tbuckley/cabot-search huggingface dataset:
Role of the oxidative DNA damage repair gene OGG1 in colorectal tumorigenesis.
Authors: Ben Kinnersley, Stephan Buch, Sergi Castellví-Bel, Susan Mary Farrington, Asta Forsti, Jochen Hampe, Kari Hemminki, Robert M W Hofstra, Emma Northwood, Claire Palles, Manuela Pinheiro, Clara Ruiz-Ponte, Clemens Schafmayer, Manuel R Teixeira, Helga Westers, Tom van Wezel, D Timothy Bishop, Ian Tomlinson, Malcolm G Dunlop, Richard S Houlston
Journal: JNCI Journal of the National Cancer Institute (2013)

Biallelic inherited mutations in the oxidative DNA damage repair gene MUTYH predispose to colorectal adenomas and colorectal carcinoma (CRC) with high penetrance. We investigated whether rare inherited variants in other oxidative DNA damage repair genes predisposed to CRC. Single marker association analyses were assessed under an allelic model with Bonferroni correction for multiple testing. All statistical tests were two-sided. A rare inherited nonsynonymous variant in OGG1 (Gly308Glu), the functional partner of MUTYH, was over-represented in case patients with advanced CRC compared with population-based control subjects (n = 36 of 2142 case patients vs n = 15 of 2175 control subjects in the training phase, P = 1.8×10(-3); and n = 22 of 1005 case patients vs n = 8 of 1389 control subjects in the validation phase, P = 4.8×10(-4); P = 1.4×10(-5) combined; odds ratio = 2.92, 95% confidence interval = 1.80 to 4.74). Glycine at residue 308 was highly conserved through evolution, and the glutamic acid substitution was predicted as likely to interfere with function. Biallelic inherited and somatic OGG1 mutations were rarely observed in OGG1 (Gly308Glu) carriers, nor did we find any associated somatic mutator phenotype. These data suggest that OGG1 (Gly308Glu) may act as a low-penetrance allele that contributes to colorectal tumorigenesis.
Pim-selective inhibitor DHPCC-9 reveals Pim kinases as potent stimulators of cancer cell migration and invasion
Authors: Niina M Santio, Riitta L Vahakoski, Eeva-Marja Rainio, Jouko A Sandholm, Sanna S Virtanen, Michelle Prudhomme, Fabrice Anizon, Pascale Moreau, Päivi J Koskinen
Journal: Molecular Cancer (2010)

Abstract Background Pim family kinases are small constitutively active serine/threonine-specific kinases, elevated levels of which have been detected in human hematopoietic malignancies as well as in solid tumours. While we and others have previously shown that the oncogenic Pim kinases stimulate survival of hematopoietic cells, we now examined their putative role in regulating motility of adherent cancer cells. For this purpose, we inhibited Pim kinase activity using a small molecule compound, 1,10-dihydropyrrolo[2,3- a ]carbazole-3-carbaldehyde (DHPCC-9), which we had recently identified as a potent and selective inhibitor for all Pim family members. Results We now demonstrate that the Pim kinase inhibitor DHPCC-9 is very effective also in cell-based assays. DHPCC-9 impairs the anti-apoptotic effects of Pim-1 in cytokine-deprived myeloid cells and inhibits intracellular phosphorylation of Pim substrates such as Bad. Moreover, DHPCC-9 slows down migration and invasion of cancer cells derived from either prostate cancer or squamocellular carcinoma patients. Silencing of Pim expression reduces cell motility, while Pim overexpression enhances it, strongly suggesting that the observed effects of DHPCC-9 are dependent on Pim kinase activity. Interestingly, DHPCC-9 also abrogates NFATc-dependent migration of cancer cells, implying that NFATc factors mediate at least part of the pro-migratory effects of Pim kinases. Conclusions Altogether, our data indicate that DHPCC-9 is not only a powerful tool to investigate physiological effects of the oncogenic Pim family kinases, but also an attractive molecule for drug development to inhibit invasiveness of Pim-overexpressing cancer cells.
Building Phylogenetic Trees from Molecular Data with MEGA
Authors: B. G. Hall
Journal: Molecular Biology and Evolution (2013)

