancet. Gastroenterology & hepatology (2016)
Targeting Fibroblast Growth Factor Receptor 1 for Treatment of Soft-Tissue Sarcoma
Authors: Priya Chudasama, Marcus Renner, Melanie Straub, Sadaf S. Mughal, Barbara Hutter, Zeynep Kosaloglu, Ron Schweßinger, Matthias Scheffler, Ingo Alldinger, Simon Schimmack, Thorsten Persigehl, Carsten Kobe, Dirk Jäger, Christof von Kalle, Peter Schirmacher, Marie-Kristin Beckhaus, Stephan Wolf, Christoph Heining, Stefan Gröschel, Jürgen Wolf, Benedikt Brors, Wilko Weichert, Hanno Glimm, Claudia Scholl, Gunhild Mechtersheimer, Katja Specht, Stefan Fröhling
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Altered FGFR1 signaling has emerged as a therapeutic target in epithelial malignancies. In contrast, the role of FGFR1 in soft-tissue sarcoma (STS) has not been established. Prompted by the detection and subsequent therapeutic inhibition of amplified FGFR1 in a patient with metastatic leiomyosarcoma, we investigated the oncogenic properties of FGFR1 and its potential as a drug target in patients with STS. Experimental Design: The frequency of FGFR1 amplification and overexpression, as assessed by FISH, microarray-based comparative genomic hybridization and mRNA expression profiling, SNP array profiling, and RNA sequencing, was determined in three patient cohorts. The sensitivity of STS cell lines with or without FGFR1 alterations to genetic and pharmacologic FGFR1 inhibition and the signaling pathways engaged by FGFR1 were investigated using viability assays, colony formation assays, and biochemical analysis. Results: Increased FGFR1 copy number was detected in 74 of 190 (38.9%; cohort 1), 13 of 79 (16.5%; cohort 2), and 80 of 254 (31.5%; cohort 3) patients. FGFR1 overexpression occurred in 16 of 79 (20.2%, cohort 2) and 39 of 254 (15.4%; cohort 3) patients. Targeting of FGFR1 by RNA interference and small-molecule inhibitors (PD173074, AZD4547, BGJ398) revealed that the requirement for FGFR1 signaling in STS cells is dictated by FGFR1 expression levels, and identified the MAPK–ERK1/2 axis as critical FGFR1 effector pathway. Conclusions: These data identify FGFR1 as a driver gene in multiple STS subtypes and support FGFR1 inhibition, guided by patient selection according to the FGFR1 expression and monitoring of MAPK–ERK1/2 signaling, as a therapeutic option in this challenging group of diseases. Clin Cancer Res; 23(4); 962–73. ©2016 AACR.
Assessment of the clinical cardiac drug‐drug interaction associated with the combination of hepatitis C virus nucleotide inhibitors and amiodarone in guinea pigs and rhesus monkeys
Authors: Christopher P. Regan, Pierre Morissette, Hillary K. Regan, Jeffery J. Travis, Pamela Gerenser, Jianzhong Wen, Kevin Fitzgerald, Shaun Gruver, Joseph J. DeGeorge, Frederick J. Sannajust
Journal: Hepatology (2016)

