tbuckley/cabot-search huggingface dataset:
Deletion of the metabolic transcriptional coactivator PGC1β induces cardiac arrhythmia
Authors: Iman S. Gurung, Gema Medina-Gomez, Adrienn Kis, Michael Baker, Vidya Velagapudi, Sudeshna Guha Neogi, Mark Campbell, Sergio Rodriguez-Cuenca, Christopher Lelliott, Ian McFarlane, Matej Oresic, Andrew A. Grace, Antonio Vidal-Puig, Christopher L.-H. Huang
Journal: Cardiovascular Research (2011)

Peroxisome proliferator-activated receptor-γ coactivators PGC1α and PGC1β modulate mitochondrial biogenesis and energy homeostasis. The function of these transcriptional coactivators is impaired in obesity, insulin resistance, and type 2 diabetes. We searched for transcriptomic, lipidomic, and electrophysiological alterations in PGC1β−/− hearts potentially associated with increased arrhythmic risk in metabolic diseases. Microarray analysis in mouse PGC1β−/− hearts confirmed down-regulation of genes related to oxidative phosphorylation and the electron transport chain and up-regulation of hypertrophy- and hypoxia-related genes. Lipidomic analysis showed increased levels of the pro-arrhythmic and pro-inflammatory lipid, lysophosphatidylcholine. PGC1β−/− mouse electrocardiograms showed irregular heartbeats and an increased incidence of polymorphic ventricular tachycardia following isoprenaline infusion. Langendorff-perfused PGC1β−/− hearts showed action potential alternans, early after-depolarizations, and ventricular tachycardia. PGC1β−/− ventricular myocytes showed oscillatory resting potentials, action potentials with early and delayed after-depolarizations, and burst firing during sustained current injection. They showed abnormal diastolic Ca2+ transients, whose amplitude and frequency were increased by isoprenaline, and Ca2+ currents with negatively shifted inactivation characteristics, with increased window currents despite unaltered levels of CACNA1C RNA transcripts. Inwardly and outward rectifying K+ currents were all increased. Quantitiative RT-PCR demonstrated increased SCN5A, KCNA5, RYR2, and Ca2+-calmodulin dependent protein kinase II expression. PGC1β−/− hearts showed a lysophospholipid-induced cardiac lipotoxicity and impaired bioenergetics accompanied by an ion channel remodelling and altered Ca2+ homeostasis, converging to produce a ventricular arrhythmic phenotype particularly during adrenergic stress. This could contribute to the increased cardiac mortality associated with both metabolic and cardiac disease attributable to lysophospholipid accumulation.
A High-Throughput Proteomic Approach Provides Distinct Signatures for Thyroid Cancer Behavior
Authors: Sonia Cheng, Stefano Serra, Moises Mercado, Shereen Ezzat, Sylvia L. Asa
Journal: Clinical Cancer Research (2011)

Well-differentiated thyroid cancer (WDTC) is the most frequent form of endocrine neoplasia. One of the main challenges in the management of this disease is distinguishing low-risk patients who can be treated by surgical resection of the lesion from those with a high likelihood of recurrence who need a more extensive approach, including total thyroidectomy and radioiodine ablation.A tissue microarray (TMA) comprising 410 cases of WDTC was constructed with risk estimates for the following features: extrathyroidal extension, lymph node metastases, and vascular invasion. The variables examined were morphologic classification, candidate genetic, and proteomic biomarkers.BRAF (Raf kinase type B) mutant carriers showed increased risk of developing invasion compared with wild-type (WT) cases. However, when classified morphologically, classic papillary thyroid carcinomas (PTC) showed much higher risk estimates for invasive features compared with follicular variant PTCs (FVPTC); within these morphologic subgroups, BRAF mutational status did not provide independent risk estimates. Staining intensities for membranous galectin-3 (Gal3), HBME-1, and CK19 and nuclear Gal3 were statistically validated as markers of aggressive behavior. Estrogen receptor beta (ERβ) was overexpressed in lesions with invasive behavior. The utility of these biomarkers remained statistically significant in the FVPTC. In contrast, a different set of biomarkers proved effective in classic PTC where upregulation of cyclin D1, loss of p27, and overexpression of ERβ were associated with invasive behavior.Different proteomic signatures validate the distinction of classic and FVPTC and provide a practical clinical mechanism to predict the thyroid cancer behavior and stratify patients for clinical management.
The Ataxia Telangiectasia–Mutated Target Site Ser18 Is Required for p53-Mediated Tumor Suppression
Authors: Heather L. Armata, David S. Garlick, Hayla K. Sluss
Journal: Cancer Research (2007)

