tbuckley/cabot-search huggingface dataset:
Carvedilol selectively inhibits oscillatory intracellular calcium changes evoked by human ?1D- and ?1B-adrenergic receptors
Authors: T KOSHIMIZU
Journal: Cardiovascular Research (2004)

Increasing evidence from clinical trials indicates that carvedilol, an antagonist of alpha1- and beta-adrenergic receptors (ARs), provides an effective treatment for chronic heart failure, whereas nonselective alpha1-AR blockade has an adverse outcome in this disease. It is, however, not clear whether carvedilol exhibits a subtype-dependent impact on three distinct alpha1-adrenergic receptors (alpha1-ARs).We determined binding properties of human ARs for carvedilol using HEK293 human embryonic kidney cells expressing a single AR subtype. Our results showed that the affinities of alpha1D-AR and alpha1B-AR for carvedilol are higher than that of the beta1-AR subtype, a major target in heart failure treatment. The affinity rank order and pKi values of ARs for carvedilol were as follows: alpha1D-AR (8.9)>alpha1B-AR (8.6)>beta1-AR (8.4)>beta2-AR (8.0)>alpha1A-AR (7.9)?alpha2C-AR (5.9)>alpha2B-AR (5.5)>alpha2A-AR (5.3). Furthermore, temporal kinetics of intracellular calcium signaling mediated via alpha1D- and alpha1B-ARs, but not via alpha1A-AR (P<0.01), showed oscillatory patterns with frequencies ranging from 0.3 to 3 per minute in human smooth muscle and HEK293 cells, which were inhibited by the therapeutic concentrations of carvedilol (10 nM) in a subtype-dependent manner. When oscillatory alpha1B-AR and non-oscillatory alpha1A-AR were co-expressed and heteromer receptors were detected with bioluminescence resonance energy transfer and co-immunoprecipitation, carvedilol suppressed only oscillatory component of global cytosolic free calcium change.These results indicate that in addition to beta-ARs, receptor inhibition by carvedilol is directed to alpha1-ARs, preferably to alpha1D- and alpha1B-AR-mediated signaling events, including intracellular calcium oscillations in vascular smooth muscle.
Sequence Complexity of Histone H1 Subtypes
Authors: Imma Ponte, Roger Vila, Pedro Suau
Journal: Molecular Biology and Evolution (2003)

H1 subtypes are involved in chromatin higher-order structure and gene regulation. H1 has a characteristic three-domain structure. We studied the length variation of the available H1 subtypes and showed that the length of the N-terminal and C-terminal domains was more variable than that of the central domain. The N-terminal and C-terminal domains were of low sequence complexity both at the nucleotide and at the amino acid level, whereas the globular domain was of high complexity. In most subtypes, low complexity was due only to cryptic simplicity, which reflects the clustering of a number of short and often imperfect sequence motifs. However, a subset of subtypes from eubacteria, plants, and invertebrates contained tandem repeats of short amino acid motifs (four to 12 residues), which could amount to a large proportion of the terminal domains. In addition, some other subtypes, such as those of Drosophila and mammalian H1t, were only marginally simple. The coexistence of these three kinds of subtypes suggests that the terminal domains could have originated in the amplification of short sequence motifs, which would then have evolved by point mutation and further slippage.
GENERATION OF CYTOTOXIC T LYMPHOCYTES IN VITRO
Authors: H. Robson MacDonald, Jean-Charles Cerottini, K. Theodor Brunner
Journal: The Journal of Experimental Medicine (1974)

Separation of cells by velocity sedimentation at unit gravity was utilized to investigate the physical properties of cytotoxic thymus-derived lymphocytes (CTL) generated in long-term mixed leukocyte cultures (MLC). In kinetic studies, CTL were found almost exclusively in the large cell fractions at the peak of the response on day 4, whereas the majority of CTL in day 14 MLC had the sedimentation properties of small lymphocytes. Reculture until day 14 of cells fractionated on the basis of size on day 4 indicated that the small CTL were derived exclusively from cells which had been large on day 4. Re-exposure of day 14 MLC cells to the original stimulating alloantigens resulted in significant cell proliferation and rapid regeneration of CTL activity. Cell fractionation experiments demonstrated that the cells in the day 14 MLC population which responded to the secondary allogeneic stimulus were small T lymphocytes, and that these cells rapidly developed into large, highly cytotoxic CTL following stimulation. Moreover, by restimulating on day 14 fractions which were selected on the basis of size on day 4, it was found that the responding small lymphocytes were themselves the progeny of cells which were large at the peak of the response. Since CTL and CTL progenitors showed concomitant changes in physical properties with time, the possibility exists that they belong to the same cell lineage, and hence that CTL can differentiate into cells which are no longer cytotoxic, but capable of mounting an anamnestic response.
Microscopic analysis of synovial fluid--the perfect diagnostic test?
Authors: A J Freemont
Journal: Annals of the Rheumatic Diseases (1996)