Phylogenetic analysis is sometimes regarded as being an intimidating, complex process that requires expertise and years of experience. In fact, it is a fairly straightforward process that can be learned quickly and applied effectively. This Protocol describes the several steps required to produce a phylogenetic tree from molecular data for novices. In the example illustrated here, the program MEGA is used to implement all those steps, thereby eliminating the need to learn several programs, and to deal with multiple file formats from one step to another (Tamura K, Peterson D, Peterson N, Stecher G, Nei M, Kumar S. 2011. MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol. 28:2731–2739). The first step, identification of a set of homologous sequences and downloading those sequences, is implemented by MEGA's own browser built on top of the Google Chrome toolkit. For the second step, alignment of those sequences, MEGA offers two different algorithms: ClustalW and MUSCLE. For the third step, construction of a phylogenetic tree from the aligned sequences, MEGA offers many different methods. Here we illustrate the maximum likelihood method, beginning with MEGA's Models feature, which permits selecting the most suitable substitution model. Finally, MEGA provides a powerful and flexible interface for the final step, actually drawing the tree for publication. Here a step-by-step protocol is presented in sufficient detail to allow a novice to start with a sequence of interest and to build a publication-quality tree illustrating the evolution of an appropriate set of homologs of that sequence. MEGA is available for use on PCs and Macs from www.megasoftware.net.
Metabolic Syndrome and All-Cause and Cardiovascular Mortality in an Italian Elderly Population
Authors: Sabina Zambon, Silvia Zanoni, Giovanna Romanato, Maria Chiara Corti, Marianna Noale, Leonardo Sartori, Estella Musacchio, Giovannella Baggio, Gaetano Crepaldi, Enzo Manzato
Journal: Diabetes Care (2008)

OBJECTIVE—The purpose of this study was to explore the association of metabolic syndrome and each of its components with all-cause and cardiovascular mortality in a general Italian elderly population. RESEARCH DESIGN AND METHODS—Metabolic syndrome, diagnosed by National Cholesterol Education Program Adult Treatment Panel III criteria, all-cause mortality, and cardiovascular mortality, was evaluated in 2,910 subjects aged ≥65 years of the Progetto Veneto Anziani (Pro.V.A.) Study during a mean follow-up time of 4.4 years. RESULTS—After multivariable adjustment, metabolic syndrome was associated with increased all-cause mortality in all subjects (hazard ratio 1.41 [95% CI 1.16–1.72], P = 0.001), among men (1.42 [1.06–1.89], P = 0.017), and among women (1.47 [1.13–1.91], P = 0.004). High glucose in all subjects (1.27 [1.02–1.59], P = 0.037) and in women (1.61 [1.16–2.24], P = 0.005) and low HDL cholesterol in women (1.48 [1.08–2.02], P = 0.014) were predictors of all-cause mortality, even independently of the interactions of different metabolic syndrome components. After multivariable adjustment, metabolic syndrome was also associated with increased cardiovascular mortality in all subjects (1.60 [1.17–2.19], P = 0.003), among men (1.66 [1.00–2.76], P = 0.051), and among women (1.60 [1.06–2.33], P = 0.025). High glucose (2.17 [1.28–3.68], P = 0.004) and low HDL cholesterol (1.78 [1.07–2.95], P = 0.026) among women predicted higher cardiovascular mortality. CONCLUSIONS—In this general Italian elderly population, among metabolic syndrome components, all-cause mortality is better predicted by high glucose in all subjects and in women and by low HDL cholesterol in women, whereas cardiovascular mortality is better predicted by high glucose and low HDL cholesterol in women.
Acquired Immuno-Deficiency Syndrome: Epidemiology, Virology, and Immunology
Authors: A Weiss, H Hollander, J Stobo
Journal: Annual Review of Medicine (1985)

Acquired immunodeficiency syndrome indicates opportunistic infection or unusual malignancy associated with a marked deficiency of cell mediated immunity in the absence of any other cause of the immune defect. This review examines epidemiology, virology, and immunology associated with this disorder. The syndrome appears to be caused by infection of at-risk individuals by a retrovirus that has tropism for a specific population of T lymphocytes.
Faster reconfiguration of NHS services is needed for next two years says NHS chief
Authors: A. O'Dowd
Journal: BMJ (2012)

