tbuckley/cabot-search huggingface dataset:
TLX1 and NOTCH coregulate transcription in T cell acute lymphoblastic leukemia cells
Authors: Irene Riz, Teresa S Hawley, Truong V Luu, Norman H Lee, Robert G Hawley
Journal: Molecular Cancer (2010)

Abstract Background The homeobox gene TLX1 (for T-cell leukemia homeobox 1 , previously known as HOX11 ) is inappropriately expressed in a major subgroup of T cell acute lymphoblastic leukemia (T-ALL) where it is strongly associated with activating NOTCH1 mutations. Despite the recognition that these genetic lesions cooperate in leukemogenesis, there have been no mechanistic studies addressing how TLX1 and NOTCH1 functionally interact to promote the leukemic phenotype. Results Global gene expression profiling after downregulation of TLX1 and inhibition of the NOTCH pathway in ALL-SIL cells revealed that TLX1 synergistically regulated more than 60% of the NOTCH-responsive genes. Structure-function analysis demonstrated that TLX1 binding to Groucho-related TLE corepressors was necessary for maximal transcriptional regulation of the NOTCH-responsive genes tested, implicating TLX1 modulation of the NOTCH-TLE regulatory network. Comparison of the dataset to publicly available biological databases indicated that the TLX1/NOTCH-coregulated genes are frequently targeted by MYC. Gain- and loss-of-function experiments confirmed that MYC was an essential mediator of TLX1/NOTCH transcriptional output and growth promotion in ALL-SIL cells, with TLX1 contributing to the NOTCH-MYC regulatory axis by posttranscriptional enhancement of MYC protein levels. Functional classification of the TLX1/NOTCH-coregulated targets also showed enrichment for genes associated with other human cancers as well as those involved in developmental processes. In particular, we found that TLX1, NOTCH and MYC coregulate CD1B and RAG1 , characteristic markers of early cortical thymocytes, and that concerted downregulation of the TLX1 and NOTCH pathways resulted in their irreversible repression. Conclusions We found that TLX1 and NOTCH synergistically regulate transcription in T-ALL, at least in part via the sharing of a TLE corepressor and by augmenting expression of MYC. We conclude that the TLX1/NOTCH/MYC network is a central determinant promoting the growth and survival of TLX1 + T-ALL cells. In addition, the TLX1/NOTCH/MYC transcriptional network coregulates genes involved in T cell development, such as CD1 and RAG family members, and therefore may prescribe the early cortical stage of differentiation arrest characteristic of the TLX1 subgroup of T-ALL.
Tumor marker kinetics predict outcome in patients with relapsed disseminated non-seminomatous germ-cell tumors
Authors: C. Massard, A. Kramar, J. Beyer, J.T. Hartmann, A. Lorch, J.L. Pico, G. Rosti, J.P. Droz, K. Fizazi
Journal: Annals of Oncology (2012)
Myozenin 2 Is a Novel Gene for Human Hypertrophic Cardiomyopathy
Authors: Adriana Osio, Lily Tan, Suet N. Chen, Raffaella Lombardi, Sherif F. Nagueh, Sanjay Shete, Robert Roberts, James T. Willerson, Ali J. Marian
Journal: Circulation Research (2007)

Hypertrophic cardiomyopathy (HCM) is a genetic disorder caused by mutations in sarcomeric proteins (excluding phenocopy). The causal genes in approximately one-third of the cases remain unknown. We identified a family comprised of 6 clinically affected members. The phenotype was characterized by early onset of symptoms, pronounced cardiac hypertrophy, and cardiac arrhythmias. We excluded MYH7, MYBPC3, TNNT2, and ACTC1 as the causal gene either by direct sequencing or by haplotype analysis. To map the putative candidate sarcomeric gene, we perforbold locus-specific haplotyping to detect cosegregation of the locus haplotype with the phenotype, followed by mutation screening. We genotyped 5 short-tandem-repeat markers that spanned a 4.4-centimorgan region on 4q26-q27 locus and encompassed myozenin 2 (MYOZ2), a Z-disk protein. The maximum logarithm of odds score was 2.03 (P=0.005). All affected members shared a common haplotype, implicating MYOZ2 as the causal gene. To detect the causal mutation, we sequenced all exons and exon-intron boundaries of MYOZ2 in 10 family members and identified a T-->C missense mutation corresponding to S48P substitution, which cosegregated with inheritance of HCM (N=6). It was absent in 4 clinically normal family members and in 658 additional normal individuals. To determine frequency of the MYOZ2 mutations in HCM, we sequenced MYOZ2 in 516 HCM probands and detected another missense mutation (I246M). It was absent in 2 normal family members and 517 controls. Both mutations affect highly conserved amino acids. We conclude MYOZ2 is a novel causal gene for human HCM.
Sustained Reverse Left Ventricular Structural Remodeling With Cardiac Resynchronization at One Year Is a Function of Etiology
Authors: Martin G. St John Sutton, Ted Plappert, Kathryn E. Hilpisch, William T. Abraham, David L. Hayes, Edward Chinchoy
Journal: Circulation (2006)

