tbuckley/cabot-search huggingface dataset:
Effects of Genital Ulcer Disease and Herpes Simplex Virus Type 2 on the Efficacy of Male Circumcision for HIV Prevention: Analyses from the Rakai Trials
Authors: Ronald H. Gray, David Serwadda, Aaron A. R. Tobian, Michael Z. Chen, Frederick Makumbi, Tara Suntoke, Godfrey Kigozi, Fred Nalugoda, Boaz Iga, Thomas C. Quinn, Lawrence H. Moulton, Oliver Laeyendecker, Steven J. Reynolds, Xiangrong Kong, Maria J. Wawer
Journal: PLoS Medicine (2009)

Randomized trials show that male circumcision (MC) reduces the incidence of HIV and herpes simplex virus type 2 (HSV-2) infections, and symptomatic genital ulcer disease (GUD). We assessed the role of GUD and HSV-2 in the protection against HIV afforded by MC.HIV-uninfected men were randomized to immediate (n = 2,756) or delayed MC (n = 2,775) in two randomized trials in Rakai, Uganda. GUD symptoms, HSV-2 status, and HIV acquisition were determined at enrollment and at 6, 12, and 24 mo of follow up. Ulcer etiology was assessed by PCR. We estimated the prevalence and prevalence risk ratios (PRRs) of GUD in circumcised versus uncircumcised men and assessed the effects of HSV-2 serostatus as a risk-modifying factor for GUD. We estimated the proportion of the effect of MC on HIV acquisition that was mediated by symptomatic GUD, and by HSV-2 infection. Circumcision significantly reduced symptomatic GUD in HSV-2-seronegative men (PRR = 0.51, 95% [confidence interval] CI 0.43-0.74), HSV-2-seropositive men (PRR = 0.66, 95% CI 0.51-0.69), and in HSV-2 seroconverters (PRR = 0.48, 95% CI 0.30-0.79). The proportion of acute ulcers due to HSV-2 detected by PCR was 48.0% in circumcised men and 39.3% in uncircumcised men (chi(2)p = 0.62). Circumcision reduced the risk of HIV acquisition in HSV-2 seronegative men (incidence rate ratio [IRR] = 0.34, 95% CI 0.15-0.81), and potentially in HSV-2 seroconverters (IRR = 0.56, 95% CI 0.19-1.57; not significant), but not in men with prevalent HSV-2 at enrollment (IRR = 0.89, 95% CI 0.49-1.60). The proportion of reduced HIV acquisition in circumcised men mediated by reductions in symptomatic GUD was 11.2% (95% CI 5.0-38.0), and the proportion mediated by reduced HSV-2 incidence was 8.6% (95% CI -1.2 to 77.1).Circumcision reduced GUD irrespective of HSV-2 status, but this reduction played only a modest role in the protective effect of circumcision on HIV acquisition.
Myocyte growth without physiological impairment in gradually induced rat cardiac hypertrophy.
Authors: F J Julian, D L Morgan, R L Moss, M Gonzalez, P Dwivedi
Journal: Circulation Research (1981)

A surgical technique was developed to place sutures around the pulmonary arteries of young rats (about 1 month old and 100 g body weight). As the operated rats grew, the pulmonary arteries were gradually constricted, leading after 4-6 weeks to the development of severe right ventricular hypertrophy with free wall weights about twice those from control rats. There were no signs of heart failure or cardiac decompensation. Collagen concentrations were the same in operated and control rats. Myocytes were isolated from right ventricles by enzymatic digestion. Autoradiographic studies showed considerable uptake in non-myocyte nuclei. Myocyte sarcomere lengths were unchanged. However, myocyte lengths and areas increased sufficiently to account for the increase in free wall weights observed. Physiological studies were done on isolated papillary muscles and ventricular strands, which were subsequently fixed. The force-generating capability at optimum length, magnitude of active compliance, and maximum speed of shortening (using four different techniques) were measured in each isolated muscle. There were no significant changes observed between operated and control rats. Microscopic examination of the muscle cross-sections confirmed that average myocyte area in the muscles obtained from operated rats was significantly increased. The results show that it is possible to obtain considerable increases in average myocyte size (by about a factor of 2) while still maintaining normal physiological function.
Short Stature in Childhood — Challenges and Choices
Authors: David B. Allen, Leona Cuttler
Journal: New England Journal of Medicine (2013)

