tbuckley/cabot-search huggingface dataset:
Assessment of Reactivities of Natural Antibodies to Endogenous RNA Tumor Virus Envelope Antigens and Virus-induced Cell Surface Antigens
Authors: Hanna Mg, Ihle Jn, Batzing Bl, Tennant Tw, Schenley Ck
Journal: Cancer Research (1975)

Summary  The autogenous humoral immune response of mice to their endogenous leukemia virus (MuLV) has been examined with respect to the reactivities of natural antibodies to MuLV envelope antigens and virus-induced cell surface antigens. The natural reactivity of MuLV envelope antigens was evaluated by means of a radioimmune precipitation assay of intact and disrupted virus, as well as by virus neutralization tests. The specificity of natural antibody for MuLV envelope antigens was determined by immunoelectron microscopy and radioimmune precipitation. Antibody reactivity to virus-induced cell-surface antigens was evaluated by immunoelectron microscopy and a complement-dependent cytotoxicity test. The strains of mice selected for study were C57BL/6, C3H/Anf, and the C57BL/6 × C3H/Anf F 1  hybrid. Although there were quantitative differences in the antibody levels among these various strains, the naturally recognized antigenic determinants of the virus were consistent,  i.e., gp68, gp43 , and  p15 . High levels of neutralizing antibody against the xenotropic BALB:virus-2 were detected in these various normal sera with the focus reduction assay; however, only marginal levels of neutralizing activity against Moloney leukemia virus were detected with the XC virus assay. No anticellular antibody could be detected in these normal sera with the complement-dependent cytotoxicity assay.
Regulators of G-Protein signaling RGS10 and RGS17 regulate chemoresistance in ovarian cancer cells
Authors: Shelley B Hooks, Phillip Callihan, Molly K Altman, Jillian H Hurst, Mourad W Ali, Mandi M Murph
Journal: Molecular Cancer (2010)

A critical therapeutic challenge in epithelial ovarian carcinoma is the development of chemoresistance among tumor cells following exposure to first line chemotherapeutics. The molecular and genetic changes that drive the development of chemoresistance are unknown, and this lack of mechanistic insight is a major obstacle in preventing and predicting the occurrence of refractory disease. We have recently shown that Regulators of G-protein Signaling (RGS) proteins negatively regulate signaling by lysophosphatidic acid (LPA), a growth factor elevated in malignant ascites fluid that triggers oncogenic growth and survival signaling in ovarian cancer cells. The goal of this study was to determine the role of RGS protein expression in ovarian cancer chemoresistance. In this study, we find that RGS2, RGS5, RGS10 and RGS17 transcripts are expressed at significantly lower levels in cells resistant to chemotherapy compared with parental, chemo-sensitive cells in gene expression datasets of multiple models of chemoresistance. Further, exposure of SKOV-3 cells to cytotoxic chemotherapy causes acute, persistent downregulation of RGS10 and RGS17 transcript expression. Direct inhibition of RGS10 or RGS17 expression using siRNA knock-down significantly reduces chemotherapy-induced cell toxicity. The effects of cisplatin, vincristine, and docetaxel are inhibited following RGS10 and RGS17 knock-down in cell viability assays and phosphatidyl serine externalization assays in SKOV-3 cells and MDR-HeyA8 cells. We further show that AKT activation is higher following RGS10 knock-down and RGS 10 and RGS17 overexpression blocked LPA mediated activation of AKT, suggesting that RGS proteins may blunt AKT survival pathways. Taken together, our data suggest that chemotherapy exposure triggers loss of RGS10 and RGS17 expression in ovarian cancer cells, and that loss of expression contributes to the development of chemoresistance, possibly through amplification of endogenous AKT signals. Our results establish RGS10 and RGS17 as novel regulators of cell survival and chemoresistance in ovarian cancer cells and suggest that their reduced expression may be diagnostic of chemoresistance.
Transmission of HIV-1 and HLA-B allele-sharing within serodiscordant heterosexual Zambian couples
Authors: M Tevfik Dorak, Jianming Tang, Ana Penman-Aguilar, Andrew O Westfall, Isaac Zulu, Elena S Lobashevsky, Nzali G Kancheya, Margaret M Schaen, Susan A Allen, Richard A Kaslow
Journal: The Lancet (2004)
Fibrinogen mediates platelet-polymorphonuclear leukocyte cooperation during immune-complex glomerulonephritis in rats.
Authors: X Wu, M H Helfrich, M A Horton, L P Feigen, J B Lefkowith
Journal: Journal of Clinical Investigation (1994)