A single intratumoral injection of IL-12 and GM-CSF-loaded slow-release microspheres induces T cell-dependent eradication of established primary and metastatic tumors in a murine lung tumor model. To determine how the delivery of cytokines directly to the microenvironment of a tumor nodule induces local and systemic antitumor T cell activity, we characterized therapy-induced phenotypic and functional changes in tumor-infiltrating T cell populations. Analysis of pretherapy tumors demonstrated that advanced primary tumors were infiltrated by CD4<sup>+</sup> and CD8<sup>+</sup> T cells with an effector/memory phenotype and CD4<sup>+</sup>CD25<sup>+</sup>Foxp3<sup>+</sup> T suppressor cells. Tumor-associated effector memory CD8<sup>+</sup> T cells displayed impaired cytotoxic function, whereas CD4<sup>+</sup>CD25<sup>+</sup>Foxp3<sup>+</sup> cells effectively inhibited T cell proliferation demonstrating functional integrity. IL-12/GM-CSF treatment promoted a rapid up-regulation of CD43 and CD69 on CD8<sup>+</sup> effector/memory T cells, augmented their ability to produce IFN-γ, and restored granzyme B expression. Importantly, treatment also induced a concomitant and progressive loss of T suppressors from the tumor. Further analysis established that activation of pre-existing effector memory T cells was short-lived and that both the effector/memory and the suppressor T cells became apoptotic within 4 days of treatment. Apoptotic death of pre-existing effector/memory and suppressor T cells was followed by infiltration of the tumor with activated, nonapoptotic CD8<sup>+</sup> effector T lymphocytes on day 7 posttherapy. Both CD8<sup>+</sup> T cell activation and T suppressor cell purge were mediated primarily by IL-12 and required IFN-γ. This study provides important insight into how local IL-12 therapy alters the immunosuppressive tumor milieu to one that is immunologically active, ultimately resulting in tumor regression.
Differential Effects of Polymorphic Alleles of <i>FGF Receptor 4</i> on Colon Cancer Growth and Metastasis
Authors: Christine Heinzle, Andrea Gsur, Monika Hunjadi, Zeynep Erdem, Christine Gauglhofer, Stefan Stättner, Josef Karner, Martin Klimpfinger, Friedrich Wrba, Andrea Reti, Balazs Hegedus, Andreas Baierl, Bettina Grasl-Kraupp, Klaus Holzmann, Michael Grusch, Walter Berger, Brigitte Marian
Journal: Cancer Research (2012)

A gly(388)arg polymorphism (rs351855) in the transmembrane domain of the fibroblast growth factor receptor (FGFR4) is associated with increased risk, staging, and metastasis in several different types of cancer. To specifically assess the impact of the polymorphic FGFR4 in colorectal cancer (CRC), we engineered CRC cell lines with distinct endogenous expression patterns to overexpress either the FGFR4(gly) or FGFR4(arg) alleles. The biologic analyses revealed an oncogenic importance for both polymorphic alleles, but FGFR4(gly) was the stronger inducer of tumor growth, whereas FGFR4(arg) was the stronger inducer of migration. An evaluation of clinical specimens revealed that FGFR4 was upregulated in 20/71 patients independent of gly(388)arg status. There was no correlation between the presence of an FGFR4(arg) allele and CRC or polyp risk in 3,471 participants of the CORSA study. However, among 182 patients with CRC, FGFR4(arg)-carriers had a fivefold higher risk of tumors that were stage II or greater. Together, our results established that both allelic forms of FGFR4 exert an oncogenic impact and may serve equally well as therapeutic targets in CRC. One important implication of our findings is that FGFR4(arg)-carriers are at a higher risk for more aggressive tumors and therefore may profit from early detection measures.
Too Much Glucagon, Too Little Insulin
Authors: Rebecca J. Brown, Ninet Sinaii, Kristina I. Rother
Journal: Diabetes Care (2008)

