tbuckley/cabot-search huggingface dataset:
Rescue of cGMP Kinase I Knockout Mice by Smooth Muscle–Specific Expression of Either Isozyme
Authors: Silke Weber, Dominik Bernhard, Robert Lukowski, Pascal Weinmeister, René Wörner, Jörg W. Wegener, Nadejda Valtcheva, Susanne Feil, Jens Schlossmann, Franz Hofmann, Robert Feil
Journal: Circulation Research (2007)

Smooth muscle expresses the Ialpha and the Ibeta isoforms of cGMP-dependent protein kinase I (cGKI). Inactivation of the murine cGKI gene prkg1 leads to multiple phenotypes and premature death at approximately 6 weeks. We reconstituted mice with the cGKIalpha or -Ibeta isozyme to test which isozyme was needed to support basic smooth muscle functions. Mice were generated by gene targeting. The cGKIalpha or the -Ibeta coding sequences were placed under the control of the SM22alpha promoter to express either isoform selectively in smooth muscle cells (SM-Ialpha or SM-Ibeta transgene). To generate smooth muscle-specific cGKIalpha or cGKIbeta rescue mice, the SM-Ialpha or SM-Ibeta transgenes were crossed on a cGKI-/- genetic background. The levels of cGKIalpha or -Ibeta expression were comparable to endogenous cGKI expression in wild-type aortic and intestinal smooth muscles. In cGKIalpha or -Ibeta rescue mice, expression of the isozymes was not detectable in non-smooth muscle tissues and cells. Median survival time of the Ialpha and Ibeta rescue mice was 52 weeks. Both isozymes mediated the 8-bromo-cGMP-induced relaxation of precontracted jejunum and aorta muscle strips. Activation of both isozymes reduced hormone- or K+-induced [Ca2+]i levels. The cGKIalpha and cGKIbeta rescue mice did not show a significant difference in intestinal passage time of BaSO4 in comparison with wild-type animals. Telemetric blood pressure measurements in conscious freely moving animals did not show differences between rescues and control mice in basal blood pressure and its regulation by DETA-NO, sodium nitroprusside, carbachol, or Y-27632. These results show that cGKI in smooth muscle is essential and that either cGKI isozyme alone can rescue basic vascular and intestinal smooth muscle functions.
Umeclidinium in patients with COPD: a randomised, placebo-controlled study
Authors: Roopa Trivedi, Nathalie Richard, Rashmi Mehta, Alison Church
Journal: European Respiratory Journal (2013)

Efficacy and safety of umeclidinium administered in a dry power inhaler were evaluated in moderate-to-very-severe chronic obstructive pulmonary disease patients. This was a randomised, placebo-controlled study assessing once-daily umeclidinium 62.5 and 125 μg over 12 weeks. The primary end-point was change from baseline in trough forced expiratory volume in 1 s (FEV 1 ) on day 85. Secondary end-points were 0–6-h weighted mean and serial forced expiratory volume in 1 s. Other end-points were transitional dyspnoea index, health outcomes (St George’s Respiratory Questionnaire), pharmacokinetics and safety. 246 patients were enrolled; 168 completed the study. On day 85, umeclidinium 62.5 and 125 μg significantly improved least squares mean change from baseline in trough FEV 1 (127 and 152 mL, respectively; p&lt;0.001) compared with placebo. On day 84, umeclidinium 62.5 and 125 μg significantly improved least squares mean change from baseline in 0–6-h weighted mean (166 and 191 mL, respectively; p&lt;0.001) and serial FEV 1 at each time point (p≤0.003). Significant improvement in least squares mean transitional dyspnoea index focal score (1.0 and 1.3 units, respectively; p≤0.05) and change from baseline St George’s Respiratory Questionnaire total score (-7.9 and -10.87 units, respectively; p&lt;0.001) were noted compared with placebo at week 12. The incidence of adverse events was low and similar across treatments. Umeclidinium 62.5 and 125 μg significantly improved lung function, dyspnoea and health status compared with placebo, and were well tolerated in chronic obstructive pulmonary disease patients over 12 weeks.
Age and the treatment of lung cancer.
Authors: J S Brown, D Eraut, C Trask, A G Davison
Journal: Thorax (1996)

