tbuckley/cabot-search huggingface dataset:
Molecular Population Genetics and the Search for Adaptive Evolution in Plants
Authors: Stephen I. Wright, Brandon S. Gaut
Journal: Molecular Biology and Evolution (2004)

The first papers on plant molecular population genetics were published approximately 10 years ago. Since that time, well over 50 additional studies of plant nucleotide polymorphism have been published, and many of these studies focused on detecting the signature of balancing or positive selection at a locus. In this review, we discuss some of the theoretical and statistical issues surrounding the detection of selection, with focus on plant populations, and we also summarize the empirical plant molecular population genetics literature. At face value, the literature suggests that a history of balancing or positive selection in plant genes is rampant. In two well-studied taxa (maize and Arabidopsis) over 20% of studied genes have been interpreted as containing the signature of selection. We argue that this is probably an overstatement of the prevalence of natural selection in plant genomes, for two reasons. First, demographic effects are difficult to incorporate and have generally not been well integrated into the plant population genetics literature. Second, the genes studied to date are not a random sample, so selected genes may be overrepresented. The next generation of studies in plant molecular population genetics requires additional sampling of local populations, explicit comparisons among loci, and improved theoretical methods to control for demography. Eventually, candidate loci should be confirmed by explicit consideration of phenotypic effects.
Cytokine gene polymorphisms in Japanese patients with hepatitis B virus infection—association between TGF-β1 polymorphisms and hepatocellular carcinoma
Authors: Kiyoshi Migita, Seiji Miyazoe, Yumi Maeda, Manabu Daikoku, Seigo Abiru, Tshihito Ueki, Koji Yano, Shinya Nagaoka, Takehiro Matsumoto, Kazuhiko Nakao, Keisuke Hamasaki, Hiroshi Yatsuhashi, Hiromi Ishibashi, Katsumi Eguchi
Journal: Journal of Hepatology (2004)
Using nitric oxide to treat tendinopathy
Authors: George A C Murrell
Journal: British Journal of Sports Medicine (2007)

Nitric oxide (NO) is a small free radical generated by a family of enzymes, the nitric oxide synthases (NOSs). Following injury to a tendon, NO is induced by all three isoforms of NOS and NOS activity is also upregulated in tendinopathy. In animal models when NOS activity is inhibited by competitive inhibitors of NOS, tendon healing is reduced. When additional NO is added, tendon healing is enhanced. In humans, in three randomised clinical trials, we have shown that NO delivered via a transdermal patch enhances the subjective and objective recovery of patients with tennis elbow, Achilles tendinosis and supraspinatus tendinosis.
Adjuvant chemotherapy for elderly patients (≥70 years) with early high-risk breast cancer: a retrospective analysis of 260 patients
Authors: A. Brunello, U. Basso, C. Pogliani, C. Ghiotto, H. Koussis, F. Lumachi, M. Iacobone, L. Vamvakas, S. Monfardini, A. Jirillo
Journal: Annals of Oncology (2005)
IL-1 enhances expansion, effector function, tissue localization, and memory response of antigen-specific CD8 T cells
Authors: Shlomo Z. Ben-Sasson, Alison Hogg, Jane Hu-Li, Paul Wingfield, Xi Chen, Michelle Crank, Stephane Caucheteux, Maya Ratner-Hurevich, Jay A. Berzofsky, Ran Nir-Paz, William E. Paul
Journal: The Journal of Experimental Medicine (2013)

Here, we show that interleukin-1 (IL-1) enhances antigen-driven CD8 T cell responses. When administered to recipients of OT-I T cell receptor transgenic CD8 T cells specific for an ovalbumin (OVA) peptide, IL-1 results in an increase in the numbers of wild-type but not IL1R1−/− OT-I cells, particularly in spleen, liver, and lung, upon immunization with OVA and lipopolysaccharide. IL-1 administration also results in an enhancement in the frequency of antigen-specific cells that are granzyme B+, have cytotoxic activity, and/ or produce interferon γ (IFN-γ). Cells primed in the presence of IL-1 display enhanced expression of granzyme B and increased capacity to produce IFN-γ when rechallenged 2 mo after priming. In three in vivo models, IL-1 enhances the protective value of weak immunogens. Thus, IL-1 has a marked enhancing effect on antigen-specific CD8 T cell expansion, differentiation, migration to the periphery, and memory.
Phosphorylation Regulates NCC Stability and Transporter Activity In Vivo
Authors: Sung-Sen Yang, Yu-Wei Fang, Min-Hua Tseng, Pei-Yi Chu, I-Shing Yu, Han-Chung Wu, Shu-Wha Lin, Tom Chau, Shinichi Uchida, Sei Sasaki, Yuh-Feng Lin, Huey-Kang Sytwu, Shih-Hua Lin
Journal: Journal of the American Society of Nephrology (2013)

