tbuckley/cabot-search huggingface dataset:
When is a study result important for athletes, clinicians and team coaches/staff?
Authors: Rasmus Oestergaard Nielsen, Michael Lejbach Bertelsen, Evert Verhagen, Mohammad Ali Mansournia, Adam Hulme, Merete Møller, Martí Casals
Journal: British Journal of Sports Medicine (2017)

How do you know if the results of a particular study are important to your team, your patients or your community? A result that is statistically significant is not necessarily a meaningful target for sports injury prevention or a treatment strategy.1–3 And if statistical significance is not enough to determine ‘importance’ or meaningfulness, then what is?

### Box 1 Definition: Minimal important difference (MID)

Minimal important difference (MID) is the smallest change in sports injury risk or treatment outcome that an athlete, a player, a coach, a clinician and/or team staff would identify as important. The size of MID is context-specific and a study result may be identified as important for some and non-important for others.

We aim to shed light on this important topic in the first of a series of editorials that will help clinicians and team staff interpret studies more critically and confidently. First, a measure of association (eg, a relative risk or an absolute risk difference) and its precision (eg, 95% CIs) allows for appropriate evaluation of study results.1 Next, a size of an association should be equal to or exceed a minimal important difference (MID) (box 1) that would affect practice. In this light, the question remains: is it possible to identify a MID in sports injury articles regardless of the measure of association used?

In this editorial, we argue that the choice of measure has consequences for the ability to …
Application of next-generation sequencing (NGS) to reveal targetable genomic alterations (GA) in patients with non-small cell lung cancer (NSCLC).
Authors: Alexey Barinov, Ilya Gagarin, Irina Demidova, Nikita Savelov, Vyacheslav Grinevich, Daniil Stroyakovskiy, Mihail Popov, Anatoly Makhson
Journal: Journal of Clinical Oncology (2014)

e19159 Background: The usage of genomic analysis is becoming increasingly informative and relevant for selection of particular therapies for patients with NSCLC. Applying pre-customized panels for NGS achieves high sensitivity and flexibility in multiplexing of samples to detect somatic mutations. The aim of this study was to screen the mutation profile of lung cancer samples with different histopathology types. Methods: In this study were involved 23 patients with NSCLC; 15 adenocarcinomas, 6 squamous cell carcinomas and 2 large cell carcinomas. Tumor DNA was isolated from fresh frozen tissues and genotyped by NGS using Illumina Miseq Amplicon Cancer panel (48 genes, 212 amplicons). Accepted data analysis cutoffs for GA coverage were ≥ 100 fold, for variant frequency ≥ 5 %, for quality score (Pherd QC) ≥ 30. Validation of mutations candidates with variant frequency higher than 10% was performed by routine PCR and Sanger sequencing, genomic alterations with lower representation level were annotated separately without validation. Results: Genotype profiles were done for 22/23 (22/23) cases (mean coverage 5720X). Entirely 526 GA were found, mean 25 (17-31) per sample, 4.6% (24) of revealed GA were observed in COSMIC database were: TP53 (10), EGFR (4), KRAS (4), and one case in ATM, FGFR3, PTEN, JAK3, STK11, FBXW7 genes; among them 37.5 % were targetable. Novel genomic alterations were found in STK11, ATM, RB1 genes with confirmed somatic status. Conclusions: Molecular profiling by NGS can be integrated into routine practice for patients with NSCLC, but customized panels demand clinical validation for specific therapeutic purposes. Gene DNA alterations Protein alterations Variant frequency, % Altered protein domain Histology PolyPhen score (HumVar) STK11 NM_000455 c.598 G>T NM_00455 p.A200S 18 protein kinase adeno 0.091(benign) ATM NM_000321 c.2084 T>A NM_000051 p.R2461C 42 FAT adeno 0.980 (probably damaging) RB1 NM_000321 c.2084 T>A NM_000321 p.M695K 85 retinoblastoma- associated protein B large cell 0.987 (probably damaging)
Aggression, predictability of the environment, and self-regulation: Reconciliation with animal research
Authors: Mattie Tops, Dimitri van der Linden
Journal: Behavioral and Brain Sciences (2017)

Abstract Apparently inconsistent with the CLASH model, animal research relates predictable environments to rigid routine behaviors and aggression. However, our work on evolutionary and neural adaptations to (un)predictable environments may be able to reconcile the CLASH model with the animal research, but also suggests complexities beyond the dichotomous approach of CLASH.
Isolation of human anti-MICA antibody from cancer patients responding to immunotherapies.
Authors: Kenneth F. May, Bettina Franz, Christopher Harvey, F. Stephen Hodi, Glenn Dranoff, Kai Wucherpfennig
Journal: Journal of Clinical Oncology (2012)

