tbuckley/cabot-search huggingface dataset:
Differential Roles of GSK-3β During Myocardial Ischemia and Ischemia/Reperfusion
Authors: Peiyong Zhai, Sebastiano Sciarretta, Jonathan Galeotti, Massimo Volpe, Junichi Sadoshima
Journal: Circulation Research (2011)

Rationale: Inhibition of glycogen synthase kinase-3 (GSK-3) protects the heart during ischemia/reperfusion (I/R), yet the underlying mechanisms of cardioprotection afforded by beta isoform-specific inhibition GSK-3 remain to be elucidated. Objective: We studied the molecular mechanism mediating the effect of GSK-3β activation/inhibition upon myocardial injury during prolonged ischemia and I/R. Methods and Results: Beta isoform–specific inhibition of GSK-3 by dominant negative GSK-3β in transgenic mice (Tg-DnGSK-3β) or in heterozygous GSK-3β knock-out mice (GSK-3β+/−) significantly increased, whereas activation of GSK-3β in constitutively active GSK-3β knock-in mice (βKI) significantly decreased, myocardial ischemic injury after prolonged ischemia. In contrast, inhibition of GSK-3β in Tg-DnGSK-3β or GSK-3β+/− significantly reduced, while activation of GSK-3β in βKI significantly enhanced, myocardial I/R injury. Inhibition of GSK-3β stimulated mTOR signaling and inhibited autophagy through a rapamycin-sensitive (mTOR dependent) mechanism. Rapamycin enhanced autophagy and, at the same time, abolished the effects of GSK-3β inhibition on both prolonged ischemic injury and I/R injury. Importantly, the influence of rapamycin over the effects of GSK-3β inhibition on myocardial injury was reversed by inhibition of autophagy. Conclusions: Our results suggest that beta isoform–specific inhibition of GSK-3 exacerbates ischemic injury but protects against I/R injury by modulating mTOR and autophagy.
The amino terminal and E2F interaction domains are critical for C/EBPα-mediated induction of granulopoietic development of hematopoietic cells
Authors: Francesco D'Alo', Lisa M. Johansen, Erik A. Nelson, Hanna S. Radomska, Erica K. Evans, Pu Zhang, Claus Nerlov, Daniel G. Tenen
Journal: Blood (2003)
HIV-1 drug resistance in antiretroviral-naive individuals in sub-Saharan Africa after rollout of antiretroviral therapy: a multicentre observational study
Authors: Raph L Hamers, Carole L Wallis, Cissy Kityo, Margaret Siwale, Kishor Mandaliya, Francesca Conradie, Mariette E Botes, Maureen Wellington, Akin Osibogun, Kim C E Sigaloff, Immaculate Nankya, Rob Schuurman, Ferdinand W Wit, Wendy S Stevens, Michèle van Vugt, Tobias F Rinke de Wit
Journal: The Lancet Infectious Diseases (2011)
COLLAGEN METABOLISM IN OSTEOLATHYRISM IN CHICK EMBRYOS: SITE OF ACTION OF ß-AMINOPROPIONITRILE
Authors: J. Donald Smiley, Henry Yeager, Morris Ziff
Journal: The Journal of Experimental Medicine (1962)

Chick embryos were sacrificed at intervals after simultaneous injection of BAPN and proline-C(14), the collagen separated into neutral salt-extractable and residue fractions, and total hydroxyproline and hydroxyproline specific radioactivity determined in each fraction. Extractable collagen, measured as hydroxyproline, increased markedly and had a higher specific activity in BAPN-treated embryos than in corresponding controls. Hydroxyproline of the residue collagen in the treated animals, however, had a lower specific activity. When proline-C(14) was injected 24 hours prior to BAPN, the specific radioactivity of the soluble collagen of treated embryos was similar to that of controls, in spite of the fact that the specific activity of the residue fraction was higher than that of the soluble fraction at the time of BAPN administration. These results suggest that the increased amount of soluble collagen in lathyrism induced by administration of BAPN does not arise from the collagen insoluble prior to administration of the drug, but rather that BAPN acts by blocking the formation of mature collagen fibers, perhaps by preventing the formation of cross-linkages between alpha-collagen chains.
Dysregulation of p53/Sp1 Control Leads to DNA Methyltransferase-1 Overexpression in Lung Cancer
Authors: Ruo-Kai Lin, Chiu-Yi Wu, Jer-Wei Chang, Li-Jung Juan, Han-Shui Hsu, Chih-Yi Chen, Yun-Yueh Lu, Yen-An Tang, Yi-Chieh Yang, Pan-Chyr Yang, Yi-Ching Wang
Journal: Cancer Research (2010)