A T60M mutation in the thiazide-sensitive sodium chloride cotransporter (NCC) is common in patients with Gitelman’s syndrome (GS). This mutation prevents Ste20-related proline and alanine-rich kinase (SPAK)/oxidative stress responsive kinase-1 (OSR1)–mediated phosphorylation of NCC and alters NCC transporter activity in vitro. Here, we examined the physiologic effects of NCC phosphorylation in vivo using a novel Ncc T58M (human T60M) knock-in mouse model. NccT58M/T58M mice exhibited typical features of GS with a blunted response to thiazide diuretics. Despite expressing normal levels of Ncc mRNA, these mice had lower levels of total Ncc and p-Ncc protein that did not change with a low-salt diet that increased p-Spak. In contrast to wild-type Ncc, which localized to the apical membrane of distal convoluted tubule cells, T58M Ncc localized primarily to the cytosolic region and caused an increase in late distal convoluted tubule volume. In MDCK cells, exogenous expression of phosphorylation-defective NCC mutants reduced total protein expression levels and membrane stability. Furthermore, our analysis found diminished total urine NCC excretion in a cohort of GS patients with homozygous NCC T60M mutations. When Wnk4D561A/+ mice, a model of pseudohypoaldosteronism type II expressing an activated Spak/Osr1-Ncc, were crossed with NccT58M/T58M mice, total Ncc and p-Ncc protein levels decreased and the GS phenotype persisted over the hypertensive phenotype. Overall, these data suggest that SPAK-mediated phosphorylation of NCC at T60 regulates NCC stability and function, and defective phosphorylation at this residue corrects the phenotype of pseudohypoaldosteronism type II.
Intrauterine exposure to carbamazepine and specific congenital malformations: systematic review and case-control study
Authors: J. Jentink, H. Dolk, M. A. Loane, J. K. Morris, D. Wellesley, E. Garne, L. de Jong-van den Berg
Journal: BMJ (2010)

<b>Objective</b> To identify specific major congenital malformations associated with use of carbamazepine in the first trimester of pregnancy. <b>Design</b> A review of all published cohort studies to identify key indications and a population based case-control study to test these indications. <b>Setting</b> Review of PubMed, Web of Science, and Embase for papers about carbamazepine exposure in the first trimester of pregnancy and specific malformations, and the EUROCAT Antiepileptic Study Database, including data from 19 European population based congenital anomaly registries, 1995-2005. <b>Participants</b> The literature review covered eight cohort studies of 2680 pregnancies with carbamazepine monotherapy exposure, and the EUROCAT dataset included 98 075 registrations of malformations covering over 3.8 million births. <b>Main outcome measures</b> Overall prevalence for a major congenital malformation after exposure to carbamazepine monotherapy in the first trimester. Odds ratios for malformations with exposure to carbamazepine among cases (five types of malformation identified in the literature review) compared with two groups of controls: other non-chromosomal registrations of malformations and chromosomal syndromes. <b>Results</b> The literature review yielded an overall prevalence for a major congenital malformation of 3.3% (95% confidence interval 2.7 to 4.2) after exposure to carbamazepine monotherapy in the first trimester. In 131 registrations of malformations, the fetus had been exposed to carbamazepine monotherapy. Spina bifida was the only specific major congenital malformation significantly associated with exposure to carbamazepine monotherapy (odds ratio 2.6 (95% confidence interval 1.2 to 5.3) compared with no antiepileptic drug), but the risk was smaller for carbamazepine than for valproic acid (0.2, 0.1 to 0.6). There was no evidence for an association with total anomalous pulmonary venous return (no cases with carbamazepine exposure), cleft lip (with or without palate) (0.2, 0.0 to 1.3), diaphragmatic hernia (0.9, 0.1 to 6.6), or hypospadias (0.7, 0.3 to 1.6) compared with no exposure to antiepileptic drugs. Further exploratory analysis suggested a higher risk of single ventricle and atrioventricular septal defect. <b>Conclusion</b> Carbamazepine teratogenicity is relatively specific to spina bifida, though the risk is less than with valproic acid. Despite the large dataset, there was not enough power to detect moderate risks for some rare major congenital malformations.
Long-term use of selective decontamination of the digestive tract does not increase antibiotic resistance: a 5-year prospective cohort study
Authors: María E. Ochoa-Ardila, Ana García-Cañas, Karen Gómez-Mediavilla, Ana González-Torralba, Inmaculada Alía, Paloma García-Hierro, Nia Taylor, Hendrick K. F. van Saene, Miguel A. de la Cal
Journal: Intensive Care Medicine (2011)
The Investigational Aurora Kinase A Inhibitor MLN8237 Induces Defects in Cell Viability and Cell-Cycle Progression in Malignant Bladder Cancer Cells <i>In Vitro</i> and <i>In Vivo</i>
Authors: Ning Zhou, Kamini Singh, Maria C. Mir, Yvonne Parker, Daniel Lindner, Robert Dreicer, Jeffrey A. Ecsedy, Zhongfa Zhang, Bin T. Teh, Alexandru Almasan, Donna E. Hansel
Journal: Clinical Cancer Research (2013)