Background— Cardiac resynchronization therapy (CRT) is an effective therapy for patients with moderate to severe heart failure and prolonged QRS duration. The purpose of this study was to determine whether reverse left ventricular (LV) remodeling and symptomatic benefit from CRT were sustained at 12 months, and if so, in what proportion of patients this occurred. Methods and Results— Serial Doppler echocardiograms were obtained at baseline and 6 and 12 months after CRT in 228 patients enrolled in the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) trial. Measurements were made of LV end-diastolic (EDV) and end-systolic (ESV) volumes, ejection fraction, LV mass, severity of mitral regurgitation (MR), peak transmitral velocities during early (E wave) and late (A wave) diastolic filling, and myocardial performance index. At both 6 and 12 months, respectively, CRT was associated with reduced LV EDV ( P &lt;0.0001 and P =0.007) and LV ESV ( P &lt;0.0001 and P &lt;0.0001), improved ejection fraction ( P &lt;0.0001 and P &lt;0.0001), regression of LV mass ( P =0.012 and P &lt;0.0001), and reduced MR ( P &lt;0.0001 and P &lt;0.0001). LV filling time, transmitral E/A ratio, and myocardial performance index all improved at 12 months compared with baseline ( P &lt;0.001, P =0.031, and P &lt;0.0001). Reverse LV remodeling with CRT occurred in more patients at 6 than at 12 months (74% versus 60%, respectively; P &lt;0.05) and was greater in patients with a nonischemic than an ischemic etiology. Conclusions— Reverse LV remodeling and symptom benefit with CRT are sustained at 12 months in patients with New York Heart Association class III/IV heart failure but occur to a lesser degree in patients with an ischemic versus a nonischemic etiology, most likely owing to the inexorable progression of ischemic disease.
Eosinophilic Esophagitis: Rapidly Advancing Insights
Authors: J. Pablo Abonia, Marc E. Rothenberg
Journal: Annual Review of Medicine (2011)

Eosinophilic esophagitis (EoE) now represents a commonly recognized disorder among both pediatric and adult patients presenting to allergy and gastroenterology clinics throughout the world. The consequences of this localized and eosinophil-predominant inflammation of the esophagus can have an outsized and profound systemic and emotional impact for patients and their families. Unlike gastroesophageal reflux disease (GERD), whose symptoms closely overlap with those of EoE, EoE represents a primarily antigen-driven disorder whose symptoms and pathology are therapeutically mitigated with either long-term dietary control or chronic steroid therapies, rather than the acid-suppressive medications that are the mainstay of GERD treatment. Beyond the dissimilarities in their responses to treatment, these disorders are distinct in their gene expression profiles, heredity, genetic underpinning, and linkage with atopy. The antigen-driven nature of EoE has been reinforced by the remarkable impact of therapies utilizing elemental formulas to control the disease as well as a number of reports linking aeroallergens to seasonal worsening of disease.
Antimicrobial Prophylaxis and Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology Clinical Practice Guideline
Authors: Christopher R. Flowers, Jerome Seidenfeld, Eric J. Bow, Clare Karten, Charise Gleason, Douglas K. Hawley, Nicole M. Kuderer, Amelia A. Langston, Kieren A. Marr, Kenneth V.I. Rolston, Scott D. Ramsey
Journal: Journal of Clinical Oncology (2013)

