tbuckley/cabot-search huggingface dataset:
Notch ligand Delta-like 4 regulates disease pathogenesis during respiratory viral infections by modulating Th2 cytokines
Authors: Matthew A. Schaller, Rupak Neupane, Brian D. Rudd, Steven L. Kunkel, Lara E. Kallal, Pamela Lincoln, John B. Lowe, Yunfang Man, Nicholas W. Lukacs
Journal: The Journal of Experimental Medicine (2007)

Recent data have indicated that an important instructive class of signals regulating the immune response is Notch ligand-mediated activation. Using quantitative polymerase chain reaction, we observed that only Delta-like 4 (dll4) was up-regulated on bone marrow-derived dendritic cells after respiratory syncytial virus (RSV) infection, and that it was dependent on MyD88-mediated pathways. Using a polyclonal antibody specific for dll4, the development of RSV-induced disease was examined. Animals treated with anti-dll4 had substantially increased airway hyperresponsiveness compared with control antibody-treated animals. When the lymphocytic lung infiltrate was examined, a significant increase in total CD4+ T cells and activated (perforin+) CD8+ T cells was observed. Isolated lung CD4+ T cells demonstrated significant increases in Th2-type cytokines and a decrease in interferon gamma, demonstrating an association with increased disease pathogenesis. Parallel in vitro studies examining the integrated role of dll4 with interleukin-12 demonstrated that, together, both of these instructive signals direct the immune response toward a more competent, less pathogenic antiviral response. These data demonstrate that dll4-mediated Notch activation is one regulator of antiviral immunity.
Role of angiotensin II in the renal effects induced by nitric oxide and prostaglandin synthesis inhibition.
Authors: M T Llinás, J D González, E Nava, F J Salazar
Journal: Journal of the American Society of Nephrology (1997)

The objective of this study was to examine the renal effects of changes in intrarenal angiotensin II levels during the administration of a cyclooxygenase inhibitor, when nitric oxide synthesis is reduced. In the first group of dogs, the administration of meclofenamate and a subpressor dose of L-NAME induced an increase (P < 0.05) in arterial pressure (14 +/- 2 mm Hg), a decrease (P < 0.05) in RBF (180 +/- 13 to 111 +/- 10 mL/min) and GFR (37 +/- 3 to 24 +/- 5 mL/min), and a reduction in the renal excretory response to a sodium load. In the second group, the administration of a converting enzyme inhibitor prevented the increase in arterial pressure, the renal vasoconstriction, and the increase in the proximal but not the distal tubular sodium reabsorption induced by the inhibition of prostaglandins and nitric oxide synthesis. In the third group, it was found that a small increase in the intrarenal angiotensin II levels, which does not produce changes in renal function in control conditions, induced a significant decrease in RBF (183 +/- 14 to 71 +/- 12 mL/min) and GFR (36 +/- 3 to 13 +/- 4 mL/min) when meclofenamate was administered and nitric oxide synthesis was slightly reduced. The results of this study suggest that renal vasoconstriction and increased proximal sodium reabsorption during the reduction of nitric oxide and prostaglandin synthesis are produced by endogenous angiotensin II levels. These results also suggest that endogenous intrarenal nitric oxide and prostaglandins may serve as homeostatic mediators of angiotensin II effects when the intrarenal levels are inappropriately elevated, as occurs in salt-sensitive hypertension.
EGFR mutation status and survival after diagnosis of brain metastasis in nonsmall cell lung cancer
Authors: A. F. Eichler, K. T. Kahle, D. L. Wang, V. A. Joshi, H. Willers, J. A. Engelman, T. J. Lynch, L. V. Sequist
Journal: Neuro-Oncology (2010)

