tbuckley/cabot-search huggingface dataset:
Cholesterol Primes Vascular Smooth Muscle to Induce Ca <sup>2</sup> Sensitization Mediated by a Sphingosylphosphorylcholine–Rho-Kinase Pathway
Authors: Noriyasu Morikage, Hiroko Kishi, Masafumi Sato, Fengling Guo, Satoshi Shirao, Takashi Yano, Masaaki Soma, Kimikazu Hamano, Kensuke Esato, Sei Kobayashi
Journal: Circulation Research (2006)

Hypercholesterolemia is a major risk factor involved in abnormal cardiovascular events. Rho-kinase–mediated Ca 2+ sensitization of vascular smooth muscle (VSM) plays a critical role in vasospasm and hypertension. We recently identified sphingosylphosphorylcholine (SPC) and Src family tyrosine kinase (Src-TK) as upstream mediators for the Rho-kinase–mediated Ca 2+ sensitization. Here we report the strong linkage between cholesterol and the Ca 2+ sensitization of VSM mediated by a novel SPC/Src-TK/Rho-kinase pathway in both humans and rabbits. The extent of the sensitization correlated well with the total cholesterol or low-density lipoprotein cholesterol levels in serum. However, an inverse correlation with the serum level of high-density lipoprotein cholesterol was observed, and a correlation with other cardiovascular risk factors was nil. When cholesterol-lowering therapy was given to patients and rabbits with hypercholesterolemia, the SPC-induced contractions diminished. Depletion of VSM cholesterol by β-cyclodextrin resulted in a loss of membrane caveolin-1, a marker of cholesterol-enriched lipid raft, and inhibited the SPC-induced Ca 2+ sensitization and translocation of Rho-kinase from cytosol to the cell membrane. Vasocontractions induced by membrane depolarization and by an adrenergic agonist were cholesterol-independent. Our data support the previously unreported concept that cholesterol potentiates the Ca 2+ sensitization of VSM mediated by a SPC/Src-TK/Rho-kinase pathway, and are also compatible with a role for cholesterol-enriched membrane microdomain, a lipid raft. This process may play an important role in the development of abnormal vascular contractions in patients with hypercholesterolemia.
Patient Anxiety About Prostate Cancer Independently Predicts Early Initiation of Androgen Deprivation Therapy for Biochemical Cancer Recurrence in Older Men: A Prospective Cohort Study
Authors: William Dale, Joshua Hemmerich, Kathryn Bylow, Supriya Mohile, Mary Mullaney, Walter M. Stadler
Journal: Journal of Clinical Oncology (2009)

Androgen deprivation therapy (ADT) is first-line therapy for patients with prostate cancer (PCA) who experience biochemical recurrence (BCR). However, the optimal timing of ADT initiation is uncertain, and earlier ADT initiation can cause toxicities that lower quality of life (QOL). We tested the hypothesis that elevated cancer anxiety leads to earlier ADT initiation for BCR in older men.We conducted a prospective cohort study of older patients with BCR of PCA (n = 67). Patients completed questionnaires at presentation and each follow-up visit until initiation of ADT. PCA-specific anxiety was measured with the Memorial Anxiety Scale for Prostate Cancer (MAX-PC). Other collected data included demographics, clinical information, and general anxiety information. Treating oncologists were surveyed about their recommendations for ADT initiation. The primary outcome was the time to ADT initiation. Univariate, multivariate logistic regression, and time-to-event analyses were conducted to evaluate whether cancer anxiety was a predictor of earlier initiation of ADT.Thirty-three percent of patients initiated ADT at the first or second clinic visit. Elevated PCA anxiety (MAX-PC > 16) was the most robust predictor in multivariate analyses of early initiation (odds ratio [OR], 9.19; P = .01). PSA also independently correlated with early initiation (OR, 1.31; P = .01). PSA did not correlate with MAX-PC.Cancer anxiety independently and robustly predicts earlier ADT initiation in older men with BCR. For older patients with PCA, earlier ADT initiation may not change life expectancy and can negatively impact QOL. PCA-specific anxiety is a potential target for a decision-making intervention in this setting.
Treatment of large airway obstruction in lung cancer using expandable metal stents inserted under direct vision via the fibreoptic bronchoscope.
Authors: G E Wilson, M J Walshaw, C R Hind
Journal: Thorax (1996)

