tbuckley/cabot-search huggingface dataset:
Bronchial obstruction and exhaled nitric oxide response during exercise in cold air
Authors: A Therminarias, MF Oddou, A Favre-Juvin, P Flore, M Delaire
Journal: European Respiratory Journal (1998)

This study examines whether exhausting exercise in cold air induces bronchial obstruction and changes in exhaled [NO] and in exhaled NO output (V'NO). Thus, eight well-trained males performed two incremental exercise tests until exhaustion, followed by 5 min of recovery in temperate (22 degrees C) and cold (-10 degrees C) environments, at random. At -10 degrees C, they were dressed in warm clothes. Ventilation (V'E), oxygen consumption (V'O2), carbon dioxide production, cardiac frequency (fC), and [NO] and V'NO were measured continuously. Before and after each test, the subjects' maximal expiratory flow-volume curves and peak expiratory flow, forced expiratory volume in one second (FEV1) and forced expiratory flow at 25 (FEF25), 50 (FEF50) and 75% (FEF75) of forced vital capacity were determined. At -10 degrees C, significant decreases in FEV1 and FEF75 were observed after exercise. At rest and at the same submaximal intensity, V'O2, V'E and fC did not differ significantly. At rest and up to approximately 50% peak V'O2, [NO] and V'NO values were lower at -10 degrees C than at 22 degrees C. Thereafter, and during recovery, the V'NO response became similar at both -10 and 22 degrees C. This study confirms that considerable hyperpnoea in cold air causes a detectable airway obstruction. This airway cooling also induces an initial decrease in the exhaled NO response. Since endogenous NO-production is involved in bronchial dilation, it cannot be excluded that this lack of production may favour the appearance of airway obstruction.
Effect of Regional Hypoxia on the Distribution of Pulmonary Blood Flow in Man
Authors: Vincent Lopez-Majano, Henry N. Wagner, Ralph H. Twining, Donald E. Tow, Victor Chernick
Journal: Circulation Research (1966)

In ten patients with chronic lung disease unilateral airway hypoxia was produced by having them breathe 100% nitrogen administered for seven minutes via a Carlens catheter while the other lung received 100% oxygen. The partition of pulmonary arterial blood flow between the two lungs was determined by radioisotope scanning following intravenous injection of I 131 macroaggregated human serum albumin (MAA) both during bilateral air breathing and unilateral hypoxia. Unilateral hypoxia produced a 42% decrease in pulmonary blood flow to the hypoxic lung due to ipsilateral vasoconstriction. The response to N 2 was greater when given to the diseased lung, suggesting that the pulmonary vascular bed of the involved lung was incapable of accepting a large increase in the proportion of the cardiac output because the vascular bed was already compromised by disease. Ventilation on the hypoxic side increased by 1.4 liters/min while there was no change on the side receiving 100% oxygen. Since unilateral hypoxia produced both a decreased blood flow and an increased ventilation, it is suggested that the lung is capable of altering regional perfusion and ventilation in a manner ideally suited to minimize the change in alveolar and pulmonary capillary oxygen tension.
CREB Is a Novel Nuclear Target of PTEN Phosphatase
Authors: Tingting Gu, Zhong Zhang, Jianli Wang, Junyi Guo, Wen Hong Shen, Yuxin Yin
Journal: Cancer Research (2011)

PTEN phosphatase is a potent tumor suppressor that regulates multiple cellular functions. In the cytoplasm, PTEN dephosphorylates its primary lipid substrate, phosphatidylinositol 3,4,5-trisphosphate, to antagonize the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway. It has also become increasingly evident that PTEN functions in the nucleus and may play an important part in transcription regulation, but its nuclear targets remain elusive. In this report, we demonstrate the transcription factor cyclic AMP response element-binding protein (CREB) is a protein target of PTEN phosphatase and that PTEN deficiency leads to CREB phosphorylation independent of the PI3K/AKT pathway. Using confocal immunofluorescence and reciprocal immunoprecipitation, we further show that PTEN colocalizes with CREB and physically interacts with CREB. Moreover, we use both in vitro and in vivo experiments to show PTEN can dephosphorylate CREB in a phosphatase-dependent manner, suggesting that CREB is a substrate of PTEN nuclear phosphatase. Loss of Pten results in an elevated RNA level of multiple CREB transcriptional targets and increased cell proliferation, which can be reversed by a nonphosphorylatable CREB mutant or knockdown of CREB. These data reveal a mechanism for PTEN modulation of CREB-mediated gene transcription and cell growth. Our study thus characterizes PTEN as a nuclear phophatase of a transcription factor and identifies CREB as a novel protein target of PTEN phosphatase, which contributes to better understanding of PTEN function in the nucleus.
Opposing Effects of Runx2 and Estradiol on Breast Cancer Cell Proliferation: <i>In Vitro</i> Identification of Reciprocally Regulated Gene Signature Related to Clinical Letrozole Responsiveness
Authors: Nyam-Osor Chimge, Sanjeev K. Baniwal, Jingqin Luo, Simon Coetzee, Omar Khalid, Benjamin P. Berman, Debu Tripathy, Matthew J. Ellis, Baruch Frenkel
Journal: Clinical Cancer Research (2011)

