tbuckley/cabot-search huggingface dataset:
Surgical Repair versus Medical Treatment of Varicocele in the Rat: Pharmacological Manipulation of the Varicocelized Testicle
Authors: Nikolaos Sofikitis, Chihiro Takahashi, Hiroyuki Kadowaki, Tsukasa Shimamoto, Hideaki Saeki, Ikuo Miyagawa, Toshiya Okazaki, Isao Nakamura
Journal: European Urology (1992)
Doctors are being denied time off for non-clinical work
Authors: Abi Rimmer
Journal: BMJ (2017)

Doctors are finding it increasingly difficult to secure time away from their trusts to undertake national work with organisations such as the General Medical Council and the Care Quality Commission.

Last month Terence Stephenson, chair of the GMC, Bruce Keogh, national medical director for NHS England, and the UK’s chief medical officers wrote to employers asking them to look “favourably” on requests from doctors applying for absence to undertake non-clinical work.1

Phil de Warren-Penny, consultant psychiatrist and member of the BMA consultant’s committee, told The BMJ that trusts were less willing to allow consultants time off for work that was not aligned with their own objectives.

“National work, even if it’s within a job plan, doesn’t lend itself to clear objectives that are aligned with the …
Antitumor activity of indenoisoquinoline inhibitors of topoisomerase 1 (TOP1) via apoptosis and autophagocytosis pathways in animal models.
Authors: Robert J. Kinders, Angie B Dull, Deborah Wilsker, Amy LeBlanc, Christina Mazcko, Melinda G. Hollingshead, Ralph E. Parchment, James H. Doroshow
Journal: Journal of Clinical Oncology (2017)

11588 Background: We performed pharmacodynamic biomarker analysis for response to a panel of three indenoisoquinolines (LMP776, LMP400 and NSC706744, J. Med. Chem. 49:7740, 2006) that have demonstrated anti-tumor activity in dogs. In preclinical xenograft models treated with indenoisoquinolines, we observed that gH2AX was not a useful biomarker for the biological activity of compound 706744, but was a reasonable biomarker of drug activity (Clin. Canc. Res. 16:5447, 2010) for the other two compounds, even though in vitro data indicated that all 3 compounds inhibited TOP1 and killed tumor cells. It has been reported that irinotecan activates autophagy (Pharm. Rev. 65:1162, 2013) which correlated with its metabolism to SN-38; we therefore developed, validated and tested an immunofluorescence microscopy assay for LC3 as a marker of autophagy. Methods: Assays were developed to evaluate apoptosis by co-localization of cleaved caspase 3 and gH2Ax, and autophagy by LC3 immunofluorescence on formalin fixed, paraffin-embedded tissue sections of xenografts models or lymphomas from outbred dogs. Percent positive cells containing LC3 puncta were quantitated using a spot morphology algorithm. Analysis of gH2AX and cleaved caspase 3 cellular co-localization was developed using a blebbing morphology algorithm (Definiens). Results: LC3 reported that indenoisoquinoline 706744 activates autophagy in vitro with the absence of cleaved caspase 3-dependent apoptosis while the -776 and -400 compounds do not activate autophagy, but instead demonstrate apoptosis in response to drug treatment. Results in animal models confirmed that both autophagy and apoptosis were active. Clinical readiness of the assays was confirmed on canine biopsy FFPE slides. Conclusions: 1,Structurally-related TOP1 inhibitors may trigger alternative pathways of cell destruction; 2,Autophagy may report drug anti-tumor activity or tumor drug resistance according to current literature. This assay may be useful for determination of pharmacodynamic pathways associated with anti-tumor activity to elucidate mechanism of action of investigational agents used in clinical trials.
Large scale, prospective screening of EGFR mutations in the blood of advanced NSCLC patients to guide treatment decisions
Authors: C. Mayo-de-las-Casas, N. Jordana-Ariza, M. Garzón-Ibañez, A. Balada-Bel, J. Bertrán-Alamillo, S. Viteri-Ramírez, N. Reguart, M.A. Muñoz-Quintana, P. Lianes-Barragan, C. Camps, E. Jantús, J. Remon-Massip, S. Calabuig, D. Aguiar, M.L. Gil, N. Viñolas, A.K. Santos-Rodríguez, M. Majem, B. García-Peláez, S. Villatoro, A. Pérez-Rosado, J.C. Monasterio, E. Ovalle, M.J. Catalán, R. Campos, D. Morales-Espinosa, A. Martínez-Bueno, M. González-Cao, X. González, I. Moya-Horno, A.E. Sosa, N. Karachaliou, R. Rosell, M.A. Molina-Vila
Journal: Annals of Oncology (2017)
Selective BCL-XL inhibition promotes apoptosis in combination with MLN8237 in medulloblastoma and pediatric glioblastoma cells
Authors: Jane Levesley, Lynette Steele, Anke Brüning-Richardson, Adam Davison, Jia Zhou, Chunyong Ding, Sean Lawler, Susan C Short
Journal: Neuro-Oncology (2017)

