tbuckley/cabot-search huggingface dataset:
Blockade of very late antigen-4 integrin binding to fibronectin with connecting segment-1 peptide reduces accelerated coronary arteriopathy in rabbit cardiac allografts.
Authors: S Molossi, M Elices, T Arrhenius, R Diaz, C Coulber, M Rabinovitch
Journal: Journal of Clinical Investigation (1995)

Graft arteriopathy, a leading cause of cardiac allograft fail- ure, is associated with increased intimal smooth muscle cells, inflammatory cells, and accumulation of extracellular matrix.We hypothesized that cellular fibronectin plays a piv- otal role in the progression of the allograft arteriopathy by directing the transendothelial trafficking of inflammatory cells through interaction of the connecting segment-i (CS1) motif with the very late antigen-4 (VLA-4) integrin, and tested this in vivo using a blocking peptide.Cholesterolfed rabbits underwent heterotopic cardiac transplantation without immunosuppression.The treatment group (n = 7) received a synthetic CS1 peptide (1 mg/kg per d, subcutane- ously), and the controls (n = 7) received an inactive peptide (1 mg/kg per d, subcutaneously).At 7-8 d after trans- plantation, hearts were harvested and sectioned for morpho- metric analysis and immunohistochemical studies.We ob- served a > 50% decrease in the incidence (P < 0.001) and severity (P < 0.001) of donor coronary artery intimal thick- ening in the CS1-treated compared with the control group.These findings correlated with reduced infiltration of T cells (P < 0.05), a trend toward decreased expression of adhesion molecules (P < 0.06), and less accumulation of fibronectin (P < 0.03).Our data suggest that the VLA-4-fibronectin interaction is critical to the progression of the allograft arte- riopathy by perpetuating the immune-inflammatory response in the vessel wall.(
Knee joint function and the energy cost of level walking in soccer players.
Authors: L J Tofts, C S Stanley, T G Barnett, J G Logan
Journal: British Journal of Sports Medicine (1998)

To study self reported knee joint problems and the energy costs of level walking in soccer players.Seventeen soccer players and twelve control subjects between 18 and 27 years old participated in the study. A questionnaire was used to establish the amount of participation in soccer and the frequency and extent of knee injuries. The physiological cost index (PCI) was used as an index of the energy costs of level walking.Soccer players had a significantly higher PCI than control subjects (p = 0.0001). Control subjects had a mean (SD) PCI of 0.23 (0.06) beats/m and soccer players had a mean PCI of 0.42 (0.12) beats/m. Some 82% of the soccer players experienced knee joint problems, whereas only 25% of the control group had problems.This study shows that college soccer players have a higher rate of self reported knee problems and higher energy costs of level walking than people who do not play soccer.
Induction of microhematuria by an IgA isotype switch variant of a monoclonal anti-Thy-1.1 antibody in the rat
Authors: Mieneke G.A. van Dixhoorn, Arko Gorter, Toshinobu Sato, Annemieke M. van der Wal, Jaap D.H. van Eendenburg, Jan Rozing, Mohamed R. Daha, Emile de Heer
Journal: Kidney International (1996)
Cardiomyopathies and sudden cardiac death caused by RyR2 mutations: Are the channels the beginning and the end?☆
Authors: I JONA, P NANASI
Journal: Cardiovascular Research (2006)

See article by Milting et al.  [3]  (pages 496–505) in this issue. 

A basic goal of medicine is to cure diseases. Acquired diseases may sometimes be prevented by various methods of exercising, by the “healthy way” of living. Inherited diseases are different; their effective treatment (provided that there is any) requires the recognition of the disease in a sufficiently early stage of life. One – and probably the most promising – way to do so is to establish the link between disorders and genetic alterations. This can be achieved by mapping the mutations corresponding to a given disease, and in the past decade a large number of mutations affecting molecules involved in calcium handling of skeletal and cardiac muscles, including the ryanodine receptor, have been identified [1]. Regarding the cardiac sarcoplasmic reticulum (SR) calcium release channel (RyR2), one of the first published mutations was presented in the pioneering work of Laitinen et al. [2]. In that study, three different RyR2 mutations (P2328S, Q4201R, and V4653F) were associated with familiar polymorphic ventricular tachycardia (FPVT), and each of them was shown to fully co-segregate with the characteristic arrhythmic phenotype. The importance of this kind of knowledge cannot be overestimated, since it makes it possible to recognize a hidden inherited cardiac disorder that exhibits no visible sign of myocardial damage while threatening with close to 30% mortality due to sudden cardiac death (SCD) upon heavy exercise.

