tbuckley/cabot-search huggingface dataset:
The kSORT Assay to Detect Renal Transplant Patients at High Risk for Acute Rejection: Results of the Multicenter AART Study
Authors: Silke Roedder, Tara Sigdel, Nathan Salomonis, Sue Hsieh, Hong Dai, Oriol Bestard, Diana Metes, Andrea Zeevi, Albin Gritsch, Jennifer Cheeseman, Camila Macedo, Ram Peddy, Mara Medeiros, Flavio Vincenti, Nancy Asher, Oscar Salvatierra, Ron Shapiro, Allan Kirk, Elaine Reed, Minnie M. Sarwal
Journal: PLoS Medicine (2014)

Minnie Sarwal and colleagues developed a gene expression assay using peripheral blood samples to detect patients with renal transplant at high risk for acute rejection. Please see later in the article for the Editors' Summary
Increased IgM B cell differentiation lymphokine production by T lymphocytes from patients with primary biliary cirrhosis
Authors: José Luis Menéndez-Caro, Melchor Alvarez-Mon, José Antonio Girón, Luis Manzano, Aurelio Garrido, Luis Abreu, Agustín Albillos, Alberto Durántez
Journal: Journal of Hepatology (1994)
Regulation of Na+, K(+)-ATPase in the rat outer medullary collecting duct during potassium depletion.
Authors: B Buffin-Meyer, J M Verbavatz, L Cheval, S Marsy, M Younes-Ibrahim, C Le Moal, A Doucet
Journal: Journal of the American Society of Nephrology (1998)

Because in outer medullary collecting ducts (OMCD) of K(+)-depleted rats, K+ secretion is abolished, whereas Na+, K(+)-ATPase, which energizes this secretion, is markedly stimulated, it has been proposed that Na+, K(+)-ATPase was mislocated to the apical cell membrane and energized K+ reabsorption. This hypothesis has been supported by paradoxical effects of ouabain in K(+)-depleted compared with normal rats. However, we have recently shown that ouabain inhibits not only Na+, K(+)-ATPase but also apical H+, K(+)-ATPase in the OMCD of K(+)-depleted rats. Therefore, this study was designed to evaluate whether previous observations were accounted for by Na+, K(+)-ATPase or by ouabain-sensitive H+, K(+)-ATPase. Na+, K(+)-ATPase was distinguished from H+, K(+)-ATPase by its insensitivity to Sch-28080. Results indicate that the hydrolytic and transport activities of Na+, K(+)-ATPase, the number of its functional units, and the expression of mRNA of its alpha 1 and beta 1 subunits were increased threefold or more in the OMCD of rats fed a K(+)-depleted diet for 2 wk. By immunofluorescence, Na+, K(+)-ATPase staining was strongly increased in K(+)-depleted rats but remained localized to the basolateral pole of OMCD principal cells. In conclusion, K+ depletion is associated with marked induction of functional Na+, K+ pumps at the basolateral pole of rat OMCD. Therefore, reduced K+ secretion might result from inhibition of apical K+ conductances and stimulation of basolateral K+ recycling. It is proposed that increased Na+, K(+)-ATPase participates in the increased Na+ reabsorption prevailing in collecting ducts of K(+)-depleted rats.
Tumor-Suppressive Effects of MBP-1 in Non–Small Cell Lung Cancer Cells
Authors: Asish K. Ghosh, Robert Steele, Jan Ryerse, Ratna B. Ray
Journal: Cancer Research (2006)

Lung cancer is the leading cause of cancer death among both men and women. Only approximately 15% of people diagnosed with non-small cell lung cancer (NSCLC) survive this disease beyond 5 years. Thus, novel therapeutic strategies are urgently needed to improve the clinical management of this devastating disease. We have previously shown the antiproliferative effect of MBP-1 on several human cancer cells. In this study, we have examined the potential of MBP-1 as a gene therapeutic candidate in regression of non-small cell lung tumor growth. We have observed that exogenous expression of MBP-1 in NSCLC cells (H1299) induces massive cell death. To determine the gene therapeutic potential of MBP-1, replication-deficient recombinant adenovirus expressing MBP-1 was given intratumorally in human lung cancer xenografts in nude mice. Our results showed a significant regression of lung tumor growth and prolonged survival on treatment with MBP-1 compared with the control groups (saline or dl312). Subsequently, the mechanism of MBP-1-mediated H1299 cell death was investigated. Our results suggested that MBP-1 induced poly(ADP-ribose) polymerase cleavage in H1299 cells; however, treatment with pan-caspase inhibitor did not protect against MBP-1-induced cell death. Cells transduced with MBP-1 displayed early plasma membrane permeability, mitochondrial damage without cytochrome c release, and extensive cytoplasmic vacuolation, yielding a morphotype that is typical of necrosis. Taken together, this study suggests that MBP-1 expression induces a novel form of necrosis-like cell death and MBP-1 could be a potential gene therapeutic candidate against non-small cell lung tumor growth.
The prevalence of asthma in children: a reversing trend
Authors: C. P. van Schayck, H. A. Smit
Journal: European Respiratory Journal (2005)

