tbuckley/cabot-search huggingface dataset:
Small Artery Remodeling Depends on Tissue-Type Transglutaminase
Authors: Erik N.T.P. Bakker, Carsten L. Buus, Jos A.E. Spaan, Jop Perree, Anuradha Ganga, Titia M. Rolf, Oana Sorop, Linda H. Bramsen, Michael J. Mulvany, Ed VanBavel
Journal: Circulation Research (2004)

Remodeling of small arteries is essential in the long-term regulation of blood pressure and blood flow to specific organs or tissues. A large part of the change in vessel diameter may occur through non-growth-related reorganization of vessel wall components. The hypothesis was tested that tissue-type transglutaminase (tTG), a cross-linking enzyme, contributes to the inward remodeling of small arteries. The in vivo inward remodeling of rat mesenteric arteries, induced by low blood flow, was attenuated by inhibition of tTG. Rat skeletal muscle arteries expressed tTG, as identified by Western blot and immunostaining. In vitro, activation of these arteries with endothelin-1 resulted in inward remodeling, which was blocked by tTG inhibitors. Small arteries obtained from rats and pigs both showed inward remodeling after exposure to exogenous transglutaminase, which was inhibited by addition of a nitric oxide donor. Enhanced expression of tTG, induced by retinoic acid, increased inward remodeling of porcine coronary arteries kept in organ culture for 3 days. The activity of tTG was dependent on pressure. Inhibition of tTG reversed remodeling, causing a substantial increase in vessel diameter. In a collagen gel contraction assay, tTG determined the compaction of collagen by smooth muscle cells. Collectively, these data show that small artery remodeling associated with chronic vasoconstriction depends on tissue-type transglutaminase. This mechanism may reveal a novel therapeutic target for pathologies associated with inward remodeling of the resistance arteries.
Autologous or Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Chemotherapy-Sensitive Mantle-Cell Lymphoma: Analysis of Transplantation Timing and Modality
Authors: Timothy S. Fenske, Mei-Jie Zhang, Jeanette Carreras, Ernesto Ayala, Linda J. Burns, Amanda Cashen, Luciano J. Costa, César O. Freytes, Robert P. Gale, Mehdi Hamadani, Leona A. Holmberg, David J. Inwards, Hillard M. Lazarus, Richard T. Maziarz, Reinhold Munker, Miguel-Angel Perales, David A. Rizzieri, Harry C. Schouten, Sonali M. Smith, Edmund K. Waller, Baldeep M. Wirk, Ginna G. Laport, David G. Maloney, Silvia Montoto, Parameswaran N. Hari
Journal: Journal of Clinical Oncology (2013)

To examine the outcomes of patients with chemotherapy-sensitive mantle-cell lymphoma (MCL) following a first hematopoietic stem-cell transplantation (HCT), comparing outcomes with autologous (auto) versus reduced-intensity conditioning allogeneic (RIC allo) HCT and with transplantation applied at different times in the disease course.In all, 519 patients who received transplantations between 1996 and 2007 and were reported to the Center for International Blood and Marrow Transplant Research were analyzed. The early transplantation cohort was defined as those patients in first partial or complete remission with no more than two lines of chemotherapy. The late transplantation cohort was defined as all the remaining patients.Auto-HCT and RIC allo-HCT resulted in similar overall survival from transplantation for both the early (at 5 years: 61% auto-HCT v 62% RIC allo-HCT; P = .951) and late cohorts (at 5 years: 44% auto-HCT v 31% RIC allo-HCT; P = .202). In both early and late transplantation cohorts, progression/relapse was lower and nonrelapse mortality was higher in the allo-HCT group. Overall survival and progression-free survival were highest in patients who underwent auto-HCT in first complete response. Multivariate analysis of survival from diagnosis identified a survival benefit favoring early HCT for both auto-HCT and RIC allo-HCT.For patients with chemotherapy-sensitive MCL, the optimal timing for HCT is early in the disease course. Outcomes are particularly favorable for patients undergoing auto-HCT in first complete remission. For those unable to achieve complete remission after two lines of chemotherapy or those with relapsed disease, either auto-HCT or RIC allo-HCT may be effective, although the chance for long-term remission and survival is lower.
Influence of patient characteristics, socioeconomic factors, geography, and systemic risk on the use of breast-sparing treatment in women enrolled in adjuvant breast cancer studies: an analysis of two intergroup trials.
Authors: K S Albain, S R Green, A S Lichter, L F Hutchins, W C Wood, I C Henderson, J N Ingle, J O'Sullivan, C K Osborne, S Martino
Journal: Journal of Clinical Oncology (1996)

