tbuckley/cabot-search huggingface dataset:
Respiratory Syncytial Virus Infection in Infants Is Associated with Predominant Th-2-like Response
Authors: MARIANA ROMÁN, WILLIAM J. CALHOUN, KIM L. HINTON, LUIS F. AVENDAÑO, VALESKA SIMON, ANA M. ESCOBAR, ALDO GAGGERO, PATRICIA V. DÍAZ
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Viral infections have been associated with cellular immune responses and production of Th-1 cytokines. Respiratory syncytial virus (RSV), however, induces virus-specific IgE, which might be a consequence of a Th-2-like activation. To test this hypothesis we quantified interferon- γ (IFN- γ ) and interleukin-4 (IL-4) in the supernatant of peripheral blood mononuclear cells cultured for 24 and 48 h in the presence or absence of phytohemaglutinin and pokeweed mitogen and the lymphocyte phenotypes to analyze subsets and their activation markers, from 15 hospitalized infants during an acute lower respiratory infection caused by RSV and 17 healthy control infants from 1 to 15 mo of age. Compared with the control infants, those infected with RSV had an increase in the number of B-cells (p < 0.02) and decreases in both CD8 + T-cells (p < 0.01) and activated CD8 + /CD25 + suppressor/ cytotoxic T-cells (p < 0.007). In RSV-infected infants, IFN- γ production was subtotally suppressed, whereas IL-4 production was decreased to a lesser degree, giving significantly (p < 0.001) increased IL-4/IFN- γ ratio compared with that in the control infants. These findings suggest a predominant Th-2-like response in RSV-infected infants, which could explain some aspects of the immunopathogenesis of RSV infection and the RSV-specific and nonspecific IgE antibody responses observed.
Inotropic Response of Cardiac Ventricular Myocytes to β-Adrenergic Stimulation With Isoproterenol Exhibits Diurnal Variation
Authors: Helen E. Collins, Glenn C. Rodrigo
Journal: Circulation Research (2010)

Rationale : Although &gt;10% of cardiac gene expression displays diurnal variations, little is known of their impact on excitation–contraction coupling. Objective : To determine whether the time of day affects excitation–contraction coupling in rat ventricles. Methods and Results : Left ventricular myocytes were isolated from rat hearts at 2 opposing time points, corresponding to the animals resting or active periods. Basal contraction and [Ca 2+ ] i was significantly greater in myocytes isolated during the resting versus active periods (cell shortening 12.4±0.3 versus 11.0±0.2%; P &lt;0.05 and systolic [Ca 2+ ] i 422±12 versus 341±9 nmol/L; P &lt;0.01. This corresponded to a greater sarcoplasmic reticulum (SR) Ca 2+ load (672±20 versus 551±13 nmol/L P &lt;0.001). The increase in systolic [Ca 2+ ] i in response to isoproterenol (&gt;3 nmol/L) was also significantly greater in resting versus active period myocytes, reflecting a greater SR Ca 2+ load at this time. This diurnal variation in response of Ca 2+ -homeostasis to isoproterenol translated to a greater incidence of arrhythmic activity in resting period myocytes. Inhibition of neuronal NO synthase during stimulation with isoproterenol, further increased systolic [Ca 2+ ] i and the percentage of arrhythmic myocytes, but this effect was significantly greater in active period versus resting period myocytes. Quantitative RT-PCR analysis revealed a 2.65-fold increase in neuronal NO synthase mRNA levels in active over resting period myocytes ( P &lt;0.05). Conclusions : The threshold for the development of arrhythmic activity in response to isoproterenol is higher during the active period of the rat. We suggest this reflects a reduction in SR Ca 2+ loading and a diurnal variation in neuronal NO synthase signaling.
Gold (I) N-heterocyclic carbene complex inhibits mouse melanoma growth by p53 upregulation
Authors: Abhishek Nandy, Sumit Kumar Dey, Sujata Das, Rudra Narayan Munda, Joydev Dinda, Krishna Das Saha
Journal: Molecular Cancer (2014)