A small subset of patients with nonsmall cell lung cancer (NSCLC) harbors mutations in the epidermal growth factor receptor (EGFR) that predict unique sensitivity to EGFR tyrosine kinase inhibitors (TKIs). The characteristics and behavior of brain metastases (BMs) in these patients have not been well described. The longitudinal records of all NSCLC patients who underwent EGFR mutation screening at our center from August 2004 to November 2008 were reviewed for eligibility, and 93 patients were identified who developed BM during the course of their disease. Survival was estimated using the Kaplan-Meier method and the log-rank test. Multivariable predictors were assessed via the Cox proportional hazards model. Among the 93 patients with BM, 41 (44%) had mutations in EGFR, including 13 exon 19 deletions and 12 L858R mutations. Eighty-three percent of patients with BM were treated initially with whole brain radiation, either alone (53%) or in combination with craniotomy for neurosurgical resection (22%) or stereotactic radiosurgery (8%). Median survival from the time of BM was 11.7 months and was longer for patients with an EGFR mutation (14.5 vs 7.6 months, P = .09). On multivariable analysis, EGFR mutation (HR: 0.50, 95% CI: 0.30-0.82), age (HR: 1.03, 95% CI: 1.00-1.05), and active extracranial disease (HR: 3.30, 95% CI: 1.70-6.41) were independently associated with survival. In NSCLC patients with BM, EGFR mutation status is associated with improved survival, independent of age, functional status, extracranial disease status, and number of BMs.
MPC-6827: A Small-Molecule Inhibitor of Microtubule Formation That Is Not a Substrate for Multidrug Resistance Pumps
Authors: Shailaja Kasibhatla, Vijay Baichwal, Sui Xiong Cai, Bruce Roth, Ira Skvortsova, Sergej Skvortsov, Peter Lukas, Nicole M. English, Nilantha Sirisoma, John Drewe, Azra Pervin, Ben Tseng, Robert O. Carlson, Christopher M. Pleiman
Journal: Cancer Research (2007)

A novel series of 4-arylaminoquinazolines were identified from a cell-based screening assay as potent apoptosis inducers. Through structure-activity relationship studies, MPC-6827 and its close structural analogue, MPI-0441138, were discovered as proapoptotic molecules and mitotic inhibitors with potencies at low nanomolar concentrations in multiple tumor cell lines. Photoaffinity and radiolabeled analogues of MPC-6827 were found to bind a 55-kDa protein, and this binding was competed by MPC-6827, paclitaxel, and colchicine, but not vinblastine. MPC-6827 effectively inhibited the polymerization of tubulin in vitro, competed with colchicine binding, and disrupted the formation of microtubules in a variety of tumor cell lines, which together showed the molecular target as tubulin. Treatment of MCF-7 breast carcinoma or Jurkat leukemia cells with MPC-6827 led to pronounced G2-M cell cycle arrest followed by apoptosis. Apoptosis, as determined by terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling assay, was preceded by loss of mitochondrial membrane potential, cytochrome c translocation from mitochondria to nuclei, activation of caspase-3, and cleavage of poly(ADP-ribose) polymerase. MPC-6827 was equipotent in an in vitro growth inhibition assay in several cancer cell lines regardless of the expression levels of the multidrug resistance ABC transporters MDR-1 (Pgp-1), MRP-1, and BCRP-1. In B16-F1 allografts and in OVCAR-3, MIAPaCa-2, MCF-7, HT-29, MDA-MB-435, and MX-1 xenografts, statistically significant tumor growth inhibition was observed with MPC-6827. These studies show that MPC-6827 is a microtubule-disrupting agent with potent and broad-spectrum in vitro and in vivo cytotoxic activities and, therefore, MPC-6827 is a promising candidate for development as a novel therapeutic for multiple cancer types.
Transfection of the c-myc oncogene into normal Epstein-Barr virus-harboring B cells results in new phenotypic and functional features resembling those of Burkitt lymphoma cells and normal centroblasts.
Authors: G Cutrona, M Ulivi, F Fais, S Roncella, M Ferrarini
Journal: The Journal of Experimental Medicine (1995)

