tbuckley/cabot-search huggingface dataset:
PATHOMECHANISMS IN CHANNELOPATHIES OF SKELETAL MUSCLE AND BRAIN
Authors: Stephen C. Cannon
Journal: Annual Review of Neuroscience (2006)

Ion channelopathies are a diverse array of human disorders caused by mutations in ion channel genes. This review focuses on the pathogenic mechanisms of channelopathies affecting skeletal muscle and brain arising from mutations of voltage-gated ion channels and fast ligand-gated ion channels expressed at the surface membrane. Derangements in channel function alter the electrical excitability of the cell and thereby increase susceptibility to transient symptomatic attacks including myasthenia, periodic paralysis, myotonic stiffness, seizures, headache, dyskinesia, or episodic ataxia. Although these disorders are rare, they stand out as exemplary cases for which disease pathogenesis can be traced from a point mutation to altered protein function, to altered cellular activity, and to clinical phenotype. The study of these disorders has provided insights on channel structure-function relations, the physiological roles of ion channels, and rational approaches toward therapeutic intervention for many disorders of cellular excitability.
The non-coding snRNA 7SK controls transcriptional termination, poising, and bidirectionality in embryonic stem cells
Authors: Gonçalo Castelo-Branco, Paulo P Amaral, Pär G Engström, Samuel C Robson, Sueli C Marques, Paul Bertone, Tony Kouzarides
Journal: Genome biology (2013)

Abstract Background Pluripotency is characterized by a unique transcriptional state, in which lineage-specification genes are poised for transcription upon exposure to appropriate stimuli, via a bivalency mechanism involving the simultaneous presence of activating and repressive methylation marks at promoter-associated histones. Recent evidence suggests that other mechanisms, such as RNA polymerase II pausing, might be operational in this process, but their regulation remains poorly understood. Results Here we identify the non-coding snRNA 7SK as a multifaceted regulator of transcription in embryonic stem cells. We find that 7SK represses a specific cohort of transcriptionally poised genes with bivalent or activating chromatin marks in these cells, suggesting a novel poising mechanism independent of Polycomb activity. Genome-wide analysis shows that 7SK also prevents transcription downstream of polyadenylation sites at several active genes, indicating that 7SK is required for normal transcriptional termination or control of 3′-UTR length. In addition, 7SK suppresses divergent upstream antisense transcription at more than 2,600 loci, including many that encode divergent long non-coding RNAs, a finding that implicates the 7SK snRNA in the control of transcriptional bidirectionality. Conclusions Our study indicates that a single non-coding RNA, the snRNA 7SK , is a gatekeeper of transcriptional termination and bidirectional transcription in embryonic stem cells and mediates transcriptional poising through a mechanism independent of chromatin bivalency.
REGULATION OF FATTY ACID OXIDATION IN SKELETAL MUSCLE
Authors: Blake B. Rasmussen, Robert R. Wolfe
Journal: Annual Review of Nutrition (1999)

▪ Abstract Researchers using animals are beginning to elucidate the control of fatty acid metabolism in muscle at the molecular and enzymatic level. This review examines the physiological data that has been collected from human subjects in the context of the proposed control mechanisms. A number of factors, including the availability of free fatty acids and the abundance of fatty acid transporters, may influence the rate of muscle fatty acid oxidation. However, the predominant point of control appears to be the rate at which fatty acyl–coenzyme A is transported into the mitochondria by the carnitine palmitoyl transferase system. In turn, evidence suggests that the intracellular concentration of malonyl–coenzyme A in muscle is an important regulator of carnitine palmitoyl transferase–I activity. Malonyl–coenzyme A is increased by glucose, which is likely the mechanism whereby glucose intake suppresses the transfer of fatty acids into the mitochondria for subsequent oxidation. In contrast, malonyl–coenzyme A levels decrease during exercise, which enables increased fatty acid oxidation. However, for any given carnitine palmitoyl transferase–I activity, there may be an effect of free fatty acid availability on fatty acid oxidation, particularly at low levels of free fatty acids. Nonetheless, the rate of glucose or glycogen metabolism is probably the primary regulator of the balance between glucose and fatty acid oxidation in muscle.
Rapid Development of Hypertension by Sorafenib: Toxicity or Target?
Authors: Benjamin D. Humphreys, Michael B. Atkins
Journal: Clinical Cancer Research (2009)

