tbuckley/cabot-search huggingface dataset:
Activated Akt Protects the Lung from Oxidant-Induced Injury and Delays Death of Mice
Authors: Yunbiao Lu, Lisa Parkyn, Leo E. Otterbein, Yasuko Kureishi, Kenneth Walsh, Anuradha Ray, Prabir Ray
Journal: The Journal of Experimental Medicine (2001)

Oxidant-induced injury to the lung causes extensive damage to lung epithelial cells. Impaired protection and repair of the lung epithelium can result in death. The serine-threonine kinase Akt has been implicated in inhibiting cell death induced by different stimuli including growth factor withdrawal, cell cycle discordance, DNA damage, and loss of cell adhesion in different cell types. However, the in vivo relevance of this prosurvival pathway has not been explored. Here we show that a constitutively active form of Akt introduced intratracheally into the lungs of mice by adenovirus gene transfer techniques protects mice from hyperoxic pulmonary damage and delays death of mice. This is the first demonstration of the in vivo protective function of Akt in the context of oxidant-induced lung injury.
IFN-Inducible Protein-10 Plays a Pivotal Role in Maintaining Slit-Diaphragm Function by Regulating Podocyte Cell-Cycle Balance
Authors: Gi Dong Han, Koichi Suzuki, Hiroko Koike, Kenji Suzuki, Hiroyuki Yoneyama, Shosaku Narumi, Fujio Shimizu, Hiroshi Kawachi
Journal: Journal of the American Society of Nephrology (2005)

IFN-inducible protein-10 (IP-10/CXCL10) is a potent chemoattractant for activated T lymphocytes and was reported recently to have several additional biologic activities. In this study, the pathophysiologic role of IP-10 in the glomerular visceral epithelial cell (podocyte) was investigated. In cultured podocytes subjected to recombinant IP-10 treatment, the expression of slit-diaphragm (SD) components nephrin and podocin clearly was heightened. Rats that had puromycin aminonucleoside nephropathy and anti–nephrin antibody–induced nephropathy and were subjected to anti–IP-10 function-blocking antibody (anti–IP-10 mAb) treatment displayed a decrease in the protein level of SD components, as well as exacerbated proteinuria. For exploration of the mechanisms of this process, the interaction between IP-10 and the cell-cycle regulatory proteins was investigated. Cultured podocytes subjected to recombinant IP-10 treatment displayed an increase in the protein level of p27Kip1, whereas the levels of cyclins E and A decreased. The expression of IP-10 and SD components was heightened by the treatment of siRNA of cyclin A, whereas these expressions were lowered by the treatment of siRNA of p27Kip1. Proteinuric rats subjected to anti–IP-10 mAb treatment displayed a heightened expression of cyclin A from the early phase of the disease, which indicates that the anti–IP-10 mAb treatment exacerbates podocyte injury by disturbing the cell-cycle balance. These results raise the possibility that IP-10 could become a novel therapeutic target in nephrotic syndrome and several diseases with altered cell-cycle balance.
CONCURRENT INFECTION WITH INFLUENZA VIRUS AND MUMPS VIRUS OR PNEUMONIA VIRUS OF MICE (PVM) AS BEARING ON THE INHIBITION OF VIRUS MULTIPLICATION BY BACTERIAL POLYSACCHARIDES
Authors: Harold S. Ginsberg, Frank L. Horsfall
Journal: The Journal of Experimental Medicine (1949)