Self-expanding metal stents have been used successfully to overcome large airway obstruction due to malignant pulmonary disease. The technique has been modified to place stents under direct vision using the fibreoptic bronchoscope. The effect of this procedure on lung function and patient well being was investigated in a large series of patients.Fifty six patients with malignant tracheobronchial tumours were treated for symptoms of life threatening airways obstruction or collapse of a lung by the insertion of an expandable metal stent(s) under local anaesthetic using a fibreoptic bronchoscope. All had inoperable cancer and 33 had relapsed after or failed to respond to radiotherapy, chemotherapy, or surgery. Forty seven had primary bronchial carcinomas and nine had metastases from other tumour sites. All but two patients had the stents inserted at one sitting. Measurements were performed in most of the patients before and after stenting and included objective measures (pulmonary function tests, arterial blood gas tensions) and non-objective measures (patient well being, performance status).Overall, 77% of patients showed symptomatic improvement. In those patients in whom measurements were performed two thirds showed improvement in forced expiratory volume in one second (FEV1), forced vital capacity (FVC), peak expiratory flow rate (PEFR) and arterial oxygen tension (PaO2). Medical Research Council dyspnoea score (MRC), Karnofsky, and visual analogue scores (for both breathing and well being) improved in 81% of patients. There were no perioperative deaths. Fifty one patients have died since the procedure with a mean survival of 77 days (range 1-477), and five patients are still alive after a mean of 207 days (range 135-274).In suitable patients with either extraluminal or intraluminal tumour, or both, the insertion of expandable metal stents using a fibreoptic bronchoscope and local anaesthetic is a valuable addition to other palliative therapies in the treatment of lung cancer.
Prespecified Candidate Biomarkers Identify Follicular Lymphoma Patients Who Achieved Longer Progression-Free Survival with Bortezomib–Rituximab Versus Rituximab
Authors: Bertrand Coiffier, Weimin Li, Erin D. Henitz, Jayaprakash D. Karkera, Reyna Favis, Dana Gaffney, Alice Shapiro, Panteli Theocharous, Yusri A. Elsayed, Helgi van de Velde, Michael E. Schaffer, Evgenii A. Osmanov, Xiaonan Hong, Adriana Scheliga, Jiri Mayer, Fritz Offner, Simon Rule, Adriana Teixeira, Joanna Romejko-Jarosinska, Sven de Vos, Michael Crump, Ofer Shpilberg, Pier Luigi Zinzani, Andrew Cakana, Dixie-Lee Esseltine, George Mulligan, Deborah Ricci
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Identify subgroups of patients with relapsed/refractory follicular lymphoma deriving substantial progression-free survival (PFS) benefit with bortezomib–rituximab versus rituximab in the phase III LYM-3001 study. Experimental Design: A total of 676 patients were randomized to five 5-week cycles of bortezomib–rituximab or rituximab. The primary end point was PFS; this prespecified analysis of candidate protein biomarkers and genes was an exploratory objective. Archived tumor tissue and whole blood samples were collected at baseline. Immunohistochemistry and genetic analyses were completed for 4 proteins and 8 genes. Results: In initial pairwise analyses, using individual single-nucleotide polymorphism genotypes, one biomarker pair (PSMB1 P11A C/G heterozygote, low CD68 expression) was associated with a significant PFS benefit with bortezomib–rituximab versus rituximab, controlling for multiple comparison corrections. The pair was analyzed under dominant, recessive, and additive genetic models, with significant association with PFS seen under the dominant model (G/G+C/G). In patients carrying this biomarker pair [PSMB1 P11A G allele, low CD68 expression (≤50 CD68-positive cells), population frequency: 43.6%], median PFS was 14.2 months with bortezomib–rituximab versus 9.1 months with rituximab (HR 0.47, P &amp;lt; 0.0001), and there was a significant overall survival benefit (HR 0.49, P = 0.0461). Response rates were higher and time to next antilymphoma therapy was longer in the bortezomib–rituximab group. In biomarker-negative patients, no significant efficacy differences were seen between treatment groups. Similar proportions of patients had high-risk features in the biomarker-positive and biomarker-negative subsets. Conclusions: Patients with PSMB1 P11A (G allele) and low CD68 expression seemed to have significantly longer PFS and greater clinical benefit with bortezomib–rituximab versus rituximab. Clin Cancer Res; 19(9); 2551–61. ©2013 AACR.
Association of hypertension with T594M mutation in β subunit of epithelial sodium channels in black people resident in London
Authors: EH Baker, YB Dong, GA Sagnella, M Rothwell, AK Onipinla, ND Markandu, FP Cappuccio, DG Cook, A Persu, P Corvol, X Jeunemaitre, ND Carter, GA MacGregor
Journal: The Lancet (1998)
THYMUS-DERIVED ROSETTES ARE NOT "HELPER" CELLS
Authors: B. E. Elliott, J. S. Haskill, M. A. Axelrad
Journal: The Journal of Experimental Medicine (1973)

