tbuckley/cabot-search huggingface dataset:
Computational identification of the normal and perturbed genetic networks involved in myeloid differentiation and acute promyelocytic leukemia
Authors: Li Wei Chang, Jacqueline E Payton, Wenlin Yuan, Timothy J Ley, Rakesh Nagarajan, Gary D Stormo
Journal: Genome biology (2008)

Acute myeloid leukemia (AML) comprises a group of diseases characterized by the abnormal development of malignant myeloid cells. Recent studies have demonstrated an important role for aberrant transcriptional regulation in AML pathophysiology. Although several transcription factors (TFs) involved in myeloid development and leukemia have been studied extensively and independently, how these TFs coordinate with others and how their dysregulation perturbs the genetic circuitry underlying myeloid differentiation is not yet known. We propose an integrated approach for mammalian genetic network construction by combining the analysis of gene expression profiling data and the identification of TF binding sites. We utilized our approach to construct the genetic circuitries operating in normal myeloid differentiation versus acute promyelocytic leukemia (APL), a subtype of AML. In the normal and disease networks, we found that multiple transcriptional regulatory cascades converge on the TFs Rora and Rxra, respectively. Furthermore, the TFs dysregulated in APL participate in a common regulatory pathway and may perturb the normal network through Fos. Finally, a model of APL pathogenesis is proposed in which the chimeric TF PML-RARα activates the dysregulation in APL through six mediator TFs. This report demonstrates the utility of our approach to construct mammalian genetic networks, and to obtain new insights regarding regulatory circuitries operating in complex diseases in humans.
Reference intervals of spinal mobility measures in normal individuals: the mobility study
Authors: Sofia Ramiro, Astrid van Tubergen, Carmen Stolwijk, Désirée van der Heijde, Patrick Royston, Robert Landewé
Journal: Annals of the Rheumatic Diseases (2014)

Objectives To establish reference intervals (RIs) for spinal mobility measures as recommended for patients with axial spondyloarthritis, and to determine the effect of age, height and gender on spinal mobility, in normal individuals. Methods A cross-sectional study (MOBILITY) was conducted among normal individuals aged 20–69 years. Recruitment was stratified by gender, age (10-year categories) and height (10 cm categories). Eleven spinal mobility measures were assessed. Age specific RIs and percentiles were derived for each measure. Results 393 volunteers were included. All spinal mobility measures decreased with increasing age. Therefore, age specific RIs were developed. The 95% RIs (2.5th and 97.5th percentiles), as well as the 5th, 10th, 25th, 50th, 75th and 90th percentiles for each spinal mobility measure and different ages are presented. Mobility percentile curves were also plotted for each of the measures. For instance, the 95% RI for lateral spinal flexion was 16.2–28.0 cm for a 25-year-old subject, 13.2–25.0 cm for a 45-year-old subject and 10.1–21.9 cm for a 65-year-old subject. After adjustment for age, there was no need for gender specific RIs, while RIs of some measures are height-adjusted. Conclusions Age specific RIs and percentiles were derived for each of the spinal mobility measures for normal individuals. These may guide clinicians when assessing the mobility of patients with axial spondyloarthritis. The RIs may serve as cut-off levels for ‘normal’ versus ‘abnormal’, whereas the mobility percentile curves may be used to assess the level of mobility of patients with axial spondyloarthritis.
Non-A, Non-B Hepatitis: A Prospective Study of a Hemodialysis Outbreak with Evaluation of a Serologic Marker in Patients and Staff
Authors: Gary Gitnick, Steven Weiss, Lacy R. Overby, Chung-Mei Ling, Ruben Chairez, Khosrow Parsa
Journal: Hepatology (1983)