Cancer treatment using gold (I) complexes is becoming popular. In this study, a gold (I) N-heterocyclic complex designated as complex 3 was synthesized, its cytotoxicity was examined, and its anti-melanoma activity was evaluated in vitro and in vivo. Viability of cancer cells was determined by MTT assay upon treatment with various concentrations of a gold (I) N-heterocyclic carbene complex (complex 3) in a dose and time dependent manner. Mouse melanoma cells B16F10 were selected for further apoptotic studies, including flowcytometric analysis of annexin binding, cell cycle arrest, intracellular ROS generation and loss in the mitochondrial membrane potential. ELISA based assays were done for caspase activities and western blots for determining the expression of various survival and apoptotic proteins. Immunocytology was performed to visualize the translocation of p53 to the nucleus. B16F10 cells were inoculated into mice and post tumor formation, complex 3 was administered. Immunohistology was performed to determine the expressions of p53, p21, NF-κB (p65 and p50), MMP-9 and VEGF. Student's t test was used for determining statistical significance. The survival rate data were analyzed by Kaplan-Meier plots. Complex 3 markedly inhibited the growth of HCT 116, HepG2, and A549, and induced apoptosis in B16F10 cells with nuclear condensation, DNA fragmentation, externalization of phosphatidylserine, activation of caspase 3 and caspase 9, PARP cleavage, downregulation of Bcl-2, upregulation of Bax, cytosolic cytochrome c elevation, ROS generation, and mitochondrial membrane potential loss indicating the involvement of an intrinsic mitochondrial death pathway. Further, upregulation of p53, p-p53 (ser 15) and p21 indicated the role of p53 in complex 3 mediated apoptosis. The complex reduced tumor size, and caused upregulation of p53 and p21 along with downregulation of NF-κB (p65 and p50), VEGF and MMP-9. These results suggest that it induced anti-melanoma effect in vitro and in vivo by modulating p53 and other apoptotic factors. The gold (I) N-heterocyclic carbene complex (C22H26N6AuO2PF6) designated as complex 3 induced ROS and p53 dependent apoptosis in B16F10 cells involving the mitochondrial death pathway along with suppression of melanoma tumor growth by regulating the levels of pro and anti apoptotic factors (p53, p21, NF-κB, VEGF and MMP-9).
HER-2/neu-Mediated Regulation of Components of the MHC Class I Antigen-Processing Pathway
Authors: Felix Herrmann, Hans-Anton Lehr, Ingo Drexler, Gerd Sutter, Jan Hengstler, Ursula Wollscheid, Barbara Seliger
Journal: Cancer Research (2004)

Abstract Because of its amplification and/or overexpression in many human tumors, the HER-2/neu proto-oncogene represents an attractive target for T-cell-mediated vaccination strategies. However, overexpression of oncogenes is often associated with defective expression of components of the MHC class I antigen-processing machinery (APM), thereby resulting in an immune escape phenotype of oncogene-transformed cells. To determine whether HER-2/neu influences the MHC class I antigen-processing pathway, the expression pattern of different APM components was examined in murine in vitro models of constitutive and tetracycline-controlled HER-2/neu expression. In comparison with HER-2/neu− control cells, HER-2/neu+ fibroblasts exhibit reduced levels of MHC class I surface antigens that were associated with impaired expression and/or function of the peptide transporter associated with antigen processing, the proteasome subunits low molecular weight protein 2 and low molecular weight protein 10, the proteasome activators PA28α and PA28β, and tapasin. These APM abnormalities resulted in reduced sensitivity to lysis by CTLs. The HER-2/neu-mediated immune escape phenotype could be corrected by IFN-γ treatment. The clinical relevance of this finding was supported by an inverse correlation between HER-2/neu and the peptide transporter associated with antigen-processing protein expression as determined by immunhistochemical analysis of a series of HER-2/neu− and HER-2/neu+ breast cancer specimens. Thus, a functional link between deficient APM component expression and HER-2/neu overexpression is proposed that might influence the design of HER-2/neu-targeted T-cell-based immunotherapeutic strategies.
Distinct high resolution genome profiles of early onset and late onset colorectal cancer integrated with gene expression data identify candidate susceptibility loci
Authors: Marianne Berg, Trude H Ågesen, Espen Thiis-Evensen, Marianne A Merok, Manuel R Teixeira, Morten H Vatn, Arild Nesbakken, Rolf I Skotheim, Ragnhild A Lothe
Journal: Molecular Cancer (2010)