The metabolic and functional alterations which occur during the acute phase of nephrotoxic nephritis (NTN) in rats, a model of immune-mediated glomerulonephritis, result from a cooperative interaction between PMNs and platelets (PLTs). In consequence, we hypothesized that fibrinogen (Fg) might play a critical role in this process and, accordingly, we found that defibrination of animals decreased both the acute phase proteinuria in NTN (approximately 70%) as well as the influx of PLTs and PMNs into the glomerulus (approximately 40-50%). In contrast, blockade of the PLT Fg receptor, alpha IIb beta 3, with the RGD peptidomimetic SC-49992 decreased proteinuria (approximately 90%) without substantially altering the influx of PMNs or PLTs. Immunocytochemistry showed a marked increase in beta 3 integrin expression in inflamed glomeruli which was prevented either by PMN or PLT depletion before disease induction. FACS and immunocytochemical analysis of glomerular cell dissociates demonstrated that beta 3 integrin expression was predominantly on intraglomerular PLTs. In vitro, activated PLTs stimulated the PMN respiratory burst, an interaction which could be inhibited by Fg receptor blockade. In sum, acute NTN is accompanied by a marked increase in glomerular beta 3 integrin expression predominantly due to the influx of PLTs which localize to the glomerulus in a PMN-dependent fashion. Fg appears to serve a major role as a coactivating stimulus for PLT-PMNs in situ via alpha IIb beta 3, potentially mediating the PMN respiratory burst which contributes to proteinuria. Fg may also play a subsidiary role in PMN/PLT comigration.
MicroRNAs involvement in fludarabine refractory chronic lymphocytic leukemia
Authors: Manuela Ferracin, Barbara Zagatti, Lara Rizzotto, Francesco Cavazzini, Angelo Veronese, Maria Ciccone, Elena Saccenti, Laura Lupini, Andrea Grilli, Cristiano De Angeli, Massimo Negrini, Antonio Cuneo
Journal: Molecular Cancer (2010)

Abstract Background Fludarabine, is one of the most active single agents in the treatment of chronic lymphocytic leukemia (CLL). Over time, however, virtually all CLL patients become fludarabine-refractory. To elucidate whether microRNAs are involved in the development of fludarabine resistance, we analyzed the expression of 723 human miRNAs before and 5-days after fludarabine mono-therapy in 17 CLL patients which were classified as responder or refractory to fludarabine treatment based on NCI criteria. Results By comparing the expression profiles of these two groups of patients, we identified a microRNA signature able to distinguish refractory from sensitive CLLs. The expression of some microRNAs was also able to predict fludarabine resistance of 12 independent CLL patients. Among the identified microRNAs, miR-148a, miR-222 and miR-21 exhibited a significantly higher expression in non-responder patients either before and after fludarabine treatment. After performing messenger RNA expression profile of the same patients, the activation of p53-responsive genes was detected in fludarabine responsive cases only, therefore suggesting a possible mechanism linked to microRNA deregulation in non-responder patients. Importantly, inhibition of miR-21 and miR-222 by anti-miRNA oligonucleotides induced a significant increase in caspase activity in fludarabine-treated p53-mutant MEG-01 cells, suggesting that miR-21 and miR-222 up-regulation may be involved in the establishment of fludarabine resistance. Conclusions This is the first report that reveals the existence of a microRNA profile that differentiate refractory and sensitive CLLs, either before and after fludarabine mono-therapy. A p53 dysfunctional pathway emerged in refractory CLLs and could contribute in explaining the observed miRNA profile. Moreover, this work indicates that specific microRNAs can be used to predict fludarabine resistance and may potentially be used as therapeutic targets, therefore establishing an important starting point for future studies.
Variants in the Glutamate-Cysteine-Ligase Gene Are Associated with Cystic Fibrosis Lung Disease
Authors: Edward F. McKone, Jing Shao, Daisy D. Frangolias, Cassie L. Keener, Cynthia A. Shephard, Federico M. Farin, Mark R. Tonelli, Peter D. Pare, Andrew J. Sandford, Moira L. Aitken, Terrance J. Kavanagh
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Background: Chronic progressive lung disease is the most serious complication of cystic fibrosis (CF). Glutathione plays an important role in the protection of the CF lung against oxidant-induced lung injury.Objectives: We hypothesized that a polymorphism in a novel candidate gene that regulates glutathione synthesis might influence CF lung disease.Methods: In a cross-sectional study, subjects were recruited from CF clinics in Seattle and multiple centers in Canada. We tested for an association between CF lung disease and a functional polymorphism in the glutamate-cysteine ligase catalytic subunit (GCLC) gene. Multiple linear regression was used to test for association between polymorphisms of GCLC and severity of CF lung disease while adjusting for age, Pseudomonas aeruginosa infection, and cystic fibrosis transmembrane conductance regulator (CFTR) genotype. Analysis was repeated for patients with CF stratified by CFTR genotype.Measurements and Main Results: A total of 440 subjects with CF participated in the study (51% male; mean [± SD] age, 26 ± 11 yr; mean FEV1, 62 ± 28% predicted). In the total population, there was a trend toward an association between GCLC genotypes and CF lung disease (linear regression coefficient [SEM], 1.68 [1.0]; p = 0.097). In the stratified analysis, there was a highly significant association between GCLC genotype and CF lung function in subjects with a milder CFTR genotype (linear regression coefficient [SEM], 5.5 (1.7); p = 0.001).Conclusions: In patients with CF with a milder CFTR genotype, there is a strong association between functional polymorphisms of the GCLC gene and CF lung disease severity.
“Catastrophic” pathways to smoking cessation: findings from national survey
Authors: Robert West, Taj Sohal
Journal: BMJ (2006)