PURPOSE To investigate the frequency of breast-sparing treatment among breast cancer patients subsequently enrolled in national cooperative group studies of adjuvant chemotherapy. PATIENTS AND METHODS A data base was formed of 5,172 patients randomized onto two intergroup trials. Lumpectomy rates were analyzed within study-defined risk strata and across geographic regions. Significant predictors of lower lumpectomy usage were determined in multivariate analyses with variables that described patient and disease characteristics, systemic risk strata, geographic region, and socioeconomic indicators based on zip code of residence. RESULTS Breast-conservation rates were 30% in the node-negative and 15% in the node-positive trials, with a wide geographic variation within each study (range, 14% to 49% and 9% to 31%, respectively). Lumpectomy use declined with increasing tumor size and did not exceed 40% even for tumors &lt; or = 1 cm with negative nodes. With increasing risk of systemic relapse, frequency of lumpectomy declined (rates for five strata in order of increasing systemic risk: 41%, 33%, 24%, 18%, and 11%), even though these strata were not known at the time of the surgical decision. A logistic model confirmed the joint significance of geographic region and systemic risk. An exploratory model that adjusted for all important variables identified the following significant predictors of lower lumpectomy use: positive nodes; many positive nodes, increased systemic risk; tumor size &gt; or = 2.0 cm; older age; South, Central or non-New England regions; and either lack of college degree or lower income levels. CONCLUSION Breast-sparing therapy was used in the minority of women subsequently accrued to two national adjuvant breast cancer studies, even though this cohort and their referring surgeons represented a select population. Although multiple concrete factors were independent predictors of lower lumpectomy rates, prospective research is needed into how patients and their physicians approach the mastectomy versus lumpectomy decision.
Regulation of elastase and plasminogen activator secretion in resident and inflammatory macrophages by receptors for the Fc domain of immunoglobulin G.
Authors: R Takemura, Z Werb
Journal: The Journal of Experimental Medicine (1984)

We have determined that the interaction of IgG-coated erythrocytes (EIgG) and complement-coated erythrocytes (EIgMC) with macrophage Fc and complement receptors, respectively, modulates the secretion of the neutral proteinases, elastase, and plasminogen activator. EIgG binding and ingestion stimulated secretion of elastase and plasminogen activator less than or equal to 6-fold and 20-fold, respectively, over the 3 d following treatment. Stimulation was dependent on the IgG titer bound to each erythrocyte and was detectable at greater than 6.2 X 10(3) molecules IgG/ erythrocyte (total 0.99 nM IgG in the culture). Cytochalasin B did not inhibit stimulation, indicating that the ingestion of ligands was not necessary. Binding of EIgG to the three subclass-specific Fc receptors (IgG2a, IgG2b/IgG1, IgG3) was effective. Stimulation of elastase secretion required continued exposure of ligands to cells for up to 24 h, whereas production of plasminogen activator, which has plasma membrane-bound forms as well as secreted forms, was stimulated by exposure for 2 h. The stimulated production of elastase and plasminogen activator by triggering Fc receptors was seen only when the initial secretion rates were low. Periodate- or thioglycollate-elicited macrophages, which have high rates of proteinase secretion, were not stimulated further. EIgMC, which are bound but not ingested by resident macrophages, stimulated elastase secretion transiently, and the rate of secretion returned to the control level by 24 h. Therefore, the mode of stimulation of neutral proteinase secretion by complement receptor differed from that of Fc receptor; stimulation by complement receptor possibly involves a limited release of enzyme from intracellular stores, rather than stimulating accelerated synthesis of enzyme. Erythrocytes coated with both complement and IgG showed both the transient increase in elastase typical of complement-mediated secretion and the sustained increase typical of Fc receptor-mediated secretion. These results suggest that macrophage Fc and complement receptors regulate secretion of proteinases by receptor-specific mechanisms.
Dimensional Approach to Delusions: Comparison Across Types and Diagnoses
Authors: Paul S. Appelbaum, Pamela Clark Robbins, Loren H. Roth
Journal: American Journal of Psychiatry (1999)

