tbuckley/cabot-search huggingface dataset:
<i>Shmt1</i> Heterozygosity Impairs Folate-Dependent Thymidylate Synthesis Capacity and Modifies Risk of <i>Apcmin</i>-Mediated Intestinal Cancer Risk
Authors: Amanda J. MacFarlane, Cheryll A. Perry, Michael F. McEntee, David M. Lin, Patrick J. Stover
Journal: Cancer Research (2011)

Abstract Folate-mediated one-carbon metabolism is required for the de novo synthesis of purines, thymidylate, and S-adenosylmethionine, the primary cellular methyl donor. Impairments in folate metabolism diminish cellular methylation potential and genome stability, which are risk factors for colorectal cancer (CRC). Cytoplasmic serine hydroxymethyltransferase (SHMT1) regulates the partitioning of folate-activated one-carbons between thymidylate and S-adenosylmethionine biosynthesis. Therefore, changes in SHMT1 expression enable the determination of the specific contributions made by thymidylate and S-adenosylmethionine biosynthesis to CRC risk. Shmt1 hemizygosity was associated with a decreased capacity for thymidylate synthesis due to downregulation of enzymes in its biosynthetic pathway, namely thymidylate synthase and cytoplasmic thymidine kinase. Significant Shmt1-dependent changes to methylation capacity, gene expression, and purine synthesis were not observed. Shmt1 hemizygosity was associated with increased risk for intestinal cancer in Apcmin/+ mice through a gene-by-diet interaction, indicating that the capacity for thymidylate synthesis modifies susceptibility to intestinal cancer in Apcmin/+ mice. Cancer Res; 71(6); 2098–107. ©2011 AACR.
Recommendations for physical activity in older adults
Authors: P. B. Sparling, B. J. Howard, D. W. Dunstan, N. Owen
Journal: BMJ (2015)

Older adults find it difficult to meet moderate and vigorous exercise targets. Given that a dose-response exists for physical activity and health benefits, <b>Phillip B Sparling and colleagues</b> argue that a change in message to reduce sedentary time and increase light activities may prove more realistic and pave the way to more intense exercise
Asthma Severity in Korean Children Assessed By the 12 Pediatric Allergists Working at Different Hospitals
Authors: Dong In Suh, DaeHyun Lim, Hyeon Jong Yang, Bong-Seong Kim, Youn Ho Shin, So-Yeon Lee, Geunhwa Park, Woo Kyung Kim, Hyo-Bin Kim, Heysung Baek, Jin-Tack Kim, Ja-Kyoung Kim
Journal: Journal of Allergy and Clinical Immunology (2015)
Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial
Authors: Iain B McInnes, Philip J Mease, Bruce Kirkham, Arthur Kavanaugh, Christopher T Ritchlin, Proton Rahman, Désirée van der Heijde, Robert Landewé, Philip G Conaghan, Alice B Gottlieb, Hanno Richards, Luminita Pricop, Gregory Ligozio, Manmath Patekar, Shephard Mpofu
Journal: The Lancet (2015)
Physical performance and training response during Ramadan observance, with particular reference to protein metabolism
Authors: Roy J Shephard
Journal: British Journal of Sports Medicine (2012)

This review examines information on the effects of Ramadan observance upon the metabolism, training and performance of athletes, with particular reference to proteins and amino acids. Increased gluconeogenesis and/or a reduced intake of protein could lead to a decrease of lean tissue, with adverse effects on muscular performance, and the lack of immediate protein ingestion could compromise responses to strength training. Actual responses vary quite widely, depending on culture and the individual's level and type of athletic involvement. In elite competitors, there is typically an increased fractional ingestion of protein with a small reduction in overall energy intake, and this may lead to small reductions of body and lean tissue mass. There are often small decreases of performance, particularly in activities requiring vigorous and/or repetitive muscular contraction. More information is needed on responses in situations where protein intake is likely to be inadequate (adolescent growth, those maintaining vegetarian diets or from poor countries and disciplines with very high overall energy needs) and when vigorous muscle training is in progress. However, in most of the situations studied to date, Ramadan observance has had only limited adverse consequences for either training or competitive performance.
Natural history of branch duct intraductal papillary-mucinous neoplasms of the pancreas without mural nodules: long-term follow-up results
Authors: S Tanno, Y Nakano, T Nishikawa, K Nakamura, J Sasajima, M Minoguchi, Y Mizukami, N Yanagawa, T Fujii, T Obara, T Okumura, Y Kohgo
Journal: Gut (2007)

