tbuckley/cabot-search huggingface dataset:
Shear Stress Induces ATP-Independent Transient Nitric Oxide Release From Vascular Endothelial Cells, Measured Directly With a Porphyrinic Microsensor
Authors: Anthony J. Kanai, Harold C. Strauss, George A. Truskey, Anne L. Crews, Saul Grunfeld, Tadeusz Malinski
Journal: Circulation Research (1995)

Abstract Shear stress causes the vascular endothelium to release nitric oxide (NO), which is an important regulator of vascular tone. However, direct measurement of NO release after the imposition of laminar flow has not been previously accomplished because of chemical (oxidative degradation) and physical (diffusion, convection, and washout) complications. Consequently, the mechanism, time course, kinetics, and Ca 2+ dependence of NO release due to shear stress remain incompletely understood. In this study, we characterized these parameters by using fura 2 fluorescence and a polymeric porphyrin/Nafion-coated carbon fiber microsensor (detection limit, 5 nmol/L; response time, 1 millisecond) to directly measure changes in [Ca 2+ ] i and NO release due to shear stress or agonist (ATP or brominated Ca 2+ ionophore [Br-A23187]) from bovine aortic endothelial cells. The cells were grown to confluence on glass coverslips, loaded with fura 2-AM, and mounted in a parallel-plate flow chamber (volume, 25 μL). The microsensor was positioned ≈100 μm above the cells with its long axis parallel to the direction of flow. Laminar flow of perfusate was maintained from 0.04 to 1.90 mL/min, which produced shear stresses of 0.2 to 10 dyne/cm 2 . Shear stress caused transient NO release 3 to 5 seconds after the initiation of flow and 1 to 3 seconds after the rise in [Ca 2+ ] i , which reached a plateau after 35 to 70 seconds. Although the amount (peak rate) of NO release increased as a function of the shear stress (0.08 to 3.80 pmol/s), because of the concomitant increase in the flow rate, the peak NO concentration (133±9 nmol/L) remained constant. Maintenance of flow resulted in additional transient NO release, with peak-to-peak intervals of 15.5±2.5 minutes. During this 13- to 18-minute period, when the cells were unresponsive to shear stress, exogenous ATP (10 μmol/L) or Br-A23187 (10 μmol/L) evoked NO release. Prior incubation of the cells with exogenous NO or the removal and EGTA (100 μmol/L) chelation of extracellular Ca 2+ blocked shear stress but not ATP-dependent NO release. The kinetics of shear stress–induced NO release (2.23±0.07 nmol/L per second) closely resembled the kinetics of Ca 2+ flux but differed markedly from the kinetics of ATP-induced NO release (5.64±0.32 nmol/L per second). These data argue that shear stress causes a Ca 2+ -mediated ATP-independent transient release of NO, where the peak rate of release but not the peak concentration depends on the level of shear stress. The transient nature of this response may be due to NO-induced inhibition of Ca 2+ influx via a mechanism yet to be determined.
Conservation and Functional Element Discovery in 20 Angiosperm Plant Genomes
Authors: D. Hupalo, A. D. Kern
Journal: Molecular Biology and Evolution (2013)

Here, we describe the construction of a phylogenetically deep, whole-genome alignment of 20 flowering plants, along with an analysis of plant genome conservation. Each included angiosperm genome was aligned to a reference genome, Arabidopsis thaliana, using the LASTZ/MULTIZ paradigm and tools from the University of California–Santa Cruz Genome Browser source code. In addition to the multiple alignment, we created a local genome browser displaying multiple tracks of newly generated genome annotation, as well as annotation sourced from published data of other research groups. An investigation into A. thaliana gene features present in the aligned A. lyrata genome revealed better conservation of start codons, stop codons, and splice sites within our alignments (51% of features from A. thaliana conserved without interruption in A. lyrata) when compared with previous publicly available plant pairwise alignments (34% of features conserved). The detailed view of conservation across angiosperms revealed not only high coding-sequence conservation but also a large set of previously uncharacterized intergenic conservation. From this, we annotated the collection of conserved features, revealing dozens of putative noncoding RNAs, including some with recorded small RNA expression. Comparing conservation between kingdoms revealed a faster decay of vertebrate genome features when compared with angiosperm genomes. Finally, conserved sequences were searched for folding RNA features, including but not limited to noncoding RNA (ncRNA) genes. Among these, we highlight a double hairpin in the 5′-untranslated region (5′-UTR) of the PRIN2 gene and a putative ncRNA with homology targeting the LAF3 protein.
Mortality Among Workers in a Nickel Refinery and Alloy Manufacturing Plant in West Virginia&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: P E Enterline, G M Marsh
Journal: JNCI Journal of the National Cancer Institute (1982)

