tbuckley/cabot-search huggingface dataset:
Abstract 3928: Inhibition of the ubiquitin proteasome system differentially regulates glucocorticoid receptor-mediated transcriptional processes
Authors: Kimberly R. Wiggins, Valerie Davis, Dhiral Phadke, Ruchir Shah, Trevor K. Archer
Journal: Cancer Research (2012)

Abstract The ubiquitin-proteasome system (UPS) plays an integral role in controlling protein turnover to modulate cellular processes such as growth, proliferation, differentiation, and apoptosis. This occurs through multiple mechanisms that rely on the regulation of numerous transcription factors such as steroid hormone nuclear receptors. The glucocorticoid receptor (GR) is a member of this receptor family and its activation promotes nuclear translocation and downstream transcriptional activity through the recruitment of co-regulatory complexes. Our goal is to understand the mechanisms by which the proteasome regulates glucocorticoid receptor-mediated gene transcription. To explore the effects of proteasome inhibition upon GR-mediated transcription, we used ChIP-Seq and microarray studies using breast cancer cells to examine GR binding and gene expression profiles after treatment with dexamethasone (dex) or dex in combination with a proteasome inhibitor, MG132 (dex + mg), for 1 hour and 18 hours. More than 14000 and 5000 GR-binding sites were apparent after both treatments in the 1 hour and 18 hour samples, respectively. GR binding sites seen during 1 hour of treatment can be mapped to more than 9000 genes while the binding sites in the 18 hour treatment samples mapped to over 5000 genes. In addition, over 55% of binding sites in all treatment groups are within 50 kilobases of annotated transcription start sites. To verify these putative interactions, we assayed the transcript levels of genes at both time periods and examined the levels of bound GR throughout the gene. The results reveal a differential regulation of genes that can be divided into three classes: dex-responsive, dex + mg-responsive, or dually responsive. Further analyses will reveal if there are clearly defined chromatin states that demarcate each class. These data provide insights into the intricate mechanisms of proteasome-mediated GR regulation and highlight proteasomal-regulated genes involved in numerous diseases and developmental disorders. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3928. doi:1538-7445.AM2012-3928
Diagnostic accuracy of clinical examination for detection of non-cephalic presentation in late pregnancy: cross sectional analytic study
Authors: Natasha Nassar, Christine L Roberts, Carolyn A Cameron, Emily C Olive
Journal: BMJ (2006)

<h3>Abstract</h3> <b>Objective</b> To examine the diagnostic accuracy of clinical examination to determine fetal presentation in late pregnancy. <b>Design</b> Cross sectional analytic study with index test of clinical examination and reference standard of ultrasonography. <b>Setting</b> Antenatal clinic in tertiary obstetric hospital in Sydney, Australia. <b>Participants</b> 1633 women with a singleton pregnancy between 35 and 37 weeks9 gestation attending antenatal clinics. <b>Intervention</b> Fetal presentation assessed by clinical examination during routine antenatal care, followed by ultrasonography to confirm the diagnosis. <b>Main outcome measures</b> Sensitivity, specificity, and positive and negative predictive values of clinical examination compared with ultrasonography. Diagnostic rates by maternal characteristics. <b>Results</b> Ultrasonography identified non-cephalic presentation in 130 (8%) women, comprising 103 (6.3%) with breech and 27 (1.7%) with transverse or oblique lie. Sensitivity of clinical examination for detecting non-cephalic presentation was 70% (95% confidence interval 62% to 78%) and specificity was 95% (94% to 96%). The positive predictive value and negative predictive value were55% and 97%, respectively. <b>Conclusions</b> Clinical examination is not sensitive enough for detection and timely management of non-cephalic presentation.
Caution on preventing neural tube defects.
Authors: V C Talwalker
Journal: BMJ (1981)