An outbreak of non-A, non-B hepatitis (NANBH) in a hemodialysis unit was prospectively studied and the clinical, biochemical, and serologic events were correlated with an experimental immunodiffusion assay for serum antigen and antibody. One hundred sixteen subjects (76 dialysis patients and 40 staff members) were studied over an 8-month period. Hepatitis was defined as two consecutive SGPT levels greater than two times the upper limit of normal occurring in two separate samples drawn greater than 7 days apart in the absence of other likely causes of liver disease. Weekly serum specimens were obtained and tested for SGPT, SGOT, alkaline phosphatase, bilirubin HBsAg, anti-HBc, anti-HBs, total anti-HAV, and anti-HAV IgM by commercial reagents, and for antigen and antibody by agar gel diffusion using reference reagents previously obtained from well-documented posttransfusion NANBH patients. Clinical evaluations were performed three times per week. Thirty patients and none of the staff developed NANBH. The NANBH patients were asymptomatic, except for two patients with jaundice. Fifteen of the 30 patients were positive for antigen which was detectable in at least one serum collected during the acute phase. Six patients and 10 staff without clinical NANBH or abnormal serology had antigen. Antigenemia was also observed in three patients with acute hepatitis B, with chronic hepatitis B in one patient and with alcoholic hepatitis in one patient. Thus, an antigen was detected in a high proportion of patients during the acute phase of NANBH, and it was also found in exposed patients who had other liver diseases.(ABSTRACT TRUNCATED AT 250 WORDS)
Features of effective computerised clinical decision support systems: meta-regression of 162 randomised trials
Authors: P. S. Roshanov, N. Fernandes, J. M. Wilczynski, B. J. Hemens, J. J. You, S. M. Handler, R. Nieuwlaat, N. M. Souza, J. Beyene, H. G. C. V. Spall, A. X. Garg, R. B. Haynes
Journal: BMJ (2013)

<b>Objectives</b> To identify factors that differentiate between effective and ineffective computerised clinical decision support systems in terms of improvements in the process of care or in patient outcomes. <b>Design</b> Meta-regression analysis of randomised controlled trials. <b>Data sources</b> A database of features and effects of these support systems derived from 162 randomised controlled trials identified in a recent systematic review. Trialists were contacted to confirm the accuracy of data and to help prioritise features for testing. <b>Main outcome measures</b> "Effective" systems were defined as those systems that improved primary (or 50% of secondary) reported outcomes of process of care or patient health. Simple and multiple logistic regression models were used to test characteristics for association with system effectiveness with several sensitivity analyses. <b>Results</b> Systems that presented advice in electronic charting or order entry system interfaces were less likely to be effective (odds ratio 0.37, 95% confidence interval 0.17 to 0.80). Systems more likely to succeed provided advice for patients in addition to practitioners (2.77, 1.07 to 7.17), required practitioners to supply a reason for over-riding advice (11.23, 1.98 to 63.72), or were evaluated by their developers (4.35, 1.66 to 11.44). These findings were robust across different statistical methods, in internal validation, and after adjustment for other potentially important factors. <b>Conclusions</b> We identified several factors that could partially explain why some systems succeed and others fail. Presenting decision support within electronic charting or order entry systems are associated with failure compared with other ways of delivering advice. Odds of success were greater for systems that required practitioners to provide reasons when over-riding advice than for systems that did not. Odds of success were also better for systems that provided advice concurrently to patients and practitioners. Finally, most systems were evaluated by their own developers and such evaluations were more likely to show benefit than those conducted by a third party.
Targeted Tumor-Penetrating siRNA Nanocomplexes for Credentialing the Ovarian Cancer Oncogene <i>ID4</i>
Authors: Yin Ren, Hiu Wing Cheung, Geoffrey von Maltzhan, Amit Agrawal, Glenn S. Cowley, Barbara A. Weir, Jesse S. Boehm, Pablo Tamayo, Alison M. Karst, Joyce F. Liu, Michelle S. Hirsch, Jill P. Mesirov, Ronny Drapkin, David E. Root, Justin Lo, Valentina Fogal, Erkki Ruoslahti, William C. Hahn, Sangeeta N. Bhatia
Journal: Science Translational Medicine (2012)

Tumor-penetrating siRNA nanocomplexes credential ID4 as a therapeutic oncogene target in human ovarian cancer.
Sortase as a Target of Anti-Infective Therapy
Authors: Anthony W. Maresso, Olaf Schneewind
Journal: Pharmacological Reviews (2008)