Preexisting infection with PVM or mumps virus does not prevent multiplication of the virus of influenza A or B in the same tissue. Similarly, pre-existing infection with one or another of the influenza viruses does not prevent multiplication of either PVM or mumps virus in the same tissue. The failure of these two groups of viruses to interfere with the multiplication of each other is discussed in relation to the mechanism of inhibition of multiplication of mumps virus and PVM by the capsular polysaccharides of Friedländer bacilli, and the ability of influenza A and influenza B viruses to multiply in the presence of large quantities of these carbohydrates. It is suggested that differences in the requirements of the two groups of viruses for host cell metabolic systems may serve to explain both the lack of interference between them and the differing effect of polysaccharides upon their multiplication.
mTOR Kinase Inhibitor AZD8055 Enhances the Immunotherapeutic Activity of an Agonist CD40 Antibody in Cancer Treatment
Authors: Qun Jiang, Jonathan M. Weiss, Timothy Back, Tim Chan, John R. Ortaldo, Sylvie Guichard, Robert H. Wiltrout
Journal: Cancer Research (2011)

mTOR is a central mediator of cancer cell growth, but it also directs immune cell differentiation and function. On this basis, we had explored the hypothesis that mTOR inhibition can enhance cancer immunotherapy. Here, we report that a combination of αCD40 agonistic antibody and the ATP-competitive mTOR kinase inhibitory drug AZD8055 elicited synergistic antitumor responses in a model of metastatic renal cell carcinoma. In contrast to the well-established mTOR inhibitor rapamycin, AZD8055 increased the infiltration, activation, and proliferation of CD8(+) T cells and natural killer cells in liver metastatic foci when combined with the CD40 agonist. AZD8055/αCD40-treated mice also display an increased incidence of matured macrophages and dendritic cells compared with that achieved in mice by αCD40 or AZD8055 treatment alone. We found that the combination treatment also increased macrophage production of TNFα, which played an indispensable role in activation of the observed antitumor immune response. Levels of Th1 cytokines, including interleukin 12, IFN-γ, TNFα, and the Th1-associated chemokines RANTES, MIG, and IP-10 were each elevated significantly in the livers of mice treated with the combinatorial therapy versus individual treatments. Notably, the AZD8055/αCD40-induced antitumor response was abolished in IFN-γ(-/-) and CD40(-/-) mice, establishing the reliance of the combination therapy on host IFN-γ and CD40 expression. Our findings offer a preclinical proof of concept that, unlike rapamycin, the ATP-competitive mTOR kinase inhibitor AZD8055 can contribute with αCD40 treatment to trigger a restructuring of the tumor immune microenvironment to trigger regressions of an established metastatic cancer.
Brief Screening Tool for Disordered Eating in Diabetes
Authors: Jessica T. Markowitz, Deborah A. Butler, Lisa K. Volkening, Jeanne E. Antisdel, Barbara J. Anderson, Lori M.B. Laffel
Journal: Diabetes Care (2009)

OBJECTIVE To update and validate a diabetes-specific screening tool for disordered eating (the Diabetes Eating Problem Survey [DEPS]) in contemporary youth with type 1 diabetes. RESEARCH DESIGN AND METHODS A total of 112 youth with type 1 diabetes, ages 13–19 years, completed the DEPS. Higher scores on the DEPS indicate more disordered eating behaviors. Youth and their parents also completed additional surveys to examine diabetes-specific family conflict, negative affect related to blood glucose monitoring, youth quality of life, and diabetes burden. Clinicians provided data on height, weight, A1C, and insulin dosing. The DEPS was revised into a shorter, updated measure and validated. RESULTS The revised 16-item DEPS (DEPS-R) displayed excellent internal consistency (Cronbach's α = 0.86). Construct validity was demonstrated by positive correlations with zBMI (P = 0.01), A1C (P = 0.001), diabetes-specific family conflict (P &amp;lt; 0.005), youth negative affect around blood glucose monitoring (P = 0.001), parental diabetes-specific burden (P = 0.0005), and negative correlations with frequency of blood glucose monitoring (P = 0.03) and quality of life (P ≤ 0.002). External validity was confirmed against clinician report of insulin restriction. CONCLUSIONS The DEPS-R is a 16-item diabetes-specific self-report measure of disordered eating that can be completed in &amp;lt;10 min. It demonstrated excellent internal consistency, construct validity, and external validity in this contemporary sample of youth with type 1 diabetes. Future studies should focus on using the DEPS-R to identify high-risk populations for prevention of and early intervention for disordered eating behaviors.
Two distinct effects of oxygen on vascular tone in isolated porcine coronary arteries.
Authors: G Rubanyi, R J Paul
Journal: Circulation Research (1985)