The average age of patients with lung cancer is increasing and there are large numbers of elderly symptomatic patients with this common disease. However, there are few data on how the treatment of this group differs from that of younger patients.From 1 January 1990 information was collected for the Southend Lung Cancer Registry on all patients with a diagnosis of lung cancer in a geographically well defined health district of the UK with a population of 325,000. Every effort was made to find new cases from all departments of the hospital, including all clinical diagnoses, histopathological and cytological reports, and necropsies. All death certificates in the district were examined, irrespective of age, for any diagnosis of lung cancer. This therefore included any patient not seen by the hospital services. The differences in initial treatment have been analysed for three age groups: under 65, 65-74 years, and over 75.The 563 cases of lung cancer diagnosed during a 30 month period were included in the study, of whom 240 (43%) were aged over 75 years. The overall mean age was 71 years (range 31-95). The incidence of lung cancer in the general population was 69 per 100,000, but in men over 75 years of age it rose to 751 per 100,000. For all patients the active treatment rate (chemotherapy, surgery, or radiotherapy) was 49%, but for patients not reviewed by a chest physician (n = 86) it was only 21%. There were large differences in initial treatment between age groups. For patients with non-small cell lung cancer (NSCLC) reviewed by a chest physician, surgery was undertaken in 18% of those under 65, 12% of the 65-74 age group, and 2.1% of those over 75. For patients with small cell lung cancer (SCLC) reviewed by a chest physician, 79% of those aged under 65, 64% of the 65-74 age group, and 41% of patients aged over 75 received chemotherapy. In patients with NSCLC reviewed by a chest physician, chemotherapy was given to 21% under 65, 6.4% in the 65-74 age group, and none over 75. If no histological diagnosis was made 37% of patients aged under 75 and only 5.4% of those over 75 received either surgery, radiotherapy, or chemotherapy. Patients not reviewed by a chest physician were less likely to have had a histological diagnosis. Differences in treatment rates with age persisted even after allowing for performance score status at presentation.Lung cancer is a common disease in the elderly and, in our district, 43% of patients were aged 75 or over at presentation. Age alone appeared to be a major factor in influencing treatment choices, and treatment was more likely if histological confirmation was obtained. Further detailed analysis of the reasons for the differences is needed. Patients referred to chest physicians were more likely to have both histological confirmation and active treatment. This study supports the contention that all patients with a diagnosis of lung cancer, irrespective of age or condition, should be assessed by an accredited chest physician.
International, Expert-Based, Consensus Statement Regarding the Management of Acute Diverticulitis
Authors: D. Peter O’Leary, Noel Lynch, Cillian Clancy, Desmond C. Winter, Eddie Myers
Journal: JAMA Surgery (2015)

This Delphi study provides consensus related to many aspects of acute diverticulitis and identifies other areas in need of research.To generate an international, expert-based, consensus statement to address controversies in the management of acute diverticulitis.This study was conducted using the Delphi technique from April 3 through October 21, 2014. A survey website was used and a panel of acute diverticulitis experts was formed via the snowball method. The top 5 acute diverticulitis experts in 5 international geographic regions were identified based on their number of publications related to acute diverticulitis.The Delphi study used 3 rounds of questions, after which the consensus statement was collated.A consensus statement related to the management of acute diverticulitis.Twenty items were selected for inclusion in the consensus statement following 3 rounds of questioning. A clear definition of uncomplicated and complicated diverticulitis is provided. In uncomplicated diverticulitis, consensus was reached regarding appropriate laboratory and radiological evaluation of patients as well as nonsurgical, surgical, and follow-up strategies. A number of important topics, including antibiotic treatment, failed to reach consensus. In addition, consensus was reached regarding many nonsurgical and surgical treatment strategies in complicated diverticulitis.Controversy continues internationally regarding the management of acute diverticulitis. This study demonstrates that there is more nonconsensus among experts than consensus regarding most issues, even in the same region. It also provides insight into the status quo regarding the treatment of acute diverticulitis and provides important direction for future research.
Does Living Near a Superfund Site Contribute to Higher PolychlorinatedBiphenyl (PCB) Exposure?
Authors: Anna L. Choi, Jonathan I. Levy, Douglas W. Dockery, Louise M. Ryan, Paige E. Tolbert, Larisa M. Altshul, Susan A. Korrick
Journal: Environmental Health Perspectives (2006)