In 2015, European and U.S. health agencies issued warning letters in response to 9 reported clinical cases of severe bradycardia/bradyarrhythmia in hepatitis C virus (HCV)‐infected patients treated with sofosbuvir (SOF) in combination with other direct acting antivirals (DAAs) and the antiarrhythmic drug, amiodarone (AMIO). We utilized preclinical in vivo models to better understand this cardiac effect, the potential pharmacological mechanism(s), and to identify a clinically translatable model to assess the drug‐drug interaction (DDI) cardiac risk of current and future HCV inhibitors. An anesthetized guinea pig model was used to elicit a SOF+AMIO‐dependent bradycardia. Detailed cardiac electrophysiological studies in this species revealed SOF+AMIO‐dependent selective nodal dysfunction, with initial, larger effects on the sinoatrial node. Further studies in conscious, rhesus monkeys revealed an emergent bradycardia and bradyarrhythmia in 3 of 4 monkeys administered SOF+AMIO, effects not observed with either agent alone. Morever, bradycardia and bradyarrhythmia were not observed in rhesus monkeys when intravenous infusion of MK‐3682 was completed after AMIO pretreatment. Conclusions : These are the first preclinical in vivo experiments reported to replicate the severe clinical SOF+AMIO cardiac DDI and provide potential in vivo mechanism of action. As such, these data provide a preclinical risk assessment paradigm, including a clinically relevant nonhuman primate model, with which to better understand cardiovascular DDI risk for this therapeutic class. Furthermore, these studies suggest that not all HCV DAAs and, in particular, not all HCV nonstructural protein 5B inhibitors may exhibit this cardiac DDI with amiodarone. Given the selective in vivo cardiac electrophysiological effect, these data enable targeted cellular/molecular mechanistic studies to more precisely identify cell types, receptors, and/or ion channels responsible for the clinical DDI. (H epatology 2016;64:1430‐1441)
Antiplatelet Therapy for Long-term Secondary Prevention After Myocardial Infarction
Authors: Marc P. Bonaca, Marc S. Sabatine
Journal: JAMA Cardiology (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
P0001 : Early monocyte dysfunction in patients who develop Systemic Inflammatory Response Syndrome (SIRS) and sepsis after hepatopancreaticobiliary surgery
Authors: R. Lahiri, Y. Derwa, Z. Bashir, E. Giles, H. Torrance, M. O’Dwyer, H. Owen, A. O’Brien, A. Stagg, S. Bhattacharya, G.R. Foster, W. Alazawi
Journal: Journal of Hepatology (2015)
Ubiquitin-Conjugating Enzyme Ubc13 Is a Critical Component of TRAF-Mediated Inflammatory Responses.
Authors: Toru Fukushima, Shu-ichi Matsuzawa, Christinia L. Kress, Jean Marie Bruey, Maryla Krajewska, Sophie Lefebvre, Juan M. Zapata, Ze’ev Ronai, John C. Reed
Journal: Blood (2006)
Final Results of a Phase Ib Trial of Atacicept to Neutralize APRIL and BLyS in Patients with Refractory or Relapsed Chronic Lymphocytic Leukemia (CLL).
Authors: David M Kofler, Barbara B Gawlik, Thomas Elter, Athos Gianella-Borradori, Clemens M Wendtner, Michael Hallek
Journal: Blood (2009)
DNA Repair in Prostate Cancer: Biology and Clinical Implications
Authors: Joaquin Mateo, Gunther Boysen, Christopher E. Barbieri, Helen E. Bryant, Elena Castro, Pete S. Nelson, David Olmos, Colin C. Pritchard, Mark A. Rubin, Johann S. de Bono
Journal: European Urology (2016)

For more precise, personalized care in prostate cancer (PC), a new classification based on molecular features relevant for prognostication and treatment stratification is needed. Genomic aberrations in the DNA damage repair pathway are common in PC, particularly in late-stage disease, and may be relevant for treatment stratification.To review current knowledge on the prevalence and clinical significance of aberrations in DNA repair genes in PC, particularly in metastatic disease.A literature search up to July 2016 was conducted, including clinical trials and preclinical basic research studies. Keywords included DNA repair, BRCA, ATM, CRPC, prostate cancer, PARP, platinum, predictive biomarkers, and hereditary cancer.We review how the DNA repair pathway is relevant to prostate carcinogenesis and progression. Data on how this may be relevant to hereditary cancer and genetic counseling are included, as well as data from clinical trials of PARP inhibitors and platinum therapeutics in PC.Relevant studies have identified genomic defects in DNA repair in PCs in 20-30% of advanced castration-resistant PC cases, a proportion of which are germline aberrations and heritable. Phase 1/2 clinical trial data, and other supporting clinical data, support the development of PARP inhibitors and DNA-damaging agents in this molecularly defined subgroup of PC following success in other cancer types. These studies may be an opportunity to improve patient care with personalized therapeutic strategies.Key literature on how genomic defects in the DNA damage repair pathway are relevant for prostate cancer biology and clinical management is reviewed. Potential implications for future changes in patient care are discussed.
β1-Adrenergic receptor deficiency in ghrelin-expressing cells causes hypoglycemia in susceptible individuals
Authors: Bharath K. Mani, Sherri Osborne-Lawrence, Prasanna Vijayaraghavan, Chelsea Hepler, Jeffrey M. Zigman
Journal: Journal of Clinical Investigation (2016)