<h3>Abstract</h3> <b>Objective</b> To assess the extent to which the prevailing model of smoking cessation (that smokers typically prepare their attempts to stop smoking in advance and that doing so increases their chances of success) is correct. <b>Design</b> Cross sectional household survey. <b>Setting</b> England. <b>Participants</b> 918 smokers who reported having made at least one quit attempt and 996 ex-smokers aged 16 and over. <b>Main outcome measures</b> Whether the most recent quit attempt was planned in advance and whether quit attempts made at least six months before resulted in at least six months9 abstinence. <b>Results</b> 48.6% of smokers reported that their most recent quit attempt was put into effect immediately the decision to quit was made. Unplanned quit attempts were more likely to succeed for at least six months: among respondents who had made a quit attempt between six months and five years previously the odds of success were 2.6 times higher (95% confidence interval 1.9 to 3.6) in unplanned attempts than in planned attempts; in quit attempts made 6-12 months previously the corresponding figure was 2.5 (1.4 to 4.7). The differences remained after controlling for age, sex, and socioeconomic group. <b>Conclusions</b> A model of the process of change based on "catastrophe theory" is proposed, in which smokers have varying levels of motivational "tension" to stop and then "triggers" in the environment result in a switch in motivational state. If that switch involves immediate renunciation of cigarettes, this can signal a more complete transformation than if it involves a plan to quit at some future point.
Predictive value of interferon-γ release assays for incident active tuberculosis: a systematic review and meta-analysis
Authors: Molebogeng X Rangaka, Katalin A Wilkinson, Judith R Glynn, Daphne Ling, Dick Menzies, Judith Mwansa-Kambafwile, Katherine Fielding, Robert J Wilkinson, Madhukar Pai
Journal: The Lancet Infectious Diseases (2011)

We aimed to assess whether interferon-γ release assays (IGRAs) can predict the development of active tuberculosis and whether the predictive ability of these tests is better than that of the tuberculin skin test (TST).
Mesenchymal Stem Cells and Their Potential as Cardiac Therapeutics
Authors: Mark F. Pittenger, Bradley J. Martin
Journal: Circulation Research (2004)

Mesenchymal stem cells (MSCs) represent a stem cell population present in adult tissues that can be isolated, expanded in culture, and characterized in vitro and in vivo. MSCs differentiate readily into chondrocytes, adipocytes, osteocytes, and they can support hematopoietic stem cells or embryonic stem cells in culture. Evidence suggests MSCs can also express phenotypic characteristics of endothelial, neural, smooth muscle, skeletal myoblasts, and cardiac myocyte cells. When introduced into the infarcted heart, MSCs prevent deleterious remodeling and improve recovery, although further understanding of MSC differentiation in the cardiac scar tissue is still needed. MSCs have been injected directly into the infarct, or they have been administered intravenously and seen to home to the site of injury. Examination of the interaction of allogeneic MSCs with cells of the immune system indicates little rejection by T cells. Persistence of allogeneic MSCs in vivo suggests their potential "off the shelf" therapeutic use for multiple recipients. Clinical use of cultured human MSCs (hMSCs) has begun for cancer patients, and recipients have received autologous or allogeneic MSCs. Research continues to support the desirable traits of MSCs for development of cellular therapeutics for many tissues, including the cardiovascular system. In summary, hMSCs isolated from adult bone marrow provide an excellent model for development of stem cell therapeutics, and their potential use in the cardiovascular system is currently under investigation in the laboratory and clinical settings.
Abstract 4263: Identifying somatic mutation hotspots across protein family alignments
Authors: Marcin Imielinski, Charles Du, Matthew Meyerson
Journal: Cancer Research (2014)