Workers from a nickel refinery at Huntington, W. Va., which received a nickel matte from smelters in Ontario, Canada, during 1922-47 were studied for excesses in sinonasal and lung cancers. Other workers who were in a nickel alloy production plant operated in conjunction with the refinery but who did not work in the refinery were also studied. Evidence is presented on the existence of a nasal cancer hazard and possibly a lung cancer hazard among workers employed in the nickel refinery. Two of these workers developed a sinonasal cancer. Evidence of a respiratory cancer hazard in other parts of the plant before or after 1947 is weak, and the observed results could be due to chance variations from the mortality experience of the standard reference populations. Among nonrefinery workers hired while the nickel refinery was in operation, 2 employees had a probable sinonasal cancer. The first employee worked in a high-temperature conversion process where nickel carbonate was decomposed to nickel oxide, and the second employee is believed to have done maintenance work in the plant where this process was used. For both cohorts combined there were slight overall excesses in lung, stomach, and prostate cancers with some evidence of a dose-response relationship for these cancers.
Effects of nedocromil and salbutamol on airway reactivity in children with asthma
Authors: A. Pfleger, E. Eber, E. Weinhandl, M.S. Zach
Journal: European Respiratory Journal (2002)

Nedocromil and salbutamol are effective drugs in preventing exercise-induced asthma (EIA). The aim of this study was to compare the protective effects of both drugs and a combination of both drugs against cold dry air-induced bronchoconstriction, using cold dry air challenges (CACh) as a surrogate for exercise. Twenty-five atopic children (mean age 13.7, range 8–18 yrs) with EIA participated in the study. Lung function tests were performed before medication, 30 min after medication and just before CACh, and 3 and 15 min after the challenge on four consecutive days. CACh consisted of a 4-min isocapnic hyperpnoea of −10°C, absolutely dry air. Treatment consisted of nedocromil (two puffs of 2 mg) plus placebo, salbutamol (two puffs of 100 µg) plus placebo, the combination of both drugs, and placebo alone, in a random order. Both active drugs were significantly more protective than placebo and the combination showed an additive effect. Mean maximum postchallenge decrease in forced expiratory volume in one second after placebo was 27±8.1%, 12±9.5% after nedocromil, 8±10.4% after salbutamol, and 4.5±6.7% after the combination of both drugs, respectively. These results suggest that both drugs protect against exercise-induced asthma. Although not as effective as salbutamol and combined medication, nedocromil can give sufficient protection for many patients.
Right coronary pressure modulates right ventricular systolic stiffness and oxygen consumption
Authors: X Bian
Journal: Cardiovascular Research (1999)

The low transmural pressure of the thin right ventricular (RV) wall may render it responsive to right coronary (RC) pressure-induced changes in systolic stiffness and account for the dependence of RV MVO2 on RC pressure (RCP).In eight dogs anesthetized with pentobarbital and fentanyl, RCP was lowered from the baseline to 30 mmHg in 10 mmHg steps by adjusting an occluder on the proximal RC. Myocardial segment length and isometric developed force were measured, and the slope of the force-length curve during ejection period (delta F/ delta SL) was used as an index of systolic myocardial stiffness. MVO2 was calculated from RC flow and arteriovenous O2 difference.As RCP was varied from 120 to 40 mmHg with positive lactate uptake, RC flow, maximum developed force (Fmax), delta F, and MVO2 decreased linearly, whereas end-diastolic length, delta SL, and other hemodynamic variables stayed constant. Thus, RV systolic stiffness fell linearly with RC pressure. When RCP was further lowered from 40 to 30 mmHg, Fmax and delta F continued to fall, end-diastolic segment length and right atrial pressure increased significantly, delta SL and RV dp/dtmax fell significantly, and delta F/delta SL reached its lowest value. RV systolic stiffness was 22% of previously reported left ventricular systolic stiffness for coronary perfusion pressure at 100 mmHg, and varied less steeply with coronary pressure.(1) Reductions in RV systolic stiffness preserve delta SL as coronary pressure is reduced over a wide range. (2) The resulting increase in RV efficiency reduces oxygen demand as oxygen supply is reduced, so ischemia is avoided. (3) RV systolic stiffness is much less than left ventricular stiffness, consistent with their anatomical and functional differences.
Resistance and Aerobic Exercise Among Adults With Diabetes in the U.S.
Authors: Lin Mu, Aaron J. Cohen, Kenneth J. Mukamal
Journal: Diabetes Care (2014)