Activated c-myc gene was introduced into the cells of three normal Epstein-Barr virus (EBV)-positive lymphoblastoid B cell lines (LCL). The cells were monitored for the appearance of new phenotypic and functional features compared with the control LCL cells transfected with plasmid that did not contain the c-myc gene. The LCL-expressing c-myc constitutively did not arrest growth in low serum concentration. However, the cell number in the cultures failed to increase because of substantial cell death. Death was due to apoptosis as demonstrated by flow cytometric analysis of propidium iodide-stained cells, by typical DNA laddering in gel electrophoresis, and by the inspection of Giemsa-stained cell smears. Apoptosis was also induced by exposing the transfected cells to antibodies directed to the immunoglobulin mu chain (a-mu-ab) irrespective of the serum concentration in the culture. Exposure of the cells to CD40 ligand (CD40L) or CD40 monoclonal antibody prevented cell apoptosis. Upon transfection with c-myc, the LCL cells acquired a vacuolated morphology that was never observed in control cells. Moreover, the expression of CD10 and CD38 was upregulated, while that of CD39 and especially CD23 was downregulated. Unlike that observed in certain Burkitt lymphoma (BL) cell lines that share the same surface phenotype (CD10+CD38+CD23-CD39-), the c-myc-transfected cells expressed lymphocyte function-associated (LFA) 1, LFA-3, and intercellular adhesion molecule 1 and grew in large clumps rather than single-cell layers. Expression of CD10 and CD38 was particularly evident on the cells undergoing apoptosis, thus suggesting a correlation between the presence of these markers and the apoptotic process. Cells placed in conditions favoring in vitro apoptosis displayed downregulation of Bcl-2 protein. Bcl-2 expression was, however, upregulated when the cells were exposed to CD40L. These data indicate that the B cells expressing c-myc constitutively acquire some of the features of normal centroblasts and of BL cells, including the expression of CD10 and CD38, and the propensity to undergo apoptosis, which can be prevented by exposure to CD40L. Therefore, these cells can serve as a model system to study both BL lymphomagenesis as well as the process of B cell selection occurring in the germinal centers.
T Cell Fate at the Single-Cell Level
Authors: Veit R. Buchholz, Ton N.M. Schumacher, Dirk H. Busch
Journal: Annual Review of Immunology (2015)

T cell responses display two key characteristics. First, a small population of epitope-specific naive T cells expands by several orders of magnitude. Second, the T cells within this proliferating population take on diverse functional and phenotypic properties that determine their ability to exert effector functions and contribute to T cell memory. Recent technological advances in lineage tracing allow us for the first time to study these processes in vivo at single-cell resolution. Here, we summarize resulting data demonstrating that although epitope-specific T cell responses are reproducibly similar at the population level, expansion potential and diversification patterns of the offspring derived from individual T cells are highly variable during both primary and recall immune responses. In spite of this stochastic response variation, individual memory T cells can serve as adult stem cells that provide robust regeneration of an epitope-specific tissue through population averaging. We discuss the relevance of these findings for T cell memory formation and clinical immunotherapy.
Chromium Treatment Has No Effect in Patients With Poorly Controlled, Insulin-Treated Type 2 Diabetes in an Obese Western Population
Authors: Nanne Kleefstra, Sebastiaan T. Houweling, Frank G.A. Jansman, Klaas H. Groenier, Rijk O.B. Gans, Betty Meyboom-de Jong, Stephan J.L. Bakker, Henk J.G. Bilo
Journal: Diabetes Care (2006)

OBJECTIVE—Chromium treatment has been reported to improve glycemic control and insulin sensitivity in specific populations of patients with type 2 diabetes. The aim of this study was to determine the effect of chromium treatment on glycemic control in a Western population of insulin-dependent patients with type 2 diabetes. RESEARCH DESIGN AND METHODS—In this 6-month double-blind study, patients with an HbA1c (A1C) &amp;gt;8% and insulin requirements of &amp;gt;50 units/day were randomly assigned to receive treatment with placebo or 500 or 1,000 μg chromium daily in the form of chromium picolinate. The primary efficacy parameter was a change in A1C. Secondary end points were changes in lipid profile, BMI, blood pressure, and insulin requirements. RESULTS—In this per-protocol analysis (n = 46), the decrease in A1C was approximately equal across the three groups (0.4%). All patients had a BMI &amp;gt;25 kg/m2. No differences were found in the secondary end points. We found a weak relationship between an increasing serum chromium concentration and improvement of the lipid profile. CONCLUSIONS—There is no evidence that high-dose chromium treatment is effective in obese Western patients with type 2 diabetes.
Recent advances in exacerbations of asthma
Authors: A. Sykes, T. Seemungal
Journal: Thorax (2008)

The major morbidity, mortality and health care costs associated with asthma are related to exacerbations. In order to reduce this massive healthcare burden, the prevention and treatment of exacerbations needs to be a greater focus for research. The following review is based on the presentations made at the first International Congress on Exacerbations of Airway Disease and summarises the current state of research on acute exacerbations of asthma.