2502 Background: Immunotherapy is a promising modality for the treatment of cancer, and elucidating the mechanism of action is crucial to guiding patient selection and developing future immunotherapeutic strategies. Engagement of the immune molecule NKG2D by the cancer antigen MICA is important for immune surveillance of many cancers. Tumors can evade immune surveillance by shedding cell surface MICA, which leads to dampening of anti-tumor immunity. Investigations by our laboratory revealed that patients responding to immunotherapy can mount antibody responses targeting MICA, which permits re-engagement of immunity. Methods: Patients with advanced cancer treated at our institution with immunotherapies (tumor cell vaccination, ipilimumab) were identified, including several with long-term clinical remissions. Plasma was analyzed for MICA reactivity to three distinct MICA alleles, and rare memory B cells reactive to MICA were isolated using tetramerized MICA protein. Immunoglobulin heavy and light chain variable domains were sequenced with single cell RT-PCR to generate recombinant monoclonal antibody. Results: Plasma from patients treated with immunotherapy revealed considerable inter-patient variation in reactivity to MICA. Patients with marked plasma reactivity (including several with sustained clinical remissions) were selected for isolation of rare memory B cells reactive to MICA. From these cells, we have generated a recombinant fully-human MICA-reactive monoclonal antibody that exhibits binding to a variety of MICA alleles. Conclusions: We have developed novel methods to analyze anti-MICA antibody responses and isolate rare memory B cells from cancer patients who gained significant clinical benefit from immunotherapy. This has facilitated the generation of fully human recombinant anti-MICA monoclonal antibody. To our knowledge, this is the first example of a specific antibody reactive to a cancer antigen isolated from a cancer patient responding to immunotherapy. As these antibody responses likely played a role in tumor destruction, these results inform the development of new antibody-based immunotherapies targeting the NKG2D-MICA pathway.
Abstract P348: High Glucose Induces Smad Activation via the Transcriptional Coregulator P300 and Contributes to Cardiac Fibrosis and Hypertrophy
Authors: Kim A Connelly,, Maral Ouzounian, Andrew Advani, Suzanne Advani, Kerri Thai, Peter P Liu, Richard E Gilbert
Journal: Circulation Research (2011)

Background: Despite advances in the treatment of heart failure (HF), the mortality remains high, particularly in those individuals with diabetes mellitus. Activated transforming growth factor beta (TGF-ß) contributes to the pathogenesis of diabetic cardiomyopathy. We hypothesized that the transcriptional co-activator p300 regulates glucose induced activation of TGF-ß via acetylation of a specific Lysine residue (Lys19) in the Mad homology 1 domain of Smad 2, and that by inhibiting p300, TGF-ß activity will be reduced and heart failure ameliorated/prevented. Methods: p300 activity and Smad acetylation in normal glucose (5.6 mmol/L - NG) and high glucose (25 mmol/L - HG) media were assessed in H9c2 rat cardiomyoblasts. [H]3 proline incorporation was assessed in cardiac fibroblasts as a marker of collagen synthesis. The role of increased p300 activity was assessed in vitro by using a known p300 inhibitor, curcumin or siRNA directed at p300 and in vivo in a hemodynamically validated model of diabetic cardiomyopathy, the (mRen)2-27 transgenic rat. Results: H9c2 cells exposed to HG demonstrated increased p300 activity c/w NG media, that was reduced by p300 inhibition using curcumin or p300 siRNA (all p&lt;0.01). Increased p300 activity in HG media increased [H]3 proline incorporation (p&lt;0.05). This effect was attenuated by treatment with curcumin/p300 siRNA (p&lt;0.01). Finally, H9c2 cells were stimulated, extracted protein was immunoprecipitated with Smad2, and lys19 acetylation assessed. Acetylation of the Lys19 was reduced in cells pre-incubated with the p300 inhibitor (p&lt;0.05). To determine the functional significance of p300 inhibition, diabetic Ren-2 rats were randomised to receive either curcumin/vehicle for 6 weeks. Curcumin treated diabetic rats had reduced cardiac hypertrophy and improved chamber compliance when c/w untreated diabetic counterparts (all p&lt;0.01). Conclusions: These findings demonstrate that high glucose increases activity of the transcriptional coregulator p300, acetylating Smad2 and promoting cardiac fibrosis and hypertrophy. Inhibition of p300 reduces cardiac hypertrophy and results in improved diastolic function. Modulation of the p300 may be a novel strategy to treat diabetes induced heart failure.
Abstract 196: Self-Organized Formation of Cardiac Pacemaker Tissues in Embryoid Bodies
Authors: Sherin I Hashem, William C Claycomb
Journal: Circulation Research (2012)