TABLE iII-Hozw,!ofteni wvives wvith smnokinlg huisbands inhale cigarette smoke passively in 3apan (calculation based onz a stuidy in Aichi Prefecture,_7apan) Length of contact in a day No of cigarettes 1.5 h 4 h 15 0 h smoked bv husband'dav' No of cigarettes No of cigarettes No of cigarettes Frequency to which they Frequency to which they Frequency to which they ( ',,) were exposed* (,) were exposed* ( ',) were exposed* 1-19 (average 10) 11.8 (0-88) 14 2 (2 55) 6-8 (8 82) 20-29 (average 25) 19 8 (2-21) 25-4 (5 88) 8 6 (22 06) 30-60 (average 45) 5-6 (3-97) 5 2 (10 59) 2 6(39-71)*Length of contact multiplied by number smoked in an hour (number smoked in an hour= average number of cigarettes smoked in a day divided by total hours awake).80 Females Males o 70 - 2 6-0 - 40 'V a, 3-0 at
Analysis of repair and mutagenesis of chromium-induced DNA damage in yeast, mammalian cells, and transgenic mice.
Authors: L Cheng, S Liu, K Dixon
Journal: Environmental Health Perspectives (1998)

Chromium (Cr) is a widespread environmental contaminant and a known human carcinogen. We have used shuttle vector systems in yeast, mammalian cells, and transgenic mice to characterize the mutational specificity and premutational DNA damage induced by Cr(VI) and its reduction intermediates in order to elucidate the mechanism by which Cr induces mutations. In the yeast system, treatment of vector-containing cells with Cr(VI) results in a dose-dependent increase in mutations in the SUP4-o target gene of the vector; mutagenesis is enhanced in an apn-1 yeast mutant, deficient in the capacity to repair oxidative-type DNA damage. In vector-containing mammalian cells, treatment with Cr(VI) also results in a dose-dependent increase in mutations in the vector target gene supF. The Cr-induced mutations in supF occurred mostly at G:C base pairs and were widely distributed across the gene, a pattern similar to those observed with ionizing radiation or hydrogen peroxide. These results support the hypothesis that Cr(VI)-induced oxidative-type DNA damage is responsible for Cr mutagenesis in the cell. Recently these studies were extended into the Big Blue transgenic mouse system in which Cr-induced mutagenesis was observed in the lung, the target organ for Cr carcinogenesis in humans. Analysis of the spectrum of these mutations will test whether Cr mutagenesis occurs by similar mechanisms in the intact animal as in cell culture systems and yeast.
The Press and the Physician Shortage
Authors: O. G. Austin
Journal: JAMA (1975)

To the Editor.—  We still read expressions of lamentation in the lay press and medical journals regarding the shortage or maldistribution of physicians. Undoubtedly many, many other middle-aged physicians have encountered a dilemma similar to mine that may have a significant effect on the number of practicing physicians.  My professional career in obstetrics-gynecology has been rewarding and usually pleasant, free of malpractice suits. Now, when my practice is being scaled down to gynecology only, the yearly premium of my professional liability insurance has reached an all time high of $10,000.00. This, plus additional overhead of basics such as rental and salaries, creates a formidable challenge to a limited practice. Perhaps retirement or acceptance of some quasimedical advisory job are more reasonable alternatives.
Treatment of chronic type B hepatitis with recombinant α-interferon induces autoantibodies not specific for autoimmune chronic hepatitis
Authors: Werner-J. Mayet, Georg Hess, Guido Gerken, Siegbert Rossol, Rita Voth, Michael Manns, Karl-Hermann Meyer ZumBüschenfelde
Journal: Hepatology (1989)

