tbuckley/cabot-search huggingface dataset:
Phase I Study of Pembrolizumab (MK-3475; Anti–PD-1 Monoclonal Antibody) in Patients with Advanced Solid Tumors
Authors: Amita Patnaik, S. Peter Kang, Drew Rasco, Kyriakos P. Papadopoulos, Jeroen Elassaiss-Schaap, Muralidhar Beeram, Ronald Drengler, Cong Chen, Lon Smith, Guillermo Espino, Kevin Gergich, Liliana Delgado, Adil Daud, Jill A. Lindia, Xiaoyun Nicole Li, Robert H. Pierce, Jennifer H. Yearley, Dianna Wu, Omar Laterza, Manfred Lehnert, Robert Iannone, Anthony W. Tolcher
Journal: Clinical Cancer Research (2015)

This phase I study evaluated the safety, maximum tolerated dose, antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in patients with advanced solid tumors.In a 3 + 3 dose escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg intravenously every 2 weeks until progression or intolerable toxicity. Seven additional patients received 10 mg/kg every 2 weeks. Thirteen patients participated in a 3-week intrapatient dose escalation (dose range, 0.005-10 mg/kg) followed by 2 or 10 mg/kg every 3 weeks. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.No dose-limiting toxicities were observed. Maximum administered dose was 10 mg/kg every 2 weeks. One patient with melanoma and one with Merkel cell carcinoma experienced complete responses of 57 and 56+ weeks' duration, respectively. Three patients with melanoma experienced partial responses. Fifteen patients with various malignancies experienced stable disease. One patient died of cryptococcal infection 92 days after pembrolizumab discontinuation, following prolonged corticosteroid use for grade 2 gastritis considered drug related. Pembrolizumab exhibited pharmacokinetic characteristics typical of humanized monoclonal antibodies. Maximum serum target engagement was reached with trough levels of doses greater than or equal to 1 mg/kg every 3 weeks. Mechanism-based translational models with a focus on intratumor exposure prediction suggested robust clinical activity would be observed at doses ≥2 mg/kg every 3 weeks.Pembrolizumab was well tolerated and associated with durable antitumor activity in multiple solid tumors. The lowest dose with full potential for antitumor activity was 2 mg/kg every 3 weeks.
Global transcriptome analysis of murine embryonic stem cell-derived cardiomyocytes
Authors: Michael Doss, Johannes Winkler, Shuhua Chen, Rita Hippler-Altenburg, Isaia Sotiriadou, Marcel Halbach, Kurt Pfannkuche, Huamin Liang, Herbert Schulz, Oliver Hummel, Norbert Hübner, Ruth Rottscheidt, Jürgen Hescheler, Agapios Sachinidis
Journal: Genome biology (2007)

Characterization of gene expression signatures for cardiomyocytes derived from embryonic stem cells will help to define their early biologic processes. A transgenic α-myosin heavy chain (MHC) embryonic stem cell lineage was generated, exhibiting puromycin resistance and expressing enhanced green fluorescent protein (EGFP) under the control of the α-MHC promoter. A puromycin-resistant, EGFP-positive, α-MHC-positive cardiomyocyte population was isolated with over 92% purity. RNA was isolated after electrophysiological characterization of the cardiomyocytes. Comprehensive transcriptome analysis of α-MHC-positive cardiomyocytes in comparison with undifferentiated α-MHC embryonic stem cells and the control population from 15-day-old embryoid bodies led to identification of 884 upregulated probe sets and 951 downregulated probe sets in α-MHC-positive cardiomyocytes. A subset of upregulated genes encodes cytoskeletal and voltage-dependent channel proteins, and proteins that participate in aerobic energy metabolism. Interestingly, mitosis, apoptosis, and Wnt signaling-associated genes were downregulated in the cardiomyocytes. In contrast, annotations for genes upregulated in the α-MHC-positive cardiomyocytes are enriched for the following Gene Ontology (GO) categories: enzyme-linked receptor protein signaling pathway (GO:0007167), protein kinase activity (GO:0004672), negative regulation of Wnt receptor signaling pathway (GO:0030178), and regulation of cell size (O:0008361). They were also enriched for the Biocarta p38 mitogen-activated protein kinase signaling pathway and Kyoto Encyclopedia of Genes and Genomes (KEGG) calcium signaling pathway. The specific pattern of gene expression in the cardiomyocytes derived from embryonic stem cells reflects the biologic, physiologic, and functional processes that take place in mature cardiomyocytes. Identification of cardiomyocyte-specific gene expression patterns and signaling pathways will contribute toward elucidating their roles in intact cardiac function.
PDE5 inhibitor efficacy is estrogen dependent in female heart disease
Authors: Hideyuki Sasaki, Takahiro Nagayama, Robert M. Blanton, Kinya Seo, Manling Zhang, Guangshuo Zhu, Dong I. Lee, Djahida Bedja, Steven Hsu, Osamu Tsukamoto, Seiji Takashima, Masafumi Kitakaze, Michael E. Mendelsohn, Richard H. Karas, David A. Kass, Eiki Takimoto
Journal: Journal of Clinical Investigation (2014)

