tbuckley/cabot-search huggingface dataset:
α1β1 Integrin-Mediated Collagen Matrix Remodeling by Rat Mesangial Cells Is Differentially Regulated by Transforming Growth Factor-β and Platelet-Derived Growth Factor-BB
Authors: SHOJI KAGAMI, SHUJI KONDO, KLEMENS LÖSTER, WERNER REUTTER, TAKASHI KUHARA, KOJI YASUTOMO, YASUHIRO KURODA
Journal: Journal of the American Society of Nephrology (1999)

Pathologic remodeling of mesangial matrix after glomerular injury is the central biologic feature of glomerular scarring (sclerosis). Transforming growth factor-beta (TGF-beta) and platelet-derived growth factor (PDGF)-BB have been implicated in the development of glomerular scarring in rat and human glomerulonephritis. To clarify molecular and cellular mechanisms involved in abnormal mesangial remodeling, this study focused on the role of alpha1beta1 integrin, a collagen/laminin receptor, in rat mesangial cells, using collagen gel contraction as an experimental model of in vivo collagen matrix remodeling and scar formation. In addition, the influence of TGF-beta and PDGF-BB on mesangial cell (MC)-mediated collagen gel contraction in association with the alpha1beta1 integrin expression was evaluated. Integrin function blocking studies using anti-alpha1, beta1 subunit antibodies indicated that MC-alpha1beta1 integrin is essentially required not only for collagen-dependent adhesion/migration, but also for gel contraction. Protein synthesis and mRNA analysis experiments demonstrated that TGF-beta, but not PDGF-BB, increases the expression of alpha1beta1 integrin in mesangial cells cultured on plastic surface and in collagen gels. The upregulation of alpha1beta1 integrin expression by TGF-beta correlated with increases in gel contraction and collagen-dependent adhesion but not migration of mesangial cells. On the other hand, PDGF-BB enhanced MC-mediated gel contraction and migration without affecting cell adhesion to collagen I. Growth factor-induced collagen-dependent adhesion, migration, and gel contraction were significantly attenuated by incubation with anti-alpha1, beta1 subunit antibodies. Thus, these data indicate that alpha1beta1 integrin-mediated collagen matrix remodeling can be modulated by TGF-beta and PDGF-BB via different mechanisms. Alpha1 integrin-mediated mesangial matrix remodeling induced by TGF-beta or PDGF-BB may be a pathogenic mechanism leading to glomerular scarring.
Effects of antihistamines in adult asthma: a meta-analysis of clinical trials
Authors: E Van Ganse, L Kaufman, MP Derde, JC Yernault, L Delaunois, W Vincken
Journal: European Respiratory Journal (1997)

A meta-analysis of clinical trials of antihistamines was performed to assess the risk-benefit ratio of this therapeutic class in asthma. Double-blind randomized placebo-controlled trials assessing lung function changes under repeated use of antihistamine in adult asthma were selected, and the quality of studies was scored. Morning peak expiratory flow rate (PEFR) was the primary outcome: an effect size was computed for each study, with a 95% confidence interval (95% CI), and a mean effect size was computed, combining all studies. Effect sizes were also determined for secondary outcomes: evening PEFR, forced expiratory volume in one second (FEV1) and daily use of inhaled beta-agonists. Nineteen studies were included in the meta-analysis. Mean quality score of studies was 59.4%; asthma was generally uncontrolled at study inclusion. Altogether, 582 antihistamine-treated and 557 placebo-treated asthma patients were evaluable. Antihistamines had little effect on airway calibre (mean increase in morning PEFR: 13 L x min(-1); 95 CI: 8-18 L x min(-1)) and on use of inhaled beta-agonists (mean reduction in daily use: 0.4 doses; 95% CI: 0-0.8 doses). Sedation occurred more often with antihistamines than with placebo (p<0.001); additional side-effects were mentioned, including weight gain, altered taste, headache and dry mouth. Respiratory and systemic effects observed after repeated use of antihistamines do not support the use of these medications in the treatment of asthma; better designed studies could affect this appraisal.
Titin is a Target of Matrix Metalloproteinase-2
Authors: Mohammad A.M. Ali, Woo Jung Cho, Bryan Hudson, Zamaneh Kassiri, Henk Granzier, Richard Schulz
Journal: Circulation (2010)