A dimensional approach to the characterization of delusions was used to examine the use of non-content-related descriptors of delusions in revealing differences across diagnostic categories and delusion types.Interviews with 1,136 acutely hospitalized psychiatric patients identified subjects as definitely or possibly delusional on the basis of screening questions derived from the Diagnostic Interview Schedule. Subjects with delusions were given the MacArthur-Maudsley Delusions Assessment Schedule, which generates scores on six dimensions of delusions. Delusions were classified by type, and diagnoses were assigned by using the DSM-III-R checklist.A total of 328 subjects (29%) were rated as definitely or possibly delusional. Their ratings on dimensions of the MacArthur-Maudsley Delusions Assessment Schedule were significantly but modestly intercorrelated. Subjects with schizophrenia generally had more intense delusions than those in other diagnostic categories. Grandiose and religious delusions were held with the greatest conviction, whereas persecutory delusions were marked by strong negative affect and a propensity to act. Factor analysis of the dimensions revealed a consistent two factor solution-"intensity and scope" and "affect and action"-regardless of the diagnosis or delusion type.The stability of the dimensional structure of delusions across diagnoses and delusion types suggests that even seemingly diverse delusions are more like than unlike each other; this is consistent with common etiologic mechanisms. The utility of a dimensional approach is indicated, in addition, by the ability to characterize delusions of different types and diagnoses so as to highlight therapeutic and other implications.
Antigen-specific, I-A-restricted suppressor hybridomas with spontaneous cytolytic activity. Functional properties and lack of rearrangement of the T cell receptor beta chain genes.
Authors: C A Blanckmeister, K Yamamoto, M M Davis, G J Hämmerling
Journal: The Journal of Experimental Medicine (1985)

T suppressor (Ts) hybridomas were produced by fusion of the III/4 T cell hybridoma with splenic T cells from CBA mice tolerized with subimmunogenic doses of bovine serum albumin (BSA). Both the Ts hybridoma cells and a suppressor factor (TsF) inhibited in an antigen-specific and I-Ak-restricted fashion the in vitro proliferative response of BSA-immunized lymph node cells. In addition to the suppressive activity, the hybridoma lines displayed spontaneous cytotoxicity against various tumor targets. The isolation of Ts subclones that are suppressive but not cytolytic, as well as the existence of the noncytolytic TsF, indicates that suppression of antigen-specific T cell proliferation is not dependent on cytolytic activity. The Ts hybridomas were I-A restricted, as are many T helper cells. Therefore, a potential similarity with respect to antigen receptor genes was expected. Southern blot analysis with a probe specific for genes encoding the beta chain of the T cell receptor on T helper and T killer cells revealed no rearrangement of the beta genes in the Ts cells. The data imply that neither the antigen receptor on the I-A-restricted Ts cells nor the receptor involved in the cytolytic interaction with tumor targets use the same beta chain constant region as T helper and T killer cells.
Topiramate for Treating Alcohol Dependence&lt;SUBTITLE&gt;A Randomized Controlled Trial&lt;/SUBTITLE&gt;
Authors: Bankole A. Johnson
Journal: JAMA (2007)

ContextHypothetically, topiramate can improve drinking outcomes among alcohol-dependent individuals by reducing alcohol's reinforcing effects through facilitation of γ-aminobutyric acid function and inhibition of glutaminergic pathways in the corticomesolimbic system.ObjectiveTo determine if topiramate is a safe and efficacious treatment for alcohol dependence.Design, Setting, and ParticipantsDouble-blind, randomized, placebo-controlled, 14-week trial of 371 men and women aged 18 to 65 years diagnosed with alcohol dependence, conducted between January 27, 2004, and August 4, 2006, at 17 US sites.InterventionsUp to 300 mg/d of topiramate (n = 183) or placebo (n = 188), along with a weekly compliance enhancement intervention.Main Outcome MeasuresPrimary efficacy variable was self-reported percentage of heavy drinking days. Secondary outcomes included other self-reported drinking measures (percentage of days abstinent and drinks per drinking day) along with the laboratory measure of alcohol consumption (plasma γ-glutamyltransferase).ResultsTreating all dropouts as relapse to baseline, topiramate was more efficacious than placebo at reducing the percentage of heavy drinking days from baseline to week 14 (mean difference, 8.44%; 95% confidence interval, 3.07%-13.80%; P = .002). Prespecified mixed-model analysis also showed that topiramate compared with placebo decreased the percentage of heavy drinking days (mean difference, 16.19%; 95% confidence interval, 10.79%-21.60%; P &lt; .001) and all other drinking outcomes (P &lt; .001 for all comparisons). Adverse events that were more common with topiramate vs placebo, respectively, included paresthesia (50.8% vs 10.6%), taste perversion (23.0% vs 4.8%), anorexia (19.7% vs 6.9%), and difficulty with concentration (14.8% vs 3.2%).ConclusionTopiramate is a promising treatment for alcohol dependence.Trial Registrationclinicaltrials.gov Identifier: NCT00210925
nm23 in ovarian cancer: correlation with clinical outcome and other clinicopathologic and biochemical prognostic parameters.
Authors: G Scambia, G Ferrandina, M Marone, P Benedetti Panici, C Giannitelli, M Piantelli, A Leone, S Mancuso
Journal: Journal of Clinical Oncology (1996)