Although branch duct intraductal papillary-mucinous neoplasms (IPMNs) of the pancreas without mural nodules are frequently observed in asymptomatic subjects, the natural history of these lesions has never been studied. The aim of this study was to elucidate the natural history of branch duct IPMNs without mural nodules.Eighty-two patients who had no apparent mural nodules on initial examination were selected for follow-up. All subjects underwent examinations by imaging modalities including endoscopic retrograde pancreatography, and were followed-up by regular examinations once or twice a year. Serial changes of the maximum cystic diameter and the appearance of mural nodules were studied during the observation periods ranging from 14 to 148 months (median, 61 months).Nine (11.0%) of 82 patients exhibited obvious progression of cystic dilatation (median, 59 months). Of these nine patients with cystic enlargement, six continued with regular follow-up examinations. Three cases underwent surgical resection, and were pathologically diagnosed as adenoma in two and borderline in one. Four patients (4.9%) showed newly developed mural nodules in dilated branch ducts (median, 105 months). Histological analysis revealed three cases classified as adenoma and one as carcinoma in situ. None of the remaining 69 patients (84.1%) showed any changes in dilated branch ducts (median, 57 months).Most branch duct IPMNs without mural nodules remained unchanged during long-term follow-up. Although follow-up with careful examination is required to detect newly developed mural nodules in dilated branch ducts, branch duct IPMNs without mural nodules can be followed-up without surgery.
Liraglutide, a Long-Acting Human Glucagon-Like Peptide-1 Analog, Given as Monotherapy Significantly Improves Glycemic Control and Lowers Body Weight Without Risk of Hypoglycemia in Patients With Type 2 Diabetes
Authors: Tina Vilsbøll, Milan Zdravkovic, Tu Le-Thi, Thure Krarup, Ole Schmitz, Jean-Pierre Courrèges, Robert Verhoeven, Ingrid Bugánová, Sten Madsbad
Journal: Diabetes Care (2007)

iraglutide is a long-acting human glucagon-like peptide-1 (GLP-1) analog (1-4), and the current study was undertaken to evaluate efficacy and safety after 14 weeks' treatment with liraglutide in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS -Main inclusion criteriawere patients aged Ն18 years with type 2 diabetes and A1C Ն7.5 and Յ10.0% (diet) or Ն7.0 and Յ9.5% (mono-oral antidiabetes drug); previous therapy was discontinued.Fasting plasma glucose (FPG) at randomization was 7-13 mmol/l.If FPG was Ͼ15 mmol/l during the study, the patient was withdrawn.The study was conducted in accordance with the Declaration of Helsinki (5).The study was double-blind, randomized (1:1:1:1), and placebo-controlled using three doses of liraglutide (0.65, 1.25, or 1.90 mg).The following main efficacy parameters were assessed: A1C, insulin, proinsulin, glucagon, fructosamine, lipids, homemeasured seven-point plasma glucose profiles, and body weight.Safety parameters (adverse events, hypoglycemic episodes, clinical laboratory parameters, antibodies against liraglutide, vital signs, electrocardiogram, and thyroid (including ultrasonography) and parathyroid parameters were assessed.Liraglutide or placebo was administered in the evening (as in the most recently completed phase 2 study) (6) as once-daily subcutaneous injections in the abdomen or thigh.
Combination Chemotherapy for Advanced Hodgkin's Disease After Failure of MOPP: ABVD and B-CAVe
Authors: W. GRAYDON HARKER
Journal: Annals of Internal Medicine (1984)

Between 1973 and 1982, 110 patients with advanced Hodgkin's disease who had had disease progression while receiving MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) chemotherapy or a relapse after a MOPP-induced complete remission were treated with either ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) (58 patients) or B-CAVe (bleomycin, lomustine, doxorubicin, and vinblastine) (52 patients) chemotherapy in concurrent nonrandomized trials. Responses were seen in 39 of 55 (71%) evaluable ABVD-treated patients—21 (38%) complete and 18 partial responses—and in 34 of 48 (71%) evaluable B-CAVe-treated patients—21 (44%) complete and 13 partial responses. The median duration of the ABVD-induced complete remissions is greater than 25 months compared with 24.3 months for B-CAVe-induced remissions. The 5-year actuarial freedom from progression is 8.5% for evaluable ABVD-treated patients and 25% for B-CAVe-treated patients (p = 0.10). Toxicity in the two treatment groups was similar, with only significant thrombocytopenia (platelet count, < 50 000/mm3) being more common with B-CAVe. Although most patients with Hodgkin's disease refractory to MOPP treatment will respond to either ABVD or B-CAVe chemotherapy, subsequent long-term disease-free survival is unusual. The need for improved treatment programs for this patient group is evident.
Tight Glycemic Control After Pediatric Cardiac Surgery in High-Risk Patient Populations
Authors: Michael S.D. Agus, Lisa A. Asaro, Garry M. Steil, Jamin L. Alexander, Melanie Silverman, David Wypij, Michael G. Gaies
Journal: Circulation (2014)