Background— Titin is the largest mammalian (≈3000 to 4000 kDa) and myofilament protein that acts as a molecular spring in the cardiac sarcomere and determines systolic and diastolic function. Loss of titin in ischemic hearts has been reported, but the mechanism of titin degradation is not well understood. Matrix metalloproteinase-2 (MMP-2) is localized to the cardiac sarcomere and, on activation in ischemia/reperfusion injury, proteolyzes specific myofilament proteins. Here we determine whether titin is an intracellular substrate for MMP-2 and if its degradation during ischemia/reperfusion contributes to cardiac contractile dysfunction. Methods and Results— Immunohistochemistry and confocal microscopy in rat and human hearts showed discrete colocalization between MMP-2 and titin in the Z-disk region of titin and that MMP-2 is localized mainly to titin near the Z disk of the cardiac sarcomere. Both purified titin and titin in skinned cardiomyocytes were proteolyzed when incubated with MMP-2 in a concentration-dependent manner, and this was prevented by MMP inhibitors. Isolated rat hearts subjected to ischemia/reperfusion injury showed cleavage of titin in ventricular extracts by gel electrophoresis, which was confirmed by reduced titin immunostaining in tissue sections. Inhibition of MMP activity with ONO-4817 prevented ischemia/reperfusion-induced titin degradation and improved the recovery of myocardial contractile function. Titin degradation was also reduced in hearts from MMP-2 knockout mice subjected to ischemia/reperfusion in vivo compared with wild-type controls. Conclusion— MMP-2 localizes to titin at the Z-disk region of the cardiac sarcomere and contributes to titin degradation in myocardial ischemia/reperfusion injury.
Neuronal COX-2 expression in human myenteric plexus in active inflammatory bowel disease
Authors: P J Roberts
Journal: Gut (2001)

<h3>BACKGROUND</h3> Inflammatory bowel disease (IBD) is associated with changes in colonic motility which may contribute to the pain and diarrhoea associated with exacerbations of this disease. These changes may be mediated by prostaglandins which are increased in this condition. Increased expression of the inducible isoform of cyclo-oxygenase (COX-2) has been found in active IBD although its cellular distribution remains uncertain. <h3>AIMS</h3> To evaluate the cellular distribution of COX-2 in active IBD. <h3>PATIENTS AND METHODS</h3> Using reverse transcription-polymerase chain reaction, in situ hybridisation, and immunohistochemistry, COX-2 expression was evaluated in 12 colectomy specimens from patients with active ulcerative colitis (UC), and six specimens from patients with Crohn9s colitis that had failed medical therapy. Histologically normal colon was obtained from 12 patients having resection for colorectal neoplasia and evaluated as above, acting as control specimens. <h3>RESULTS</h3> All specimens expressed COX-2 mRNA, with some 6–8-fold increase in inflamed tissues on densitometric analysis (both UC and Crohn9s) compared with controls. In situ hybridisation localised this mRNA to myenteric neural cells, surrounding smooth muscle cells, and inflammatory cells of the lamina propria in the IBD specimens, with some weaker labelling seen in the epithelium. No COX-2 labelling was seen in normal tissues. Immunohistochemistry confirmed these sites of COX-2 expression in all inflamed specimens, with absence of immunoreactivity in control tissues. <h3>CONCLUSIONS</h3> These findings provide the first evidence of COX-2 expression in neural cells of the myenteric plexus in active IBD which, via increased prostaglandin synthesis at this site, may contribute to the dysmotilty seen in this condition.
The association between sedentary leisure and physical activity in middle-aged adults
Authors: Nicola W Burton, Asaduzzaman Khan, Wendy J Brown, Gavin Turrell
Journal: British Journal of Sports Medicine (2011)

