tbuckley/cabot-search huggingface dataset:
IMMUNE RESPONSES IN VITRO
Authors: Carl W. Pierce
Journal: The Journal of Experimental Medicine (1969)

A cell suspension culture system combined with a procedure which separates most macrophages from lymphoid cells was used to investigate some of the cellular requirements for direct and indirect plaque-forming cell responses by nonprimed and primed mouse spleen cells in vitro. The plaque-forming cell response to heterologous erythrocytes in cultures of nonprimed spleen cells required both macrophages and lymphoid cells for its development. A significant indirect plaque-forming cell response did not develop in cultures of nonprimed spleen cells. In contrast, cultures of separated or macrophage-poor lymphoid cells from primed mice exhibited increasing responses relative to the response of unseparated spleen cells as the interval after priming increased. The cultures of separated lymphoid cells were not entirely free of phagocytic cells. Despite some evidence which suggests that these phagocytic cells had little function in the response, one cannot ascertain whether the lymphoid cells were responding directly to a second contact with antigen or whether the few contaminating phagocytic cells were performing a function essential to the response by the lymphoid cells. Physiologically different populations of cells appear to develop after priming and are able to respond in vitro in a macrophage-poor culture. Some of the properties of these populations suggest that they are "memory cell" pools containing precursors of direct and indirect plaque-forming cells highly susceptible to a second antigenic stimulus.
4.83 million died from smoking related disease in 2000
Authors: J M Douse
Journal: Thorax (2003)

▴ Ezzati M, Lopez AD. Estimates of global mortality attributable to smoking in 2000. Lancet2003;362:847–52 [OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4] Using lung cancer mortality as an indirect marker for smoking risk, Ezzati and Lopez expanded the Peto-Lopez method to estimate global mortality due to smoking in 2000. The American Cancer Society Prevention Study and the work of Liu et al … [1]: {openurl}?query=rft.jtitle%253DLancet%26rft.stitle%253DLancet%26rft.aulast%253DEzzati%26rft.auinit1%253DM.%26rft.volume%253D362%26rft.issue%253D9387%26rft.spage%253D847%26rft.epage%253D852%26rft.atitle%253DEstimates%2Bof%2Bglobal%2Bmortality%2Battributable%2Bto%2Bsmoking%2Bin%2B2000.%26rft_id%253Dinfo%253Adoi%252F10.1016%252FS0140-6736%252803%252914338-3%26rft_id%253Dinfo%253Apmid%252F13678970%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1016/S0140-6736(03)14338-3&link_type=DOI [3]: /lookup/external-ref?access_num=13678970&link_type=MED&atom=%2Fthoraxjnl%2F58%2F12%2F1057.2.atom [4]: /lookup/external-ref?access_num=000185329400007&link_type=ISI
Patient Pretenders Weave Tangled "Web" of Deceit
Authors: Joan Stephenson
Journal: JAMA (1998)

IN a New Yorker cartoon that appeared in 1993, one cyberspace-cruising dog tells his canine pal, "On the Internet, nobody knows you're a dog." The point, as anyone who has spent much time online knows all too well, is that the medium is unusually conducive to deception.
Genz-644282, a Novel Non-Camptothecin Topoisomerase I Inhibitor for Cancer Treatment
Authors: Leslie S. Kurtzberg, Stephanie Roth, Roy Krumbholz, Jennifer Crawford, Christy Bormann, Sarah Dunham, Min Yao, Cecile Rouleau, Rebecca G. Bagley, Xian-Jie Yu, Fei Wang, Steven M. Schmid, Edmond J. LaVoie, Beverly A. Teicher
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Genz-644282 [8,9-dimethoxy-5-(2-N-methylaminoethyl)-2,3-methylenedioxy-5H-dibenzo[c,h][1,6]naphthyridin-6-one] has emerged as a promising candidate for antitumor agents. This report describes the bone marrow colony-forming unit, granulocyte macrophage (CFU-GM) and tumor cell CFU activity of topoisomerase I (Top1) inhibitors, such as Genz-644282, topotecan, irinotecan/SN-38, and ARC-111, and examines their activity in several human tumor xenograft models. Experimental Design: Colony-forming assays were conducted with mouse and human bone marrow and eight human tumor cell lines. In addition, 29 human tumor cell lines representing a range of histology and potential resistance mechanisms were assayed for sensitivity to Genz-644282 in a 72-hour exposure assay. The efficacy of Genz-644282 was compared with standard anticancer drugs (i.e., irinotecan, docetaxel, and dacarbazine) in human tumor xenografts of colon cancer, renal cell carcinoma, non–small cell lung cancer, and melanoma. Results: Human bone marrow CFU-GM was more sensitive to the Top1 inhibitors than was mouse bone marrow CFU-GM. The ratio of mouse to human IC90 values was more than 10 for the camptothecins and less than 10 for Genz-644282, which had more potency as a cytotoxic agent toward human tumor cells in culture than the camptothecins in the colony-forming and 72-hour proliferation assays. Genz-644282 has superior or equal antitumor activity in the human tumor xenografts than the standard drug comparators. Conclusions: On the basis of preclinical activity and safety, Genz-644282 was selected for development and is currently undergoing phase 1 clinical trial. Clin Cancer Res; 17(9); 2777–87. ©2011 AACR.
Critical role of Bcl11b in suppressor function of T regulatory cells and prevention of inflammatory bowel disease
Authors: Jeffrey VanValkenburgh, Diana I. Albu, Chandra Bapanpally, Sarah Casanova, Danielle Califano, David M. Jones, Leszek Ignatowicz, Shimpei Kawamoto, Sidonia Fagarasan, Nancy A. Jenkins, Neal G. Copeland, Pentao Liu, Dorina Avram
Journal: The Journal of Experimental Medicine (2011)