The relation between PO2 and vessel tone was studied in isolated porcine left descending coronary artery rings. Porcine left descending coronary artery mounted isometrically and equilibrated in Krebs-bicarbonate solution (37 degrees C, pH 7.4, when gassed with 95% oxygen + 5% carbon dioxide) exhibited spontaneous basal tone. Decreasing bath PO2 to 40%, 20%, and 12% elicited sustained increases in basal tension which were reversible, ranging between 10% and 20% of the contraction induced by 40 mM potassium chloride. Further decreases in PO2 to near zero (anoxia) resulted in relaxation to baseline. Cyclooxygenase inhibitors indomethacin (5.5 X 10(-6) M), aspirin (5 X 10(-5) M), and meclofenamate (10(-5) M) decreased vascular tone and totally prevented coronary vasoconstriction induced by lowering bath PO2 to 12% or 40% but did not affect anoxic vasorelaxation. Neither basal tone nor the vasoconstriction induced by decreases in bath PO2 were influenced by the antihistaminergic drug pyribenzamine (10(5) M) or by the alpha-adrenergic blocker phentolamine (10(-6]. Isoproterenol (10(-9) to 10(-8) M) or an elevation of the bath potassium concentration from 5.9 to 11 mM significantly augmented coronary vasoconstriction induced by lowering bath PO2 from 95% to 40%. Elevation of the bath potassium chloride concentration to 40 mM further increased isometric force but inhibited the vasoconstriction in response to decreasing PO2 from 95% to 40%. Anoxia relaxed contractions induced by 40 mM potassium chloride, histamine, or ouabain. The data suggest the existence of two distinct oxygen-sensitive mechanisms in porcine coronary arteries, both of which regulate vascular tone. One is activated at relative high PO2 values (10-40%), and the vasoconstriction induced by this mechanism is mediated by vascular prostaglandin synthesis. The other is expressed at low PO2 values (near zero), and the depression of mechanical activity by this mechanism may be related to limitation of oxidative energy metabolism. The first mechanism can be augmented by beta-adrenoceptor stimulation indicative of an interaction between vascular prostaglandin synthesis and beta-adrenergic mechanisms in the coronary artery wall.
Population based study of social and productive activities as predictors of survival among elderly Americans
Authors: T. A Glass, C. M. de Leon, R. A Marottoli, L. F Berkman
Journal: BMJ (1999)

To examine any association between social, productive, and physical activity and 13 year survival in older people.Prospective cohort study with annual mortality follow up. Activity and other measures were assessed by structured interviews at baseline in the participants' homes. Proportional hazards models were used to model survival from time of initial interview.City of New Haven, Connecticut, United States.2761 men and women from a random population sample of 2812 people aged 65 and older.Mortality from all causes during 13 years of follow up.All three types of activity were independently associated with survival after age, sex, race/ethnicity, marital status, income, body mass index, smoking, functional disability, and history of cancer, diabetes, stroke, and myocardial infarction were controlled for.Social and productive activities that involve little or no enhancement of fitness lower the risk of all cause mortality as much as fitness activities do. This suggests that in addition to increased cardiopulmonary fitness, activity may confer survival benefits through psychosocial pathways. Social and productive activities that require less physical exertion may complement exercise programmes and may constitute alternative interventions for frail elderly people.
An Imprinted Locus Epistatically Influences <i>Nstr1</i> and <i>Nstr2</i> to Control Resistance to Nerve Sheath Tumors in a Neurofibromatosis Type 1 Mouse Model
Authors: Karlyne M. Reilly, Karl W. Broman, Roderick T. Bronson, Shirley Tsang, Dagan A. Loisel, Emily S. Christy, Zhonghe Sun, John Diehl, David J. Munroe, Robert G. Tuskan
Journal: Cancer Research (2006)