Abstract In cancer, somatic driver mutations often target “hotspots” of paralogous residues across evolutionarily related members of a single protein family. These hotspots usually confer a dominant oncogenic function, such as constitutive catalytic activity or binding. These hotspots generally represent the most “druggable” genetic alterations. Examples of protein families targeted in such a manner include the Ras and receptor Tyrosine Kinase family. Protein family hotspots are not directly assessed by standard computational approaches for statistically nominating genes under positive somatic selection, such as MutSig, InVex, or MuSic. These methods only assess single genes for statistical enrichment of total mutation burden or the presence of mutation hotspots. As a result, such approaches are only powered to detect protein family hotspots in cases where each (or at least one) protein family member is very frequently mutated (e.g. KRAS, NRAS, HRAS). They are not powered to detect hotspots in highly functionally redundant families, of which each member may be only mutated in &amp;lt;&amp;lt;1% of a tumor type. To directly identify such protein-family hotspots, we have developed a computational framework, MutPfam. This framework superimposes mutation data onto Pfam (http://pfam.sanger.ac.uk/) (protein family and subfamily multiple sequence alignments and identifies statistically significant hotspots. We demonstate our method on protein families involved in the catalysis of small-molecular catabolism using the TCGA Pan-Cancer dataset (https://tcga-data.nci.nih.gov/) comprising somatic mutation calls for 4608 whole-exome sequenced patients and 21 tumor types. As we demonstrate, our framework enables the de novo discovery of mutation hotspots across protein families. Though developed for somatic mutation analysis, this framework could also be applied to the analysis of inherited mutations. Computational issues meriting future investigation include (1) alternate definitions of protein alignments and sub-families (e.g. involving three dimensional structure, biophysical constraints) (2) improved statistical modeling of the local background mutation rate (incorporating local genomic covariates that mediate heterogeneity) (3) incorporation of variant functional impact scores for missense variants. Citation Format: Marcin Imielinski, Charles Du, Matthew Meyerson. Identifying somatic mutation hotspots across protein family alignments. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4263. doi:10.1158/1538-7445.AM2014-4263
The Immunobiology of T Cells with Invariant gammadelta Antigen Receptors
Authors: J P Allison, W L Havran
Journal: Annual Review of Immunology (1991)

T cells bearing specific gamma delta TCR are the major lymphoid population in certain epithelial tissues. There are striking differences between these and peripheral T cells. The epithelial gamma delta T cells exhibit highly restricted V gene use, preferential pairing of TCR chains, and lack of diversity at the junctions creating populations of cells with virtually identical TCR in particular epithelia. Generation of certain epithelial gamma delta populations appears to be restricted to a discrete stage early in development. The restricted localization and expression of invariant antigen receptors may equip the epithelial gamma delta T cells to perform specialized functions which differ from those of circulating alpha beta and gamma delta TCR+ cells. This review provides a summary of the characterization of gamma delta T cells found in epithelial tissues and speculates on the in vivo role of these cells.
Identification of Novel Human CTL Epitopes and Their Agonist Epitopes of Mesothelin
Authors: Junko Yokokawa, Claudia Palena, Philip Arlen, Raffit Hassan, Mitchell Ho, Ira Pastan, Jeffrey Schlom, Kwong Y. Tsang
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Mesothelin is overexpressed in many pancreatic and ovarian cancers, mesotheliomas, and other tumor types. Clinical trials are ongoing using immunotoxins to target mesothelin, and patients immunized with allogeneic pancreatic tumor cell lines have shown immune responses to previously defined mesothelin epitopes. The purpose of this study was to define novel mesothelin CTL epitopes and, more importantly, agonist epitopes that would more efficiently activate human T cells to more efficiently lyse human tumors. Experimental Design and Results: Two novel mesothelin HLA-A2 epitopes were defined. T-cell lines generated from one of these epitopes were shown to lyse pancreatic and ovarian tumor cells. Several agonist epitopes were defined and were shown to (a) have higher affinity and avidity for HLA-A2, (b) activate mesothelin-specific T cells from normal individuals or cancer patients to a greater degree than the native epitope in terms of induction of higher levels of IFN-γ and the chemokine lymphotactin, and (c) lyse several mesothelin-expressing tumor types in a MHC-restricted manner more effectively than T cells generated using the native peptide. External beam radiation of tumor cells at nontoxic levels was shown to enhance the expression of mesothelin and other accessory molecules, resulting in a modest but statistically significant increase in tumor cell lysis by mesothelin-specific T cells. Conclusions: The identification of novel CTL agonist epitopes supports and extends observations that mesothelin is a potential target for immunotherapy of pancreatic and ovarian cancers, as well as mesotheliomas.
CXCL1 induced by prostaglandin E2 promotes angiogenesis in colorectal cancer
Authors: Dingzhi Wang, Haibin Wang, Joanne Brown, Takiko Daikoku, Wei Ning, Qiong Shi, Ann Richmond, Robert Strieter, Sudhansu K. Dey, Raymond N. DuBois
Journal: The Journal of Experimental Medicine (2006)

