tbuckley/cabot-search huggingface dataset:
Research ethics committees in the UK--the pressure is now on research and development departments
Authors: R. Al-Shahi
Journal: Journal of the Royal Society of Medicine (2005)

Picture this. You have a research question of international importance. Against the odds, you have secured non-commercial funding for a well-designed multicentre project that will answer the question. Naturally, you must obtain research ethics committee (REC) approval. You apply to an REC online. After clarifying questions about your application on just one occasion, you get a decision at no charge, within 60 days, and it is valid for the whole of your country.

While this scenario is a fantasy in countries such as the USA,1 Canada,2 and Australia,3 a recent Department of Health (DoH) report celebrates this new era of REC operation in the UK.4 But to what extent do the procedures in the UK meet this ideal, and have they improved? Do other regulatory hurdles lurk in the shadow cast by the mighty new REC system? In other words, is British researchers' long battle against red tape over?
GP120: Target for Neutralizing HIV-1 Antibodies
Authors: Ralph Pantophlet, Dennis R. Burton
Journal: Annual Review of Immunology (2006)

The glycoprotein (gp) 120 subunit is an important part of the envelope spikes that decorate the surface of HIV-1 and a major target for neutralizing antibodies. However, immunization with recombinant gp120 does not elicit neutralizing antibodies against multiple HIV-1 isolates (broadly neutralizing antibodies), and gp120 failed to demonstrate vaccine efficacy in recent clinical trials. Ongoing crystallographic studies of gp120 molecules from HIV-1 and SIV increasingly reveal how conserved regions, which are the targets of broadly neutralizing antibodies, are concealed from immune recognition. Based on this structural insight and that from studies of antibody structures, a number of strategies are being pursued to design immunogens that can elicit broadly neutralizing antibodies to gp120. These include (a) the construction of mimics of the viral envelope spike and (b) the design of antigens specifically tailored to induce broadly neutralizing antibodies.
Transcriptional Silencing of the Death Gene BNIP3 by Cooperative Action of NF-κB and Histone Deacetylase 1 in Ventricular Myocytes
Authors: James Shaw, Tong Zhang, Marek Rzeszutek, Natalia Yurkova, Delphine Baetz, James R. Davie, Lorrie A. Kirshenbaum
Journal: Circulation Research (2006)

Earlier we identified a survival role for NF-kappaB in ventricular myocytes, however, the underlying mechanism was undefined. In this report we provide new mechanistic evidence that the hypoxia-inducible death factor BNIP3 is transcriptionally silenced by NF-kappaB through a mechanism that involves the cooperative actions of HDAC1. Activation of the NF-kappaB signaling pathway in ventricular myocytes suppressed basal and hypoxia-inducible BNIP3 gene activity. Basal Bnip3 gene expression was increased in cells derived from p65(-/-) deficient mice. The histone deacetylase (HDAC) inhibitor Trichostatin A (TSA 10 nM) suppressed the inhibitory actions of NF-kappaB on Bnip3 gene transcription. Basal and hypoxia- induced Bnip3 transcription was repressed by wild type but not a catalytically inactive mutant of HDAC1. Immunoprecipitation assays verified interaction of HDAC1 with wild type p65 NF-kappaB and mutations of p65 defective for transactivation in ventricular myocytes. Deletion analysis revealed canonical NF-kappaB elements within the Bnip3 promoter to be important for repression of Bnip3 gene expression by HDAC1. Further, the ability of HDAC1 to repress Bnip3 gene transcription was lost in cells derived from p65(-/-) deficient mice but was restored by repletion of p65 NF-kappaB into p65(-/-) cells. Mutations of p65 NF-kappaB defective for DNA binding but not for transactivation abrogated the inhibitory actions of HDAC1 on the Bnip3 gene transcription. Together, our findings provide new mechanistic insight into the cytoprotective actions conferred by NF-kappaB that extend to the active transcriptional repression of the death factor Bnip3 through a mechanism that is mutually dependent on HDAC-1.
The immunology of virus infection in asthma
Authors: S.D. Message, S.L. Johnston
Journal: European Respiratory Journal (2001)

