tbuckley/cabot-search huggingface dataset:
Delocalization of the Microtubule Motor Dynein from Mitotic Spindles by the Human Papillomavirus E7 Oncoprotein Is Not Sufficient for Induction of Multipolar Mitoses
Authors: Christine L. Nguyen, Margaret E. McLaughlin-Drubin, Karl Münger
Journal: Cancer Research (2008)

Abstract Dynein is a minus end–directed microtubule motor that transports numerous cargoes throughout the cell. During mitosis, dynein motor activity is necessary for the positioning of spindle microtubules and has also been implicated in inactivating the spindle assembly checkpoint. Mutations in dynein motor and/or accessory proteins are associated with human disease, including cancer, and the delocalization of dynein from mitotic spindles has been correlated with an increased incidence of multipolar spindle formation in some cancer cells that contain supernumerary centrosomes. The high-risk human papillomavirus type 16 (HPV16) E7 oncoprotein induces centrosome overduplication and has been shown to cause multipolar mitotic spindle formation, a diagnostic hallmark of HPV-associated neoplasias. Here, we show that HPV16 E7 expression leads to an increased population of mitotic cells with dynein delocalized from the mitotic spindle. This function maps to sequences of HPV16 E7 that are distinct from the region necessary for centrosome overduplication. However, contrary to previous reports, we provide evidence that dynein delocalization by HPV16 E7 is neither necessary nor sufficient to cause the formation of multipolar mitoses. [Cancer Res 2008;68(21):8715–22]
Two Cases of Calcified Amorphous Tumor Mimicking Mitral Valve Vegetation
Authors: Mikiko Fujiwara, Hiroyuki Watanabe, Takako Iino, Yusuke Kobukai, Kazuyuki Ishibashi, Hiroshi Yamamoto, Kenji Iino, Fumio Yamamoto, Hiroshi Ito
Journal: Circulation (2012)
Endothelin-1, via ET <sub>A</sub> Receptor and Independently of Transforming Growth Factor-β, Increases the Connective Tissue Growth Factor in Vascular Smooth Muscle Cells
Authors: Juan Rodriguez-Vita, Marta Ruiz-Ortega, Mónica Rupérez, Vanessa Esteban, Elsa Sanchez-López, Juan José Plaza, Jesús Egido
Journal: Circulation Research (2005)

Endothelin (ET)-1 is a potent vasoconstrictor that participates in cardiovascular diseases. Connective tissue growth factor (CTGF) is a novel fibrotic mediator that is overexpressed in human atherosclerotic lesions, myocardial infarction, and experimental models of hypertension. In vascular smooth muscle cells (VSMCs), CTGF regulates cell proliferation/apoptosis, migration, and extracellular matrix (ECM) accumulation. Our aim was to investigate whether ET-1 could regulate CTGF and to investigate the potential role of ET-1 in vascular fibrosis. In growth-arrested rat VSMCs, ET-1 upregulated CTGF mRNA expression, promoter activity, and protein production. The blockade of CTGF by a CTGF antisense oligonucleotide decreased FN and type I collagen expression in ET-1–treated cells, showing that CTGF participates in ET-1–induced ECM accumulation. The ET A , but not ET B , antagonist diminished ET-1–induced CTGF expression gene and production. Several intracellular signals elicited by ET-1, via ET A receptors, are involved in CTGF synthesis, including activation of RhoA/Rho-kinase and mitogen-activated protein kinase and production of reactive oxygen species. CTGF is a mediator of TGF-β– and angiotensin (Ang) II–induced fibrosis. In VSMCs, ET-1 did not upregulate TGF-β gene or protein. The presence of neutralizing transforming growth factor (TGF)-β antibody did not modify ET-1–induced CTGF production, showing a TGF-β–independent regulation. We have also found an interrelationship between Ang II and ET-1 because the ET A antagonist diminished CTGF upregulation caused by Ang II. Collectively, our results show that, in cultured VSMCs, ET-1, independently of TGF-β and through the activation of several intracellular signals via ET A receptors, regulates CTGF. This novel finding suggests that CTGF could be a mediator of the profibrotic effects of ET-1 in vascular diseases.
Balancing and Directional Selection at Exon-2 of the MHC DQB1 Locus among Populations of Odontocete Cetaceans
Authors: D. Vassilakos, A. Natoli, M. Dahlheim, A. R. Hoelzel
Journal: Molecular Biology and Evolution (2008)