The article by Milting et al. in this issue of Cardiovascular Research reports two new single nucleotide polymorphisms (G1885E and G1886S) … 

* Corresponding author. Tel.: +36 52 416634; fax: +36 52 432289. Email address: nanasi{at}phys.dote.hu
Differences in Airway Inflammation in Patients with Fixed Airflow Obstruction Due to Asthma or Chronic Obstructive Pulmonary Disease
Authors: Leonardo M. Fabbri, Micaela Romagnoli, Lorenzo Corbetta, Gianluca Casoni, Kamelija Busljetic, Graziella Turato, Guido Ligabue, Adalberto Ciaccia, Marina Saetta, Alberto Papi
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

To determine whether patients with fixed airflow obstruction have distinct pathologic and functional characteristics depending on a history of either asthma or chronic obstructive pulmonary disease (COPD), we characterized 46 consecutive outpatients presenting with fixed airflow obstruction by clinical history, pulmonary function tests, exhaled nitric oxide, sputum analysis, bronchoalveolar lavage, bronchial biopsy, and high-resolution computed tomography chest scans. Subjects with a history of COPD (n = 27) and subjects with a history of asthma (n = 19) had a similar degree of fixed airflow obstruction (FEV1: 56 ± 2 versus 56 ± 3% predicted) and airway hyperresponsiveness (PC20FEV1: 2.81 [3.1] versus 1.17 [3.3]). Subjects with a history of asthma had significantly more eosinophils in peripheral blood, sputum, bronchoalveolar lavage, and airway mucosa; fewer neutrophils in sputum and bronchoalveolar lavage fluid; a higher CD4+/CD8+ ratio of T cells infiltrating the airway mucosa; and a thicker reticular layer of the epithelial basement membrane. They also had significantly lower residual volume, higher diffusing capacity, higher exhaled nitric oxide, lower high-resolution computed tomography scan emphysema score, and greater reversibility to bronchodilator and steroids. In conclusion, despite similar fixed airflow obstruction, subjects with a history of asthma have distinct characteristics compared with subjects with a history of COPD and should be properly identified and treated.
Colon Cancer–Specific Cytochrome P450 2W1 Converts Duocarmycin Analogues into Potent Tumor Cytotoxins
Authors: Sandra Travica, Klaus Pors, Paul M. Loadman, Steven D. Shnyder, Inger Johansson, Mohammed N. Alandas, Helen M. Sheldrake, Souren Mkrtchian, Laurence H. Patterson, Magnus Ingelman-Sundberg
Journal: Clinical Cancer Research (2013)

Cytochrome P450 2W1 (CYP2W1) is a monooxygenase detected in 30% of colon cancers, whereas its expression in nontransformed adult tissues is absent, rendering it a tumor-specific drug target for development of novel colon cancer chemotherapy. Previously, we have identified duocarmycin synthetic derivatives as CYP2W1 substrates. In this study, we investigated whether two of these compounds, ICT2705 and ICT2706, could be activated by CYP2W1 into potent antitumor agents.The cytotoxic activity of ICT2705 and ICT2706 in vitro was tested in colon cancer cell lines expressing CYP2W1, and in vivo studies with ICT2706 were conducted on severe combined immunodeficient mice bearing CYP2W1-positive colon cancer xenografts.Cells expressing CYP2W1 suffer rapid loss of viability following treatment with ICT2705 and ICT2706, whereas the CYP2W1-positive human colon cancer xenografts display arrested growth in the mice treated with ICT2706. The specific cytotoxic metabolite generated by CYP2W1 metabolism of ICT2706 was identified in vitro. The cytotoxic events were accompanied by an accumulation of phosphorylated H2A.X histone, indicating DNA damage as a mechanism for cancer cell toxicity. This cytotoxic effect is most likely propagated by a bystander killing mechanism shown in colon cancer cells. Pharmacokinetic analysis of ICT2706 in mice identified higher concentration of the compound in tumor than in plasma, indicating preferential accumulation of drug in the target tissue.Our findings suggest a novel approach for treatment of colon cancer that uses a locoregional activation of systemically inactive prodrug by the tumor-specific activator enzyme CYP2W1.
Single Versus Sequential High-Dose Chemotherapy in Patients With Relapsed or Refractory Germ Cell Tumors: A Prospective Randomized Multicenter Trial of the German Testicular Cancer Study Group
Authors: Anja Lorch, Christian Kollmannsberger, Joerg Thomas Hartmann, Bernd Metzner, Ingo G.H. Schmidt-Wolf, Wolfgang E. Berdel, Florian Weissinger, Jan Schleicher, Gerlinde Egerer, Antje Haas, Rebekka Schirren, Jörg Beyer, Carsten Bokemeyer, Oliver Rick
Journal: Journal of Clinical Oncology (2007)