This article reviews evaluation of short stature in childhood and options for management of idiopathic cases (e.g., familial short stature or constitutional delay of growth and puberty), including observation and reassurance, growth hormone treatment, and low-dose oral oxandrolone in boys.
Pharmacokinetic-Pharmacodynamic Relationships of Imatinib and Its Main Metabolite in Patients with Advanced Gastrointestinal Stromal Tumors
Authors: Catherine Delbaldo, Etienne Chatelut, Micheline Ré, Alain Deroussent, Sophie Séronie-Vivien, Aurore Jambu, Patrice Berthaud, Axel Le Cesne, Jean-Yves Blay, Gilles Vassal
Journal: Clinical Cancer Research (2006)

Abstract Purpose: This study explored factors affecting the pharmacokinetic variability of imatinib and CGP 74588, and the pharmacokinetic-pharmacodynamic correlations in patients with advanced gastrointestinal stromal tumors. Experimental Design: Thirty-five patients with advanced gastrointestinal stromal tumors received 400 mg of imatinib daily. Six blood samples were drawn: before intake, during 1- to 3- and 6- to 9-hour intervals after intake on day 1, and before intake on days 2, 30, and 60. Plasma imatinib and CGP 74588 concentrations were quantified by reverse-phase high-performance liquid chromatography coupled with tandem mass spectrometry, and analyzed by the population pharmacokinetic method (NONMEM program). The influence of 17 covariates on imatinib clearance (CL) and CGP 74588 clearance (CLM/fm) was studied. These covariates included clinical and biological variables and occasion (OCC = 0 for pharmacokinetic data corresponding to the first administration, or OCC = 1 for the day 30 or 60 administrations). Results: The best regression formulas were: CL (L/h) = 7.97 (AAG/1.15)−0.52, and CLM/fm (L/h) = 58.6 (AAG/1.15)−0.60 × 0.55OCC, with the plasma α1-acid glycoprotein (AAG) levels indicating that both clearance values decreased at a higher AAG level. A significant time-dependent decrease in CLM/fm was evidenced with a mean (+SD) CGP 74588/imatinib area under the curve (AUC) ratio of 0.25 (±0.07) at steady state, compared with 0.14 (±0.03) on day 1. Hematologic toxicity was correlated with pharmacokinetic variables: the correlation observed with the estimated unbound imatinib AUC at steady-state (r = 0.56, P &amp;lt; 0.001) was larger than that of the total imatinib AUC (r = 0.32, NS). Conclusions: The plasma AAG levels influenced imatinib pharmacokinetics. A protein-binding phenomenon needs to be considered when exploring the correlations between pharmacokinetics and pharmacodynamics.
CBP Loss Cooperates with PTEN Haploinsufficiency to Drive Prostate Cancer: Implications for Epigenetic Therapy
Authors: Liya Ding, Shuai Chen, Ping Liu, Yunqian Pan, Jian Zhong, Kevin M. Regan, Liguo Wang, Chunrong Yu, Anthony Rizzardi, Liang Cheng, Jun Zhang, Stephen C. Schmechel, John C. Cheville, Jan Van Deursen, Donald J. Tindall, Haojie Huang
Journal: Cancer Research (2014)

Abstract Despite the high incidence and mortality of prostate cancer, the etiology of this disease is not fully understood. In this study, we develop functional evidence for CBP and PTEN interaction in prostate cancer based on findings of their correlate expression in the human disease. Cbppc−/−;Ptenpc+/− mice exhibited higher cell proliferation in the prostate and an early onset of high-grade prostatic intraepithelial neoplasia. Levels of EZH2 methyltransferase were increased along with its Thr350 phosphorylation in both mouse Cbp−/−; Pten+/− and human prostate cancer cells. CBP loss and PTEN deficiency cooperated to trigger a switch from K27-acetylated histone H3 to K27-trimethylated bulk histones in a manner associated with decreased expression of the growth inhibitory EZH2 target genes DAB2IP, p27KIP1, and p21CIP1. Conversely, treatment with the histone deacetylase inhibitor panobinostat reversed this switch, in a manner associated with tumor suppression in Cbppc−/−;Ptenpc+/− mice. Our findings show how CBP and PTEN interact to mediate tumor suppression in the prostate, establishing a central role for histone modification in the etiology of prostate cancer and providing a rationale for clinical evaluation of epigenetic-targeted therapy in patients with prostate cancer. Cancer Res; 74(7); 2050–61. ©2014 AACR.
AAL881, a Novel Small Molecule Inhibitor of RAF and Vascular Endothelial Growth Factor Receptor Activities, Blocks the Growth of Malignant Glioma
Authors: Sith Sathornsumetee, Anita B. Hjelmeland, Stephen T. Keir, Roger E. McLendon, David Batt, Timothy Ramsey, Naeem Yusuff, B.K. Ahmed Rasheed, Mark W. Kieran, Andrea Laforme, Darell D. Bigner, Henry S. Friedman, Jeremy N. Rich
Journal: Cancer Research (2006)