OBJECTIVE—To determine the time course of changes in glucagon and insulin secretion in children with recently diagnosed type 1 diabetes. RESEARCH DESIGN AND METHODS—Glucagon and C-peptide concentrations were determined in response to standard mixed meals in 23 patients with type 1 diabetes aged 9.4 ± 4.6 years, beginning within 6 weeks of diagnosis, and every 3 months thereafter for 1 year. RESULTS—Glucagon secretion in response to a physiologic stimulus (mixed meal) increased by 37% over 12 months, while C-peptide secretion declined by 45%. Fasting glucagon concentrations remained within the normal (nondiabetic) reference range. CONCLUSIONS—Postprandial hyperglucagonemia worsens significantly during the first year after diagnosis of type 1 diabetes and may represent a distinct therapeutic target. Fasting glucagon values may underestimate the severity of hyperglucagonemia. The opposing directions of abnormal glucagon and C-peptide secretion over time support the link between dysregulated glucagon secretion and declining β-cell function.
A Functional Genetic Link between Distinct Developmental Language Disorders
Authors: Sonja C. Vernes, Dianne F. Newbury, Brett S. Abrahams, Laura Winchester, Jérôme Nicod, Matthias Groszer, Maricela Alarcón, Peter L. Oliver, Kay E. Davies, Daniel H. Geschwind, Anthony P. Monaco, Simon E. Fisher
Journal: New England Journal of Medicine (2008)

Rare mutations affecting the FOXP2 transcription factor cause a monogenic speech and language disorder. We hypothesized that neural pathways downstream of FOXP2 influence more common phenotypes, such as specific language impairment.
More evidence of nephrotoxicity with renin-angiotensin-aldosterone system blockers
Authors: J. M. F. de Oliveira
Journal: BMJ (2013)

Lapi and colleagues provide more evidence that renin-angiotensin-aldosterone system (RAAS) blockers can be nephrotoxic in the long term in certain populations1 2—namely, older patients with chronic kidney disease, with or without diabetes.3

A few …
Circulating miRNAs in cancer: from detection to therapy
Authors: Wen-Tao Wang, Yue-Qin Chen
Journal: Journal of Hematology & Oncology (2014)

Since the discovery of circulating microRNAs (miRNAs) in body fluids, an increasing number of studies have focused on their potential as non-invasive biomarkers and as therapeutic targets or tools for many diseases, particularly for cancers. Because of their stability, miRNAs are easily detectable in body fluids. Extracellular miRNAs have potential as biomarkers for the prediction and prognosis of cancer. Moreover, they also enable communication between cells within the tumor microenvironment, thereby influencing tumorigenesis. In this review, we summarize the progresses made over the past decade regarding circulating miRNAs, from the development of detection methods to their clinical application as biomarkers and therapeutic tools for cancer. We also discuss the advantages and limitations of different detection methods and the pathways of circulating miRNAs in cell-cell communication, in addition to their clinical pharmacokinetics and toxicity in human organs. Finally, we highlight the potential of circulating miRNAs in clinical applications for cancer.
A Brief Targeted Review of Susceptibility Factors, Environmental Exposures, Asthma Incidence, and Recommendations for Future Asthma Incidence Research
Authors: Karin Yeatts, Peter Sly, Stephanie Shore, Scott Weiss, Fernando Martinez, Andrew Geller, Philip Bromberg, Paul Enright, Hillel Koren, David Weissman, MaryJane Selgrade
Journal: Environmental Health Perspectives (2006)