We assessed determinants of cord serum polychlorinated biphenyl (PCB) levels among 720 infants born between 1993 and 1998 to mothers living near a PCB-contaminated Superfund site in Massachusetts, measuring the sum of 51 PCB congeners (capital sigmaPCB) and ascertaining maternal address, diet, sociodemographics, and exposure risk factors. Addresses were geocoded to obtain distance to the Superfund site and neighborhood characteristics. We modeled log10(capital sigmaPCB) as a function of potential individual and neighborhood risk factors, mapping model residuals to assess spatial correlates of PCB exposure. Similar analyses were performed for light (mono-tetra) and heavy (penta-deca) PCBs to assess potential differences in exposure pathways as a function of relative volatility. PCB-118 (relatively prevalent in site sediments and cord serum) was assessed separately. The geometric mean of capital sigmaPCB levels was 0.40 (range, 0.068-18.14) ng/g serum. Maternal age and birthplace were the strongest predictors of capital sigmaPCB levels. Maternal consumption of organ meat and local dairy products was associated with higher and smoking and previous lactation with lower capital sigmaPCB levels. Infants born later in the study had lower capital sigmaPCB levels, likely due to temporal declines in exposure and site remediation in 1994-1995. No association was found between capital sigmaPCB levels and residential distance from the Superfund site. Similar results were found with light and heavy PCBs and PCB-118. Previously reported demographic (age) and other (lactation, smoking, diet) correlates of PCB exposure, as well as local factors (consumption of local dairy products and Superfund site dredging) but not residential proximity to the site, were important determinants of cord serum PCB levels in the study community.
Hemodynamic evaluation of molsidomine: A vasodilator with antianginal properties in patients with alcoholic cirrhosis
Authors: Jean Pierre Vinel, Jean-Luc Monnin, Jean-Marc Combis, Paul Cales, Herve Desmorat, Jean-Pierre Pascal
Journal: Hepatology (1990)

Organic nitrates were reported to reduce portohepatic venous pressure gradient in patients with cirrhosis. However, these drugs lower arterial pressure and are well known to induce tolerance. The aim of the present study was to assess the hemodynamic effects of molsidomine, an antianginal agent, which does not induce tolerance and has little effect on arterial pressure in patients with normal liver, in 13 patients with alcoholic cirrhosis. Wedged hepatic vein pressure (-11%, p less than 0.01), portohepatic venous pressure gradient (-15%, p less than 0.005), hepatic blood flow (-17.4%, p less than 0.005), mean arterial pressure (-13.5%, p less than 0.01) and cardiac output (-17%, p less than 0.001) were significantly reduced by molsidomine. Free hepatic vein pressure, intrinsic hepatic clearance indocyanine green, heart rate and systemic vascular resistances were not significantly modified. There was no correlation between the decrease in portohepatic venous pressure gradient and the reduction in mean arterial pressure on one hand and the decrease in cardiac output on the other hand. We therefore conclude that in patients with cirrhosis, molsidomine has effects similar to nitrates on systemic and splanchnic hemodynamics.
A Podocyte-Based Automated Screening Assay Identifies Protective Small Molecules
Authors: Ha Won Lee, Samia Q. Khan, Mohd Hafeez Faridi, Changli Wei, Nicholas J. Tardi, Mehmet M. Altintas, Hatem A. Elshabrawy, Steve Mangos, Kevin L. Quick, Sanja Sever, Jochen Reiser, Vineet Gupta
Journal: Journal of the American Society of Nephrology (2015)

Podocyte injury and loss mark an early step in the pathogenesis of various glomerular diseases, making these cells excellent targets for therapeutics. However, cell-based high-throughput screening assays for the rational development of podocyte-directed therapeutics are currently lacking. Here, we describe a novel high-content screening-based phenotypic assay that analyzes thousands of podocytes per assay condition in 96-well plates to quantitatively measure dose-dependent changes in multiple cellular features. Our assay consistently produced a Z' value >0.44, making it suitable for compound screening. On screening with >2100 pharmacologically active agents, we identified 24 small molecules that protected podocytes against injury in vitro (1% hit rate). Among the identified hits, we confirmed an β1-integrin agonist, pyrintegrin, as a podocyte-protective agent. Treatment with pyrintegrin prevented damage-induced decreases in F-actin stress fibers, focal adhesions, and active β1-integrin levels in cultured cells. In vivo, administration of pyrintegrin protected mice from LPS-induced podocyte foot process effacement and proteinuria. Analysis of the murine glomeruli showed that LPS administration reduced the levels of active β1 integrin in the podocytes, which was prevented by cotreatment with pyrintegrin. In rats, pyrintegrin reduced peak proteinuria caused by puromycin aminonucleoside-induced nephropathy. Our findings identify pyrintegrin as a potential therapeutic candidate and show the use of podocyte-based screening assays for identifying novel therapeutics for proteinuric kidney diseases.
Anti-Neutrophil Cytoplasmic Antibodies Stimulate Release of Neutrophil Microparticles
Authors: Ying Hong, Despina Eleftheriou, Abdullah A.K. Hussain, Fiona E. Price-Kuehne, Caroline O. Savage, David Jayne, Mark A. Little, Alan D. Salama, Nigel J. Klein, Paul A. Brogan
Journal: Journal of the American Society of Nephrology (2011)

