tbuckley/cabot-search huggingface dataset:
Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo.
Authors: D Boczkowski, S K Nair, D Snyder, E Gilboa
Journal: The Journal of Experimental Medicine (1996)

Immunization with defined tumor antigens is currently limited to a small number of cancers where candidates for tumor rejection antigens have been identified. In this study we investigated whether pulsing dendritic cells (DC) with tumor-derived RNA is an effective way to induce CTL and tumor immunity. DC pulsed with in vitro synthesized chicken ovalbumin (OVA) RNA were more effective than OVA peptide-pulsed DC in stimulating primary, OVA-specific CTL responses in vitro. DC pulsed with unfractionated RNA (total or polyA+) from OVA-expressing tumor cells were as effective as DC pulsed with OVA peptide at stimulating CTL responses. Induction of OVA-specific CTL was abrogated when polyA+ RNA from OVA-expressing cells was treated with an OVA-specific antisense oligodeoxynucleotide and RNase H, showing that sensitization of DC was indeed mediated by OVA RNA. Mice vaccinated with DC pulsed with RNA from OVA-expressing tumor cells were protected against a challenge with OVA-expressing tumor cells. In the poorly immunogenic, highly metastatic, B16/F10.9 tumor model a dramatic reduction in lung metastases was observed in mice vaccinated with DC pulsed with tumor-derived RNA (total or polyA+, but not polyA- RNA). The finding that RNA transcribed in vitro from cDNA cloned in a bacterial plasmid was highly effective in sensitizing DC shows that amplification of the antigenic content from a small number of tumor cells is feasible, thus expanding the potential use of RNA-pulsed DC-based vaccines for patients bearing very small, possibly microscopic, tumors.
Mesenchymal stromal cell transplantation contributes to collateral response in tissue ischemia through release of arteriogenic cytokines
Authors: Tim D. Kinnaird, Eugenio Stabile, Mary Susan Burnett, Matie Shou, Yi Fu Zhou, Richard Baffour, Cheol Whan Lee, Shmuel Fuchs, Stephen E. Epstein
Journal: Journal of the American College of Cardiology (2003)
Accelerated Thymic Maturation and Autoreactive T Cells in Bronchopulmonary Dysplasia
Authors: Dennis Rosen, Jong-Hwan Lee, Frank Cuttitta, Fatema Rafiqi, Simone Degan, Mary E. Sunday
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Bronchopulmonary dysplasia (BPD), a chronic lung disease of newborns triggered by oxygen and barotrauma, is characterized by arrested alveolarization. Increased levels of bombesin-like peptides shortly after birth mediate lung injury: anti-bombesin antibody 2A11 protects against BPD in two baboon models. The role of adaptive immunity in BPD has not been explored previously.Our goal was to test the hypothesis that thymic architecture and/or T-cell function is altered with BPD, leading to autoimmunity and immunodeficiency.Thymic structure was analyzed by histopathology of thymic architecture and immunohistochemistry for thymic maturation markers (terminal deoxynucleotidyl transferase, proliferating cell nuclear antigen, CD4, and CD8). Thymic cortical epithelial cells (nurse cells) were studied using HLA-DR and protein gene product 9.5 as markers. Functional analysis was performed with "mixed lymphocyte reaction" of thymocyte or splenocyte responder cells with autologous lung cells as the stimulators.2A11 treatment attenuates thymic cortical involution in BPD animals, sustaining terminal deoxynucleotidyl transferase-positive prothymocytes and thymocyte proliferation. BPD animals have increased CD4(+) cells in thymic cortex and lung interstitium, which are reduced by 2A11. Conversely, cortical protein gene product 9.5/HLA-DR-positive thymic nurse cells are depleted in BPD animals, but are preserved by 2A11-treatment. Whereas fetal thymocytes and splenocytes respond to phythemagglutinin/ionomycin and to a lesser extent, to autologous lung, BPD thymocytes and splenocytes are phythemagglutinin/ionomycin-unresponsive, and yet react strongly to autologous lung. The 2A11 normalizes these responses.These observations suggest that bombesin-like peptides mediate premature thymic maturation and thymic nurse-cell depletion, leading to autoreactive T cells that could contribute to lung injury.
Adult socioeconomic, educational, social, and psychological outcomes of childhood obesity: a national birth cohort study
Authors: Russell M Viner, Tim J Cole
Journal: BMJ (2005)