<h3>Abstract</h3> Histone H3 lysine 4 methylation (H3K4me) is extensively regulated by numerous writer and eraser enzymes in mammals. Nine H3K4me enzymes are associated with neurodevelopmental disorders to date, indicating their important roles in the brain. However, interplay among H3K4me enzymes during brain development remains largely unknown. Here, we show functional interactions of a writer-eraser duo, <i>KMT2A</i> and <i>KDM5C</i>, which are responsible for Wiedemann-Steiner Syndrome (WDSTS), and mental retardation X-linked syndromic Claes-Jensen type (MRXSCJ), respectively. Despite opposite enzymatic activities, the two mouse models deficient for either <i>Kmt2a</i> or <i>Kdm5c</i> shared reduced dendritic spines and increased aggression. Double mutation of <i>Kmt2a</i> and <i>Kdm5c</i> clearly reversed dendritic morphology, key behavioral traits including aggression, and partially corrected altered transcriptomes and H3K4me landscapes. Thus, our study uncovers common yet mutually suppressive aspects of the WDSTS and MRXSCJ models and provides a proof of principle for balancing a single writer-eraser pair to ameliorate their associated disorders.
Specific oral tolerance induction in food allergy in children: efficacy and clinical patterns of reaction
Authors: U. Staden, C. Rolinck‐Werninghaus, F. Brewe, U. Wahn, B. Niggemann, K. Beyer
Journal: Allergy (2007)

Background: Specific oral tolerance induction (SOTI) seems to be a promising treatment of food allergy. Specific oral tolerance induction and elimination diet were compared with respect to efficacy rate and patterns of clinical reaction. Methods: Children with challenge proven immunoglobulin E (IgE)‐mediated cow’s milk (CM) allergy or hen’s egg (HE) allergy were randomly assigned to SOTI or elimination diet as a control group. Specific oral tolerance induction treatment was performed at home on a daily basis according to a study protocol with fresh CM or lyophilized HE protein. Re‐evaluation of clinically relevant food allergy was performed by food challenge after a median of 21 months. Children in the SOTI group received a secondary elimination diet for 2 months prior to follow‐up challenge to evaluate persistence of induced oral tolerance. Results: At follow‐up challenge, nine of 25 children (36%) showed permanent tolerance in the SOTI group, three of 25 (12%) were tolerant with regular intake and four of 25 (16%) were partial responders. In the control group, seven of 20 children (35%) were tolerant. Allergen‐specific immunoglobulin E decreased significantly both in children who developed natural tolerance during the elimination diet ( P &lt; 0.05) and in those with SOTI ( P &lt; 0.001). Conclusions: Specific oral tolerance induction seems a valid treatment option for patients with persistent food allergy. Indications may be given if avoidance cannot be guaranteed or for those who are eager to eat the food in question. Advantages of SOTI are the increased threshold dose for allergic reactions and the substantially reduced risk of severe allergic reactions after inadvertent ingestion of the allergen. However, careful monitoring during SOTI is mandatory.
Protective effects of a glucocorticoid on downregulation of pulmonary beta 2-adrenergic receptors in vivo.
Authors: J C Mak, M Nishikawa, H Shirasaki, K Miyayasu, P J Barnes
Journal: Journal of Clinical Investigation (1995)

We investigated the in vivo effects of a glucocorticoid on beta-agonist-induced downregulation of beta 1- and beta 2-adrenergic receptors (determined by [125I]iodocyanopindolol binding), mRNA expression (assessed by Northern blotting), and gene transcription (using nuclear run-on assays) in rat lung. Dexamethasone (Dex) (0.2 mg/kg/d, days 1-8) increased beta 1- and beta 2-receptor numbers by 70 and 69% above control, respectively, but did not change their mRNA expression. Isoproterenol (Iso) (0.96 mg/kg/d, days 2-8) decreased beta 1- and beta 2-receptor numbers by 48 and 51%, respectively, and also reduced mRNA expression by 69 and 57%, respectively. The combination of Dex and Iso resulted in no net change in beta 2-receptor number and its mRNA expression, although there was a significant reduction in beta 1-receptor number and mRNA expression. The mapping of beta 1- and beta 2-receptors by receptor autoradiography confirmed these findings over alveoli, epithelium, endothelium, and airway and vascular smooth muscle. We also measured the activation of the transcription factor, cyclic AMP response element binding protein (CREB) using an electrophoretic mobility shift assay. CREB-like DNA-binding activity was decreased after Iso treatment but this decrease was prevented after treatment with Dex. Nuclear run-on assays revealed that the transcription rate of the beta 1-receptor gene did not alter after Dex treatment, but was reduced after Iso treatment. The transcription rate of the beta 2-receptor gene was increased after Dex treatment by approximately twofold, but there was no change after Iso treatment. We conclude that glucocorticoids can prevent homologous downregulation of beta 2-receptor number and mRNA expression at the transcriptional level without affecting beta 1-receptors and that the transcription factor CREB may be involved in this phenomenon. Such an effect may have clinical implications for preventing the development of tolerance to beta 2-agonists in asthmatic patients treated with beta-agonist bronchodilators.
Nuremberg lamentation: for the forgotten victims of medical science
Authors: W. E Seidelman
Journal: BMJ (1996)