The mechanisms by which anti-neutrophil cytoplasmic antibodies (ANCAs) may contribute to the pathogenesis of ANCA-associated vasculitis are not well understood. In this study, both polyclonal ANCAs isolated from patients and chimeric proteinase 3–ANCA induced the release of neutrophil microparticles from primed neutrophils. These microparticles expressed a variety of markers, including the ANCA autoantigens proteinase 3 and myeloperoxidase. They bound endothelial cells via a CD18-mediated mechanism and induced an increase in endothelial intercellular adhesion molecule-1 expression, production of endothelial reactive oxygen species, and release of endothelial IL-6 and IL-8. Removal of the neutrophil microparticles by filtration or inhibition of reactive oxygen species production with antioxidants abolished microparticle-mediated endothelial activation. In addition, these microparticles promoted the generation of thrombin. In vivo, we detected more neutrophil microparticles in the plasma of children with ANCA-associated vasculitis compared with that in healthy controls or those with inactive vasculitis. Taken together, these results support a role for neutrophil microparticles in the pathogenesis of ANCA-associated vasculitis, potentially providing a target for future therapeutics.
Maternal dietary patterns and preterm delivery: results from large prospective cohort study
Authors: L. Englund-Ogge, A. L. Brantsaeter, V. Sengpiel, M. Haugen, B. E. Birgisdottir, R. Myhre, H. M. Meltzer, B. Jacobsson
Journal: BMJ (2014)

To examine whether an association exists between maternal dietary patterns and risk of preterm delivery.Prospective cohort study.Norway, between 2002 and 2008.66 000 pregnant women (singletons, answered food frequency questionnaire, no missing information about parity or previously preterm delivery, pregnancy duration between 22+0 and 41+6 gestational weeks, no diabetes, first enrolment pregnancy).Hazard ratio for preterm delivery according to level of adherence to three distinct dietary patterns interpreted as "prudent" (for example, vegetables, fruits, oils, water as beverage, whole grain cereals, fibre rich bread), "Western" (salty and sweet snacks, white bread, desserts, processed meat products), and "traditional" (potatoes, fish).After adjustment for covariates, high scores on the "prudent" pattern were associated with significantly reduced risk of preterm delivery hazard ratio for the highest versus the lowest third (0.88, 95% confidence interval 0.80 to 0.97). The prudent pattern was also associated with a significantly lower risk of late and spontaneous preterm delivery. No independent association with preterm delivery was found for the "Western" pattern. The "traditional" pattern was associated with reduced risk of preterm delivery for the highest versus the lowest third (hazard ratio 0.91, 0.83 to 0.99).This study showed that women adhering to a "prudent" or a "traditional" dietary pattern during pregnancy were at lower risk of preterm delivery compared with other women. Although these findings cannot establish causality, they support dietary advice to pregnant women to eat a balanced diet including vegetables, fruit, whole grains, and fish and to drink water. Our results indicate that increasing the intake of foods associated with a prudent dietary pattern is more important than totally excluding processed food, fast food, junk food, and snacks.
Interleukin 3 protects murine bone marrow cells from apoptosis induced by DNA damaging agents.
Authors: M K Collins, J Marvel, P Malde, A Lopez-Rivas
Journal: The Journal of Experimental Medicine (1992)