The pacemaker tissues of the heart are a complex set of specialized cells that initiate the rhythmic heart beat. The sinoatrial node (SAN) serves as the primary pacemaker, whereas the atrioventricular node (AVN) serves as a subsidiary pacemaker under conditions of SAN failure. The elucidation of genetic networks regulating the development of these tissues is crucial for understanding the mechanisms underlying arrhythmias and for the design of biological pacemakers. At present, there is no in vitro model system in which these specialized cells are defined or targeted. Here we report efficient self-organized formation of the two pacemaker nodes in three-dimensional aggregate cultures of mouse embryonic stem (ES) cells known as embryoid bodies (EBs), as well as the isolation of ES cell-derived AVN cells. A Shox2-lacZ knockin ES cell line carrying a Cx30.2 enhancer-RFP construct was used to generate EBs. The Shox2 gene, a determinant of the SAN genetic cascade, was used to delineate the SAN in EBs. The Cx30.2 enhancer was used to direct RFP expression to the AVN in EBs. Using live fluorescent imaging and immunohistochemistry, we demonstrate that these genetic markers reproducibly delineate cell clusters which express nodal proteins. These clusters are functionally connected with, and consistently located adjacent to the contracting region of the EB in an organized manner. We demonstrate that EBs generated using Shox2 knockout ES cells exhibit a hypoplastic SAN phenotype that includes reduction in spontaneous contraction rates and altered expression of Shox2 downstream targets. We isolated an ES cell-derived AVN cell line using a genetic selection technique and demonstrated that these cells display nodal characteristics such as calcium dependent spontaneous depolarizations and an AVN gene expression profile. When these cells were grown as three-dimensional aggregates they induced synchronous contraction of surrounding cardiac myocytes in co-culture experiments. Using molecular markers, we have generated a reproducible model system and have isolated an AVN cell line that will be invaluable tools for studying the molecular pathways regulating the development of the cardiac pacemaker tissues and molecular composition of these specialized cells.
<i>KIR3DL1</i>/<i>HL</i><i>A-B</i> Subtypes Govern Acute Myelogenous Leukemia Relapse After Hematopoietic Cell Transplantation
Authors: Jeanette E. Boudreau, Fabio Giglio, Ted A. Gooley, Philip A. Stevenson, Jean-Benoît Le Luduec, Brian C. Shaffer, Raja Rajalingam, Lihua Hou, Carolyn Katovich Hurley, Harriet Noreen, Elaine F. Reed, Neng Yu, Cynthia Vierra-Green, Michael Haagenson, Mari Malkki, Effie W. Petersdorf, Stephen Spellman, Katharine C. Hsu
Journal: Journal of Clinical Oncology (2017)

Purpose Disease relapse remains a major challenge to successful outcomes in patients who undergo allogeneic hematopoietic cell transplantation (HCT). Donor natural killer (NK) cell alloreactivity in HCT can control leukemic relapse, but capturing alloreactivity in HLA-matched HCT has been elusive. HLA expression on leukemia cells-upregulated in the post-HCT environment-signals for NK cell inhibition via inhibitory killer immunoglobulin-like (KIR) receptors and interrupts their antitumor activity. We hypothesized that varied strengths of inhibition among subtypes of the ubiquitous KIR3DL1 and its cognate ligand, HLA-B, would titrate NK reactivity against acute myelogenous leukemia (AML). Patients and Methods By using an algorithm that was based on polymorphism-driven expression levels and specificities, we predicted and tested inhibitory and cytotoxic NK potential on the basis of KIR3DL1/HLA-B subtype combinations in vitro and evaluated their impact in 1,328 patients with AML who underwent HCT from 9/10 or 10/10 HLA-matched unrelated donors. Results Segregated by KIR3DL1 subtype, NK cells demonstrated reproducible patterns of strong, weak, or noninhibition by target cells with defined HLA-B subtypes, which translated into discrete cytotoxic hierarchies against AML. In patients, KIR3DL1 and HLA-B subtype combinations that were predictive of weak inhibition or noninhibition were associated with significantly lower relapse (hazard ratio [HR], 0.72; P = .004) and overall mortality (HR, 0.84; P = .030) compared with strong inhibition combinations. The greatest effects were evident in the high-risk group of patients with all KIR ligands (relapse: HR, 0.54; P < .001; and mortality: HR, 0.74; P < .008). Beneficial effects of weak and noninhibiting KIR3DL1 and HLA-B subtype combinations were separate from and additive to the benefit of donor activating KIR2DS1. Conclusion Consideration of KIR3DL1-mediated inhibition in donor selection for HLA-matched HCT may achieve superior graft versus leukemia effects, lower risk for relapse, and an increase in survival among patients with AML.
Salvage high-dose chemotherapy in female patients with relapsed/refractory germ-cell tumors: a retrospective analysis of the European Group for Blood and Marrow Transplantation (EBMT)
Authors: U. De Giorgi, S. Richard, M. Badoglio, E. Kanfer, J.H. Bourrhis, E. Nicolas-Virelizier, K. Vettenranta, B. Lioure, S. Martin, P. Dreger, M.K. Schuler, K. Thomson, E. Scarpi, G. Rosti, F. Selle, G. Mangili, F. Lanza, M. Bregni
Journal: Annals of Oncology (2017)
Early Hospital Discharge after Myocardial Infarction
Authors: Adolph M. Hutter, Victor W. Sidel, Kenneth I. Shine, Roman W. DeSanctis
Journal: New England Journal of Medicine (1973)

