tbuckley/cabot-search huggingface dataset:
Unravelling salt transport in cystic fibrosis
Authors: P G Noone, K W Southern
Journal: Thorax (2004)

Sodium hyperabsorption may be a key therapeutic target in CF

Cystic fibrosis (CF) lung disease is characterised by thick viscid airway secretions, the development of progressive airways obstruction and bronchiectasis, and colonisation with specific bacteria, notably Pseudomonas aeruginosa .1 Although the precise pathogenic pathways in CF are still debated (see below), airway epithelial ion transport has been known to be defective in CF for two decades. This can be assessed in the airway in vivo by measuring potential difference (PD)—that is, the voltage generated across an electrically tight epithelium by the active transport of charged sodium and chloride ions.2 In patients with CF the magnitude of sodium absorption across airway epithelia and the response to the sodium channel blocker amiloride are substantially increased compared with normal subjects, coupled with an inability to secrete chloride ions.3 In the 1990s the putative gene (the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene) was cloned4 and the affected protein was identified as a gated chloride channel,5 supporting the hypothesis that CF is linked to abnormal transepithelial ion transport.

Despite this clear link between abnormal ion transport and CF, the pathogenesis of lung disease in CF is complex, and much effort has been expended trying to elucidate the pathways involved in the development of airways disease. One hypothesis suggests that lung disease in CF develops in large part because of the deranged ion transport, resulting in a reduction in airway surface liquid volume and compromised mucociliary clearance.6 These abnormal mechanisms set up a cycle of retained airway secretions, accumulation of mucus with infection and inflammation in the airways, ultimately leading to airway destruction, respiratory failure, and death from lung disease.

Recent in vitro studies on airway cell cultures grown to confluence with an air/liquid interface have yielded further insights …
Effect of mechanical strain on gastric cellular migration and proliferation during mucosal healing: role of Rho dependent and Rac dependent cytoskeletal reorganisation
Authors: T Osada, S Watanabe, H Tanaka, M Hirose, A Miyazaki, N Sato
Journal: Gut (1999)

Various factors affect gastric wound healing. The influence of physical stimulation on gastric mucosal cells during the process of gastric wound healing is not completely understood.To assess the role of a physical stimulant, in this case mechanical strain, on gastric mucosal restoration.Mechanical strain was applied to adherent rat gastric mucosal cells (RGM1) cultured confluently on collagen type I coated silicone elastomer membrane in order to increase the dimension by an average of 5% and 10% at 5 cycles/minute for 72 hours after wounding. Repair of the wound was monitored every 12 hours for up to 72 hours using an inverted phase contrast microscope. Cell proliferation was detected using 5-bromodeoxyuridine staining. The cytoskeletal protein actin, a component of focal adhesion plaque protein, vinculin, and the small GTP-binding proteins RhoA and Rac1 were detected by immunohistochemistry in the cells located at the margin of and remote from the wound.The cells located at the margin of the wound showed the greatest migration and proliferation and were found to express more rudimentary lamellipodia and filopodia in the absence of mechanical strain. Vinculin, RhoA, and Rac1 were also strongly expressed in the wound margin. Under conditions of mechanical strain, the speed of migration of cells slowed and fewer proliferating cells were detected around the wound in a strain strength dependent manner. Lamellipodial formation, vinculin, RhoA, and Rac1 were poorly expressed in the same area. However, in cells located more than 1 mm from the wound edge, cytoskeletal rearrangement, and the expression of vinculin, RhoA, and Rac1 were not influenced by mechanical strain.Migration and proliferation of RGM1 cells in culture during wound healing were inhibited by mechanical strain, which caused dysfunction of the cytoskeletal and cell adhesion systems. It is suggested that physical stimulants such as mechanical strain may play a role in gastric wound healing in vivo by modifying cellular migration and proliferation.
The Effect of Increased Coverage of Participatory Women’s Groups on Neonatal Mortality in Bangladesh
Authors: Edward Fottrell, Kishwar Azad, Abdul Kuddus, Layla Younes, Sanjit Shaha, Tasmin Nahar, Bedowra Haq Aumon, Munir Hossen, James Beard, Tanvir Hossain, Anni-Maria Pulkki-Brannstrom, Jolene Skordis-Worrall, Audrey Prost, Anthony Costello, Tanja A. J. Houweling
Journal: JAMA Pediatrics (2013)