Fifty years after the Nuremberg medical trial there remain many unanswered questions about the role of the German medical profession during the Third Reich. Other than the question of human experimentation, important ethical challenges arising from medicine in Nazi Germany which have continuing relevance were not addressed at Nuremberg. The underlying moral question is that of the exercise of professional power and its impact on vulnerable people seeking medical care. Sensitisation to the obligations of professional power may be achieved by an annual commemoration and lament to the memory of the victims of medical abuse which would serve as a recurring reminder of the physician's vulnerability and fallibility.
CXCL11 Attenuates Bleomycin-induced Pulmonary Fibrosis via Inhibition of Vascular Remodeling
Authors: Marie D. Burdick, Lynne A. Murray, Michael P. Keane, Ying Ying Xue, David A. Zisman, John A. Belperio, Robert M. Strieter
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Aberrant vascular remodeling is a central hallmark for the development and progression of idiopathic pulmonary fibrosis. The mechanisms underlying the pathophysiologic alterations, however, are poorly understood. A recent phase II trial of interferon γ-1b has demonstrated a trend toward a decrease in profibrotic and proangiogenic biologic markers, and upregulation of lung CXCL11 mRNA and bronchoalveolar lavage fluid and plasma protein levels of CXCL11. We hypothesized that net aberrant vascular remodeling seen during the pathogenesis of fibroplasia and deposition of extracellular matrix during bleomycin-induced pulmonary fibrosis can be attenuated by treatment with the angiostatic ELR− CXC chemokine, CXCL11. In a preclinical model, systemic administration of CXCL11 reduced pulmonary collagen deposition, procollagen gene expression, and histopathologic fibroplasia and extracellular matrix deposition in the lung of bleomycin-treated mice. CXCL11 treatment significantly reduced bleomycin-induced pulmonary fibrosis without altering specific lung leukocyte populations. CXCR3 is not expressed on fibroblasts and CXCL11 had no direct functional effect on pulmonary fibroblasts. The angiogenic activity in the lung was significantly decreased, however, and CXCL11 treatment reduced the total number of endothelial cells in the lung following bleomycin exposure. The results suggest that CXCL11 inhibits pulmonary fibrosis by altering aberrant vascular remodeling.
A Phase I Dose Defining Study for MK-2206 Combined with Gefitinib in NSCLC Population Enriched with EGFR Mutation
Authors: C.-C. Lin, C.-J. Yu, C.-C. Ho, K.-Y. Chen, J.-Y. Shih, Z.-Z. Lin, Y.-L. Lin, W.-Y. Liao, S.-H. Tsai, L. Yan, J. C.-H. Yang
Journal: Annals of Oncology (2015)
Rapid DNA Methylation Changes after Exposure to Traffic Particles
Authors: Andrea Baccarelli, Robert O. Wright, Valentina Bollati, Letizia Tarantini, Augusto A. Litonjua, Helen H. Suh, Antonella Zanobetti, David Sparrow, Pantel S. Vokonas, Joel Schwartz
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Exposure to particulate air pollution has been related to increased hospitalization and death, particularly from cardiovascular disease. Lower blood DNA methylation content is found in processes related to cardiovascular outcomes, such as oxidative stress, aging, and atherosclerosis.We evaluated whether particulate pollution modifies DNA methylation in heavily methylated sequences with high representation throughout the human genome.We measured DNA methylation of long interspersed nucleotide element (LINE)-1 and Alu repetitive elements by quantitative polymerase chain reaction-pyrosequencing of 1,097 blood samples from 718 elderly participants in the Boston area Normative Aging Study. We used covariate-adjusted mixed models to account for within-subject correlation in repeated measures. We estimated the effects on DNA methylation of ambient particulate pollutants (black carbon, particulate matter with aerodynamic diameter < or = 2.5 microm [PM2.5], or sulfate) in multiple time windows (4 h to 7 d) before the examination. We estimated standardized regression coefficients (beta) expressing the fraction of a standard deviation change in DNA methylation associated with a standard deviation increase in exposure.Repetitive element DNA methylation varied in association with time-related variables, such as day of the week and season. LINE-1 methylation decreased after recent exposure to higher black carbon (beta = -0.11; 95% confidence interval [CI], -0.18 to -0.04; P = 0.002) and PM2.5 (beta = -0.13; 95% CI, -0.19 to -0.06; P < 0.001 for the 7-d moving average). In two-pollutant models, only black carbon, a tracer of traffic particles, was significantly associated with LINE-1 methylation (beta = -0.09; 95% CI, -0.17 to -0.01; P = 0.03). No association was found with Alu methylation (P > 0.12).We found decreased repeated-element methylation after exposure to traffic particles. Whether decreased methylation mediates exposure-related health effects remains to be determined.
Travelling in time with COPD
Authors: J. R. Hurst, P. M. A. Calverley
Journal: Thorax (2010)