Rosettes against SRBC were made from normal spleen cells. Although T rosettes tend to dissociate, they could be stabilized with 0.05% sodium azide. A clear separation of nonrosettes, T rosettes, and B rosettes was obtained by subjecting the suspension of splenic rosettes to velocity sedimentation at unit gravity. Each fraction was injected with either normal bone marrow cells or normal thymus cells with antigen into 650-R-irradiated hosts. Direct plaque-forming cells (PFC) were assayed in the spleens 7 days later. Synergism with thymus cells occurred only in the B-rosette fraction; PFC precursors therefore sedimented as B rosettes. Synergism with bone marrow cells occurred only in the nonrosette small lymphocyte fraction; helper cells therefore did not bind detectable numbers of sheep red blood cells (SRBC). Thus T rosettes are not helper cells in the direct PFC response of bone marrow B cells to SRBC.
Effects of angiotensin II generated by an angiotensin converting enzyme-independent pathway on left ventricular performance in the conscious baboon.
Authors: B D Hoit, Y Shao, A Kinoshita, M Gabel, A Husain, R A Walsh
Journal: Journal of Clinical Investigation (1995)

Human chymase is a serine proteinase that converts angiotensin (Ang) I to Ang II independent of angiotensin converting enzyme (ACE) in vitro. The effects of chymase on systemic hemodynamics and left ventricular function in vivo were studied in nine conscious baboons instrumented with a LV micromanometer and LV minor axis and wall thickness sonomicrometer crystal pairs. Measurements were made at baseline and after [Pro11DAla12] Ang I, a specific substrate for human chymase, was given in consecutive fashion as a 0.1 mg bolus, an hour-long intravenous infusion of 5 mg, a 3 mg bolus, and after 5 mg of an Ang II receptor antagonist. [Pro11DAla12]Ang I significantly increased LV systolic and diastolic pressure, LV end-diastolic and end systolic dimensions and the time constant of LV relaxation and significantly decreased LV fractional shortening and wall thickening. Administration of a specific Ang II receptor antagonist reversed all the hemodynamic changes. In separate studies, similar results were obtained in six of the baboons with ACE blockade (20 mg, intravenous captopril). Post-mortem studies indicated that chymase-like activity was widely distributed in multiple tissues. Thus, in primates, Ang I is converted into Ang II by an enzyme with chymase-like activity. This study provides the first in vivo evidence of an ACE-independent pathway for Ang II production.
Pharmacology of Selectin Inhibitors in Ischemia/Reperfusion States
Authors: David J. Lefer
Journal: The Annual Review of Pharmacology and Toxicology (2000)