To assess the clinical significance of the interaction between estrogen and Runx2 signaling, previously shown in vitro.MCF7/Rx2(dox) breast cancer cells were treated with estradiol and/or doxycycline to induce Runx2, and global gene expression was profiled to define genes regulated by estradiol, Runx2, or both. Anchorage-independent growth was assessed by soft-agar colony formation assays. Expression of gene sets defined using the MCF7/Rx2(dox) system was analyzed in pre- and on-treatment biopsies from hormone receptor-positive patients undergoing neoadjuvant letrozole treatment in two independent studies, and short-term changes in gene expression were correlated with tumor size reduction or Ki67 index at surgery.Reflecting its oncogenic property, estradiol strongly promoted soft-agar colony formation, whereas Runx2 blocked this process suggesting tumor suppressor property. Transcriptome analysis of MCF7/Rx2(dox) cells treated with estradiol and/or doxycycline showed reciprocal attenuation of Runx2 and estrogen signaling. Correspondingly in breast cancer tumors, expression of estradiol- and Runx2-regulated genes was inversely correlated, and letrozole increased expression of Runx2-stimulated genes, as defined in the MCF7/Rx2(dox) model. Of particular interest was a gene set upregulated by estradiol and downregulated by Runx2 in vitro; its short-term response to letrozole treatment associated with tumor size reduction and Ki67 index at surgery better than other estradiol-regulated gene sets.This work provides clinical evidence for the importance of antagonism between Runx2 and E2 signaling in breast cancer. Likely sensing the tension between them, letrozole responsiveness of a genomic node, positively regulated by estradiol and negatively regulated by Runx2 in vitro, best correlated with the clinical efficacy of letrozole treatment.
A Tumorigenic MLL-Homeobox Network in Human Glioblastoma Stem Cells
Authors: Marco Gallo, Jenny Ho, Fiona J. Coutinho, Robert Vanner, Lilian Lee, Renee Head, Erick K. M. Ling, Ian D. Clarke, Peter B. Dirks
Journal: Cancer Research (2012)

Abstract Glioblastoma growth is driven by cancer cells that have stem cell properties, but molecular determinants of their tumorigenic behavior are poorly defined. In cancer, altered activity of the epigenetic modifiers Polycomb and Trithorax complexes may contribute to the neoplastic phenotype. Here, we provide the first mechanistic insights into the role of the Trithorax protein mixed lineage leukemia (MLL) in maintaining cancer stem cell characteristics in human glioblastoma. We found that MLL directly activates the Homeobox gene HOXA10. In turn, HOXA10 activates a downstream Homeobox network and other genes previously characterized for their role in tumorigenesis. The MLL–Homeobox axis we identified significantly contributes to the tumorigenic potential of glioblastoma stem cells. Our studies suggest a role for MLL in contributing to the epigenetic heterogeneity between tumor-initiating and non–tumor-initiating cells in glioblastoma. Cancer Res; 73(1); 417–27. ©2012 AACR.
CXCR4<sup>+</sup> granulocytes reflect fungal cystic fibrosis lung disease
Authors: Melanie Carevic, Anurag Singh, Nikolaus Rieber, Olaf Eickmeier, Matthias Griese, Andreas Hector, Dominik Hartl
Journal: European Respiratory Journal (2015)

Cystic fibrosis airways are frequently colonised with fungi. However, the interaction of these fungi with immune cells and the clinical relevance in cystic fibrosis lung disease are incompletely understood. We characterised granulocytes in airway fluids and peripheral blood from cystic fibrosis patients with and without fungal colonisation, non-cystic fibrosis disease controls and healthy control subjects cross-sectionally and longitudinally and correlated these findings with lung function parameters. Cystic fibrosis patients with chronic fungal colonisation by Aspergillus fumigatus were characterised by an accumulation of a distinct granulocyte subset, expressing the HIV coreceptor CXCR4. Percentages of airway CXCR4 + granulocytes correlated with lung disease severity in patients with cystic fibrosis. These studies demonstrate that chronic fungal colonisation with A. fumigatus in cystic fibrosis patients is associated with CXCR4 + airway granulocytes, which may serve as a potential biomarker and therapeutic target in fungal cystic fibrosis lung disease.
Tissue Engineering of Ligaments
Authors: G. Vunjak-Novakovic, Gregory Altman, Rebecca Horan, David L. Kaplan
Journal: Annual Review of Biomedical Engineering (2004)