Overexpression of DNA 5'-cytosine-methyltransferases (DNMT), which are enzymes that methylate the cytosine residue of CpGs, is involved in many cancers. However, the mechanism of DNMT overexpression remains unclear. Here, we showed that wild-type p53 negatively regulated DNMT1 expression by forming a complex with specificity protein 1 (Sp1) protein and chromatin modifiers on the DNMT1 promoter. However, the stoichiometry between p53 and Sp1 determined whether Sp1 acts as a transcription activator or corepressor. Low level of exogenous Sp1 enhanced the repressive activity of endogenous p53 on the DNMT1 promoter whereas high level of Sp1 upregulated DNMT1 gene expression level in A549 (p53 wild-type) cells. In H1299 (p53 null) cells, exogenous Sp1 induced DNMT1 expression in a dose-dependent manner. We also discovered a new mechanism whereby high level of Sp1, via its COOH-terminal domain, induced interaction between p53 and MDM2, resulting in degradation of p53 by MDM2-mediated ubiquitination. Clinical data from 102 lung cancer patients indicated that overexpression of DNMT1 was associated with p53 mutation (P = 0.014) and high expression of Sp1 protein (P = 0.006). In addition, patients with overexpression of both DNMT1 and Sp1 proteins showed poor prognosis (P = 0.037). Our cell and clinical data provided compelling evidence that deregulation of DNMT1 is associated with gain of transcriptional activation of Sp1 and/or loss of repression of p53. DNMT1 overexpression results in epigenetic alteration of multiple tumor suppressor genes and ultimately leads to lung tumorigenesis and poor prognosis.
The soap bubble: Phenomenal state or perceptual system dynamics?
Authors: Slobodan Marković
Journal: Behavioral and Brain Sciences (2003)

The Gestalt Bubble model describes a subjective phenomenal experience (what is seen) without taking into account the extraphenomenal constraints of perceptual experience (why it is seen as it is). If it intends to be an explanatory model, then it has to include either stimulus or neural constraints, or both.
Antibody to interleukin-5 inhibits virus-induced airway hyperresponsiveness to histamine in guinea pigs.
Authors: A J van Oosterhout, I van Ark, G Folkerts, H J van der Linde, H F Savelkoul, A K Verheyen, F P Nijkamp
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

In humans, respiratory viral infections lead to increased airway responsiveness and exacerbations of asthma. In the present study, the role of interleukin-5 (IL-5) in virus-induced airway hyperresponsiveness and inflammation was examined in guinea pigs. In animals treated with control antibody, parainfluenza-3 virus significantly potentiated (219%) the histamine-induced increase in lung resistance compared with vehicle treatment. In addition, viral infection significantly increased (130 to 450%) the responsiveness of isolated tracheal segments to histamine in animals treated with control antibody. In guinea pigs treated with control antibody, the numbers of eosinophils (226%), neutrophils (1,380%), and monocytes (626%) in bronchoalveolar lavage fluid were significantly increased after viral infection. The level of major basic protein in bronchoalveolar lavage fluid was not altered after viral infection. In addition, electron microscopic examination of eosinophils in airway tissue and alveolar lumen did not point to increased degranulation after viral infection. In guinea pigs treated with antibody to IL-5 the virus-induced airway hyperresponsiveness to histamine both in vivo and in vitro was almost completely inhibited. In guinea pigs treated with anti-IL-5, viral infection significantly increased the numbers of eosinophils (234%), neutrophils (1,255%), and monocytes (617%) in bronchoalveolar lavage fluid. These data suggest that IL-5 plays an important role in airway hyperresponsiveness to histamine but not in the infiltration of eosinophils after respiratory viral infection.
A novel urine peptide biomarker-based algorithm for the prognosis of necrotising enterocolitis in human infants
Authors: Karl G Sylvester, Xuefeng B Ling, G Y Liu, Zachary J Kastenberg, Jun Ji, Zhongkai Hu, Sihua Peng, Ken Lau, Fizan Abdullah, Mary L Brandt, Richard A Ehrenkranz, Mary Catherine Harris, Timothy C Lee, Joyce Simpson, Corinna Bowers, R Lawrence Moss
Journal: Gut (2013)