Ghrelin is an orexigenic gastric peptide hormone secreted when caloric intake is limited. Ghrelin also regulates blood glucose, as emphasized by the hypoglycemia that is induced by caloric restriction in mouse models of deficient ghrelin signaling. Here, we hypothesized that activation of β1-adrenergic receptors (β1ARs) localized to ghrelin cells is required for caloric restriction-associated ghrelin release and the ensuing protective glucoregulatory response. In mice lacking the β1AR specifically in ghrelin-expressing cells, ghrelin secretion was markedly blunted, resulting in profound hypoglycemia and prevalent mortality upon severe caloric restriction. Replacement of ghrelin blocked the effects of caloric restriction in β1AR-deficient mice. We also determined that treating calorically restricted juvenile WT mice with beta blockers led to reduced plasma ghrelin and hypoglycemia, the latter of which is similar to the life-threatening, fasting-induced hypoglycemia observed in infants treated with beta blockers. These findings highlight the critical functions of ghrelin in preventing hypoglycemia and promoting survival during severe caloric restriction and the requirement for ghrelin cell-expressed β1ARs in these processes. Moreover, these results indicate a potential role for ghrelin in mediating beta blocker-associated hypoglycemia in susceptible individuals, such as young children.
A Phase II Study Of The Efficacy and Safety Of An Intensified Schedule Of Azacitidine (AZA) In Intermediate-2 and High Risk MDS Patients
Authors: Lionel Ades, Agnès Guerci-Bresler, Pascale Cony Makhoul, Laurence Legros, Jacques Delaunay, Christian Recher, Kristell Desseaux, Benedicte Samey, Sylvie Chevret, Pierre Fenaux
Journal: Blood (2013)
Self-Responsibility for Our Good Health—Reply
Authors: Mingyang Song, Edward Giovannucci
Journal: JAMA Oncology (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Macrophage-derived microvesicles’ pathogenic role in acute lung injury
Authors: Jae W Lee
Journal: Thorax (2016)

Once considered cellular debris or, more recently, as biomarkers of disease progression, extracellular vesicles (EVs), comprised of exosomes, microvesicles (MVs) and apoptotic bodies, released by living and dying eukaryotic cells are now recognised as important mediators of cellular communication and function.1 EVs are a heterogeneous population of anucleate vesicles with a diameter of 100–1000 nm that are released from intracellular compartments as exosomes or by budding off the plasma membrane as MVs in response to diverse physiological, pathophysiological or external stimulus. Despite its importance in various organ injuries and cancer,2 ,3 the role of EVs in the pathogenesis of acute lung injury (ALI) is still largely unexplored.4–6 In the current issue of Thorax , Soni et al 7 studied the temporal pattern of EV release in early ALI and found that MVs from alveolar macrophages were the predominant source and played a significant role as potent initiators of the inflammatory response in part by the transfer of its cargo, the cytokine tumour necrosis factor (TNF), to target cells.

By inducing ALI with intratracheal instillation of lipopolysaccharide (LPS) in C57BL6 mice, the authors found that MVs released into the injured alveolus were mainly from alveolar macrophages initially by flow cytometry, peaking at 1 hour and followed soon thereafter by MVs released by alveolar epithelial cells and neutrophils by 4 hours. More importantly, the MVs in the bronchoalveolar fluid (BALF) at 1 hour contained a substantial amount of TNF but low levels …
Barriers To Clinical Trial Enrolment For Teenagers and Young Adults With Acute Lymphoblastic Leukaemia: The Impact of Age Eligibility Criteria
Authors: Lorna Anne Fern, Clare Rowntree, Rachael E Hough, Ajay J Vora, Adele Fielding, Chris Mitchell, Nicholas Goulden, Robert Alston, Jillian Birch, O'hara Catherine, Jeremy Whelan
Journal: Blood (2013)
CPX-351 IN AML after failed induction with cytarabine and daunorubicin.
Authors: J. E. Lancet, E. J. Feldman, J. E. Cortes, D. Hogge, M. S. Tallman, T. Kovacsovics, A. C. Louie
Journal: Journal of Clinical Oncology (2010)