Our previous randomized, clinical trial showed that postoperative tight glycemic control (TGC) for children undergoing cardiac surgery did not reduce the rate of health care-associated infections compared with standard care (STD). Heterogeneity of treatment effect may exist within this population.We performed a post hoc exploratory analysis of 980 children from birth to 36 months of age at the time of cardiac surgery who were randomized to postoperative TGC or STD in the intensive care unit. Significant interactions were observed between treatment group and both neonate (age ≤30 days; P=0.03) and intraoperative glucocorticoid exposure (P=0.03) on the risk of infection. The rate and incidence of infections in subjects ≤60 days old were significantly increased in the TGC compared with the STD group (rate: 13.5 versus 3.7 infections per 1000 cardiac intensive care unit days, P=0.01; incidence: 13% versus 4%, P=0.02), whereas infections among those >60 days of age were significantly reduced in the TGC compared with the STD group (rate: 5.0 versus 14.1 infections per 1000 cardiac intensive care unit days, P=0.02; incidence: 2% versus 5%, P=0.03); the interaction of treatment group by age subgroup was highly significant (P=0.001). Multivariable logistic regression controlling for the main effects revealed that previous cardiac surgery, chromosomal anomaly, and delayed sternal closure were independently associated with increased risk of infection.This exploratory analysis demonstrated that TGC may lower the risk of infection in children >60 days of age at the time of cardiac surgery compared with children receiving STD. Meta-analyses of past and ongoing clinical trials are necessary to confirm these findings before clinical practice is altered.http://www.clinicaltrials.gov. Unique identifier: NCT00443599.
Inferring the Effects of Demography and Selection on Drosophila melanogaster Populations from a Chromosome-Wide Scan of DNA Variation
Authors: Lino Ometto, Sascha Glinka, David De Lorenzo, Wolfgang Stephan
Journal: Molecular Biology and Evolution (2005)

Identifying regions of the Drosophila melanogaster genome that have been recent targets of positive Darwinian selection will provide evidence for adaptations that have helped this species to colonize temperate habitats. We have begun a search for such genomic regions by analyzing multiple loci (about 250) dispersed across the X chromosome in a putatively ancestral population from East Africa and a derived European population. For both populations we found evidence for past changes in population size. We estimated that a major bottleneck associated with the colonization of Europe occurred about 3,500–16,000 years ago. We also found that while this bottleneck can account for most of the reduction in variation observed in the European sample, there is a deficit of polymorphism in some genomic regions that cannot be explained by demography alone.
Disrupted Expression of CXCL5 in Colorectal Cancer Is Associated with Rapid Tumor Formation in Rats and Poor Prognosis in Patients
Authors: Frank M. Speetjens, Peter J.K. Kuppen, Maro H. Sandel, Anand G. Menon, Danny Burg, Cornelis J.H. van de Velde, Rob A.E.M. Tollenaar, Hans J.G.M. de Bont, J. Fred Nagelkerke
Journal: Clinical Cancer Research (2008)

We isolated a subline (CC531M) from the CC531S rat colon carcinoma cell line, which grows and metastasizes much more rapidly than CC531S. We found, using RNA expression profiling, that one of the major changes in the CC531M cell line was a 5.8-fold reduction of the chemokine CXCL5. The purpose of this study was to determine the effect of CXCL5 expression on colorectal tumor growth and metastasis.CC531 clones were generated with either knockdown or restored expression of CXCL5. These clones were inoculated in the liver of rats. In addition, in two independent cohorts of colorectal cancer patients, the level of CXCL5 expression was determined and associated to clinical variables.Knockdown of CXCL5 expression in CC531S resulted in rapid tumor growth and increased number of metastasis, whereas restored expression of CXCL5 in CC531M resulted in a return of the "mild" tumor growth pattern of the parental cell line CC531S. In vitro, no difference was found in proliferation rate between clones with either high or low expression of CXCL5, suggesting that environmental interactions directed by CXCL5 determine tumor outgrowth. Finally, the importance of our findings was established for patients with colorectal cancer. We found that low expression of CXCL5 was significantly associated with poor prognosis for colorectal cancer patients. CXCL5 showed a trend (P = 0.05) for a positive correlation with intratumoral CD8(+) T-cell infiltration, suggesting a possible explanation for the observed poorer prognosis.Our results show that CXCL5 is important in growth and development of colorectal cancer, implicating a future role in both cancer therapy and diagnosis.
CXCR3-dependent accumulation and activation of perivascular macrophages is necessary for homeostatic arterial remodeling to hemodynamic stresses
Authors: Jing Zhou, Paul C.Y. Tang, Lingfeng Qin, Peter M. Gayed, Wei Li, Eleni A. Skokos, Themis R. Kyriakides, Jordan S. Pober, George Tellides
Journal: The Journal of Experimental Medicine (2010)