Abstract The p53 tumor suppressor is phosphorylated at multiple sites within its NH2-terminal region. One of these phosphorylation sites (mouse Ser18 and human Ser15) is a substrate for the ataxia telangiectasia–mutated (ATM) and ATM-related (ATR) protein kinases. Studies of p53S18A mice (with a germ-line mutation that replaces Ser18 with Ala) have indicated that ATM/ATR phosphorylation of p53 Ser18 is required for normal DNA damage–induced PUMA expression and apoptosis but not for DNA damage–induced cell cycle arrest. Unlike p53-null mice, p53S18A mice did not succumb to early-onset tumors. This finding suggested that phosphorylation of p53 Ser18 was not required for p53-dependent tumor suppression. Here we report that the survival of p53S18A mice was compromised and that they spontaneously developed late-onset lymphomas (between ages 1 and 2 years). These mice also developed several malignancies, including fibrosarcoma, leukemia, leiomyosarcoma, and myxosarcoma, which are unusual in p53 mutant mice. Furthermore, we found that lymphoma development was linked with apoptotic defects. In addition, p53S18A animals exhibited several aging-associated phenotypes early, and murine embryonic fibroblasts from these animals underwent early senescence in culture. Together, these data indicate that the ATM/ATR phosphorylation site Ser18 on p53 contributes to tumor suppression in vivo. [Cancer Res 2007;67(24):11696–703]
Parents' quality of life and respiratory symptoms in young children with mild wheeze
Authors: L.M. Osman, A.D.G. Baxter-Jones, P.J. Helms
Journal: European Respiratory Journal (2001)

The Paediatric Asthma Caregiver's Quality of Life Questionnaire (PACQLQ), measures the impact of child asthma symptoms on family activity (CGAct) and parental anxiety (CGEmot). It has not been validated for families of children &lt;7 yrs, with wheezing illness. This study assessed the sensitivity of the PACQLQ to symptom change in 62 preschool children with wheezing illness. The median age of children was 3 yrs (range 0.8–6 yrs). At entry and 3-month follow-up, parents recorded child respiratory symptoms in a 1-month diary and completed the PACQLQ. On average, children in the study had 7 symptomatic days per month. On entry, mothers ≤30 yrs had worse scores than those &gt;30 (p&lt;0.02), and mothers in less affluent socioeconomic groups had worse scores than those in higher groups (p=0.05). Change in symptom scores and symptom free days between entry and follow-up was associated with change in PACQLQ scores (r=0.54–0.57, p&lt;0.001). Thirty-three parents had absolute change in PACQLQ of &lt;0.5 over three months (which has been previously defined as not being clinically significant). Compared to parents with higher PACQLQ change, parents with PACQLQ scores &lt;0.5, did not differ in frequency of child symptoms or in social-demographic factors, but had better quality of life scores on entry to the study (p&lt;0.01). It is concluded that the Paediatric Asthma Caregiver's Quality of Life Questionnaire is sensitive to group measures of child symptom change over 3 months, among preschool children, and this supports its use as an outcome measure in clinical trials. The absolute impact of child symptoms on parent quality of life varies among parents.
A Genome-Wide Significant Linkage for Severe Depression on Chromosome 3: The Depression Network Study
Authors: Gerome Breen, Bradley Todd Webb, Amy W. Butler, Edwin J.C.G. van den Oord, Federica Tozzi, Nick Craddock, Mike Gill, Ania Korszun, Wolfgang Maier, Lefkos Middleton, Ole Mors, Michael J. Owen, Sarah Cohen-Woods, Julia Perry, Nicholas W. Galwey, Ruchi Upmanyu, Ian Craig, Cathryn M. Lewis, Mandy Ng, Shyama Brewster, Martin Preisig, Marcella Rietschel, Lisa Jones, Jo Knight, John Rice, Pierandrea Muglia, Anne E. Farmer, Peter McGuffin
Journal: American Journal of Psychiatry (2011)

