tbuckley/cabot-search huggingface dataset:
Pediatric Phase I Trial Design Using Maximum Target Inhibition as the Primary Endpoint
Authors: Holly Meany, Frank M. Balis, Alberta Aikin, Patricia Whitcomb, Robert F. Murphy, Seth M. Steinberg, Brigitte C. Widemann, Elizabeth Fox
Journal: JNCI Journal of the National Cancer Institute (2010)

The extent to which a drug inhibits a target responsible for a therapeutic effect is a more rational primary endpoint for dose-finding studies of more selective anticancer drugs than the conventional endpoint of dose-limiting toxicity (DLT) used for cytotoxic agents. An adaptive phase I trial design incorporating maximum target inhibition as the primary endpoint was developed to define the optimal dose of talabostat, a dipeptidyl peptidase (DPP) inhibitor, in children with relapsed or refractory solid tumors. The relationship between dose and effect (percent inhibition of serum DPP-4) was assessed using a maximum effect model. Maximum target inhibition was defined as greater than 90% DPP-4 inhibition in five or more of six patients 24 hours post-dose. If DLT was to occur, the trial would adapt to a traditional phase I design with a more conservative dose escalation. At the 600 μg/m 2 dose level, serum DPP-4 inhibition at 24 hours was 85%. No talabostat-related DLT occurred. The maximum effect model predicted that 1200 μg/m 2 of talabostat would maximally inhibit DPP-4. This adaptive trial design appears to be feasible, safe, and efficient and warrants further evaluation for development of molecularly targeted agents.
Correlated Asymmetry of Sequence and Functional Divergence Between Duplicate Proteins of Saccharomyces cerevisiae
Authors: Seong-Ho Kim, Soojin V. Yi
Journal: Molecular Biology and Evolution (2006)

The role of sequence divergence in functional divergence of duplicate genes is a topic of great interest. In this study, we compare the numbers of amino acid substitutions in each sequence since two yeast duplicates diverged, using a preduplication ancestral outgroup. Using this strategy, we explored the relationship between sequence divergence and functional divergence between duplicate partners. We show that the degree of relative functional asymmetry between duplicate proteins is proportional to the relative sequence divergence between them. Furthermore, of the two duplicates, the copy closer to their ancestral sequence (fewer number of amino acid substitutions) interacts with more proteins and affects fitness more severely when deleted. Therefore, asymmetric sequence divergence between duplicates is correlated with asymmetric functional divergence and may underlie the duplicate's role in genetic robustness against mutations. Among the functional traits considered, protein abundance appears to have the strongest correlation with the nonsynonymous divergence between duplicates. Taken together with the results from whole-genome analyses, our results indicate that within-species duplicates are subject to the same evolutionary force that acts on interspecific sequence and functional divergence. In particular, we detect signs of purifying selection on the more slowly evolving duplicate.
Anticytokine Therapy — A New Era in the Treatment of Rheumatoid Arthritis?
Authors: James R. O'Dell
Journal: New England Journal of Medicine (1999)

With the clinical availability of two different approaches to decrease the activity of tumor necrosis factor (TNF), a new era in the treatment of rheumatoid arthritis has begun. In this issue of the Journal, Weinblatt and colleagues report significant improvement when etanercept was added to therapy with methotrexate for patients with rheumatoid arthritis.1 TNF plays a pivotal role in the host's immune system.2 It is an important mediator of local inflammation that appears to be vital in keeping infections localized. The release of TNF-α results in local activation of vascular endothelium, release of nitric oxide with vasodilatation, and increased vascular . . .
Herbal Extract of<i>Wedelia chinensis</i>Attenuates Androgen Receptor Activity and Orthotopic Growth of Prostate Cancer in Nude Mice
Authors: Chin-Hsien Tsai, Feng-Min Lin, Yu-Chih Yang, Ming-Ting Lee, Tai-Lung Cha, Guan-James Wu, Shih-Chuan Hsieh, Pei-Wen Hsiao
Journal: Clinical Cancer Research (2009)