Murine bone marrow-derived cells, dependent on interleukin 3 (IL-3) for their growth in culture, undergo programmed cell, or apoptosis, upon cytokine withdrawal. Here it is reported that a variety of DNA damaging agents cause a more rapid onset of apoptosis in a factor-dependent cell line, BAF3, deprived of IL-3. In contrast, when cultured in the presence of IL-3, or other growth promoting factors, BAF3 cells are highly resistant to X-irradiation and the cytotoxic drugs etoposide and cisplatin. Overexpression of the bcl2 gene product also protects BAF3 cells from DNA damage. The presence of IL-3 is not required during the initial events of DNA damage or its repair. In the absence of IL-3, cells still complete the repair of DNA breaks within 15 min, and continue to cycle for 5 h. At this time, IL-3 is necessary to prevent the accelerated onset of DNA cleavage from a G2 arrest point.
On-Pump versus Off-Pump Coronary-Artery Bypass Surgery
Authors: A. Laurie Shroyer, Frederick L. Grover, Brack Hattler, Joseph F. Collins, Gerald O. McDonald, Elizabeth Kozora, John C. Lucke, Janet H. Baltz, Dimitri Novitzky
Journal: New England Journal of Medicine (2009)

Coronary-artery bypass grafting (CABG) has traditionally been performed with the use of cardiopulmonary bypass (on-pump CABG). CABG without cardiopulmonary bypass (off-pump CABG) might reduce the number of complications related to the heart-lung machine.We randomly assigned 2203 patients scheduled for urgent or elective CABG to either on-pump or off-pump procedures. The primary short-term end point was a composite of death or complications (reoperation, new mechanical support, cardiac arrest, coma, stroke, or renal failure) before discharge or within 30 days after surgery. The primary long-term end point was a composite of death from any cause, a repeat revascularization procedure, or a nonfatal myocardial infarction within 1 year after surgery. Secondary end points included the completeness of revascularization, graft patency at 1 year, neuropsychological outcomes, and the use of major resources.There was no significant difference between off-pump and on-pump CABG in the rate of the 30-day composite outcome (7.0% and 5.6%, respectively; P=0.19). The rate of the 1-year composite outcome was higher for off-pump than for on-pump CABG (9.9% vs. 7.4%, P=0.04). The proportion of patients with fewer grafts completed than originally planned was higher with off-pump CABG than with on-pump CABG (17.8% vs. 11.1%, P<0.001). Follow-up angiograms in 1371 patients who underwent 4093 grafts revealed that the overall rate of graft patency was lower in the off-pump group than in the on-pump group (82.6% vs. 87.8%, P<0.01). There were no treatment-based differences in neuropsychological outcomes or short-term use of major resources.At 1 year of follow-up, patients in the off-pump group had worse composite outcomes and poorer graft patency than did patients in the on-pump group. No significant differences between the techniques were found in neuropsychological outcomes or use of major resources. (ClinicalTrials.gov number, NCT00032630.).
Cytoplasmic Estrogen Receptor in Breast Cancer
Authors: Allison W. Welsh, Donald R. Lannin, Gregory S. Young, Mark E. Sherman, Jonine D. Figueroa, N. Lynn Henry, Lisa Ryden, Chungyeul Kim, Richard R. Love, Rachel Schiff, David L. Rimm
Journal: Clinical Cancer Research (2011)

Abstract Purpose: In addition to genomic signaling, it is accepted that estrogen receptor-α (ERα) has nonnuclear signaling functions, which correlate with tamoxifen resistance in preclinical models. However, evidence for cytoplasmic ER localization in human breast tumors is less established. We sought to determine the presence and implications of nonnuclear ER in clinical specimens. Experimental Design: A panel of ERα-specific antibodies (SP1, MC20, F10, 60c, and 1D5) was validated by Western blot and quantitative immunofluorescent (QIF) analysis of cell lines and patient controls. Then eight retrospective cohorts collected on tissue microarrays were assessed for cytoplasmic ER. Four cohorts were from Yale (YTMA 49, 107, 130, and 128) and four others (NCI YTMA 99, South Swedish Breast Cancer Group SBII, NSABP B14, and a Vietnamese Cohort) from other sites around the world. Results: Four of the antibodies specifically recognized ER by Western and QIF analysis, showed linear increases in amounts of ER in cell line series with progressively increasing ER, and the antibodies were reproducible on YTMA 49 with Pearson correlations (r2 values) ranging from 0.87 to 0.94. One antibody with striking cytoplasmic staining (MC20) failed validation. We found evidence for specific cytoplasmic staining with the other four antibodies across eight cohorts. The average incidence was 1.5%, ranging from 0 to 3.2%. Conclusions: Our data show ERα is present in the cytoplasm in a number of cases using multiple antibodies while reinforcing the importance of antibody validation. In nearly 3,200 cases, cytoplasmic ER is present at very low incidence, suggesting its measurement is unlikely to be of routine clinical value. Clin Cancer Res; 18(1); 118–26. ©2011 AACR.