Abstract Background CNS tumors, including medulloblastoma and pediatric glioblastoma (pGBM) account for the majority of solid pediatric malignancies. There remains an unmet need to identify novel treatment approaches in poor prognosis and relapsed pediatric brain tumors, where therapeutic options are limited. Small-molecule B-cell lymphoma 2 (BCL-2) family inhibitors may enhance tumor cell killing when combined with conventional and targeted chemotherapeutic agents. We investigated the effect of disrupting BCL-2 and B cell lymphoma-extra large (BCL-XL) protein function using ABT-263, ABT-199 and WEHI-539 in medulloblastoma and pGBM cells following treatment with MLN8237, an Aurora kinase inhibitor under investigation as a novel agent for the treatment of malignant brain tumors. Methods Tumor cell growth and viability were determined by MTT/WST-1 assays and flow cytometry. Effects on cell phenotype, cell cycle progression, and ploidy were determined by live cell imaging and DNA content analysis. Apoptosis was determined by annexin V/propidium iodide staining and time-lapse microscopy and confirmed by measuring caspase-3/7 activity and western blotting and by short interfering RNA (siRNA) knockdown of BCL-2 associated X protein/BCL-2 antagonist killer (BAX/BAK). Results ABT-263, in combination with MLN8237, reduced mitotic slippage and polyploidy and promoted the elimination of mitotically defective cells via a BAX/BAK-dependent, caspase-mediated apoptotic pathway. The BCL-XL antagonist, WEHI-539, significantly augmented tumor cell killing when used in combination with MLN8237, as well as sensitized resistant brain tumor cells to a novel BAX activator, SMBA1. In addition, siRNA-mediated knockdown of BCL-XL sensitized pGBM and medulloblastoma cells to MLN8237 and mimicked the effect of combination drug treatment. Conclusion Selective small-molecule inhibitors of BCL-XL may enhance the efficacy of MLN8237 and other targeted chemotherapeutic agents.
Combination Therapy Shrinks Melanoma Brain Metastases
Authors: Anita Slomski
Journal: JAMA (2017)

The COMBI-MB phase 2 trial is the first to evaluate a combination of precision medicine therapies in patients with melanoma metastasized to the brain—a group typically excluded from trials. The results, reported in Lancet Oncology, showed a significant, if short-lived, benefit.
Abstract 74: The Role of Fibroblast-specific Canonical Tgfβ Signaling in Cardiac Fibrosis
Authors: Hadi Khalil, Onur Kanisicak, Robert N. Correll, Michelle Sargent, Jeffery D. Molkentin
Journal: Circulation Research (2015)