α-Synuclein (α-syn) has been implicated in the pathogenesis of many neurodegenerative disorders, including Parkinson9s disease. These disorders are characterized by various neurological and psychiatric symptoms based on progressive neuropathological alterations. Whether the neurodegenerative process might be halted or even reversed is presently unknown. Therefore, conditional mouse models are powerful tools to analyze the relationship between transgene expression and progression of the disease. To explore whether α-syn solely originates and further incites these alterations, we generated conditional mouse models by using the tet-regulatable system. Mice expressing high levels of human wild-type α-syn in midbrain and forebrain regions developed nigral and hippocampal neuropathology, including reduced neurogenesis and neurodegeneration in absence of fibrillary inclusions, leading to cognitive impairment and progressive motor decline. Turning off transgene expression in symptomatic mice halted progression but did not reverse the symptoms. Thus, our data suggest that approaches targeting α-syn-induced pathological pathways might be of benefit rather in early disease stages. Furthermore, α-syn-associated cytotoxicity is independent of filamentous inclusion body formation in our conditional mouse model.
Role of thyroid hormone homeostasis in obesity-prone and obesity-resistant mice fed a high-fat diet
Authors: Shu-Fang Xia, Xiao-Mei Duan, Li-Yue Hao, Li-Ting Li, Xiang-Rong Cheng, Zhen-Xing Xie, Yi Qiao, Li-Rong Li, Xue Tang, Yong-Hui Shi, Guo-Wei Le
Journal: Metabolism (2015)
Current achievements and future research directions in ovarian tissue culture, in vitro follicle development and transplantation: implications for fertility preservation
Authors: J. Smitz, M. M. Dolmans, J. Donnez, J. E. Fortune, O. Hovatta, K. Jewgenow, H. M. Picton, C. Plancha, L. D. Shea, R. L. Stouffer, E. E. Telfer, T. K. Woodruff, M. B. Zelinski
Journal: Human Reproduction Update (2010)

BACKGROUNDFemale cancer patients are offered 'banking' of gametes before starting fertility-threatening cancer therapy. Transplants of fresh and frozen ovarian tissue between healthy fertile and infertile women have demonstrated the utility of the tissue banked for restoration of endocrine and fertility function. Additional methods, like follicle culture and isolated follicle transplantation, are in development.
IMMUNE RESPONSES IN VITRO
Authors: Carl W. Pierce, Susan M. Solliday, Richard Asofsky
Journal: The Journal of Experimental Medicine (1972)

Suppression of Ig class-specific PFC responses by class-specific antibody to mouse immunoglobulin was studied in cultures of spleen cells from immunized mice. In contrast to cultures from normal mice where anti-µ suppressed responses in all Ig classes, anti-µ had progressively less suppressive effect on γ1 and γ2 responses in cultures from immunized mice with time after immunization. This was most pronounced at 10 days after immunization when anti-µ suppressed γM and γA responses, but had no or slight effect on γ1 or γ2 responses which were still suppressed with anti-γ1 and anti-γ2. These changes in precursor cell susceptibility to anti-µ were antigen specific.
Mucosal tumour necrosis factor alpha and interleukin-6 in patients with Helicobacter pylori associated gastritis.
Authors: J E Crabtree, T M Shallcross, R V Heatley, J I Wyatt
Journal: Gut (1991)

The production of tumour necrosis factor alpha (TNF alpha) and interleukin-6 by human antral mucosa during short term culture in vitro has been measured by enzyme linked immunosorbent assay. TNF alpha and interleukin-6 concentrations in culture supernatants were significantly greater (p less than 0.001) in patients infected with Helicobacter pylori, all of whom had chronic gastritis, than in patients who were H pylori negative with histologically normal gastric mucosa. Among H pylori colonised patients, TNF alpha concentrations were significantly higher in those with active gastritis and neutrophil infiltration into the epithelium than in those with inactive gastritis. In contrast, interleukin-6 concentrations were raised in both active and inactive gastritis. This study shows that H pylori gastritis is associated with increased gastric mucosal production of TNF alpha and interleukin-6 and that the nature of the mucosal cytokine response varies with the immunohistology of the disease. Inflammatory cytokines generated locally within the gastric mucosa could be relevant to the gastric physiology of H pylori infection.