In several countries it has been observed that there has been no further increase in the prevalence of asthma. This study aimed to look at asthma prevalence in children during the past 15–30 years in The Netherlands. Both general practice registration (Continuous Morbidity Registration, Nijmegen) and surveys of the public health service in Limburg (Southern parts of the Netherlands) were used for this purpose. The general practice registration showed that after a five-fold increase in asthma prevalence during the 1980s and 1990s a downward trend seemed to occur around the turn of the century. The public health service confirms a clear decrease in wheezing and dyspnoea in children during the late 1990s. Thus far, there has been no satisfactory explanation for this observation.
Concurrent inspiratory muscle and cardiovascular training differentially improves both perceptions of effort and 5000 m running performance compared with cardiovascular training alone
Authors: A M Edwards, C Wells, R Butterly
Journal: British Journal of Sports Medicine (2008)

Objective: To examine whether inspiratory muscle training (IMT) is a useful additional technique with which to augment cardiovascular exercise training adaptations. Methods: 16 healthy untrained males agreed to participate in the study and were randomly assigned to training (TRA; n = 8) and placebo (PLA; n = 8) groups. Pre- and post-training measurements of spirometry and maximal inspiratory mouth pressure (MIP) were taken in addition to i) maximal aerobic power (VO 2max ) and ii) 5000 m run time-trial. All subjects completed the same 4 week cardiovascular training programme which consisted of three running sessions (CV1: 5×1000 m, CV2: 3×1600 m, SP1: 20 min run) in each of the 4 weeks. IMT was performed daily by both groups using an inspiratory muscle trainer (POWERbreathe). TRA completed 30 maximal inspirations while PLA inspired 30 times against a negligible resistance. Results: Mean MIP increased significantly in both groups (TRA: 14.5 (SD 6.8)% change, PLA: 7.8 (7.4)% change) from pre- to post-training (p&lt;0.01) but was not significantly related to changes in running performance. Mean CV1 training-repetition runs improved similarly in both groups, but RPE evaluations were significantly reduced in TRA (15.7 (0.7)) compared with PLA (16.6 (0.8)) at week 4 (p&lt;0.05). Pre- to post-training changes in VO 2max were well-matched between both TRA (+2.1 (2.3)%) and PLA (+1.3 (2.4)%) while post-intervention 5000 m performance was significantly augmented in TRA compared with PLA (TRA: 4.3 (1.6)%, PLA: 2.2 (1.9)%, p&lt;0.05). Conclusions: The addition of IMT to a cardiovascular training programme augments 5000 m running performance but exerts no additional influence over VO 2max compared with a cardiovascular-training group. This is probably due to IMT-induced reduction in perceived effort at high ventilatory rates, which is of greater consequence to longer duration time-trial performances than incremental tests of VO 2max .
Anti-Integrin Therapy
Authors: Christian W. Hamm
Journal: Annual Review of Medicine (2003)

The glycoprotein IIb/IIIa integrin receptor binds fibrinogen and is therefore a final common pathway responsible for platelet aggregation. One antibody (abciximab) and two synthetic compounds (tirofiban and eptifibatide) are clinically available to antagonize the function of this receptor. Several large-scale studies have documented the benefit of these compounds in acute coronary syndromes and during percutaneous interventions. Current data suggest that abciximab is the preferred drug in the catheterization laboratory, whereas the other compounds reduce risk for patients with unstable angina before coronary interventions are performed. The highest benefit is achieved in diabetic patients and in patients with elevated troponins. Adverse reactions are rare, and bleeding complications are minor when weight-adjusted heparin is given. Oral compounds have been associated with excess mortality, precluding their clinical use.
Phase III randomized study of two fluorouracil combinations with either interferon alfa-2a or leucovorin for advanced colorectal cancer. Corfu-A Study Group.
Journal: Journal of Clinical Oncology (1995)