Objective: The purpose of this study was to find loci for major depression via linkage analysis of a large sibling pair sample. Method: The authors conducted a genome-wide linkage analysis of 839 families consisting of 971 affected sibling pairs with severe recurrent major depression, comprising waves I and II of the Depression Network Study cohort. In addition to examining affected status, linkage analyses in the full data set were performed using diagnoses restricted by impairment severity, and association mapping of hits in a large case-control data set was attempted. Results: The authors identified genome-wide significant linkage to chromosome 3p25-26 when the diagnoses were restricted by severity, which was a maximum LOD score of 4.0 centered at the linkage marker D3S1515. The linkage signal identified was genome-wide significant after correction for the multiple phenotypes tested, although subsequent association mapping of the region in a genome-wide association study of a U.K. depression sample did not provide significant results. Conclusions: The authors report a genome-wide significant locus for depression that implicates genes that are highly plausible for involvement in the etiology of recurrent depression. Despite the fact that association mapping in the region was negative, the linkage finding was replicated by another group who found genome-wide-significant linkage for depression in the same region. This suggests that 3p25-26 is a new locus for severe recurrent depression. This represents the first report of a genome-wide significant locus for depression that also has an independent genome-wide significant replication.
Upregulated JAG1 Enhances Cell Proliferation in Adrenocortical Carcinoma
Authors: Derek P. Simon, Thomas J. Giordano, Gary D. Hammer
Journal: Clinical Cancer Research (2012)

