tbuckley/cabot-search huggingface dataset:
Heterodimerization of β <sub>1</sub> - and β <sub>2</sub> -Adrenergic Receptor Subtypes Optimizes β-Adrenergic Modulation of Cardiac Contractility
Authors: Wei-Zhong Zhu, Khalid Chakir, Shengjun Zhang, Dongmei Yang, Catherine Lavoie, Michel Bouvier, Terence E. Hébert, Edward G. Lakatta, Heping Cheng, Rui-Ping Xiao
Journal: Circulation Research (2005)

Intermolecular interactions between members of both similar and divergent G protein-coupled receptor subfamilies have been shown in various experimental systems. Here, we demonstrate heterodimerization of predominant beta-adrenergic receptor (betaAR) subtypes expressed in the heart, beta1AR, and beta2AR, and its physiological relevance. In intact adult-mouse cardiac myocytes lacking native beta1AR and beta2AR, coexpression of both betaAR subtypes led to receptor heterodimerization, as evidenced by their coimmunoprecipitation, colocalization at optical resolution, and markedly increased binding affinity for subtype-selective ligands. As a result, the dose-response curve of myocyte contraction to betaAR agonist stimulation with isoproterenol (ISO) was shifted leftward by approximately 1.5 orders of magnitude, and the response of cellular cAMP formation to ISO was enhanced concomitantly, indicating that intermolecular interactions of betaAR subtypes resulted in sensitization of these receptors in response to agonist stimulation. In contrast, the presence of beta1AR greatly suppressed ligand-independent spontaneous activity of coexisting beta2ARs. Thus, heterodimerization of beta1AR and beta2AR in intact cardiac myocytes creates a novel population of betaARs with distinct functional and pharmacological properties, resulting in enhanced signaling efficiency in response to agonist stimulation while silencing ligand-independent receptor activation, thereby optimizing beta-adrenergic modulation of cardiac contractility.
Pharmacogenetic Predictors of Adverse Events and Response to Chemotherapy in Metastatic Colorectal Cancer: Results From North American Gastrointestinal Intergroup Trial N9741
Authors: Howard L. McLeod, Daniel J. Sargent, Sharon Marsh, Erin M. Green, Cristi R. King, Charles S. Fuchs, Ramesh K. Ramanathan, Stephen K. Williamson, Brian P. Findlay, Stephen N. Thibodeau, Axel Grothey, Roscoe F. Morton, Richard M. Goldberg
Journal: Journal of Clinical Oncology (2010)

Purpose With three available chemotherapy drugs for advanced colorectal cancer (CRC), response rate (RR) and survival outcomes have improved with associated morbidity, accentuating the need for tools to select optimal individualized treatment. Pharmacogenetics identifies the likelihood of adverse events or response based on variants in genes involved in drug transport, metabolism, and cellular targets. Patients and Methods Germline DNA was extracted from 520 patients on the North American Gastrointestinal Intergroup N9741 study. Three study arms were evaluated: IFL (fluorouracil [FU] + irinotecan [IRN]), FOLFOX (FU + oxaliplatin), and IROX (IRN + oxaliplatin). Information on adverse events, response, and disease-free survival was available. Thirty-four variants in 15 candidate genes for analysis based on previous associations with adverse events or outcome were assessed. Genotyping was performed using pyrosequencing. Results All variants were polymorphic. The homozygous UGT1A1*28 allele observed in 9% of patients was associated with risk of grade 4 neutropenia in patients on IROX (55% v 15%; P = .002). Deletion in GSTM1 was associated with grade 4 neutropenia after FOLFOX (28% v 16%; P = .02). Patients with a homozygous variant genotype for GSTP1 were more likely to discontinue FOLFOX because of neurotoxicity (24% v 10%; P = .01). The presence of a CYP3A5 variant was significantly associated with RR on IFL (29% v 60%; P = .0074). Most previously published genotype-toxicity or -efficacy relationships were not validated in this study. Conclusion This study provides a platform to evaluate pharmacogenetic predictors of response or severe adverse events in advanced CRC. Pharmacogenetic studies can be conducted in multicenter trials, and our findings demonstrate that with continued research, clinical application is practical.
Phase I Dose Escalation of Iodine-131–Metaiodobenzylguanidine With Myeloablative Chemotherapy and Autologous Stem-Cell Transplantation in Refractory Neuroblastoma: A New Approaches to Neuroblastoma Therapy Consortium Study
Authors: Katherine K. Matthay, Jessica C. Tan, Judith G. Villablanca, Gregory A. Yanik, Janet Veatch, Benjamin Franc, Eilish Twomey, Biljana Horn, C. Patrick Reynolds, Susan Groshen, Robert C. Seeger, John M. Maris
Journal: Journal of Clinical Oncology (2006)