Cancer is a complex disease in which cells acquire many genetic and epigenetic alterations. We have examined how three types of alterations, mutations in tumor suppressor genes, changes in an imprinted locus, and polymorphic loci, interact to affect tumor susceptibility in a mouse model of neurofibromatosis type 1 (NF1). Mutations in tumor suppressor genes such as TP53 and in oncogenes such as KRAS have major effects on tumorigenesis due to the central roles of these genes in cell proliferation and cell survival. Imprinted genes expressed from only one parental chromosome affect tumorigenesis if their monoallelic expression is lost or duplicated. Because imprinted loci are within regions deleted or amplified in cancer, the parental origin of genomic rearrangements could affect tumorigenesis. Gene polymorphisms can vary tumor incidence by affecting rate-limiting steps in tumorigenesis within tumor cells or surrounding stroma. In our mouse model of NF1, the incidence of tumors mutant for the tumor suppressor genes Nf1 and Trp53 is strongly modified by a linked imprinted locus acting epistatically on two unlinked polymorphic loci, Nstr1 and Nstr2. This interaction of an imprinted locus and polymorphic susceptibility loci has profound implications for human mapping studies where the parental contribution of alleles is often unknown.
Physical and functional association of the cbl protooncogen product with an src-family protein tyrosine kinase, p53/56lyn, in the B cell antigen receptor-mediated signaling.
Authors: T Tezuka, H Umemori, N Fusaki, T Yagi, M Takata, T Kurosaki, T Yamamoto
Journal: The Journal of Experimental Medicine (1996)

To identify novel signal transducers involved in signaling mediated by the Src-family protein tyrosine kinases (PTKs), we used a yeast two-hybrid system with a probe corresponding to the regulatory region of p56lyn, a member of Src-family PTKs. One of the isolated clones contained the COOH-terminal 470 amino acid residues of p120c-cbl, the product of the cellular homologue of the v-cbl retroviral oncogene. p120c-cbl is a cytoplasmic protein with nuclear protein-like motifs. Here we show in vivo association of p120c-cbl with p53/56lyn. After stimulation of the B cell antigen receptor (BCR), p120c-cbl was rapidly tyrosine phosphorylated. Studies with lyn- or syk-negative chicken B cells demonstrated that p53/56lyn, but not p72syk, was crucial for tyrosine phosphorylation of p120c-cbl upon stimulation of the BCR. We also show the importance of p59fyn in tyrosine phosphorylation of p120c-cbl in the T-cell receptor-mediated signaling using fyn-overexpressing T cell hybridomas and splenic T cells from fyn-deficient mice. These results suggest that p120c-cbl is an important substrate of Src-family PTKs in the intracellular signaling mediated by the antigen receptors
Severity and outcomes of hospitalised community-acquired pneumonia in COPD patients
Authors: A Liapikou, E Polverino, S Ewig, C Cillóniz, M A Marcos, J Mensa, S Bello, I Martin-Loeches, R Menéndez, A Torres
Journal: European Respiratory Journal (2011)