Dysregulated CD4+ T cell responses and alterations in T regulatory cells (Treg cells) play a critical role in autoimmune diseases, including inflammatory bowel disease (IBD). The current study demonstrates that removal of Bcl11b at the double-positive stage of T cell development or only in Treg cells causes IBD because of proinflammatory cytokine-producing CD4+ T cells infiltrating the colon. Provision of WT Treg cells prevented IBD, demonstrating that alterations in Treg cells are responsible for the disease. Furthermore, Bcl11b-deficient Treg cells had reduced suppressor activity with altered gene expression profiles, including reduced expression of the genes encoding Foxp3 and IL-10, and up-regulation of genes encoding proinflammatory cytokines. Additionally, the absence of Bcl11b altered the induction of Foxp3 expression and reduced the generation of induced Treg cells (iTreg cells) after Tgf-β treatment of conventional CD4+ T cells. Bcl11b bound to Foxp3 and IL-10 promoters, as well as to critical conserved noncoding sequences within the Foxp3 and IL-10 loci, and mutating the Bcl11b binding site in the Foxp3 promoter reduced expression of a luciferase reporter gene. These experiments demonstrate that Bcl11b is indispensable for Treg suppressor function and for maintenance of optimal Foxp3 and IL-10 gene expression, as well as for the induction of Foxp3 expression in conventional CD4+ T cells in response to Tgf-β and generation of iTreg cells.
Testing for Hepatitis C Virus Infection Should Be Routine for Persons at Increased Risk for Infection
Authors: Miriam J. Alter, Leonard B. Seeff, Bruce R. Bacon, David L. Thomas, Michael O. Rigsby, Adrian M. Di Bisceglie
Journal: Annals of Internal Medicine (2004)

In the United States, chronic hepatitis C virus (HCV) infection affects an estimated 3 million persons, most younger than 50 years of age. It is one of the leading causes of chronic liver disease morbidity and mortality and the most common indication for liver transplantation. Effective treatment can eradicate the virus and eliminate or reduce liver inflammation and fibrosis, and counseling and immunization can modify or prevent the adverse effect of cofactors (for example, alcohol consumption or co-infections) on disease progression. However, controversy surrounds the need to routinely identify asymptomatic HCV-infected persons. Because no data currently demonstrate that treatment or other interventions will reduce future cases of HCV-related chronic disease and deaths, the U.S. Preventive Services Task Force found insufficient evidence to recommend for or against routine screening for HCV infection in adults at high risk. Chronic hepatitis C would require many years of follow-up to determine the incidence of complication after treatment of or other interventions in asymptomatic persons. It seems inappropriate to wait several decades to measure the impact of early identification of this viral infection when current data support a positive therapeutic effect that points to long-term benefits. In addition, treatment and other interventions must be provided before cirrhosis or liver failure occurs. Therefore, medical and public health professionals should continue the practice of screening persons for risk factors; offering testing to those at increased risk for HCV infection; and providing infected persons with appropriate counseling, medical evaluation, and treatment.
Caspase Activation Is Required for Terminal Erythroid Differentiation
Authors: Yael Zermati, Carmen Garrido, Sophie Amsellem, Serge Fishelson, Didier Bouscary, Françoise Valensi, Bruno Varet, Eric Solary, Olivier Hermine
Journal: The Journal of Experimental Medicine (2001)