The respiratory tract is commonly infected by a range of viruses with overlapping pathologies. The majority of episodic exacerbations of asthma are associated with viral infection, in particular with rhinovirus infections. Experimental rhinovirus infection in human volunteers provides a useful model of natural virus-induced asthma. The asthmatic airway is characterized by an infiltrate of eosinophils and T-lymphocytes expressing the type 2 cytokines interleukin (IL)-4, IL-5 and IL-13. An effective antiviral immune response requires early viral clearance and appropriate termination of the immune response to minimize associated immunopathology and tissue damage. The antiviral immune response is made up of innate (nonspecific) and specific components, and requires the coordinated actions of many different cell types including neutrophils, macrophages, eosinophils, dendritic cells, epithelial cells, mast cells, natural killer cells and B- and T-lymphocytes. Coordination of this response involves numerous cytokines and chemokines. T-lymphocytes expressing type 1 cytokines including interferon-γ play a key role. Pre-existing asthmatic inflammation in the lower airway may modify the immune response to viral infection by altering the balance of T-cell cytokine expression from type 1 towards a type 2 in what is always a mixed response. The consequence is delayed viral clearance, persistent virus-induced inflammation and amplification of the allergic inflammation.
Mutants in the ADP-ribosyltransferase Cleft of Cholera Toxin Lack Diarrheagenicity but Retain Adjuvanticity
Authors: Shingo Yamamoto, Yoshifumi Takeda, Masafumi Yamamoto, Hisao Kurazono, Koichi Imaoka, Miho Yamamoto, Kohtaro Fujihashi, Masatoshi Noda, Hiroshi Kiyono, Jerry R. McGhee
Journal: The Journal of Experimental Medicine (1997)

Cholera toxin (CT), the most commonly used mucosal adjuvant in experimental animals, is unsuitable for humans because of potent diarrhea-inducing properties. We have constructed two CT-A subunit mutants, e.g., serine→ phenylalanine at position 61 (S61F), and glutamic acid→ lysine at 112 (E112K) by site-directed mutagenesis. Neither mutant CT (mCT), in contrast to native CT (nCT), induced adenosine diphosphate-ribosylation, cyclic adenosine monophosphate formation, or fluid accumulation in ligated mouse ileal loops. Both mCTs retained adjuvant properties, since mice given ovalbumin (OVA) subcutaneously with mCTs or nCT, but not OVA alone developed high-titered serum anti-OVA immunoglobulin G (IgG) antibodies (Abs) which were largely of IgG1 and IgG2b subclasses. Although nCT induced brisk IgE Ab responses, both mCTs elicited lower anti-OVA IgE Abs. OVA-specific CD4+ T cells were induced by nCT and by mCTs, and quantitative analysis of secreted cytokines and mRNA revealed a T helper cell 2 (Th2)-type response. These results now show that the toxic properties of CT can be separated from adjuvanticity, and the mCTs induce Ab responses via a Th2 cell pathway.
Newly Diagnosed Asthma In The Elderly: Is It Really Different?
Authors: Bilun Gemicioglu, Oznur Abadoglu, Levent Akyildiz, Hasan Bayram, Aykut Cilli, Arif Cimrin, Hakan Gunen, Zeynep Misirligil, Tevfik Ozlu, Mecit Suerdem, Esra Uzaslan
Journal: Journal of Allergy and Clinical Immunology (2014)
The activity of the metabolic form of hepatic phosphatidate phosphohydrolase correlates with the severity of alcoholic fatty liver in human beings
Authors: Christopher P. Day, Oliver F. W. James, Ashley J. M. St. Brown, Mark K. Bennett, Ian N. Fleming, Stephen J. Yeaman
Journal: Hepatology (1993)