To determine the maximum-tolerated dose (MTD) and toxicity of iodine-131-metaiodobenzylguanidine ((131)I-MIBG) with carboplatin, etoposide, melphalan (CEM) and autologous stem-cell transplantation (ASCT) in refractory neuroblastoma.Twenty-four children with primary refractory neuroblastoma and no prior ASCT were entered; 22 were assessable for toxicity and response. (131)I-MIBG was administered on day -21, CEM was administered on days -7 to -4, and ASCT was performed on day 0, followed by 13-cis-retinoic acid. (131)I-MIBG was escalated in groups of three to six patients, stratified by corrected glomerular filtration rate (GFR).The MTD for patients with normal GFR (> or = 100 mL/min/1.73 m2) was 131I-MIBG 12 mCi/kg, carboplatin 1,500 mg/m2, etoposide 1,200 mg/m2, and melphalan 210 mg/m2. In the low-GFR cohort, at the initial dose level using 12 mCi/kg of 131I-MIBG and reduced chemotherapy, one in six patients had dose limiting toxicity (DLT), including veno-occlusive disease (VOD). Three more patients in this group had grade 3 or 4 hepatotoxicity, and two had VOD, without meeting DLT criteria. There was only one death as a result of toxicity among all 24 patients. All assessable patients engrafted, with median time for neutrophils > or = 500/microL of 10 days and median time for platelets > or = 20,000/microL of 26 days. Six of 22 assessable patients had complete or partial response, and 15 patients had mixed response or stable disease. The estimated probability of event-free survival and survival from the day of MIBG infusion for all patients at 3 years was 0.31 +/- 0.10 and 0.58 +/- 0.10, respectively.131I-MIBG with myeloablative chemotherapy is feasible and effective for patients with neuroblastoma exhibiting de novo resistance to chemotherapy.
Functional Autonomy in Multinodular Goiter
Authors: J. Martin Miller
Journal: JAMA (1970)

Forty-six of 70 patients with large multinodular goiters had significant radioactive iodine uptake after liothyromine sodium (T<sub>3</sub>) administration. The scintiscan patterns during suppression were comparable to those of 49 patients with similar goiters and non-Graves' hyperthyroidism. The distribution of radioactive iodine uptake varied from localization in one of the many nodules to a patchy but diffuse picture which microscopically involved several types of follicular architecture. It is hypothesized that the gradual increment of the autonomous tissue causes transition from a euthyroid to a hyperthyroid state based on gland autonomy rather than on a humoral stimulator. Autonomous function must be suspected in all large multinodular goiters and evaluated before levothyroxine sodium treatment. If such function is present, a "replacement" dose of thyroid hormone will actually be an additive one, and hyperthyroidism may be produced.
A CLINICAL LECTURE ON GASTRO-ENTEROSTOMY
Authors: J. C. Renton
Journal: BMJ (1912)