PURPOSE The aim of the study was to define the prognostic role of the metastasis suppressor gene, nm23, in 106 primary ovarian cancer patients. PATIENTS AND METHODS Northern and Western blotting analysis of nm23-H1 and nm23-H2 expression were performed in a subset of ovarian tumors. Immunohistochemical analysis was performed on formalin-fixed paraffin-embedded specimens from 106 primary ovarian carcinomas by the antihuman nm23 monoclonal antibody. RESULTS Northern and Western blotting analysis demonstrated a direct association between nm23-H1 and nm23-H2 levels. Moreover, an overall concordance of 86.7% between Northern blotting and immunohistochemical data was observed. Sixty-six specimens (68%) showed a positive nm23-H1 immunoreaction. The percentage of nm23-H1 positivity was higher in lymph node-negative (70%) than in lymph node-positive cases (44%) (P = .049). Moreover, the percentage of complete/partial responses to chemotherapy was higher in nm23-H1-positive (69%) than in nm23-H1-negative (44%) patients (P = .03). The percentage of epidermal growth factor receptor (EGFR) positive cases was lower in nm23-H1-positive (44%) than in nm23-H1-negative immunostained (72%) samples (P = .012). Lower ras/p21 levels (median, 1.77 absorbance units) were found in nm23-H1-positive than in nm23-H1-negative samples (median, 2.63 absorbance units) (P = .03). The 6-year progression-free survival (PFS) rate of nm23-H1-positive cases was 50% (95% confidence interval [CI], 33 to 67) versus 12% (95% CI, -2 to 26) for nm23-H1-negative patients (P = .0056). In multivariate analysis, only stage, ascites, and nm23-H1 content retained independent prognostic roles. CONCLUSION The assessment of nm23 content may provide useful information for prognostic characterization of ovarian cancer patients.
Y-Box Binding Protein-1 Induces the Expression of <i>CD44</i> and <i>CD49f</i> Leading to Enhanced Self-Renewal, Mammosphere Growth, and Drug Resistance
Authors: Karen To, Abbas Fotovati, Kristen M. Reipas, Jennifer H. Law, Kaiji Hu, Jing Wang, Arezoo Astanehe, Alastair H. Davies, Lawrence Lee, Anna L. Stratford, Afshin Raouf, Pauline Johnson, Isabelle M. Berquin, Hans-Dieter Royer, Connie J. Eaves, Sandra E. Dunn
Journal: Cancer Research (2010)

Abstract Y-box binding protein-1 (YB-1) is an oncogenic transcription/translation factor expressed in &amp;gt;40% of breast cancers, where it is associated with poor prognosis, disease recurrence, and drug resistance. We questioned whether this may be linked to the ability of YB-1 to induce the expression of genes linked to cancer stem cells such as CD44 and CD49f. Herein, we report that YB-1 binds the CD44 and CD49f promoters to transcriptionally upregulate their expressions. The introduction of wild-type (WT) YB-1 or activated P-YB-1S102 stimulated the production of CD44 and CD49f in MDA-MB-231 and SUM 149 breast cancer cell lines. YB-1–transfected cells also bound to the CD44 ligand hyaluronan more than the control cells. Similarly, YB-1 was induced in immortalized breast epithelial cells and upregulated CD44. Conversely, silencing YB-1 decreased CD44 expression as well as reporter activity in SUM 149 cells. In mice, expression of YB-1 in the mammary gland induces CD44 and CD49f with associated hyperplasia. Further, activated mutant YB-1S102D enhances self-renewal, primary and secondary mammosphere growth, and soft-agar colony growth, which were reversible via loss of CD44 or CD49f. We next addressed the consequence of this system on therapeutic responsiveness. Here, we show that paclitaxel induces P-YB-1S102 expression, nuclear localization of activated YB-1, and CD44 expression. The overexpression of WT YB-1 promotes mammosphere growth in the presence of paclitaxel. Importantly, targeting YB-1 sensitized the CD44High/CD24Low cells to paclitaxel. In conclusion, YB-1 promotes cancer cell growth and drug resistance through its induction of CD44 and CD49f. Cancer Res; 70(7); 2840–51
Gene Cluster Analysis Method Identifies Horizontally Transferred Genes with High Reliability and Indicates that They Provide the Main Mechanism of Operon Gain in 8 Species of γ-Proteobacteria
Authors: Keiichi Homma, Satoshi Fukuchi, Yoji Nakamura, Takashi Gojobori, Ken Nishikawa
Journal: Molecular Biology and Evolution (2006)