Abstract Blood pressure elevation is likely a pharmacodynamic marker of VEGF signaling pathway (VSP) inhibition and could be useful for optimizing safe and effective VSP inhibitor dosing. Blood pressure rises on the first day of treatment, facilitating design and interpretation of future trials aiming to correlate blood pressure changes with clinical outcomes. (Clin Cancer Res 2009;15(19):5947–9)
Response to a Monovalent 2009 Influenza A (H1N1) Vaccine
Authors: Michael E. Greenberg, Michael H. Lai, Gunter F. Hartel, Christine H. Wichems, Charmaine Gittleson, Jillian Bennet, Gail Dawson, Wilson Hu, Connie Leggio, Diane Washington, Russell L. Basser
Journal: New England Journal of Medicine (2009)

A novel 2009 influenza A (H1N1) virus is responsible for the first influenza pandemic in 41 years. A safe and effective vaccine is needed. A randomized, observer-blind, parallel-group trial evaluating two doses of an inactivated, split-virus 2009 H1N1 vaccine in healthy adults between the ages of 18 and 64 years is ongoing at a single site in Australia.
Efficacy of platelet-rich plasma injections in osteoarthritis of the knee: a systematic review and meta-analysis
Authors: Augustinus B M Laudy, Eric W P Bakker, Mark Rekers, Maarten H Moen
Journal: British Journal of Sports Medicine (2014)

Background The effectiveness of platelet-rich plasma (PRP) injections for osteoarthritis (OA) is still controversial. We investigated the effect of PRP injections in patients with knee OA based on decreasing pain, improving function, global assessment and changes regarding joint imaging. Methods We performed a comprehensive, systematic literature search in computerised databases (MEDLINE, EMBASE, CINAHL, CENTRAL, Web of Science and PEDro) until June 2014 for randomised or non-randomised controlled trials. These were graded for risk of bias and a level of evidence was provided. If possible, meta-analysis was performed. Results Ten trials were included. In these, intra-articular PRP injections were more effective for pain reduction (mean difference (MD) −2.45; 95% CI −2.92 to −1.98; p value &lt;0.00001 and MD −2.07; 95% CI −2.59 to −1.55; p value &lt;0.00001, single and double PRP injections, respectively) compared with placebo at 6 months postinjection. Intra-articular PRP injections were compared with hyaluronic acid and showed a statistically significant difference in favour of PRP on pain reduction based on the visual analogue scale and numeric rating scale (standardised mean difference −0.92; 95% CI −1.20 to −0.63; p value &lt;0.00001) at 6 months postinjection. Almost all trials revealed a high risk of bias. Conclusions On the basis of the current evidence, PRP injections reduced pain more effectively than did placebo injections in OA of the knee (level of evidence: limited due to a high risk of bias). This significant effect on pain was also seen when PRP injections were compared with hyaluronic acid injections (level of evidence: moderate due to a generally high risk of bias). Additionally, function improved significantly more when PRP injections were compared with controls (limited to moderate evidence). More large randomised studies of good quality and low risk of bias are needed to test whether PRP injections should be a routine part of management of patients with OA of the knee.
Circulating Tumor Cells: A Novel Prognostic Factor for Newly Diagnosed Metastatic Breast Cancer
Authors: Massimo Cristofanilli, Daniel F. Hayes, G. Thomas Budd, Mathew J. Ellis, Alison Stopeck, James M. Reuben, Gerald V. Doyle, Jeri Matera, W. Jeffrey Allard, M. Craig Miller, Herbert A. Fritsche, Gabriel N. Hortobagyi, Leon W.M.M. Terstappen
Journal: Journal of Clinical Oncology (2005)

Metastatic breast cancer (MBC) is incurable; its treatment is palliative. We investigated whether the presence of circulating tumor cells (CTCs) predicts treatment efficacy, progression-free survival (PFS), and overall survival (OS) in patients with newly diagnosed MBC who were about to start first-line therapy.One hundred seventy-seven patients with measurable MBC were enrolled onto a prospective study. Eighty-three of the 177 patients were entering first-line treatment, and these patients are the focus of this analysis. CTCs from 7.5 mL of whole blood drawn before treatment initiation (baseline) and monthly thereafter for up to 6 months were isolated and enumerated using immunomagnetics.The mean (+/- standard deviation) follow-up time was 11.1 +/- 4.4 months (median, 12.2 months). Forty-three patients (52%) had > or = five CTCs at baseline. The median PFS was 7.2 months (95% CI, 4.9 to 9.4 months), and the median OS was more than 18 months. Patients with > or = five CTCs at baseline and at first follow-up (4 weeks) had a worse prognosis than patients with less than five CTCs (baseline: median PFS, 4.9 v 9.5 months, respectively; log-rank, P = .0014; median OS, 14.2 v > 18 months, respectively; log-rank, P = .0048; first follow-up: median PFS, 2.1 v 8.9 months, respectively; log-rank, P = .0070; median OS, 11.1 v > 18 months, respectively; log-rank, P = .0029). CTCs before and after the initiation of therapy were strong, independent prognostic factors.Detection of CTCs before initiation of first-line therapy in patients with MBC is highly predictive of PFS and OS. This technology can aid in appropriate patient stratification and design of tailored treatments.
Predictors and Prevalence of Paraganglioma Syndrome Associated With Mutations of the &lt;EMPH TYPE="ITAL"&gt;SDHC&lt;/EMPH&gt; Gene
Authors: Francesca Schiavi
Journal: JAMA (2005)