<h3>Abstract</h3> <b>Objectives</b> To assess adult socioeconomic, educational, social, and psychological outcomes of childhood obesity by using nationally representative data. <b>Design</b> 1970 British birth cohort. <b>Participants</b> 16 567 babies born in Great Britain 5-11 April 1970 and followed up at 5, 10, and 29-30 years. <b>Main outcome measures</b> Obesity at age 10 and 30 years. Self reported socioeconomic, educational, psychological, and social outcomes at 30 years. Odds ratios were calculated for the risk of each adult outcome associated with obesity in childhood only, obesity in adulthood only, and persistent child and adult obesity, compared with those obese at neither period. <b>Results</b> Of the 8490 participants with data on body mass index at 10 and 30 years, 4.3% were obese at 10 years and 16.3% at 30 years. Obesity in childhood only was not associated with adult social class, income, years of schooling, educational attainment, relationships, or psychological morbidity in either sex after adjustment for confounding factors. Persistent obesity was not associated with any adverse adult outcomes in men, though it was associated among women with a higher risk of never having been gainfully employed (odds ratio 1.9, 95% confidence interval 1.1 to 3.3) and not having a current partner (2.0, 1.3 to 3.3). <b>Conclusions</b> Obesity limited to childhood has little impact on adult outcomes. Persistent obesity in women is associated with poorer employment and relationship outcomes. Efforts to reduce the socioeconomic and psychosocial burden of obesity in adult life should focus on prevention of the persistence of obesity from childhood into adulthood.
Association between interleukin-1 receptor antagonist (IL-1ra) gene polymorphism and early and late-onset psoriasis
Authors: J.K. Tarlow, M.J. Cork, F.E. Clay, M. Schmitt-Egenolf, A.M. Crane, C. Stierle, W.-H. Eoehncke, T.H. Eiermann, A.I.F. Blakemore, S.S. Bleehen, W. Sterry, G.W. Duff
Journal: British Journal of Dermatology (1997)
Cartilage and bone metabolism in rheumatoid arthritis. Differences between rapid and slow progression of disease identified by serum markers of cartilage metabolism.
Authors: B Månsson, D Carey, M Alini, M Ionescu, L C Rosenberg, A R Poole, D Heinegård, T Saxne
Journal: Journal of Clinical Investigation (1995)

Serum concentrations of specific cartilage and bone molecules reflecting tissue turnover were measured in two well-defined patient groups with early rheumatoid arthritis with distinctly different disease outcome to see if early differences in their levels are prognostic of the rate of joint destruction. Compared with a matched normal population, increased concentrations of cartilage oligomeric matrix protein (COMP) were found in all patients who developed rapid hip joint destruction. In contrast, levels of a putative marker of cartilage aggrecan synthesis, the chondroitin sulfate epitope 846, were increased only in patients with slow joint destruction. Levels of bone sialoprotein (BSP) were increased in both groups, as were levels of the C-propeptide of type II procollagen (CPII), a marker of collagen II synthesis. The increased concentrations of the 846 epitope in patients with slow joint destruction suggest increased aggrecan synthesis. The low levels of the 846 epitope in patients with rapid joint destruction, concomitant with elevated levels of CPII, suggest a selective increase in collagen synthesis. The elevated BSP levels indicate an increased bone turnover in both groups. Thus elevated serum levels of COMP may indicate an unfavorable prognosis for rapid joint destruction, whereas elevated 846 epitope indicates a more favorable prognosis.
Modulation of Activation-Loop Phosphorylation by JAK Inhibitors Is Binding Mode Dependent
Authors: Rita Andraos, Zhiyan Qian, Débora Bonenfant, Joëlle Rubert, Eric Vangrevelinghe, Clemens Scheufler, Fanny Marque, Catherine H. Régnier, Alain De Pover, Hugues Ryckelynck, Neha Bhagwat, Priya Koppikar, Aviva Goel, Lorenza Wyder, Gisele Tavares, Fabienne Baffert, Carole Pissot-Soldermann, Paul W. Manley, Christoph Gaul, Hans Voshol, Ross L. Levine, William R. Sellers, Francesco Hofmann, Thomas Radimerski
Journal: Cancer Discovery (2012)

