tbuckley/cabot-search huggingface dataset:
Identification of a serine protease as a major allergen (Per a 10) of <i>Periplaneta americana</i>
Authors: V. T. Sudha, N. Arora, S. N. Gaur, S. Pasha, B. P. Singh
Journal: Allergy (2008)

Background: Cockroach allergens are associated with the development of asthma, but none of these has been characterized for proteolytic activity. This study was undertaken to isolate and characterize a protease from Periplaneta americana and determine its allergenicity. Methods: A serine protease was isolated from P. americana extract using benzamidine sepharose column and characterized by immunobiochemical methods. Allergenicity of the protease was assessed by enzyme‐linked immunosorbent assay, immunoblot, intradermal testing, histamine release and peripheral blood mononuclear cells (PBMCs) proliferation. Results: Affinity purified protein of ∼28 kDa (Per a 10) showed a single band of activity in gelatin zymogram and agarose plate assay. N‐terminal sequence (IVGGRPAQI) revealed similarity with mite serine protease allergens and insect trypsins. It demonstrated proteolytic activity with azocollagen &gt; gelatin &gt; defatted‐milk &gt; casein including serine protease specific substrate, N ‐benzoyl‐arginine‐ethyl‐ester‐hydrochloride. It was inhibited by serine protease inhibitors, namely aprotinin &gt; pefabloc &gt; AEBSF &gt; PMSF &gt; benzamidine &gt; antipain &gt; leupeptin and trypsin‐specific inhibitor (tosyl‐lysyl‐chloromethyl‐ketone) suggesting it to be a trypsin‐like serine protease. Per a 10 was recognized as a major allergen, showing IgE reactivity with &gt;80% of cockroach sensitized patients by skin tests and immunoblot. It could induce significant histamine release ( P &lt; 0.05) in blood and secretion of interleukin‐4 (IL‐4) ( P &lt; 0.05) and IL‐5 ( P &lt; 0.05) in culture supernatant of PBMCs from cockroach hypersensitive patients, suggesting a strong allergenic potency. Conclusion: A serine protease isolated from P. americana was demonstrated to be a major allergen (Per a 10). It has a potential for component‐based diagnosis of allergy and will be useful in elucidating the mechanism of allergy.
Colorectal and Other Cancer Risks for Carriers and Noncarriers From Families With a DNA Mismatch Repair Gene Mutation: A Prospective Cohort Study
Authors: Aung Ko Win, Joanne P. Young, Noralane M. Lindor, Katherine M. Tucker, Dennis J. Ahnen, Graeme P. Young, Daniel D. Buchanan, Mark Clendenning, Graham G. Giles, Ingrid Winship, Finlay A. Macrae, Jack Goldblatt, Melissa C. Southey, Julie Arnold, Stephen N. Thibodeau, Shanaka R. Gunawardena, Bharati Bapat, John A. Baron, Graham Casey, Steven Gallinger, Loïc Le Marchand, Polly A. Newcomb, Robert W. Haile, John L. Hopper, Mark A. Jenkins
Journal: Journal of Clinical Oncology (2012)

To determine whether cancer risks for carriers and noncarriers from families with a mismatch repair (MMR) gene mutation are increased above the risks of the general population.We prospectively followed a cohort of 446 unaffected carriers of an MMR gene mutation (MLH1, n = 161; MSH2, n = 222; MSH6, n = 47; and PMS2, n = 16) and 1,029 their unaffected relatives who did not carry a mutation every 5 years at recruitment centers of the Colon Cancer Family Registry. For comparison of cancer risk with the general population, we estimated country-, age-, and sex-specific standardized incidence ratios (SIRs) of cancer for carriers and noncarriers.Over a median follow-up of 5 years, mutation carriers had an increased risk of colorectal cancer (CRC; SIR, 20.48; 95% CI, 11.71 to 33.27; P < .001), endometrial cancer (SIR, 30.62; 95% CI, 11.24 to 66.64; P < .001), ovarian cancer (SIR, 18.81; 95% CI, 3.88 to 54.95; P < .001), renal cancer (SIR, 11.22; 95% CI, 2.31 to 32.79; P < .001), pancreatic cancer (SIR, 10.68; 95% CI, 2.68 to 47.70; P = .001), gastric cancer (SIR, 9.78; 95% CI, 1.18 to 35.30; P = .009), urinary bladder cancer (SIR, 9.51; 95% CI, 1.15 to 34.37; P = .009), and female breast cancer (SIR, 3.95; 95% CI, 1.59 to 8.13; P = .001). We found no evidence of their noncarrier relatives having an increased risk of any cancer, including CRC (SIR, 1.02; 95% CI, 0.33 to 2.39; P = .97).We confirmed that carriers of an MMR gene mutation were at increased risk of a wide variety of cancers, including some cancers not previously recognized as being a result of MMR mutations, and found no evidence of an increased risk of cancer for their noncarrier relatives.
Nitric oxide inhibits Kv4.3 and human cardiac transient outward potassium current (Ito1)
Authors: R. Gomez, L. Nunez, M. Vaquero, I. Amoros, A. Barana, T. de Prada, C. Macaya, L. Maroto, E. Rodriguez, R. Caballero, A. Lopez-Farre, J. Tamargo, E. Delpon
Journal: Cardiovascular Research (2008)