Heart failure is a progressive disease characterized by cardiomyocyte loss, interstitial fibrosis, and chamber remodeling. During physiological conditions cardiac fibroblasts contribute to the homeostatic maintenance of myocardial structure as well as the maintenance of biochemical, mechanical and electrical properties of the heart. Injury and/or cytokine stimulation activate fibroblasts which transdifferentiate into myofibroblasts. These newly formed cells secrete extracellular matrix (ECM) for wound healing and tissue remodeling through their contractile activity. Fibrosis mediated by these cells can initially be a beneficial response that acutely scarifies areas after an infarct to prevent wall rupture. However, during chronic disease states such as heart failure, persistent recruitment and activation of fibroblasts leads to excessive deposition of ECM that results in stiffening and pathological remodeling of the ventricles. During chronic heart disease, cardiomyocytes, immune cells and fibroblasts secrete the cytokine transforming growth factor-TGFβ, which activates fibroblasts and promotes their conversion to myofibroblasts. Manipulation of TGFβ by losartan, which antagonizes angiotensin II (AngII) and aspects of TGFβ signaling, has shown some anti-fibrotic effects in cardiovascular remodeling. Also deletion of Tgfbr1 (type I TGFβ receptor) in cardiomyocytes or a TGFβ blocking antibody reduced the fibrotic response after pressure overload. However heart failure was not improved because deleterious TGFβ signaling in fibroblasts persisted. We therefore utilized a novel fibroblast-specific inducible Cre-expressing mouse line (Periostin-MerCreMer) to examine the canonical (Smad2/3) TGFβ signaling within fibroblasts to determine how these cells and their activation mediate disease in heart failure. Our data indicate that fibroblast-specific deletion of Smad3 but not Smad2 was sufficient to significantly inhibit myocardial fibrosis. Smad2/3 double nulls were also generated and analyzed, as were TGFBR1 and TGFBR2 loxp targeted mice, also crossed with the Postn-MerCreMer knockin allele to achieve specificity in activated fibroblasts.
The role of microRNAs in driving EGFR-TKI resistance in NSCLC cell lines
Authors: A. Perez, M. Castiglia, F. Passiglia, N. Barraco, A. Cangemi, D. Fanale, A. Listì, R. Maragliano, D. Massihnia, F. Di Piazza, S. Vieni, V. Calò, S. Rizzo, L. Incorvaia, V. Bazan, A. Russo
Journal: Annals of Oncology (2016)
Phase I clinical trials in oncology: A review of the old and a look at the new.
Authors: Bryan M. Fellman, Kenneth R. Hess
Journal: Journal of Clinical Oncology (2017)

e14030 Background: In Phase I oncology trials the primary goal is to assess dose limiting toxicities (DLT) and estimate the maximum tolerated dose (MTD). The classical 3+3 design is still used in greater than 90% of studies. We review the classical 3+3 design and two new model-based designs: Bayesian Optimal Interval (BOIN) design and the recently updated modified toxicity probability interval (mTPI-2) design. These designs are easy to implement like the 3+3 using a simple table to guide dose escalation/de-escalation. As opposed to the 3+3 design, these designs can target a DLT rate well above or below the standard 33% target. In general, an expansion cohort is added to 3+3 designs to verify safety and get an early efficacy signal. In the 3+3 expansion cohort it is unclear how to proceed if excessive toxicity is observed; whereas, with BOIN and mTPI-2, expansion can be built in with toxicity monitoring and MTD updating. Methods: We carefully explain how computer simulations can be used to evaluate phase I designs and present results from simulations comparing the designs under several true dose toxicity curves. Results: We show that BOIN and mTPI-2 have better performance than the 3+3. These new designs select the true MTD at a much higher rate and treat a higher percentage of patients at the MTD. The new designs generally tend to allocate fewer patients to high toxicity doses and fewer patients to low toxicity doses, thus ensuring high ethical standards. Unlike older Bayesian designs (e.g., modified continual reassessment method), the newer designs do not require a statistician to update the model during the course of the trial. Readily available, free software make these designs simple to implement. Conclusions: We recommend the use of the new model-based designs over the classical 3+3 design.
Leukotrienes and sex: strange bedfellows?
Authors: Lewis J. Smith
Journal: Journal of Clinical Investigation (2017)