Aim The aim of this study was to examine the association between time spent in sedentary leisure and physical activity level in mid-aged men and women. Methods Data were from the 2007 HABITAT study in Brisbane, Australia. A mail survey sent to 17 000 adults (40–65 years) provided 11 037 responses (68.5%), and 9121 (82.6%) were analysed. Sedentary leisure was quantified as hours/day spent sitting watching television, in home computer use, in general leisure, and overall, on a usual week and weekend day. Physical activity level (no activity, low, recommended, high, very high) included walking, moderate and vigorous activity combined into a measure of MET.min/week. Data were analysed separately for men and women using multilevel multinomial logistic regression with adjustment for sociodemographic and health variables. Results The only significant negative associations were between watching television on a week day and high activity in men (0.91; 0.83–0.98), and home computer use on a weekend day and very high activity in men (0.89; 0.81–0.98). For both men and women, there were significant positive associations between overall sedentary leisure time on a week day and very high activity (men: 1.07, 1.02–1.13; women: 1.10, 1.04–1.16), home computer use on a week day and very high activity (men: 1.11, 1.01–1.22; women: 1.15, 1.04–1.27) and general leisure on a week day and most activity levels. Conclusions Sedentary leisure is mainly independent of physical activity and does not preclude meeting physical activity recommendations.
Phase II trial of the farnesyltransferase inhibitor tipifarnib plus fulvestrant in hormone receptor-positive metastatic breast cancer: New York Cancer Consortium Trial P6205
Authors: T. Li, P.J. Christos, J.A. Sparano, D.L. Hershman, S. Hoschander, K. O’Brien, J.J. Wright, L.T. Vahdat
Journal: Annals of Oncology (2009)
Glutamine Synthetase Immunostaining Correlates with Pathologic Features of Hepatocellular Carcinoma and Better Survival after Radiofrequency Thermal Ablation
Authors: Barbara Dal Bello, Laura Rosa, Nicoletta Campanini, Carmine Tinelli, Francesca Torello Viera, Gioacchino D'Ambrosio, Sandro Rossi, Enrico M. Silini
Journal: Clinical Cancer Research (2010)

Activation of the wnt pathway identifies a subgroup of hepatocellular carcinomas (HCC) with specific epidemiologic and genetic profiles. Wnt activation is predicted by mutation and/or nuclear translocation of beta-catenin and by glutamine synthetase (GS) immunoreactivity. We investigated whether GS staining associates with specific pathologic features of HCC and with survival after radiofrequency thermal ablation.Monoistitutional retrospective-prospective study in a tertiary hospital setting. Two hundred and seven cirrhotics (mean age, 70 years; 63% males, 82.1% hepatitis C virus positive) with early HCC were consecutively treated with radiofrequency thermal ablation (RFTA). Mean tumor size was 2.7 cm; 20.3% of patients had multiple nodules; and median follow-up was 36 months with 54.6% overall mortality. Tumor samples were mainly obtained by biopsy (92,5%) and examined by H&E and immunostaining for beta-catenin and GS. Main outcome measures were overall and tumor-specific mortality by Kaplan-Meier analysis and Cox proportional hazard models corrected for competing risks.Ninety-one patients (43.9%) had GS-positive HCCs by immunostaining. These tumors had larger size (P = 0.012) and characteristic histology (low grade, pseudoacini, hydropic changes, bile staining, lack of steatosis, and fibrosis). Other clinical or treatment variables were similar between groups. Variables correlating with tumor-specific and overall mortality by univariate analysis were tumor recurrence, advanced disease, posttreatment alpha-fetoprotein levels, and GS staining. Yearly, overall mortality rate was lower in GS-positive patients (12.4 versus 20% yearly; P = 0.006). By multivariate analysis, GS immunostaining correlated with reduced specific (hazard ratio, 0.58; 95% confidence interval, 0.34-0.97) and overall mortality (hazard ratio, 0.62; 95% confidence interval, 0.40-0.96).Standard histology and GS status identify a HCC subset with distinct clinical and pathologic features.
The HCMV membrane glycoprotein US10 selectively targets HLA-G for degradation
Authors: Boyoun Park, Eric Spooner, Brandy L. Houser, Jack L. Strominger, Hidde L. Ploegh
Journal: The Journal of Experimental Medicine (2010)