The rise in antibiotic-resistant bacteria is a major concern, in particular because it includes many different species of pathogenic microbes. These "superbugs" are further characterized by high levels of virulence and disease-associated mortality. There seems to be few new antibiotics in the drug discovery pipeline; recent work has sought to define and validate new drug targets. The assembly of surface proteins and pili in the cell wall envelope of Gram-positive bacteria is catalyzed by sortase. Sortase cleaves a conserved C-terminal sequence of these polypeptides to generate an acyl-enzyme intermediate. The acyl-enzyme is next resolved by nucleophilic attack by the amino groups within cell wall cross-bridges or pilin proteins, thereby covalently attaching the polypeptides to the cell wall or the next pilin subunit. Sortase substrates function as adhesins, internalins, blood clotting and immune evasion factors, and transporters for nutrients across the microbial cell wall envelope; without them, most pathogens cannot sustain an infection. Here we review what is known about sortase catalysis and surface protein function, how surface protein anchoring can be inhibited, and what prospects such inhibition may have for anti-infective therapy.
A Randomized Trial of Prolonged Co-trimoxazole in HIV-Infected Children in Africa
Authors: Mutsawashe Bwakura-Dangarembizi, Lindsay Kendall, Sabrina Bakeera-Kitaka, Patricia Nahirya-Ntege, Rosette Keishanyu, Kusum Nathoo, Moira J. Spyer, Adeodata Kekitiinwa, Joseph Lutaakome, Tawanda Mhute, Philip Kasirye, Paula Munderi, Victor Musiime, Diana M. Gibb, A. Sarah Walker, Andrew J. Prendergast
Journal: New England Journal of Medicine (2014)

Co-trimoxazole (fixed-dose trimethoprim-sulfamethoxazole) prophylaxis administered before antiretroviral therapy (ART) reduces morbidity in children infected with the human immunodeficiency virus (HIV). We investigated whether children and adolescents receiving long-term ART in sub-Saharan Africa could discontinue co-trimoxazole.We conducted a randomized, noninferiority trial of stopping versus continuing daily open-label co-trimoxazole in children and adolescents in Uganda and Zimbabwe. Eligible participants were older than 3 years of age, had been receiving ART for more than 96 weeks, were using insecticide-treated bed nets (in malaria-endemic areas), and had not had Pneumocystis jirovecii pneumonia. Coprimary end points were hospitalization or death and adverse events of grade 3 or 4.A total of 758 participants were randomly assigned to stop or continue co-trimoxazole (382 and 376 participants, respectively), after receiving ART for a median of 2.1 years (interquartile range, 1.8 to 2.3). The median age was 7.9 years (interquartile range, 4.6 to 11.1), and the median CD4 T-cell percentage was 33% (interquartile range, 26 to 39). Participants who stopped co-trimoxazole had higher rates of hospitalization or death than those who continued (72 participants [19%] vs. 48 [13%]; hazard ratio, 1.64; 95% confidence interval [CI], 1.14 to 2.37; P = 0.007; noninferiority not shown). There was no evidence of variation across ages (P=0.93 for interaction). A total of 2 participants in the prophylaxis-stopped group (1%) died, as did 3 in the prophylaxis-continued group (1%). Most hospitalizations in the prophylaxis-stopped group were for malaria (49 events, vs. 21 in the prophylaxis-continued group) or infections other than malaria (53 vs. 25), particularly pneumonia, sepsis, and meningitis. Rates of adverse events of grade 3 or 4 were similar in the two groups (hazard ratio, 1.20; 95% CI, 0.83 to 1.72; P=0.33), but more grade 4 adverse events occurred in the prophylaxis-stopped group (hazard ratio, 2.04; 95% CI, 0.99 to 4.22; P=0.05), with anemia accounting for the largest number of events (12, vs. 2 with continued prophylaxis).Continuing co-trimoxazole prophylaxis after 96 weeks of ART was beneficial, as compared with stopping prophylaxis, with fewer hospitalizations for both malaria and infection not related to malaria. (Funded by the United Kingdom Medical Research Council and others; ARROW Current Controlled Trials number, ISRCTN24791884.).
Medicaid Managed Care and the Distribution of Societal Costs for Persons With Severe Mental Illness
Authors: David L Shern, Kristine Jones, Huey Jen Chen, Neil Jordan, Josefa Ramoni-Perazzi, Roger A Boothroyd
Journal: American Journal of Psychiatry (2008)