Leukotrienes are proinflammatory lipid mediators that have been shown to be upregulated in several diseases, including asthma, aspirin-exacerbated respiratory disease (AERD), inflammatory bowel disease, and acute respiratory distress syndrome. Leukotrienes have been explored as therapeutic targets for these diseases and others; however, leukotriene inhibitors have had limited success in the clinic. There are noted differences in the incidence of leukotriene-mediated diseases in males and females, but sex as a factor in the response to leukotriene inhibitors has not been fully explored. In this issue of the JCI, Pace and colleagues present evidence that there are sex-specific differences in the effectiveness of certain leukotriene inhibitors and link the differences in response to the presence of androgens. The results of this study indicate that sex needs to be taken into consideration in the future evaluation of leukotriene inhibitors to treat disease.
02.20 Regulation of interleukin 17 receptor d (il17rd) in synovial fibroblasts from rheumatoid arthritis patients and its function in collagen induced arthritis
Authors: Marlieke Molendijk, Adriana MC Mus, Patrick S Asmawidjaja, Erik Lubberts
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> IL17RD is a member of the IL17 receptor family. In contrast to the other IL17 receptors, IL17RA, -RB, -RC and -RE, little is known about the ligand and function of IL17RD. Recently, IL17RD has been described to negatively regulate a selection of IL17A responsive genes. IL17RD is therefore proposed to limit IL17A signalling. In this study we examined how IL17RD expression could be regulated and whether a reduction of IL17RD contributes to the development of Rheumatoid Arthritis. <h3>Materials and Methods</h3> Human synovial fibroblasts from Rheumatoid Arthritis (RA) patients were stimulated with tumour necrosis factor α (TNFα), interleukin 1 β (IL1β) or IL17A for 4 and 24 hours. Human synovial fibroblasts were further stimulated with TNFα for 48 and 72 hours. IL17RD expression levels were measured via qPCR. Collagen induced arthritis (CIA) was induced in IL17RD knockout mice and wildtype littermates. At days 1 and 21, mice were immunised intradermally with chicken collagen type II in complete Freund's adjuvant (CFA). Mice were scored 3 times a week for clinical disease defined as swollen joints with a maximum score of 8. Due to ethical reasons, mice were removed from the experiments when they reached a score of 6. <h3>Results</h3> Human synovial fibroblasts from RA patients have baseline expression of IL17RD. Upon stimulation with TNFα a significant downregulation of IL17RD expression was measured from 24 hours onwards. IL1β stimulation had a similar effect as TNFα on IL17RD expression, resulting in a significant downregulation at 4 and 24 hours. Lack of IL-17RD did not result in differences in CIA severity, but preliminary data suggest changes in the incidence between IL-17RD knockout mice compared to wild type littermates. <h3>Conclusions</h3> An inflammatory environment causes synovial fibroblasts to downregulate IL17RD expression. Lack of IL17RD did not influence the severity of CIA.
Junior doctor contract is making paediatric rotas more difficult to fill, finds survey
Authors: Zosia Kmietowicz
Journal: BMJ (2017)

Two thirds (67%) of directors responsible for paediatric staffing in the UK have said that the new contract for junior doctors has had a negative effect on filling rotas, a survey has found.

One respondent to the survey from the Royal College of Paediatrics and Child Health said, “The impact of the contract is to make working hours and conditions less attractive and therefore likely to deter doctors from wanting to enter the specialty of paediatrics.”

Of the 211 inpatient paediatric and neonatal units in the UK, clinical directors or workforce leads from 132 responded to the college’s seventh survey on rota gaps …
Incidence and severity of cardiotoxicity in metastatic renal cell carcinoma (RCC) patients treated with targeted therapies.
Authors: Philip S Hall, Ronald Witteles, Sandy Srinivas, Lauren Christine Harshman
Journal: Journal of Clinical Oncology (2012)

4610 Background: Almost all patients with advanced RCC are treated with therapies targeting the hypoxia inducible factor axis. The potential for these agents to cause cardiovascular (CV) toxicity has been increasingly recognized but the overall incidence and extent have not been well described. We sought to identify and characterize the incidence and severity of CV toxicity among RCC patients treated with targeted therapies. Methods: Between 2004 and 2011, all RCC patients treated with targeted therapies directed against the VEGF or mTOR axes were identified at our institution. The incidence of hypertension, left ventricular (LV) dysfunction, changes in serum markers of CV toxicity (e.g., troponin I, NT-proBNP) and heart failure were assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE v.4.0). Results: Cardiovascular toxicity developed in 116 of 159 patients (73%). Excluding hypertension, 52 of 159 (33%) developed cardiovascular toxicity. Cardiac toxicity ranged from asymptomatic drops in LV ejection fraction (LVEF) to rises in NT-proBNP to severe heart failure. Asymptomatic cardiotoxicity as defined by decrease in LVEF or increase in NT-proBNP occurred in 43 patients (27%). Symptomatic heart failure (grade 2-3) and grade 3-4 decrease in LVEF each occurred in 4%. Sunitinib was the most frequently used and most common offending agent, with 66 of 101 sunitinib-treated patients (65%) developing a form of CV toxicity, or 32 of 101 (32%) excluding hypertension. However, it was notable that CV toxicity was observed in 68%, 66%, and 51% of patients treated with bevacizumab, sorafenib, and pazopanib as well. The mTOR inhibitors elicited significantly less CV toxicity, but sample sizes were small. Conclusions: Cardiovascular toxicity is an important adverse event related to targeted therapy administration. Close monitoring for the development of CV toxicity with the use of these agents should become standard of care as early detection of asymptomatic patients could preempt symptomatic toxicity and reduce treatment-related morbidity and mortality.
Summary of responses
Authors: Sharon Davies
Journal: BMJ (2007)

Why do people ignore poverty on their doorstep?1

They don't, says Peter West. “Many people help, for example, through reading schemes in schools and by working in many different community groups. In addition, many British people give money to charities to help improve the social conditions of poor people.”2

It is not surprising that rich Britons concentrate their charitable efforts on poverty in the developing world, adds Rachel Walpole. “It is not a matter of whether or not our fellow Britons are poor through their own choices; it is just that in worldwide terms, they are rich.”