Community-based interventions can reduce neonatal mortality when health systems are weak. Population coverage of target groups may be an important determinant of their effect on behavior and mortality. A women's group trial at coverage of 1 group per 1414 population in rural Bangladesh showed no effect on neonatal mortality, despite a similar intervention having a significant effect on neonatal and maternal death in comparable settings.
The PP2A inhibitor SET regulates natural killer cell IFN-γ production
Authors: Rossana Trotta, David Ciarlariello, Jessica Dal Col, Jeffrey Allard, Paolo Neviani, Ramasamy Santhanam, Hsiaoyin Mao, Brian Becknell, Jianhua Yu, Amy K. Ferketich, Brittany Thomas, Aalok Modi, Bradley W. Blaser, Danilo Perrotti, Michael A. Caligiuri
Journal: The Journal of Experimental Medicine (2007)

Monokines (i.e., interleukin [IL]-12, -18, and -15) induce natural killer (NK) cells to produce interferon-γ (IFN-γ), which is a critical factor for immune surveillance of cancer and monocyte clearance of infection. We show that SET, which is a potent inhibitor of protein phosphatase type 2A (PP2A) activity, is highly expressed in human CD56bright NK cells, which produce more IFN-γ than CD56dim NK cells. SET was up-regulated upon monokine stimulation of primary human NK cells. Furthermore, ectopic overexpression of SET significantly enhanced IFN-γ gene expression in monokine-stimulated NK cells. In contrast, RNAi-mediated suppression of SET expression renders NK cells inefficient in producing high levels of IFN-γ in response to monokine costimulation. Mechanistically, suppression of PP2A activity by SET is important for IFN-γ gene expression in NK cells. In fact, treatment of primary human NK cells with the PP2A activator 1,9-dideoxy-forskolin, as well as administration of the drug to C57BL/6 mice, significantly reduced NK-dependent IFN-γ production in response to monokine treatment. Further, SET knockdown or pharmacologic activation of PP2A diminished extracellular signal-regulated kinase 1/2, p65RelA, signal transducer and activator of transduction 4 (STAT4), and STAT5 activity in monokine-stimulated NK cells, potentially contributing to the reduction in IFN-γ gene expression. Thus, SET expression is essential for suppressing PP2A phosphatase activity that would otherwise limit NK cell antitumoral and/or antiinflammatory functions by impairing NK cell production of IFN-γ.
Nocturnal gastro-oesophageal reflux, asthma and symptoms of OSA: a longitudinal, general population study
Authors: Össur I. Emilsson, Anna Bengtsson, Karl A. Franklin, Kjell Torén, Bryndís Benediktsdóttir, Amir Farkhooy, Joost Weyler, Sandra Dom, Wilfried De Backer, Thorarinn Gislason, Christer Janson
Journal: European Respiratory Journal (2012)

Nocturnal gastro-oesophageal reflux (nGOR) is associated with asthma and obstructive sleep apnoea (OSA). Our aim was to investigate whether nGOR is a risk factor for onset of asthma and onset of respiratory and OSA symptoms in a prospective population-based study. We invited 2640 subjects from Iceland, Sweden and Belgium for two evaluations over a 9-year interval. They participated in structured interviews, answered questionnaires, and underwent spirometries and methacholine challenge testing. nGOR was defined by reported symptoms. Subjects with persistent nGOR (n=123) had an independent increased risk of new asthma at follow-up (OR 2.3, 95% CI 1.1–4.9). Persistent nGOR was independently related to onset of respiratory symptoms (OR 3.0, 95% CI 1.6–5.6). The risk of developing symptoms of OSA was increased in subjects with new and persistent nGOR (OR 2.2, 95% CI 1.3–1.6, and OR 2.0, 95% CI 1.0–3.7, respectively). No significant association was found between nGOR and lung function or bronchial responsiveness. Persistent symptoms of nGOR contribute to the development of asthma and respiratory symptoms. New onset of OSA symptoms is higher among subjects with symptoms of nGOR. These findings provide evidence that nGOR may play a role in the genesis of respiratory symptoms and diseases.
Genetic abnormalities in pancreatic cancer.
Authors: Patrick S Moore, Stefania Beghelli, Giuseppe Zamboni, Aldo Scarpa
Journal: Molecular Cancer (2003)