<h3>Objective</h3> Necrotising enterocolitis (NEC) is a major source of neonatal morbidity and mortality. The management of infants with NEC is currently complicated by our inability to accurately identify those at risk for progression of disease prior to the development of irreversible intestinal necrosis. We hypothesised that integrated analysis of clinical parameters in combination with urine peptide biomarkers would lead to improved prognostic accuracy in the NEC population. <h3>Design</h3> Infants under suspicion of having NEC (n=550) were prospectively enrolled from a consortium consisting of eight university-based paediatric teaching hospitals. Twenty-seven clinical parameters were used to construct a multivariate predictor of NEC progression. Liquid chromatography/mass spectrometry was used to profile the urine peptidomes from a subset of this population (n=65) to discover novel biomarkers of NEC progression. An ensemble model for the prediction of disease progression was then created using clinical and biomarker data. <h3>Results</h3> The use of clinical parameters alone resulted in a receiver-operator characteristic curve with an area under the curve of 0.817 and left 40.1% of all patients in an ‘indeterminate’ risk group. Three validated urine peptide biomarkers (fibrinogen peptides: FGA1826, FGA1883 and FGA2659) produced a receiver-operator characteristic area under the curve of 0.856. The integration of clinical parameters with urine biomarkers in an ensemble model resulted in the correct prediction of NEC outcomes in all cases tested. <h3>Conclusions</h3> Ensemble modelling combining clinical parameters with biomarker analysis dramatically improves our ability to identify the population at risk for developing progressive NEC.
Pembrolizumab versus Ipilimumab in Advanced Melanoma
Authors: Caroline Robert, Jacob Schachter, Georgina V. Long, Ana Arance, Jean Jacques Grob, Laurent Mortier, Adil Daud, Matteo S. Carlino, Catriona McNeil, Michal Lotem, James Larkin, Paul Lorigan, Bart Neyns, Christian U. Blank, Omid Hamid, Christine Mateus, Ronnie Shapira-Frommer, Michele Kosh, Honghong Zhou, Nageatte Ibrahim, Scot Ebbinghaus, Antoni Ribas
Journal: New England Journal of Medicine (2015)

The immune checkpoint inhibitor ipilimumab is the standard-of-care treatment for patients with advanced melanoma. Pembrolizumab inhibits the programmed cell death 1 (PD-1) immune checkpoint and has antitumor activity in patients with advanced melanoma.In this randomized, controlled, phase 3 study, we assigned 834 patients with advanced melanoma in a 1:1:1 ratio to receive pembrolizumab (at a dose of 10 mg per kilogram of body weight) every 2 weeks or every 3 weeks or four doses of ipilimumab (at 3 mg per kilogram) every 3 weeks. Primary end points were progression-free and overall survival.The estimated 6-month progression-free-survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio for disease progression, 0.58; P<0.001 for both pembrolizumab regimens versus ipilimumab; 95% confidence intervals [CIs], 0.46 to 0.72 and 0.47 to 0.72, respectively). Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63; 95% CI, 0.47 to 0.83; P=0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69; 95% CI, 0.52 to 0.90; P=0.0036). The response rate was improved with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%) (P<0.001 for both comparisons). Responses were ongoing in 89.4%, 96.7%, and 87.9% of patients, respectively, after a median follow-up of 7.9 months. Efficacy was similar in the two pembrolizumab groups. Rates of treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups (13.3% and 10.1%) than in the ipilimumab group (19.9%).The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. (Funded by Merck Sharp & Dohme; KEYNOTE-006 ClinicalTrials.gov number, NCT01866319.).
COX-2 Drives Metastatic Breast Cells from Brain Lesions into the Cerebrospinal Fluid and Systemic Circulation
Authors: Joshua E. Allen, Akshal S. Patel, Varun V. Prabhu, David T. Dicker, Jonas M. Sheehan, Michael J. Glantz, Wafik S. El-Deiry
Journal: Cancer Research (2014)

Abstract Breast cancer is among the most common malignancies that metastasize to the brain, with 15% to 20% of patients with metastatic breast cancer eventually developing brain metastases. We previously reported a method to enumerate tumor cells in the cerebrospinal fluid (CSF) of patients with breast cancer with central nervous system (CNS) metastases, a setting that lacks sufficiently informative biomarkers. Here, we show that breast cancer cells can spontaneously disseminate into the CSF from brain lesions in mice in a COX-2–dependent manner and can escape from the CNS to systemic circulation. Enumeration of tumor cells in the peripheral blood (circulating tumor cells, CTC) and CSF (cerebrospinal fluid tumor cells, CSFTC) of nine breast cancer patients with brain metastases revealed dynamic changes in tumor cell burden in both the peripheral blood and CSF compartments that correlated with clinical disease progression. Interestingly, four of the enrolled patients exhibited rapid intercompartmental transitioning of the disease reflected in the CTC and CSFTC counts that preceded corresponding evidence by clinical imaging or neurologic symptoms. Two of these patients had systemic disease recurrence involving the primary malignant site. Intercompartmental cycling of tumor cells may represent an important mechanism for disease persistence and recurrence that may involve tumor self-seeding. Our findings demonstrate the involvement of COX-2 in the genesis of CSFTCs and suggest that COX-2 inhibitors should be investigated in patients with breast cancer with brain metastases for their ability to reduce CSFTC counts and prevent systemic recurrence. Cancer Res; 74(9); 2385–90. ©2014 AACR.
Gene driven power athletes? Genetic variation in muscular strength and power
Authors: G Beunen, M Thomis
Journal: British Journal of Sports Medicine (2006)