Despite more than 70,000 new cases of bladder cancer in the United States annually, patients with advanced disease have a poor prognosis due to limited treatment modalities. We evaluated Aurora kinase A, identified as an upregulated candidate molecule in bladder cancer, as a potential therapeutic target.Gene expression in human bladder cancer samples was evaluated using RNA microarray and quantitative reverse transcriptase PCR. Effects of the Aurora kinase A inhibitor MLN8237 (Millennium) on cell dynamics in malignant T24 and UM-UC-3 and papilloma-derived RT4 bladder cells were evaluated in vitro and in vivo in a mouse xenograft model.A set of 13 genes involved in the mitotic spindle checkpoint, including Aurora kinases A and B, were upregulated in human urothelial carcinoma compared with normal urothelium. The Aurora kinase A inhibitor MLN8237 induced cell-cycle arrest, aneuploidy, mitotic spindle failure, and apoptosis in the human bladder cancer cell lines T24 and UM-UC-3. MLN8237 also arrested tumor growth when administered orally over 4 weeks in a mouse bladder cancer xenograft model. Finally, in vitro sequential administration of MLN8237 with either paclitaxel or gemcitabine resulted in synergistic cytotoxic effects in T24 cells.Mitotic spindle checkpoint dysfunction is a common characteristic of human urothelial carcinoma and can be exploited with pharmacologic Aurora A inhibition. Given our demonstration of the ability of the Aurora A inhibitor MLN8237 to inhibit growth of bladder cancer in vitro and in vivo, we conclude that Aurora kinase inhibitors warrant further therapeutic investigation in bladder cancer.
Deficient CD40-TRAF6 signaling in leukocytes prevents atherosclerosis by skewing the immune response toward an antiinflammatory profile
Authors: Esther Lutgens, Dirk Lievens, Linda Beckers, Erwin Wijnands, Oliver Soehnlein, Alma Zernecke, Tom Seijkens, David Engel, Jack Cleutjens, Anna M. Keller, Shalin H. Naik, Louis Boon, Hafid Ait Oufella, Ziad Mallat, Cory L. Ahonen, Randolph J. Noelle, Menno P. de Winther, Mat J. Daemen, Erik A. Biessen, Christian Weber
Journal: The Journal of Experimental Medicine (2010)