The diversity of exon-2 (peptide-binding region) of the DQB1 locus (Class II, major histocompatibility complex, MHC) was investigated on an extended sample of populations of three focal cetacean species (two sibling delphinid species and another in the same family). We tested the hypothesis that dolphin populations with a worldwide distribution across different habitats and geographic regions will be under differential selective pressure by comparing DQB1 variation with variation at neutral markers and by investigating putative functional residues within the exon-2 sequence at the population level. Variation at the DQB1 locus was not correlated to neutral differentiation (assessed by comparison with microsatellite DNA markers), and overall FST values were significantly lower for the MHC locus, consistent with expectations for balancing selection. Measures of heterozygosity and dn/ds ratios were also consistent with balancing selection. However, outliers in the FST comparisons and the analysis of putative functional residues suggested incidences of directional selection in local populations.
Decreases in Diabetes-Free Life Expectancy in the U.S. and the Role of Obesity
Authors: Solveig A. Cunningham, Fernando Riosmena, Jing Wang, James P. Boyle, Deborah B. Rolka, Linda S. Geiss
Journal: Diabetes Care (2011)

OBJECTIVE With increasing life expectancy in the U.S., it is important to know whether a longer life expectancy means a longer healthy life span or a prolonged period of later-life morbidity. This study examines changes in lifetime without diabetes, a leading cause of morbidity in later life. RESEARCH DESIGN AND METHODS Using demographic methods and nationally representative data, we estimated changes in diabetes-free life expectancy between 1980–1989 and 2000–2004 for adult men and women in the U.S., estimated the contribution of changes in age-specific diabetes rates, and examined the changing effects of weight status on diabetes risks. RESULTS While life expectancy at age 18 for men and women increased between the 1980s and the 2000s, diabetes-free life expectancy at age 18 decreased by 1.7 years for men and 1.5 years for women. The proportion of 18-year-olds who would develop diabetes in their lifetimes increased by almost 50% among women and almost doubled among men. Obese individuals experienced the greatest losses in diabetes-free life expectancy during this period, estimated at 5.6 years for men and 2.5 years for women. CONCLUSIONS Diabetes-free life expectancy decreased for both men and women between 1980–1989 and 2000–2004, and these decreases are almost entirely attributable to large increases in diabetes incidence among obese individuals.
Chromosomal Instability Selects Gene Copy-Number Variants Encoding Core Regulators of Proliferation in ER+ Breast Cancer
Authors: David Endesfelder, Rebecca A. Burrell, Nnennaya Kanu, Nicholas McGranahan, Mike Howell, Peter J. Parker, Julian Downward, Charles Swanton, Maik Kschischo
Journal: Cancer Research (2014)

Chromosomal instability (CIN) is associated with poor outcome in epithelial malignancies, including breast carcinomas. Evidence suggests that prognostic signatures in estrogen receptor-positive (ER(+)) breast cancer define tumors with CIN and high proliferative potential. Intriguingly, CIN induction in lower eukaryotic cells and human cells is context dependent, typically resulting in a proliferation disadvantage but conferring a fitness benefit under strong selection pressures. We hypothesized that CIN permits accelerated genomic evolution through the generation of diverse DNA copy-number events that may be selected during disease development. In support of this hypothesis, we found evidence for selection of gene amplification of core regulators of proliferation in CIN-associated cancer genomes. Stable DNA copy-number amplifications of the core regulators TPX2 and UBE2C were associated with expression of a gene module involved in proliferation. The module genes were enriched within prognostic signature gene sets for ER(+) breast cancer, providing a logical connection between CIN and prognostic signature expression. Our results provide a framework to decipher the impact of intratumor heterogeneity on key cancer phenotypes, and they suggest that CIN provides a permissive landscape for selection of copy-number alterations that drive cancer proliferation.
Regional colon transit in patients with dys-synergic defaecation or slow transit in patients with constipation
Authors: Sara Nullens, Tyler Nelsen, Michael Camilleri, Duane Burton, Deborah Eckert, Johanna Iturrino, Maria Vazquez-Roque, Alan R Zinsmeister
Journal: Gut (2011)