The incidence and mortality of pancreatic adenocarcinoma are nearly coincident having a five-year survival of less than 5%. Enormous advances have been made in our knowledge of the molecular alterations commonly present in ductal cancer and other pancreatic malignancies. One significant outcome of these studies is the recognition that common ductal cancers have a distinct molecular fingerprint compared to other nonductal or endocrine tumors. Ductal carcinomas typically show alteration of K-ras, p53, p16INK 4, DPC4 and FHIT, while other pancreatic tumor types show different aberrations. Among those tumors arising from the exocrine pancreas, only ampullary cancers have a molecular fingerprint that may involve some of the same genes most frequently altered in common ductal cancers. Significant molecular heterogeneity also exists among pancreatic endocrine tumors. Nonfunctioning pancreatic endocrine tumors have frequent mutations in MEN-1 and may be further subdivided into two clinically relevant subgroups based on the amount of chromosomal alterations. The present review will provide a brief overview of the genetic alterations that have been identified in the various subgroups of pancreatic tumors. These results have important implications for the development of genetic screening tests, early diagnosis, and prognostic genetic markers.
Effects of a non-steroidal anti-inflammatory drug on delayed onset muscle soreness and indices of damage.
Authors: A E Donnelly, K McCormick, R J Maughan, P H Whiting, P M Clarkson
Journal: British Journal of Sports Medicine (1988)

Twenty untrained male volunteers were required to run downhill for 45 minutes on a motor driven treadmill to induce muscle soreness. The volunteers took diclofenac or placebo before and for 72 hours after two runs 10 weeks apart, in a randomised double blind crossover design. Subjective soreness was assessed before and at intervals up to 72 hours after each run; venous blood samples, collected at the same time intervals, were used to estimate serum activities of creatine kinase, lactate dehydrogenase and aspartate aminotransferase and serum concentrations of creatinine and urea. Subjective soreness and the biochemical parameters increased after both runs, although the serum enzyme response to the second run was reduced. Diclofenac had no influence on the serum biochemical response to downhill running. Although overall soreness was not affected by diclofenac, individual soreness measurements were reduced by diclofenac at the first period of the study. These results suggest that diclofenac does not influence muscle damage, but may slightly reduce the associated soreness.
Comment on “Tracking donor-reactive T cells: Evidence for clonal deletion in tolerant kidney transplant patients”
Authors: Guy Gorochov, Martin Larsen, Christophe Parizot, Hélène Brisson, Mikalai Nienen, Leon Kuchenbecker, Nina Babel, Avidan U. Neumann
Journal: Science Translational Medicine (2015)

Difficulties in tracking of bona fide alloreactive clones may limit understanding of the mechanisms of spontaneous tolerance.
A new ATP-sensitive potassium channel opener protects endothelial function in cultured aortic endothelial cells
Authors: H WANG, C LONG, Z DUAN, C SHI, G JIA, Y ZHANG
Journal: Cardiovascular Research (2006)

Endothelial dysfunction is an early risk factor for cardiovascular disease and hypertension. Mechanisms that participate in endothelial dysfunction include reduced nitric oxide (NO) generation and increased endothelin-1 (ET-1) generation. Endothelial ATP-sensitive potassium (K(ATP)) channels are responsible for maintaining the resting potential of endothelial cells and modulating the release of vasoactive compounds. We hypothesized that activation of endothelial K(ATP) channels might result in the protection against endothelial dysfunction.Using cultured bovine or rat aortic endothelial cells, we examined the effects of a new K(ATP) channels opener, iptakalim, on the secretion of vasoactive substances. We also investigated its effects on the expression of adhesion molecules in metabolically disturbed cultured endothelial cells.In cultured aortic endothelial cells, iptakalim caused a concentration-dependent inhibition of ET-1 release and synthesis that correlated with reduced levels of mRNA for ET-1 and endothelin-converting enzyme. These effects of iptakalim were significantly inhibited by pretreatment with glibenclamide (a K(ATP) channel blocker) for 1 h. Similarly, iptakalim enhanced the release of NO in a concentration-dependent manner and increased basal levels of free intracellular calcium. Iptakalim at the concentrations of 100 and 1000 microM increased the activities of NO synthase (NOS) significantly. After the activity of NOS was blocked by L-N(omega)-nitro-arginine methyl ester (L-NAME), the inhibition of iptakalim on ET-1 release was abolished. In endothelial cell models of metabolic disturbance induced by low-density lipoprotein, homocysteine, or hyperglycemia, treatment with iptakalim could inhibit the overexpression of monocyte chemoattractant protein-1 (MCP-1), Intercellular adhesive molecule-1 (ICAM-1), and vascular cell adhesive molecule-1 (VCAM-1) mRNA.Iptakalim is a promising drug that could protect against endothelial dysfunction through activating K(ATP) channels in endothelial cells.
P-selectin Glycoprotein Ligand-1 Mediates L-Selectin–dependent Leukocyte Rolling in Venules
Authors: Markus Sperandio, Michael L. Smith, S. Bradley Forlow, Timothy S. Olson, Lijun Xia, Rodger P. McEver, Klaus Ley
Journal: The Journal of Experimental Medicine (2003)