The CD40-CD40 ligand (CD40L) signaling axis plays an important role in immunological pathways. Consequently, this dyad is involved in chronic inflammatory diseases, including atherosclerosis. Inhibition of CD40L in apolipoprotein E (Apoe)-deficient (Apoe(-/-)) mice not only reduced atherosclerosis but also conferred a clinically favorable plaque phenotype that was low in inflammation and high in fibrosis. Blockade of CD40L may not be therapeutically feasible, as long-term inhibition will compromise systemic immune responses. Conceivably, more targeted intervention strategies in CD40 signaling will have less deleterious side effects. We report that deficiency in hematopoietic CD40 reduces atherosclerosis and induces features of plaque stability. To elucidate the role of CD40-tumor necrosis factor receptor-associated factor (TRAF) signaling in atherosclerosis, we examined disease progression in mice deficient in CD40 and its associated signaling intermediates. Absence of CD40-TRAF6 but not CD40-TRAF2/3/5 signaling abolishes atherosclerosis and confers plaque fibrosis in Apoe(-/-) mice. Mice with defective CD40-TRAF6 signaling display a reduced blood count of Ly6C(high) monocytes, an impaired recruitment of Ly6C(+) monocytes to the arterial wall, and polarization of macrophages toward an antiinflammatory regulatory M2 signature. These data unveil a role for CD40-TRAF6, but not CD40-TRAF2/3/5, interactions in atherosclerosis and establish that targeting specific components of the CD40-CD40L pathway harbors the potential to achieve therapeutic effects in atherosclerosis.
ΔNp63 Promotes Pediatric Neuroblastoma and Osteosarcoma by Regulating Tumor Angiogenesis
Authors: Hemant K. Bid, Ryan D. Roberts, Maren Cam, Anthony Audino, Raushan T. Kurmasheva, Jiayuh Lin, Peter J. Houghton, Hakan Cam
Journal: Cancer Research (2013)

Abstract The tumor suppressor gene p53 and its family members p63/p73 are critical determinants of tumorigenesis. ΔNp63 is a splice variant of p63, which lacks the N-terminal transactivation domain. It is thought to antagonize p53-, p63-, and p73-dependent translation, thus blocking their tumor suppressor activity. In our studies of the pediatric solid tumors neuroblastoma and osteosarcoma, we find overexpression of ΔNp63; however, there is no correlation of ΔNp63 expression with p53 mutation status. Our data suggest that ΔNp63 itself endows cells with a gain-of-function that leads to malignant transformation, a function independent of any p53 antagonism. Here, we demonstrate that ΔNp63 overexpression, independent of p53, increases secretion of interleukin (IL)-6 and IL-8, leading to elevated phosphorylation of STAT3 (Tyr-705). We show that elevated phosphorylation of STAT3 leads to stabilization of hypoxia-inducible factor 1α (HIF-1α) protein, resulting in VEGF secretion. We also show human clinical data, which suggest a mechanistic role for ΔNp63 in osteosarcoma metastasis. In summary, our studies reveal the mechanism by which ΔNp63, as a master transcription factor, modulates tumor angiogenesis. Cancer Res; 74(1); 320–9. ©2013 AACR.
Prevalence of Renal Insufficiency in Individuals with Hypertension and Obesity/Overweight
Authors: Pablo Gomez, Luis Miguel Ruilope, Vivencio Barrios, Jorge Navarro, Miguel Angel Prieto, Olga Gonzalez, Lucía Guerrero, Miguel Angel Sanchez Zamorano, Claudia Filozof
Journal: Journal of the American Society of Nephrology (2006)

Overweight and obesity are associated with increased cardiovascular risk. Some studies have demonstrated that they also can result in renal damage. The aim of this study was to assess the prevalence of renal insufficiency (RI), defined as a GFR <60 ml/min per 1.73 m2, in a cohort of 4585 patients who attended primary care with essential hypertension and a body mass index > or =25 kg/m2. The patients were classified as overweight and obese according to body mass index (25 to 29.9 and > or =30 kg/m2, respectively). Abdominal obesity was defined as a waist circumference > or =88 and 102 cm in women and men, respectively. Both groups had a high prevalence of metabolic syndrome (Adult Treatment Panel III). The prevalence of RI was high in both the overweight group (22.7%; 95% confidence interval [CI] 20.6 to 24.9) and in the obese group (22.8%; 95% CI 21.0 to 24.7). The presence of diabetes increased the risk for RI (odds ratio 1.83; 95% CI 1.55 to 2.16). The prevalence of RI was greater in patients with abdominal obesity (23 versus 17%; P < 0.001). In the presence of abdominal obesity, cardiovascular risk factors and components of the metabolic syndrome also were more prevalent. The higher risk for RI with abdominal obesity persisted even after adjustment for dyslipidemia, elevated blood glucose levels, and other variables that are associated with RI (adjusted odds ratio 1.40; 95% CI 0.84 to 2.33). It was concluded that patients who have hypertension and visceral obesity and attend primary care present a higher prevalence of metabolic syndrome and RI.
On the Role of Dendritic Cells in Peripheral T Cell Tolerance and Modulation of Autoimmunity
Authors: Kevin L. Legge, Randal K. Gregg, Roberto Maldonado-Lopez, Lequn Li, Jacque C. Caprio, Muriel Moser, Habib Zaghouani
Journal: The Journal of Experimental Medicine (2002)