Recombinant human alpha-interferon is now under intensive investigation as therapy for chronic Type B hepatitis. Recent reports have suggested that prolonged alpha-interferon therapy may induce autoimmune reactions. We have evaluated the problem of autoimmunity related to alpha-interferon therapy by testing for 15 different antibodies in the sera of 31 patients treated with alpha-interferon. No patient had autoantibodies before treatment; 27 (87%) of 31 patients developed at least one autoantibody. Eleven patients had antinuclear antibodies and 21 had smooth muscle antibodies, both of which usually developed during alpha-interferon therapy. In contrast, antibodies to endocrine organs such as thyroid microsomal, thyroglobulin and parietal cell antibodies arose in 12 patients, but usually several months after alpha-interferon treatment. The appearance of these autoantibodies did not correlate with disease activity or response to alpha-interferon. No patient developed autoantibodies specifically associated with autoimmune liver diseases such as liver kidney microsomal antibodies, autoantibodies to soluble liver antigen and the primary biliary cirrhosis specific subtypes of antimitochondrial antibodies. These results suggest that prolonged alpha-interferon therapy can induce autoantibody production and, in susceptible patients, may lead to autoimmune disorders.
Radon and Lung Cancer in Mines and Homes
Authors: Naomi H. Harley
Journal: New England Journal of Medicine (1984)

The bronchial disease now known to be lung cancer was reported to have caused many deaths among miners in central Europe almost 400 years ago.1. Epidemiologic studies do not generally prove causality, but evidence from many sources provides convincing data to identify the responsible agent as radon. Four large studies of lung cancer in underground miners indicate that radon daughters are the most important factor in the genesis of this disease.2 3 4 5 Previous studies have been criticized because other carcinogens in under-ground mines blur the effect of radon daughters and because the exposure history of miners is never well known, . . .
Presence of Human Polyomavirus 6 in Mutation-Specific BRAF Inhibitor–Induced Epithelial Proliferations
Authors: David Schrama, Leopold Groesser, Selma Ugurel, Christian Hafner, Diana V. Pastrana, Christopher B. Buck, Lorenzo Cerroni, Anna Theiler, Jürgen C. Becker
Journal: JAMA Dermatology (2014)

A frequent adverse effect of mutation-specific BRAF inhibitor therapy is the induction of epithelial proliferations including cutaneous squamous cell carcinomas. To date, the only factor identified contributing to their development is the activation of the mitogen-activated signal transduction cascade by mutations in the RAS genes. However, these mutations explain only 60% of the tumors; hence, it is important to identify what is causing the remaining tumors.
Inactivation of beef brain alpha-ketoglutarate dehydrogenase complex by valproic acid and valproic acid metabolites. Possible mechanism of anticonvulsant and toxic actions.
Authors: A S Luder, J K Parks, F Frerman, W D Parker
Journal: Journal of Clinical Investigation (1990)

The anticonvulsant valproic acid (VPA, 2-n-propylpentanoic acid) causes inhibition of the citric acid cycle and elevations of central nervous system (CNS) gamma-aminobutyric acid (GABA) levels, which correlates with anticonvulsant action. No unifying mechanism for these actions of VPA has won general acceptance. alpha-Ketoglutarate dehydrogenase complex (KDHC) is a critical control enzyme in the CNS. We hypothesized that VPA may be an inhibitor of this enzyme since decreased KDHC activity would reduce substrate flux through the citric acid cycle and may increase flux into GABA synthesis. To test this hypothesis, inhibition of purified beef brain KDHC by VPA and its metabolites 2-n-propylpent-2-enoic acid (delta 2,3 VPE) and their coenzyme A (CoA) derivatives were studied. Preincubation of the NADH-reduced enzyme with delta 2,3 VPE, VPA-CoA, and delta 2,3 VPE-CoA caused time-dependent inactivation, reversible by addition of CoA. Under steady-state conditions, delta 2,3 VPE and VPA-CoA were competitive inhibitors of KDHC and delta 2,3 VPE-CoA was a mixed inhibitor. These observations have implications for the molecular mechanisms of VPA action. VPA derivatives cause inactivation and inhibition of KDHC, which may explain the anticonvulsant and some toxic actions of VPA.
Junior doctors' working practices
Authors: D. M I C Wawman
Journal: BMJ (1992)