Human cytomegalovirus (HCMV) encodes an endoplasmic reticulum (ER)-resident transmembrane glycoprotein, US10, expressed early in the replicative cycle of HCMV as part of the same cluster that encodes the known immunoevasins US2, US3, US6, and US11. We show that US10 down-regulates cell surface expression of HLA-G, but not that of classical class I MHC molecules. The unique and short cytoplasmic tail of HLA-G (RKKSSD) is essential in its role as a US10 substrate, and a tri-leucine motif in the cytoplasmic tail of US10 is responsible for down-regulation of HLA-G. Both the kinetics of HLA-G degradation and the mechanisms responsible appear to be distinct from those used by the US2 and US11 pathways, suggesting the existence of a third route of protein dislocation from the ER. We show that US10-mediated degradation of HLA-G interferes with HLA-G–mediated NK cell inhibition. Given the role of HLA-G in protecting the fetus from attack by the maternal immune system and in directing the differentiation of human dendritic cells to promote the evolution of regulatory T cells, HCMV likely targets the HLA-G–dependent axis of immune recognition no less efficiently than it interferes with classical class I MHC–restricted antigen presentation.
Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial
Authors: Timothy D Girard, John P Kress, Barry D Fuchs, Jason WW Thomason, William D Schweickert, Brenda T Pun, Darren B Taichman, Jan G Dunn, Anne S Pohlman, Paul A Kinniry, James C Jackson, Angelo E Canonico, Richard W Light, Ayumi K Shintani, Jennifer L Thompson, Sharon M Gordon, Jesse B Hall, Robert S Dittus, Gordon R Bernard, E Wesley Ely
Journal: The Lancet (2008)
Aptamer-Mediated Blockade of IL4Rα Triggers Apoptosis of MDSCs and Limits Tumor Progression
Authors: Felix Roth, Adriana C. De La Fuente, Jennifer L. Vella, Alessia Zoso, Luca Inverardi, Paolo Serafini
Journal: Cancer Research (2012)

In addition to promoting tumor progression and metastasis by enhancing angiogenesis and invasion, myeloid-derived suppressor cells (MDSC) and tumor-associated macrophage (TAM) also inhibit antitumor T-cell functions and limit the efficacy of immunotherapeutic interventions. Despite the importance of these leukocyte populations, a simple method for their specific depletion has not been developed. In this study, we generated an RNA aptamer that blocks the murine or human IL-4 receptor-α (IL4Rα or CD124) that is critical for MDSC suppression function. In tumor-bearing mice, this anti-IL4Rα aptamer preferentially targeted MDSCs and TAM and unexpectedly promoted their elimination, an effect that was associated with an increased number of tumor-infiltrating T cells and a reduction in tumor growth. Mechanistic investigations of aptamer-triggered apoptosis in MDSCs confirmed the importance of IL4Ra-STAT6 pathway activation in MDSC survival. Our findings define a straightforward strategy to deplete MDSCs and TAMs in vivo, and they strengthen the concept that IL4Rα signaling is pivotal for MDSC survival. More broadly, these findings suggest therapeutic strategies based on IL4Rα signaling blockades to arrest an important cellular mechanism of tumoral immune escape mediated by MDSCs and TAM in cancer.
Interleukin 15 Is Required for Proliferative Renewal of Virus-specific Memory CD8 T Cells
Authors: Todd C. Becker, E. John Wherry, David Boone, Kaja Murali-Krishna, Rustom Antia, Averil Ma, Rafi Ahmed
Journal: The Journal of Experimental Medicine (2002)

The generation and efficient maintenance of antigen-specific memory T cells is essential for long-lasting immunological protection. In this study, we examined the role of interleukin (IL)-15 in the generation and maintenance of virus-specific memory CD8 T cells using mice deficient in either IL-15 or the IL-15 receptor α chain. Both cytokine- and receptor-deficient mice made potent primary CD8 T cell responses to infection with lymphocytic choriomeningitis virus (LCMV), effectively cleared the virus and generated a pool of antigen-specific memory CD8 T cells that were phenotypically and functionally similar to memory CD8 T cells present in IL-15+/+ mice. However, longitudinal analysis revealed a slow attrition of virus-specific memory CD8 T cells in the absence of IL-15 signals.This loss of CD8 T cells was due to a severe defect in the proliferative renewal of antigen-specific memory CD8 T cells in IL-15−/− mice. Taken together, these results show that IL-15 is not essential for the generation of memory CD8 T cells, but is required for homeostatic proliferation to maintain populations of memory cells over long periods of time.
Computed tomographic estimation of lung dimensions throughout the growth period
Authors: P. A. de Jong, F. R. Long, J. C. Wong, P. J. Merkus, H. A. Tiddens, J. C. Hogg, H. O. Coxson
Journal: European Respiratory Journal (2006)