Janus kinase (JAK) inhibitors are being developed for the treatment of rheumatoid arthritis, psoriasis, myeloproliferative neoplasms, and leukemias. Most of these drugs target the ATP-binding pocket and stabilize the active conformation of the JAK kinases. This type I binding mode can lead to an increase in JAK activation loop phosphorylation, despite blockade of kinase function. Here we report that stabilizing the inactive state via type II inhibition acts in the opposite manner, leading to a loss of activation loop phosphorylation. We used X-ray crystallography to corroborate the binding mode and report for the first time the crystal structure of the JAK2 kinase domain in an inactive conformation. Importantly, JAK inhibitor-induced activation loop phosphorylation requires receptor interaction, as well as intact kinase and pseudokinase domains. Hence, depending on the respective conformation stabilized by a JAK inhibitor, hyperphosphorylation of the activation loop may or may not be elicited.
Cardiac protein kinases: the cardiomyocyte kinome and differential kinase expression in human failing hearts
Authors: Stephen J. Fuller, Sally A. Osborne, Sam J. Leonard, Michelle A. Hardyman, George Vaniotis, Bruce G. Allen, Peter H. Sugden, Angela Clerk
Journal: Cardiovascular Research (2015)

AimsProtein kinases are potential therapeutic targets for heart failure, but most studies of cardiac protein kinases derive from other systems, an approach that fails to account for specific kinases expressed in the heart and the contractile cardiomyocytes. We aimed to define the cardiomyocyte kinome (i.e. the protein kinases expressed in cardiomyocytes) and identify kinases with altered expression in human failing hearts.
Risk factors for symptomatic urinary tract infection in women with diabetes.
Authors: S E Geerlings, R P Stolk, M J Camps, P M Netten, T J Collet, A I Hoepelman
Journal: Diabetes Care (2000)

OBJECTIVE: Women with diabetes have urinary tract infections (UTIs) more often than women without diabetes. The aim of the present multicenter study was to evaluate which clinical characteristics are associated with the development of a symptomatic UTI during an 18-month follow-up period. RESEARCH DESIGN AND METHODS: Patients with either type 1 or type 2 diabetes who were between 18 and 75 years of age were included. Follow-up results were available for 589 of the 636 women included in this study. All patients were interviewed, their medical history was noted, and at least one uncontaminated urine culture was collected at the moment of study entry. RESULTS: Of the 589 women, 115 (20%) developed a symptomatic UTI, 96 (83%) of whom were prescribed antimicrobial therapy A total of 34 women (14%) with type 1 diabetes developed a UTI. The most important risk factor for these women was sexual intercourse during the week before entry into the study (44% without vs. 53% with sexual intercourse, relative risk [RR] = 3.0, P = 0.01). A total of 81 (23%) women with type 2 diabetes developed a UTI. The most important risk factor for these women was the presence of asymptomatic bacteriuria (ASB) at baseline (25% without vs. 42% with ASB, RR = 1.65, P = 0.04). CONCLUSIONS: Risk factors for developing a UTI are the presence of ASB for women with type 2 diabetes and sexual intercourse during the week before entry into the study for women with type 1 diabetes.
Clinical Significance of <i>miR-146a</i> in Gastric Cancer Cases
Authors: Ryunosuke Kogo, Koshi Mimori, Fumiaki Tanaka, Shizuo Komune, Masaki Mori
Journal: Clinical Cancer Research (2011)