Relative to research on effects of environmental exposures on exacerbation of existing asthma, little research on incident asthma and environmental exposures has been conducted. However, this research is needed to better devise strategies for the prevention of asthma. The U.S. Environmental Protection Agency (EPA) and National Institute of Environmental Health Sciences held a conference in October 2004 to collaboratively discuss a future research agenda in this area. The first three articles in this mini-monograph summarize the discussion on potential putative environmental exposure; they include an overview of asthma and conclusions of the workshop participants with respect to public health actions that could currently be applied to the problem and research needs to better understand and control the induction and incidence of asthma, the potential role of indoor/outdoor air pollutants in the induction of asthma), and biologics in the induction of asthma. Susceptibility is a key concept in the U.S. EPA "Asthma Research Strategy" document and is associated with the U.S. EPA framework of protecting vulnerable populations from potentially harmful environmental exposures. Genetics, age, and lifestyle (obesity, diet) are major susceptibility factors in the induction of asthma and can interact with environmental exposures either synergistically or antagonistically. Therefore, in this fourth and last article we consider a number of "susceptibility factors" that potentially influence the asthmatic response to environmental exposures and propose a framework for developing research hypotheses regarding the effects of environmental exposures on asthma incidence and induction.
Cause-Specific Colostomy Rates After Radiotherapy for Anal Cancer: A Danish Multicentre Cohort Study
Authors: Kåre G. Sunesen, Mette Nørgaard, Lilli Lundby, Hanne Havsteen, Steen Buntzen, Ole Thorlacius-Ussing, Søren Laurberg
Journal: Journal of Clinical Oncology (2011)

In anal cancer, colostomy-free survival is a measure of anal sphincter preservation after treatment with radiotherapy or chemoradiotherapy. Failure to control anal cancer and complications of treatment are alternative indications for colostomy. However, no data exist on cause-specific colostomy rates. We examined this in a cohort study.Through national registries and review of medical records, we identified patients with anal cancer diagnosed from 1995 to 2003 who had curative-intent radiotherapy or chemoradiotherapy in four Danish centers. We computed cumulative incidence of tumor-related colostomy and therapy-related colostomy, treating colostomy and death as competing events. Follow-up started at completion of radiotherapy and continued throughout 2008. We used competing risk regression to compute hazard ratios (HRs) to compare the cumulative incidence of cause-specific colostomies between age, sex, tumor size, chemotherapy, and local excision before radiotherapy.We included 235 patients with anal cancer. The 5-year cumulative incidences of tumor-related and therapy-related colostomy were 26% (95% CI, 21% to 32%) and 8% (95% CI, 5% to 12%), respectively. Tumor size greater than 6 cm versus less than 4 cm was a risk factor for tumor-related colostomy (adjusted HR, 3.8; 95% CI, 1.7 to 8.1), and local excision before radiotherapy was a risk factor for therapy-related colostomy (adjusted HR, 4.5; 95% CI, 1.5 to 13.5).After curative-intent radiotherapy or chemoradiotherapy, one third of patients had a colostomy, of which one third were related to therapy. Large tumor size was associated with a higher risk of tumor-related colostomy, whereas history of prior excision was associated with an increased incidence of therapy-related colostomy.
Dietary Therapy Mitigates Persistent Wake Deficits Caused by Mild Traumatic Brain Injury
Authors: Miranda M. Lim, Jaclynn Elkind, Guoxiang Xiong, Ray Galante, Jingxu Zhu, Lin Zhang, Jie Lian, Julianna Rodin, Nicholas N. Kuzma, Allan I. Pack, Akiva S. Cohen
Journal: Science Translational Medicine (2013)

Sleep disorders are highly prevalent in patients with traumatic brain injury (TBI) and can significantly impair cognitive rehabilitation. No proven therapies exist to mitigate the neurocognitive consequences of TBI. We show that mild brain injury in mice causes a persistent inability to maintain wakefulness and decreases orexin neuron activation during wakefulness. We gave mice a dietary supplement of branched-chain amino acids (BCAAs), precursors for de novo glutamate synthesis in the brain. BCAA therapy reinstated activation of orexin neurons and improved wake deficits in mice with mild brain injury. Our data suggest that dietary BCAA intervention, acting in part through orexin, can ameliorate injury-induced sleep disturbances and may facilitate cognitive rehabilitation after brain injury.
Treatment of carrageenan induced arthritis by the platelet activating factor antagonist BN 50730.
Authors: P Hilliquin, J Natour, J Aissa, P Guinot, S Laoussadi, J Benveniste, C J Menkes, B Arnoux
Journal: Annals of the Rheumatic Diseases (1995)