Diabetes affects muscle and bone health and is characterized by osteoporosis and reduced bone quality (1). Resistance training improves insulin sensitivity, HbA1c, lipid profile, blood pressure, bone development, physical performance, and quality of life (2,3), and serves as a promising intervention for diabetes management. Indeed, the American Diabetes Association (ADA) has published specific guidelines on resistance exercise for adults with diabetes that exceed those for the general public (4). To ascertain adherence to guidelines for resistance training and aerobic exercise, we examined the proportion of diabetic Americans who meet these guidelines.

We used the 2011 administration of the Behavioral Risk Factor Surveillance System (BRFSS) conducted by the Centers for Disease Control and Prevention (CDC). In this large, anonymous telephone survey, respondents reported, during the past month, 1 ) the frequency and duration of the two leisure-time aerobic activities …
Breath Methane Excretion in Patients With Unresected Colorectal Cancer&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: D A Karlin, R D Jones, J R Stroehlein, A J Mastromarino, G D Potter
Journal: JNCI Journal of the National Cancer Institute (1982)

The objective of our study was to verify or refute the observation that patients with unresected colorectal cancer are more likely to be breath methane excretors than the general population. Intracolonic heme had no effect on breath methane excretion of 11 normal volunteers given oral hemoglobin. Laxative-enema colonoscopy preparation had a profound effect on the subsequent measurement of breath methane. Three of 4 volunteer methane excretors became nonexcretors, and 2 remained nonexcretors for 21 days and 7 months, respectively. No significant difference was found in the frequency and the amount of breath methane excretion in 55 patients with unresected colorectal cancer and in 99 control subjects. However, 13 patients with unresected descending or sigmoid colon cancers were almost twice as likely to be breath methane excretors as 38 patients with colorectal cancer at other sites.
865 THE PROTEIN PHOSPHATASE ACTIVITY OF PTEN CONTROLS THE CHOLESTEROL METABOLISM IN HEPATOCYTES AND PREVENTS HCV SECRETION BY INFECTED CELLS
Authors: M. Peyrou, S. Clement, C. Maier, L. Bourgoin, E. Branche, S. Conzelmann, V. Kaddai, M. Foti, F. Negro
Journal: Journal of Hepatology (2012)
Combined Microsatellite Instability, <i>MLH1</i> Methylation Analysis, and Immunohistochemistry for Lynch Syndrome Screening in Endometrial Cancers From GOG210: An NRG Oncology and Gynecologic Oncology Group Study
Authors: Paul J. Goodfellow, Caroline C. Billingsley, Heather A. Lankes, Shamshad Ali, David E. Cohn, Russell J. Broaddus, Nilsa Ramirez, Colin C. Pritchard, Heather Hampel, Alexis S. Chassen, Luke V. Simmons, Amy P. Schmidt, Feng Gao, Louise A. Brinton, Floor Backes, Lisa M. Landrum, Melissa A. Geller, Paul A. DiSilvestro, Michael L. Pearl, Shashikant B. Lele, Matthew A. Powell, Richard J. Zaino, David Mutch
Journal: Journal of Clinical Oncology (2015)