Inhibition of cGMP-specific phosphodiesterase 5 (PDE5) ameliorates pathological cardiac remodeling and has been gaining attention as a potential therapy for heart failure. Despite promising results in males, the efficacy of the PDE5 inhibitor sildenafil in female cardiac pathologies has not been determined and might be affected by estrogen levels, given the hormone's involvement in cGMP synthesis. Here, we determined that the heart-protective effect of sildenafil in female mice depends on the presence of estrogen via a mechanism that involves myocyte eNOS-dependent cGMP synthesis and the cGMP-dependent protein kinase Iα (PKGIα). Sildenafil treatment failed to exert antiremodeling properties in female pathological hearts from Gαq-overexpressing or pressure-overloaded mice after ovary removal; however, estrogen replacement restored the effectiveness of sildenafil in these animals. In females, sildenafil-elicited myocardial PKG activity required estrogen, which stimulated tonic cardiomyocyte cGMP synthesis via an eNOS/soluble guanylate cyclase pathway. In contrast, eNOS activation, cGMP synthesis, and sildenafil efficacy were not estrogen dependent in male hearts. Estrogen and sildenafil had no impact on pressure-overloaded hearts from animals expressing dysfunctional PKGIα, indicating that PKGIα mediates antiremodeling effects. These results support the importance of sex differences in the use of PDE5 inhibitors for treating heart disease and the critical role of estrogen status when these agents are used in females.
Ischemia Imaging and Plaque Imaging in Diabetes: Complementary Tools to Improve Cardiovascular Risk Management
Authors: Martin K. Rutter, Richard W. Nesto
Journal: Diabetes Care (2006)

founded by the fact that some patients had one leg randomized to receive active MIRE and the other leg randomized to receive placebo MIRE.In the majority of subjects, both legs received the same treatment, but, in any case, we have no reason to question the value of random assignment.In addition, all subjects in the Leonard study (3) had one leg in the active group and the other leg in the placebo group.Finally, when peforming monofilament testing, we used the "yes-no" method of testing, which is equally accurate and faster than the "forced-choice" method (4).We concur with Dr. Burke that only valid and reliable testing methods should be used.While it is disappointing to discover that a promising new treatment may not be effective, patient treatment should be based on credible evidence.We hope that more randomized, placebo-controlled studies are conducted to either support or refute the results of our study and to help determine the rightful place of MIRE in the treatment of patients with peripheral neuropathy.
Mobilization of two retroelements, ZAM and Idefix, in a novel unstable line of Drosophila melanogaster
Authors: S. Desset, C. Conte, P. Dimitri, V. Calco, B. Dastugue, C. Vaury
Journal: Molecular Biology and Evolution (1999)

We describe a novel transposition system in a line of Drosophila melanogaster called RevI in which two retroelements are mobilized. These elements are the retroelement ZAM, recently described in the literature, and a novel element designated Idefix. Like ZAM, Idefix displays the structural features of a vertebrate retrovirus. Its three open reading frames encode predicted products resembling the products of the gag, pol, and env genes of retroviruses. In situ hybridization and Southern analyses performed on the RevI genome revealed the presence of some 20 copies of ZAM and Idefix, whereas ZAM is absent and Idefix is present in only four copies on the chromosomal arms of the original parental line. From RevI, a series of mutations affecting eye coloration has been recovered. The genetic and molecular analyses of these mutations have shown that most of them affected the white locus through three rounds of mutational events. The first mutational event was previously shown to be caused by a ZAM insertion 3 kb upstream of the transcription start site of white. It confers a red-brick phenotype to the orange eye coloration of the parental line. The second event results from the insertion of an Idefix copy 1.7 kb upstream of the transcription start site of the white gene, which modifies the red-brick phenotype to orange. This second mutational event was recovered as a recurrent specific mutation in 11 independent individuals. The third event results from an additional Idefix located 1.7 kb upstream of white that is responsible for the full reversion of the orange phenotype to red-brick. The fact that such mutations due to recurrent appearances of both ZAM and Idefix at the white locus result in such a variety of phenotypes brings to light a new molecular system in which the interference of mobile elements with the correct expression of the host gene can be tested.
Use of Health Services by Hospitalized Medically Ill Depressed Elderly Patients
Authors: H G Koenig, M Kuchibhatla
Journal: American Journal of Psychiatry (1998)

