tbuckley/cabot-search huggingface dataset:
Activation of <i>SOX2</i> Expression by BRD4-NUT Oncogenic Fusion Drives Neoplastic Transformation in NUT Midline Carcinoma
Authors: Ranran Wang, Wei Liu, Christine M. Helfer, James E. Bradner, Jason L. Hornick, Susan M. Janicki, Christopher A. French, Jianxin You
Journal: Cancer Research (2014)

Abstract BRD4 is implicated in the pathogenesis of a number of different cancers. It is also the target of translocation t(15;19) that accounts for the highly aggressive NUT midline carcinoma (NMC). We discovered that t(15;19) NMC cells display the ability to grow into stem cell–like spheres and express an exceptionally high level of the stem cell marker, SOX2. The BRD4-NUT fusion oncogene resulting from t(15;19) translocation is required for the abnormal activation of SOX2, which drives the stem cell–like proliferation and cellular transformation in NMC cells. SOX2 knockdown phenocopies the effects of BRD4-NUT inhibition, whereas ectopic SOX2 expression rescues the phenotype. The BRD4-NUT–induced abnormal SOX2 activation was observed in multiple NMC cell lines as well as in NMC primary tumors. We further demonstrate that BRD4-NUT oncoprotein recruits p300 to stimulate transcription activation and that inhibition of p300 represses SOX2 transcription in NMC cells. These studies identify this stem cell marker as a novel BRD4-NUT target that supports the highly aggressive transforming activity of t(15;19) carcinomas. Our study provides new mechanistic insights for understanding how alteration of BRD4 function by BRD4-NUT oncogene leads to the highly malignant NMC carcinoma. Because abnormal stem cell self-renewal is frequently observed during tumor formation and metastasis, the aberrant stem cell–like proliferation associated with BRD4 dysregulation observed in NMC carcinoma may have implications for studying the oncogenic mechanism of other BRD4-associated tumors. Cancer Res; 74(12); 3332–43. ©2014 AACR.
Imaging and Therapy with Rituximab Anti-CD20 Immunotherapy in an Animal Model of Central Nervous System Lymphoma
Authors: Leslie L. Muldoon, Seth J. Lewin, Edit Dósa, Dale F. Kraemer, Michael A. Pagel, Nancy D. Doolittle, Edward A. Neuwelt
Journal: Clinical Cancer Research (2011)

To evaluate the effect of rituximab monoclonal antibody (mAb) on MRI tumor volumetrics and efficacy in a rat model of central nervous system (CNS) lymphoma when delivery to the brain was optimized with osmotic blood-brain barrier disruption (BBBD).Female nude rats with intracerebral MC116 human B-cell lymphoma xenografts underwent baseline MRI and were randomized into 5 groups (n = 6 per group): (i) BBBD saline control; (ii) methotrexate with BBBD; (iii) rituximab with BBBD; (iv) rituximab and methotrexate with BBBD; and (v) intravenous rituximab. Tumor volumes were assessed by MRI at 1 week, and rats were followed for survival.BBBD increased delivery of yttrium-90-radiolabeled mAb in the model of CNS lymphoma. Control rats showed 201 ± 102% increase in tumor volume on MRI 1 week after entering the study and median 14-day survival (range: 6-33). Tumor growth on MRI was slowed in the methotrexate treatment group, but survival time (median: 7 days; range: 5-12) was not different from controls. Among 17 evaluable rats treated with rituximab, 10 showed decreased tumor volume on MRI. All rituximab groups had increased survival compared with control, with a combined median of 43 days (range: 20-60, P < 0.001). There were no differences by route of delivery or combination with methotrexate.Rituximab was effective at decreasing tumor volume and improving survival in a model of CNS lymphoma and was not affected by combination with methotrexate or by BBBD. We suggest that rituximab warrants further study in human primary CNS lymphoma.
PSYCHIATRY AND HIGHER EDUCATION IN FINLAND
Authors: KAUKO KAILA
Journal: American Journal of Psychiatry (1958)