Paraganglioma syndrome includes inherited head and neck paragangliomas (HNPs) and adrenal or extra-adrenal pheochromocytomas and are classified according to the susceptibility genes SDHB, SDHC, and SDHD. In contrast with those with germline mutations of the SDHB and SDHD genes, clinical and genetic data on patients with mutations of SDHC are scarce.To determine the prevalence and clinical characteristics of SDHC mutation carriers compared with patients with SDHB and SDHD mutations and with sporadic cases.Genetic screening for SDHC mutations in an international HNP registry of 121 unrelated index cases and in 371 sporadic cases from a pheochromocytoma registry, conducted January 1, 2001, until December 31, 2004. Identified index cases and affected relatives were clinically evaluated.Prevalence of and clinical findings for SDHC mutation-associated HNPs vs those with SDHB and SDHD mutations.The prevalence of SDHC carriers was 4% in HNP but 0% in pheochromocytoma index cases. None of the SDHC mutation carriers had signs of pheochromocytoma. We compared HNPs in 22 SDHC mutation carriers with the HNPs of SDHB (n = 15) and SDHD (n = 42) mutation carriers and with 90 patients with sporadic HNPs. Location, number of tumors, malignancy, and age were different: more carotid body tumors were found in SDHC (13/22 [59%]) than in sporadic HNPs (29/90 [32%], P = .03), as well as fewer instances of multiple tumors in SDHC (2/22) than in SDHD (24/42; P<.001), 0 malignant tumors in SDHC vs 6/15 in SDHB (P = .002), and younger age at diagnosis in SDHC than in sporadic HNPs (45 vs 52 years; P = .03).Patients with HNP, but not those with pheochromocytoma, harbor SDHC mutations in addition to those in SDHB and SDHD. In total, more than one quarter of HNP patients carry a mutation in 1 of these 3 genes. Head and neck paragangliomas associated with SDHC mutations are virtually exclusively benign and seldom multifocal. Analysis for germline mutations of SDHC is recommended in apparently sporadic HNP to identify risk of inheritance.
Scalpels, Beams, Drugs, and Dreams: Challenges of Stage IIIA-N2 Non-Small-Cell Lung Cancer
Authors: D. H. Johnson, V. W. Rusch, A. T. Turrisi
Journal: JNCI Journal of the National Cancer Institute (2007)

Approximately 30% of patients who are newly diagnosed with non -small-cell lung cancers (NSCLCs) have locally advanced disease, i.e., stages IIIA and IIIB in the current staging system ( 1 ).Roughly 10% will be classified as stage IIIA-N2 on the basis of metastasis to the ipsilateral mediastinal lymph nodes ( 2 ).Furthermore, in a small proportion of patients, metastatic disease will be detected from primary tumor and lymph node specimens obtained during an operative procedure ( 2 ).Patients with stage IIIA-N2 NSCLC often have a good prognosis after surgery, but today, many will also be treated with postoperative adjuvant chemotherapy ( 3 , 4 ).In contrast, patients who have bulky mediastinal nodal involvement that is easily detected on a routine chest radiograph have poor prognosis after surgery alone ( 5 ) .Today, however, N2 disease is often initially suspected when mediastinal node enlargement (i.e., >1.0-cm short-axis diameter) is detected on a staging chest computed tomography (CT) scan, but increasingly sophisticated imaging technologies, such as positron emission tomography (PET), integrated CT/PET, and endoscopic ultrasound (± fine-needle biopsy), have enhanced the detection of N2 disease ( 6 , 7 ).For the past 15 years or so, patients with stage Scalpels, Beams, Drugs, and Dreams: Challenges of Stage IIIA-N2 Non -Small-Cell Lung Cancer
Noninvasive Measurements of Infarct Size After Thrombolysis With a Necrosis-Avid MRI Contrast Agent
Authors: Sorin V. Pislaru, Yicheng Ni, Cristina Pislaru, Hilde Bosmans, Yi Miao, Jan Bogaert, Steven Dymarkowski, Wolfhard Semmler, Guy Marchal, Frans J. Van de Werf
Journal: Circulation (1999)