Chronic obstructive pulmonary disease (COPD) is a frequent comorbidity in patients with community-acquired pneumonia (CAP). We investigated the impact of COPD on outcomes of CAP patients. We prospectively studied the clinical presentation of 1,379 patients admitted with CAP during a 4-yr period. A comparative analysis of disease severity and course was performed between 212 patients with COPD, as confirmed by spirometry, and 1,167 non-COPD patients. COPD patients (mean forced expiratory volume in 1 s 47.7 ± 16.3% predicted) were older and more likely to have previously received antibiotics (37.1% versus 28.3%; p<0.01) than those without COPD. They presented with more severe respiratory failure (arterial oxygen tension/inspiratory oxygen fraction 270.4 versus 287.8; p<0.01) and more severe pneumonia (pneumonia severity index 118.3 versus 108.5; p<0.001) compared with non-COPD patients. However, COPD patients had less multilobar infiltration (44 (21%) versus 349 (30%); p<0.01) and fewer pulmonary complications (24 (14%) versus 241 (24%); p<0.01). A total of 89 (6.5%) patients died within 30 days. COPD patients had no significant difference in their 30-day mortality rate compared with non-COPD patients (nine (4.2%) patients versus 81 (7%); p = 0.14). Despite worse clinical presentation, COPD patients had a similar mortality rate compared to non-COPD patients. Previous antibiotic treatment and the decreased incidence of pulmonary complications in COPD may account for these findings.
Direct in vivo VH to JH rearrangement violating the 12/23 rule
Authors: Sergei B. Koralov, Tatiana I. Novobrantseva, Konrad Hochedlinger, Rudolf Jaenisch, Klaus Rajewsky
Journal: The Journal of Experimental Medicine (2005)

V(D)J recombination at the immunoglobulin heavy chain (IgH) locus follows the 12/23 rule to ensure the correct assembly of the variable region gene segments. Here, we report characterization of an in vivo model that allowed us to study recombination violating the 12/23 rule, namely a mouse strain lacking canonical D elements in its IgH locus. We demonstrate that VH to JH joining can support the generation of all B cell subsets. However, the process is inefficient in that B cells and antibodies derived from the DH-less allele are not detectable if the latter is combined with a wild-type IgH allele. There is no preferential usage of any particular VH gene family or JH element in VHJH junctions, indicating that 23/23-guided recombination is possible, but is a low frequency event at the IgH locus in vivo.
Prolongation of survival of rat cardiac allografts by T cell vaccination.
Authors: O M Shapira, E Mor, T Reshef, R A Pfeffermann, I R Cohen
Journal: Journal of Clinical Investigation (1993)

Administration of attenuated, activated autoimmune T lymphocytes to syngeneic mice and rats has been shown to prevent or induce remission of experimental autoimmune diseases specific for the autoimmune T cells. The process has been termed "T cell vaccination." In a recent study, T cell vaccination was done using T cells sensitized to rat alloantigens. The procedure produced a significant reduction of the mixed lymphocyte reaction (MLR) against allogeneic cells. The reduction in MLR was not specific: Vaccination with T cells specific for stimulator cells of one allotype led to a reduced MLR stimulated by cells of another allotype. The present study was undertaken to examine whether T cell vaccination can induce tolerance to transplantation antigens in vivo. We used the model of heterotopic cardiac transplantation in rats. We now report that vaccinating rats with syngeneic, activated, alloantigen-primed T lymphocytes significantly prolonged survival of rat cardiac allografts. The effect of T cell vaccination was most evident when the T cells had been obtained from rats specifically sensitized against the donor rats: Brown-Norway (BN) allografts in control Wistar rats survived 8.5 +/- 0.4 d while BN allografts survived 29.2 +/- 7.1 d in Wistar rats that had been vaccinated with Wistar anti-BN cells. Vaccination of Wistar rats with Wistar anti-hooded T cells prolonged survival of BN heart allografts to a lesser but significant degree (13.0 +/- 1.1 d). Thus, T cell vaccination of recipients can prolong survival of allografts.
Enhanced Antitumor Effect of Oncolytic Adenovirus Expressing Interleukin-12 and B7-1 in an Immunocompetent Murine Model
Authors: Young-Sook Lee, Joo-Hang Kim, Kyung-Ju Choi, Il-Kyu Choi, Hoguen Kim, Sungae Cho, Byoung Chul Cho, Chae-Ok Yun
Journal: Clinical Cancer Research (2006)