A prospective randomized controlled study compared a two-week and three-week hospital stay in 138 patients with uncomplicated but definite myocardial infarction. Patients with severe ventricular arrhythmias, heart block, hypotension, persistence of coronary pain or congestive heart failure into the fifth day, or a prior myocardial infarction within the preceding six months were excluded. During the six month follow-up period there was no difference between the 69 two-week and the 69 three-week patients in frequency of return to work, anxiety or depression, development of angina or congestive heart failure, aneurysm formation, acute coronary insufficiency, myocardial infarction or death. There appears to be no additional benefit to the patient with an uncomplicated myocardial infarction from a three-week as compared to a two-week hospital stay. (N Engl J Med 288:1141–1144, 1973)
Autologous stem cell transplantation (ASCT) followed by consolidation chemotherapy for multiple myeloma (MM)
Authors: I. Gojo, A. Murthy, A. Passas, G. Tricot, R. Fenton, B. Mookerjee, B. Meisenberg, N. Takebe, S. R. Frankel, C. Sarkodee-Adoo, M. R. Heyman, K. Ruehle, R. Smith, T. Cher, A. Rapoport
Journal: Blood (2000)
Genomic Characterization of Murine Monocytes Reveals C/EBPβ Transcription Factor Dependence of Ly6C − Cells
Authors: Alexander Mildner, Jörg Schönheit, Amir Giladi, Eyal David, David Lara-Astiaso, Erika Lorenzo-Vivas, Franziska Paul, Louise Chappell-Maor, Josef Priller, Achim Leutz, Ido Amit, Steffen Jung
Journal: Immunity (2017)
Lysosomal Storage Diseases
Authors: Edwin H. Kolodny
Journal: New England Journal of Medicine (1976)

The concept of lysosomal storage disease, proposed by Hers in 1965,1 embraces more than 25 genetic diseases with distinctive biochemical profiles (Table 1). Although relatively rare, these conditions have excited considerable interest among physicians and biochemists because they are amenable to heterozygote detection and prenatal diagnosis and are potentially treatable.Lysosomes are single membrane-bound cytoplasmic particles present in all cells. They contain hydrolytic enzymes that degrade proteins, polysaccharides and nucleic acids in an acid pH environment. Vacuoles containing cellular components to be degraded and foreign materials engulfed by the cell fuse with the primary lysosomes to form secondary lysosomes. Although . . .
ACC/AHA Classification of Care Metrics: Performance Measures and Quality Metrics
Authors: Robert O. Bonow, Frederick A. Masoudi, John S. Rumsfeld, Elizabeth DeLong, N.A. Mark Estes, David C. Goff, Kathleen Grady, Lee A. Green, Ann R. Loth, Eric D. Peterson, Ileana L. Piña, Martha J. Radford, David M. Shahian
Journal: Journal of the American College of Cardiology (2008)
Patient Dismissal by Primary Care Practices
Authors: Ann S. O’Malley, Kaylyn Swankoski, Deborah Peikes, Jesse Crosson, Nancy Duda, Timothy Day, Shannon Heitkamp
Journal: JAMA Internal Medicine (2017)