Purpose The best screening practice for Lynch syndrome (LS) in endometrial cancer (EC) remains unknown. We sought to determine whether tumor microsatellite instability (MSI) typing along with immunohistochemistry (IHC) and MLH1 methylation analysis can help identify women with LS. Patients and Methods ECs from GOG210 patients were assessed for MSI, MLH1 methylation, and mismatch repair (MMR) protein expression. Each tumor was classified as having normal MMR, defective MMR associated with MLH1 methylation, or probable MMR mutation (ie, defective MMR but no methylation). Cancer family history and demographic and clinical features were compared for the three groups. Lynch mutation testing was performed for a subset of women. Results Analysis of 1,002 ECs suggested possible MMR mutation in 11.8% of tumors. The number of patients with a family history suggestive of LS was highest among women whose tumors were classified as probable MMR mutation (P = .001). Lynch mutations were identified in 41% of patient cases classified as probable mutation (21 of 51 tested). One of the MSH6 Lynch mutations was identified in a patient whose tumor had intact MSH6 expression. Age at diagnosis was younger for mutation carriers than noncarriers (54.3 v 62.3 years; P &lt; .01), with five carriers diagnosed at age &gt; 60 years. Conclusion Combined MSI, methylation, and IHC analysis may prove useful in Lynch screening in EC. Twenty-four percent of mutation carriers presented with ECs at age &gt; 60 years, and one carrier had an MSI-positive tumor with no IHC defect. Restricting Lynch testing to women diagnosed at age &lt; 60 years or to women with IHC defects could result in missing a substantial fraction of genetic disease.
Mutant N-RAS Protects Colorectal Cancer Cells from Stress-Induced Apoptosis and Contributes to Cancer Development and Progression
Authors: Yufang Wang, Sérgia Velho, Efsevia Vakiani, Shouyong Peng, Adam J. Bass, Gerald C. Chu, Jessica Gierut, James M. Bugni, Channing J. Der, Mark Philips, David B. Solit, Kevin M. Haigis
Journal: Cancer Discovery (2012)

Abstract N-RAS is one member of a family of oncoproteins that are commonly mutated in cancer. Activating mutations in NRAS occur in a subset of colorectal cancers, but little is known about how the mutant protein contributes to the onset and progression of the disease. Using genetically engineered mice, we find that mutant N-RAS strongly promotes tumorigenesis in the context of inflammation. The protumorigenic nature of mutant N-RAS is related to its antiapoptotic function, which is mediated by activation of a noncanonical mitogen-activated protein kinase pathway that signals through STAT3. As a result, inhibition of MAP–ERK kinase selectively induces apoptosis in autochthonous colonic tumors expressing mutant N-RAS. The translational significance of this finding is highlighted by our observation that NRAS mutation correlates with a less favorable clinical outcome for patients with colorectal cancer. These data show for the first time the important role that N-RAS plays in colorectal cancer. Significance: Little is known about N-RAS function in normal biology or in cancer. Our study links the antiapoptotic function of mutant N-RAS to its ability to promote colorectal cancer in an inflammatory context. In addition, our study pinpoints a therapeutic strategy for this distinct colorectal cancer subtype. Cancer Discov; 3(3); 294–307. ©2013 AACR. This article is highlighted in the In This Issue feature, p. 239
Chimeric Transcript Generated by cis-Splicing of Adjacent Genes Regulates Prostate Cancer Cell Proliferation
Authors: Yanmei Zhang, Mei Gong, Huiling Yuan, Hong G. Park, Henry F. Frierson, Hui Li
Journal: Cancer Discovery (2012)

Gene fusion is a common event in cancer. The fusion RNA and protein products often play causal roles in tumorigenesis and therefore represent ideal diagnostic and therapeutic targets. Formerly, fusion chimeric products in cancer were thought to be produced solely by chromosomal translocation. Here, we show that a chimeric SLC45A3-ELK4 RNA is generated in the absence of chromosomal rearrangement. We showed that it is not a product of RNA trans-splicing, but formed by cis-splicing of adjacent genes/read-through. The binding of CCCTC-binding factor (CTCF) to the insulator sequences inversely correlates with the expression of the chimera transcript. The SLC45A3-ELK4 fusion, but not wild-type, ELK4 plays important roles in regulating cell growth in both androgen-dependent and -independent prostate cancer cells. The level of the chimeric transcript correlates with disease progression, with the highest levels in prostate cancer metastases. Our results suggest that gene fusions can arise from cis-splicing of adjacent genes without corresponding DNA changes.With the absence of corresponding DNA rearrangement, chimeric fusion SLC45A3-ELK4 transcript in prostate cancer cells is generated by cis-splicing of adjacent genes/gene read-through instead of trans-splicing. SLC45A3-ELK4 controls prostate cancer cell proliferation, and the chimera level correlates with prostate cancer disease progression.
Enhanced cytotoxicity of allogeneic NK cells with killer immunoglobulin-like receptor ligand incompatibility against melanoma and renal cell carcinoma cells
Authors: Takehito Igarashi, Jason Wynberg, Ramprasad Srinivasan, Brian Becknell, J. Phillip McCoy, Yoshiyuki Takahashi, Dante A. Suffredini, W. Marston Linehan, Michael A. Caligiuri, Richard W. Childs
Journal: Blood (2004)
Suppression of Casein Kinase 1α in Melanoma Cells Induces a Switch in β-Catenin Signaling to Promote Metastasis
Authors: Tobias Sinnberg, Moritz Menzel, Susanne Kaesler, Tilo Biedermann, Birgit Sauer, Sven Nahnsen, Michael Schwarz, Claus Garbe, Birgit Schittek
Journal: Cancer Research (2010)