APRIL I3, Sfir1 2. junction of-the vagina witb tlhe cervix.Soue surgeons close the incision transversely, and leave the line of suture running across the vaginal wall.-But this pulls down the cervix into a position not far above the urethral orifice, and so shortens the, anterior vaginal wall.This pulls down and retroverts tlhe uterus, and leaves it lying in the axis of thle pelvis started on a career of prolapse.This is the way to make sure of recurrence of the trouble.After the
Assessing the Determinants of Evolutionary Rates in the Presence of Noise
Authors: J. B. Plotkin, H. B. Fraser
Journal: Molecular Biology and Evolution (2007)

Although protein sequences are known to evolve at vastly different rates, little is known about what determines their rate of evolution. However, a recent study using principal component regression (PCR) has concluded that evolutionary rates in yeast are primarily governed by a single determinant related to translation frequency. Here, we demonstrate that noise in biological data can confound PCRs, leading to spurious conclusions. When equalizing noise levels across 7 predictor variables used in previous studies, we find no evidence that protein evolution is dominated by a single determinant. Our results indicate that a variety of factors--including expression level, gene dispensability, and protein-protein interactions--may independently affect evolutionary rates in yeast. More accurate measurements or more sophisticated statistical techniques will be required to determine which one, if any, of these factors dominates protein evolution.
Neurally-mediated increase in calcineurin activity regulates cardiac contractile function in absence of hypertrophy
Authors: J Li
Journal: Cardiovascular Research (2003)

The calcineurin pathway has been involved in the development of cardiac hypertrophy, yet it remains unknown whether calcineurin activity can be regulated in myocardium independently from hypertrophy and cardiac load.To test that hypothesis, we measured calcineurin activity in a rat model of infrarenal aortic constriction (IR), which affects neurohormonal pathways without increasing cardiac afterload.In this model, there was no change in arterial pressure over the 4-week experimental period, and the left ventricle/body weight ratio did not increase. At 2 weeks after IR, calcineurin activity was increased 1.8-fold (P<0.05) and remained elevated at 4 weeks (1.7-fold, P<0.05). Similarly, the cardiac activity of calcium calmodulin kinase II (CaMKII) was increased significantly after IR, which confirms a regulation of Ca(2+)-dependent enzymes in this model. In cardiac myocytes, the increased activity of calcineurin was accompanied by a significant decrease in L-type Ca(2+) channel activity (I(Ca)) and contraction velocity (-dL/dt). Cardiac denervation prevented the activation of calcineurin after IR, which demonstrates that a neurohormonal mechanism is responsible for the changes in enzymatic activity. In addition, cardiac denervation suppressed the effects of IR on I(Ca) and -dL/dt, which shows that calcineurin activation is related to altered contractility. However, action potential duration, the densities of inward rectifier K(+) currents (I(K1)), and outward K(+) currents (I(to) and I(K)) were not altered in IR myocytes.Calcineurin can be activated in the heart through a neural stimulus, which induces alterations in Ca(2+) currents and contractility. These effects occur in the absence of myocyte hypertrophy, electrophysiological changes in action potential, and K(+) channel currents.
Randomized Short-term Trial of Two AutoCPAP Devices versus Fixed Continuous Positive Airway Pressure for the Treatment of Sleep Apnea
Authors: Oliver Senn, Thomas Brack, Felix Matthews, Erich W. Russi, Konrad E. Bloch
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

We evaluated the efficacy of two different continuous positive airway pressure devices with automatic mask pressure adjustment (autoCPAP) in comparison with fixed CPAP in treating obstructive sleep apnea syndrome in 29 patients. The mean (+/- SE) apnea-hypopnea index was 46 +/- 4 per hour and the Epworth score was 14.2 +/- 0.7. Patients were treated over three consecutive 1-month periods with three regimens in random order: an autoCPAP device responding to apnea-hypopnea and snoring, another autoCPAP device responding to snoring and changes in flow contour, and fixed CPAP at the 90th pressure percentile titrated by autoCPAP over 2 weeks. Allowed pressure in the autoCPAP mode was 4 to 15 cm H2O. At the end of each treatment period, symptoms, quality of life, vigilance, and nocturnal breathing disturbances were evaluated. All three treatment modalities improved symptoms, quality-of-life domains, and apnea-hypopnea index significantly and to a similar degree. Mean (+/- SE) maintenance-of-wakefulness time increased by 4.5 +/- 1.8, 6.0 +/- 1.5, and 6.1 +/- 1.4 minutes with DeVilbiss AutoAdjust LT, AutoSet T, and fixed-pressure CPAP, respectively (p<0.001 vs. baseline, p=not significant for comparisons among the three modalities). We conclude that both autoCPAP devices were equally effective as fixed-pressure CPAP in improving major outcomes during short-term therapy of sleep apnea.
Integration of Genetic and Immunological Insights into a Model of Celiac Disease Pathogenesis
Authors: Valérie Abadie, Ludvig M. Sollid, Luis B. Barreiro, Bana Jabri
Journal: Annual Review of Immunology (2011)