Recently, the selectin family of glycoprotein adhesion molecules (P-selectin, E-selectin, and L-selectin) has been implicated in the pathogenesis of a number of inflammatory disease states. The selectins modulate the early adhesive interactions between circulating neutrophils and the endothelium. Both P-selectin and E-selectin can be expressed on the surface of endothelial cells following stimulation by a number of inflammatory mediators. In contrast, L-selectin is constitutively expressed on the surface of neutrophils at very high levels. In addition, neutrophils also express ligands for the endothelial selectins, including the carbohydrate sialyl Lewis x and the high-affinity ligand P-selectin glycoprotein ligand 1, which facilitate neutrophil-endothelial interactions. Selectins have been extensively investigated in ischemia/reperfusion injury states. The study of selectin involvement in ischemia/ reperfusion injury has been facilitated by the development of highly specific selectin antagonists, including monoclonal antibodies, carbohydrates, small molecule inhibitors, and soluble forms of P-selectin glycoprotein ligand 1. This article reviews the results of current studies of selectin antagonists in experimental models of ischemia/ reperfusion injury.
Metabolic Alterations and Systemic Inflammation in Obstructive Sleep Apnea among Nonobese and Obese Prepubertal Children
Authors: David Gozal, Oscar Sans Capdevila, Leila Kheirandish-Gozal
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Rationale: Obstructive sleep apnea (OSA) has been associated with a higher prevalence and severity of the metabolic syndrome in adult patients, even after controlling for obesity. In contrast, OSA in prepubertal children does not appear to correlate with the magnitude of such metabolic derangements.Objectives: To further establish the potential mechanistic role of OSA in metabolic regulation in prepubertal children.Methods: Fasting glucose, insulin, C-reactive protein, apolipoprotein B, and serum lipid concentrations were determined during the initial polysomnographic diagnosis of OSA and 6–12 months after adenotonsillectomy in both obese and nonobese children.Measurements and Main Results: Sixty-two children with OSA (37 obese and 25 nonobese), age 7.40 ± 2.6 years (mean ± SD) completed the study. After adenotonsillectomy, significant improvements in apnea–hypopnea index and sleep fragmentation occurred, particularly among nonobese children. In nonobese children, adenotonsillectomy was associated with mild increases in body mass index z scores, no changes in either fasting glucose or insulin, significant increases in high-density lipoprotein and reciprocal decreases in low-density lipoprotein, and reductions in plasma C-reactive protein and apolipoprotein B levels. In obese children, adenotonsillectomy did not result in body mass index or glucose changes, but was associated with marked improvements in all other measures.Conclusions: OSA does not appear to induce insulin resistance in nonobese pediatric patients but seems to play a significant role in obese patients. The significant improvements in lipid profiles, C-reactive protein, and apolipoprotein B after adenotonsillectomy in the two groups suggest a pathogenic role for OSA in lipid homeostasis and systemic inflammation independent of the degree of adiposity.
MMP-1 and Pro-MMP-10 as Potential Urinary Pharmacodynamic Biomarkers of FGFR3-Targeted Therapy in Patients with Bladder Cancer
Authors: Xiangnan Du, Benjamin C. Lin, Qian-Rena Wang, Hao Li, Ellen Ingalla, Janet Tien, Isabelle Rooney, Avi Ashkenazi, Elicia Penuel, Jing Qing
Journal: Clinical Cancer Research (2014)

The aim of this study was to identify noninvasive pharmacodynamic biomarkers of FGFR3-targeted therapies in bladder cancer to facilitate the clinical development of experimental agent targeting FGFR3.Potential soluble pharmacodynamic biomarkers of FGFR3 were identified using a combination of transcriptional profiling and biochemical analyses in preclinical models. Two matrix metalloproteinases (MMP), MMP-1 and MMP-10, were selected for further studies in human bladder cancer xenograft models treated with a specific anti-FGFR3 monoclonal antibody, R3Mab. Serum and urinary levels of MMP-1 and MMP-10 were determined in healthy donors and patients with bladder cancer. The modulation of MMP-1 and MMP-10 by R3Mab in patients with bladder cancer was further evaluated in a phase I dose-escalation study.MMP-1 and MMP-10 mRNA and protein were downmodulated by FGFR3 shRNA and R3Mab in bladder cancer cell lines. FGFR3 signaling promoted the expression and secretion of MMP-1 and pro-MMP-10 in a MEK-dependent fashion. In bladder cancer xenograft models, R3Mab substantially blocked tumor progression and reduced the protein levels of human MMP-1 and pro-MMP-10 in tumor tissues as well as in mouse serum. Furthermore, both MMP-1 and pro-MMP-10 were elevated in the urine of patients with advanced bladder cancer. In a phase I dose-escalation trial, R3Mab administration resulted in an acute reduction of urinary MMP-1 and pro-MMP-10 levels in patients with bladder cancer.These findings reveal a critical role of FGFR3 in regulating MMP-1 and pro-MMP-10 expression and secretion, and identify urinary MMP-1 and pro-MMP-10 as potential pharmacodynamic biomarkers for R3Mab in patients with bladder cancer.
A Model to Select Chemotherapy Regimens for Phase III Trials for Extensive-Stage Small-Cell Lung Cancer
Authors: T. T. Chen
Journal: JNCI Journal of the National Cancer Institute (2000)