<h3>Objective</h3> To differentiate dys-synergic defaecation (DD) from normal function and slow transit constipation (STC). <h3>Methods</h3> The medical records of 1411 patients evaluated by a single gastroenterologist over a 16-year period at a tertiary medical centre were reviewed. DD was characterised by anorectal manometry and balloon expulsion test. There were 390 patients with DD, and 61 with STC without DD. Transit data from 211 healthy individuals served as controls. The primary endpoints were overall colonic transit (geometric centre) at 24 h and 48 h (GC24 and GC48). Regional transit was measured as ascending colon half-emptying time (AC t<sub>1/2</sub>) and residual content in descending rectosigmoid colon and stool (DRS). <h3>Results</h3> Age and body mass index were similar in the STC and DD groups. DD was associated with smaller perineal descent and a greater difference in rectoanal pressure than STC. Both STC and DD were associated with lower GC24 and GC48 and slower AC t<sub>1/2</sub> than controls. GC48 differentiated DD from healthy controls (p&lt;0.001) and DD from STC (p=0.007). AC t<sub>1/2</sub> values differentiated healthy controls from DD (p=0.006) and STC (p&lt;0.001) and were associated with constipation (DD vs STC, p=0.007). The regional content of DRS at 48 h discriminated DD from STC (AUC=0.82) and stool content at 48 h, increasing the odds for DD over STC (OR per 5% in stool 2.4, 95% CI 1.1 to 5.5, p=0.03). <h3>Conclusions</h3> DD is associated with delayed overall colonic transit at 48 h and AC t<sub>1/2</sub> compared with healthy controls. Regional scintigraphic transit profiles differentiate DD from STC and facilitate identification of a subgroup of patients with constipation.
CYCLIC AMP SIGNALING AND GENE REGULATION
Authors: Philip B. Daniel, William H. Walker, Joel F. Habener
Journal: Annual Review of Nutrition (1998)

▪ Abstract Cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger produced in cells in response to hormones and nutrients. The production of cAMP is dependent upon the actions of many different proteins that affect its synthesis and degradation. An important function of cAMP is to activate the phosphorylating enzyme, protein kinase A. The key roles of cAMP and protein kinase A in the phosphorylation and regulation of enzyme substrates involved in intermediary metabolism are well known. A newly discovered role for protein kinase A is in the phosphorylation and activation of transcription factors that are critical for the control of the transcription of genes in response to elevated levels of cAMP.
A Developmental fMRI Study of Self-Regulatory Control in Tourette’s Syndrome
Authors: Rachel Marsh, Hongtu Zhu, Zhishun Wang, Pawel Skudlarski, Bradley S. Peterson
Journal: American Journal of Psychiatry (2007)