The difficulties and mental disturbances of Finnish university and college students are in most instances due to personal factors, retarded or otherwise disturbed emotional growth and maturation interwoven with family relations, and insufficient attainment of independence and adulthood. The significance of intellectual difficulties is of minor importance among the factors referred to above, since even in the cases where marked intellectual difficulties were found/p=m-/ i.e., in about one-fifth of the total number examined and given psychotherapy/p=m-/emotional disturbances proved to be the primary reason. Rather loose social ties among the students, the lack of campus life, and the reticent Finnish character favour the fatal isolation from suitable company. Finnish students live in great financial and housing difficulties, which considerably increase the already serious pressure and strain of the college years. University students are very susceptible to short intensive psychotherapy. It would be most desirable that the students should have their own ( full-time) psychiatrist. The fact that an uncommonly high number of students/p=m-/more than one-third of the entire student body of Helsinki University/p=m-/discontinue their studies is probably in most cases due to emotional disturbances, though the students themselves provide every other possible cause for their failures.
ECT Stimulus Intensity: Are Present ECT Devices Too Limited?
Authors: A D Krystal, M D Dean, R D Weiner, L A Tramontozzi, K M Connor, V H Lindahl, R W Massie
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: The maximum output charge for ECT devices is limited to 576 millicoulombs in the United States, although there are no data ensuring that this limit will allow consistently effective treatments. The authors examined whether this limit has a negative impact on therapeutic response and, therefore, whether a higher stimulus charge should be available.METHOD: They retrospectively reviewed the records of 471 patients who received a clinical index course of ECT at Duke University between 1991 and 1998. These patients received conservative stimulus dosing of 2.25 times seizure threshold for unilateral ECT and 1.5 times seizure threshold for bilateral ECT.RESULTS: Seventy-two (15%) of the 471 patients required the maximum stimulus intensity during their index ECT course. Of these, 24 (5% of the total) had either a short EEG seizure (less than 25 seconds) or had no seizure at the maximum level. Strategies to augment therapeutic response with caffeine, ketamine, or hyperventilation were used in 14 of the 24 patients, and data on therapeutic response were available for 22 of the 24. Only seven (32%) of these 22 patients were considered ECT responders, compared with 242 (66%) of the remaining 364 patients for whom data on response to ECT were available. Older age and pre-ECT course EEG slowing were predictors of requiring the maximum stimulus level.CONCLUSIONS: The maximum available stimulus output was therapeutically insufficient for 5% of the patients studied even when available means to augment response were instituted. This percentage would likely be even larger with the use of a less conservative dosing protocol for unilateral ECT. Increases in maximum stimulus output for ECT devices should be considered as a means to ensure adequate treatment response.
Environmental Toxins and Parkinson's Disease
Authors: Samuel M. Goldman
Journal: The Annual Review of Pharmacology and Toxicology (2013)

Parkinson's disease (PD) is a chronic, progressive, disabling neurodegenerative disorder that begins in mid to late life and is characterized by motor impairment, autonomic dysfunction, and, in many, psychological and cognitive changes. Recent advances have helped delineate pathogenetic mechanisms, yet the cause of PD in most individuals is unknown. Although at least 15 genes and genetic loci have been associated with PD, identified genetic causes are responsible for only a few percent of cases. Epidemiologic studies have found increased risk of PD associated with exposure to environmental toxicants such as pesticides, solvents, metals, and other pollutants, and many of these compounds recapitulate PD pathology in animal models. This review summarizes the environmental toxicology of PD, highlighting the consistency of observations across cellular, animal, and human studies of PD pathogenesis.
The impact of benzodiazepines on occurrence of pneumonia and mortality from pneumonia: a nested case-control and survival analysis in a population-based cohort: Table 1
Authors: Usman Iqbal, Shabbir Syed-Abdul, Phung Anh Nguyen, Wen-Shan Jian, Yu-Chuan (Jack) Li
Journal: Thorax (2013)

The impact of benzodiazepines on occurrence of pneumonia and mortality from pneumonia: a nested case-control and survival analysis in a population-based cohort
Letter by Bonaque et al Regarding Article, “Cardiac Biomarkers Are Associated With an Increased Risk of Stroke and Death in Patients With Atrial Fibrillation: A Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Substudy”
Authors: Juan C. Bonaque, Germán Merchán, Ichiro Ikuta
Journal: Circulation (2013)
Ca2+ homeostasis and structural and functional remodelling of airway smooth muscle in asthma
Authors: K. Mahn, O. O. Ojo, G. Chadwick, P. I. Aaronson, J. P. T. Ward, T. H. Lee
Journal: Thorax (2010)