Recently, it has become clear that dendritic cells (DCs) are essential for the priming of T cell responses. However, their role in the maintenance of peripheral T cell tolerance remains largely undefined. Herein, an antigen-presenting cell (APC) transfer system was devised and applied to experimental allergic encephalomyelitis (EAE), to evaluate the contribution that DCs play in peripheral T cell tolerance. The CD8alpha(-)CD4(+) subset, a minor population among splenic DCs, was found to mediate both tolerance and bystander suppression against diverse T cell specificities. Aggregated (agg) Ig-myelin oligodendrocyte glycoprotein (MOG), an Ig chimera carrying the MOG 35-55 peptide, binds and cross-links FcgammaR on APC leading to efficient peptide presentation and interleukin (IL)-10 production. Furthermore, administration of agg Ig-MOG into diseased mice induces relief from clinical EAE involving multiple epitopes. Such recovery could not occur in FcgammaR-deficient mice where both uptake of Ig-MOG and IL-10 production are compromised. However, reconstitution of these mice with DC populations incorporating the CD8alpha(-)CD4(+) subset restored Ig-MOG-mediated reversal of EAE. Transfer of CD8alpha(+) or even CD8alpha(-)CD4(-) DCs had no effect on the disease. These findings strongly implicate DCs in peripheral tolerance and emphasize their functional potency, as a small population of DCs was able to support effective suppression of autoimmunity.
Directional coronary collateral growth with chronic circumflex occlusion in the dog.
Authors: K W Scheel, R J Rodriguez, L A Ingram
Journal: Circulation Research (1977)

The object of this study was to determine whether coronary collateral resistances were dependent on the direction of perfusion and to investigate whether a pattern of collateral growth with gradual circumflex occlusion could be discerned. In 12 dogs an Ameroid occluder was placed on the circumflex for 1 month, and six dogs for 3 months; 12 dogs served as controls. The circumflex, left anterior descending, and right coronary arteries were separately but simultaneously perfused in an isolated heart preparation in which the vasculature was maximally dilated with dipyridamole. Collateral flows were determined by measuring retrograde flows for two vessels simultaneously. The results showed that collateral flows from the right to the left coronaries in control dogs were 3.5-fold larger than when these collateral beds were perfused in the opposite direction. This difference in the 1- and 3-month Ameroid groups was approximately 20-fold. Relative to the control group, the collateral resistances from right to left coronary vessels were an average of 10-fold less in the 1- and 3-month groups, but there was no significant differences in resistance in the collaterals perfused from the left to the right. The results strongly suggest that collateral proliferation occurs in response to hypoxia rather than to a pressure gradient, and that collateral development is toward the hypoxid area.
Sensitivity and Specificity of Echocardiographic Diagnosis of Pericardial Effusion
Authors: MICHAEL S. HOROWITZ, CLIFFORD S. SCHULTZ, EDWARD B. STINSON, DONALD C. HARRISON, RICHARD L. POPP
Journal: Circulation (1974)

In order to evaluate the reliability and sensitivity of echocardiograms for detecting and quantitating pericardial effusion, 41 patients had echocardiograms on the day prior to cardiac operation. A fluid trap was used to aspirate the pericardium at operation. Thirty-nine of 41 patients had echocardiograms of diagnostic quality. In 25 patients, the echocardiogram was negative for pericardial effusion, with 0-16 ml identified at operation. In 13 patients, the echocardiogram was positive for pericardial effusion, with 15-775 ml aspirated at operation. A transition of patterns of relative posterior epicardial-pericardial movement was noted as the pericardial fluid volume increased. More than 15 ml was always found when a posterior echo-free space persisted throughout the cardiac cycle between a flat pericardium relative to the epicardium. In the presence of such a posterior echo-free space, a large anterior echo-free space made a moderately large pericardial effusion likely. In the absence of this diagnostic posterior echo-free space, an anterior echo-free space had no diagnostic significance, as it was found in 11 patients with less than 16 ml of pericardial effusion. A small posterior echo-free space persisting throughout the cardiac cycle between pericardial and epicardial echoes demonstrating virtually identical movements was found in two patients without any surgical evidence for pericardial effusion, but with evidence of adhesive fibrocalcific pericardial disease. A method of estimating pericardial volume is proposed, which uses the difference between the cubed diameters at the end-diastole of the pericardium and epicardium.