Casein kinase 1 alpha (CK1alpha) is a multifunctional Ser/Thr kinase that phosphorylates several substrates. Among those is beta-catenin, an important player in cell adhesion and Wnt signaling. Phosphorylation of beta-catenin by CK1alpha at Ser45 is the priming reaction for the proteasomal degradation of beta-catenin. Interestingly, aside from this role in beta-catenin degradation, very little is known about the expression and functional role of CK1alpha in tumor cells. Here, we show that CK1alpha expression in different tumor types is either strongly suppressed or completely lost during tumor progression and that CK1alpha is a key factor determining beta-catenin stability and transcriptional activity in tumor cells. CK1alpha reexpression in metastatic melanoma cells reduces growth in vitro and metastasis formation in vivo, and induces cell cycle arrest and apoptosis, whereas suppression of CK1alpha in primary melanoma cells induces invasive tumor growth. Inactivation of CK1alpha promotes tumor progression by regulating a switch in beta-catenin-mediated signaling. These results show that melanoma cells developed an efficient new mechanism to activate the beta-catenin signaling pathway and define CK1alpha as a novel tumor suppressor.
Prone ventilation reduces mortality in patients with acute respiratory failure and severe hypoxemia: systematic review and meta-analysis
Authors: Sachin Sud, Jan O. Friedrich, Paolo Taccone, Federico Polli, Neill K. J. Adhikari, Roberto Latini, Antonio Pesenti, Claude Guérin, Jordi Mancebo, Martha A. Q. Curley, Rafael Fernandez, Ming-Cheng Chan, Pascal Beuret, Gregor Voggenreiter, Maneesh Sud, Gianni Tognoni, Luciano Gattinoni
Journal: Intensive Care Medicine (2010)
Body Mass, Fat-Free Body Mass, and Prognosis in Patients with Chronic Obstructive Pulmonary Disease from a Random Population Sample
Authors: Jørgen Vestbo, Eva Prescott, Thomas Almdal, Morten Dahl, Børge G. Nordestgaard, Teis Andersen, Thorkild I. A. Sørensen, Peter Lange
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Low body mass index (BMI) is a marker of poor prognosis in chronic obstructive pulmonary disease (COPD). In the general population, the harmful effect of low BMI is due to the deleterious effects of a low fat-free mass index (FFMI; fat-free mass/weight(2)).We explored distribution of low FFMI and its association with prognosis in a population-based cohort of patients with COPD.We used data on 1,898 patients with COPD identified in a population-based epidemiologic study in Copenhagen. FFM was measured using bioelectrical impedance analysis. Patients were followed up for a mean of 7 yr and the association between BMI and FFMI and mortality was examined taking age, sex, smoking, and lung function into account.The mean FFMI was 16.0 kg/m(2) for women and 18.7 kg/m(2) for men. Among subjects with normal BMI, 26.1% had an FFMI lower than the lowest 10th percentile of the general population. BMI and FFMI were significant predictors of mortality, independent of relevant covariates. Being in the lowest 10th percentile of the general population for FFMI was associated with a hazard ratio of 1.5 (95% confidence interval, 1.2-1.8) for overall mortality and 2.4 (1.4-4.0) for COPD-related mortality. FFMI was also a predictor of overall mortality when analyses were restricted to subjects with normal BMI.FFMI provides information in addition to BMI and assessment of FFM should be considered in the routine assessment of COPD.