Asthma is characterised by airway hyper-responsiveness and remodelling, and there is mounting evidence that alterations in the phenotype of airway smooth muscle (ASM) play a central role in these processes. Although the concept that dysregulation of ASM Ca<sup>2+</sup> homeostasis may underlie at least part of these alterations has been around for many years, it is only relatively recently that the availability of ASM biopsies from subjects with mild and moderate asthma has allowed it to be properly investigated. In this article, critical components of the pathobiology of asthmatic ASM, including contractile function, proliferation, cell migration and secretion of proinflammatory cytokines and chemokines, are reviewed and related to associated changes in ASM Ca<sup>2+</sup> homeostasis. Based on this evidence, it is proposed that a unifying mechanism for the abnormal asthmatic phenotype is dysregulation of Ca<sup>2+</sup> homeostasis caused at least in part by a downregulation in expression and function of sarcoendoplasmic Ca<sup>2+</sup> ATPases (SERCAs).
Double Heterozygous Mutations Involving Both <i>HNF1A</i>/MODY3 and <i>HNF4A</i>/MODY1 Genes
Authors: Gabriele Forlani, Stefano Zucchini, Antonio Di Rocco, Raffaella Di Luzio, Mirella Scipione, Elena Marasco, Giovanni Romeo, Giulio Marchesini, Vilma Mantovani
Journal: Diabetes Care (2010)

OBJECTIVE We describe a maturity-onset diabetes of the young (MODY) case with mutations involving both HNF4A and HNF1A genes. RESEARCH DESIGN AND METHODS A male patient was diagnosed with diabetes at age 17; the metabolic control rapidly worsened to insulin requirement. At that time no relatives were known to be affected by diabetes, which was diagnosed years later in both the parents (father at age 50 years, mother at age 54 years) and the sister (at age 32 years, during pregnancy). RESULTS The genetic screening showed a double heterozygosity for the mutation p.E508K in the HNF1A/MODY3 gene and the novel variant p.R80Q in the HNF4A/MODY1 gene. The genetic testing of the family showed that the father carried the MODY3 mutation while the mother, the sister, and her two children carried the MODY1 mutation. CONCLUSIONS MODY1 and MODY3 mutations may interact by chance to give a more severe form of diabetes (younger age at presentation and early need of insulin therapy to control hyperglycemia).
Multicentre phase II study of cisplatin–etoposide chemotherapy for advanced large-cell neuroendocrine lung carcinoma: the GFPC 0302 study
Authors: J. Le Treut, M.C. Sault, H. Lena, P.J. Souquet, A. Vergnenegre, H. Le Caer, H. Berard, S. Boffa, I. Monnet, D. Damotte, C. Chouaid
Journal: Annals of Oncology (2013)
Effect of isradipine on endothelin-1 plasma concentrations in patients with Raynaud's phenomenon.
Authors: L La Civita, D Giuggioli, M G Del Chicca, G Longombardo, G Pasero, C Ferri
Journal: Annals of the Rheumatic Diseases (1996)

Type H RP (n = 19) 2/17 50 (15) 6-7 (3-9) 90** 85t 84 37 32tValues are number, or mean (SD), as relevant.*Transient mild arthromyalgias; **arthromyalgias and oesophageal dismotility in three, sclerodactyly in seven, or autoimmune tyreopathy in two subjects.tAntinuclear antibody in 15 subjects; antiextractable nuclear antigen antibody in four (two ribonucleoprotein and two SS-A); anticentromere antibody in five;anti-smooth muscle antibody in one.tA scleroderma-like pattern was present in two patients.
Environmental Health Research and the Observer’s Dilemma
Authors: David B. Resnik
Journal: Environmental Health Perspectives (2009)

BackgroundEnvironmental health researchers frequently study people in occupational, educational, recreational, or domestic settings who are exposed to hazardous agents.Objective/discussionDeciding whether—and how—to inform research subjects about risks they face in their environment can be a challenging task for investigators. Because legal rules and professional guidelines do not cover this topic, investigators must carefully consider their ethical obligations in light of the facts and circumstances.ConclusionTo navigate through this dilemma, investigators should consider the evidence for the risks, the nature of the risks, the usefulness of risk information to the subjects, and the effects on the study and community of informing subjects about risks.
Immunotherapy for Prostate Cancer: Biology and Therapeutic Approaches
Authors: Edward Cha, Lawrence Fong
Journal: Journal of Clinical Oncology (2011)