To compare single versus sequential high-dose chemotherapy (HDCT) as first or subsequent salvage treatment in patients with relapsed or refractory germ cell tumors (GCTs).Between November 1999 and November 2004, 230 patients were planned to be recruited in a prospective, randomized, multicenter trial comparing one cycle of cisplatin 100 mg/m2, etoposide 375 mg/m2, and ifosfamide 6 g/m2 (VIP) plus three cycles of high-dose carboplatin 1,500 mg/m2 and etoposide 1,500 mg/m2 (CE; arm A) versus three cycles of VIP plus one cycle of high-dose carboplatin 2,200 mg/m2, etoposide 1,800 mg/m2, and cyclophosphamide 6,400 mg/m2 (CEC; arm B).The study was stopped prematurely after recruitment of 216 patients as a result of excess treatment-related mortality in arm B. One hundred eleven (51%) of 216 patients were randomly assigned to sequential HDCT, and 105 (47%) of 216 patients were randomly assigned to single HDCT. Five (2%) of 216 patients had to be excluded because of non-GCT histologies at review. With a median follow-up time of 36 months, 109 (52%) of 211 patients were alive, and 91 (43%) of 211 patients were progression free. At 1 year, event-free, progression-free, and overall survival rates were 40%, 53%, and 80%, respectively, in arm A compared with 37%, 49%, and 61%, respectively, in arm B (P > .05 for all comparisons). Treatment-related deaths, mainly as a result of sepsis and cardiac toxicity, were less frequent in arm A (four of 108 patients, 4%) compared with arm B (16 of 103 patients, 16%; P < .01).We found no difference in survival probabilities between single HDCT using CE and sequential HDCT using CEC. Sequential HDCT was better tolerated and resulted in fewer treatment-related deaths.
FCGR3A gene polymorphisms may correlate with response to frontline R-CHOP therapy for diffuse large B-cell lymphoma
Authors: D. H. Kim, H. D. Jung, J. G. Kim, J.-J. Lee, D.-H. Yang, Y. H. Park, Y. R. Do, H. J. Shin, M. K. Kim, M. S. Hyun, S. K. Sohn
Journal: Blood (2006)
Survival After Breast Cancer in Ashkenazi Jewish BRCA1 and BRCA2 Mutation Carriers
Authors: J. S. Lee, S. Wacholder, J. P. Struewing, M. McAdams, D. Pee, L. C. Brody, M. A. Tucker, P. Hartge
Journal: JNCI Journal of the National Cancer Institute (1999)

Studies of survival following breast and ovarian cancers in BRCA1 and/or BRCA2 mutation carriers have yielded conflicting results. We undertook an analysis of a community-based study of Ashkenazi Jews to investigate the effect of three founder mutations in BRCA1 and BRCA2 on survival among patients with breast or ovarian cancer.We collected blood samples and questionnaire data from 5318 Ashkenazi Jewish volunteers. The blood samples were tested for 185delAG (two nucleotide deletion) and 5382insC (single nucleotide insertion) mutations in BRCA1 and the 6174delT (single nucleotide deletion) mutation in BRCA2. To estimate survival differences in the affected relatives according to their BRCA1 and/or BRCA2 mutation carrier status, we devised and applied a novel extension of the kin-cohort method.Fifty mutation carriers reported that 58 of their first-degree relatives had been diagnosed with breast cancer and 10 with ovarian cancer; 907 noncarriers reported 979 first-degree relatives with breast cancer and 116 with ovarian cancer. Kaplan-Meier estimates of median survival after breast cancer were 16 years (95% confidence interval [CI] = 11-40) in the relatives of carriers and 18 years (95% CI = 15-22) in the relatives of noncarriers, a difference that was not statistically significant (two-sided P = .87). There was also no difference in survival times among the 126 first-degree relatives with ovarian cancer. We found no survival difference between patients with breast or ovarian cancer who were inferred carriers of BRCA1 and/or BRCA2 mutations and noncarriers.Carriers of BRCA1 and BRCA2 mutations appeared to have neither better nor worse survival prognosis.
Detection of evolutionarily stable fragments of cellular pathways by hierarchical clustering of phyletic patterns
Authors: Galina V Glazko, Arcady R Mushegian
Journal: Genome biology (2004)