Managed care financing strategies that involve financial risk to insurers can reduce budgeted health expenditures. However, resource substitution may occur and negate apparent savings in budgeted expenditures. These substitutions may be important for individuals with disabling illnesses. The distribution of societal costs for adults with mental illnesses enrolled in plans that differ in their financial risk is examined to evaluate the degree to which risk-based financing strategies result in net savings or in the differential distribution of costs across public or private payers.Six hundred twenty-eight adults with severe mental illnesses enrolled in three Medicaid plans that differ in financial risk arrangements were followed for 1 year to determine the distribution of resource use across Medicaid and other payers. Self-reported service use was obtained through interviews. Cost data were derived from self-reported expenditure, administrative, or agency data. Statistical procedures were used to control for preexisting group differences.Managed care was associated with a tendency toward reduced overall costs to Medicaid. However, private expenditures for managed care enrollees offset decreased Medicaid expenditures, resulting in no net difference in societal costs associated with managed care.Understanding the distribution of societal costs is essential in evaluating health care financing strategies. For adults with mental illnesses, efforts to manage Medicaid expenditures may result in substituting individual and family resources for Medicaid services. Government must focus on the distribution of societal costs since risk-based financing strategies may redistribute costs across the fragmented human services sector and result in unintended system inefficiencies.
Relationship between depression and exacerbations in COPD
Authors: J. K. Quint, R. Baghai-Ravary, G. C. Donaldson, J. A. Wedzicha
Journal: European Respiratory Journal (2008)

Chronic obstructive pulmonary disease is associated with exacerbations. Some patients are prone to frequent exacerbations and these individuals have a worse quality of life, greater limitation of their daily activity and faster disease progression than patients with less frequent exacerbations. A prospective study in a well-characterised cohort was performed and it was assessed whether depression, as determined by the Centre for Epidemiologic Studies Depression Scale, was related to exacerbation frequency, systemic inflammation and various social factors. The associations of any increase in depressive symptoms at exacerbation were also investigated. Frequent exacerbators had a significantly higher median (interquartile range) baseline depression score than infrequent exacerbators (17.0 (7.0–25.0) and 12.0 (6.0–18.0), respectively). Depressed patients spend significantly less time outdoors and had significantly worse quality of life as measured by the St George's Respiratory Questionnaire. Depression increased significantly in patients from baseline to exacerbation (12.5 (5.0–19.0) and 19.5 (12.0–28.0) respectively). The present study is the first to show a relationship between depression and exacerbation frequency in patients with chronic obstructive pulmonary disease. The finding that frequent exacerbators are more depressed than infrequent exacerbators is relevant, as exacerbation frequency is an important outcome measure in chronic obstructive pulmonary disease.
Multi-level sensorimotor interactions
Authors: Stefan Vogt, Heiko Hecht
Journal: Behavioral and Brain Sciences (2001)

We share the authors' general approach to the study of perception and action, but rather than singling out a particular level of “late perceptual” and “early motor” processing for sensorimotor interactions, we argue that these can arise at multiple levels during action preparation and execution. Recent data on action-perception transfer are used to illustrate this perspective.
3D‐Printed Atsttrin‐Incorporated Alginate/Hydroxyapatite Scaffold Promotes Bone Defect Regeneration with TNF/TNFR Signaling Involvement
Authors: Quan Wang, Qingqing Xia, Yan Wu, Xiaolei Zhang, Feiqiu Wen, Xiaowen Chen, Shufang Zhang, Boon Chin Heng, Yong He, Hong‐Wei Ouyang
Journal: Advanced Healthcare Materials (2015)