Although prostate cancer was not historically considered to be a particularly immune-responsive cancer, recent clinical trials have demonstrated that immunotherapy for prostate cancer can lead to improvements in overall survival (OS). These studies include randomized controlled trials with sipuleucel-T and another with PROSTVAC-VF, both of which rely on stimulating the immune system to target prostate proteins. This review discusses the most promising developments over the past year in immune-based therapy for prostate cancer and the opportunities that lie ahead. Recent randomized immunotherapy trials in prostate cancer have demonstrated improvements in OS but without the concomitant improvements in progression-free survival. This uncoupling of survival from clinical response poses challenges to clinical management, because conventional measures of objective response cannot be used to identify patients benefiting from treatment. There is a significant need to identify immunologic or clinical surrogates for survival so that clinical benefit can be assessed in a timely manner. Immunotherapy is now an established treatment approach for prostate cancer, with multiple clinical trials demonstrating improvements in OS. Significant challenges to this modality remain, including determining best clinical setting for immunotherapy, identifying patients who benefit, and defining relevant clinical and immunologic end points. Nevertheless, the broader availability of novel immunotherapies will provide opportunities not only to target different components of the immune system but also to combine immunotherapies with other treatments for improved clinical efficacy.
Risk Factors for Traumatic and Bloody Lumbar Puncture in Children With Acute Lymphoblastic Leukemia
Authors: Scott C Howard, Amar J Gajjar, Cheng Cheng, Stephen B Kritchevsky, Grant W Somes, Patricia L Harrison, Raul C Ribeiro, Gaston K Rivera, Jeffrey E Rubnitz, John T Sandlund, Alberto J de Armendi, Bassem I Razzouk, Ching-Hon Pui
Journal: JAMA (2002)

ContextTraumatic or bloody lumbar puncture (LP) reduces the diagnostic value of the procedure and may worsen the outcome of patients with acute lymphoblastic leukemia (ALL). Little is known about the risk factors for traumatic and bloody LP.ObjectivesTo determine the risk factors for traumatic and bloody LP.Design, Setting, and PatientsRetrospective cohort study of 956 consecutive patients with newly diagnosed childhood ALL who were treated at a pediatric cancer center between February 1984 and July 1998.InterventionsAll patients underwent a diagnostic LP followed by a median of 4 LPs to instill intrathecal chemotherapy.Main Outcome MeasureTraumatic LP was defined as an LP in which cerebrospinal fluid contained at least 10 red blood cells (RBCs) per microliter and bloody LP as one in which the cerebrospinal fluid contained at least 500 RBCs per microliter.ResultsOf the 5609 LPs evaluated, 1643 (29%) were traumatic and 581 (10%) were bloody. The estimated odds ratios (ORs) and 95% confidence intervals (CIs) for traumatic LP were 1.5 (95% CI, 1.2-1.8) for black vs white race, 2.3 (95% CI, 1.7-3.0) for age younger than 1 year vs 1 year or older, 1.4 (95% CI, 1.2-1.7) for early vs recent (dedicated procedure area and general anesthesia) treatment era, 1.5 (95% CI, 1.2-1.8) for platelet count of 100 × 103/µL or more vs less than 100 × 103/µL, 10.8 (95% CI, 7.7-15.2) for short (1 day) vs longer (>15 days) interval since the previous LP, and 1.4 (95% CI, 1.1-1.8) for the least vs the most experienced practitioners. Analyses for bloody LP yielded similar results.ConclusionsThe unmodifiable risk factors for traumatic and bloody LP include black race, age younger than 1 year, a traumatic or bloody previous LP performed within the past 2 weeks, and a previous LP performed when the platelet count was 50 × 103/µL or less. Modifiable risk factors include procedural factors reflected in treatment era, platelet count of 100 × 103/µL or less, an interval of 15 days or less between LPs, and a less experienced practitioner.
Prognostic Value of Nutritional Status in Chronic Obstructive Pulmonary Disease
Authors: CHARLOTTE LANDBO, EVA PRESCOTT, PETER LANGE, JØRGEN VESTBO, THOMAS P. ALMDAL
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