Strength phenotypes are under strong genetic control, but much research is still required

Muscular strength and power are important components of fitness essential for the execution of a variety of daily and sporting activities. Static or isometric strength, explosive strength or power, and dynamic (sometimes called functional) strength are generally considered in epidemiological studies.

Analyses of the genetic determinants of strength provide information concerning the contribution of both genes and environmental factors. Interaction effects between genes and environment (the dependence of weight training response on genes) and the identification of genes or coding variants in relation to strength characteristics are also of interest.

Power and strength show normal variation in the general population, as is typical for quantitative, multifactorial phenotypes that are influenced by both multiple genes (polygenic) and environmental factors. The search for the genetic basis of muscular strength and power is based on two approaches: the unmeasured genotype approach (top down) and the measured genotype approach (bottom up).

When the measured genotype is not available, inferences concerning genetic influences on a phenotype are based on statistical analyses of the distributions of strength measures in related individuals and families based on the theoretical framework of biometrical genetics. Twin and family studies are the two major strategies used to identify genetic and environmental contributions to muscular strength. The heritability coefficient derived thereof is specific for the studied population and can be estimated using ANOVA or genetic modelling techniques.

Two major complementary strategies are available in humans to identify genes using the measured genotype approach. The first method is localisation and identification by quantitative …
Lynch Syndrome–Associated Breast Cancers: Clinicopathologic Characteristics of a Case Series from the Colon Cancer Family Registry
Authors: Michael D. Walsh, Daniel D. Buchanan, Margaret C. Cummings, Sally-Ann Pearson, Sven T. Arnold, Mark Clendenning, Rhiannon Walters, Diane M. McKeone, Amanda B. Spurdle, John L. Hopper, Mark A. Jenkins, Kerry D. Phillips, Graeme K. Suthers, Jill George, Jack Goldblatt, Amanda Muir, Kathy Tucker, Elise Pelzer, Michael R. Gattas, Sonja Woodall, Susan Parry, Finlay A. Macrae, Robert W. Haile, John A. Baron, John D. Potter, Loic Le Marchand, Bharati Bapat, Stephen N. Thibodeau, Noralane M. Lindor, Michael A. McGuckin, Joanne P. Young
Journal: Clinical Cancer Research (2010)

Abstract Purpose: The recognition of breast cancer as a spectrum tumor in Lynch syndrome remains controversial. The aim of this study was to explore features of breast cancers arising in Lynch syndrome families. Experimental Design: This observational study involved 107 cases of breast cancer identified from the Colorectal Cancer Family Registry (Colon CFR) from 90 families in which (a) both breast and colon cancer co-occurred, (b) families met either modified Amsterdam criteria, or had at least one early-onset (&amp;lt;50 years) colorectal cancer, and (c) breast tissue was available within the biospecimen repository for mismatch repair (MMR) testing. Eligibility criteria for enrollment in the Colon CFR are available online. Breast cancers were reviewed by one pathologist. Tumor sections were stained for MLH1, PMS2, MSH2, and MSH6, and underwent microsatellite instability testing. Results: Breast cancer arose in 35 mutation carriers, and of these, 18 (51%) showed immunohistochemical absence of MMR protein corresponding to the MMR gene mutation segregating the family. MMR-deficient breast cancers were more likely to be poorly differentiated (P = 0.005) with a high mitotic index (P = 0.002), steroid hormone receptor–negative (estrogen receptor, P = 0.031; progesterone receptor, P = 0.022), and to have peritumoral lymphocytes (P = 0.015), confluent necrosis (P = 0.002), and growth in solid sheets (P &amp;lt; 0.001) similar to their colorectal counterparts. No difference in age of onset was noted between the MMR-deficient and MMR-intact groups. Conclusions: MMR deficiency was identified in 51% of breast cancers arising in known mutation carriers. Breast cancer therefore may represent a valid tissue option for the detection of MMR deficiency in which spectrum tumors are lacking. Clin Cancer Res; 16(7); 2214–24. ©2010 AACR.
Referee's ruderies: LPG and the BMJ.
Authors: S Lock, P Waterworth
Journal: BMJ (1979)