High expression levels of pro‐inflammatory tumor necrosis factor (TNF)‐α within bone defects can decelerate and impair bone regeneration. However, there are few available bone scaffolds with anti‐inflammatory function. The progranulin (PGRN)‐derived engineered protein, Atsttrin, is known to exert antagonistic effects on the TNF‐α function. Hence, this study investigates whether 3D‐printed Atsttrin‐incorporated alginate(Alg)/hydroxyapatite(nHAp) scaffolds can facilitate bone healing through affecting the TNF/TNFR signaling. A 3D bioprinting system is used to fabricate Atsttrin‐Alg/nHAp composite scaffolds, and the Atsttrin release from this scaffold is characterized, followed by evaluation of its efficacy on bone regeneration both in vitro and in vivo. The 3D‐printed Atsttrin‐Alg/nHAp scaffold exhibits a precisely defined structure, can sustain Atsttrin release for at least 5 days, has negligible cytotoxicity, and supports cell adhesion. Atsttrin can also attenuate the suppressive effects of TNF‐α on BMP‐2‐induced osteoblastic differentiation in vitro. The 3D‐printed Atsttrin‐Alg/nHAp scaffold significantly reduces the number of TNF‐α positive cells within wound sites, 7 days after post‐calvarial defect surgery. Additionally, histological staining and X‐ray scanning results also show that the 3D‐printed Atsttrin‐Alg/nHAp scaffold enhances the regeneration of mice calvarial bone defects. These findings thus demonstrate that the precise structure and anti‐inflammatory properties of 3D‐printed Atsttrin‐Alg/nHAp scaffolds may promote bone defect repair.
A study of familial lupus erythematosus-likes disease and hereditary angio-oedema treated with danazol
Authors: P. YOUINOU, J.C. DORVAL, J. CLEDES, J.P. LEROY, P. MIOSSEC, R. MASSE
Journal: British Journal of Dermatology (1983)

Journal Article A study of familial lupus erythematosus‐likes disease and hereditary angio‐oedema treated with danazol Get access P. YOUINOU, P. YOUINOU University Hospital Medical School, Brest, France Dr P. Youinou, 34 Chepstow Villas, London Wii. Search for other works by this author on: Oxford Academic Google Scholar J.C. DORVAL, J.C. DORVAL University Hospital Medical School, Brest, France Search for other works by this author on: Oxford Academic Google Scholar J. CLEDES, J. CLEDES University Hospital Medical School, Brest, France Search for other works by this author on: Oxford Academic Google Scholar J.P. LEROY, J.P. LEROY University Hospital Medical School, Brest, France Search for other works by this author on: Oxford Academic Google Scholar P. MIOSSEC, P. MIOSSEC University Hospital Medical School, Brest, France Search for other works by this author on: Oxford Academic Google Scholar R. MASSE R. MASSE University Hospital Medical School, Brest, France Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 108, Issue 6, 1 June 1983, Pages 717–722, https://doi.org/10.1111/j.1365-2133.1983.tb01085.x Published: 01 June 1983 Article history Accepted: 28 October 1982 Published: 01 June 1983
Chaperone proteins and brain tumors: Potential targets and possible therapeutics
Authors: Michael W. Graner, Darell D. Bigner
Journal: Neuro-Oncology (2005)

Chaperone proteins are most notable for the proteo- and cyotoprotective capacities they afford during cellular stress. Under conditions of cellular normalcy, chaperones still play integral roles in the folding of nascent polypeptides into functional entities, in assisting in intracellular/intraorganellar transport, in assembly and maintenance of multi-subunit protein complexes, and in aiding and abetting the degradation of senescent proteins. Tumors frequently have relatively enhanced needs for chaperone number and activity because of the stresses of rapid proliferation, increased metabolism, and overall genetic instability. Thus, it may be possible to take advantage of this reliance that tumor cells have on chaperones by pharmacologic and biologic means. Certain chaperones are abundant in the brain, which implies important roles for them. While it is presumed that the requirements of brain tumors for chaperone proteins are similar to those of any other cell type, tumor or otherwise, very little inquiry has been directed at the possibility of using chaperone proteins as therapeutic targets or even as therapeutic agents against central nervous system malignancies. This review highlights some of the research on the functions of chaperone proteins, on what can be done to modify those functions, and on the physiological responses that tumors and organisms can have to chaperone-targeted or chaperone-based therapies. In particular, this review will also underscore areas of research where brain tumors have been part of the field, although in general those instances are few and far between. This relative dearth of research devoted to chaperone protein targets and therapeutics in brain tumors reveals much untrodden turf to explore for potential treatments of these dreadfully refractive diseases.