Increased esterification of fatty acids to triglyceride is common to most of the mechanisms proposed to explain the causation of alcoholic fatty liver. However, it is unclear whether this is caused by increased substrate supply or whether direct stimulation of the enzymes of the esterification pathway occurs after excessive alcohol intake. The rate-limiting step in triglyceride synthesis is catalyzed by the enzyme phosphatidate phosphohydrolase, which is present in the cytosol and microsomes and is sensitive to inhibition by N-ethylmaleimide. This enzyme is physically distinct from a second form of phosphatidate phosphohydrolase that is located predominantly in the plasma membrane, is insensitive to N-ethylmaleimide inhibition and has a putative role in cell-signaling. We have investigated whether the activity of the N-ethylmaleimide-sensitive (“metabolic”) form of phosphatidate phosphohydrolase is increased in patients with alcoholic liver disease and whether any increased activity correlates with the severity of steatosis. N-ethylmaleimide-sensitive and -insensitive phosphatidate phosphohydrolase activities were measured in needle liver biopsy specimens from 42 alcoholic patients and 6 patients with primary biliary cirrhosis and in wedge biopsy specimens from 6 normal patients undergoing routine cholecystectomy. Steatosis was “scored” on coded slides from 0 to 3. N-ethylmaleimide-sensitive activity was higher in alcoholic biopsy specimens scoring 3 (3.25 ± 0.4 units/mg protein, n = 10) than in those scoring either 0 (1.21 ± 0.2, n = 14) or 1 to 2 (1.58 ± 0.2, n = 18), and it was also higher than in biopsy specimens from normal and primary biliary cirrhosis patients (1.65 ± 0.3, n = 12; p &lt; 0.0001, analysis of variance). No differences were found in age, weight, cumulative or current alcohol intake, coexistent cirrhosis or N-ethylmaleimide-insensitive activity between the groups of alcoholic patients with different fat scores. These results demonstrate that the activity of metabolic, N-ethylmaleimide-sensitive phosphatidate phosphohydrolase is increased in some patients with alcoholic liver disease. That this increase was only observed in patients with severe alcoholic steatosis suggests that the activity of this enzyme may play a role in the pathogenesis of alcoholic fatty liver and may, in part, explain differences in susceptibility to this common complication of alcohol abuse. (HEPATOLOGY 1993;18:832-838).
Brain-derived Neurotrophic Factor in Platelets and Airflow Limitation in Asthma
Authors: Marek Lommatzsch, Katharina Schloetcke, Jens Klotz, Katharina Schuhbaeck, Doerte Zingler, Christiana Zingler, Olaf Schulte-Herbrüggen, Hartmut Gill, Peter Schuff-Werner, Johann Christian Virchow
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Brain-derived neurotrophic factor (BDNF), a key mediator of neuronal plasticity, contributes to airway obstruction and hyperresponsiveness in a model of allergic asthma. BDNF is stored in human platelets and circulates in human plasma, but the significance of BDNF in this compartment is poorly understood. We investigated the relationship between platelet and plasma BDNF levels and pulmonary function in a cohort of 26 adult patients with recently diagnosed allergic asthma. BDNF levels in serum, platelets, and plasma were significantly increased in participants with asthma, as compared with 26 age- and sex-matched control subjects. In steroid-naive patients, but not in patients using inhaled corticosteroids, enhanced platelet BDNF levels correlated with parameters of airway obstruction and airway hyperresponsiveness to histamine. Experiments with activated peripheral blood mononuclear cells revealed that corticosteroids such as fluticasone effectively suppress BDNF secretion. In conclusion, we demonstrate that enhanced platelet BDNF is associated with airflow limitation and airway hyperresponsiveness in asthma. In addition, we provide evidence that corticosteroids suppress BDNF production by activated immune cells.
Detection of small hepatocellular carcinomas in cirrhotic livers using iodised oil computed tomography
Authors: J Saada, S Bhattacharya, A P Dhillon, R Dick, A K Burroughs, K Rolles, B R Davidson
Journal: Gut (1997)