The profiles of microRNAs change significantly in gastric cancer. MiR-146a is reported to be a tumor suppressor in pancreatic cancer, breast cancer, and prostate cancer. We investigated the clinical significance of miR-146a in gastric cancer, in particular focusing on hypothetical miR-146a target genes, such as epidermal growth factor receptor (EGFR) and interleukin-1 receptor-associated kinase (IRAK1).We examined miR-146a levels in 90 gastric cancer samples by q-real-time (qRT)-PCR and analyzed the association between miR-146a levels and clinicopathologic factors and prognosis. The regulation of EGFR and IRAK1 by miR-146a was examined with miR-146a-transfected gastric cancer cells. Moreover, we analyzed the association between miR-146a levels and the G/C single nucleotide polymorphism (SNP) within pre-miR-146a seed sequences in 76 gastric cancer samples, using direct sequencing of genomic DNA.In 90 clinical samples of gastric cancer, miR-146a levels in cancer tissues were significantly lower than those in the corresponding noncancerous tissue (P < 0.001). Lower levels of miR-146a were associated with lymph node metastasis and venous invasion (P < 0.05). Moreover, a lower level of miR-146a was an independent prognostic factor for overall survival (P = 0.003). Ectopic expression of miR-146a inhibited migration and invasion and downregulated EGFR and IRAK1 expression in gastric cancer cells. In addition, G/C SNP within the pre-miR-146a seed sequence significantly reduced miR-146a levels in the GG genotype compared with the CC genotype.MiR-146a contains an SNP, which is associated with mature miR-146a expression. MiR-146a targeting of EGFR and IRAK1 is an independent prognostic factor in gastric cancer cases.
Somatic mosaicism for the<i>COL7A1</i>mutation p.Gly2034Arg in the unaffected mother of a patient with dystrophic epidermolysis bullosa pruriginosa
Authors: P.C. van den Akker, A.M.G. Pasmooij, R. Meijer, H. Scheffer, M.F. Jonkman
Journal: British Journal of Dermatology (2014)

Dystrophic epidermolysis bullosa (DEB) is a heritable blistering disorder caused by mutations in the type VII collagen gene, COL7A1. Although revertant mosaicism is well known in DEB, 'forward' somatic mosaicism, in which a pathogenic mutation arises on a wild-type (WT) background, extending beyond the germ cells, has not been reported. It is therefore unknown what proportion of sporadic dominant DEB (DDEB) cases result from de novo mutations or somatic mosaic parents. In the clinically unaffected mother of a patient with DDEB pruriginosa due to the p.Gly2034Arg mutation, we identified the p.Gly2034Arg mutation in a proportion of lymphocytes and skin cells (mutational load 10-25%). Our data emphasize that forward mosaicism occurs in DDEB and highlight that mutation analysis should always be performed in the parents of sporadic DDEB patients to confirm the de novo status of the mutation. Ultimately, this will reveal the frequency of true de novo mutations and somatic mosaicism in parents, which has important implications for genetic counselling. Our data indicate that the threshold of mutant type VII procollagen to develop DDEB must be higher than 10-25%, which provides a rationale for therapeutic approaches aimed at increasing the WT : mutant type VII collagen ratio.
Restoring E-Cadherin Expression Increases Sensitivity to Epidermal Growth Factor Receptor Inhibitors in Lung Cancer Cell Lines
Authors: Samir E. Witta, Robert M. Gemmill, Fred R. Hirsch, Christopher D. Coldren, Karla Hedman, Larisa Ravdel, Barbara Helfrich, Rafal Dziadziuszko, Daniel C. Chan, Michio Sugita, Zeng Chan, Anna Baron, Wilbur Franklin, Harry A. Drabkin, Luc Girard, Adi F. Gazdar, John D. Minna, Paul A. Bunn
Journal: Cancer Research (2006)