The purpose of this study was to examine the expression and molecular significance of JAG1, a ligand for the Notch developmental signaling pathway, in adrenocortical carcinoma (ACC).Human microarray data were analyzed for genes expressing ligands for the Notch pathway and validated with quantitative real-time PCR (QPCR) and immunoblots of RNA and protein, respectively. ACC cells lines were assessed for Notch pathway member expression by immunoblot, QPCR, and immunofluorescence. Notch pathway activity was also determined using a reporter gene (luciferase) activation. Proliferation experiments using a Jag1 knockdown strategy (Jag1KD) and an inhibitor of Notch-dependent transcription (DNMaml) used a coculture system with fluorescence-activated cell-sorting (FACS) analysis. Tumor stage and mitotic rate of human ACC samples were correlated to JAG1 expression.The Notch ligand JAG1 mRNA and protein are upregulated in ACCs. JAG1 upregulation can be modeled in the Y1 mouse ACC cell line that expresses Jag1, Notch receptors, downstream signaling molecules, and exhibits density-dependent Notch activation. Jag1 enhances cell proliferation through activation of canonical Notch signaling as shown through Jag1KD and coculture experiments. Inhibition of Notch signaling at the level of postreceptor signaling (DNMaml), results in similar inhibition of cell proliferation. Analysis of clinical data indicates that Jag1 expression correlates with both grade and stage of ACCs, supporting a role of JAG1-dependent Notch activation in late-stage ACCs.JAG1 is the primary upregulated Notch ligand in ACCs and enhances ACC cell proliferation and tumor aggressiveness in a non-cell-autonomous manner through activation of Notch signaling in adjacent cells.
FOXP3+ Regulatory T Cells Affect the Development and Progression of Hepatocarcinogenesis
Authors: Noritoshi Kobayashi, Nobuyoshi Hiraoka, Wataru Yamagami, Hidenori Ojima, Yae Kanai, Tomoo Kosuge, Atsushi Nakajima, Setsuo Hirohashi
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Tumor-infiltrating lymphocytes represent the host immune response to cancer. CD4+CD25+FOXP3+ regulatory T cells (Tregs) suppress the immune reaction. The aim of the present study was to investigate the clinicopathologic significance and roles of Tregs and CD8+ T cells during hepatocarcinogenesis. Experimental Design: We examined the infiltration of FOXP3+ Tregs and CD8+ T cells in the tumor stroma and nontumorous liver parenchyma using 323 hepatic nodules including precursor lesions, early hepatocellular carcinoma (HCC), and advanced HCC, along with 39 intrahepatic cholangiocarcinomas and 59 metastatic liver adenocarcinomas. We did immunohistochemical comparative studies. Results: The prevalence of Tregs was significantly higher in HCC than in the nontumorous liver (P &amp;lt; 0.001). The patient group with a high prevalence of Tregs infiltrating HCC showed a significantly lower survival rate (P = 0.007). Multivariate analysis revealed that the prevalence of Tregs infiltrating HCC was an independent prognostic factor. The prevalence of Tregs increased in a stepwise manner (P &amp;lt; 0.001) and that of CD8+ T cells decreased during the progression of hepatocarcinogenesis (P &amp;lt; 0.001). Regardless of the presence of hepatitis virus infection or histopathologic evidence of hepatitis, the prevalence of Tregs was significantly increased in nontumorous liver bearing primary hepatic tumors. Conclusions: Tregs play a role in controlling the immune response to HCC during the progression of hepatocarcinogenesis. It has been suggested that primary hepatic cancers develop in liver that is immunosuppressed by a marked infiltration of Tregs. A high prevalence of Tregs infiltrating HCC is thought to be an unfavorable prognostic indicator.
Benign asbestos pleural effusion: diagnosis and course.
Authors: B W Robinson, A W Musk
Journal: Thorax (1981)

We have reviewed 22 patients with benign asbestos pleural effusion seen over a 17-year period. The mean duration of exposure to asbestos was 5.5 years and the mean interval between exposure and presentation was 16.3 years. In five the effusion was asymptomatic. Fever was uncommon but in 15 of 21 patients the ESR was elevated. Leucocytosis was noted in seven of 20 patients. Autoantibodies were rarely detected. The pleural fluid was usually blood-stained and the volume aspirated was rarely larger than 500 ml. Pleural biopsies revealed established pleural fibrosis and/or inflammatory infiltration with fibrinous exudate and mesothelial and fibroblastic proliferation. A positive mantoux test was noted in eight of 12 patients but there was no other evidence of tuberculosis. The mean duration to spontaneous resolution of the effusion was 4.3 months. During a follow-up period of 28.1 years from initial exposure to asbestos (mean 22.8 years) and up to 17.2 years from initial presentation with a pleural effusion (mean 6.3 years) seven patients had a single recurrence and only one patient had multiple pleural effusions. Only three patients experienced persistent pleural pain. It was not possible to predict the likelihood of recurrence of an effusion or the persistence of pleural pain from the data at presentation. No patient subsequently developed mesothelioma or other neoplasm.
Sustained virological response with 29 days of Debio 025 monotherapy in hepatitis C virus genotype 3
Authors: H. Patel, E. J. Heathcote
Journal: Gut (2010)

