tbuckley/cabot-search huggingface dataset:
Ligand Binding Sites of Inducible Costimulator and High Avidity Mutants with Improved Function
Authors: Shengdian Wang, Gefeng Zhu, Koji Tamada, Lieping Chen, Jürgen Bajorath
Journal: The Journal of Experimental Medicine (2002)

Interaction between inducible costimulator (ICOS) and its ligand is implicated in the induction of cell-mediated and humoral immune responses. However, the molecular details of this interaction are unknown. We report here a mutagenesis analysis of residues in ICOS that are critical for ligand binding. A three-dimensional model of the extracellular immunoglobulin-like domain of ICOS was used to map the residues conserved within the CD28 family. This analysis identified a surface patch containing the characteristic "PPP" sequence and is conserved in human and mouse ICOS. Mutations in this region of human ICOS reduce or abolish ligand binding. Our results suggest that the ligand binding site in ICOS maps to a region overlapping yet distinct from the CD80/CD86 binding sites in CD28 and cytotoxic T lymphocyte antigen (CTLA)-4. Thus, the analysis suggests that differences in ligand binding specificity between these related costimulatory molecules have evolved by utilization of overlapping regions with different patterns of conserved and nonconserved residues. Two site-specific mutants generated in the course of our studies bound ICOS ligand with higher avidity than wild-type ICOS. An S76E mutant protein of ICOS blocked T cell costimulatory function of ICOS ligand and inhibited T cell response to allogeneic antigens superior to wild-type ICOS. Our studies thus identified critical residues involving in ICOS receptor-ligand interaction and provide new modulators for immune responses.
Determination of Genotype Combinations That Can Predict the Outcome of the Treatment of Alcohol Dependence Using the 5-HT<sub>3</sub>Antagonist Ondansetron
Authors: Bankole A. Johnson, Chamindi Seneviratne, Xin-Qun Wang, Nassima Ait-Daoud, Ming D. Li
Journal: American Journal of Psychiatry (2013)

The authors previously reported that the 5'-HTTLPR-LL and rs1042173-TT (SLC6A4-LL/TT) genotypes in the serotonin transporter gene predicted a significant reduction in the severity of alcohol consumption among alcoholics receiving the 5-HT3 antagonist ondansetron. In this study, they explored additional markers of ondansetron treatment response in alcoholics by examining polymorphisms in the HTR3A and HTR3B genes, which regulate directly the function and binding of 5-HT3 receptors to ondansetron.The authors genotyped one rare and 18 common single-nucleotide polymorphisms in HTR3A and HTR3B in the same sample that they genotyped for SLC6A4-LL/TT in the previous randomized, double-blind, 11-week clinical trial. Participants were 283 European Americans who received oral ondansetron (4 mg/kg of body weight twice daily) or placebo along with weekly cognitive-behavioral therapy. Associations of individual and combined genotypes with treatment response on drinking outcomes were analyzed.Individuals carrying one or more of genotypes rs1150226-AG and rs1176713-GG in HTR3A and rs17614942-AC in HTR3B showed a significant overall mean difference between ondansetron and placebo in drinks per drinking day (22.50; effect size=0.867), percentage of heavy drinking days (220.58%; effect size=0.780), and percentage of days abstinent (18.18%; effect size=0.683). Combining these HTR3A/HTR3B and SLC6A4-LL/TT genotypes increased the target cohort from approaching 20% (identified in the previous study) to 34%.The authors present initial evidence suggesting that a combined fivemarker genotype panel can be used to predict the outcome of treatment of alcohol dependence with ondansetron. Additional, larger pharmacogenetic studies would help to validate these results.
Second generation logarithmic estimates of single-pool variable volume Kt/V
Authors: J T Daugirdas
Journal: Journal of the American Society of Nephrology (1993)

The original formula proposed to estimate variable-volume single-pool (VVSP) Kt/V was Kt/V = -In(R - 0.008 * t - f * UF/W), where in the Kt/V range of 0.7 to 1.3, f = 1.0 (* denotes multiplication). This formula tends to overestimate Kt/V as the Kt/V increases above 1.3. Because higher Kt/V values are now commonly delivered, the validity of both the urea generation term (0.008 * f) and correction for UF/W were explored by solving VVSP equations for simulated hemodialysis situations, with Kt/V ranging from 0.6 to 2.6. The analysis led to the development of a second-generation formula, namely: Kt/V = -In(R - 0.008 * t) + (4-3.5 * R) * UF/W. The first and second generation formulas were then used to estimate the modeled VVSP Kt/V in 500 modeling sessions in which the Kt/V ranged widely from 0.7 to 2.1. An analysis of error showed that this second-generation formula eliminated the overestimation of Kt/V in the high ranges found with the first-generation formula. Also, total error (absolute value percent error + 2 SD) was reduced with the second-generation formula. These results led to the proposal of a new formula that can be used for a very wide range of delivered Kt/V.
Structural studies on induced antibodies with defined idiotypic specificities. IX. Framework differences in the heavy- and light-chain-variable regions of monoclonal anti-p-azophenylarsonate antibodies from A/J mice differing with respect to a cross-reactive idiotype.
Authors: P Estess, E Lamoyi, A Nisonoff, J D Capra
Journal: The Journal of Experimental Medicine (1980)