OBJECTIVE: The authors examined whether depression is associated with greater use of health services by elderly medical patients before and during hospitalization. METHOD: Depression and recent use of health services were assessed in 542 patients aged 60 or over who were consecutively admitted to university medical services. Depression was measured by using the Center for Epidemiologic Studies Depression Scale, the Hamilton Depression Rating Scale, and the depressive disorders section of the National Institute of Mental Health Diagnostic Interview Schedule, which was administered by a psychiatrist. RESULTS: After age, sex, race, education, and severity of medical illness were controlled for, Hamilton depression score significantly predicted hospital days in the past year, hospital days and total inpatient days (hospital plus nursing home) in the past 3 months, and number of outpatient medical visits in the past 3 months. Depressed patients had more hospital days in the past year and had more hospital days, total inpatient days, and outpatient medical visits in the past 3 months than did nondepressed patients. Associations between depression and length of index hospital stay, home health visits, nursing home days, and number of prescription medications disappeared when severity of medical illness was controlled. Mental health visits were no more common among depressed than nondepressed patients. CONCLUSIONS: Depressed elderly medical inpatients used more hospital and outpatient medical services than nondepressed patients, but they did not receive more mental health services. Efforts by primary care physicians and third-party payers to identify and treat depression in this population are needed. (Am J Psychiatry 1998; 155:871–877)
Education by a Nurse Increases Response of Patients With Chronic Hepatitis C to Therapy With Peginterferon-α2a and Ribavirin
Authors: Dominique Larrey, Annie Salse, Didier Ribard, Olivier Boutet, Valérie Hyrailles–Blanc, Birame Niang, Georges Philippe Pageaux, Emmanuel Vaucher, Jean Pierre Arpurt, Guy Boulay, Natalia Karlova, Jean Pierre Daures
Journal: Clinical Gastroenterology and Hepatology (2011)
Severe Endothelial Dysfunction After Sirolimus-Eluting Stent Implantation
Authors: Kiyoaki Maekawa, Kenji Kawamoto, Soichiro Fuke, Ryo Yoshioka, Hironori Saito, Tetsuya Sato, Toru Hioka
Journal: Circulation (2006)

A 40-year-old man with a recent anterior myocardial infarc- tion but with no history of coronary spasm and no risk factors for endothelial dysfunction such as diabetes mellitus, hypertension, smoking, or hypercholesterolemia was admitted to our hospital.Coronary angiography showed diffuse 90% proximal left anterior descending artery stenosis (Figure 1A).He received a sirolimus-eluting stent (Cypher, Cordis Corporation, Miami Lakes, Fla) to treat diffuse long left anterior descending stenosis on January 20, 2005 (Figure 1B).After predilation, 3 Cypher stents (2.5ϫ28 mm, 2.5ϫ28 mm, and 3.0ϫ23 mm) were deployed, overlapping 3 mm at nominal pressure.Overlapped segments were postdilated at 18 atm.Finally, complete expansion was obtained, and the lesion was fully covered.The patient remained asymptomatic after stenting.Follow-up angiography at 6 months on June 9, 2005, showed 0% stenosis (Figure 2A).To evaluate endothelium-dependent vasomotor response, we performed intracoronary infusion of acetylcholine at 0.14 g/min over a period of 2 minutes, yielding estimated intracoronary concentrations of 10 Ϫ8 mol/L.Angiography repeated immediately after acetylcholine infusion showed total occlusion at the middle portion of the stents (Figure 2B) associated with chest pain and ST elevation.No vasoconstrictive response was observed in any other coronary artery.Intracoronary nitroglycerin (250 g, bolus) quickly and completely resolved this angiographic obstruction (Figure 2C).In this case, severe vasoconstrictive response was produced by small-dose intracoronary acetylcholine infusion.This phenomenon indicated severe endothelial dysfunction in the sirolimus-eluting stent at 6 months after stenting, suggesting delayed reendothelialization with inadequate endothelial coverage in the long sirolimus-eluting stents.
Meta-Analysis of Nicotinamide Treatment in Patients With Recent-Onset IDDM
Authors: Paolo Pozzilli, Peter D Browne, Hubert Kolb
Journal: Diabetes Care (1996)