Wedelia chinensis is a common ingredient of anti-inflammatory herbal medicines in Taiwan and southern China. Inflammation is involved in promoting tumor growth, invasion, and metastasis. This study aims to test the biological effects in vivo of W. chinensis extract on prostate cancer.The in vivo efficacy and mechanisms of action of oral administration of a standardized extract of W. chinensis were analyzed in animals bearing a subcutaneous or orthotopic prostate cancer xenograft.Exposure of prostate cancer cells to W. chinensis extract induced apoptosis selectively in androgen receptor (AR)-positive prostate cancer cells and shifted the proportion in each phase of cell cycle toward G(2)-M phase in AR-negative prostate cancer cells. Oral herbal extract (4 or 40 mg/kg/d for 24-28 days) attenuated the growth of prostate tumors in nude mice implanted at both subcutaneous (31% and 44%, respectively) and orthotopic (49% and 49%, respectively) sites. The tumor suppression effects were associated with increased apoptosis and lower proliferation in tumor cells as well as reduced tumor angiogenesis. The antitumor effect of W. chinensis extract was correlated with accumulation of the principle active compounds wedelolactone, luteolin, and apigenin in vivo.Anticancer action of W. chinensis extract was due to three active compounds that inhibit the AR signaling pathway. Oral administration of W. chinensis extract impeded prostate cancer tumorigenesis. Future studies of W. chinensis for chemoprevention or complementary medicine against prostate cancer in humans are thus warranted.
Endogenous retrovirus control is impaired in B cells from patients with systemic lupus erythematosus
Authors: Y. Renaudineau, C. Le Dantec, J.-O. Pers, P. Youinou
Journal: Annals of the Rheumatic Diseases (2010)

Systemic lupus erythematosus (SLE) is a heterogenous autoimmune disease of unknown origin. A defect in DNA methylation has been demonstrated in T and B cells from patients with SLE. The aim of the study was to analyse several methylation-sensitive genes in B cells from SLE patients.

Samples were B cell-enriched …
Regularities of the physical world and the absence of their internalization
Authors: Heiko Hecht
Journal: Behavioral and Brain Sciences (2001)

The notion of internalization put forth by Roger Shepard continues to be appealing and challenging. He suggests that we have internalized, during our evolutionary development, environmental regularities, or constraints. Internalization solves one of the hardest problems of perceptual psychology: the underspecification problem. That is the problem of how well-defined perceptual experience is generated from the often ambiguous and incomplete sensory stimulation. Yet, the notion of internalization creates new problems that may outweigh the solution of the underspecification problem. To support this claim, I first examine the concept of internalization, breaking it down into several distinct interpretations. These range from well-resolved dynamic regularities to ill-resolved statistical regularities. As a function of the interpretation the researcher selects, an empirical test of the internalization hypothesis may be straightforward or it may become virtually impossible. I then attempt to cover the range of interpretations by drawing on examples from different domains of visual event perception. Unfortunately, the experimental tests regarding most candidate regularities, such as gravitational acceleration, fail to support the concept of internalization. This suggests that narrow interpretations of the concept should be given up in favor of more abstract interpretations. However, the latter are not easily amenable to empirical testing. There is nonetheless a way to test these abstract interpretations by contrasting internalization with the opposite concept: externalization of body dynamics. I summarize evidence for such a projection of body constraints onto external objects. Based on the combined evidence of well-resolved and ill-resolved regularities, the value of the notion of internalization has to be reassessed.
17β-Estradiol Attenuates the Development of Pressure-Overload Hypertrophy
Authors: Martin van Eickels, Christian Grohé, Jack P.M. Cleutjens, Ben J. Janssen, Hein J.J. Wellens, Pieter A. Doevendans
Journal: Circulation (2001)

Background — Cardiac hypertrophy is an independent risk factor for cardiovascular morbidity and mortality in men and in women. Epidemiological studies indicate that estrogen replacement therapy is cardioprotective; the mechanisms involved in this process, however, are poorly understood. We therefore studied the effect of 17β-estradiol (E 2 ) on the development of pressure-overload hypertrophy. Methods and Results — Ovariectomized mice receiving E 2 or placebo underwent transverse aortic constriction (TAC) or sham operation. TAC led to a significant increase in ventricular mass compared with sham operation. E 2 treatment reduced cardiac hypertrophy by 31% and 26% compared with placebo 4 and 8 weeks after TAC, whereas it had no effect on the degree of pressure overload, as determined by hemodynamic measurements. Furthermore, E 2 blocked the increased phosphorylation of p38-mitogen-activated protein kinase (MAPK) observed in the placebo-treated animals with TAC. No differences were observed in the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) 1/2 between the groups. E 2 had no effect on the expression of angiotensin-converting enzyme (ACE) or the angiotensin II type 1 receptor. Ventricular atrial natriuretic peptide (ANP) expression was detected only in the animals with TAC. Compared with placebo, E 2 treatment led to an increased expression of ANP in animals with pressure overload. Conclusions — Here, we show that E 2 attenuates the hypertrophic response to pressure overload in mice. This observation demonstrates that hormone replacement therapy with E 2 has direct effects on the heart and may be beneficial in the treatment of postmenopausal women to reduce cardiac hypertrophy.
Initiating Insulin as Part of the Treating To Target in Type 2 Diabetes (4-T) Trial
Authors: Nicholas Jenkins, Nina Hallowell, Andrew J. Farmer, Rury R. Holman, Julia Lawton
Journal: Diabetes Care (2010)