Amino terminal amino acid sequence analyses have been performed on the heavy and light chains of induced monoclonal antibodies with specificity for the hapten p-azophenylarsonate. Four of the eight antibodies react with conventional antisera to the previously described A/J anti-arsonate cross-reactive idiotype (CRI). Of the 16 chains analyzed, all but one contain sequence differences in their first framework segment (residues 1-30) that distinguish them from the heavy- and light-chain sequences found in anti-arsonate antibodies isolated from A/J serum or ascites fluid. The presence of such framework differences appears to be independent of whether or not the hybridoma antibodies bear the CRI. In spite of the framework substitutions, all four of the CRI-positive hybridoma antibodies have variable (V)-region frameworks that are very similar to each other and to the CRI-positive molecules found in A/J serum. Two of the four CRI-negative molecules are also structurally similar to the serum antibodies. Two others, however, are strikingly different from any serum anti-arsonate antibody thus far described and appear to reflect a completely separate repertoire of anti-arsonate antibodies in the A/J MOUSE. In addition, serological analyses with an anti-idiotypic antiserum generated against a CRI-positive hybridoma product suggest that each monoclonal antibody may possess individual antigenic specificities different from the determinant(s) detected with the conventional rabbit anti-CRI. The consistent appearance of framework substitutions in what has been thought to be a homogeneous antibody population has important implications for our understanding of the generation of antibody diversity and for the precise chemical definition of an idiotype.
Treatment slows moderate to severe Alzheimer's disease
Authors: J. Hopkins Tanne
Journal: BMJ (2003)

For the first time, a treatment has been shown to slow the mental and physical decline of patients with moderate to severe Alzheimer's disease by about six months ( New England Journal of Medicine 2003;348:1333-41).

The US researchers conducted a double blind, randomised controlled trial of memantine. The drug had been marketed in Germany by Merz Pharmaceuticals for a decade for Parkinson's disease and other neurodegenerative diseases before being licensed in May 2002 by the European Union …
Uniparental Trisomy of a Mutated <i>HRAS</i> Proto-Oncogene in Embryonal Rhabdomyosarcoma of a Patient With Costello Syndrome
Authors: Jan Menke, Silke Pauli, Matthias Sigler, Ingrid Kühnle, Moneef Shoukier, Barbara Zoll, Christina Ganster, Gabriela Salinas-Riester, Inga-Marie Schaefer
Journal: Journal of Clinical Oncology (2014)
Transient telomere dysfunction induces chromosomal instability and promotes carcinogenesis
Authors: Yvonne Begus-Nahrmann, Daniel Hartmann, Johann Kraus, Parisa Eshraghi, Annika Scheffold, Melanie Grieb, Volker Rasche, Peter Schirmacher, Han-Wong Lee, Hans A. Kestler, André Lechel, K. Lenhard Rudolph
Journal: Journal of Clinical Investigation (2012)

Telomere shortening limits the proliferative capacity of a cell, but perhaps surprisingly, shortening is also known to be associated with increased rates of tumor initiation. A current hypothesis suggests that telomere dysfunction increases tumor initiation by induction of chromosomal instability, but that initiated tumors need to reactivate telomerase for genome stabilization and tumor progression. This concept has not been tested in vivo, since appropriate mouse models were lacking. Here, we analyzed hepatocarcinogenesis in a mouse model of inducible telomere dysfunction on a telomerase-proficient background, in telomerase knockout mice with chronic telomere dysfunction (G3 mTerc-/-), and in WT mice with functional telomeres and telomerase. Transient or chronic telomere dysfunction enhanced the rates of chromosomal aberrations during hepatocarcinogenesis, but only telomerase-proficient mice exhibited significantly increased rates of macroscopic tumor formation in response to telomere dysfunction. In contrast, telomere dysfunction resulted in pronounced accumulation of DNA damage, cell-cycle arrest, and apoptosis in telomerase-deficient liver tumors. Together, these data provide in vivo evidence that transient telomere dysfunction during early or late stages of tumorigenesis promotes chromosomal instability and carcinogenesis in telomerase-proficient mice.
Glomerular Filtration Rate, Cardiorenal End Points, and All-Cause Mortality in Type 2 Diabetic Patients
Authors: Wing Yee So, Alice P.S. Kong, Ronald C.W. Ma, Risa Ozaki, Cheuk Chun Szeto, Norman N. Chan, Vanessa Ng, Chung Shun Ho, Christopher W.K. Lam, Chun Chung Chow, Clive S. Cockram, Juliana C.N. Chan, Peter C.Y. Tong
Journal: Diabetes Care (2006)