Chronic atrial fibrillation (CAF) is characterized by a shortening of the plateau phase of the action potentials (AP) and a decrease in the bioavailability of nitric oxide (NO). In this study, we analysed the effects of NO on Kv4.3 (I(Kv4.3)) and on human transient outward K(+) (I(to1)) currents as well as the signalling pathways responsible for them. We also analysed the expression of NO synthase 3 (NOS3) in patients with CAF.I(Kv4.3) and I(to1) currents were recorded in Chinese hamster ovary cells and in human atrial and mouse ventricular dissociated myocytes using the whole-cell patch clamp. The expression of NOS3 was analysed by western blotting. AP were recorded using conventional microelectrode techniques in mouse atrial preparations. NO and NO donors inhibited I(Kv4.3) and human I(to1) in a concentration- and voltage-dependent manner (IC(50) for NO: 375.0 +/- 48 nM) as a consequence of the activation of adenylate cyclase and the subsequent activation of the cAMP-dependent protein kinase and the serine-threonine phosphatase 2A. The density of the I(to1) recorded in ventricular myocytes from wild-type (WT) and NOS3-deficient mice (NOS3(-/-)) was not significantly different. Furthermore, the duration of atrial AP repolarization in WT and NOS3(-/-) mice was not different. The increase in NO levels to 200 nM prolonged the plateau phase of the mouse atrial AP and lengthened the AP duration measured at 20 and 50% of repolarization of the human atrial CAF-remodelled AP as determined using a mathematical model. However, the expression of NOS3 was not modified in left atrial appendages from CAF patients.Our results suggested that the increase in the atrial NO bioavailability could partially restore the duration of the plateau phase of CAF-remodelled AP by inhibiting the I(to1) as a result of the activation of non-canonical enzymatic pathways.
Connexin43 in cardiomyocyte mitochondria contributes to mitochondrial potassium uptake
Authors: Elisabet Miro-Casas, Marisol Ruiz-Meana, Esperanza Agullo, Sabine Stahlhofen, Antonio Rodrı́guez-Sinovas, Alberto Cabestrero, Inmaculada Jorge, Iratxe Torre, Jesus Vazquez, Kerstin Boengler, Rainer Schulz, Gerd Heusch, David Garcia-Dorado
Journal: Cardiovascular Research (2009)

AimsConnexin43 is present at the inner membrane of cardiomyocyte mitochondria (mCx43), but its function remains unknown.
Switzerland has opened door to genetic discrimination, say ethicists
Authors: Jane Burgermeister
Journal: BMJ (2004)

Body set up to increase numbers taking part in trials 365, 149 A new body was launched last week to get the NHS and industry working more closely together to increase the number of patients taking part in clinical trials.The UK Clinical Research Collaboration will bring together key players to speed up the development of medicines in five areas-Alzheimer's disease, stroke, diabetes, mental health, and children's medicine.Representatives from the NHS, industry, the Medical Research Council and other funding bodies, medical charities, and the National Institute for Clinical Excellence (NICE) will make up the new body.Using the successful National Cancer Research Networks organisation as a model, the collaboration will use an initial £24m ($44m; €36m) to set up similar research networks in the five new areas.
NASH and insulin resistance: Insulin hypersecretion and specific association with the insulin resistance syndrome
Authors: Shivakumar Chitturi, Shehan Abeygunasekera, Geoffrey C. Farrell, Jane Holmes-Walker, Jason M. Hui, Caroline Fung, Rooshdiya Karim, Rita Lin, Dev Samarasinghe, Christopher Liddle, Martin Weltman, Jacob George
Journal: Hepatology (2002)