Abstract Background Estimates suggest that up to 30% of colorectal cancers (CRC) may develop due to an increased genetic risk. The mean age at diagnosis for CRC is about 70 years. Time of disease onset 20 years younger than the mean age is assumed to be indicative of genetic susceptibility. We have compared high resolution tumor genome copy number variation (CNV) (Roche NimbleGen, 385 000 oligo CGH array) in microsatellite stable (MSS) tumors from two age groups, including 23 young at onset patients without known hereditary syndromes and with a median age of 44 years (range: 28-53) and 17 elderly patients with median age 79 years (range: 69-87). Our aim was to identify differences in the tumor genomes between these groups and pinpoint potential susceptibility loci. Integration analysis of CNV and genome wide mRNA expression data, available for the same tumors, was performed to identify a restricted candidate gene list. Results The total fraction of the genome with aberrant copy number, the overall genomic profile and the TP53 mutation spectrum were similar between the two age groups. However, both the number of chromosomal aberrations and the number of breakpoints differed significantly between the groups. Gains of 2q35, 10q21.3-22.1, 10q22.3 and 19q13.2-13.31 and losses from 1p31.3, 1q21.1, 2q21.2, 4p16.1-q28.3, 10p11.1 and 19p12, positions that in total contain more than 500 genes, were found significantly more often in the early onset group as compared to the late onset group. Integration analysis revealed a covariation of DNA copy number at these sites and mRNA expression for 107 of the genes. Seven of these genes, CLC, EIF4E , LTBP4, PLA2G12A, PPAT , RG9MTD2 , and ZNF574 , had significantly different mRNA expression comparing median expression levels across the transcriptome between the two groups. Conclusions Ten genomic loci, containing more than 500 protein coding genes, are identified as more often altered in tumors from early onset versus late onset CRC. Integration of genome and transcriptome data identifies seven novel candidate genes with the potential to identify an increased risk for CRC.
Siblings of Patients With Severe Chronic Obstructive Pulmonary Disease Have a Significant Risk of Airflow Obstruction
Authors: SEAN C. McCLOSKEY, BIPEN D. PATEL, SUSAN J. HINCHLIFFE, ELAINE D. REID, NICHOLAS J. WAREHAM, DAVID A. LOMAS
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Although familial clustering has been described, few studies have quantified the risk of airflow obstruction in siblings of patients with chronic obstructive pulmonary disease (COPD). One hundred fifty-two subjects with airflow obstruction and a low gas transfer factor (but without PiZ α1-antitrypsin deficiency) were identified and 150 were enrolled in the study. Complete data were obtained from 173 of 221 siblings of these subjects. Forty-four of 126 current or ex-smoking siblings had airflow obstruction (FEV1/FVC < 0.7) and 36 also had a FEV1 < 80% predicted, in keeping with COPD. One hundred eleven current or ex-smoking siblings were matched for age, sex, and smoking history with 419 subjects, without a known family history of COPD, from the European Prospective Investigation of Cancer (EPIC)-Norfolk cohort. The prevalence of COPD was much lower in the EPIC group (9.3%) when compared with the siblings (31.5%; odds ratio, 4.70; 95% confidence interval, 2.63 to 8.41). The odds ratio for COPD in siblings with less than a 30 pack-year smoking history was 5.39 (95% confidence interval, 2.49 to 11.67) when compared with matched control subjects. Taken together these results demonstrate a significant familial risk of airflow obstruction in smoking siblings of patients with severe COPD.
An activating mutation in the <i>CSF3R</i> gene induces a hereditary chronic neutrophilia
Authors: Isabelle Plo, Yanyan Zhang, Jean-Pierre Le Couédic, Mayuka Nakatake, Jean-Michel Boulet, Miki Itaya, Steven O. Smith, Najet Debili, Stefan N. Constantinescu, William Vainchenker, Fawzia Louache, Stéphane de Botton
Journal: The Journal of Experimental Medicine (2009)