OBJECTIVE—Chronic kidney disease (CKD) predicts cardiovascular disease (CVD) in the general population. We investigated the effects of stages of renal function using the estimated glomerular filtration rate (eGFR) on all-cause mortality and cardiovascular end points in a prospective cohort of Chinese type 2 diabetic patients. RESEARCH DESIGN AND METHODS—Between 1995 and 2000, 4,421 patients without macrovascular disease or end-stage renal disease were recruited. Renal function was assessed by eGFR, as calculated by the abbreviated Modification of Diet in Renal Disease Study Group formula. Clinical end points included all-cause mortality, cardiovascular end point (cardiovascular death, new admissions due to angina, myocardial infarction, stroke, revascularization, or heart failure), and renal end point (reduction in eGFR by &amp;gt;50%, progression of eGFR to stage 5, or dialysis or renal death). RESULTS—After a median follow-up period of 39.4 months (interquartile range 20.3–55), all-cause mortality rate increased from 1.2% (95% CI 0.8–1.7) to 18.3% (9.1–27.5) (P for trend &amp;lt;0.001) as renal function deteriorated from stage 1 (eGFR ≥90 ml/min per 1.73 m2) to stage 4 (15–29 ml/min per 1.73 m2). The respective rate of new cardiovascular end points also increased from 2.6% (2.0–3.3) to 25.3% (15.0–35.7) (P for trend &amp;lt;0.001). After adjustment for covariates (age, sex, albuminuria, use of renin-angiotensin-aldosterone system [RAAS] inhibitors, lipids, blood pressure, and glycemic control), hazard ratios across different stages of eGFR (≥90, 60–89, 30–59, and 15–29 ml/min per 1.73 m2) for all-cause mortality were 1.00, 1.27, 2.34, and 9.82 (P for trend &amp;lt;0.001), for cardiovascular end points were 1.00, 1.04, 1.05, and 3.23 (P for trend &amp;lt;0.001), and for renal end points were 1.00, 1.36, 3.34, and 27.3 (P for trend &amp;lt;0.001), respectively. CONCLUSIONS—Chinese type 2 diabetic patients with reduced eGFR were at high risk of developing cardiovascular end points and all-cause mortality, independent of albuminuria and metabolic control.
Nebulized Hypertonic Saline for Bronchiolitis in the Emergency Department
Authors: Todd A. Florin, Kathy N. Shaw, Marlena Kittick, Stephen Yakscoe, Joseph J. Zorc
Journal: JAMA Pediatrics (2014)

IMPORTANCEAcute bronchiolitis is the most frequent lower respiratory tract infection in infants, yet there are no effective therapies available.Current evidence is unclear about the role of hypertonic saline (HS) for the acute treatment of bronchiolitis.OBJECTIVE To determine whether nebulized 3% HS compared with normal saline (NS) improves respiratory distress in infants with bronchiolitis not responding to standard treatments in the emergency department. DESIGN, SETTING, AND PARTICIPANTSA randomized clinical trial with blinding of investigators, health care providers, and parents was conducted at a single urban pediatric ED.The participants included children aged 2 to less than 24 months with their first episode of bronchiolitis and a Respiratory Distress Assessment Instrument score of 4 to 15 after nasal suctioning and a trial of nebulized albuterol.INTERVENTIONS Patients were randomized to receive either nebulized 3% HS (HS group) or NS (NS group). MAIN OUTCOMES AND MEASURESThe primary outcome was change in respiratory distress at 1 hour after the intervention, as measured by the Respiratory Assessment Change Score (a decrease indicates improvement).Secondary outcomes included vital signs, oxygen saturation, hospitalization, physician clinical impression, parental assessment, and adverse events. RESULTSThe 31 patients enrolled in each treatment arm had similar baseline demographic and clinical characteristics.At 1 hour after the intervention, the HS group demonstrated significantly less improvement in the median Respiratory Assessment Change Score compared with the NS group (HS, -1 [interquartile range, -5 to 1] vs NS, -5 [interquartile range, -6 to -2]; P = .01).There were no significant differences in heart rate, oxygen saturation, hospitalization rate, or other outcomes.There were no adverse events. CONCLUSIONS AND RELEVANCEInfants with bronchiolitis and persistent respiratory distress after standard treatment in the emergency department had less improvement after receiving 3% HS compared with those who received NS.Based on these results and the existing evidence, administration of a single dose of 3% HS does not appear to be indicated to treat bronchiolitis in the acute care setting.
CIMETIDINE, THE IMMUNE SYSTEM, AND CANCER
Authors: Ian Fraser, P.R.F Bell, C Burtin, P Scheinmann, J.C Salomon, G Lespinats, N.R Peden, E.J.S Boyd, R.A Brown, J.H Gibbs, R.C Potts, K.G Wormsley, J Swanson Beck, StellaC Knight
Journal: The Lancet (1981)
Acyl-CoA Synthetase VL3 Knockdown Inhibits Human Glioma Cell Proliferation and Tumorigenicity
Authors: Zhengtong Pei, Peng Sun, Ping Huang, Bachchu Lal, John Laterra, Paul A. Watkins
Journal: Cancer Research (2009)