care, the number of patients who are assigned to aggressive ambition and hence loses many with the government have offered the following, which generalists is far lower than the number Marsh more caring qualities, an emphasis that the women is what every junior doctor wants?proposes.Thus Marsh's statement that what in our care would doubtless reverse.In addressing(1) Non-medical staff trained to carry out should be done can be done in half the number of these problems the college must clarify its attitude phlebotomy, intravenous drug administration, visits is not supported by the American experience, to research and ensure that training can be electrocardiography, portering, and routine We have half the number of visits, twice the cost completed within the NHS.clerical work and to find empty beds.for the same level of care, and far less effective DAVID HOWE(2) Overtime pay equal to daytime rates.prevention than in the United Kingdom.Department of Obstetrics and Gynaecology, (3) A half day off work after a busy night on call.General practice in Britain is, with all of its Princess Anne Hospital, The government's failure to implement these faults, a model of efficient, personalised, accessible Suthampton S09 4HA demands boldly and swiftly indicates a brutality care compared with what is available in other IButSTringnobercs M71930146(7
The effect of coenzyme Q10 on infarct size in a rabbit model of ischemia/reperfusion
Authors: Y. Birnbaum, S. L. Hale, R. A. Kloner
Journal: Cardiovascular Research (1996)

Coenzyme Q10 has been found to enhance recovery of function after reperfusion in numerous experimental acute ischemia-reperfusion models. We assessed whether coenzyme Q10, administered intravenously either during or 1 h before ischemia, can limit infarct size in the rabbit.Anesthetized open-chest rabbits were subjected to 30 min of coronary artery occlusion and 4 h of reperfusion. In Protocol 1, 12 min after beginning of ischemia rabbits were randomized to intravenous infusion of 30 mg coenzyme Q10 (Eisai Co., Japan) (n = 10) or vehicle (n = 10). In Protocol 2, rabbits were randomized to 30 mg coenzyme Q10 (n = 6) or vehicle (n = 6) treatment 60 min before ischemia. Ischemic zone at risk (IZ) was assessed by blue dye and necrotic zone (NZ) by tetrazolium staining.In both protocols, coenzyme Q10 did not alter heart rate, mean blood pressure, or regional myocardial blood flows in either the ischemic or non-ischemic zones during ischemia or reperfusion. No difference was found in IZ (as fraction of LV weight) (Protocol 1: 0.24 +/- 0.02 vs. 0.25 +/- 0.02; Protocol 2: 0.28 +/- 0.02 vs. 0.28 +/- 0.03, in the control vs. coenzyme Q10 groups, respectively). The NZ/IZ ratio was comparable between the groups in both protocols (Protocol 1: 0.22 +/- 0.04 vs. 0.26 +/- 0.04; Protocol 2: 0.21 +/- 0.06 vs. 0.30 +/- 0.06, in the control vs. coenzyme Q10 groups, respectively).Coenzyme Q10, administered acutely either during or 60 min before myocardial ischemia, does not attenuate infarct size in the rabbit.
Learning Diagnostic Restraint
Authors: David B. Reuben
Journal: New England Journal of Medicine (1984)

Recently, I had a disagreement with a house officer over diagnostic strategies in a hospitalized patient of mine. The patient, a 73-year-old woman whom I knew well, had hypertension, long-standing poorly controlled diabetes, and hypothyroidism for which she was taking replacement thyroxine. Five years earlier she had had a stroke and had been left with a moderate disability that limited her activity to independent living in housing for the elderly and occasional visits to a senior citizens' center and family members' homes. She now presented with abrupt onset of congestive heart failure without a clear cause, which responded promptly to . . .
Diagnostic and prognostic evaluation of phenotypic markers TRAF1, MUM1, BCL2 and CD15 in cutaneous CD30-positive lymphoproliferative disorders
Authors: M.F. Benner, P.M. Jansen, C.J.L.M. Meijer, R. Willemze
Journal: British Journal of Dermatology (2009)