Background —Gadophrin-2 is a new MRI contrast agent with high affinity for necrotic myocardium. The aim of the study was to evaluate whether noninvasive measurements of infarct size after thrombolysis are possible with gadophrin-2–enhanced MRI. Methods and Results —Coronary artery thrombosis was induced in 3 groups of dogs by the copper-coil technique. Thrombolytic therapy together with aspirin and heparin was initiated after 90 minutes of occlusion. One day (group A), 2 days (group B), or 6 days (group C) after infarction, gadophrin-2 was injected intravenously (50 μmol · kg −1 ). In vivo T1-weighted segmented turbo-FLASH, in vivo T2-weighted segmented half-Fourier turbo spin echo (HASTE), and T1- and T2-weighted spin-echo MRI of the excised heart were performed 24 hours after gadophrin-2 injection. Regions of strong enhancement were observed on T1-weighted images. Planimetry of short-axis MR images and of corresponding triphenyltetrazolium chloride (TTC)-stained left ventricular (LV) slices showed a close correlation between the enhanced areas and TTC-negative areas for both in vivo ( r 2 =0.98, P &lt;0.0001; mean difference, 0.9±2.0% [SD] of the LV volume [LVV]) and postmortem ( r 2 =0.99, P &lt;0.0001; mean difference, 0.9±1.4% of LVV) measurements. T2-weighted images overestimated the infarct size by 8.1±5.4% of LVV. The mean infarct size was 10.8±11.6% of LVV (group A), 22.4±11.7% (group B), and 5.1±9.3% (group C). Conclusions —In this animal model, in vivo gadophrin-2–enhanced MRI could precisely determine infarct size after thrombolytic therapy. This technique may be very useful for the noninvasive evaluation of infarct size after reperfusion for AMI.
Gc-globulin (vitamin D-binding protein) enhances the neutrophil chemotactic activity of C5a and C5a des Arg.
Authors: R R Kew, R O Webster
Journal: Journal of Clinical Investigation (1988)

Several serum proteins have been shown to be important in modulating leukocyte chemotaxis and inflammation. We investigated the possibility that the multifunctional serum protein Gc-globulin (vitamin D-binding protein) may also enhance the neutrophil chemotactic activity of complement-derived peptides. Purified Gc-globulin by itself did not induce chemotaxis of human neutrophils. However, as little as 0.01 nM Gc-globulin greatly enhanced the neutrophil chemotactic activity of C5a and its derivative, C5a des Arg over a wide concentration range. The effect was most pronounced at nonchemotactic doses of C5a (0.01 nM) and C5a des Arg (1 nM). Gc-globulin was unable to augment the neutrophil chemotactic activity of FMLP and leukotriene B4. This enhancing activity was not due to a nonspecific effect of anionic proteins since other purified serum proteins, of similar size and charge as Gc-globulin (alpha 1 acid glycoprotein, alpha 2 HS glycoprotein, alpha 2 histidine-rich glycoprotein), could not increase the chemotactic activity of C5a des Arg. Serum depleted of Gc-globulin by immunoaffinity chromatography totally lacked chemotactic enhancing activity for C5a des Arg. Gc-globulin-depleted serum activated with zymosan also had significantly less chemotactic activity than control- (sham-depleted) activated serum. Finally, radioiodinated C5a or C5a des Arg formed a 1:1 complex with purified Gc-globulin when analyzed by gel filtration chromatography. These results indicate that Gc-globulin is the major chemotactic enhancing factor in serum and may function as an up-regulator of the chemotactic activity of C5-derived peptides.
Dual color fluorescence analysis of peripheral T cell subsets in hepatitis B virus-induced liver disease
Authors: Kiyoshi Hasegawa, Katsumi Yamauchi, Takaji Furukawa, Hiroshi Obata
Journal: Hepatology (1988)