PURPOSE To compare the efficacy and toxicity profiles of a combination of fluorouracil (5-FU) with recombinant human interferon alfa-2a (Roferon-A; Hoffman La-Roche AG, Basel, Switzerland) versus the combination of 5-FU with leucovorin (LV) in the treatment of advanced colorectal cancer. PATIENTS AND METHODS A total of 496 previously untreated colorectal cancer patients were randomized to receive either Roferon-A (9 MIU) subcutaneously three times per week, with 5-FU (750 mg/m2/d) by continuous intravenous (i.v.) infusion (CIV) on days 1 to 5, then, after a 9-day hiatus, as a weekly i.v. bolus at the same dose (IFN/5-FU); or LV (200 mg/m2/d) by i.v. infusion plus 5-FU (370 mg/m2/d) by i.v. bolus on days 1 to 5, repeated every 4 weeks (LV/5-FU). RESULTS There were no significant differences between IFN/5-FU and LV/5-FU in the overall response rate (21% v 18%), duration of response (7.3 v 6.2 months), or survival time (median, 11.0 v 11.3 months). Toxicity profiles differed; constitutional symptoms and myelosuppression were more frequent and more severe with IFN/5-FU, and gastrointestinal symptoms with LV/5-FU. More patients interrupted treatment for adverse events (AEs) with IFN/5-FU than with LV/5-FU. Five treatment-related deaths occurred with each regimen. CONCLUSION The combination IFN/5-FU produced response rates, response durations, and survival times similar to those with LV/5-FU. Biochemical modulation of 5-FU by either IFN or LV appears to result in equivalent efficacy; however, fewer patients were able to tolerate the specified IFN/5-FU combination used in this study.
<i>In vivo</i>depletion of CD8<sup>+</sup>T cells restores hair growth in the DEBR model for alopecia areata
Authors: K. J. McELWEE, E. M. SPIERS, R. F. OLIVER
Journal: British Journal of Dermatology (1996)

Alopecia areata (AA) is a putative autoimmune disease in which anagen hair follicles are the target of immune cell attack. While both CD4+ and CD8+ T lymphocytes are prominent in the infiltrate, their respective roles in the pathogenesis of AA remain unknown. Here we directly investigated the activity of CD8+ cells in the inhibition of hair growth using the Dundee experimental bald rat (DEBR) model for AA. Eight lesional DEBRs were fully depleted of their CD8+ cells by intraperitoneal injection of OX-8 monoclonal antibody (MoAb) specific for these cells over a 15-day therapy course. A control group of eight lesional rats was injected with the irrelevant MoAb OX-21. Sequential blood samples were analysed by flow cytometry to observe changes in the CD8+ cell population and macrophotography used to record changes in hair growth activity. All eight CD8+ depleted rats started to regrow hair within 29 days from the start of treatment, the final response ranging from sparse regrowth to a near normal coat. While two rats maintained their new pelage, the remainder lost hair as the CD8+ population in peripheral blood increased. Two of the control rats also showed hair regrowth over the experimental period of 156 days. These results suggest that CD8+ cells play an active part in the pathogenesis of AA. As hair production did not fully recover in all animals, immune mechanisms other than CD8+ cells may be involved in effecting hair loss. However, analysis of CD8+ cell levels in the skin of CD8+ depleted rats may help resolve their full importance in AA.
Recent Advances in Cancer Therapy Targeting Proteins Involved in DNA Double-Strand Break Repair
Authors: Emma Bolderson, Derek J. Richard, Bin-Bing S. Zhou, Kum Kum Khanna
Journal: Clinical Cancer Research (2009)

Damage to genetic material represents a persistent and ubiquitous threat to genomic stability. Once DNA damage is detected, a multifaceted signaling network is activated that halts the cell cycle, initiates repair, and in some instances induces apoptotic cell death. In this article, we will review DNA damage surveillance networks, which maintain the stability of our genome, and discuss the efforts underway to identify chemotherapeutic compounds targeting the core components of DNA double-strand breaks (DSB) response pathway. The majority of tumor cells have defects in maintaining genomic stability owing to the loss of an appropriate response to DNA damage. New anticancer agents are exploiting this vulnerability of cancer cells to enhance therapeutic indexes, with limited normal tissue toxicity. Recently inhibitors of the checkpoint kinases Chk1 and Chk2 have been shown to sensitize tumor cells to DNA damaging agents. In addition, the treatment of BRCA1- or BRCA2-deficient tumor cells with poly(ADP-ribose) polymerase (PARP) inhibitors also leads to specific tumor killing. Due to the numerous roles of p53 in genomic stability and its defects in many human cancers, therapeutic agents that restore p53 activity in tumors are the subject of multiple clinical trials. In this article we highlight the proteins mentioned above and catalog several additional players in the DNA damage response pathway, including ATM, DNA-PK, and the MRN complex, which might be amenable to pharmacological interventions and lead to new approaches to sensitize cancer cells to radio- and chemotherapy. The challenge is how to identify those patients most receptive to these treatments.
Distinct mutations in two patients with leukocyte adhesion deficiency and their functional correlates.
Authors: A J Wardlaw, M L Hibbs, S A Stacker, T A Springer
Journal: The Journal of Experimental Medicine (1990)