OBJECTIVE To explore patients' and health professionals' experiences of initiating insulin as part of the Treating To Target in Type 2 Diabetes (4-T) randomized controlled trial. RESEARCH DESIGN AND METHODS Interviews were conducted with 45 trial participants and 21 health professionals and thematically analyzed. RESULTS Patients were generally psychologically insulin receptive when approached to participate in the 4-T trial. Their receptiveness arose largely from their personal experiences observing intensifying prior treatments and deteriorating blood glucose control over time, which led them to engage with and accept the idea that their diabetes was progressive. Health professionals also fostered receptiveness by drawing on their clinical experience to manage patients' anxieties about initiating insulin. CONCLUSIONS Previous studies may have overemphasized the problem of psychological insulin resistance and overlooked factors and treatment experiences that may promote insulin receptiveness among type 2 patients.
Abnormal Gene Expression Profiles in Unaffected Parents of Patients with Hereditary-Type Retinoblastoma
Authors: Eric Y. Chuang, Xi Chen, Mong-Hsun Tsai, Hailing Yan, Chuan-Yuan Li, James B. Mitchell, Hatsumi Nagasawa, Paul F. Wilson, Yuanlin Peng, Markus M. Fitzek, Joel S. Bedford, John B. Little
Journal: Cancer Research (2006)

Abstract The hereditary form of retinoblastoma (Rb) is associated with a germ line mutation in one RB allele and is characterized by the occurrence of multiple, bilateral Rb tumors and a predisposition to the development of second cancers. In an earlier study, we observed an unexpected hypersensitivity to ionizing radiation in skin fibroblasts derived from unaffected parents of children with hereditary Rb. In at least four of these five families, there was no family history of Rb, indicating a new germ line mutation. We hypothesize that the increased parental cell sensitivity to radiation may reflect the presence of an as yet unrecognized genetic abnormality occurring in one or both parents of children with Rb. In the present study, we use DNA microarray technology to determine whether differences in gene expression profiles occurred in the unaffected parents of patients with hereditary Rb relative to normal individuals. Microarray analyses were validated by quantitative reverse transcription-PCR measurements. A distinct difference was observed in the patterns of gene expression between unaffected Rb parents and normal controls. By use of the prediction analysis for microarrays and principal component analysis methodologies, significant differences between the two groups were identified when as few as nine genes were analyzed. Further study of this phenomenon may offer a new insight into the genetic mechanisms of Rb and perhaps more broadly in cancer biology. (Cancer Res 2006; 66(7): 3428-33)
Annual lung function changes in young patients with chronic lung disease
Authors: P.J.F.M. Merkus, H.A.W.M. Tiddens, J.C. de Jongste
Journal: European Respiratory Journal (2002)

Reference equations for ventilatory function that use different statistical models may introduce artifacts that affect the estimated change of lung function during growth in young subjects. The effect of differently modelled reference equations on the estimated annual change of forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) in young patients with chronic lung disease was assessed. Four frequently used reference equations were used to describe the longitudinal changes of FEV1 and FVC in 52 patients (23 females) with cystic fibrosis (CF) during a mean follow-up of 3.9 yrs. Choice of reference equations directly affected value and, most importantly, estimated annual change of FVC and FEV1. Mean+/-SD annual change of FEV1 varied from 2.2+/-6.2 to -2.2+/-3.6% of predicted. For two reference equations the estimated individual changes of FEV1 and FVC in CF were positively correlated with mean individual age. This probably reflects underestimation of deteriorating lung function. Variability of annual change was independent of age only when reference equations that were designed to accurately predict lung function during the pubertal growth spurt were used. These findings have implications for patient care and clinical research.
A β-Arrestin–Biased Agonist of the Parathyroid Hormone Receptor (PTH1R) Promotes Bone Formation Independent of G Protein Activation
Authors: Diane Gesty-Palmer, Pat Flannery, Ling Yuan, Leonor Corsino, Robert Spurney, Robert J. Lefkowitz, Louis M. Luttrell
Journal: Science Translational Medicine (2009)