Sustained changes in blood flow modulate the size of conduit arteries through structural alterations of the vessel wall that are dependent on the transient accumulation and activation of perivascular macrophages. The leukocytic infiltrate appears to be confined to the adventitia, is responsible for medial remodeling, and resolves once hemodynamic stresses have normalized without obvious intimal changes. We report that inward remodeling of the mouse common carotid artery after ligation of the ipsilateral external carotid artery is dependent on the chemokine receptor CXCR3. Wild-type myeloid cells restored flow-mediated vascular remodeling in CXCR3-deficient recipients, adventitia-infiltrating macrophages of Gr1low resident phenotype expressed CXCR3, the perivascular accumulation of macrophages was dependent on CXCR3 signaling, and the CXCR3 ligand IP-10 was sufficient to recruit monocytes to the adventitia. CXCR3 also contributed to selective features of macrophage activation required for extracellular matrix turnover, such as production of the transglutaminase factor XIII A subunit. Human adventitial macrophages displaying a CD14+/CD16+ resident phenotype, but not circulating monocytes, expressed CXCR3, and such cells were more frequent at sites of disturbed flow. Our observations reveal a CXCR3-dependent accumulation and activation of perivascular macrophages as a necessary step in homeostatic arterial remodeling triggered by hemodynamic stress in mice and possibly in humans as well.
Time to re-evaluate gender segregation in athletics?
Authors: Bennett Foddy, Julian Savulescu
Journal: British Journal of Sports Medicine (2010)

The case of Caster Semenya provides a vivid illustration of the ways in which natural genetic variation can generate large differences in athletic performance. But since we normally segregate athletic sports along the lines of this particular variation-gender-her case also highlights problems with the current approach to justice in sporting competition. Female athletes seem to have a valid complaint when they are made to compete against athletes who are, in one sense or another, male. But once we recognise that gender is not a binary quantity, sex segregation in competitive sport must be seen as an inconsistent and unjust policy, no matter what stance we take on the goals of sport or on the regulation of doping.
Endothelial Lipase Concentrations Are Increased in Metabolic Syndrome and Associated with Coronary Atherosclerosis
Authors: Karen O Badellino, Megan L Wolfe, Muredach P Reilly, Daniel J Rader
Journal: PLoS Medicine (2005)

Endothelial lipase (EL), a new member of the lipase family, has been shown to modulate high-density lipoprotein (HDL-C) metabolism and atherosclerosis in mouse models. We hypothesized that EL concentrations would be associated with decreased HDL-C and increased atherosclerosis in humans.Healthy individuals with a family history of premature coronary heart disease (n = 858) were recruited as part of the Study of the Inherited Risk of Atherosclerosis. Blood was drawn in the fasting state before and, in a subgroup (n = 510), after administration of a single dose of intravenous heparin. Plasma lipids were measured enzymatically, lipoprotein subclasses were assessed by nuclear magnetic resonance, and coronary artery calcification (CAC) was quantified by electron beam computed tomography. Plasma EL mass was measured using a newly developed enzyme-linked immunosorbent assay. Median EL mass in pre-heparin plasma was 442 (interquartile range = 324-617) ng/ml. Median post-heparin mass was approximately 3-fold higher, 1,313 (888-1,927) ng/ml. The correlation between pre-heparin EL mass and post-heparin EL mass was 0.46 (p < 0.001). EL mass concentrations in both pre- and post-heparin plasma significantly correlated with all NCEP ATPIII-defined metabolic syndrome factors: waist circumference (r = 0.28 and 0.22, respectively, p < 0.001 for each), blood pressure (r = 0.18 and 0.24, p < 0.001 for each), triglycerides (r = 0.22, p < 0.001; and 0.13, p = 0.004), HDL cholesterol (r = -0.11, p = 0.002; and -0.18, p < 0.001), and fasting glucose (r = 0.11 and 0.16, p = 0.001 for both). EL mass in both routine (odds ratio [OR] = 1.67, p = 0.01) and post-heparin (OR = 2.42, p = 0.003) plasma was associated with CAC as determined by ordinal regression after adjustment for age, gender, waist circumference, vasoactive medications, hormone replacement therapy (women), and established cardiovascular risk factors.We report, to our knowledge for the first time, that human plasma EL concentrations, in both post-heparin and routine pre-heparin plasma, are significantly associated with metabolic syndrome features and with subclinical atherosclerosis. EL may be a pro-atherogenic factor in humans, especially in overweight individuals and those with metabolic syndrome.
Characterization of Lyt-2-, L3T4- class I-specific cytolytic clones in C3H-gld/gld mice. Implications for functions of accessory molecules and programmed development.
Authors: K Yui, Y Hashimoto, S Wadsworth, M I Greene
Journal: The Journal of Experimental Medicine (1987)