OBJECTIVE Nicotinamide, a vitamin of the B group, has in vitro actions capable of interfering with the pathogenetic process leading to IDDM. Since 1987, several studies have evaluated nicotinamide as a means of protecting β-cells from end-stage destruction in insulin-treated patients with newly diagnosed IDDM. The aim of the study was to determine whether nicotinamide protects residual β-cell function when given at IDDM diagnosis. RESEARCH DESIGN AND METHODS We performed a meta-analysis of the integrated parameters of metabolic control (C-peptide, glycosylated hemoglobin, insulin dose) in 10 randomized (5 of which were placebo) controlled trials conducted in recent-onset IDDM patients for a total of 211 nicotinamide-treated patients. Data on the adverse effects of nicotinamide were also collected from an additional four trials to yield a grand total of 291 nicotinamide-receiving patients. RESULTS One year after diagnosis, baseline C-peptide was significantly higher in nicotinamide-treated patients, compared with control patients (0.73 ± 0.65 vs. 0.32 ± 0.56 ng/ml, P &amp;lt; 0.005). This statistical difference remained also when the five placebo-controlled trials only were considered (P &amp;lt; 0.05). No differences were observed in the insulin dose required or glycosylated hemoglobin values between nicotinamide and control patients. Adverse effects were reported in few patients (transient elevation of transaminase, n = 2; skin rash, n = 2; recurrent hypoglycemia, n = 2). CONCLUSIONS This combined analysis demonstrates a therapeutic effect of nicotinamide in preserving residual β-cell function when given at IDDM diagnosis in addition to insulin. Since adverse effects were negligible, we suggest that prolonged use of nicotinamide after IDDM diagnosis should be tested to see whether residual β-cell function can be preserved for longer periods.
RARγ is critical for maintaining a balance between hematopoietic stem cell self-renewal and differentiation
Authors: Louise E. Purton, Sebastian Dworkin, Gemma Haines Olsen, Carl R. Walkley, Stewart A. Fabb, Steven J. Collins, Pierre Chambon
Journal: The Journal of Experimental Medicine (2006)

Hematopoietic stem cells (HSCs) sustain lifelong production of all blood cell types through finely balanced divisions leading to self-renewal and differentiation. Although several genes influencing HSC self-renewal have been identified, to date no gene has been described that, when activated, enhances HSC self-renewal and, when inactivated [corrected] promotes HSC differentiation. We observe that the retinoic acid receptor (RAR)gamma is selectively expressed in primitive hematopoietic precursors and that the bone marrow of RARgamma knockout mice exhibit markedly reduced numbers of HSCs associated with increased numbers of more mature progenitor cells compared with wild-type mice. In contrast, RARalpha is widely expressed in hematopoietic cells, but RARalpha knockout mice do not exhibit any HSC or progenitor abnormalities. Primitive hematopoietic precursors overexpressing RARalpha differentiate predominantly to granulocytes in short-term culture, whereas those overexpressing RARgamma exhibit a much more undifferentiated phenotype. Furthermore, loss of RARgamma abrogated the potentiating effects of all-trans retinoic acid on the maintenance of HSCs in ex vivo culture. Finally, pharmacological activation of RARgamma ex vivo promotes HSC self-renewal, as demonstrated by serial transplant studies. We conclude that the RARs have distinct roles in hematopoiesis and that RARgamma is a critical physiological and pharmacological regulator of the balance between HSC self-renewal and differentiation.
Phase I Study of Single-Agent AZD1775 (MK-1775), a Wee1 Kinase Inhibitor, in Patients With Refractory Solid Tumors
Authors: Khanh Do, Deborah Wilsker, Jiuping Ji, Jennifer Zlott, Tomoko Freshwater, Robert J. Kinders, Jerry Collins, Alice P. Chen, James H. Doroshow, Shivaani Kummar
Journal: Journal of Clinical Oncology (2015)

Wee1 tyrosine kinase phosphorylates and inactivates cyclin-dependent kinase (Cdk) 1/2 in response to DNA damage. AZD1775 is a first-in-class inhibitor of Wee1 kinase with single-agent antitumor activity in preclinical models. We conducted a phase I study of single-agent AZD1775 in adult patients with refractory solid tumors to determine its maximum-tolerated dose (MTD), pharmacokinetics, and modulation of phosphorylated Tyr15-Cdk (pY15-Cdk) and phosphorylated histone H2AX (γH2AX) levels in paired tumor biopsies.
Mechanotherapy: how physical therapists’ prescription of exercise promotes tissue repair
Authors: K M Khan, A Scott
Journal: British Journal of Sports Medicine (2009)