To provide guidelines on antimicrobial prophylaxis for adult neutropenic oncology outpatients and on selection and treatment as outpatients of those with fever and neutropenia.A literature search identified relevant studies published in English. Primary outcomes included: development of fever and/or infections in afebrile neutropenic outpatients and recovery without complications and overall mortality in febrile neutropenic outpatients. Secondary outcomes included: in afebrile neutropenic outpatients, infection-related mortality; in outpatients with fever and neutropenia, defervescence without regimen change, time to defervescence, infectious complications, and recurrent fever; and in both groups, hospital admissions, duration, and adverse effects of antimicrobials. An Expert Panel developed guidelines based on extracted data and informal consensus.Forty-seven articles from 43 studies met selection criteria.Antibacterial and antifungal prophylaxis are only recommended for patients expected to have < 100 neutrophils/μL for > 7 days, unless other factors increase risks for complications or mortality to similar levels. Inpatient treatment is standard to manage febrile neutropenic episodes, although carefully selected patients may be managed as outpatients after systematic assessment beginning with a validated risk index (eg, Multinational Association for Supportive Care in Cancer [MASCC] score or Talcott's rules). Patients with MASCC scores ≥ 21 or in Talcott group 4, and without other risk factors, can be managed safely as outpatients. Febrile neutropenic patients should receive initial doses of empirical antibacterial therapy within an hour of triage and should either be monitored for at least 4 hours to determine suitability for outpatient management or be admitted to the hospital. An oral fluoroquinolone plus amoxicillin/clavulanate (or plus clindamycin if penicillin allergic) is recommended as empiric therapy, unless fluoroquinolone prophylaxis was used before fever developed.
A Comparison of PAM50 Intrinsic Subtyping with Immunohistochemistry and Clinical Prognostic Factors in Tamoxifen-Treated Estrogen Receptor–Positive Breast Cancer
Authors: Torsten O. Nielsen, Joel S. Parker, Samuel Leung, David Voduc, Mark Ebbert, Tammi Vickery, Sherri R. Davies, Jacqueline Snider, Inge J. Stijleman, Jerry Reed, Maggie C.U. Cheang, Elaine R. Mardis, Charles M. Perou, Philip S. Bernard, Matthew J. Ellis
Journal: Clinical Cancer Research (2010)

Abstract Purpose: To compare clinical, immunohistochemical (IHC), and gene expression models of prognosis applicable to formalin-fixed, paraffin-embedded blocks in a large series of estrogen receptor (ER)–positive breast cancers from patients uniformly treated with adjuvant tamoxifen. Experimental Design: Quantitative real-time reverse transcription-PCR (qRT-PCR) assays for 50 genes identifying intrinsic breast cancer subtypes were completed on 786 specimens linked to clinical (median follow-up, 11.7 years) and IHC [ER, progesterone receptor (PR), HER2, and Ki67] data. Performance of predefined intrinsic subtype and risk-of-relapse scores was assessed using multivariable Cox models and Kaplan-Meier analysis. Harrell's C-index was used to compare fixed models trained in independent data sets, including proliferation signatures. Results: Despite clinical ER positivity, 10% of cases were assigned to nonluminal subtypes. qRT-PCR signatures for proliferation genes gave more prognostic information than clinical assays for hormone receptors or Ki67. In Cox models incorporating standard prognostic variables, hazard ratios for breast cancer disease-specific survival over the first 5 years of follow-up, relative to the most common luminal A subtype, are 1.99 [95% confidence interval (CI), 1.09-3.64] for luminal B, 3.65 (95% CI, 1.64-8.16) for HER2-enriched subtype, and 17.71 (95% CI, 1.71-183.33) for the basal-like subtype. For node-negative disease, PAM50 qRT-PCR–based risk assignment weighted for tumor size and proliferation identifies a group with &amp;gt;95% 10-year survival without chemotherapy. In node-positive disease, PAM50-based prognostic models were also superior. Conclusion: The PAM50 gene expression test for intrinsic biological subtype can be applied to large series of formalin-fixed, paraffin-embedded breast cancers, and gives more prognostic information than clinical factors and IHC using standard cut points. Clin Cancer Res; 16(21); 5222–32. ©2010 AACR.
Aberrant Transcription from an Unrelated Promoter Can Result in <i>MDR-1</i> Expression following Drug Selection <i>In vitro</i> and in Relapsed Lymphoma Samples
Authors: Lyn Mickley Huff, Zheng Wang, Angel Iglesias, Tito Fojo, Jong-Seok Lee
Journal: Cancer Research (2005)