Malignant gliomas are highly proliferative and angiogenic cancers resistant to conventional therapies. Although RAS and RAF mutations are uncommon in gliomas, RAS activity is increased in gliomas. Additionally, vascular endothelial growth factor and its cognate receptors are highly expressed in gliomas. We now report that AAL881, a novel low-molecular weight inhibitor of the kinase activities associated with B-RAF, C-RAF (RAF-1), and VEGF receptor-2 (VEGFR2), showed activity against glioma cell lines and xenografts. In culture, AAL881 inhibited the downstream effectors of RAF in a concentration-dependent manner, with inhibition of proliferation associated with a G(1) cell cycle arrest, induction of apoptosis, and decreased colony formation. AAL881 decreased the proliferation of bovine aortic endothelial cells as well as the tumor cell secretion of vascular endothelial growth factor and inhibited the invasion of glioma cells through an artificial extracellular matrix. Orally administered AAL881 was well tolerated with minimal weight loss in non-tumor-bearing mice. Established s.c. human malignant glioma xenografts grown in immunocompromised mice treated with a 10-day course of oral AAL881 exhibited growth delays relative to control tumors, frequently resulting in long-term complete regressions. AAL881 treatment extended the survival of immunocompromised mice bearing orthotopic glioma xenografts compared with placebo controls. The intraparenchymal portions of orthotopic AAL881-treated tumors underwent widespread necrosis consistent with vascular disruption compared with the subarachnoid elements. These effects are distinct from our prior experience with VEGFR2 inhibitors, suggesting that targeting RAF itself or in combination with VEGFR2 induces profound tumor responses in gliomas and may serve as a novel therapeutic approach in patients with malignant gliomas.
Training and competence assessment in GI endoscopy: a systematic review
Authors: Vivian E Ekkelenkamp, Arjun D Koch, Robert A de Man, Ernst J Kuipers
Journal: Gut (2015)

Training procedural skills in GI endoscopy once focused on threshold numbers. As threshold numbers poorly reflect individual competence, the focus gradually shifts towards a more individual approach. Tools to assess and document individual learning progress are being developed and incorporated in dedicated training curricula. However, there is a lack of consensus and training guidelines differ worldwide, which reflects uncertainties on optimal set-up of a training programme.The primary aim of this systematic review was to evaluate the currently available literature for the use of training and assessment methods in GI endoscopy. Second, we aimed to identify the role of simulator-based training as well as the value of continuous competence assessment in patient-based training. Third, we aimed to propose a structured training curriculum based on the presented evidence.A literature search was carried out in the available medical and educational literature databases. The results were systematically reviewed and studies were included using a predefined protocol with independent assessment by two reviewers and a final consensus round.The literature search yielded 5846 studies. Ninety-four relevant studies on simulators, assessment methods, learning curves and training programmes for GI endoscopy met the inclusion criteria. Twenty-seven studies on simulator validation were included. Good validity was demonstrated for four simulators. Twenty-three studies reported on simulator training and learning curves, including 17 randomised control trials. Increased performance on a virtual reality (VR) simulator was shown in all studies. Improved performance in patient-based assessment was demonstrated in 14 studies. Four studies reported on the use of simulators for assessment of competence levels. Current simulators lack the discriminative power to determine competence levels in patient-based endoscopy. Eight out of 14 studies on colonoscopy, endoscopic retrograde cholangiopancreatography and endosonography reported on learning curves in patient-based endoscopy and proved the value of this approach for measuring performance. Ten studies explored the numbers needed to gain competence, but the proposed thresholds varied widely between them. Five out of nine studies describing the development and evaluation of assessment tools for GI endoscopy provided insight into the performance of endoscopists. Five out of seven studies proved that intense training programmes result in good performance.The use of validated VR simulators in the early training setting accelerates the learning of practical skills. Learning curves are valuable for the continuous assessment of performance and are more relevant than threshold numbers. Future research will strengthen these conclusions by evaluating simulation-based as well as patient-based training in GI endoscopy. A complete curriculum with the assessment of competence throughout training needs to be developed for all GI endoscopy procedures.
Innate immune responses during respiratory tract infection with a bacterial pathogen induce allergic airway sensitization
Authors: Nicolas W.J. Schröder, Timothy R. Crother, Yoshikazu Naiki, Shuang Chen, Michelle H. Wong, Atilla Yilmaz, Anatoly Slepenkin, Danica Schulte, Randa Alsabeh, Terence M. Doherty, Ellena Peterson, Andre E. Nel, Moshe Arditi
Journal: Journal of Allergy and Clinical Immunology (2008)
The Empirical Status of Psychodynamic Therapies
Authors: Mary Beth Connolly Gibbons, Paul Crits-Christoph, Bridget Hearon
Journal: Annual Review of Clinical Psychology (2008)