The cysteine proteases known as caspases play a central role in most apoptotic pathways. Here, we show that caspase inhibitors arrest the maturation of human erythroid progenitors at early stages of differentiation, before nucleus and chromatin condensation. Effector caspases such as caspase-3 are transiently activated through the mitochondrial pathway during erythroblast differentiation and cleave proteins involved in nucleus integrity (lamin B) and chromatin condensation (acinus) without inducing cell death and cleavage of GATA-1. These observations indicate a new function for caspases as key proteases in the process of erythroid differentiation.
Clinical Pharmacokinetics of Irinotecan and Its Metabolites: A Population Analysis
Authors: Rujia Xie, Ron H.J. Mathijssen, Alex Sparreboom, Jaap Verweij, Mats O. Karlsson
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To build population pharmacokinetic (PK) models for irinotecan (CPT-11) and its currently identified metabolites. PATIENTS AND METHODS: Seventy cancer patients (24 women and 46 men) received 90-minute intravenous infusions of CPT-11 in the dose range of 175 to 300 mg/m 2 . The PK models were developed to describe plasma concentration profiles of the lactone and carboxylate forms of CPT-11 and 7-ethyl-10-hydroxycamptothecin (SN-38) and the total forms of SN-38 glucuronide (SN-38G), 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC), and 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin (NPC) by using NONMEM. RESULTS: The interconversion between the lactone and carboxylate forms of CPT-11 was relatively rapid, with an equilibration half-life of 14 minutes in the central compartment and hydrolysis occurring at a rate five times faster than lactonization. The same interconversion also occurred in peripheral compartments. CPT-11 lactone had extensive tissue distribution (steady-state volume of distribution [Vss], 445 L) compared with the carboxylate form (Vss, 78 L, excluding peripherally formed CPT-11 carboxylate). Clearance (CL) was higher for the lactone form (74.3 L/h) compared with the carboxylate form (12.3 L/h). During metabolite data modeling, goodness of fit indicated a preference of SN-38 and NPC to be formed out of the lactone form of CPT-11, whereas APC could be modeled best by presuming formation from CPT-11 carboxylate. The interconversion between SN-38 lactone and carboxylate was slower than that of CPT-11, with the lactone form dominating at equilibrium. The CLs for SN-38 lactone and carboxylate were similar, but the lactone form had more extensive tissue distribution. CONCLUSION: Plasma data of CPT-11 and metabolites could be adequately described by this compartmental model, which may be useful in predicting the time courses, including interindividual variability, of all characterized substances after intravenous administrations of CPT-11.
Retinal vascular permeability suppression by topical application of a novel VEGFR2/Src kinase inhibitor in mice and rabbits
Authors: Lea Scheppke, Edith Aguilar, Ray F. Gariano, Ruth Jacobson, John Hood, John Doukas, Jon Cao, Glenn Noronha, Shiyin Yee, Sara Weis, Michael B. Martin, Richard Soll, David A. Cheresh, Martin Friedlander
Journal: Journal of Clinical Investigation (2008)

Retinal and choroidal vascular diseases, with their associated abnormalities in vascular permeability, account for the majority of patients with vision loss in industrialized nations. VEGF is upregulated in ischemic retinopathies such as diabetes and is known to dramatically alter vascular permeability in a number of nonocular tissues via Src kinase-regulated signaling pathways. VEGF antagonists are currently in clinical use for treating the new blood vessels and retinal edema associated with neovascular eye diseases, but such therapies require repeated intraocular injections. We have found that vascular leakage following intravitreal administration of VEGF in mice was abolished by systemic or topical delivery of what we believe is a novel VEGFR2/Src kinase inhibitor; this was confirmed in rabbits. The relevance of Src inhibition to VEGF-associated alterations in vascular permeability was further substantiated by genetic studies in which VEGF injection or laser-induced vascular permeability failed to augment retinal vascular permeability in Src-/- and Yes-/- mice (Src and Yes are ubiquitously expressed Src kinase family members; Src-/- and Yes-/- mice lacking expression of these kinases show no vascular leak in response to VEGF). These findings establish a role for Src kinase in VEGF-mediated retinal vascular permeability and establish a potentially safe and painless topically applied therapeutic option for treating vision loss due to neovascular-associated retinal edema.
Bufavirus genotype 3 in Turkish children with severe diarrhoea
Authors: A. Altay, T. Yahiro, G. Bozdayi, T. Matsumoto, F. Sahin, S. Ozkan, A. Nishizono, M. Söderlund-Venermo, K. Ahmed
Journal: Clinical Microbiology and Infection (2015)