Abstract The development of drug resistance in the treatment of cancer remains a major problem. The hallmark of multidrug resistance is cross-resistance to multiple structurally unrelated compounds. The MDR-1 gene encoding P-glycoprotein mediates one of the most extensively studied mechanisms of drug resistance. Previous studies led to the proposal that two promoters control expression of the MDR-1 gene, and these were designated the upstream and downstream promoters. In the present article, we provide evidence that transcripts originating from the putative upstream promoter of MDR-1 are in fact aberrant transcripts whose expression is regulated by nearby genomic sequences that include a human endogenous retroviral long terminal repeat (LTR). Expression of this LTR occurs in all cells. We show that following drug selection, especially in cases where gene amplification has occurred, MDR-1 transcripts can begin near this retroviral LTR with transcription proceeding in the direction opposite of the usual LTR transcription. Because expression of these aberrant MDR-1 transcripts (AMT) is found primarily in drug-resistant cell lines, we conclude that the development of drug resistance or the attendant drug exposure might have a role in the activation of this phenomenon or the selection of cells expressing AMTs. Demonstration of similar aberrant transcripts in tumor samples obtained from patients with relapsed lymphoma suggests that this phenomenon may also occur clinically. (Cancer Res 2005; 65(24): 11694-703)
Abnormalities of Dorsolateral Prefrontal Function in Women With Premenstrual Dysphoric Disorder: A Multimodal Neuroimaging Study
Authors: Erica B. Baller, Shau-Ming Wei, Philip D. Kohn, David R. Rubinow, Gabriela Alarcón, Peter J. Schmidt, Karen F. Berman
Journal: American Journal of Psychiatry (2013)

To investigate the neural substrate of premenstrual dysphoric disorder (PMDD), the authors used [15O]H2O positron emission tomography (PET) regional cerebral blood flow (rCBF) and blood-oxygen-level-dependent (BOLD) functional MRI (fMRI) signal measurements during working memory in conjunction with a 6-month hormone manipulation protocol.PET and fMRI scans were obtained from women with prospectively confirmed PMDD and asymptomatic comparison subjects while they completed the n-back task during three hormone conditions: ovarian suppression induced by the gonadotropin-releasing hormone agonist leuprolide acetate, leuprolide plus estradiol, and leuprolide plus progesterone. Fifteen patients and 15 matched comparison subjects underwent PET imaging. Fourteen patients and 14 comparison subjects underwent fMRI. For each hormone condition, rCBF was measured with [15O]H2O PET, and BOLD signal was measured with fMRI, both during an n-back working memory paradigm. Global Assessment of Functioning Scale (GAF) scores and clinical characteristics were obtained for each patient before hormone manipulation, and symptoms were measured before and during the protocol.In both the PET and fMRI studies, a main effect of diagnosis was observed, with PMDD patients showing greater prefrontal activation than comparison subjects. In the patient group, the degree to which dorsolateral prefrontal cortex activation was abnormally increased correlated with several dimensions of disease: disability as indicated by GAF scores, age at symptom onset, duration of PMDD, and differences in pre- and postmenses PMDD symptoms.Abnormal working memory activation in PMDD, specifically in the dorsolateral prefrontal cortex, is related to PMDD severity, symptoms, age at onset, and disease burden. These results support the clinical relevance of the findings and the proposal that dorsolateral prefrontal cortex dysfunction represents a substrate of risk for PMDD. The concordance of the fMRI and PET data attests to the neurobiological validity of the results.
The Cost of Maternity Care in Rural Hospitals
Authors: Herman A. Hein
Journal: JAMA (1978)

FEDERAL health planners, in the first draft of proposed national guidelines for health planning, observed: Facilities not located in SMSAs [Standard Metropolitan Service Areas] of over 100,000 population should provide at least 500 deliveries annually.... Below 500 deliveries, the quality of care and efficiency are decreased significantly.<sup>1</sup> This opinion should be critically examined because it is likely to influence the availability of health care, especially in rural areas. Iowa, for example, with a population of 2.8 million people, has 129 hospitals that provide maternity care; of these, 105 (81%) had fewer than 500 deliveries in 1977. <h3>Methods</h3> A questionnaire designed by us was sent to administrators of Iowa hospitals with maternity services. Figure 1 shows the items assessed on the questionnaire. One hundred twenty-eight questionnaires were sent (the tertiary center at the University of Iowa was not included), and 103 responses were obtained (80% ). Four of the hospitals responded
New concepts for expressing forced expiratory volume in 1 s arising from survival analysis
Authors: M. R. Miller, O. F. Pedersen
Journal: European Respiratory Journal (2009)