The lack of a universally accepted definition for an exacerbation of asthma creates difficulties for interpretation of clinical research and trial results. Recently, an ERS/ATS task force addressed this, and to encourage uniformity defined moderate and severe exacerbations based on the actions of the patient and physician rather than symptoms (unpublished information). These definitions are a step forward for trial design and interpretation but it is acknowledged that no single definition will fit all clinical research needs.

Approximately 80% of asthma exacerbations are associated with respiratory viral infections, and rhinoviruses (RV) are responsible for about two-thirds of these.1 Despite the importance of viral infections, a combination of interacting factors is likely to be involved. A synergistic interaction between allergen sensitisation, allergen exposure and virus infection has been detected in adult patients with asthma during acute exacerbations. Sensitised, exposed and infected patients had a significantly increased risk of admission for exacerbations.2 An even greater interaction exists in children.3

The role of RV in exacerbations has been investigated in a human experimental model in patients with mild asthma. During acute infection, patients with asthma had increased lower respiratory tract symptoms, falls in lung function and increases in bronchial hyperresponsiveness compared with those without asthma. Virus load correlated strongly with asthma symptoms and hyperresponsiveness, implicating severity of infection as the main determinant of exacerbation severity (data submitted for publication). Interferon β production …
Multi-Institutional Reciprocal Validation Study of Computed Tomography Predictors of Suboptimal Primary Cytoreduction in Patients With Advanced Ovarian Cancer
Authors: Allison E. Axtell, Margaret H. Lee, Robert E. Bristow, Sean C. Dowdy, William A. Cliby, Steven Raman, John P. Weaver, Mojan Gabbay, Michael Ngo, Scott Lentz, Ilana Cass, Andrew J. Li, Beth Y. Karlan, Christine H. Holschneider
Journal: Journal of Clinical Oncology (2007)

Purpose Identify features on preoperative computed tomography (CT) scans to predict suboptimal primary cytoreduction in patients treated for advanced ovarian cancer in institution A. Reciprocally cross validate the predictors identified with those from two previously published cohorts from institutions B and C. Patients and Methods Preoperative CT scans from patients with stage III/IV epithelial ovarian cancer who underwent primary cytoreduction in institution A between 1999 and 2005 were retrospectively reviewed by radiologists blinded to surgical outcome. Fourteen criteria were assessed. Crossvalidation was performed by applying predictive model A to the patients from cohorts B and C, and reciprocally applying predictive models B and C to cohort A. Results Sixty-five patients from institution A were included. The rate of optimal cytoreduction (≤ 1 cm residual disease) was 78%. Diaphragm disease and large bowel mesentery implants were the only CT predictors of suboptimal cytoreduction on univariate (P &lt; .02) and multivariate analysis (P &lt; .02). In combination (model A), these predictors had a sensitivity of 79%, a specificity of 75%, and an accuracy of 77% for suboptimal cytoreduction. When model A was applied to cohorts B and C, accuracy rates dropped to 34% and 64%, respectively. Reciprocally, models B and C had accuracy rates of 93% and 79% in their original cohorts, which fell to 74% and 48% in cohort A. Conclusion The high accuracy rates of CT predictors of suboptimal cytoreduction in the original cohorts could not be confirmed in the cross validation. Preoperative CT predictors should be used with caution when deciding between surgical cytoreduction and neoadjuvant chemotherapy.
A Susceptibility Locus on Chromosome 6q Greatly Increases Lung Cancer Risk among Light and Never Smokers
Authors: Christopher I. Amos, Susan M. Pinney, Yafang Li, Elena Kupert, Juwon Lee, Mariza A. de Andrade, Ping Yang, Ann G. Schwartz, Pam R. Fain, Adi Gazdar, John Minna, Jonathan S. Wiest, Dong Zeng, Henry Rothschild, Diptasri Mandal, Ming You, Teresa Coons, Colette Gaba, Joan E. Bailey-Wilson, Marshall W. Anderson
Journal: Cancer Research (2010)