Recently a parvovirus called bufavirus (BuV) has been implicated as a causative agent of diarrhoea. To further reveal the epidemiology and genetic characteristics of BuV, this study was performed in Turkish children with diarrhoea. BuV was detected in 1.4% (8/583) of stool samples. All stool samples from healthy children (n = 148) were negative for BuV. Diarrhoea in BuV-positive patients was severe and occurred mainly during the colder months of the year. Complete genome sequences were generated from four BuVs. Only BuV3 was found, which was genetically and phylogenetically similar to Bhutanese BuV3, indicating that BuV3 is prevalent in Asian countries.
Protein Targeting in the Neuron
Authors: R B Kelly, E Grote
Journal: Annual Review of Neuroscience (1993)

The morphology of the neuron is essential to its function. Each mor­ phological specialization of the neuron, the dendrite, the dendritic spines, the axon, the axon hillock, the nodes of Ranvier, the active zone, and the synaptic vesicle appears to have a unique protein composition. To explain the architecture of the neuron in molecular terms, therefore, we need to know how unique proteins achieve their distributions within the cell. Because neurons have such morphological complexity, we may wonder whether they have evolved unique mechanisms of protein sorting, or use the same mechanisms found in non neuronal cells. Although scanty, the existing data on sorting of proteins in neuronal cells can still be adequately explained by mechanisms that exist in other cell types. What may be surprising is the diversity of sorting mechanisms that are used. In this review, we summarize evidence for selective targeting, selective retention, selective stabilization, selective exclusion, and RNA targeting. Protein sorting is conveniently divided into two issues: how proteins are targeted to organelles and how organelles reach their cellular destination. A second major subdivision is between sorting mechanisms that are inherent to cells and occur in dissociated cells and those that are induced by a cell's interaction with other cells or with extracellular matrix. In this review, we attempt to organize the available data into these conventional categories. It is also conventional to review membrane protein targeting or cytoskeletal assembly as two separate topics. Because the morphology
Bimodal Distribution of Angiographic Measures of Restenosis Six Months After Coronary Stent Placement
Authors: Albert Schömig, Adnan Kastrati, Shpend Elezi, Helmut Schühlen, Josef Dirschinger, Felix Dannegger, Manfred Wilhelm, Kurt Ulm
Journal: Circulation (1997)

Background Restenosis has been perceived as the tail end of a normal distribution of the response of the vessel to the intervention. However, recent studies have described a bimodal distribution for de novo lesions after percutaneous transluminal coronary angioplasty. This finding suggests that some lesions may be more susceptible for restenosis. Whether this holds true for a wider spectrum of lesions undergoing stent placement is not yet known. The present study analyzes the frequency distribution of angiographic indexes of restenosis 6 months after coronary stent implantation. Methods and Results Quantitative angiographic evaluation was performed in 1084 lesions of 1084 patients before, immediately after, and 6 months after successful Palmaz-Schatz stent placement; this represented 80.4% of patients eligible for follow-up angiography. Principal end points of the analysis were angiographic indexes of restenosis at 6 months. Twenty-two lesions that became totally occluded at follow-up were excluded from most parts of the analysis. Diameter stenosis, minimal luminal diameter (MLD), and lumen loss at 6 months did not follow a normal pattern; the bimodal pattern was demonstrated through deconvolution that yielded two separate normal components delineating two lesion populations, which developed distinctively different degrees of lumen renarrowing. The first and larger subgroup of lesions, which was less prone to restenosis, was centered around a mean value of 27% for diameter stenosis and 2.19 mm for MLD, whereas the second subgroup, with a greater tendency for restenosis, was situated around a mean value of 68% for diameter stenosis and 0.76 mm for MLD. The intersection point between the two theoretical normal distribution components was 53.5% for diameter stenosis and 1.09 mm for MLD at follow-up. Conclusions Frequency-distribution curves of angiographic indexes of restenosis after coronary stent placement have a bimodal pattern, suggesting the existence of two distinct populations with different propensity to restenosis. These findings may encourage future efforts for the timely identification of the subset with a higher risk as the target of specific antirestenotic strategies.
Taccalonolide Binding to Tubulin Imparts Microtubule Stability and Potent <i>In Vivo</i> Activity
Authors: A.L. Risinger, J. Li, M.J. Bennett, C.C. Rohena, J. Peng, D.C. Schriemer, S.L. Mooberry
Journal: Cancer Research (2013)