The formation mechanism of operons remains unresolved: operons may form by rearrangements within a genome or by acquisition of genes from other species, that is, horizontal gene transfer (HGT). One hindrance to its elucidation is the unavailability of a method to accurately identify HGT, although it is generally considered to occur. It is critically important first to select horizontally transferred (HT) genes reliably and then to determine the extent to which HGT is involved in operon formation. For this purpose, we considered indels in terms of gene clusters instead of individual genes and chose candidates of HT genes in 8 species of Escherichia, Shigella, and Salmonella based on the minimization of indels. To select a benchmark set of positively HT genes against which we can evaluate the candidate set, we devised another procedure using intergenetic alignments. Comparison with the benchmark set demonstrated the absence of a significant number of false positives in the candidate set, showing the high reliability of the method. Analyses of Escherichia coli K-12 operons revealed that although ∼20 operons were probably gained from the last common ancestor of the 8 γ-proteobacteria, deletion of intervening genes accounts for the formation of no operons, whereas horizontal transfer expanded 2 operons and introduced 4 entire operons. Based on these observations and reasoning, we suggest that the main mechanism of operon gain is HGT rather than intragenomic rearrangements. We propose that genes with related essential functions tend to reside in conserved operons, whereas genes in nonconserved operons mostly confer slight advantage to the organisms and frequently undergo horizontal transfer and decay. HT genes constitute at least 5.5% of the genes in the 8 species and approximately 45% of which originate from other γ-proteobacteria. Genes involved in viral functions and mobile and extrachromosomal element functions are HT more often than expected. This finding indicates frequent mediation of HGT by bacteriophages. On the other hand, not only informational genes (those involved in transcription, translation, and related processes) but also operational genes (those involved in housekeeping) are HT less frequently than expected.
Comparison of different dosage nebulised budesonide in COPD exacerbation
Authors: Elif Yilmazel Ucar, Omer Araz, Deniz Ozturk, Metin Akgun, Leyla Saglam, Metin Gorguner
Journal: European Respiratory Journal (2012)

Objective: To compare the efficacy and safety of different dosage nebulised budesonide (NB) in the treatment of acute exacerbations of chronic obstructive pulmonary disease (COPD).

Design: Randomised, double-blind,parallel-group trial.

Patients and interventions: A total of 64 patients who had moderate to severe acute exacerbations of COPD and required hospitalisation were enrolled in the study. The patients were randomized into three groups. Group 1 received systemic (intravenous) prednisolone 40 mg daily (n= 28), group 2 received 4 mg NB daily (n=20), group 3 received 8 mg NB daily (n=18). Airway obstruction [forced vitale capacity (FVC), forced expiratuar volume 1 second (FEV1)] was evaulated at admission and discharged. Arterial partial pressure of oxygen (PaO2), carbon dioxide(PaCO2), pH, and oxygen saturation (SaO2) were evaulated at 24 and 48 hours, and at day 10.

Results: There were no significant differences between groups at baseline. In groups, differences were significant for FVC,FEV1, PaO2, and SaO2 (p=0,000), but not for PaCO2 and pH, in comparison with their baseline values. There were no significant differences between groups for all parameters at all time periods. While blood glucose exhibited an upward trend only group 1 (8 patients), oral monoliazis and hoarseness were observed in group 2 and 3 (5 patient). But the differences were not statistically significant (p=0,69).

Conclusions: Nebulised budesonide is effective and safety in the treatment of COPD exacerbation. There is no significant difference in terms of efficacy and safety between 4 mg and 8 mg nebulised budesonide.