The contribution of lipid metabolic pathways to malignancy is poorly understood. Expression of the fatty acyl-CoA synthetase ACSVL3 was found to be markedly elevated in clinical malignant glioma specimens but nearly undetectable in normal glia. ACSVL3 levels correlated with the malignant behavior of human glioma cell lines and glioma cells propagated as xenografts. ACSVL3 expression was induced by the activation of oncogenic receptor tyrosine kinases (RTK) c-Met and epidermal growth factor receptor. Inhibiting c-Met activation with neutralizing anti-hepatocyte growth factor monoclonal antibodies reduced ACSVL3 expression concurrent with tumor growth inhibition in vivo. ACSVL3 expression knockdown using RNA interference, which decreased long-chain fatty acid activation, inhibited anchorage-dependent and anchorage-independent glioma cell growth by approximately 70% and approximately 90%, respectively. ACSVL3-depleted cells were less tumorigenic than control cells, and subcutaneous xenografts grew approximately 60% slower than control tumors. Orthotopic xenografts produced by ACSVL3-depleted cells were 82% to 86% smaller than control xenografts. ACSVL3 knockdown disrupted Akt function as evidenced by RTK-induced transient decreases in total and phosphorylated Akt, as well as glycogen synthase kinase 3beta, via a caspase-dependent mechanism. Expressing constitutively active myr-Akt rescued cells from the anchorage-dependent and anchorage-independent growth inhibitory effects of ACSVL3 depletion. These studies show that ACSVL3 maintains oncogenic properties of malignant glioma cells via a mechanism that involves, in part, the regulation of Akt function.
Meta-Analysis
Authors: K. Scott Brimble, Michelle Walker, Peter J. Margetts, Kiran K. Kundhal, Christian G. Rabbat
Journal: Journal of the American Society of Nephrology (2006)

Peritoneal membrane solute transport in peritoneal dialysis (PD) patients is assessed by the peritoneal equilibration test, which measures the ratio of creatinine in the dialysate to plasma after a standardized 4-h dwell (D/P<sub>c</sub>). Patients then are classified as high, high-average, low-average, or low transporters on the basis of this result. A meta-analysis of observational studies was carried out to characterize the relationship between D/P<sub>c</sub> and mortality and technique failure in patients who are on PD. Citations were identified in Medline by using a combination of Medical Subject Heading search terms and key words related to PD, peritoneal membrane permeability/transport, and mortality and technique failure. The table of contents of relevant journals and bibliographies of relevant citations were reviewed in duplicate. Twenty studies that met study criteria were identified. Nineteen studies were pooled to generate a summary mortality relative risk of 1.15 for every 0.1 increase in the D/P<sub>c</sub> (95% confidence interval 1.07 to 1.23; <i>P</i> &lt; 001). This result equated to an increased mortality risk of 21.9, 45.7, and 77.3% in low-average, high-average, and high transporters, respectively, as compared with patients with low transport status. Meta-regression analysis showed that the proportion of patients who were on continuous cycler PD within a study was inversely proportional to the mortality risk (<i>P</i> = 0.05). The pooled summary relative risk for death-censored technique failure was 1.18 (95% confidence interval 0.96 to 1.46; <i>P</i> = 0.12) for every 0.1 increase in the D/P<sub>c</sub>. This meta-analysis demonstrates that a higher peritoneal membrane solute transport rate is associated with a higher mortality risk and a trend to higher technique failure.
High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis
Authors: Philippe Goyette, Gabrielle Boucher, Dermot Mallon, Eva Ellinghaus, Luke Jostins, Hailiang Huang, Stephan Ripke, Elena S Gusareva, Vito Annese, Stephen L Hauser, Jorge R Oksenberg, Ingo Thomsen, Stephen Leslie, Mark J Daly, Kristel Van Steen, Richard H Duerr, Jeffrey C Barrett, Dermot P B McGovern, L Philip Schumm, James A Traherne, Mary N Carrington, Vasilis Kosmoliaptsis, Tom H Karlsen, Andre Franke, John D Rioux
Journal: Nature Genetics (2015)
Acute polyarticular gout.
Authors: D A Raddatz, M L Mahowald, P J Bilka
Journal: Annals of the Rheumatic Diseases (1983)