But choice formed the main thread of the responses.2

Our choices define and divide us, says Alison Munns, who lists as her competing interests “inner ‘new town' GP, socialist, mother, observer of the genetic inheritance of incapacity benefit (families where no adult has worked in two generations), sponsor of an African child, and supporter of local charities.” She describes waiting for her son to finish karate training in “a community hall full of children who are courteous, respectful, and working hard. In sharp contrast outside are children of the same age trampling on the flower beds and hurling stones and abuse at the shop windows. It is not cash, connections, or class that separate them. Someone made a choice.”

“You did,” responds L S Lewis. And it is indeed cash, connections, or class that separate them.

But Munns responds that the karate club is in no way posh. “I know that some in the club have very little in terms of material possessions. I know that some of the children outside have more in the way of material possessions than my child. They or their families made the choice to spend that which they have (time and money) in the way that they do. We will get nowhere in understanding or changing our world by saying that those families who choose to let their children damage property and insult adults have no choice when other families (who objectively have less resource) do not behave in that way.”

Choice requires insight, points out Richard Bartley, quoting Ruskin: “Education is not that one knows more, but that one behaves differently.”

Indeed, so the state must act as a catalyst that allows people to drag themselves out of poverty by making better choices, says Ben Dean. “At the moment we are using the wrong approach, reinforcing the culture of the helpless victim.”

Munns concludes: “I know why I make the choices I do. Other people know why they make the choices that they do. But we shy away from asking about them. Much easier to say they have no choice or that they do not have the capacity to make a true choice as they lack insight. I don't think as a society we want to hear the answers that we would get if we did ask. But if we don't the elephant stays in the room.”
PI3K and Calcium Signaling in Cardiovascular Disease
Authors: Alessandra Ghigo, Muriel Laffargue, Mingchuan Li, Emilio Hirsch
Journal: Circulation Research (2017)

Receptor signaling relays on intracellular events amplified by secondary and tertiary messenger molecules. In cardiomyocytes and smooth muscle cells, cyclic AMP (cAMP) and subsequent calcium (Ca2+) fluxes are the best characterized receptor-regulated signaling events. However, most of receptors able to modify contractility and other intracellular responses signal through a variety of other messengers, and whether these signaling events are interconnected has long remained unclear. For example, the PI3K (phosphoinositide 3-kinase) pathway connected to the production of the lipid second messenger PIP3/PtdIns(3,4,5)P3 (phosphatidylinositol (3,4,5)-trisphosphate) is potentially involved in metabolic regulation, activation of hypertrophy, and survival pathways. Recent studies, highlighted in this review, started to interconnect PI3K pathway activation to Ca2+ signaling. This interdependency, by balancing contractility with metabolic control, is crucial for cells of the cardiovascular system and is emerging to play key roles in disease development. Better understanding of the interplay between Ca2+ and PI3K signaling is, thus, expected to provide new ground for therapeutic intervention. This review explores the emerging molecular mechanisms linking Ca2+ and PI3K signaling in health and disease.
Association of the Priority Review Voucher With Neglected Tropical Disease Drug and Vaccine Development
Authors: Nina Jain, Thomas Hwang, Jessica M. Franklin, Aaron S. Kesselheim
Journal: JAMA (2017)

This study uses commercial pharmaceutical database data to evaluate the number of new drugs and vaccines for neglected tropical diseases entering phase 1 clinical trials before and after introduction in 2007 of a priority review voucher program to incentivize development.
Artificial Intelligence-Based Assessment of Left Ventricular Filling Pressures From 2-Dimensional Cardiac Ultrasound Images
Authors: Alaa Mabrouk Salem Omar, Khader Shameer, Sukrit Narula, Mohamed Ahmed Abdel Rahman, Osama Rifaie, Jagat Narula, Joel T. Dudley, Partho P. Sengupta
Journal: JACC. Cardiovascular imaging (2017)