The taccalonolides are highly acetylated steroids that stabilize cellular microtubules and overcome multiple mechanisms of taxane resistance. Recently, two potent taccalonolides, AF and AJ, were identified that bind to tubulin directly and enhance microtubule polymerization. Extensive studies were conducted to characterize these new taccalonolides. AF and AJ caused aberrant mitotic spindles and bundling of interphase microtubules that differed from the effects of either paclitaxel or laulimalide. AJ also distinctly affected microtubule polymerization in that it enhanced the rate and extent of polymerization in the absence of any noticeable effect on microtubule nucleation. In addition, the resulting microtubules were found to be profoundly cold stable. These data, along with studies showing synergistic antiproliferative effects between AJ and either paclitaxel or laulimalide, suggest a distinct binding site. Direct binding studies demonstrated that AJ could not be displaced from microtubules by paclitaxel, laulimalide, or denaturing conditions, suggesting irreversible binding of AJ to microtubules. Mass spectrometry confirmed a covalent interaction of AJ with a peptide of β-tubulin containing the cyclostreptin-binding sites. Importantly, AJ imparts strong inter-protofilament stability in a manner different from other microtubule stabilizers that covalently bind to tubulin, consistent with the distinct effects of the taccalonolides as compared with other stabilizers. AF was found to be a potent and effective antitumor agent that caused tumor regression in the MDA-MB-231 breast cancer xenograft model. The antitumor efficacy of some taccalonolides, which stabilize microtubules in a manner different from other microtubule stabilizers, provides the impetus to explore the therapeutic potential of this site.
Health Behaviors Among Women of Reproductive Age With and Without a History of Gestational Diabetes Mellitus
Authors: Edith C. Kieffer, Brandy Sinco, Catherine Kim
Journal: Diabetes Care (2006)

To estimate the prevalence of several health-related behaviors among women of reproductive age with and without a history of gestational diabetes mellitus (hGDM).We performed a cross-sectional study using the 2001-2003 Behavioral Risk Factor Surveillance System, a national population-based random sample telephone survey. Participants were 177,420 women aged 18-44 years with and without self-reported hGDM. Outcome measures included meeting physical activity and fruit and vegetable guidelines, sedentary activity level, and current smoking.Approximately 3% (n = 4,718) of women aged 18-44 years reported physician-diagnosed hGDM. Women with hGDM had higher BMIs, were significantly older, were less often educated or employed, and were more often Hispanic or African American, married, and living with children. Women with hGDM reported worse self-rated health than women without hGDM. In unadjusted and multivariate adjusted comparisons, there were no significant differences in levels of physical activity, fruit and vegetable consumption, or smoking among women with and without hGDM. However, women with hGDM who lived with children were significantly less likely to meet fruit and vegetable consumption guidelines (odds ratio 0.78 [95% CI 0.63-0.97]; P < 0.05) and more likely to smoke (1.21 [1.01-1.47]; P < 0.05) than their counterparts without hGDM.Despite their elevated risk for future diabetes, women with hGDM who lived with children were less likely to meet fruit and vegetable consumption guidelines and more likely to smoke than women with children who did not have hGDM.
Hepatic STAMP2 alleviates high fat diet-induced hepatic steatosis and insulin resistance
Authors: Hye Y. Kim, So Y. Park, Mi H. Lee, Jee H. Rho, Yoo J. Oh, Hye U. Jung, Seung H. Yoo, Na Y. Jeong, Hye J. Lee, SungHwan Suh, Su Y. Seo, JaeHun Cheong, Jin S. Jeong, Young H. Yoo
Journal: Journal of Hepatology (2015)
Treatment of Injuries of the Hands and Fingers
Authors: J. H. Houghton
Journal: BMJ (1857)

III. TRAUMATIC TETANUS.A case of tetanus occurred here a short time since, in which the disease presented the peculiarity of having followed a mere blow on the nose.It terminated fatally in a fortnight with persistent trismus, but only one attack of general spasms.The treatment was by musk and opium.IV. SINGULAR ACCIDENTS.