CD30 is expressed in various types of cutaneous lymphomas, including lymphomatoid papulosis (LyP), primary cutaneous anaplastic large cell lymphoma (C-ALCL), some cases of mycosis fungoides showing large cell transformation (MF-TR) and skin localizations of systemic anaplastic lymphoma kinase (ALK)-positive or ALK-negative ALCL. Differentiation between these entities is often not possible on the basis of histology alone, but several markers, including TRAF1, MUM1 and BCL2, have been reported to provide additional diagnostic information.To evaluate the diagnostic and prognostic significance of these markers in a large group of cutaneous CD30-positive lymphoproliferations.An immunohistochemical study on the expression of TRAF1, MUM1, BCL2 and CD15 was performed on skin biopsies from 28 patients with C-ALCL, 39 patients with LyP, 11 patients with CD30-positive MF-TR, two with ALK-positive ALCL and six with ALK-negative ALCL. In addition, the prognostic significance of these markers was evaluated.TRAF1 was expressed in roughly 70-80% and MUM1 was expressed in 70-100% of all the groups of cutaneous CD30-positive lymphoproliferations. Highest levels of BCL2 were expressed in MF-TR (73%), in contrast to 21% in C-ALCL and 36% in LyP. Highest levels of CD15 were expressed in C-ALCL (43%), compared with 18% in LyP and 9% in MF-TR. A relationship with survival was not clear.The results of the present study suggest that TRAF1, MUM1, BCL2 and CD15 cannot be considered as useful diagnostic or prognostic marker in cutaneous CD30-positive lymphoproliferations. Differentiation between these different conditions should be based on a combination of clinical, histological and immunophenotypical criteria.
Peginterferon alfa-2b and ribavirin in patients with hepatitis C virus and decompensated cirrhosis: A controlled study
Authors: Angelo Iacobellis, Massimo Siciliano, Francesco Perri, Brigida E. Annicchiarico, Gioacchino Leandro, Nazario Caruso, Laura Accadia, Giuseppe Bombardieri, Angelo Andriulli
Journal: Journal of Hepatology (2006)
Treatment of insulin resistance with metformin in naïve genotype 1 chronic hepatitis C patients receiving peginterferon alfa-2a plus ribavirin
Authors: Manuel Romero‐Gómez, Moisés Diago, Raúl J. Andrade, José L. Calleja, Javier Salmerón, Conrado M. Fernández‐Rodríguez, Ricard Solà, Javier García‐Samaniego, Juan M. Herrerías, Manuel De la Mata, Ricardo Moreno‐Otero, Óscar Nuñez, Antonio Olveira, Santiago Durán, Ramón Planas
Journal: Hepatology (2009)

Insulin resistance affects sustained virological response (SVR) in chronic hepatitis C. To know whether adding metformin to standard antiviral treatment improves SVR, we conducted a prospective, multicentered, randomized, double-blinded, placebo-controlled trial in 19 Spanish hospitals, including 123 consecutive patients with genotype 1 chronic hepatitis C and insulin resistance. Patients were randomized to receive either metformin (arm A; n = 59) or placebo (arm B; n = 64) in addition to peginterferon alfa-2a (180 microg/week) and ribavirin (1000-1200 mg/day). The primary end point was SVR, and secondary endpoints were viral clearance at weeks 12, 24, and 48, and changes in the homeostasis model assessment (HOMA) index over the first 24 weeks. There were no differences between arms at baseline. In the intent-to-treat analysis, SVR was observed in 53% versus 42% in arm A and arm B, respectively (P = NS). In the subgroup analyses, SVR was higher in females (n = 54) receiving metformin: arm A, 58% (15/26) versus 29% (8/28) arm B (P = 0.03). In the per protocol analysis (PPA; n = 101), SVR was 67% in arm A and 49% in arm B (P = 0.06). Viral decline during the first 12 weeks was greater in females receiving metformin: -4.88 (1.18) versus -4.0 (1.44) (P = 0.021), whereas no differences were seen in males. The triple therapy was well tolerated, but diarrhea was more often seen in arm A (34% versus 11%; P < 0.05).Adding metformin to peginterferon and ribavirin was safe and improved insulin sensitivity. Although the study failed to show a statistically significant difference between arms, it did show an improved SVR in females.
Impact of digital ulcers on disability and health-related quality of life in systemic sclerosis
Authors: L Mouthon, C Mestre-Stanislas, A Bérezné, F Rannou, P Guilpain, M Revel, C Pagnoux, L Guillevin, J Fermanian, S Poiraudeau
Journal: Annals of the Rheumatic Diseases (2009)