We identify an autosomal mutation in the CSF3R gene in a family with a chronic neutrophilia. This T617N mutation energetically favors dimerization of the granulocyte colony-stimulating factor (G-CSF) receptor transmembrane domain, and thus, strongly promotes constitutive activation of the receptor and hypersensitivity to G-CSF for proliferation and differentiation, which ultimately leads to chronic neutrophilia. Mutant hematopoietic stem cells yield a myeloproliferative-like disorder in xenotransplantation and syngenic mouse bone marrow engraftment assays. The survey of 12 affected individuals during three generations indicates that only one patient had a myelodysplastic syndrome. Our data thus indicate that mutations in the CSF3R gene can be responsible for hereditary neutrophilia mimicking a myeloproliferative disorder.
Three-Gene Immunohistochemical Panel Adds to Clinical Staging Algorithms to Predict Prognosis for Patients With Esophageal Adenocarcinoma
Authors: Chin-Ann J. Ong, Joel Shapiro, Katie S. Nason, Jon M. Davison, Xinxue Liu, Caryn Ross-Innes, Maria O'Donovan, Winand N.M. Dinjens, Katharina Biermann, Nicholas Shannon, Susannah Worster, Laura K.E. Schulz, James D. Luketich, Bas P.L. Wijnhoven, Richard H. Hardwick, Rebecca C. Fitzgerald
Journal: Journal of Clinical Oncology (2013)

Esophageal adenocarcinoma (EAC) is a highly aggressive disease with poor long-term survival. Despite growing knowledge of its biology, no molecular biomarkers are currently used in routine clinical practice to determine prognosis or aid clinical decision making. Hence, this study set out to identify and validate a small, clinically applicable immunohistochemistry (IHC) panel for prognostication in patients with EAC.We recently identified eight molecular prognostic biomarkers using two different genomic platforms. IHC scores of these biomarkers from a UK multicenter cohort (N = 374) were used in univariate Cox regression analysis to determine the smallest biomarker panel with the greatest prognostic power with potential therapeutic relevance. This new panel was validated in two independent cohorts of patients with EAC who had undergone curative esophagectomy from the United States and Europe (N = 666).Three of the eight previously identified prognostic molecular biomarkers (epidermal growth factor receptor [EGFR], tripartite motif-containing 44 [TRIM44], and sirtuin 2 [SIRT2]) had the strongest correlation with long-term survival in patients with EAC. Applying these three biomarkers as an IHC panel to the validation cohort segregated patients into two different prognostic groups (P < .01). Adjusting for known survival covariates, including clinical staging criteria, the IHC panel remained an independent predictor, with incremental adverse overall survival (OS) for each positive biomarker (hazard ratio, 1.20; 95% CI, 1.03 to 1.40 per biomarker; P = .02).We identified and validated a clinically applicable IHC biomarker panel, consisting of EGFR, TRIM44, and SIRT2, that is independently associated with OS and provides additional prognostic information to current survival predictors such as stage.
Terminal Duct Lobular Unit Involution of the Normal Breast: Implications for Breast Cancer Etiology
Authors: Jonine D. Figueroa, Ruth M. Pfeiffer, Deesha A. Patel, Laura Linville, Louise A. Brinton, Gretchen L. Gierach, Xiaohong R. Yang, Daphne Papathomas, Daniel Visscher, Carolyn Mies, Amy C. Degnim, William F. Anderson, Stephen Hewitt, Zeina G. Khodr, Susan E. Clare, Anna Maria Storniolo, Mark E. Sherman
Journal: JNCI Journal of the National Cancer Institute (2014)

BackgroundGreater degrees of terminal duct lobular unit (TDLU) involution have been linked to lower breast cancer risk; however, factors that influence this process are poorly characterized.
Simultaneous Blockade of Multiple Immune System Inhibitory Checkpoints Enhances Antitumor Activity Mediated by Interleukin-15 in a Murine Metastatic Colon Carcinoma Model
Authors: Ping Yu, Jason C. Steel, Meili Zhang, John C. Morris, Thomas A. Waldmann
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Interleukin 15 (IL-15) is a promising cytokine for immunotherapy of cancer due to its ability to stimulate the immunity of natural killer, B, and T cells. Its effectiveness, however, may be limited by inhibitory checkpoints and pathways that can attenuate immune responses. Finding strategies to abrogate these negative regulators and enhance the efficacy of IL-15 is a critical challenge. Experimental Design: In a preclinical study, we evaluated IL-15 combined with antibodies to block the negative immune regulators cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death ligand 1 (PD-L1) in a metastatic murine CT26 colon carcinoma model. Results: IL-15 treatment resulted in a significant prolongation of survival in mice with metastatic tumor. Administration of IL-15, however, also increased expression of PD-1 on the surface of CD8+ T cells including CD8+CD44high memory phenotype T cells. Moreover, IL-15 also increased the secretion of the immunosuppressive cytokine, IL-10. Combining IL-15 with anti-PD-L1 and anti-CTLA-4 (multiple immune checkpoint blockade) exhibited greater CTL killing and IFNγ secretion. Moreover, this combination resulted in a significant reduction in surface expression of PD-1 on CD8+ T cells, a decrease in IL-10 secretion, and led to significantly longer survival of tumor-bearing animals compared with mice treated with IL-15 alone or combined singularly with anti-PD-L1 or anti-CTLA-4. Conclusions: Combining the immune stimulatory properties of IL-15 with the simultaneous removal of 2 critical immune system inhibitory checkpoints, we showed enhancement of immune responses leading to increased antitumor activity. Clin Cancer Res; 16(24); 6019–28. ©2010 AACR.
Recurrent orbital pain and diplopia in a 12 year old boy
Authors: F Falcini
Journal: Annals of the Rheumatic Diseases (2002)