6572 Background: CPX-351 is a formulation that co-encapsulates a 5:1 synergistic molar ratio of cytarabine and daunorubicin within liposomes that is being evaluated in a randomized Phase 2b trial against conventional cytarabine + daunorubicin (7 + 3) in older patients (pts) with newly diagnosed AML. Interim analyses for safety and CR rate were presented at the 2009 ASH on the first 85 pts. Control arm pts with persistent leukemia after 7 + 3 were permitted to crossover to receive CPX-351 and this report presents information for all crossover pts. Methods: Pts were 60-75 yrs of age with previously untreated primary or secondary (history of prior chemotherapy or MDS) AML, LVEF > 50% and ECOG PS 0-2. Pts with known favorable cytogenetics, evidence of active second malignancy or active bacterial infection, or with cumulative daunorubicin exposure > 368 mg/m2 were excluded. Eighty pts were to be randomized to CPX-351 (100 u/m2; D 1, 3, and 5; by 90 min infusion) and 40 pts to 7 + 3 (cytarabine 100 mg/m2/d for 7 days by continuous infusion + daunorubicin 60 mg/m2; D 1,2 and 3 by IV push). Pts thought by the treating physician to be unlikely to respond based on the Day 14 bone marrow were crossed over and were to be analyzed separately and censored for survival analysis at 1 year. Results: By October 2009 126 pts had been randomized and treated, with 41 pts assigned to 7 + 3 control. Ten pts were crossed over to CPX-351 treatment: median age was 68.5 (64-75), 4 had primary AML (standard risk) and 6 had 2° AML (high risk). Karyotyping was not evaluable in one pt but revealed single (3), double (1), triple (1), and no karyotypic abnormalities (4) among 9 other pts. Prior to crossover 9 pt had one and 1 pt had two cycles of 7 + 3. After crossover 4 of 10 pts responded (3CR + 1 CRi) to one course of CPX-351; including 2 with 1° and 2 with 2° AML. Responders had none (2 pt) or two (1 pt) or three (1 pt) karyotypic abnormalities. Conclusions: CPX-351 may offer benefit to newly diagnosed pts who fail conventional cytarabine and daunorubicin. CPX-351- induced CRs in pts with persistent AML following 7+3 treatment in the phase I study and in this phase II study suggesting activity in this patient population and deserves further study. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celator Pharmaceuticals Inc. Celator Pharmaceuticals Inc.
Surgical training must ensure continued production of specialist surgeons
Authors: Helen Mohan, Rhiannon Harries, Adam Williams
Journal: BMJ (2016)

In their recent paper, Sahni and colleagues demonstrate the importance of surgeon specialisation and volume in achieving lower mortality rates.1 The Association of Surgeons in Training (ASiT) is a firm advocate for excellence in surgical training and supports training to the highest degree of specialisation.2 …
HPV-Related Oropharynx Cancer in the United Kingdom: An Evolution in the Understanding of Disease Etiology
Authors: Andrew G. Schache, Ned G. Powell, Kate S. Cuschieri, Max Robinson, Sam Leary, Hisham Mehanna, Davy Rapozo, Anna Long, Heather Cubie, Elizabeth Junor, Hannah Monaghan, Kevin J. Harrington, Christopher M. Nutting, Ulrike Schick, Andy S. Lau, Navdeep Upile, Jon Sheard, Kath Brougham, Catharine M.L. West, Ken Oguejiofor, Steve Thomas, Andy R. Ness, Miranda Pring, Gareth J. Thomas, Emma V. King, Dennis J. McCance, Jacqueline A. James, Michael Moran, Phil Sloan, Richard J. Shaw, Mererid Evans, Terry M. Jones
Journal: Cancer Research (2016)

Abstract A rising incidence of oropharyngeal squamous cell carcinoma (OPSCC) incidence has occurred throughout the developed world, where it has been attributed to an increasing impact of human papillomavirus (HPV) on disease etiology. This report presents the findings of a multicenter cross-sectional retrospective study aimed at determining the proportion of HPV-positive and HPV-negative OPSCC within the United Kingdom. Archival tumor tissue blocks from 1,602 patients previously diagnosed with OPSCC (2002–2011) were collated from 11 centers. HPV status was determined with three validated commercial tests to provide valid data for 1,474 cases in total. Corresponding national incidence data from the same decade were obtained from UK Cancer registries. The overall proportion of HPV+ OPSCC between 2002 and 2011 was 51.8% [95% confidence interval (CI), 49.3–54.4], and this remained unchanged throughout the decade [unadjusted RR = 1.00 (95% CI, 0.99–1.02)]. However, over the same period, the incidence of OPSCC in the broader UK population underwent a 2-fold increase [age-standardized rate 2002: 2.1 (95% CI, 1.9–2.2); 2011: 4.1 (95% CI, 4.0–4.3)]. Although the number of OPSCCs diagnosed within the United Kingdom from 2002 to 2011 nearly doubled, the proportion of HPV+ cases remained static at approximately 50%. Our results argue that the rapidly increasing incidence of OPSCC in the United Kingdom cannot be solely attributable to the influence of HPV. The parallel increase in HPV+ and HPV− cases we documented warrants further investigation, so that appropriate future prevention strategies for both types of disease can be implemented. Cancer Res; 76(22); 6598–606. ©2016 AACR.