Cigarette smoking is the major cause for lung cancer, but genetic factors also affect susceptibility. We studied families that included multiple relatives affected by lung cancer. Results from linkage analysis showed strong evidence that a region of chromosome 6q affects lung cancer risk. To characterize the effects that this region of chromosome 6q region has on lung cancer risk, we identified a haplotype that segregated with lung cancer. We then performed Cox regression analysis to estimate the differential effects that smoking behaviors have on lung cancer risk according to whether each individual carried a risk-associated haplotype or could not be classified and was assigned unknown haplotypic status. We divided smoking exposures into never smokers, light smokers (<20 pack-years), moderate smokers (20 to <40 pack-years), and heavy smokers (>or=40 pack-years). Comparing results according to smoking behavior stratified by carrier status, compared with never smokers, there was weakly increasing risk for increasing smoking behaviors, with the hazards ratios being 3.44, 4.91, and 5.18, respectively, for light, moderate, or heavy smokers, whereas among the individuals from families without the risk haplotype, the risks associated with smoking increased strongly with exposure, the hazards ratios being, respectively, 4.25, 9.17, and 11.89 for light, moderate, and heavy smokers. The never smoking carriers had a 4.71-fold higher risk than the never smoking individuals without known risk haplotypes. These results identify a region of chromosome 6q that increases risk for lung cancer and that confers particularly higher risks to never and light smokers.
Control of Ventricular Fibrillation during Induced Hypothermia in Cats after Differential Depletion of Cardiac Catecholamine Stores with Prenylamine (Segontin)
Authors: KAI C. NIELSEN, CHRISTER OWMAN
Journal: Circulation Research (1967)

The role of adrenergic mechanisms for the development of ventricular fibrillation during induced hypothermia was studied in cats. Prenylamine (60 mg/kg) caused a disappearance of the adrenergic transmitter in the muscular nerves; those to the vessels were only slightly affected. Thus pretreated, animals can be cooled to 17.8 to 17°C rectal temperature, and subsequently rewarmed, without developing ventricular fibrillation. Blood pressure was maintained with metaraminol. Without pretreatment the animals constantly develop ventricular fibrillation at 23 to 18.6°C. When prenylamine was given in a dose (20 mg/kg) that does not overtly affect the norepinephrine content of the cardiac adrenergic nerves, ventricular fibrillation was not prevented. In one group of animals receiving 60 mg/kg of prenylamine, norepinephrine instead of metaraminol was infused to maintain the blood pressure during cooling. These animals developed ventricular fibrillation (or cardiac standstill). Fluorescence microscopy showed that the infusion had restored the norepinephrine content in the cardiac nerves previously depleted of their endogenous transmitter by prenylamine. The incidence of ventricular fibrillation seems to be related to the number of intact adrenergic nerves present in relation to the cardiac muscles. Hypothermia caused a distinct release of transmitter from the cardiac adrenergic nerves.
Doha agreement meeting on terminology and definitions in groin pain in athletes
Authors: Adam Weir, Peter Brukner, Eamonn Delahunt, Jan Ekstrand, Damian Griffin, Karim M Khan, Greg Lovell, William C Meyers, Ulrike Muschaweck, John Orchard, Hannu Paajanen, Marc Philippon, Gilles Reboul, Philip Robinson, Anthony G Schache, Ernest Schilders, Andreas Serner, Holly Silvers, Kristian Thorborg, Timothy Tyler, Geoffrey Verrall, Robert-Jan de Vos, Zarko Vuckovic, Per Hölmich
Journal: British Journal of Sports Medicine (2015)

Background Heterogeneous taxonomy of groin injuries in athletes adds confusion to this complicated area. Aim The ‘Doha agreement meeting on terminology and definitions in groin pain in athletes’ was convened to attempt to resolve this problem. Our aim was to agree on a standard terminology, along with accompanying definitions. Methods A one-day agreement meeting was held on 4 November 2014. Twenty-four international experts from 14 different countries participated. Systematic reviews were performed to give an up-to-date synthesis of the current evidence on major topics concerning groin pain in athletes. All members participated in a Delphi questionnaire prior to the meeting. Results Unanimous agreement was reached on the following terminology. The classification system has three major subheadings of groin pain in athletes: 1. Defined clinical entities for groin pain: Adductor-related, iliopsoas-related, inguinal-related and pubic-related groin pain. 2. Hip-related groin pain. 3. Other causes of groin pain in athletes. The definitions are included in this paper. Conclusions The Doha agreement meeting on terminology and definitions in groin pain in athletes reached a consensus on a clinically based taxonomy using three major categories. These definitions and terminology are based on history and physical examination to categorise athletes, making it simple and suitable for both clinical practice and research.