Chronic inflammation is a well-known risk factor for cancer. Proinflammatory mediators such as prostaglandin E2 (PGE2) promote colorectal tumor growth by stimulating angiogenesis, cell invasion, and cell growth, and inhibiting apoptosis. Molecules that regulate tumor-associated angiogenesis provide promising therapeutic targets for treatment of colorectal cancer (CRC) as indicated by the recent development of the novel anti-angiogenic agent bevacizumab (Avastin). However, use of this drug only prolongs survival by several months, highlighting the importance of finding more effective treatment regimens. We report here that PGE2 induces expression of CXCL1 (growth-regulated oncogene α), a pro-angiogenic chemokine, in human CRC cells. More importantly, CXCL1 released from carcinoma cells induces microvascular endothelial cell migration and tube formation in vitro. Furthermore, PGE2 promotes tumor growth in vivo by induction of CXCL1 expression, which results in increased tumor microvessel formation. These results have potential clinical significance because we found that CXCL1 expression correlates with PGE2 levels in human CRCs. Collectively, our findings show for the first time that CXCL1 is regulated by PGE2 and indicate that CXCL1 inhibitors should be evaluated further as potential anti-angiogenic agents for treatment of CRC.
The chronic effects of concussion on gait
Authors: D Martini, M Sabin, S Depesa, E Leal, T Negrete, J Sosnoff, S Broglio
Journal: British Journal of Sports Medicine (2011)

Background Concussion has a clear effect on motor control with acute alterations in gait documented up to 30 days post injury. These changes include increased stance time and decreased velocity. It is unknown if alterations persist beyond one month post-injury. Objective To evaluate the chronic effects of concussion on gait in individuals with and without an injury history. Design A cross-sectional study. Setting A laboratory setting. Participants 68 individuals ages 18–35 years (37 males, 20.8±1.9 years, 171.0±9.8 cm, 74.5±14.8 kg) were divided in two groups based on self-report of previous concussion history (zero (n=40) and one or more (n=28, 2.0±1.4 previous concussions, 6.3±4.1 years prior)). Interventions All participants completed a gait assessment during four conditions: unobstructed (Con1) and obstructed (Con3) walking without a cognitive task; and unobstructed (Con2) and obstructed (Con4) walking with a cognitive task. The cognitive task was a modified Brooks Spatial Task, requiring the recall of digits one through eight in a four-by-four matrix. Obstructed walking involved stepping over two 29.5 cm blocks that divided the walkway into thirds. Main outcome measures Gait velocity and percent time in single limb stance (SLS%) and double limb stance (DLS%) were evaluated with multiple mixed model analyses of variance (group (2) x condition (4)) with repeated measures on condition. Results Previously concussed individuals walked slower in during Con1 (p=0.02). Significant group effects were seen for SLS% and DLS%. The concussed group demonstrated significantly shorter SLS% during Con3 (p&lt;0.000) and Con4 (p=0.001). Similarly the concussed group had significantly longer DLS% during Con1 (p=0.003), Con3 (p=0.001), and Con4 (p=0.001). Conclusion Our findings indicate that individuals reporting a previous history of concussion adopt a slower and more stable/conservative gait strategy than our non-concussed controls.