Nonalcoholic steatohepatitis (NASH) is often linked with disorders that are clearly associated with insulin resistance (IR): obesity, type 2 diabetes mellitus, and hypertriglyceridemia. We tested the hypotheses that (1) IR is an essential requirement for the development of NASH and (2) a high association between IR and liver disease is relatively specific for NASH. We measured body mass index (BMI), waist/hip ratio, and fasting serum lipid, insulin, C-peptide, and glucose levels in 66 patients with NASH (21 with advanced fibrosis and 45 with mild fibrosis). IR was determined by the homeostasis model assessment (HOMA). We also determined the strength of the association of NASH with insulin resistance syndrome (IRS) as defined by World Health Organization criteria. To assess whether the finding of IR was relatively specific to NASH rather than simply to obesity or liver disease, we compared the results of a subset of 36 patients with less-severe NASH with 36 age- and sex-matched patients with chronic hepatitis C virus (HCV) of comparable fibrotic severity. IR was confirmed in 65 patients (98%) with NASH, and 55 (87%) fulfilled minimum criteria for IRS. IR was found in lean as well as in overweight and obese patients. The IR values and the prevalence of IRS (75% vs. 8.3%) were significantly higher in those with NASH than in comparable cases of HCV. Hyperinsulinemia was attributable to increased insulin secretion rather than decreased hepatic extraction. In conclusion, most patients with NASH have IRS, and there is a near-universal association between NASH and IR irrespective of obesity. IR is present in mild as well as advanced cases of NASH but is unusual in chronic HCV of similar fibrotic severity.
CCR5 Levels and Expression Pattern Correlate with Infectability by Macrophage-tropic HIV-1, In Vitro
Authors: Lijun Wu, William A. Paxton, Nasim Kassam, Nancy Ruffing, James B. Rottman, Nancy Sullivan, Hyeryun Choe, Joseph Sodroski, Walter Newman, Richard A. Koup, Charles R. Mackay
Journal: The Journal of Experimental Medicine (1997)

Chemokine receptors serve as coreceptors for HIV entry into CD4+ cells. Their expression is thought to determine the tropism of viral strains for different cell types, and also to influence susceptibility to infection and rates of disease progression. Of the chemokine receptors, CCR5 is the most important for viral transmission, since CCR5 is the principal receptor for primary, macrophage-tropic viruses, and individuals homozygous for a defective CCR5 allele (Δ32/ Δ32) are highly resistant to infection with HIV-1. In this study, CCR5-specific mAbs were generated using transfectants expressing high levels of CCR5. The specificity of these mAbs was confirmed using a broad panel of chemokine receptor transfectants, and by their non-reactivity with T cells from Δ32/Δ32 individuals. CCR5 showed a distinct pattern of expression, being abundant on long-term activated, IL-2–stimulated T cells, on a subset of effector/memory T cells in blood, and on tissue macrophages. A comparison of normal and CCR5 Δ32 heterozygotes revealed markedly reduced expression of CCR5 on T cells from the heterozygotes. There was considerable individual to individual variability in the expression of CCR5 on blood T cells, that related to factors other than CCR5 genotype. Low expression of CCR5 correlated with the reduced infectability of T cells with macrophage-tropic HIV-1, in vitro. Anti-CCR5 mAbs inhibited the infection of PBMC by macrophage-tropic HIV-1 in vitro, but did not inhibit infection by T cell–tropic virus. Anti-CCR5 mAbs were poor inhibitors of chemokine binding, indicating that HIV-1 and ligands bind to separate, but overlapping regions of CCR5. These results illustrate many of the important biological features of CCR5, and demonstrate the feasibility of blocking macrophage-tropic HIV-1 entry into cells with an anti-CCR5 reagent.
B-cell reconstitution for SCID: Should a conditioning regimen be used in SCID treatment?
Authors: Elie Haddad, Sandrine Leroy, Rebecca H. Buckley
Journal: Journal of Allergy and Clinical Immunology (2013)