We report the first demonstration of Thy-1+, Lyt-2-, L3T4- MHC-specific CTL clones derived from the Lyt-2-, L3T4- subset of lymph node cells of C3H-gld/gld mice. These clones express alpha/beta heterodimeric TCRs on the cell surface and specifically recognize class I molecules on target cells. Lyt-2 and L3T4 molecules are therefore not essential for the induction, recognition, and killing of antigen-specific CTL. In addition, these studies suggest that antigen specificity development for class I structures may occur before Lyt-2 gene activation in the differentiation of T cells.
Metastasis-Associated Protein 1/Nucleosome Remodeling and Histone Deacetylase Complex in Cancer
Authors: Da-Qiang Li, Suresh B. Pakala, Sujit S. Nair, Jeyanthy Eswaran, Rakesh Kumar
Journal: Cancer Research (2012)

Abstract Cancer cells frequently exhibit deregulation of coregulatory molecules to drive the process of growth and metastasis. One such group of ubiquitously expressed coregulators is the metastasis-associated protein (MTA) family, a critical component of the nucleosome remodeling and histone deacetylase (NuRD) complex. MTA1 occupies a special place in cancer biology because of its dual corepressor or coactivator nature and widespread overexpression in human cancers. Here, we highlight recent advances in our understanding of the vital roles of MTA1 on transformation, epithelial–mesenchymal transition, and the functions of key cancer-relevant molecules such as a nexus of multiple oncogenes and tumor suppressors. In addition to its paramount role in oncogenesis, we reveal several new physiologic functions of MTA1 related to DNA damage, inflammatory responses, and infection, in which MTA1 functions as a permissive “gate keeper” for cancer-causing parasites. Further, these discoveries unraveled the versatile multidimensional modes of action of MTA1, which are independent of the NuRD complex and/or transcription. Given the emerging roles of MTA1 in DNA repair, inflammation, and parasitism, we discuss the possibility of MTA1-targeted therapy for use not only in combating cancer but also in other inflammation and pathogen-driven pathologic conditions. Cancer Res; 72(2); 387–94. ©2012 AACR.
Longitudinal analysis of sarcoidosis blood transcriptomic signatures and disease outcomes
Authors: Robert Su, Michael M. Li, Nirav R. Bhakta, Owen D. Solberg, Eli P.B. Darnell, Joris Ramstein, Suresh Garudadri, Melissa Ho, Prescott G. Woodruff, Laura L. Koth
Journal: European Respiratory Journal (2014)

Previously, we demonstrated concordance in differentially expressed genes in sarcoidosis blood and lung, implicating shared dysfunction of specific immune pathways. In the present study, we hypothesised that expression levels of candidate genes in sarcoidosis blood could predict and track with disease outcomes longitudinally. We applied Ingenuity Pathway Analysis to a cross-sectional derivation microarray dataset (n=38) to identify canonical pathways and candidate genes associated with sarcoidosis. In a separate longitudinal sarcoidosis cohort (n=103), we serially measured 48 candidate gene transcripts, and assessed their relation to disease chronicity and severity. In the cross-sectional derivation study, pathway analysis showed upregulation of genes related to interferon signalling and the role of pattern recognition receptors, and downregulation of T-cell receptor (TCR) signalling pathways in sarcoidosis. In the longitudinal cohort, factor analysis confirmed coregulation of genes marking these pathways and identified CXCL9 as an additional candidate pathway. CXCL9 and TCR factors discriminated between chronic versus nonprogressive disease, and CXCL9 predicted disease outcomes longitudinally. Interferon factor was similarly increased in both disease phenotypes. Factors associated with lung function decline included decreased TCR factor and increased CXCL9. These findings demonstrate blood transcriptomic signatures reflecting TCR signalling and CXCL9 predict sarcoidosis chronicity and correlate with disease severity longitudinally.