The epidermal growth factor receptor (EGFR) is overexpressed in the majority of non-small cell lung cancers (NSCLC). EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib, produce 9% to 27% response rates in NSCLC patients. E-Cadherin, a calcium-dependent adhesion molecule, plays an important role in NSCLC prognosis and progression, and interacts with EGFR. The zinc finger transcriptional repressor, ZEB1, inhibits E-cadherin expression by recruiting histone deacetylases (HDAC). We identified a significant correlation between sensitivity to gefitinib and expression of E-cadherin, and ZEB1, suggesting their predictive value for responsiveness to EGFR-tyrosine kinase inhibitors. E-Cadherin transfection into a gefitinib-resistant line increased its sensitivity to gefitinib. Pretreating resistant cell lines with the HDAC inhibitor, MS-275, induced E-cadherin along with EGFR and led to a growth-inhibitory and apoptotic effect of gefitinib similar to that in gefitinib-sensitive NSCLC cell lines including those harboring EGFR mutations. Thus, combined HDAC inhibitor and gefitinib treatment represents a novel pharmacologic strategy for overcoming resistance to EGFR inhibitors in patients with lung cancer.
The extracellular domain of CD45 controls association with the CD4-T cell receptor complex and the response to antigen-specific stimulation.
Authors: D Leitenberg, T J Novak, D Farber, B R Smith, K Bottomly
Journal: The Journal of Experimental Medicine (1996)

The CD45 tyrosine phosphatase plays an important role in regulating T lymphocyte activation, but the function of the different isoforms of CD45 is not known. T cell transfectants have been prepared that express individual CD45 isoforms in cells with a well-defined T cell receptor (TCR) from the D10 T helper 2 clone. We find that cells bearing low molecular weight CD45 isoforms are far more efficient in responding to stimulation with peptide and antigen-presenting cells compared with cells bearing high molecular weight CD45 isoforms. One hypothesis for the preferential activation of cells that express low molecular weight CD45 isoforms is that they interact with other cell surface antigens important in TCR signaling, altering their phosphorylation status and affecting the character of the signal transduction pathway. In this report, using cells expressing single isoforms, we demonstrate that low molecular weight isoforms of CD45 preferentially associate with CD4 and the TCR complex compared with high molecular weight isoforms. The molecular basis for this interaction was further examined using a glycosyl phosphatidyl inositol (GPI)-linked form of CD45Null (lacking tyrosine phosphatase domains), which preferentially associated with CD4 compared with GPI-linked CD45ABC, and cytoplasmic tail mutants of CD4, which retained the ability to coassociate. Using this panel of transfectants, it is clear that the interaction between CD4 and CD45 does not require the cytoplasmic domains of CD45, but is dependent on the specific external domain of the various isoforms: low molecular weight species were more likely to associate with the CD4-TCR complex than the higher molecular weight isoforms, and their ability to coassociate correlated with the magnitude of the response to specific antigen.
Global Promoter Methylation Analysis Reveals Novel Candidate Tumor Suppressor Genes in Natural Killer Cell Lymphoma
Authors: Can Küçük, Xiaozhou Hu, Bei Jiang, David Klinkebiel, Huimin Geng, Qiang Gong, Alyssa Bouska, Javeed Iqbal, Philippe Gaulard, Timothy W. McKeithan, Wing C. Chan
Journal: Clinical Cancer Research (2015)