Tissue engineering is emerging as a significant clinical option to address tissue and organ failure by implanting biological substitutes for the compromised tissues. As compared to the transplantation of cells alone, engineered tissues offer the potential advantage of immediate functionality. Engineered tissues can also serve as physiologically relevant models for controlled studies of cells and tissues designed to distinguish the effects of specific signals from the complex milieu of factors present in vivo. A high number of ligament failures and the lack of adequate options to fully restore joint functions have prompted the need to develop new tissue engineering strategies. We discuss the requirements for ligament reconstruction, the available treatment options and their limitations, and then focus on the tissue engineering of ligaments. One representative tissue engineering system involving the integrated use of adult human stem cells, custom-designed scaffolds, and advanced bioreactors with dynamic loading is described.
Treatment Trends, Risk of Lymph Node Metastasis, and Outcomes for Localized Esophageal Cancer
Authors: R. P. Merkow, K. Y. Bilimoria, R. N. Keswani, J. Chung, K. L. Sherman, L. M. Knab, M. C. Posner, D. J. Bentrem
Journal: JNCI Journal of the National Cancer Institute (2014)

Endoscopic resection is increasingly used to treat localized, early-stage esophageal cancer. We sought to assess its adoption, characterize the risks of nodal metastases, and define differences in procedural mortality and 5-year survival between endoscopic and surgical resection in the United States. From the National Cancer Data Base, patients with T1a and T1b lesions were identified. Treatment patterns were characterized, and hierarchical regression methods were used to define predictors and evaluate outcomes. All statistical tests were two-sided. Five thousand three hundred ninety patients were identified and underwent endoscopic (26.5%) or surgical resection (73.5%). Endoscopic resection increased from 19.0% to 53.0% for T1a lesions ( P < .001) and from 6.6% to 20.9% for T1b cancers ( P < .001). The strongest predictors of endoscopic resection were depth of invasion (T1a vs T1b: odds ratio [OR] = 4.45; 95% confidence interval [CI] = 3.76 to 5.27) and patient age of 75 years or older (vs age less than 55 years: OR = 4.86; 95% CI = 3.60 to 6.57). Among patients undergoing surgery, lymph node metastasis was 5.0% for T1a and 16.6% for T1b lesions. Predictors of nodal metastases included tumor size greater than 2cm (vs. <2cm) and intermediate-/high-grade lesions (vs low grade). For example, 0.5% of patients with low-grade T1a lesions less than 2cm had lymph node involvement. The risk of 30-day mortality was less after endoscopic resection (hazard ratio [HR] = 0.33; 95% CI = 0.19 to 0.58) but greater for conditional 5-year survival (HR = 1.63; 95% CI = 1.07 to 2.47). Endoscopic resection has become the most common treatment of T1a esophageal cancer and has increased for T1b cancers. It remains important to balance the risk of nodal metastases and procedural risk when counseling patients regarding their treatment options.
Cerivastatin, a Hydroxymethylglutaryl Coenzyme A Reductase Inhibitor, Improves Endothelial Function in Elderly Diabetic Patients Within 3 Days
Authors: Taku Tsunekawa, Toshio Hayashi, Hatsuyo Kano, Daigo Sumi, Hisako Matsui-Hirai, Navin Kumar Thakur, Kensuke Egashira, Akihisa Iguchi
Journal: Circulation (2001)