Background —The detection of hepatocellular cancers (HCC) is a major role of preoperative imaging in patients with end stage liver disease being considered for orthotopic liver transplantation (OLT). Aims —To assess the sensitivity of iodised oil computed tomography (IOCT). Patients and methods —A prospective evaluation in 50 consecutive patients undergoing OLT included ultrasound scan, contrast enhanced CT, angiography (with intra-arterial injection of iodised oil), and a second CT (IOCT) 10 days later. Following transplantation the explant liver was serially sectioned for pathological evaluation. Soft tissue radiographs of the liver slices were used to match histological lesions with CT findings. Results —Eleven patients were excluded due to protocol violations. Of the remaining 39, histological evaluation revealed no cancers in 33 explant livers, in keeping with negative preoperative imaging. Six explant livers contained 55 HCCs, 84% of which were less than 1 cm in diameter. Pretransplant IOCT detected 3/6 patients with cancer (50%) but only 7% of cancerous lesions. Ultrasound, contrast CT, and angiography each detected 2/6 patients with cancer and 4% of cancerous lesions. Conclusion —IOCT is an insensitive method for the detection of small HCCs in livers with advanced cirrhosis but in this study was slightly superior to ultrasound, CT, and angiography.
Expression of BMP-7 and USAG-1 (a BMP antagonist) in kidney development and injury
Authors: M. Tanaka, S. Endo, T. Okuda, A.N. Economides, D.M. Valenzuela, A.J. Murphy, E. Robertson, T. Sakurai, A. Fukatsu, G.D. Yancopoulos, T. Kita, M. Yanagita
Journal: Kidney International (2007)
The Renal Na+-Dependent Dicarboxylate Transporter, NaDC-3, Translocates Dimethyl- and Disulfhydryl-Compounds and Contributes to Renal Heavy Metal Detoxification
Authors: Birgitta C. Burckhardt, Britta Drinkuth, Christine Menzel, Angela Ko[Combining Diaeresis]nig, Ju[Combining Diaeresis]rgen Steffgen, Stephen H. Wright, Gerhard Burckhardt
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. The active transport of Krebs cycle intermediates, such as succinate, α-ketoglutarate, and citrate, is mediated by sodium-coupled transporters found in the luminal (NaDC-1) and basolateral plasma membranes (NaDC-3) of proximal tubule cells. This study used the two-electrode voltage clamp technique to examine steady-state currents associated with the influx of three sodium ions and one divalent dicarboxylate into oocytes expressing the sodium-dicarboxylate transporter from winter flounder kidney, fNaDC-3. The substrate concentration, where half-maximal current was observed (K0.5), was 30 μM for succinate. Besides 2,2-dimethylsuccinate, fNaDC-3 also accepted 2,3-dimethylsuccinate and the oral lead-chelating agent, meso-2,3-dimercaptosuccinate (DMSA or Succimer). Whereas the K0.5 for succinate and 2,2-dimethylsuccinate was independent of membrane voltage within −90 and −10 mV, K0.5 for 2,3-dimethylsuccinate and 2,3-dimercaptosuccinate increased with decreasing voltage, indicating a critical role of the position of the methyl- or sulfhydryl-group in voltage-sensitive affinity. In addition to meso-2,3-dimercaptosuccinate, fNaDC-3 translocated dimercaptopropane-1-sulfonate (DMPS or Dimaval), an oral chelator for the treatment of mercury intoxication. The chelates formed by HgCl2 and DMSA or DMPS and by Pb(NO3)2 and DMSA, however, were not translocated by fNaDC-3. The data suggest that NaDC-3 is an essential component in the delivery of uncomplexed antidotes for renal heavy metal detoxification.
Assessment of the rate of long-term complete remission off therapy in patients with pemphigus treated with different regimens including medium- and high-dose corticosteroids
Authors: Naif Almugairen, Valerie Hospital, Christophe Bedane, Sophie Duvert-Lehembre, Damien Picard, Anne-Fleur Tronquoy, Estelle Houivet, Michel D'incan, Pascal Joly
Journal: Journal of the American Academy of Dermatology (2013)
A novel variant of the beta-subunit of the amiloride-sensitive sodium channel in African Americans.
Authors: Y R Su, M P Rutkowski, C A Klanke, X Wu, Y Cui, R Y Pun, V Carter, M Reif, A G Menon
Journal: Journal of the American Society of Nephrology (1996)

The amiloride-sensitive sodium channel is responsible for the rate-limiting step of sodium reabsorption in the distal renal tubule, and thus may play a key role in the maintenance of sodium balance and blood pressure. In this study, a genetic variant that results in a change of threonine to methionine at amino acid 594 (T594 M) in the carboxy-terminus of the beta-subunit of the amiloride-sensitive sodium channel has been identified. This variant was present in 6.1% of African-American subjects (N = 231) but was not seen in Caucasians (N = 192). Whole cell voltage clamp of B-lymphocytes from individuals with the T594 M variant showed similar basal membrane slope conductance, compared with the wild-type but increased response to cAMP analog.
Benzo[a]pyrene diol epoxide suppresses retinoic acid receptor-β2 expression by recruiting DNA (cytosine-5-)-methyltransferase 3A
Authors: Fei Ye, Xiao-Chun Xu
Journal: Molecular Cancer (2010)