The goal of the current review is to examine the evidence for the efficacy of dynamic psychotherapy, primarily focusing on studies that meet the rigorous criteria proposed by Chambless &amp; Hollon (1998) . We examine whether any progress has been made over the past decade in evaluating the efficacy of dynamic psychotherapy using well-controlled randomized designs. Over the past decade, multiple studies have been published supporting the efficacy of dynamic psychotherapy for the treatment of specific mental disorders. Dynamic psychotherapy should now be included as a possibly efficacious treatment for panic disorder and borderline personality disorder, as well as the original designation of possibly efficacious in the treatment of opiate dependence. In the context of medication usage, dynamic psychotherapy should be considered efficacious in the treatment of major depressive disorder (MDD). Studies suggest that dynamic psychotherapy has great promise as a monotherapy for MDD and alcohol dependence and thus should be evaluated further.
The rules versus similarity distinction
Authors: Emmanuel M. Pothos
Journal: Behavioral and Brain Sciences (2005)

The distinction between rules and similarity is central to our understanding of much of cognitive psychology. Two aspects of existing research have motivated the present work. First, in different cognitive psychology areas we typically see different conceptions of rules and similarity; for example, rules in language appear to be of a different kind compared to rules in categorization. Second, rules processes are typically modeled as separate from similarity ones; for example, in a learning experiment, rules and similarity influences would be described on the basis of separate models. In the present article, I assume that the rules versus similarity distinction can be understood in the same way in learning, reasoning, categorization, and language, and that a unified model for rules and similarity is appropriate. A rules process is considered to be a similarity one where only a single or a small subset of an object's properties are involved. Hence, rules and overall similarity operations are extremes in a single continuum of similarity operations. It is argued that this viewpoint allows adequate coverage of theory and empirical findings in learning, reasoning, categorization, and language, and also a reassessment of the objectives in research on rules versus similarity.
Detection of High-Risk Atherosclerotic Plaques with Ultrasound Molecular Imaging of Glycoprotein IIb/IIIa Receptor on Activated Platelets
Authors: Shengcun Guo, Shuxin Shen, Junfen Wang, He Wang, Meiyu Li, Ying Liu, Fanfan Hou, Yulin Liao, Jianping Bin
Journal: Theranostics (2015)

Objective: Ultrasound molecular imaging (UMI) of glycoprotein (GP) IIb/IIIa receptor on activated platelets offers a unique means of identifying high-risk atherosclerosis.We hypothesized that contrast-enhanced ultrasound with microbubbles (MBs) targeted to GP IIb/IIIa could be used to detect and quantify activated platelets on the surface of advanced plaques.Methods and Results: A mouse model of advanced atherosclerosis was generated by maintaining apolipoprotein E-deficient (ApoE -/-) mice on a hypercholesterolemic diet (HCD).The three other experimental groups consisted of ApoE -/-and wild-type (C57BL/6) mice fed a normal chow diet and C57BL/6 mice on an HCD diet.Plaque formation was confirmed by histological and immunohistochemical methods using light, fluorescence, and electron microscopy.Mice were injected with a lipid MB-conjugated cyclic Arg-Gly-Asp peptide or nonspecific control peptide, and the abdominal aorta was examined by UMI.The accumulation of GP IIb/IIIa and activated platelets on the surface of atherosclerotic plaques was highest in the ApoE -/-+HCD group, followed by ApoE -/-+chow, C57BL/6+HCD, and C57BL/6+chow groups (P<0.05).Notably, GP IIb/IIIa expression was associated with the vulnerability index and necrotic center/fiber cap ratio (P<0.05), and contrast video intensity from adhered cyclic Arg-Gly-Asp-modified MBs (MB-cRGDs) was correlated with GP IIb/IIIa expression on the plaque surface (P<0.05).Conclusion: GP IIb/IIIa of activated platelets on the atherosclerotic endothelium is a biomarker for high-risk plaques that can be quantified by UMI using MB-cRGDs, providing a noninvasive means for detecting high-risk plaques and preventing acute cardiovascular events.
Long-term outcomes with concurrent carboplatin, paclitaxel and radiation therapy for locally advanced, inoperable head and neck cancer
Authors: S.S. Agarwala, E. Cano, D.E. Heron, J. Johnson, E. Myers, V. Sandulache, S. Bahri, R. Ferris, Y. Wang, A. Argiris
Journal: Annals of Oncology (2007)
Miniature Inverted-Repeat Transposable Elements (MITEs) Have Been Accumulated through Amplification Bursts and Play Important Roles in Gene Expression and Species Diversity in Oryza sativa
Authors: C. Lu, J. Chen, Y. Zhang, Q. Hu, W. Su, H. Kuang
Journal: Molecular Biology and Evolution (2011)