Leukocyte rolling in postcapillary venules of inflamed tissues is reduced in L-selectin–deficient mice and mice treated with L-selectin blocking antibodies, but the glycoprotein ligand for L-selectin in inflamed venules is unknown. Here, we show that L-selectin–dependent rolling after P-selectin blockade is completely absent in P-selectin glycoprotein ligand-1 (PSGL-1)−/− mice or wild-type mice treated with a PSGL-1 blocking monoclonal antibody. Immunohistochemistry and flow cytometry failed to show PSGL-1 expression on resting or inflamed endothelium or on platelets. To investigate whether leukocyte-expressed PSGL-1 is mediating L-selectin–dependent rolling, we reconstituted lethally irradiated wild-type mice with PSGL-1−/− bone marrow cells. These chimeric mice showed no L-selectin–dependent rolling, suggesting that leukocyte-expressed PSGL-1 mediates L-selectin–dependent rolling. Frame-to-frame video analysis of L-selectin–dependent rolling in wild-type mice showed that the majority of observed L-selectin–dependent leukocyte rolling was between free flowing leukocytes and already adherent leukocytes or possibly leukocyte fragments, followed by E-selectin–dependent leukocyte rolling along the endothelium. Leukocyte rolling was significantly slower for leukocyte–endothelial than leukocyte–leukocyte interactions. We conclude that leukocyte-expressed PSGL-1 serves as the main L-selectin ligand in inflamed postcapillary venules. L-selectin binding to PSGL-1 initiates tethering events that enable L-selectin–independent leukocyte-endothelial interactions. These findings provide a molecular mechanism for the inflammatory defects seen in L-selectin–deficient mice.
Soluble ErbB3 Levels in Bone Marrow and Plasma of Men with Prostate Cancer
Authors: Sue-Hwa Lin, Yu-Chen Lee, Michel B. Choueiri, Sijin Wen, Paul Mathew, Xiangcang Ye, Kim-Anh Do, Nora M. Navone, Jeri Kim, Shi-Ming Tu, Li-Yuan Yu-Lee, Christopher J. Logothetis
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Prostate cancer tends to metastasize to bone and induce osteoblastic lesions. We identified a soluble form of ErbB3 (sErbB3), p45-sErbB3, in bone marrow supernatant from men with prostate cancer bone metastasis and showed that p45-sErbB3 enhances bone formation. We aimed to understand clinical implications of sErbB3 by establishing an ELISA to detect sErbB3 levels in bone marrow and plasma samples. Experimental Design: We did ELISAs on marrow from 108 men [34 with androgen-dependent disease, 30 with androgen-independent disease (AI) but negative bone scan (AI/BS−), and 44 with AI and positive bone scan (AI/BS+)], sequential marrow from 5 men during treatment, plasma from 52 men before and after docetaxel treatment, and plasma from 95 men ages ≥70 years old without prostate cancer. Results: Some men with clinically detectable bone metastasis had high sErbB3 levels. Within the AI/BS− group, higher sErbB3 levels seemed to yield lower rates of bone metastasis. In the AI/BS+ group, detectable bone metastases took longer to appear in men with higher sErbB3 levels than in men with lower sErbB3 levels (median, 82 versus 41 months). However, high sErbB3 levels did not confer survival benefit after metastasis development. Among men with metastatic progression in bone, docetaxel treatment reduced plasma sErbB3 (P &amp;lt; 0.0001) but did not affect bone-specific alkaline phosphatase (P = 0.206) or prostate-specific antigen (P = 0.906). sErbB3 was also detected in men without prostate cancer. Conclusions: The apparent correlation between higher sErbB3 levels and longer time to bone metastasis suggests that sErbB3 participates in progression in bone of prostate cancer.
Correlation Between Financial Relationships With Commercial Interests and Research Prominence at an Oncology Meeting
Authors: Beverly Moy, Angela R. Bradbury, Paul R. Helft, Brian L. Egleston, Moktar Sheikh-Salah, Jeffrey Peppercorn
Journal: Journal of Clinical Oncology (2013)