OBJECTIVE--To evaluate the role of platelet activating factor (PAF) in the early stage of arthritis. METHODS--Arthritis was induced in rabbits by weekly intra-articular injections of carrageenan. A PAF receptor antagonist, BN 50730, was used as a preventive or curative agent. RESULTS--BN 50730 was able partially to prevent the development of arthritis, and was also active on established arthritis. The joint arthritis scores of BN treated animals were significantly lower than those of the non-treated animals. The blood concentrations of PAF, PAF bound to lipoproteins (lipo-PAF), and its precursor, lyso-PAF, were not correlated with clinical variations. CONCLUSIONS--The present data demonstrate a therapeutic action of a PAF antagonist in experimental arthritis and suggest a critical role for PAF during the early stage of arthritis.
Effects of Mixing Glargine and Short-Acting Insulin Analogs on Glucose Control
Authors: Walid Kaplan, Luisa M. Rodriguez, O’Brian E. Smith, Morey W. Haymond, Rubina A. Heptulla
Journal: Diabetes Care (2004)

Intensive insulin management improves glycemic control and lowers the risks of long-term microvascular complications (1). Several new insulin analogs (2) are in use to improve glycemic control in type 1 diabetes. Glargine in particular is a “basal insulin” (3) and found to be relatively peakless. Glargine is thought to provide glucose profiles similar to insulin pumps (4). Although some clinical studies suggest that glargine lasts 24 h in children with diabetes (5), to date there have been no formal pharmacokinetic and pharmacodynamic data to make that claim in the pediatric population. In fact, clinical observations in pediatric type 1 diabetes suggest that glargine action may be <24 h. This would entail twice-daily glargine dosing and short-acting insulin analogs (SAIs), such as lispro and aspart, given separately three to four times per day, resulting in improved glycemic control but compromising compliance and increasing complexity of management (6). In this study, we tested the hypothesis that mixing glargine with SAIs and dividing the dose of glargine into twice- versus once-daily dosing would not adversely affect glycemic control as assessed by a continuous glucose monitoring system (CGMS).

The protocol was approved by the institutional review board of the Baylor College of Medicine, and consent was obtained before each study. Subjects were recruited from Texas Children’s Hospital Diabetes Care Center, Houston, Texas. Subjects had type 1 diabetes for at least 1 year with no other chronic illness and were on …
Subsequent Neoplasms in 5-Year Survivors of Childhood Cancer: The Childhood Cancer Survivor Study
Authors: Debra L. Friedman, John Whitton, Wendy Leisenring, Ann C. Mertens, Sue Hammond, Marilyn Stovall, Sarah S. Donaldson, Anna T. Meadows, Leslie L. Robison, Joseph P. Neglia
Journal: JNCI Journal of the National Cancer Institute (2010)

BackgroundThe occurrence of subsequent neoplasms has direct impact on the quantity and quality of life in cancer survivors. We have expanded our analysis of these events in the Childhood Cancer Survivor Study (CCSS) to better understand the occurrence of these events as the survivor population ages.
Effects of Ramadan fasting on 60 min of endurance running performance in moderately trained men
Authors: Abdul Rashid Aziz, Mohamed Faizul Wahid, Weileen Png, Carolyn V Jesuvadian
Journal: British Journal of Sports Medicine (2010)

Objective This study examines the effects of Ramadan fasting on endurance performance. Method Using a crossover design, 10 moderately trained, active Muslim men performed 60 min runs on a treadmill in the fasted (Ramadan, RAM) and non-fasted (Control, CON) state on two separate counterbalanced occasions. After familiarisation, four subjects performed their CON trial 1 week before Ramadan, while the other six subjects performed their CON trial 1 week after the Ramadan month. The subjects' last meals were standardised before their exercise trials. The 60 min continuous endurance running criteria test consisted of 30 min preloading run at 65% maximum oxygen consumption (Vo 2max ) intensity speed, followed by another 30 min time trial (TT) where subjects manually adjusted their speeds so as to cover the greatest possible distance. Results Subjects ran significantly further during the 30 min TT run in the CON compared to RAM condition (5649±715 vs 5448±847 m, p=0.023). Blood glucose concentration was significantly lower (4.5±0.3 vs 4.9±0.4 mmol/l, p=0.003) and urine specific gravity was significantly higher (1.018±0.006 vs 1.006±0.004, p=0.001) at the start of exercise in the RAM condition than in CON. Physiological responses during the 30 min TT run (mean heart rate, blood lactate and ratings of perceived exertion) were, however, not significantly different between the two conditions (all p&gt;0.05). There were also no significant differences in the subjects' daytime sleepiness or mood profile between the RAM and CON conditions (all p&gt;0.05). Conclusion Ramadan fasting has a small yet significant negative impact on endurance running performance, although the impact varies across individuals.