To encompass all the qualities of a great man in a short obituary notice is impossible.In a private letter to the BMJ Paul Garrod complained that it had done both Lord Adrian and Lord Cohen of Birkenhead less than justice, and of his own obituary some have observed that it omitted important aspects of his career.Why, for example, given his background of a lifetime's work at what was then one of the stuffiest, most hierarchical, and least research-minded of all teaching hospitals, was nothing said of his bravery when at the age of 70 he went to the Royal Postgraduate Medical School-where healthy irreverence ruled, rank and connection counting for nothing and achievement in research for everything?Why, again, was no comment made about his failure to be honoured?Apart from a doctorate from Glasgow University during the Lister celebrations in 1965 and an honorary fellowship from a royal college only a year before his death, both the state and other institu- tions apparently ignored his consider- able claims to recognition.LawrenceThe longer obituary notices now being prepared for some of the learned
Poloxamer 188 Facilitates the Repair of Alveolus Resident Cells in Ventilator-injured Lungs
Authors: Maria Plataki, Yang D. Lee, Deborah L. Rasmussen, Rolf D. Hubmayr
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Wounded alveolus resident cells are identified in human and experimental acute respiratory distress syndrome models. Poloxamer 188 (P188) is an amphiphilic macromolecule shown to have plasma membrane-sealing properties in various cell types.To investigate whether P188 (1) protects alveolus resident cells from necrosis and (2) is associated with reduced ventilator-induced lung injury in live rats, isolated perfused rat lungs, and scratch and stretch-wounded alveolar epithelial cells.Seventy-four live rats and 18 isolated perfused rat lungs were ventilated with injurious or protective strategies while infused with P188 or control solution. Alveolar epithelial cell monolayers were subjected to scratch or stretch wounding in the presence or absence of P188.P188 was associated with fewer mortally wounded alveolar cells in live rats and isolated perfused lungs. In vitro, P188 reduced the number of injured and necrotic cells, suggesting that P188 promotes cell repair and renders plasma membranes more resilient to deforming stress. The enhanced cell survival was accompanied by improvement in conventional measures of lung injury (peak airway pressure, wet-to-dry weight ratio) only in the ex vivo-perfused lung preparation and not in the live animal model.P188 facilitates plasma membrane repair in alveolus resident cells, but has no salutary effects on lung mechanics or vascular barrier properties in live animals. This discordance may have pathophysiological significance for the interdependence of different injury mechanisms and therapeutic implications regarding the benefits of prolonging the life of stress-activated cells.
Calcineurin regulates innate antifungal immunity in neutrophils
Authors: Matthew B. Greenblatt, Antonios Aliprantis, Bella Hu, Laurie H. Glimcher
Journal: The Journal of Experimental Medicine (2010)

Patients taking immunosuppressive drugs, like cyclosporine A (CsA), that inhibit calcineurin are highly susceptible to disseminated fungal infections, although it is unclear how these drugs suppress resistance to these opportunistic pathogens. We show that in a mouse model of disseminated Candida albicans infection, CsA-induced susceptibility to fungal infection maps to the innate immune system. To further define the cell types targeted by CsA, we generated mice with a conditional deletion of calcineurin B (CnB) in neutrophils. These mice displayed markedly decreased resistance to infection with C. albicans, and both CnB-deficient and CsA-treated neutrophils showed a defect in the ex vivo killing of C. albicans. In response to the fungal-derived pathogen-associated molecular pattern zymosan, neutrophils lacking CnB displayed impaired up-regulation of genes (IL-10, Cox2, Egr1, and Egr2) regulated by nuclear factor of activated T cells, the best characterized CnB substrate. This activity was Myd88 independent and was reproduced by stimulation with the β(1,3) glucan curdlan, indicating that dectin-1, rather than toll-like receptors, is the upstream activator of calcineurin. Our results suggest that disseminated fungal infections seen in CsA-treated patients are not just a general consequence of systemic suppression of adaptive immunity but are, rather, a result of the specific blockade of evolutionarily conserved innate pathways for fungal resistance.
Stanford V program for locally extensive and advanced Hodgkin lymphoma: the Memorial Sloan-Kettering Cancer Center experience
Authors: S.M. Edwards-Bennett, L.M. Jacks, C.H. Moskowitz, E.J. Wu, Z. Zhang, A. Noy, C.S. Portlock, D.J. Straus, A.D. Zelenetz, J. Yahalom
Journal: Annals of Oncology (2009)