A previously healthy 12 year old boy was referred to our unit in May 2000, with a history of persistent ocular pain and recurrent diplopia. The first disease manifestation had started three years before, when the patient suddenly presented with diplopia and painful periorbital and eyelid oedema. Limited abduction of the right eye was present. The treating ophthalmologist, after a thorough investigation that excluded brain tumours, orbital masses, and myasthenia gravis, prescribed naproxen (20 mg/kg/day) and systemic corticosteroid treatment (prednisone 1 mg/kg/day, tapered and withdrawn after 15 days); symptoms recovered completely in two weeks. A first magnetic resonance imaging (MRI) scan of the orbit had shown first degree exophthalmus of the right eye and oedema and thickening of the right rectus lateralis muscle (fig 1). Since then the boy had many episodes of ocular pain and diplopia, lasting from two to four weeks, affecting …
Insulin Causes [Ca <sup>2+</sup> ] <sub>i</sub> -Dependent and [Ca <sup>2+</sup> ] <sub>i</sub> -Independent Positive Inotropic Effects in Failing Human Myocardium
Authors: Dirk von Lewinski, Sebastian Bruns, Stefanie Walther, Harald Kögler, Burkert Pieske
Journal: Circulation (2005)

Background— Insulin has been shown to exert positive inotropic effects in several in vitro and in vivo models, but signal transduction and substrate dependency remain unclear. We examined inotropic responses and signal transduction mechanisms of insulin in human myocardium. Methods and Results— Experiments were performed in isolated trabeculae from end-stage failing hearts of 58 nondiabetic and 3 diabetic patients undergoing heart transplantation. The effect of insulin (0.3 and 3 IU/L) on isometric twitch force (37°C, 1 Hz) was tested in the presence of glucose or pyruvate as energetic substrate. Furthermore, intracellular Ca 2+ transients (aequorin method), sarcoplasmic reticulum (SR) Ca 2+ content (rapid cooling contractures), and myofilament Ca 2+ sensitivity (semiskinned fibers) were assessed. In addition, potential signaling pathways were tested by blocking glycolysis, PI-3-kinase, protein kinase C, diacylglycerol kinase, insulin-like growth factor-1 receptors, or transsarcolemmal Ca 2+ entry via the Na + /Ca 2+ exchanger. Insulin exerted concentration-dependent and partially substrate-dependent positive inotropic effects. The phosphatidylinositol-3-kinase inhibitor wortmannin and the Na 2+ /Ca 2+ exchanger reverse-mode inhibitor KB-R7943 completely or partially prevented the functional effects of insulin. In contrast, insulin-like growth factor-1 receptor blockade, protein kinase C inhibition, and diacylglycerol kinase blockade were without effect. The inotropic response was associated with increases in intracellular Ca 2+ transients, SR Ca 2+ content, and increased myofilament Ca 2+ sensitivity. Conclusions— Insulin exerts Ca 2+ -dependent and -independent positive inotropic effects through a phosphatidylinositol-3-kinase–dependent pathway in failing human myocardium. The increased [Ca 2+ ] i originates at least in part from enhanced reverse-mode Na + /Ca 2+ exchange and consequently increased SR-Ca 2+ load. These nongenomic functional effects of insulin may be of clinical relevance, eg, during insulin-glucose-potassium infusions.