Mechanotransduction is the physiological process where cells sense and respond to mechanical loads. This paper reclaims the term “mechanotherapy” and presents the current scientific knowledge underpinning how load may be used therapeutically to stimulate tissue repair and remodelling in tendon, muscle, cartilage and bone. The purpose of this short article is to answer a frequently asked question “How precisely does exercise promote tissue healing?” This is a fundamental question for clinicians who prescribe exercise for tendinopathies, muscle tears, non-inflammatory arthropathies and even controlled loading after fractures. High-quality randomised controlled trials and systematic reviews show that various forms of exercise or movement prescription benefit patients with a wide range of musculoskeletal problems.1 – 4 But what happens at the tissue level to promote repair and remodelling of tendon, muscle, articular cartilage and bone? The one-word answer is “mechanotransduction”, but rather than finishing there and limiting this paper to 95 words, we provide a short illustrated introduction to this remarkable, ubiquitous, non-neural, physiological process. We also re-introduce the term “mechanotherapy” to distinguish therapeutics (exercise prescription specifically to treat injuries) from the homeostatic role of mechanotransduction. Strictly speaking, mechanotransduction maintains normal musculoskeletal structures in the absence of injury. After first outlining the process of mechanotransduction, we provide well-known clinical therapeutic examples of mechanotherapy–turning movement into tissue healing.
An Open Trial of Morning Light Therapy for Treatment of Antepartum Depression
Authors: Dan A. Oren, Katherine L. Wisner, Margaret Spinelli, C. Neill Epperson, Kathleen S. Peindl, Jiuan Su Terman, Michael Terman
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: About 5% of pregnant women meet criteria for major depression. No pharmacotherapy is specifically approved for antepartum depression; novel treatment approaches may be welcome. The authors explored the use of morning bright light therapy for antepartum depression. METHOD: An open trial of bright light therapy in an A-B-A design was conducted for 3–5 weeks in 16 pregnant patients with major depression. The Hamilton Depression Rating Scale, Seasonal Affective Disorders Version, was administered to assess changes in mood. A follow-up questionnaire was used to assess outcome after delivery. RESULTS: After 3 weeks of treatment, mean depression ratings improved by 49%. Benefits were seen through 5 weeks of treatment. There was no evidence of adverse effects of light therapy on pregnancy. CONCLUSIONS: These data provide evidence that morning light therapy has an antidepressant effect during pregnancy. A randomized controlled trial is warranted to test this alternative to medication.
GC-MS of volatile components of fermented wheat germ extract
Authors: Oluwatosin K. Yusuf, Clement O. Bewaji
Journal: Journal of Clinical Oncology (2011)

Wheat has been used as food and folk medicine. We have earlier reported that the administration of ethyl acetate extract of ferrmented wheat at 300 mg/kg body weight have anti-trypanosomal activity. To better understand the active constituent for anti-trypanosomal properties, the crude extract was partially purified using column chromatography to give fractions A, B and C, which were further characterized by gas chromatographic – mass spectral (GC/MS) analysis. The fractions identified 12, 14 and 23 compounds respectively. The major volatile compounds were classified into oxygenated hydrocarbon (manool, hexadecyl acetate and butyl dodecanoate) and n-hydrocarbon (1- eicosene).

	 

	Key words: Wheat seeds, volatile compound, GC-MS, Retention index (KI).
Payment for Quality: Guiding Principles and Recommendations
Authors: Vincent Bufalino, Eric D. Peterson, Gregory L. Burke, Kenneth A. LaBresh, Daniel W. Jones, David P. Faxon, Adolfo M. Valadez, Lawrence M. Brass, Valere B. Fulwider, Renee Smith, Harlan M. Krumholz
Journal: Circulation (2006)

Payment-for-quality programs are emerging in the wake of rising healthcare costs and a demonstrated need for quality improvement in healthcare delivery in the United States. These programs, also known as "pay-for-performance" or "pay-for-value" programs, attempt to realign financial incentives with the quality of care delivered. The American Heart Association's Reimbursement, Coverage, and Access Policy Development Workgroup provides in this statement a set of principles and recommendations for the development, implementation, and evaluation of these programs. The statement also suggests future areas for research around the realignment of financial incentives to improve both the quality of care delivered and patient outcomes.