Celiac disease (CD) is a gluten-sensitive enteropathy that develops in genetically susceptible individuals by exposure to cereal gluten proteins. This review integrates insights from immunological studies with results of recent genetic genome-wide association studies into a disease model. Genetic data, among others, suggest that viral infections are implicated and that natural killer effector pathways are important in the pathogenesis of CD, but most prominently these data converge with existing immunological findings that CD is primarily a T cell-mediated immune disorder in which CD4(+) T cells that recognize gluten peptides in the context of major histocompatibility class II molecules play a central role. Comparison of genetic pathways as well as genetic susceptibility loci between CD and other autoimmune and inflammatory disorders reveals that CD bears stronger resemblance to T cell-mediated organ-specific autoimmune than to inflammatory diseases. Finally, we present evidence suggesting that the high prevalence of CD in modern societies may be the by-product of past selection for increased immune responses to combat infections in populations in which agriculture and cereals were introduced early on in the post-Neolithic period.
Insulin-like Growth Factor-I Receptor Blockade Improves Outcome in Mouse Model of Lung Injury
Authors: Jung-Eun Choi, Sung-soon Lee, Donald A. Sunde, Isham Huizar, Kathy L. Haugk, Victor J. Thannickal, Ragini Vittal, Stephen R. Plymate, Lynn M. Schnapp
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Rationale: The insulin-like growth factor-I (IGF-I) pathway is an important determinant of survival and proliferation in many cells. However, little is known about the role of the IGF-I pathway in lung injury. We previously showed elevated levels of IGF-I in bronchoalveolar lavage fluid from patients with acute respiratory distress syndrome. Furthermore, immunodepletion of IGF from acute respiratory distress syndrome bronchoalveolar lavage increased fibroblast apoptosis.Objectives: We examined the effect of blockade of type 1 IGF tyrosine kinase receptor (IGF-IR) in a murine model of bleomycin-induced lung injury and fibrosis.Methods: Mice were treated with a monoclonal antibody against the IGF-I receptor (A12) or vehicle after intratracheal bleomycin instillation.Measurements and Main Results: Mice treated with A12 antibody had significantly improved survival after bleomycin injury compared with control mice. Both groups of mice had a similar degree of fibrosis on days 7 and 14, but by Day 28 the A12-treated group had significantly less fibrosis. Delayed treatment with A12 also resulted in decreased fibrosis. A12-treated mice had significantly decreased apoptotic cells on Day 28 compared with control mice. We confirmed that A12 treatment induced mouse lung fibroblast apoptosis in vitro. In addition, IGF-I increased lung fibroblast migration. The primary pathway activated by IGF-I in lung fibroblasts was the insulin receptor substrate-2/phosphatidylinositol 3-kinase/Akt axis.Conclusions: IGF-I regulated survival and migration of fibrogenic cells in the lung. Blockade of the IGF pathway increased fibroblast apoptosis and subsequent resolution of pulmonary fibrosis. Thus, IGF-IR may be a potential target for treatment of lung injury and fibrosis.
Clinical and Correlative Results of SWOG S0354: A Phase II Trial of CNTO328 (Siltuximab), a Monoclonal Antibody against Interleukin-6, in Chemotherapy-Pretreated Patients with Castration-Resistant Prostate Cancer
Authors: Tanya B. Dorff, Bryan Goldman, Jacek K. Pinski, Philip C. Mack, Primo N. Lara, Peter J. Van Veldhuizen, David I. Quinn, Nicholas J. Vogelzang, Ian M. Thompson, Maha H.A. Hussain
Journal: Clinical Cancer Research (2010)