Spirometric lung function is partly determined by sex, age and height (Ht). Commonly, lung function is expressed as a percentage of the predicted value (PP) in order to account for these effects. Since the PP method retains sex, age and Ht bias, forced expiratory volume in 1 s (FEV(1)) standardised by powers of Ht and by a new sex-specific lower limit (FEV(1) quotient (FEV(1)Q)) were investigated to determine which method best predicted all-cause mortality in >26,967 patients and normal subjects. On multivariate analysis, FEV(1)Q was the best predictor, with a hazard ratio for the worst decile of 6.9 compared to 4.1 for FEV(1)PP. On univariate analysis, the hazard ratios were 18.8 compared to 6.1, respectively; FEV(1) x Ht(-3) was the next-best predictor of survival. Median survival was calculated for simple cut-off values of FEV(1)Q and FEV(1) x Ht(-3). These survival curves were accurately fitted (r(2) = 1.0) by both FEV(1)Q and FEV(1) x Ht(-3) values expressed polynomially, and so an individual's test result could be used to estimate survival (with sd for median survival of 0.22 and 0.61 yrs, respectively). It is concluded that lung function impairment should be expressed in a new way, here termed the FEV(1)Q, or, alternatively, as FEV(1) x Ht(-3), since these indices best relate spirometric lung function to all-cause mortality and survival.
A phase II trial of short course fludarabine, mitoxantrone, rituximab followed by 90Y-ibritumomab tiuxetan in untreated intermediate/high-risk follicular lymphoma
Authors: P.L. Zinzani, M. Tani, A. Pulsoni, A. De Renzo, V. Stefoni, A. Broccoli, G.C. Montini, M. Fina, C. Pellegrini, L. Gandolfi, E. Cavalieri, F. Torelli, F. Scopinaro, L. Argnani, F. Quirini, E. Derenzini, M. Rossi, S. Pileri, S. Fanti, M. Baccarani
Journal: Annals of Oncology (2011)
Treatment of Duchenne muscular dystrophy with ciclosporin A: a randomised, double-blind, placebo-controlled multicentre trial
Authors: Janbernd Kirschner, Joachim Schessl, Ulrike Schara, Bernd Reitter, Georg M Stettner, Elke Hobbiebrunken, Ekkehard Wilichowski, Günther Bernert, Simone Weiss, Florian Stehling, Gert Wiegand, Wolfgang Müller-Felber, Simone Thiele, Ulrike Grieben, Maja von der Hagen, Jürg Lütschg, Claudia Schmoor, Gabriele Ihorst, Rudolf Korinthenberg
Journal: The Lancet Neurology (2010)
Dynamic hyperinflation and tolerance to interval exercise in patients with advanced COPD
Authors: I. Vogiatzis, S. Nanas, E. Kastanakis, O. Georgiadou, O. Papazahou, Ch. Roussos
Journal: European Respiratory Journal (2004)

Dynamic hyperinflation (DH) contributes importantly to the limitation of constant-load exercise (CLE) in patients with chronic obstructive pulmonary disease (COPD). However, its role in the limitation of interval exercise (IE) remains to be explored. The change (Delta) in inspiratory capacity (IC) was measured to reflect changes in DH in 27 COPD patients (forced expiratory volume in one second mean+/-SEM % predicted: 40+/-3) at the end of a symptom-limited CLE test at 80% of peak work capacity (WRmax) and an IE test at 100% WRmax (30 s of work, alternated with 30 s of unloaded pedalling). At the limit of tolerance in both IE and CLE, patients exhibited similar DH (DeltaIC: 0.39+/-0.05 L and 0.45+/-0.05 L, respectively). However, exercise endurance time (t end) for IE (32.7+/-3.0 min) was significantly greater than for CLE (10.3+/-1.6 min). The IE t end correlated with resting IC, expressed as % pred normal. At 30 and 90% of total IE t end, DeltaIC (0.43+/-0.06 and 0.39+/-0.05 L, respectively) and minute ventilation (31.1+/-1.6 and 32.7+/-2.2 L.min(-1), respectively) were not significantly different. Resting hyperinflation helps to explain the limitation of interval exercise. Implementation of interval exercise for rehabilitation should provide important clinical benefits because it prolongs exercise endurance time and allows sustaining higher stable ventilation.
A Study of Alcoholism in Half Siblings
Authors: MARC A. SCHUCKIT, DONALD A. GOODWIN, GEORGE WINOKUR
Journal: American Journal of Psychiatry (1972)

The authors studied the incidence of alcoholism in children who had an alcoholic biologic parent but who were raised by nonalcoholic parent figures and in children who did not have an alcoholic biologic parent and who were raised by alcoholic parent figures. Similarly, children with and without alcoholic biologic parents who shared their childhood homes with alcoholic probands were compared. For each comparison of genetic and environmental factors, the genetic factor seemed to he more closely associated with the development of alcoholism.
Evaluation of Safety, Tolerability and Activity of Temsirolimus in Patients (Pts) with Advanced or Metastatic Renal Cell Carcinoma (A/Mrcc) in Routine Clinical Practice
Authors: M. Woike, L. Bergmann, T. Steiner, P.J. Goebell, T. Göhler, H. Harich, E. Herrmann, U. Rebmann, D. Kalanovic
Journal: Annals of Oncology (2014)