Phyletic patterns denote the presence and absence of orthologous genes in completely sequenced genomes and are used to infer functional links between genes, on the assumption that genes involved in the same pathway or functional system are co-inherited by the same set of genomes. However, this basic premise has not been quantitatively tested, and the limits of applicability of the phyletic-pattern method remain unknown.We characterized a hierarchy of 3,688 phyletic patterns encompassing more than 5,000 known protein-coding genes from 66 complete microbial genomes, using different distances, clustering algorithms, and measures of cluster quality. The most sensitive set of parameters recovered 223 clusters, each consisting of genes that belong to the same metabolic pathway or functional system. Fifty-six clusters included unexpected genes with plausible functional links to the rest of the cluster. Only a small percentage of known pathways and multiprotein complexes are co-inherited as one cluster; most are split into many clusters, indicating that gene loss and displacement has occurred in the evolution of most pathways.Phyletic patterns of functionally linked genes are perturbed by differential gains, losses and displacements of orthologous genes in different species, reflecting the high plasticity of microbial genomes. Groups of genes that are co-inherited can, however, be recovered by hierarchical clustering, and may represent elementary functional modules of cellular metabolism. The phyletic patterns approach alone can confidently predict the functional linkages for about 24% of the entire data set.
Genome-wide investigation reveals pathogen-specific and shared signatures in the response of Caenorhabditis elegans to infection
Authors: Daniel Wong, Daphne Bazopoulou, Nathalie Pujol, Nektarios Tavernarakis, Jonathan J Ewbank
Journal: Genome biology (2007)

There are striking similarities between the innate immune systems of invertebrates and vertebrates. Caenorhabditis elegans is increasingly used as a model for the study of innate immunity. Evidence is accumulating that C. elegans mounts distinct responses to different pathogens, but the true extent of this specificity is unclear. Here, we employ direct comparative genomic analyses to explore the nature of the host immune response. Using whole-genome microarrays representing 20,334 genes, we analyzed the transcriptional response of C. elegans to four bacterial pathogens. Different bacteria provoke pathogen-specific signatures within the host, involving differential regulation of 3.5-5% of all genes. These include genes that encode potential pathogen-recognition and antimicrobial proteins. Additionally, variance analysis revealed a robust signature shared by the pathogens, involving 22 genes associated with proteolysis, cell death and stress responses. The expression of these genes, including those that mediate necrosis, is similarly altered following infection with three bacterial pathogens. We show that necrosis aggravates pathogenesis and accelerates the death of the host. Our results suggest that in C. elegans, different infections trigger both specific responses and responses shared by several pathogens, involving immune defense genes. The response shared by pathogens involves necrotic cell death, which has been associated with infection in humans. Our results are the first indication that necrosis is important for disease susceptibility in C. elegans. This opens the way for detailed study of the means by which certain bacteria exploit conserved elements of host cell-death machinery to increase their effective virulence.
Harmful effect of adipose tissue on liver lesions in patients with alcoholic liver disease
Authors: Sylvie Naveau, Anne-Marie Cassard-Doulcier, Micheline Njiké-Nakseu, Laurence Bouchet-Delbos, Nadège Barri-Ova, Hédia Boujedidi, Barbara Dauvois, Axel Balian, Sophie Maitre, Sophie Prévot, Ibrahim Dagher, Hélène Agostini, Liliane Grangeot-Keros, Dominique Emilie, Gabriel Perlemuter
Journal: Journal of Hepatology (2010)
Increased Susceptibility of Thymocytes to Apoptosis in Mice Lacking AIM, a Novel Murine Macrophage-derived Soluble Factor Belonging to the Scavenger Receptor Cysteine-rich Domain Superfamily
Authors: Toru Miyazaki, Yumiko Hirokami, Nobuyuki Matsuhashi, Hisakazu Takatsuka, Makoto Naito
Journal: The Journal of Experimental Medicine (1999)

Apoptosis of cells must be regulated both positively and negatively in response to a variety of stimuli in the body. Various environmental stresses are known to initiate apoptosis via differential signal transduction cascades. However, induction of signals that may inhibit apoptosis is poorly understood, although a number of intracellular molecules that mediate inhibition of apoptosis have been identified. Here we present a novel murine macrophage-specific 54-kD secreted protein which inhibits apoptosis (termed AIM, for apoptosis inhibitor expressed by macrophages). AIM belongs to the macrophage scavenger receptor cysteine-rich domain superfamily (SRCR-SF), members of which share a highly homologous conserved cysteine-rich domain. In AIM-deficient mice, the thymocyte numbers were diminished to half those in wild-type mice, and CD4/CD8 double-positive (DP) thymocytes were strikingly more susceptible to apoptosis induced by both dexamethasone and irradiation in vivo. Recombinant AIM protein significantly inhibited cell death of DP thymocytes in response to a variety of stimuli in vitro. These results indicate that in the thymus, AIM functions in trans to induce resistance to apoptosis within DP cells, and thus supports the viability of DP thymocytes before thymic selection.
Opposing roles of STAT1 and STAT3 in T cell–mediated hepatitis: regulation by SOCS
Authors: Feng Hong, Barbara Jaruga, Won Ho Kim, Svetlana Radaeva, Osama N. El-Assal, Zhigang Tian, Van-Anh Nguyen, Bin Gao
Journal: Journal of Clinical Investigation (2002)