About 40% of the therapeutic agents in use today exert their effects through seven-transmembrane receptors (7TMRs). When activated by ligands, these receptors trigger two pathways that independently transduce signals to the cell: one through heterotrimeric GTP-binding proteins (G proteins) and one through beta-arrestins; so-called biased agonists can selectively activate these distinct pathways. Here, we investigate selective activation of these pathways through the use of a biased agonist for the type 1 parathyroid hormone (PTH)-PTH-related protein receptor (PTH1R), (D-Trp(12),Tyr(34))-PTH(7-34) (PTH-betaarr), which activates beta-arrestin but not classic G protein signaling. In mice, PTH-betaarr induces anabolic bone formation, as does the nonselective agonist PTH(1-34), which activates both mechanisms. In beta-arrestin2-null mice, the increase in bone mineral density evoked by PTH(1-34) is attenuated and that stimulated by PTH-betaarr is ablated. The beta-arrestin2-dependent pathway contributes primarily to trabecular bone formation and does not stimulate bone resorption. These results show that a biased agonist selective for the beta-arrestin pathway can elicit a response in vivo distinct from that elicited by nonselective agonists. Ligands with these properties may form the basis for improved 7TMR-directed pharmacologic agents with enhanced therapeutic specificity.
Development of an Fc-Enhanced Anti–B7-H3 Monoclonal Antibody with Potent Antitumor Activity
Authors: Deryk Loo, Ralph F. Alderson, Francine Z. Chen, Ling Huang, Wenjun Zhang, Sergey Gorlatov, Steve Burke, Valentina Ciccarone, Hua Li, Yinhua Yang, Tom Son, Yan Chen, Ann N. Easton, Jonathan C. Li, Jill R. Rillema, Monica Licea, Claudia Fieger, Tony W. Liang, Jennie P. Mather, Scott Koenig, Stanford J. Stewart, Syd Johnson, Ezio Bonvini, Paul A. Moore
Journal: Clinical Cancer Research (2012)

The goal of this research was to harness a monoclonal antibody (mAb) discovery platform to identify cell-surface antigens highly expressed on cancer and develop, through Fc optimization, potent mAb therapies toward these tumor-specific antigens.Fifty independent mAbs targeting the cell-surface immunoregulatory B7-H3 protein were obtained through independent intact cell-based immunizations using human tissue progenitor cells, cancer cell lines, or cell lines displaying cancer stem cell properties. Binding studies revealed this natively reactive B7-H3 mAb panel to bind a range of independent B7-H3 epitopes. Immunohistochemical analyses showed that a subset displayed strong reactivity to a broad range of human cancers while exhibiting limited binding to normal human tissues. A B7-H3 mAb displaying exquisite tumor/normal differential binding was selected for humanization and incorporation of an Fc domain modified to enhance effector-mediated antitumor function via increased affinity for the activating receptor CD16A and decreased binding to the inhibitory receptor CD32B.MGA271, the resulting engineered anti-B7-H3 mAb, mediates potent antibody-dependent cellular cytotoxicity against a broad range of tumor cell types. Furthermore, in human CD16A-bearing transgenic mice, MGA271 exhibited potent antitumor activity in B7-H3-expressing xenograft models of renal cell and bladder carcinoma. Toxicology studies carried out in cynomolgus monkeys revealed no significant test article-related safety findings.This data supports evaluation of MGA271 clinical utility in B7-H3-expressing cancer, while validating a combination of a nontarget biased approach of intact cell immunizations and immunohistochemistry to identify novel cancer antigens with Fc-based mAb engineering to enable potent antitumor activity.
EPIDEMIOLOGICAL STUDY OF INJURY IN BRITISH CYCLING: 2011–2013
Authors: D Palmer-Green, P Burt, R Jaques, G Hunter
Journal: British Journal of Sports Medicine (2014)