Many more phase II studies have favorable outcomes than the subsequent phase III trials. We used historical data from phase II and phase III studies for patients with extensive-stage small-cell lung cancer (SCLC) to generate a statistical model to provide assistance in selecting chemotherapy regimens from phase II studies for subsequent use in phase III randomized studies.Information from 21 phase III trials for patients with extensive-stage SCLC initiated during the period from 1972 through 1990 was reviewed to identify those that were preceded by phase II studies of the same regimen. We used data from all the trial pairs to develop a statistical model in which the number of patients, the median survival of patients, and the number of deaths observed in the phase II trial are used to estimate the statistical power of the subsequent phase III trial. All statistical tests were two-sided.Nine phase II studies were identified that preceded phase III trials of the same regimen. The regimens from two phase II studies with the greatest expected power in the phase III trial (0. 62 and 0.58) both demonstrated significantly prolonged survival when compared with standard treatment in subsequent phase III trials (P<. 001 and P =.002, respectively). The regimens from six of the other phase II studies, for which the median power expected in the phase III trial was 0.28 (range, 0.19-0.52), showed no difference when compared with standard treatment in a phase III trial.Phase II studies for particular regimens that have an expected power of greater than 0.55 provide a reasonable basis for proceeding with a phase III trial.
Macrophages Promote the Invasion of Breast Carcinoma Cells via a Colony-Stimulating Factor-1/Epidermal Growth Factor Paracrine Loop
Authors: Sumanta Goswami, Erik Sahai, Jeffrey B. Wyckoff, Michael Cammer, Dianne Cox, Fiona J. Pixley, E. Richard Stanley, Jeffrey E. Segall, John S. Condeelis
Journal: Cancer Research (2005)

Abstract Previous studies have shown that macrophages and tumor cells are comigratory in mammary tumors and that these cell types are mutually dependent for invasion. Here we show that macrophages and tumor cells are necessary and sufficient for comigration and invasion into collagen I and that this process involves a paracrine loop. Macrophages express epidermal growth factor (EGF), which promotes the formation of elongated protrusions and cell invasion by carcinoma cells. Colony stimulating factor 1 (CSF-1) produced by carcinoma cells promotes the expression of EGF by macrophages. In addition, EGF promotes the expression of CSF-1 by carcinoma cells thereby generating a positive feedback loop. Disruption of this loop by blockade of either EGF receptor or CSF-1 receptor signaling is sufficient to inhibit both macrophage and tumor cell migration and invasion.
‘Is it normal?’ A simple question that often lacks an easy answer
Authors: Selaine Niedel, Martin McKee
Journal: Journal of the Royal Society of Medicine (2014)

Anyone experiencing a change in bodily function must ask ‘is this normal or is it a manifestation of a serious disease’? Often the answer will be obvious, but not always; individuals may delay seeking medical advice until they believe their condition is ‘doctorable’, worthy of utilising a physician’s time. 1 The problems are greatest at the extremes of age. First, any problems will arise in bodies that are anyway undergoing a series of often quite marked changes that are entirely normal. Young children experience marked changes in body size and shape and in the ability to do things, such as walk and control their bodily functions. Very old people may also experience changes, but in the opposite direction as they lose body mass from muscles and bones; they become unable to do things that once were easy, again including walking and controlling their bodily functions. Second, those at the extremes of age are also often dependent on others to recognise the changes to their bodies, to interpret them, and to determine which may require responses by health professionals and which are ‘normal’.
Carotid body and cardiorespiratory alterations in intermittent hypoxia: the oxidative link
Authors: R Del Rio, E A Moya, R Iturriaga
Journal: European Respiratory Journal (2009)

Intermittent hypoxia, a feature of obstructive sleep apnoea, potentiates ventilatory hypoxic responses, alters heart rate variability and produces hypertension, partially owing to an enhanced carotid body responsiveness to hypoxia. Since oxidative stress is a potential mediator of both chemosensory and cardiorespiratory alterations, we hypothesised that an antioxidant treatment may prevent these alterations. Accordingly, we studied the effects of ascorbic acid (1.25 g.L(-1) drinking water) on plasma lipid peroxidation, nitrotyrosine and inducible nitric oxide synthase (iNOS) immunoreactivity in the carotid body, ventilatory and carotid chemosensory responses to acute hypoxia, heart rate variability and arterial blood pressure in male Sprague-Dawley rats exposed to 5% O(2); 12 episodes.h(-1); 8 h.day(-1) or sham condition for 21 days. Intermittent hypoxia increased plasma lipid peroxidation, nitrotyrosine and iNOS expression in the carotid body, enhanced carotid chemosensory and ventilatory hypoxic responses, modified heart rate variability and produced hypertension. Ascorbic acid prevented the increased plasma lipid peroxidation and nitrotyrosine formation within the carotid body, and the enhanced carotid chemosensory and ventilatory responses to hypoxia, as well as heart rate variability alterations and hypertension. The present results support an essential role for oxidative stress in the generation of carotid body chemosensory potentiation and systemic cardiorespiratory alterations induced by intermittent hypoxia.