Two patients with leukocyte adhesion deficiency (LAD), one with a moderate phenotype (patient 14) and one with a severe phenotype (patient 2) who had been shown to have a normal sized beta subunit protein precursor, were analyzed in an attempt to determine the molecular basis for their disease. RNase mapping located possible mutations to two distinct but adjacent regions of the beta subunit cDNA. Sequencing of patient-derived cDNA clones in this region revealed a C for T difference at amino acid 149 in patient 14 which resulted in the substitution of a leucine for a proline, and an A for G substitution at amino acid 169 in patient 2 which mutated a glycine to an arginine. The mutated amino acids are in a region of the cDNA that is highly conserved between the beta subunits of the integrin family and are identical in all known integrin beta subunits. Co-transfection of the beta subunit cDNA containing the patient 2 mutation with the wild-type alpha subunit of LFA-1 in a mammalian expression system resulted in no expression of LFA-1. In the case of the mutation in patient 14 there was markedly diminished expression of LFA-1 with loss of function and loss of the epitope for a number of anti-beta mAbs. Normal half-life of the mutant beta subunits, and previous demonstration of a lack of alpha/beta complex formation during biosynthesis in patient cells, suggest a defect in association with the alpha subunit. Association with beta is required for expression of the alpha subunit of LFA-1. Loss of functional expression with both of these beta subunit mutations suggests that they lie in a site critical for association with the alpha subunit.
Supervised Walking Groups to Increase Physical Activity in Type 2 Diabetic Patients
Authors: Carlo Negri, Elisabetta Bacchi, Susanna Morgante, Diego Soave, Alessandra Marques, Elisabetta Menghini, Michele Muggeo, Enzo Bonora, Paolo Moghetti
Journal: Diabetes Care (2010)

To evaluate the impact of an exercise program organized into supervised walking groups in subjects with type 2 diabetes.Fifty-nine diabetic subjects were randomized to a control group receiving standard lifestyle recommendations or an intervention group assigned to three supervised walking sessions per week and counseling. Changes in metabolic features, weight, 6-min walk test, prescription of antidiabetic medications, and overall physical activity were assessed.Functional capacity and overall physical activity were higher in the intervention group, whereas metabolic changes were not different between groups after 4 months. However, in subjects who attended at least 50% of scheduled walking sessions, changes in A1C and fasting glucose were greater than in control subjects. Discontinuation or reduction of antidiabetic drugs occurred in 33% of these patients versus 5% of control subjects (P<0.05).Supervised walking may be beneficial in diabetic subjects, but metabolic improvement requires adequate compliance.
The Risks of Risk Adjustment
Authors: Lisa I. lezzoni
Journal: JAMA (1997)

<h3>Context.</h3> —Risk adjustment is essential before comparing patient outcomes across hospitals. Hospital report cards around the country use different risk adjustment methods. <h3>Objectives.</h3> —To examine the history and current practices of risk adjusting hospital death rates and consider the implications for using risk-adjusted mortality comparisons to assess quality. <h3>Data Sources and Study Selection.</h3> —This article examines severity measures used in states and regions to produce comparisons of risk-adjusted hospital death rates. Detailed results are presented from a study comparing current commercial severity measures using a single database. It included adults admitted for acute myocardial infarction (n=11 880), coronary artery bypass graft surgery (n=7765), pneumonia (n=18016), and stroke (n=9407). Logistic regressions within each condition predicted in-hospital death using severity scores. Odds ratios for in-hospital death were compared across pairs of severity measures. For each hospital, z scores compared actual and expected death rates. <h3>Results.</h3> —The severity measure called Disease Staging had the highest c statistic (which measures how well a severity measure discriminates between patients who lived and those who died) for acute myocardial infarction, 0.86; the measure called All Patient Refined Diagnosis Related Groups had the highest for coronary artery bypass graft surgery, 0.83; and the measure, MedisGroups, had the highest for pneumonia, 0.85 and stroke, 0.87. Different severity measures predicted different probabilities of death for many patients. Severity measures frequently disagreed about which hospitals had particularly low or high z scores. Agreement in identifying low- and high-mortality hospitals between severity-adjusted and unadjusted death rates was often better than agreement between severity measures. <h3>Conclusions.</h3> —Severity does not explain differences in death rates across hospitals. Different severity measures frequently produce different impressions about relative hospital performance. Severity-adjusted mortality rates alone are unlikely to isolate quality differences across hospitals.
Mutation in Glycerol-3-Phosphate Dehydrogenase 1–Like Gene ( <i>GPD1-L</i> ) Decreases Cardiac Na <sup>+</sup> Current and Causes Inherited Arrhythmias
Authors: Barry London, Michael Michalec, Haider Mehdi, Xiaodong Zhu, Laurie Kerchner, Shamarendra Sanyal, Prakash C. Viswanathan, Arnold E. Pfahnl, Lijuan L. Shang, Mohan Madhusudanan, Catherine J. Baty, Stephen Lagana, Ryan Aleong, Rebecca Gutmann, Michael J. Ackerman, Dennis M. McNamara, Raul Weiss, Samuel C. Dudley
Journal: Circulation (2007)