Objective: To assess the impact of digital ulcers (DUs) on disability and health-related quality of life (HRQoL) in systemic sclerosis (SSc). Methods: Two hundred and thirteen patients with SSc were evaluated at four annual meetings of a patient society between 2004 and 2007 (n = 177) or during hospital stay (n = 36). HRQoL was assessed by the SF-36, global disability by the health assessment questionnaire (HAQ), hand disability by the Cochin Hand Function Scale (CHFS) and global hand and wrist mobility by the Kapandji index. Results: Sixty-seven patients (31.4%) had at least one DU at the time of evaluation. Patients with DUs showed significantly more pitting scars (p&lt;0.001) and calcinosis (p&lt;0.0001) than others. Patients with DU had significantly greater HAQ (mean (SD) 1.218 (0.723) vs 0.930 (0.717), p = 0.008), CHFS (mean (SD) 27.38 (20.68) vs 16.73 (18.19), p&lt;0.0001) and aesthetic prejudice (mean (SD) 6.1 (2.2) vs 3.9 (2.5), p&lt;0.0001) scores than others. Hand and wrist mobility were significantly diminished in patients with DU (mean (SD) Kapandji score 75.3 (22.8) vs 81.7 (19.2), p&lt;0.0001). The presence of a DU did not significantly alter the physical component but influenced the mental component (mean (SD) 43.38 (12.53) vs 39.58 (9.54), p = 0.026) of the SF36. Conclusion: Patients with SSc with DUs have reduced wrist and hand mobility, increased global and hand disabilities and decreased mental component of HRQoL.
Systemic Correction of Storage Disease in MPS I NOD/SCID Mice Using the Sleeping Beauty Transposon System
Authors: Elena L Aronovich, Jason B Bell, Shaukat A Khan, Lalitha R Belur, Roland Gunther, Brenda Koniar, Patricia A Schachern, Josh B Parker, Cathy S Carlson, Chester B Whitley, R Scott McIvor, Pankaj Gupta, Perry B Hackett
Journal: Molecular Therapy (2009)

The Sleeping Beauty (SB) transposon system is a nonviral vector that directs transgene integration into vertebrate genomes. We hydrodynamically delivered SB transposon plasmids encoding human alpha-L-iduronidase (hIDUA) at two DNA doses, with and without an SB transposase gene, to NOD.129(B6)-Prkdc(scid) IDUA(tm1Clk)/J mice. In transposon-treated, nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice with mucopolysaccharidosis type I (MPS I), plasma IDUA persisted for 18 weeks at levels up to several hundred-fold wild-type (WT) activity, depending on DNA dose and gender. IDUA activity was present in all examined somatic organs, as well as in the brain, and correlated with both glycosaminoglycan (GAG) reduction in these organs and level of expression in the liver, the target of transposon delivery. IDUA activity was higher in the treated males than in females. In females, omission of transposase source resulted in significantly lower IDUA levels and incomplete GAG reduction in some organs, confirming the positive effect of transposition on long-term IDUA expression and correction of the disease. The SB transposon system proved efficacious in correcting several clinical manifestations of MPS I in mice, including thickening of the zygomatic arch, hepatomegaly, and accumulation of foamy macrophages in bone marrow and synovium, implying potential effectiveness of this approach in treatment of human MPS I.