Interleukin-6 (IL-6) facilitates cancer cell survival via pleotrophic effects. We conducted a multicenter phase II study of CNTO328 (siltuximab) as second-line therapy for men with castration-resistant prostate cancer.
Diabetes and Obesity
Authors: Zachary T. Bloomgarden
Journal: Diabetes Care (2007)

Perspectives on the News commentaries are part of a free monthly CME activity.The Mount Sinai School of Medicine, New York, New York, designates this activity for 2.0 AMA PRA Category 1 credits.If you wish to participate, review this article and visit www.diabetes.procampus.net to complete a posttest and receive a certificate.The Mount Sinai School
NHS changes have disrupted scrutiny of antibiotic prescribing in general practice, MPs hear
Authors: A. O'Dowd
Journal: BMJ (2014)

Changes to NHS structures and bodies have led to a gap in monitoring and persuading GPs to prescribe fewer antibiotics, MPs have been told.

Efforts to curb the growth of resistance to antibiotics—such as the government’s antimicrobial resistance strategy1 published in September 2013—have been destabilised by the NHS reorganisation, witnesses told MPs on the House of Commons Science and Technology Committee.

The committee, holding an evidence session on 8 January as part of its inquiry into antimicrobial resistance, asked how effective “clinician focused initiatives” such as the Department of Health’s Antimicrobial Stewardship: Start Smart—Then Focus guidance2 for hospitals were in dealing with this issue.

Michael Moore, national clinical champion for antimicrobial stewardship for …
Phase I evaluation of telatinib, a VEGF receptor tyrosine kinase inhibitor, in combination with bevacizumab in subjects with advanced solid tumors
Authors: M.H.G. Langenberg, P.O. Witteveen, J. Roodhart, M.P. Lolkema, H.M.W. Verheul, M. Mergui-Roelvink, E. Brendel, J. Krätzschmar, B. Loembé, A. Nol-Boekel, O. Christensen, J.H.M. Schellens, E.E. Voest
Journal: Annals of Oncology (2011)
Association of genetic instability of lymphocytes with increased IgE in children living in areas of Belarus contaminated with Cs137
Authors: L.P. Titov, D. Charnashey, E. Kirylchyk, P. Rytik, S. Melnov, L.M. Du Buske, H.C. Schroder, W. Muller
Journal: Journal of Allergy and Clinical Immunology (2003)
Mixed-Meal Tolerance Test Versus Glucagon Stimulation Test for the Assessment of β-Cell Function in Therapeutic Trials in Type 1 Diabetes
Authors: Carla J. Greenbaum, Thomas Mandrup-Poulsen, Paula Friedenberg McGee, Tadej Battelino, Burkhard Haastert, Johnny Ludvigsson, Paolo Pozzilli, John M. Lachin, Hubert Kolb
Journal: Diabetes Care (2008)

Beta-cell function in type 1 diabetes clinical trials is commonly measured by C-peptide response to a secretagogue in either a mixed-meal tolerance test (MMTT) or a glucagon stimulation test (GST). The Type 1 Diabetes TrialNet Research Group and the European C-peptide Trial (ECPT) Study Group conducted parallel randomized studies to compare the sensitivity, reproducibility, and tolerability of these procedures.In randomized sequences, 148 TrialNet subjects completed 549 tests with up to 2 MMTT and 2 GST tests on separate days, and 118 ECPT subjects completed 348 tests (up to 3 each) with either two MMTTs or two GSTs.Among individuals with up to 4 years' duration of type 1 diabetes, >85% had measurable stimulated C-peptide values. The MMTT stimulus produced significantly higher concentrations of C-peptide than the GST. Whereas both tests were highly reproducible, the MMTT was significantly more so (R(2) = 0.96 for peak C-peptide response). Overall, the majority of subjects preferred the MMTT, and there were few adverse events. Some older subjects preferred the shorter duration of the GST. Nausea was reported in the majority of GST studies, particularly in the young age-group.The MMTT is preferred for the assessment of beta-cell function in therapeutic trials in type 1 diabetes.
Eosinophils in eosinophilic pneumonia
Authors: C Albera, P Ghio
Journal: European Respiratory Journal (1996)