Little is known about the effects of financial relationships between biomedical researchers and industry (financial conflicts of interest [FCOIs]) on research prominence. We examined the prevalence of FCOIs in oncology and associations between FCOIs and research prominence among abstracts presented at American Society of Clinical Oncology (ASCO) annual meetings.We analyzed 20,718 abstracts presented at ASCO meetings in 2006 and 2008 to 2011. Measures included the following: financial relationships, peer review score (PRS), and meeting placement prominence (descending order of prominence: plenary session, clinical science symposium, oral presentation, poster discussion, general posters, and publish only).Of 20,718 abstracts, 36% reported at least one author with an FCOI. The proportion of abstracts with any FCOI increased from 33% in 2006 to 38% in 2011 (P < .001). Abstracts with FCOIs had significantly higher meeting prominence compared with publish only and general poster abstracts. The odds ratios compared with general posters were 7.3 for plenary session, 2.2 for clinical science symposium, 1.9 for oral presentation, and 1.7 for poster discussion (P < .001). Abstracts with FCOIs had significantly better PRSs compared with those without FCOIs. For all abstracts, PRS was 2.76 (95% CI, 2.75 to 2.77) with FCOIs compared with 3.01 (95% CI, 3.001 to 3.02) without FCOIs (P < .001). Omitting publish-only abstracts, PRS was 2.62 (95% CI, 2.61 to 2.63) with FCOIs compared with 2.73 without FCOIs (95% CI, 2.71 to 2.73).Abstracts with FCOIs had more prominent meeting placement and better PRSs. FCOIs were reported more frequently by year, suggesting an increasing influence of industry on cancer research, greater disclosure, or both.
rAAV6-microdystrophin preserves muscle function and extends lifespan in severely dystrophic mice
Authors: Paul Gregorevic, James M Allen, Elina Minami, Michael J Blankinship, Miki Haraguchi, Leonard Meuse, Eric Finn, Marvin E Adams, Stanley C Froehner, Charles E Murry, Jeffrey S Chamberlain
Journal: Nature Medicine (2006)
Cholangiocarcinomas express fas ligand and disable the fas receptor
Authors: Florencia G. Que, Vy A. Phan, Van H. Phan, Adrianne Celli, Kenneth Batts, Nicholas F. LaRusso, Gregory J. Gores
Journal: Hepatology (1999)

Cholangiocarcinoma is a highly-malignant adenocarcinoma originating from cholangiocytes. Current concepts support escape from immune surveillance using aberrant expression of Fas ligand (FasL) and dysregulation of receptor (FasR) signaling as a potential mechanism for tumor progression. Our aims were to determine if altered expression of FasR and FasL or changes in expression of FLICE inhibitor (I-FLICE) allow cholangiocarcinoma cells to escape immune surveillance. Human cholangiocarcinoma cell lines were evaluated for the functional expression of FasR and FasL by (1) quantitating apoptosis after incubation of cells with agonistic antibodies and (2) an in vitro cell death assay involving coculture of cholangiocarcinoma cells with Fas-sensitive thymocytes. I-FLICE antisense treatment was performed by stable transfection with complementary DNA (cDNA) for I-FLICE in the reverse orientation. We found that normal cholangiocytes in vivo express FasL. Human cholangiocarcinoma cell lines express both FasL and FasR and I-FLICE. FasL expressed by cholangiocarcinomas in vitro induced lymphocyte cell death (70% after 24 hours). Despite the expression of FasR, exposure of the cells to agonistic antibodies (500 ng/mL) induced only minimal apoptosis in the Jurkat cells. Antisense treatment of cholangiocarcinomas in vitro with I-FLICE reduced protein expression of I-FLICE by 90% to 95% and increased Fas-mediated apoptosis 2-fold. We concluded that cholangiocarcinomas escape immune surveillance either by disabling FasR signaling through the expression of I-FLICE and/or increased FasL expression to induce apoptosis of invading T cells. Reduction of I-FLICE expression in cholangiocarcinoma cells restored Fas-mediated apoptosis. Therapeutic maneuvers to inhibit expression of I-FLICE may aid in the treatment of cholangiocarcinoma.