Tobacco smoke is an important risk factor for various human cancers, including esophageal cancer. How benzo [a]pyrene diol epoxide (BPDE), a carcinogen present in tobacco smoke as well as in environmental pollution, induces esophageal carcinogenesis has yet to be defined. In this study, we investigated the molecular mechanism responsible for BPDE-suppressed expression of retinoic acid receptor-beta2 (RAR-beta2) in esophageal cancer cells. We treated esophageal cancer cells with BPDE before performing methylation-specific polymerase chain reaction (MSP) to find that BPDE induced methylation of the RAR-beta2 gene promoter. We then performed chromatin immunoprecipitation (ChIP) assays to find that BPDE recruited genes of the methylation machinery into the RAR-beta2 gene promoter. We found that BPDE recruited DNA (cytosine-5-)-methyltransferase 3 alpha (DNMT3A), but not beta (DNMT3B), in a time-dependent manner to methylate the RAR-beta2 gene promoter, which we confirmed by reverse transcription-polymerase chain reaction (RT-PCR) analysis of the reduced RAR-beta2 expression in these BPDE-treated esophageal cancer cell lines. However, BPDE did not significantly change DNMT3A expression, but it slightly reduced DNMT3B expression. DNA methylase inhibitor 5-aza-2'-deoxycytidine (5-Aza) and DNMT3A small hairpin RNA (shRNA) vector antagonized the effects of BPDE on RAR-beta2 expressions. Transient transfection of the DNMT3A shRNA vector also antagonized BPDE's effects on expression of RAR-beta2, c-Jun, phosphorylated extracellular signal-regulated protein kinases 1/2 (ERK1/2), and cyclooxygenase-2 (COX-2), suggesting a possible therapeutic effect. The results of this study form the link between the esophageal cancer risk factor BPDE and the reduced RAR-beta2 expression.
Positive selection on the H3 hemagglutinin gene of human influenza virus A
Authors: R. M. Bush, W. M. Fitch, C. A. Bender, N. J. Cox
Journal: Molecular Biology and Evolution (1999)

The hemagglutinin (HA) gene of influenza viruses encodes the major surface antigen against which neutralizing antibodies are produced during infection or vaccination. We examined temporal variation in the HA1 domain of HA genes of human influenza A (H3N2) viruses in order to identify positively selected codons. Positive selection is defined for our purposes as a significant excess of nonsilent over silent nucleotide substitutions. If past mutations at positively selected codons conferred a selective advantage on the virus, then additional changes at these positions may predict which emerging strains will predominate and cause epidemics. We previously reported that a 38% excess of mutations occurred on the tip or terminal branches of the phylogenetic tree of 254 HA genes of influenza A (H3N2) viruses. Possible explanations for this excess include processes other than viral evolution during replication in human hosts. Of particular concern are mutations that occur during adaptation of viruses for growth in embryonated chicken eggs in the laboratory. Because the present study includes 357 HA sequences (a 40% increase), we were able to separately analyze those mutations assigned to internal branches. This allowed us to determine whether mutations on terminal and internal branches exhibit different patterns of selection at the level of individual codons. Additional improvements over our previous analysis include correction for a skew in the distribution of amino acid replacements across codons and analysis of a population of phylogenetic trees rather than a single tree. The latter improvement allowed us to ascertain whether minor variation in tree structure had a significant effect on our estimate of the codons under positive selection. This method also estimates that 75.6% of the nonsilent mutations are deleterious and have been removed by selection prior to sampling. Using the larger data set and the modified methods, we confirmed a large (40%) excess of changes on the terminal branches. We also found an excess of changes on branches leading to egg-grown isolates. Furthermore, 9 of the 18 amino acid codons, identified as being under positive selection to change when we used only mutations assigned to internal branches, were not under positive selection on the terminal branches. Thus, although there is overlap between the selected codons on terminal and internal branches, the codons under positive selection on the terminal branches differ from those on the internal branches. We also observed that there is an excess of positively selected codons associated with the receptor-binding site and with the antibody-combining sites. This association may explain why the positively selected codons are restricted in their distribution along the sequence. Our results suggest that future studies of positive selection should focus on changes assigned to the internal branches, as certain of these changes may have predictive value for identifying future successful epidemic variants.
Short-Term Treatment With Ranolazine Improves Mechanical Efficiency in Dogs With Chronic Heart Failure
Authors: Margaret P. Chandler, William C. Stanley, Hideaki Morita, George Suzuki, Bridgette A. Roth, Brent Blackburn, Andrew Wolff, Hani N. Sabbah
Journal: Circulation Research (2002)

The present study assesses whether ranolazine increases left ventricular (LV) function without an increase in myocardial oxygen consumption (MV̇ o 2 ) and thus improves LV mechanical efficiency in dogs with heart failure (HF). Ranolazine did not change MV̇ o 2 and LV mechanical efficiency increased (22.4±2.8% to 30.9±3.4% ( P &lt;0.05). In contrast, dobutamine significantly increased MV̇ o 2 and did not improve mechanical efficiency. Thus, short-term treatment with ranolazine improved LV function without an increase in MV̇ o 2 , resulting in an increased myocardial mechanical efficiency in dogs with HF.