The aim of the current study was to use computed tomography (CT) to estimate airway wall and lumen, and arterial and parenchyma dimensions in children throughout the growth period, and to provide normative data to study alterations caused by pulmonary disease. Clinical CT scans reported as normal that were performed in children for nonpulmonary and noncardiac reasons were analysed for lung weight, gas volume, lung expansion, lung surface/volume ratio, airway wall area, airway lumen area, airway lumen perimeter, arterial area and airway surface length/area ratio. The age range of the 50 subjects was 0–17.2 yrs. The data showed only little increase in lung expansion throughout childhood (n = 32). There was substantial variability in lung expansion between subjects. Airway wall and lumen and arterial area were exponentially associated with subjects' height (n = 50). Airway surface length/area ratio was linearly associated to alveolar surface/volume ratio. The data from the current study provide normative computed tomography estimates of airway wall and lumen, and arterial and parenchyma dimensions throughout the growth period that may be useful for the study of alterations in disease.
Life threatening intra-abdominal sepsis in patients on anti-TNF- therapy
Authors: S Goode
Journal: Gut (2005)

remaining unchanged in the proximal colon (32% v 30%) (fig 1).Increased TNF-a concentrations have been reported in both Crohn's disease and ulcerative colitis. 5 6For the first time, this case report showed that TNF-a overexpression was also present in SCAD.It is known that high TNF-a levels detected in Crohn's disease are reduced by infliximab therapy. 7Similarly, a dramatic decrease in histological activity with profound TNF-a downregulation in the SCAD tract occurred in our patient after infliximab.These observations suggest that SCAD pathogenesis may mirror the pathogenetic models proposed for IBD.It has already been reported that SCAD can fade into a more classic ulcerative colitis picture. 8In our case, although the two IBD pictures presented with similar TNF-a concentrations before therapy, complete endoscopic and histological regression was limited to the SCAD tract while only partial endoscopic improvement occurred in the nondiverticular ulcerative colitis-like picture.Interestingly, persistence of histological activity was associated with high TNF-a expression.This is the first case in which two simultaneous varieties of IBD have shown a different response to infliximab in the same patient.However, due to the more aggressive clinical behaviour of the SCAD, infliximab therapy was successful in annihilating the long term steroid dependence of our patient.This implies that a much deeper knowledge of the pathogenesis of IBD needs to be pursued before preventing a patient from a potentially life saving therapy.In conclusion, our case report showed that the pathogenesis of SCAD can be sustained by TNF-a activity and reversed by specific therapy.Moreover, an associated ulcerative colitis may show a different degree of response to infliximab.Such different behaviours suggest that the more we struggle to unravel the inflammatory puzzle, the more puzzling the pathogenetic enigma of IBD appears to be.
Hyperbaric Oxygen Therapy for Radionecrosis: Clear Advice From Confusing Data
Authors: Gerard Laden
Journal: Journal of Clinical Oncology (2005)

TO THE EDITOR: The study by Annane et al violated an ethical principle by exposing the control group to the potentially serious risk of acute decompression illness; a risk not present in the treatment group. The trial involved the control group breathing a gas mixture of 9% oxygen and 91% nitrogen at treatment pressure (the placebo) to simulate breathing air at atmospheric pressure. This procedure requires mandatory decompression (controlled return to atmospheric pressure) to de-nitrogen the patients. This decompression was not a requirement for the oxygenbreathing (treatment) group. Decompression dives are not advised by some sports scuba diving organizations. Additionally, Annane et al, are mistaken in stating “a similar placebo has recently been used to evaluate HBO [hyperbaric oxygen therapy].” In the trial, they found that the control arm breathed a mixture of 60% nitrogen, 40% oxygen, negating the risk of decompression illness. Another issue requiring clarification is the number of patients who actually completed their prescribed treatment sessions. For example, the data show that at least 75% of the treatment group failed to receive the protocol minimum of 30 treatments. Furthermore, 26 of patients (48.1%) in stage A mandibular osteoradionecrosis at enrolment progressed to stage B, thus requiring them to complete a total of 40 sessions. No clear information is given about the compliance of these patients. Their Table 2 also indicated that very few sessions were stopped due to complications. Thus the question arises, why did at least 75% of patients not complete 30 treatments and what of the subgroup requiring 40? Additionally, it is unclear how in Table 2 there can be two patients with two sessions “discontinued due to complications,” but only one patient with two sessions in which complication arose. Other anomalies detract the reader from accepting the trial design and execution. For example, as with development, the evolution of osteoradionecrosis is variable. How was this variable accounted for in the small numbers involved in the triangular test? It would also be of interest to know how many of the 12 participating centers used hyperbaric oxygen before the trial and how many (if any) have continued with its use. As the accompanying editorial points out, this study is “under-powered.” Therefore, to conclude with an unequivocal statement based on a trial involving literally only a handful of compliant patients is surprising. This study does, however, highlight that further research is urgently needed before giving any definitive advice about treating this painful and debilitating condition.