Charybdotoxin (ChTX) and iberiotoxin (IbTX), two potent peptidyl blockers of the high conductance Ca(2+)-activated K+ channel (PK,Ca) were used to probe the role of this channel in regulating the contractility of various smooth muscles isolated from the guinea pig. Of the spontaneously contracting tissues that have been investigated, bladder and taenia coli are affected by ChTX, whereas portal vein and uterus are relatively insensitive. In the former two tissues, ChTX (10-100 nM) produces a concentration-dependent increase in contractility, with bladder being most sensitive to action of the toxin. ChTX also causes a contracture of quiescent aortic rings, although not affecting indomethacin-treated trachea. In order to demonstrate that the effects of ChTX are due specifically to blockage of PK,Ca, rather than to inhibition of some other K+ channel, two other inhibitors of PK,Ca were monitored. IbTX (10-100 nM), a selective inhibitor of PK,Ca, and tetraethylammonium ion, which blocks PK,Ca at low (0.1-3 mM) concentrations, both increase the myogenic activity of bladder, but not portal vein. In addition, IbTX causes a sustained contracture of aorta. Taken together, these data indicate that the increased contractility of certain guinea pig smooth muscles produced by ChTX, IbTX and tetraethylammonium ion is the result of selective inhibition of PK,Ca. It is suggested that in spontaneously active bladder and taenia coli, PK,Ca provides a repolarization pathway after tissue depolarization, whereas in quiescent aorta, PK,Ca maintains cellular resting potential. In contrast, in indomethacin-treated trachealis muscle, ChTX-sensitive K+ channel pathways are not involved in controlling resting tension.(ABSTRACT TRUNCATED AT 250 WORDS)
Magnocellular Neurosecretory System
Authors: A J Silverman, E A Zimmerman
Journal: Annual Review of Neuroscience (1983)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
Luteolin Reduces Lipopolysaccharide-induced Lethal Toxicity and Expression of Proinflammatory Molecules in Mice
Authors: ANASTASIA KOTANIDOU, ANGELIKI XAGORARI, ELENI BAGLI, PANAGIOTA KITSANTA, THEODORE FOTSIS, ANDREAS PAPAPETROPOULOS, CHARIS ROUSSOS
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Luteolin is a flavonoid that has been shown to reduce proinflammatory molecule expression in vitro. In the present study, we have tested the ability of luteolin to inhibit lipopolysaccharide (LPS)- induced lethal toxicity and proinflammatory molecule expression in vivo. Mice receiving LPS (Salmonella enteriditis LPS, 32 mg/kg, intraperitoneally) exhibited high mortality with only 4.1% of the animals surviving seven days after the LPS challenge. On the contrary, mice that had received luteolin (0.2 mg/kg, intraperitoneally) before LPS showed an increased survival rate with 48% remaining alive on Day 7. To investigate the mechanism by which luteolin affords protection against LPS toxicity we measured intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor-alpha (TNF-alpha) production in response to LPS in the presence or absence of luteolin pretreatment. Treatment of animals with LPS increased serum TNF-alpha levels in a time-dependent manner. The increase in peak serum TNF-alpha levels was sensitive to luteolin pretreatment. Luteolin pretreatment also reduced LPS-stimulated ICAM-1 expression in the liver and abolished leukocyte infiltration in the liver and lung. We conclude that luteolin protects against LPS-induced lethal toxicity, possibly by inhibiting proinflammatory molecule (TNF-alpha, ICAM-1) expression in vivo and reducing leukocyte infiltration in tissues.
Mutations and homologous recombination induced in mammalian cells by metabolites of benzo[a]pyrene and 1-nitropyrene.
Authors: V M Maher, J D Patton, J L Yang, Y Y Wang, L L Yang, A E Aust, N Bhattacharyya, J J McCormick
Journal: Environmental Health Perspectives (1987)