By using dual color fluorescence analysis, peripheral T cells can be divided into four different subsets, Leu-2a + , Leu-2a + 15 − , Leu-3a + 8 + and Leu-3a + 8 − cells. The ratio of these T cell subsets in hepatitis B virus-induced hepatitis patients was studied and compared with that of controls. No significant difference was found in acute hepatitis and chronic hepatitis, but an elevation of Leu-2a + 15 − (29.5 ± 2.8% vs. 18.8 ± 4.1%, p &lt; 0.05) as well as a reduction of Leu-2a + 15 + cells (3.2 ± 0.7% vs. 10.4 ± 3.2%, p &lt; 0.05) were found in fulminant hepatitis patients. In addition, serial studies of two fulminant hepatitis patients revealed that the imbalance of these two Leu-2a cells was only found in the acute phase, but not in the recovery phase. These results indicate that the imbalance of these two Leu-2a cells is associated with the clinical status of patients with fulminant hepatitis.
Adipose Tissue Lipolysis Is Upregulated in Lean and Obese Men During Acute Resistance Exercise
Authors: Athanasios Chatzinikolaou, Ioannis Fatouros, Anatoli Petridou, Athanasios Jamurtas, Alexandra Avloniti, Ioannis Douroudos, George Mastorakos, Christina Lazaropoulou, Ioannis Papassotiriou, Symeon Tournis, Asimina Mitrakou, Vassilis Mougios
Journal: Diabetes Care (2008)

OBJECTIVE—To investigate the effect of acute resistance exercise on adipose tissue triacylglycerol lipase activity (TGLA) in lean and obese men. RESEARCH DESIGN AND METHODS—Nine lean and eight obese men performed 30 min of circuit resistance exercise. Adipose tissue and blood were sampled during exercise for TGLA, metabolite, and hormone determinations. Respiratory exchange ratio (RER) was measured throughout exercise. RESULTS—Energy expenditure of exercise relative to body mass was higher in the lean and RER was higher in the obese men, suggesting lower fat oxidation. TGLA increased 18-fold at 5 min of exercise in the lean men and 16-fold at 10 min of exercise in the obese men. The delayed lipolytic activation in the obese men was reflected in serum nonesterified fatty acid and glycerol concentrations. Plasma insulin increased in the obese but did not change in the lean men. CONCLUSIONS—Resistance exercise upregulated adipose tissue lipolysis and enhanced energy expenditure in lean and obese men, with a delayed lipolytic activation in the obese men.
Preparation of kinase-biased compounds in the search for lead inhibitors of kinase targets
Authors: Justine Y.Q. Lai, Steven Langston, Ruth Adams, Rebekah E. Beevers, Richard Boyce, Svenja Burckhardt, James Cobb, Yvonne Ferguson, Eva Figueroa, Neil Grimster, Andrew H. Henry, Nawaz Khan, Kerry Jenkins, Mark W. Jones, Robert Judkins, Jeremy Major, Abid Masood, James Nally, Helen Payne, Lloyd Payne, Gilles Raphy, Tony Raynham, John Reader, Val�rie Reader, Alison Reid, Parminder Ruprah, Michael Shaw, Hannah Sore, Matthew Stirling, Adam Talbot, Jess Taylor, Stephen Thompson, Hiroki Wada, David Walker
Journal: Medicinal Research Reviews (2004)

This work describes the preparation of approximately 13,000 compounds for rapid identification of hits in high-throughput screening (HTS). These compounds were designed as potential serine/threonine or tyrosine kinase inhibitors. The library consists of various scaffolds, e.g., purines, oxindoles, and imidazoles, whereby each core scaffold generally includes the hydrogen bond acceptor/donor properties known to be important for kinase binding. Several of these are based upon literature kinase templates, or adaptations of them to provide novelty. The routes to their preparation are outlined. A variety of automation techniques were used to prepare >500 compounds per scaffold. Where applicable, scavenger resins were employed to remove excess reagents and when necessary, preparative high performance liquid chromatography (HPLC) was used for purification. These compounds were screened against an ‘in-house’ kinase panel. The success rate in HTS was significantly higher than the corporate compound collection. © 2004 Wiley Periodicals, Inc.
Gastroduodenal mucosa in uraemia: endoscopic and histological correlation and prevalence of helicobacter-like organisms.
Authors: A Wee, J Y Kang, M S Ho, H L Choong, A Y Wu, I H Sutherland
Journal: Gut (1990)

This study aimed to determine the prevalence of endoscopic and histological gastroduodenitis as well as helicobacter-like organisms in patients with end stage renal failure undergoing maintenance dialysis treatment. A total of 322 out of 422 patients in our dialysis programme underwent endoscopy and gastroduodenal biopsy specimens were taken from 260. Endoscopic gastroduodenitis occurred in 158 (49%). Histological gastritis occurred in the gastric body or antrum in 134 patients (52%) and duodenitis in 52 (21%). There was no correlation between endoscopic and histological gastritis in contrast to a significant correlation for duodenitis. Helicobacter-like organisms occurred in the body or antrum in 81 (31%). Their presence was associated with gastritis--in particular acute and acute on chronic gastritis rather than chronic gastritis. Patients with gastritis were significantly older than those without (p less than 0.001) and had lower basal and peak acid outputs.