We report here on 41 male patients with acute polyarticular gout seen in 3 years. Acute polyarticular gout continues to masquerade as other commoner rheumatological disorders such as septic arthritis, rheumatoid arthritis, degenerative joint disease, and even hemiparesis. Almost all of these patients had clues to the diagnosis of acute gout in their medical history. These clues included a past history of intermittent acute gout, prior attacks of polyarticular arthritis, previous hyperuricaemia, and/or obvious tophi. The patients all responded promptly to nonsteroidal anti-inflammatory drugs. We observed serious toxic drug reactions in 8 patients.
CD4+ T cell activation and tolerance induction in B cell knockout mice.
Authors: J A Phillips, C G Romball, M V Hobbs, D N Ernst, L Shultz, W O Weigle
Journal: The Journal of Experimental Medicine (1996)

B cell knockout mice microMT/microMT were used to examine the requirement for B cell antigen (Ag) presentation in the establishment of CD4+ T cell tolerance. CD4+T cells from microMT mice injected with exogenous protein Ag in adjuvant responded to in vitro challenge by transcription of cytokine mRNA, cytokine secretion, and proliferation. Peripheral tolerance could be established in microMT mice with a single dose of deaggragated protein. This tolerance was manifested by a loss of T cell proliferation and cytokine production (including both T helper cell type 1 [Th1]- and Th2-related cytokines), indicating that B cells are not required for the induction of peripheral T cell tolerance and suggesting that the dual zone tolerance theory is not applicable to all protein Ags and is not mediated through Ag presentation by B cells.
Effects of exercise training on oxygen uptake kinetic responses in women with type 2 diabetes.
Authors: S L Brandenburg, J E Reusch, T A Bauer, B W Jeffers, W R Hiatt, J G Regensteiner
Journal: Diabetes Care (1999)

OBJECTIVE: Women with uncomplicated type 2 diabetes have both a decreased maximal oxygen consumption (VO2max) and slowed oxygen uptake (VO2) kinetics at the onset of exercise compared with nondiabetic women. These abnormalities are seen not only at maximal workloads, but also at the onset of low-level exercise. To evaluate the hypothesis that VO2max and VO2 kinetics would improve with exercise training in untrained people with type 2 diabetes, we measured these parameters in premenopausal sedentary women before and after 3 months of supervised exercise training. RESEARCH DESIGN AND METHODS: A total of 8 women with type 2 diabetes, 9 overweight nondiabetic women, and 10 lean nondiabetic women were studied. At baseline and after 3 months of exercise training, subjects underwent bicycle ergometer testing to obtain VO2max and VO2 kinetics data. RESULTS: On entry, women with type 2 diabetes had the lowest VO2max and slowest VO2 kinetics of the three groups. After exercise training, the women with type 2 diabetes improved their VO2max more than the lean and overweight control women: 28 vs. 5 and 8%, respectively (P &amp;lt; 0.05 for the diabetic group vs. both control groups). In the group with diabetes, VO2 kinetics improved by 39 and 22% at 20 and 30 W, respectively. For the control subjects, VO2 kinetics did not improve at any workload in either group. CONCLUSIONS: Despite beginning with the lowest VO2max and slowest VO2 kinetics, subjects with type 2 diabetes benefited more from an exercise training program than did control subjects. These findings suggest that in addition to its known metabolic effects, exercise training in individuals with type 2 diabetes may be an effective therapy to improve the cardiovascular response to exercise and to overcome low-level exercise impairment as reflected by improved VO2max and VO2 kinetics. If the ability to make circulatory adjustments at the beginning of exercise at low workloads is improved by an exercise training program, as suggested by the VO2 kinetics data, the clinical significance of exercise for people with type 2 diabetes is clear.