Idiopathic eosinophilic pneumonia (IEP) is an uncom-mon disease of unknown aetiology characterized by theaccumulation of eosinophils in the lung, variable bloodeosinophilia and peripheral opacities on the chest radio-gram. The response to steroid treatment is dramatic butrelapses are frequent, requiring the use of long-termsteroid treatment [1].Eosinophils are primarily tissue cells, containing intheir granules many preformed proinflammatory andcytotoxic mediators [2]. They are also able to synthe-size many other substances that defend the host againstexogenous stimuli [3]; under normal conditions theeosinophil number in those tissues that have contact withthe environment is 200–400 times greater than in theblood [4]. An abnormally high accumulation of thesecells within the lung, frequency reaching up to 50% ofthe total alveolar cell population [5], is the hallmark ofIEP, but the role of the eosinophil in the immunopatho-genesis of lung damage in this disorder is still not com-pletely elucidated [4].Eosinophils accumulated within both interstitium andsmall air spaces [1] are hypodense and widely degran-ulated cells. They show typical morpho-functional char-acteristics of activated cells and are able to damageparenchymal lung structures by releasing a variety oftoxic substances [6]. Consequently, two major points needto be investigated and discussed: 1) how do eosinophilscause parenchymal injury? 2) how are eosinophils recruit-ed and activated at the site of inflammation?
Perfect ALKemy: Optimizing the Use of ALK-Directed Therapies in Lung Cancer
Authors: Katerina Politi, Scott Gettinger
Journal: Clinical Cancer Research (2014)

Abstract Mutations in ALK are a common mechanism of acquired resistance to small molecule ALK inhibitors in ALK-rearranged lung cancer. Different mutants exhibit differential sensitivity to ALK inhibitors. Matching the mutational profile of the tumor with the appropriate ALK inhibitor is likely to be important to maximize benefit for patients. Clin Cancer Res; 20(22); 5576–8. ©2014 AACR.
Inducible Costimulator Protein (Icos) Controls T Helper Cell Subset Polarization after Virus and Parasite Infection
Authors: Manfred Kopf, Anthony J. Coyle, Nicole Schmitz, Marijke Barner, Annette Oxenius, Awen Gallimore, Jose-Carlos Gutierrez-Ramos, Martin F. Bachmann
Journal: The Journal of Experimental Medicine (2000)

It has been shown that certain pathogens can trigger efficient T cell responses in the absence of CD28, a key costimulatory receptor expressed on resting T cells. Inducible costimulator protein (ICOS) is an inducible costimulator structurally and functionally related to CD28. Here, we show that in the absence of CD28 both T helper cell type 1 (Th1) and Th2 responses were impaired but not abrogated after infection with lymphocytic choriomeningitis virus (LCMV), vesicular stomatitis virus (VSV), and the nematode Nippostrongylus brasiliensis. Inhibition of ICOS in CD28-deficient mice further reduced Th1/Th2 polarization. Blocking of ICOS alone had a limited but significant capacity to downregulate Th subset development. In contrast, cytotoxic T lymphocyte (CTL) responses, which are regulated to a minor and major extent by CD28 after LCMV and VSV infection, respectively, remained unaffected by blocking ICOS. Together, our results demonstrate that ICOS regulates both CD28-dependent and CD28-independent CD4+ subset (Th1 and Th2) responses but not CTL responses in vivo.