This survey study examines the prevalence of and reasons for patient dismissal among primary care practices participating in the Comprehensive Primary Care initiative and a matched sample of comparison practices.
Idiopathic Nephrotic Syndrome in Adults
Authors: J. Churg, E. Grishman, M. H. Goldstein, S. L. Yunis, J. G. Porush
Journal: New England Journal of Medicine (1965)

THE nephrotic syndrome, a clinical entity characterized by edema, proteinuria, hypoalbuminemia and hypercholesterolemia, may occur in the adult during the course of either a primary renal disease or a systemic disease involving the kidney. In the former group the nephrotic syndrome often appears as part of the natural course of proliferative glomerulonephritis. However, a significant number of adults without clinical or pathological evidence of glomerulonephritis may present a nephrotic syndrome. This report is concerned with an analysis of these cases of nephrotic syndrome of unknown etiology.On the basis of observations obtained by light-microscope study of renal tissue, the nephrotic . . .
Review: Strategies to improve provider adoption and implementation of clinical practice guidelines were assessed
Authors: Daniel I. Steinberg
Journal: Annals of Internal Medicine (2017)

Source Citation Chan WV, Pearson TA, Bennett GC, et al. ACC/AHA special report: clinical practice guideline implementation strategies: a summary of systematic reviews by the NHLBI Implementation Science Work Group: A report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Circulation. 2017;135:e122-e137. 28126839*
Abstract #4090: In vitro and in vivo evaluation of novel VEGF-binding proteins, sFLT01 and sFLT02
Authors: Rebecca Bagley, Min Yao, Leslie Kurtzberg, William Weber, Hillard Rubin, Kerry Culm-Merdek, Christine Burnett, Lucy Yen, Elizabeth Isenberger, Cindy Rogers, Cecile Rouleau, Peter Pechan, William Brondyk, Abraham Scaria, Johanne Kaplan, Beverly Teicher
Journal: Cancer Research (2009)

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

Vascular endothelial growth factor (VEGF) is essential for promoting the growth of blood vessels. Anti-angiogenic agents targeting VEGF or its receptors have shown clinical value in combination with chemotherapy. In the current study we have compared two novel engineered soluble hybrid forms of VEGFR1, sFLT01 (80 KD) and sFLT02 (52 KD). sFLT01 and sFLT02 bind to both human and murine VEGF. sFLT01 and sFLT02 were evaluated in vitro in VEGF binding assays whereby the free or unbound VEGF is quantified by ELISA and the activity of sFLT01 and sFLT02 were compared in endothelial cell-based proliferation assays. sFLT01 and sFLT02 were also evaluated for anti-tumor activity in vivo in the A673 sarcoma xenograft model. sFLT01 and sFLT02 were delivered by intraperitoneal injection twice a week at doses that were matched on a molar basis, ranging from 3-5 mg/kg. Microvessel density (MVD) and vessel integrity were analyzed by immunohistochemical methods with antibodies against CD31 for endothelial cells and against NG2 or smooth muscle actin for pericytes. The results indicate that sFLT01 and sFLT02 bound to human VEGF with affinities comparable to other known high affinity VEGF binders and equally inhibited VEGF-driven HUVEC proliferation with IC90 values of approximately 1-3 nM. In vivo however, when dosed at equivalent molar amounts, sFLT01 was more effective than sFLT02. Subcutaneous A673 tumors were inhibited more effectively with sFLT01 than with sFLT02. sFLT01 was also efficacious when treatment began when the A673 tumors were larger, 400-500 mm3 in size, whereas sFLT02 was not. MVD was reduced by 10-fold in the A673 model after three doses of sFLT01 compared to control. The blood vessels of these tumors were more immature demonstrating less pericyte involvement. The effect of sFLT02 on MVD was less pronounced. The discrepancy between the in vitro and in vivo performance of the two molecules may be due to the shorter half-life of the smaller size sFLT02 (4.1 hrs vs. 6.3 days for sFLT01) and it may be that higher, more frequent doses are required to achieve similar efficacy. sFLT01 in combination with cyclophosphamide prolonged survival compared with either agent delivered as a single agent in the A673 tumor model. Direct comparisons between sFLT01 and sFLT02 in combination with cyclophosphamide are ongoing.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4090.
Lymphangioma-like Kaposi's sarcoma.
Authors: R.W. GANGE, E. WILSON JONES
Journal: British Journal of Dermatology (1979)

Details of three patients with Kaposi's sarcoma are presented. Each case, although clinically typical, displayed unusual histological changes suggestive of lymphangioendothelioma. The significance of these changes with regard to the histogenesis of Kaposi's sarcoma is discussed.