Objective: Disturbances in the maturation of neural systems that mediate self-regulatory processes may contribute to the development of Tourette's syndrome by releasing motor and vocal tics from regulatory control. The purpose of this study was to examine the age correlates of functional activity in neural circuits that subserve self-regulatory control in children and adults with Tourette's syndrome. Method: The participants were 136 children and adults, which included 66 Tourette's syndrome patients and 70 healthy comparison subjects. During performance of the Stroop interference task, the authors compared the functional magnetic resonance imaging (fMRI) blood-oxygen-level dependent response in patients with Tourette's syndrome with that of healthy comparison subjects. General linear modeling of Stroop-related activations was used to compare the differential effects of age and behavioral performance on changes in self-regulatory control between the two diagnostic groups. Results: Although the correlations of age with behavioral performance on the Stroop task were similar between patients with Tourette's syndrome and healthy comparison subjects, the two groups differed significantly in their correlations of age with the magnitude of regional brain activation during the task. Interactions of age with diagnosis were detected in the ventral prefrontal (Brodmann's areas 10 and 24) and posterior cingulate cortices (Brodmann's area 31), and post hoc analyses indicated that subjects with Tourette's syndrome deactivated these regions less with advancing age. Greater activation of bilateral frontostriatal regions (Brodmann's areas 9/46, 45/46; lenticular nucleus; and thalamus) accompanied poorer performance in the patient group, which—in the presence of normal behavioral performance on the Stroop task—suggests that greater activation of the frontostriatal systems helps to maintain task performance in individuals with Tourette's syndrome. Conclusions: Normative developmental correlates of activity in frontostriatal circuits that subserve self-regulatory control are disturbed in persons with Tourette's syndrome. These aberrant developmental correlates are likely a consequence of greater anatomical and functional disturbances in these circuits in adults with Tourette's syndrome, which leads to impaired regulation of tic behaviors. Reduced default-mode processing in ventral prefrontal and posterior cingulate cortices in adults with Tourette's syndrome suggests the presence of greater difficulty in engaging mental processes that become active when freed from the demands of more challenging cognitive tasks. However, individuals with Tourette's syndrome appear to co-opt normal developmental processes in circuits that subserve age-related improvement in self-regulatory control while presumably struggling to maintain adequate task performance.
Microglia isolated from patients with glioma gain antitumor activities on poly (I:C) stimulation
Authors: Tim Kees, Jennifer Lohr, Johannes Noack, Rodrigo Mora, Georg Gdynia, Grischa Tödt, Aurélie Ernst, Bernhard Radlwimmer, Christine S. Falk, Christel Herold-Mende, Anne Régnier-Vigouroux
Journal: Neuro-Oncology (2011)

The role of microglia, the brain-resident macrophages, in glioma biology is still a matter of debate. Clinical observations and in vitro studies in the mouse model indicate that microglia and macrophages that infiltrate the brain tumor tissue in high numbers play a tumor-supportive role. Here, we provide evidence that human microglia isolated from brain tumors indeed support tumor cell growth, migration, and invasion. However, after stimulation with the Toll-like receptor 3 agonist poly (I:C), microglia secrete factors that exerted toxic and suppressive effects on different glioblastoma cell lines, as assessed in cytotoxicity, migration, and tumor cell spheroid invasion assays. Remarkably, these effects were tumor-specific because the microglial factors impaired neither growth nor viability of astrocytes and neurons. Culture supernatants of tumor cells inhibited the poly (I:C) induction of this microglial M1-like, oncotoxic profile. Microglia stimulation before coculture with tumor cells circumvented the tumor-mediated suppression, as demonstrated by the ability to kill and phagocytose glioma cells. Our results show, for the first time to our knowledge, that human microglia exert tumor-supporting functions that are overridden by tumor-suppressing activities gained after poly (I:C) stimulation.
Serotonin States and Social Anxiety
Authors: Murray B. Stein, Anne M. Andrews
Journal: JAMA Psychiatry (2015)

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Detection of Diverse Bacterial Signatures in Atherosclerotic Lesions of Patients With Coronary Heart Disease
Authors: Stephan J. Ott, Nour Eddine El Mokhtari, Meike Musfeldt, Stephan Hellmig, Sandra Freitag, Ateequr Rehman, Tanja Kühbacher, S. Nikolaus, Pawel Namsolleck, Michael Blaut, Jochen Hampe, Hany Sahly, Alexander Reinecke, Nils Haake, Rainer Günther, Dietmar Krüger, Markus Lins, Gunhild Herrmann, Ulrich R. Fölsch, Rüdiger Simon, Stefan Schreiber
Journal: Circulation (2006)