Background— Brugada syndrome is a rare, autosomal-dominant, male-predominant form of idiopathic ventricular fibrillation characterized by a right bundle-branch block and ST elevation in the right precordial leads of the surface ECG. Mutations in the cardiac Na + channel SCN5A on chromosome 3p21 cause ≈20% of the cases of Brugada syndrome; most mutations decrease inward Na + current, some by preventing trafficking of the channels to the surface membrane. We previously used positional cloning to identify a new locus on chromosome 3p24 in a large family with Brugada syndrome and excluded SCN5A as a candidate gene. Methods and Results— We used direct sequencing to identify a mutation (A280V) in a conserved amino acid of the glycerol-3-phosphate dehydrogenase 1–like ( GPD1-L ) gene. The mutation was present in all affected individuals and absent in &gt;500 control subjects. GPD1-L RNA and protein are abundant in the heart. Compared with wild-type GPD1-L, coexpression of A280V GPD1-L with SCN5A in HEK cells reduced inward Na + currents by ≈50% ( P &lt;0.005). Wild-type GPD1-L localized near the cell surface to a greater extent than A280V GPD1-L. Coexpression of A280V GPD1-L with SCN5A reduced SCN5A cell surface expression by 31±5% ( P =0.01). Conclusions— GPD1-L is a novel gene that may affect trafficking of the cardiac Na + channel to the cell surface. A GPD1-L mutation decreases SCN5A surface membrane expression, reduces inward Na + current, and causes Brugada syndrome.
The Risk of Switch to Mania in Patients With Bipolar Disorder During Treatment With an Antidepressant Alone and in Combination With a Mood Stabilizer
Authors: Alexander Viktorin, Paul Lichtenstein, Michael E. Thase, Henrik Larsson, Cecilia Lundholm, Patrik K.E. Magnusson, Mikael Landén
Journal: American Journal of Psychiatry (2014)

This study examined the risk of antidepressant-induced manic switch in patients with bipolar disorder treated either with antidepressant monotherapy or with an antidepressant in conjunction with a mood stabilizer.Using Swedish national registries, the authors identified 3,240 patients with bipolar disorder who started treatment with an antidepressant and had no antidepressant treatment during the previous year. Patients were categorized into those receiving antidepressant monotherapy and those receiving an antidepressant plus a mood stabilizer. A within-individual design was used to control for confounding by disorder severity, genetic makeup, and early environmental factors. Cox regression analyses conditioned on individual were used to compare the rate of mania 0-3 months and 3-9 months after the start of antidepressant treatment with a preceding non-treatment period.Nearly 35% of the patients were treated with antidepressant monotherapy. The increased risk of treatment-emergent mania was confined to patients on antidepressant monotherapy (hazard ratio=2.83, 95% CI=1.12, 7.19). Among patients treated with a concurrent mood stabilizer, no acute change in risk of mania was observed during the 3 months after the start of antidepressant treatment (hazard ratio=0.79, 95% CI=0.54, 1.15), and a decreased risk was observed during the period 3-9 months after treatment initiation (hazard ratio=0.63, 95% CI=0.42, 0.93).In this national registry study, antidepressant monotherapy was associated with an increased risk of mania. However, no risk of mania was seen in patients receiving an antidepressant while treated with a mood stabilizer. The results highlight the importance of avoiding antidepressant monotherapy in the treatment of bipolar disorder.