T cell–mediated fulminant hepatitis is a life-threatening event for which the underlying mechanism is not fully understood. Injection of concanavalin A (Con A) into mice recapitulates the histological and pathological sequelae of T cell–mediated hepatitis. In this model, both signal transducer and activator of transcription factor 1 (STAT1) and STAT3 are activated in the liver. Disruption of the STAT1 gene by way of genetic knockout attenuates liver injury, suppresses CD4+ and NK T cell activation, and downregulates expression of proapoptotic interferon regulatory factor-1 protein and suppressor of cytokine signaling-1 (SOCS1), but enhances STAT3 activation and STAT3-controlled antiapoptotic signals. Studies from IFN-γ–deficient mice indicate that IFN-γ not only is the major cytokine responsible for STAT1 activation but also partially accounts for STAT3 activation. Moreover, downregulation of STAT3 activation in IL-6–deficient mice is associated with decreased STAT3-controlled antiapoptotic signals and expression of SOCS3, but upregulation of STAT1 activation and STAT1-induced proapoptotic signals and exacerbation of liver injury. Taken together, these findings suggest that STAT1 plays a harmful role in Con A–mediated hepatitis by activation of CD4+ and NK T cells and directly inducing hepatocyte death, whereas STAT3 protects against liver injury by suppression of IFN-γ signaling and induction of antiapoptotic protein Bcl-XL. STAT1 and STAT3 in hepatocytes also negatively regulate one another through the induction of SOCS.
Systemic Endothelial Dysfunction in Adults With Cyanotic Congenital Heart Disease
Authors: Erwin Oechslin, Wolfgang Kiowski, Ruth Schindler, Alain Bernheim, Barbara Julius, Hans Peter Brunner-La Rocca
Journal: Circulation (2005)

Secondary erythrocytosis results in increased shear stress in cyanotic congenital heart disease (CCHD), which may modify the balance between vasodilators and vasoconstrictors and affect systemic endothelial function. Because no data are available on systemic vasomotion, systemic endothelial function and nitric oxide (NO) availability were investigated in CCHD patients.Responses to arterial endothelium-dependent (acetylcholine [Ach]) and -independent (sodium nitroprusside [SNP]) vasodilation, NO synthase blockade (NG-monomethyl-L-arginine [L-NMMA]), endothelin-1 (ET-1), and ET-1 receptor blockade by BQ-123 in 11 CCHD patients (O2 saturation <90%; mean+/-SD, 79+/-1%; mean+/-SD age, 39+/-2 years) were compared with those in 10 age-matched healthy referents by using forearm venous occlusion plethysmography. Resting forearm blood flow (FBF) was lower in CCHD patients than in referents (2.4+/-0.2 versus 3.5+/-0.4 mL.min(-1).100 mL(-1) of forearm volume [FAV], P<0.05). Although the response to SNP was similar in both groups (CCHD, 2.0+/-0.3 to 8.3+/-1.0; referents, 3.6+/-0.7 to 11.9+/-1.2 mL.min(-1).100 mL(-1) of FAV; P>0.1), the response to Ach was markedly reduced in CCHD (maximal increase in FBF, 2.8+/-0.8 versus 37.5+/-4.4 mL.min(-1).100 mL(-1) of FAV; P<0.0001). l-NMMA was less effective in CCHD (decrease in FBF, 25+/-6% versus 40+/-4%; P<0.05). ET-1 caused less vasoconstriction in the CCHD group (-25+/-9% versus -51+/-7%, P<0.05), but the response to BQ-123 was similar in both groups (32+/-9% versus 27+/-9%).Systemic endothelial dysfunction is evident in CCHD patients as shown by strikingly reduced endothelial vasodilation to Ach. The response to exogenous ET-1 is reduced, possibly because of elevated endogenous ET-1 levels, but the effects of endogenous ET-1 on arterial tone are not enhanced, as indicated by the similar response to ET-1 blockade.