Background— Bacterial infection has been discussed as a potential etiologic factor in the pathophysiology of coronary heart disease (CHD). This study analyzes molecular phylogenies to systematically explore the presence, frequency, and diversity of bacteria in atherosclerotic lesions in patients with CHD. Methods and Results— We investigated 16S rDNA signatures in atherosclerotic tissue obtained through catheter-based atherectomy of 38 patients with CHD, control material from postmortem patients (n=15), and heart-beating organ donors (n=11) using clone libraries, denaturating gradient gel analysis, and fluorescence in situ hybridization. Bacterial DNA was found in all CHD patients by conserved PCR but not in control material or in any of the normal/unaffected coronary arteries. Presence of bacteria in atherosclerotic lesions was confirmed by fluorescence in situ hybridization. A high overall bacterial diversity of &gt;50 different species, among them Staphylococcus species, Proteus vulgaris , Klebsiella pneumoniae , and Streptococcus species, was demonstrated in &gt;1500 clones from a combined library and confirmed by denaturating gradient gel analysis. Mean bacterial diversity in atheromas was high, with a score of 12.33±3.81 (range, 5 to 22). A specific PCR detected Chlamydia species in 51.5% of CHD patients. Conclusions— Detection of a broad variety of molecular signatures in all CHD specimens suggests that diverse bacterial colonization may be more important than a single pathogen. Our observation does not allow us to conclude that bacteria are the causative agent in the etiopathogenesis of CHD. However, bacterial agents could have secondarily colonized atheromatous lesions and could act as an additional factor accelerating disease progression.
Negative Regulation of T Cell Receptor–Lipid Raft Interaction by Cytotoxic T Lymphocyte–associated Antigen 4
Authors: Shunsuke Chikuma, John B. Imboden, Jeffrey A. Bluestone
Journal: The Journal of Experimental Medicine (2003)

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is an essential negative regulator of T cell activation. Recent evidence suggests that CTLA-4 association with the immunological synapse during contact with antigen-presenting cells is important for its inhibitory function. In the present study, we observed a direct interaction of CTLA-4 with the phosphorylated form of T cell receptor (TCR)zeta within the glycolipid-enriched microdomains associated with the T cell signaling complex. In this setting, CTLA-4 regulated the accumulation/retention of TCRzeta in the signaling complex, as the lipid raft fractions from CTLA-4KO T cells contained significantly higher amounts of the TCR components when compared with wild-type littermates. In contrast, coligation of CTLA-4 with the TCR during T cell activation selectively decreased the amount of TCRzeta that accumulated in the rafts. These results suggest that CTLA-4 functions to regulate T cell signaling by controlling TCR accumulation and/or retention within this a critical component of the immunological synapse.
Epidermal growth factor receptor (EGFR) status and K-Ras mutations in colorectal cancer
Authors: G. Milano, M.-C. Etienne-Grimaldi, L. Dahan, M. Francoual, J.-P. Spano, D. Benchimol, M. Chazal, C. Letoublon, T. André, F.-N. Gilly, J.-R. Delpero, J.-L. Formento
Journal: Annals of Oncology (2008)
Glycemic Thresholds for Diabetes-Specific Retinopathy
Authors: Stephen Colagiuri, Crystal M.Y. Lee, Tien Y. Wong, Beverley Balkau, Jonathan E. Shaw, Knut Borch-Johnsen
Journal: Diabetes Care (2010)

OBJECTIVE To re-evaluate the relationship between glycemia and diabetic retinopathy. RESEARCH DESIGN AND METHODS We conducted a data-pooling analysis of nine studies from five countries with 44,623 participants aged 20–79 years with gradable retinal photographs. The relationship between diabetes-specific retinopathy (defined as moderate or more severe retinopathy) and three glycemic measures (fasting plasma glucose [FPG; n = 41,411], 2-h post oral glucose load plasma glucose [2-h PG; n = 21,334], and A1C [n = 28,010]) was examined. RESULTS When diabetes-specific retinopathy was plotted against continuous glycemic measures, a curvilinear relationship was observed for FPG and A1C. Diabetes-specific retinopathy prevalence was low for FPG &amp;lt;6.0 mmol/l and A1C &amp;lt;6.0% but increased above these levels. Based on vigintile (20 groups with equal numbers) distributions, glycemic thresholds for diabetes-specific retinopathy were observed over the range of 6.4–6.8 mmol/l for FPG, 9.8–10.6 mmol/l for 2-h PG, and 6.3–6.7% for A1C. Thresholds for diabetes-specific retinopathy from receiver-operating characteristic curve analyses were 6.6 mmol/l for FPG, 13.0 mmol/l for 2-h PG, and 6.4% for A1C. CONCLUSIONS This study broadens the evidence based on diabetes diagnostic criteria. A narrow threshold range for diabetes-specific retinopathy was identified for FPG and A1C but not for 2-h PG. The combined analyses suggest that the current diabetes diagnostic level for FPG could be lowered to 6.5 mmol/l and that an A1C of 6.5% is a suitable alternative diagnostic criterion.