Metabolites of two structurally related chemical carcinogens, benzo[a]pyrene and 1-nitropyrene, were compared for their ability to cause cytotoxicity and induce mutations in normally repairing or nucleotide excision repair-deficient diploid human fibroblasts; for their ability to induce mutations in a defined gene sequence, supF, when a plasmid containing adducts formed by these carcinogens replicates in human 293 cells; and for their ability to induce homologous recombination between duplicated genes in mouse L cells. Both of the metabolites tested, i.e., (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha, epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) and 1-nitrosopyrene (1-NOP), form adducts on guanine. BPDE binds principally at the N2 position of guanine; 1-NOP binds to guanine at the C8 position. Results of the studies in diploid human cells indicated that when compared on the basis of equal numbers of DNA adducts, BPDE is more effective than 1-NOP in inducing mutations in DNA repair-proficient cells, but when compared in repair-deficient xeroderma pigmentosum human cells that do not remove such adducts from their DNA, the frequency of mutants induced per adduct is equal. These results suggest that during the time available for repair of potentially mutagenic lesions, repair-proficient human cells excise 1-NOP adducts more rapidly than they excise BPDE adducts. Molecular analysis of the specific kinds of mutations induced when a plasmid containing BPDE residues was allowed to replicate in human cells showed that BPDE induces mainly base substitution mutations, predominantly G:C to T:A transversions.(ABSTRACT TRUNCATED AT 250 WORDS)
Thrombophilic gene mutations in cirrhosis with portal vein thrombosis
Authors: Ö. Erkan, A.M. Bozdayi, A. Bozbaş, S. Dişibeyaz, M. Özcan, H. Bozkaya, K. Bahar, S. Karayalçin, A. Özden, C. Yurdaydin, Ö. Uzunalimoǧlu
Journal: Journal of Hepatology (2001)
Comparison of British and American Thoracic Societies' reintroduction guidelines for anti-tuberculous therapy induced liver injury
Authors: Faisal Faiyaz Zuberi, Bader Faiyaz Zuberi, Nimrah Bader, Syed Khalid Ali, Farhana Mumtaz, Tehseen Fatima
Journal: European Respiratory Journal (2013)

Background: There are many different guidelines for reintroduction of anti-tuberculous therapy (ATT) after drug induced liver injury (DILI)  Aims & Objective: This study was designed to compare two reintroduction regimes as advised by British Thoracic Society (BTS) and American Thoracic Society (ATS) in terms of efficacy.  Methods: Patients of either sex of age 18-60 years who develop DILI after ATT were selected after informed consent. Patients were randomly allocated to two groups, Group-I (BTS) received reintroduction as H = 100mg/day from day 1, maximum dose from day 4; R = 150 mg/day from day 8, maximum from day 11; and Z = 500 mg/day from 15, maximum from day 18. Group-II (ATS) received reintroduction as R = maximum dose from day 1, H = maximum dose from day 8, Z maximum dose from day 15.  Relapse rates were compared using χ2 test. ROC curve were plotted for DILI recurrence with age, BMI and albumin. P value of   Results: Total of 326 patients were selected, ATT was reintroduced as per Group allocation. Recurrence of DILI was seen in 34 (10.4%) patients out of which 16 (9.8%) were from Group-I while 18 (11.1%) were from Group-II (p = 0.72). ROC plot showed significant area under curve for BMI and albumin for recurrence of TB DILI with area under curve for BMI and albumin of 0.953 and 0.988 respectively.  Conclusion: There is no significant difference in recurrence of TB DILI by either recommended guidelines of BTS and ATS.
Skin Temperature Response of Normal Human Subjects to Various Conditions
Authors: WALTER REDISCH, EDWARD SHECKMAN, J. MURRAY STEELE
Journal: Circulation (1952)

Ten healthy volunteers (five males and five females), 25 to 41 years of age, were exposed to several different environmental conditions in a constant temperature room. It was found that at 20 C. and about 55 per cent humidity, about five hours after the last meal, the behavior of the temperature of the toe in contrast to that of the finger was consistent, reliable and reproducible. These conditions, somewhat cooler than those frequently used, were deemed suitable for testing vasodilator drugs or procedures.