Background Prevention of injury in elite sport can have not only athlete health benefits but also potential positive performance gains. As the first step towards prevention, valid injury surveillance data is needed. Objective Provide injury epidemiology information on the British Cycling squad (road/track endurance; track sprint; MTB; BMX). Design Longitudinal prospective surveillance study, recording injury data. Definitions for injury, time-loss and performance-restriction were used to identify the rate and severity of athlete injuries. Setting British Cycling National training centre, including domestic and international training/competition venues during the 2011/12–2012/13 seasons. Participants 61 (16 female; 45 male) National team athletes. Interventions Standardised report forms for injuries completed by medical staff. Main outcome measure Injury rate, severity and causes. Results There were 95 injuries each lasting 16 days, equating 35% of the squad sustaining at least one injury per season. Training injuries were more prevalent (n=77; 30% vs. n=18; 11%), but competition injuries more severe (27d vs . 14d). The majority of competition injuries (83%) resulted in time-loss and training injuries (75%) in performance-restriction. Injury prevalence and severity was highest for the BMX squad and lowest for the endurance squad. Injuries to the lumbar spine (29%), knee (18%) and shoulder/clavicle (14%) were most common, with 17, 9, and 23 days lost per injury, respectively. Overuse (gradual/sudden onset: 58%) and recurrent (35%) were the most common causes of injury, with contact – static object (32d) most severe. Weight training related lumbar spine injuries in the sprint squad and road cycling related shoulder/clavicle and knee injuries in the endurance squad caused the greatest burden in terms of total days lost. Conclusions Prevention initiatives targeting common and severe injuries may be beneficial in reducing the number of athlete days lost to training/competition.
Penumopericardium and tension pneumopericardium after closed-chest injury.
Authors: S Westaby
Journal: Thorax (1977)

Three recent cases of pneumopericardium after closed-chest injury are described. The mechanism of pericardial inflation suspected in each was pleuropericardial laceration in the presence of an intrathoracic air leak. Deflation of the pericardium was achieved by underwater seal drainage of the right pleural cavity in the first patient, during thoracotomy for repair of tracheobronchial rupture in the second, and by subxiphoid pericardiotomy in the last. Haemodynamic changes after escape of air from the periion pneumopericardium and air tamponade.
Mutations in GDI1 are responsible for X-linked non-specific mental retardation
Authors: Patrizia D'Adamo, Andrea Menegon, Cristiana Lo Nigro, Marina Grasso, Massimo Gulisano, Filippo Tamanini, Thierry Bienvenu, Agi K. Gedeon, Ben Oostra, Shih-Kwang Wu, Anurag Tandon, Flavia Valtorta, William E. Balch, Jamel Chelly, Daniela Toniolo
Journal: Nature Genetics (1998)
Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models
Authors: Craig Brooks, Qingqing Wei, Sung-Gyu Cho, Zheng Dong
Journal: Journal of Clinical Investigation (2009)

The mechanism of mitochondrial damage, a key contributor to renal tubular cell death during acute kidney injury, remains largely unknown. Here, we have demonstrated a striking morphological change of mitochondria in experimental models of renal ischemia/reperfusion and cisplatin-induced nephrotoxicity. This change contributed to mitochondrial outer membrane permeabilization, release of apoptogenic factors, and consequent apoptosis. Following either ATP depletion or cisplatin treatment of rat renal tubular cells, mitochondrial fragmentation was observed prior to cytochrome c release and apoptosis. This mitochondrial fragmentation was inhibited by Bcl2 but not by caspase inhibitors. Dynamin-related protein 1 (Drp1), a critical mitochondrial fission protein, translocated to mitochondria early during tubular cell injury, and both siRNA knockdown of Drp1 and expression of a dominant-negative Drp1 attenuated mitochondrial fragmentation, cytochrome c release, caspase activation, and apoptosis. Further in vivo analysis revealed that mitochondrial fragmentation also occurred in proximal tubular cells in mice during renal ischemia/reperfusion and cisplatin-induced nephrotoxicity. Notably, both tubular cell apoptosis and acute kidney injury were attenuated by mdivi-1, a newly identified pharmacological inhibitor of Drp1. This study demonstrates a rapid regulation of mitochondrial dynamics during acute kidney injury and identifies mitochondrial fragmentation as what we believe to be a novel mechanism contributing to mitochondrial damage and apoptosis in vivo in mouse models of disease.