Miniature inverted–repeat transposable elements (MITEs) are predicted to play important roles on genome evolution. We developed a BLASTN-based approach for de novo identification of MITEs and systematically analyzed MITEs in rice genome. The genome of rice cultivar Nipponbare (Oryza sativa ssp. japonica) harbors 178,533 MITE-related sequences classified into 338 families. Pairwise nucleotide diversity and phylogenetic tree analysis indicated that individual MITE families were resulted from one or multiple rounds of amplification bursts. The timing of amplification burst varied considerably between different MITE families or subfamilies. MITEs are associated with 23,623 (58.2%) genes in rice genome. At least 7,887 MITEs are transcribed and more than 3,463 were transcribed with rice genes. The MITE sequences transcribed with rice coding genes form 1,130 pairs of potential natural sense/antisense transcripts. MITEs generate 23.5% (183,837 of 781,885) of all small RNAs identified from rice. Some MITE families generated small RNAs mainly from the terminals, while other families generated small RNAs predominantly from the central region. More than half (51.8%) of the MITE-derived small RNAs were generated exclusively by MITEs located away from genes. Genome-wide analysis showed that genes associated with MITEs have significantly lower expression than genes away from MITEs. Approximately 14.8% of loci with full-length MITEs have presence/absence polymorphism between rice cultivars 93-11 (O. sativa ssp. indica) and Nipponbare. Considering that different sets of genes may be regulated by MITE-derived small RNAs in different genotypes, MITEs provide considerable diversity for O. sativa.
Thought as word dynamics
Authors: Paul J. M. Jorion
Journal: Behavioral and Brain Sciences (1999)

A Hebbian model for speech generation opens a number of paths. A cross-linguistic scheme of functional relationships (inspired by Aristotle) dispenses with distraction by the “parts of speech” distinctions, while bridging the gap between “content” and “structure” words. A gradient model identifies emotional and rational dynamics and shows speech generation as a process where a speaker's dissatisfaction gets minimized.
Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer
Authors: Lucia De Monte, Michele Reni, Elena Tassi, Daniela Clavenna, Ilenia Papa, Helios Recalde, Marco Braga, Valerio Di Carlo, Claudio Doglioni, Maria Pia Protti
Journal: The Journal of Experimental Medicine (2011)

Pancreatic cancer is a very aggressive disease characterized by a marked desmoplasia with a predominant Th2 (GATA-3+) over Th1 (T-bet+) lymphoid infiltrate. We found that the ratio of GATA-3+/T-bet+ tumor-infiltrating lymphoid cells is an independent predictive marker of patient survival. Patients surgically treated for stage IB/III disease with a ratio inferior to the median value had a statistically significant prolonged overall survival, implying an active role for Th2 responses in disease progression. Thymic stromal lymphopoietin (TSLP), which favors Th2 cell polarization through myeloid dendritic cell (DC) conditioning, was secreted by cancer-associated fibroblasts (CAFs) after activation with tumor-derived tumor necrosis factor α and interleukin 1β. TSLP-containing supernatants from activated CAFs induced in vitro myeloid DCs to up-regulate the TSLP receptor (TSLPR), secrete Th2-attracting chemokines, and acquire TSLP-dependent Th2-polarizing capability in vitro. In vivo, Th2 chemoattractants were expressed in the tumor and in the stroma, and TSLPR-expressing DCs were present in the tumor stroma and in tumor-draining but not in nondraining lymph nodes. Collectively, this study identifies in pancreatic cancer a cross talk between tumor cells and CAFs, resulting in a TSLP-dependent induction of Th2-type inflammation which associates with reduced patient survival. Thus, blocking TSLP production by CAFs might help to improve prognosis in pancreatic cancer.