Background The short-term effects of hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) on endothelial function at doses that do not affect plasma lipid levels are not known. Methods and Results We investigated the short-term effects of cerivastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, on endothelial function and endothelium-related products in elderly diabetic patients. Twenty-seven elderly diabetic patients (aged 69.3±3.4 years), with or without mild hypercholesterolemia, were enrolled in this study, which tested cerivastatin treatment (0.15 mg/d) for 3 days. Endothelium-dependent flow-mediated dilatation, endothelium-independent dilatation by nitroglycerin in the brachial artery, nitric oxide-related products (nitrite/nitrate and cGMP), endothelium-related products (von Willebrand Factor, soluble vascular cell adhesion molecule-1, and soluble intercellular adhesion molecule-1), and a marker of oxidant stress (8-isoprostane) were assessed. Levels of plasma lipids were not changed before and after treatment with cerivastatin. Flow-mediated dilatation was significantly increased by cerivastatin treatment, as were plasma nitrite/nitrate levels (from 16.9±3.4 to 22.0±3.7 μmol/L, P &lt;0.05) and cGMP values. The percent of nitroglycerin-induced dilatation was not changed. Plasma concentrations of 8-isoprostane decreased, and levels of soluble vascular cell adhesion molecule also tended to decrease with cerivastatin. Conclusions Improvement of endothelial function was in line with antiatherosclerotic effects. Cerivastatin improved impaired endothelial function in the short-term without affecting lipid profiles in elderly diabetic patients. This effect may be partly due to upregulation of endothelial nitric oxide synthase.
Calcium influx through L-type CaV1.2 Ca2+ channels regulates mandibular development
Authors: Kapil V. Ramachandran, Jessica A. Hennessey, Adam S. Barnett, Xinhe Yin, Harriett A. Stadt, Erika Foster, Raj A. Shah, Masayuki Yazawa, Ricardo E. Dolmetsch, Margaret L. Kirby, Geoffrey S. Pitt
Journal: Journal of Clinical Investigation (2013)

The identification of a gain-of-function mutation in CACNA1C as the cause of Timothy Syndrome (TS), a rare disorder characterized by cardiac arrhythmias and syndactyly, highlighted unexpected roles for the L-type voltage-gated Ca2+ channel CaV1.2 in nonexcitable cells. How abnormal Ca2+ influx through CaV1.2 underlies phenotypes such as the accompanying syndactyly or craniofacial abnormalities in the majority of affected individuals is not readily explained by established CaV1.2 roles. Here, we show that CaV1.2 is expressed in the first and second pharyngeal arches within the subset of cells that give rise to jaw primordia. Gain-of-function and loss-of-function studies in mouse, in concert with knockdown/rescue and pharmacological approaches in zebrafish, demonstrated that Ca2+ influx through CaV1.2 regulates jaw development. Cranial neural crest migration was unaffected by CaV1.2 knockdown, suggesting a role for CaV1.2 later in development. Focusing on the mandible, we observed that cellular hypertrophy and hyperplasia depended upon Ca2+ signals through CaV1.2, including those that activated the calcineurin signaling pathway. Together, these results provide new insights into the role of voltage-gated Ca2+ channels in nonexcitable cells during development.
Failure of Anterior Cingulate Activation and Connectivity With the Amygdala During Implicit Regulation of Emotional Processing in Generalized Anxiety Disorder
Authors: Amit Etkin, Katherine E. Prater, Fumiko Hoeft, Vinod Menon, Alan F. Schatzberg
Journal: American Journal of Psychiatry (2010)

Objective Clinical data suggest that abnormalities in the regulation of emotional processing contribute to the pathophysiology of generalized anxiety disorder, yet these abnormalities remain poorly understood at the neurobiological level. The authors recently reported that in healthy volunteers the pregenual anterior cingulate regulates emotional conflict on a trial-by-trial basis by dampening activity in the amygdala. The authors also showed that this process is specific to the regulation of emotional, compared to nonemotional, conflict. Here the authors examined whether this form of noninstructed emotion regulation is perturbed in generalized anxiety disorder. Method Seventeen patients with generalized anxiety disorder and 24 healthy comparison subjects underwent functional MRI while performing an emotional conflict task that involved categorizing facial affect while ignoring overlaid affect label words. Behavioral and neural measures were used to compare trial-by-trial changes in conflict regulation. Results Comparison subjects effectively regulated emotional conflict from trial to trial, even though they were unaware of having done so. By contrast, patients with generalized anxiety disorder were completely unable to regulate emotional conflict and failed to engage the pregenual anterior cingulate in ways that would dampen amygdalar activity. Moreover, performance and brain activation were correlated with symptoms and could be used to accurately classify the two groups. Conclusions These data demonstrate that patients with generalized anxiety disorder show significant deficits in the noninstructed and spontaneous regulation of emotional processing. Conceptualization of anxiety as importantly involving abnormalities in emotion regulation, particularly a type occurring outside of awareness, may open up avenues for novel treatments, such as by targeting the medial prefrontal cortex.
Patient and Psychiatrist Ratings of Hypothetical Schizophrenia Research Protocols: Assessment of Harm Potential and Factors Influencing Participation Decisions
Authors: Laura Weiss Roberts, Teddy D. Warner, Janet L. Brody, Brian Roberts, John Lauriello, Constantine Lyketsos
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: A central ethical issue in schizophrenia research is whether participants are able to provide informed consent, particularly for protocols entailing medication washouts or placebo treatments. Few data show how patients with schizophrenia and psychiatrists assess such scientific designs regarding potential harm, willingness to participate, and the relative influence of clinicians, family members, and financial incentives upon participation decisions. METHOD: In this preliminary study, structured interviews were conducted with schizophrenia patients (N=59), and parallel surveys were completed by attending and resident psychiatrists (N=70). Four hypothetical research protocols were rated. Patients were asked about their own views; psychiatrists provided both their personal views and predictions of patient views. RESULTS: Patients and psychiatrists both perceived substantially different levels of harm across the four protocols, identifying significantly greater harm for medication washouts or placebo treatments. Participants were less willing to enroll in protocols perceived as more harmful. Schizophrenia patients found enrollment decisions relatively easy. Patients and psychiatrists indicated that doctor recommendations, monetary incentives, and, to a lesser extent, family preferences had a mild influence on participation decisions. CONCLUSIONS: Given hypothetical protocols with variable design elements, schizophrenia patients and psychiatrists made meaningful and discerning harm assessments and participation decisions. These findings suggest that schizophrenia patients may have strengths in the research consent process that may not be fully recognized. The impact of outside influences upon research enrollment decisions remains uncertain. While psychiatrists were often accurate in predicting patient responses, data suggest the importance of clarifying views of individual patients regarding specific protocols.
The Value of C-Reactive Protein and Procalcitonin in the Differentiation of Infectious Fever and Tumor-Related Fever in Solid Tumors
Authors: B.F. Gonçalves, L. Pinho, N. Bonito, J.P. Folques Vicente, M.M. Teixeira, H. Gervásio, F. Valido, N. Cunha, P. Gama
Journal: Annals of Oncology (2014)
Screening for Colorectal Cancer
Authors: Jill Jin
Journal: JAMA (2021)