Abstract Purpose: We investigated whether an armed viral platform, where lytic property of a viral infection is coupled to viral-mediated delivery of therapeutic genes, could increase the therapeutic potential of a viral-based therapy. Experimental Design: We generated interleukin (IL)-12-expressing oncolytic adenovirus (YKL-IL-12) and IL-12- and B7-1-expressing (YKL-IL12/B7) oncolytic adenovirus. Therapeutic efficacy of these newly engineered adenoviruses was then evaluated in vivo using an immunocompetent mouse bearing murine melanoma B16-F10 tumors. Overall survival was assessed with the Kaplan-Meier method. The induction of immune cell cytotoxicity was assessed by CTL assay, IFN-γ enzyme-linked immunospot assay, and immunohistochemical studies. Results: YKL-IL12/B7 oncolytic adenovirus, expressing both IL-12 and B7-1, showed a higher incidence of complete tumor regression compared with the analogous oncolytic adenovirus, YKL-1, or IL-12-expressing, YKL-IL12. Significant survival advantage was also seen in response to YKL-IL12/B7. Moreover, IL-12 and IFN-γ levels produced in tumors treated with YKL-IL12/B7 was significantly greater than those treated with YKL-IL12. The enhanced survival advantage was mediated by the induction of immune cell cytotoxicity. In agreement with these results, massive infiltration of CD4+ and CD8+ T cells into tissues surrounding the necrotic area of the tumor was observed following in situ delivery of YKL-IL12/B7. Conclusion: Combination of oncolysis and the enhancement of antitumor immune response by oncolytic adenovirus expressing both IL-12 and B7-1 elicits potent antitumor effect and survival advantage.
Differences in the Mix of Patients Among Medical Specialties and Systems of Care
Authors: Richard L. Kravitz
Journal: JAMA (1992)

<h3>Objective.</h3> —To determine differences in the mix of patients among medical specialties and among organizational systems of care. <h3>Study Design.</h3> —Cross-sectional analysis of 20 158 adults (≥18 years of age) who visited providers' offices during 9-day screening periods in 1986. Patient and physician information was obtained by self-administered, standardized questionnaires. <h3>Setting.</h3> —Offices of 349 physicians practicing family medicine, internal medicine, endocrinology, and cardiology within health maintenance organizations, large multispecialty groups, and solo or small single-specialty group practices in three major US cities. <h3>Outcome Measures.</h3> —Demographic characteristics, prevalence of chronic disease, disease-specific severity of illness, and functional status and well-being. <h3>Results.</h3> —Among patients with selected physician-reported chronic illnesses (diabetes, hypertension, recent myocardial infarction, or congestive heart failure), increasing levels of severity were associated with decreasing levels of functional status and well-being and with increased hospitalizations, more physician visits, and higher numbers of prescription drugs. Compared with patients of general internists, patients of cardiologists were older (56 vs 47 years,<i>P</i>&lt;.01), had worse functional status and well-being scores (<i>P</i>&lt;.01), and carried more chronic diagnoses (mean 1.32 vs 1.02,<i>P</i>&lt;.01); patients of family practitioners were younger (40 vs 47 years,<i>P</i>&lt;.01) and more functional (<i>P</i>&lt;.01), carried fewer chronic diagnoses (0.70 vs 1.02,<i>P</i>&lt;.01), and (among diabetic patients only) had lower disease-specific severity scores (2.06 vs 2.30 on a five-point scale,<i>P</i>&lt;.01). Compared with patients in health maintenance organizations, patients visiting solo practitioners under fee-for-service payment were older (50 vs 45 years,<i>P</i>&lt;.01) and sicker (had worse physical functioning) and had a higher mean number of chronic diagnoses (1.10 vs 0.93,<i>P</i>&lt;.01). <h3>Conclusion.</h3> —Patient mix is related to utilization and differs significantly across medical specialties and systems of care. These differences must be taken into account when interpreting variations in utilization and outcomes across specialties and systems, and when considering alternative policies for payment. (<i>JAMA</i>. 1992;267:1617-1623)