The association between low body mass index (BMI) and poor prognosis in patients with chronic obstructive pulmonary disease (COPD) is a common clinical observation. We prospectively examined whether BMI is an independent predictor of mortality in subjects with COPD from the Copenhagen City Heart Study. In total, 1,218 men and 914 women, aged 21 to 89 yr, with airway obstruction defined as an FEV1-to-FVC ratio of less than 0.7, were included in the analyses. Spirometric values, BMI, smoking habits, and respiratory symptoms were assessed at the time of study enrollment, and mortality from COPD and from all causes during 17 yr of follow-up was analyzed with multivariate Cox regression models. After adjustment for age, ventilatory function, and smoking habits, low BMI was predictive of a poor prognosis (i.e., higher mortality), with relative risks (RRs) in underweight subjects as compared with that in subjects of normal weight of 1.64 (95% confidence interval [CI]: 1.20 to 2.23) in men and 1.42 (95% CI: 1.07 to 1.89) in women. However, the association between BMI and survival differed significantly with stage of COPD. In mild and moderate COPD there was a nonsignificant U-shaped relationship, with the lowest risk occurring in normal-weight to overweight subjects, whereas in severe COPD, mortality continued to decrease with increasing BMI (test for trend: p < 0.001). Similar results were found for COPD-related deaths, with the strongest associations found in severe COPD (RR for low versus high BMI: 7.11 [95% CI: 2.97 to 17.05]). We conclude that low BMI is an independent risk factor for mortality in subjects with COPD, and that the association is strongest in subjects with severe COPD. Landbo C, Prescott E, Lange P, Vestbo J, Almdal TP. Prognostic value of nutritional status in chronic obstructive pulmonary disease.
Response of the left ventricular end-systolic pressure-volume relation in conscious dogs to a wide range of contractile states.
Authors: W C Little, C P Cheng, T Peterson, J Vinten-Johansen
Journal: Circulation (1988)

We assessed the linearity and slope of the left ventricular end-systolic pressure (PES)-volume (VES) relation over a wide range of contractile states in conscious dogs. The animals were instrumented to determine left ventricular volume from ultrasonic left ventricular internal dimensions and measure left ventricular pressure with a micromanometer. Studies were performed 1-2 weeks after instrumentation while the animals were conscious. Contractile state was increased by incremental infusion of dobutamine (0, 2, 4, 6, and 8 micrograms/kg/min i.v.) and decreased by verapamil (10 mg i.v.) given after autonomic blockade. The 44 +/- 11 mm Hg (mean +/- SD) portion of the PES-VES relation generated by bicaval occlusion demonstrated a slight but consistent nonlinearity, apparent as a concavity toward the volume axis. This nonlinearity, present at all inotropic states, did not prevent the PES-VES relation from being well approximated by a straight line (r = 0.984 +/- 0.020, SEE = 2.1 +/- 1.4 mm Hg); furthermore, the slope of the PES-VES line provided a sensitive index of contractile state, progressively increasing with incremental doses of dobutamine and decreasing in response to verapamil. The volume-axis intercept of the linear approximation of the PES-VES relation was 2.9 +/- 3.3 ml less (p less than 0.05) than the volume-axis intercept of the nonlinear quadratic fit. Thus, the linear PES-VES relation, whose slope is sensitive to a wide variety of inotropic states, is a reasonable and useful description of the left ventricle in the range of PES-VES points that can be produced by bicaval occlusion in the conscious dog. However, linear extrapolation of the relation beyond the range of data points may not be accurate.
A Systematic Review of Adherence With Medications for Diabetes
Authors: Joyce A. Cramer
Journal: Diabetes Care (2004)

The purpose of this study was to determine the extent to which patients omit doses of medications prescribed for diabetes.A literature search (1966-2003) was performed to identify reports with quantitative data on adherence with oral hypoglycemic agents (OHAs) and insulin and correlations between adherence rates and glycemic control. Adequate documentation of adherence was found in 15 retrospective studies of OHA prescription refill rates, 5 prospective electronic monitoring OHA studies, and 3 retrospective insulin studies.Retrospective analyses showed that adherence to OHA therapy ranged from 36 to 93% in patients remaining on treatment for 6-24 months. Prospective electronic monitoring studies documented that patients took 67-85% of OHA doses as prescribed. Electronic monitoring identified poor compliers for interventions that improved adherence (61-79%; P < 0.05). Young patients filled prescriptions for one-third of prescribed insulin doses. Insulin adherence among patients with type 2 diabetes was 62-64%.This review confirms that many patients for whom diabetes medication was prescribed were poor compliers with treatment, including both OHAs and insulin. However, electronic monitoring systems were useful in improving adherence for individual patients. Similar electronic monitoring systems for insulin administration could help healthcare providers determine patients needing additional support.