To identify tumor suppressor genes epigenetically silenced by promoter hypermethylation in extranodal natural killer cell lymphoma (NKCL).Promoter methylation was analyzed with global and locus-specific methylation assays in NKCL cases and NK cell lines. Gene expression profiles were used to identify genes for which aberrant promoter methylation was associated with transcriptional silencing. Selected DNA methylations were validated by RRBS, pyrosequencing, or q-MSP. Decitabine treatment was performed to evaluate reactivation of methylated genes. The tumor suppressor effect of silenced genes was evaluated functionally by reintroducing them into NK cell lines.We observed significant promoter hypermethylation in most NKCL samples compared with normal NK cells. Correlation of global promoter methylation with gene expression profiles identified 95 genes with strong evidence for being silenced because of promoter methylation, including BCL2L11 (BIM), DAPK1, PTPN6 (SHP1), TET2, SOCS6, and ASNS. Known tumor suppressor genes were significantly overrepresented in this set of genes. Decitabine treatment of NK cell lines was associated with reexpression of all 10 selected methylated and silenced genes. Ectopic expression of frequently silenced BIM in two BIM-nonexpressing NK cell lines led to increased apoptosis and eventual elimination of BIM-transduced cells. It also sensitized these cell lines to chemotherapy-induced apoptosis. Similarly, reintroduction of SOCS6 significantly inhibited growth in SOCS6-nonexpressing NK cell lines. NK cell lines lacking ASNS expression showed increased sensitivity to treatment with l-asparaginase. Reintroduction of ASNS reduced drug sensitivity.Promoter region hypermethylation is frequent in NKCL, and aberrantly methylated genes are pathologically and clinically significant.
PROGNOSTIC IMPACT OF GLYCOSYLATED HEMOGLOBIN DURING MID-TERM PERIOD IN PATIENTS WITH DIABETES MELLITUS COMPLICATED BY ACUTE MYOCARDIAL INFARCTION
Authors: Min Goo Lee, Myung Ho Jeong, Young Keun Ahn, Hyo&ndash;Soo Kim, Young&ndash;Jo Kim, Seung&ndash;Woon Rha, Shung Chull Chae, Seung&ndash;Ho Hur
Journal: Journal of the American College of Cardiology (2012)
p73 Expression Is Associated with the Cellular Radiosensitivity in Cervical Cancer after Radiotherapy
Authors: Stephanie Si Liu, Rebecca Ching-Yu Leung, Kelvin Yuen-Kwong Chan, Pui-Man Chiu, Annie Nga-Yin Cheung, Kar-Fai Tam, Tong-Yow Ng, Ling-Chui Wong, Hextan Yuen-Sheung Ngan
Journal: Clinical Cancer Research (2004)

Abstract Apoptosis is one of the causes of cell death in cervical cancer following radiotherapy (S. S. Liu et al., Eur. J. Cancer, 37: 1104–1110, 2001). By studying the gene expression profile with cDNA apoptotic array, the p73 gene was found overexpressed in radiosensitive cervical cancers when compared with radioresistant ones. To investigate the role of the p73 gene in relation to clinical assessment of radiosensitivity in cervical cancer based on the findings of residual tumor cells in cervical biopsies after completion of radiotherapy, we studied the protein expression of p73 in 59 cervical cancers after radiotherapy and 68 normal cervices using immunohistochemistry. The expression of p73 was found to be significantly increased in cancer samples and, more importantly, in those samples sensitive to radiotherapy (P &amp;lt; 0.001). The overexpression of p73 actually predicted a better prognosis in cervical cancer patients (P &amp;lt; 0.001). To investigate the possible involvement of p73 downstream genes, the protein expressions of p21 and Bax were studied. The expression of p21, but not Bax, was found to be positively correlated with the expression of p73 (P = 0.001). Furthermore, the epigenetic regulation of p73 expression via DNA methylation was also investigated in 103 cervical cancers and 124 normals. Hypermethylation of p73 gene was observed in 38.8% of cervical cancers, and it was significantly associated with reduced or absent p73 expression (P &amp;lt; 0.001). Reactivation of p73 expression in two cervical cancer cell lines by demethylation treatment supported the role of methylation in the regulation of p73 expression. Our findings suggested that p73 expression was related to the radiosensitivity of cervical cancer cells and may play an important role in the regulation of cellular radiosensitivity.