US Preventive Services Task Force; Karina W. Davidson, PhD, MASc; Michael J. Barry, MD; Carol M. Mangione, MD, MSPH; Michael Cabana, MD, MA, MPH; Aaron B. Caughey, MD, PhD; Esa M. Davis, MD, MPH; Katrina E. Donahue, MD, MPH; Chyke A. Doubeni, MD, MPH; Alex H. Krist, MD, MPH; Martha Kubik, PhD, RN; Li Li, MD, PhD, MPH; Gbenga Ogedegbe, MD, MPH; Douglas K. Owens, MD, MS; Lori Pbert, PhD; Michael Silverstein, MD, MPH; James Stevermer, MD, MSPH; Chien-Wen Tseng, MD, MPH, MSEE; John B. Wong, MD
The novel inotropic agent CGP 48506 alters force primarily by Ca2+-independent mechanisms in porcine skinned trabeculae
Authors: S Palmer
Journal: Cardiovascular Research (1996)

Objectives: The aim was to determine whether, and by what mechanism(s), a novel inotropic agent 5-methyl-6-phenyl-1,3,5,6-tetrahydro-3, 6-methano-1, 5-benzodiazocine-2,4-dione (BA 41899) and its enantiomers directly alter the Ca2+ sensitivity of cardiac myofilaments. Methods: Porcine ventricular trabeculae were permeabilised with Triton X-100. The relationship between force and pCa (−log[Ca2+]) was determined in the presence and absence of ATP. Troponin I was extracted, using vanadate, to produce unregulated maximally activated myofilaments. Force and actomyosin ATPase activity were measured simultaneously to determine tension cost (ATPase activity/tension). The effects of the (+) enantiomer (CGP 48506) on the twitch of intact muscle were demonstrated using rat papillary muscle. Results: 100 μM BA 41899 had a pronounced Ca2+ sensitising effect on force production by porcine skinned cardiac fibres, increasing the pCa required for 50% maximal activation by 0.64 units, while suppressing maximum force by 18.3%. Resting tension was unaffected. These actions were primarily caused by CGP 48506 and were concentration dependent. At concentrations less than 100 μM, CGP 48506 also increased twitch amplitude in intact papillary muscles with no effect on resting tension, whereas 100 μM CGP 48506 increased resting force due to a slowing of relaxation. 100 μM CGP 48506 potentiated Ca2+-independent rigor tension in skinned trabeculae, indicating a Ca2+ sensitising mechanism unrelated to Ca2+ binding to troponin C. Tension cost was unaffected by 100 μM CGP 48506 over the entire range of activating Ca2+ concentrations. Suppression of maximum force by CGP 48506 was independent of both Ca2+ concentration and the regulatory troponin complex. Conclusions: Both the increase in Ca2+ sensitivity during submaximal activation and the depression of maximum force which are induced by CGP 48506 in skinned trabeculae occur at least partly through Ca2+-independent mechanisms.