Bone marrow transplantation has resulted in life-saving sustained T-cell reconstitution in many infants with severe combined immunodeficiency (SCID), but correction of B-cell function has been more problematic. At the annual meeting of the Primary Immunodeficiency Treatment Consortium held in Boston, Massachusetts, on April 27, 2012, a debate was held regarding the use of pretransplantation conditioning versus no pretransplantation conditioning in an effort to address this problem. Reviews of the literature were made by both debaters, and there was agreement that there was a higher rate of B-cell chimerism and a lower number of patients who required ongoing immunoglobulin replacement therapy in centers that used pretransplantation conditioning. However, there were still patients who required immunoglobulin replacement in those centers, and therefore pretransplantation conditioning did not guarantee development of B-cell function. Dr Rebecca H. Buckley presented data on B-cell function according to the molecular defect of the patient, and showed that patients with IL-7 receptor α, ADA, and CD3 chain gene mutations can have normal B-cell function after transplantation with only host B cells. Dr Elie Haddad presented a statistical analysis of B-cell function in published reports and showed that only a conditioning regimen that contained busulfan was significantly associated with better B-cell function after transplantation. The question is whether the risk of immediate and long-term toxicity with use of busulfan is justified, particularly in patients with SCID with DNA repair defects and in very young newborns with SCID who will be detected by using newborn screening.
MYC-Dependent Regulation and Prognostic Role of CIP2A in Gastric Cancer
Authors: Anchit Khanna, Camilla Böckelman, Annabrita Hemmes, Melissa R Junttila, Jan-Patrik Wiksten, Mikael Lundin, Siina Junnila, Daniel J Murphy, Gerard I Evan, Caj Haglund, Jukka Westermarck, Ari Ristimäki
Journal: JNCI Journal of the National Cancer Institute (2009)

BackgroundCancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified human oncoprotein that stabilizes the c-Myc (MYC) protein. However, the clinical relevance of CIP2A to human cancers had not been demonstrated, but the mechanism of its regulation and its clinical role in cancer were completely unknown.
Reduction of ciliary beat frequency in vitro by sputum from patients with bronchiectasis: a serine proteinase effect.
Authors: L A Smallman, S L Hill, R A Stockley
Journal: Thorax (1984)

Specialist infertility practice was studied in a group of 708 couples within a population of residents of a single health district in England. They represented an annual incidence of 1.2 couples for every 1000 of the population. At least one in six couples needed specialist help at some time in their lives because of an average of infertility of 21/2 years, 71% of whom were trying for their first baby. Those attending gynaecology clinics made up 10% of new and 22% of all attendances. Failure of ovulation (amenorrhoea or oligomenorrhoea) occurred in 21% of cases and was successfully treated (two year conception rates of 96% and 78%). Tubal damage (14%) had a poor outlook (19%) despite surgery. Endometriosis accounted for infertility in 6%, although seldom because of tubal damage, cervical mucus defects or dysfunction in 3%, and coital failure in up to 6%. Sperm defects or dysfunction were the commonest defined cause of infertility (24%) and led to a poor chance of pregnancy (0-27%) without donor insemination. Obstructive azoospermia or primary spermatogenic failure was uncommon (2%) and hormonal causes of male infertility rare. Infertility was unexplained in 28% and the chance of pregnancy (overall 72%) was mainly determined by duration of infertility. In vitro fertilisation could benefit 80% of cases of tubal damage and 25% of unexplained infertility--that is, 18% of all cases, representing up to 216 new cases each year per million of the total population.
Function and Bulk of Respiratory and Limb Muscles in Patients with Cystic Fibrosis
Authors: Christophe Pinet, Marie Cassart, Pietro Scillia, Michel Lamotte, Christiane Knoop, Georges Casimir, Christian Mélot, Marc Estenne
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Inspiratory muscle weakness due to lung hyperinflation and muscle wasting may occur in cystic fibrosis. We therefore measured diaphragm function and bulk in 18 stable patients with cystic fibrosis and 15 matched control subjects; the abdominal and quadriceps muscles were studied for comparison. We assessed diaphragm mass, abdominal muscle thickness, twitch transdiaphragmatic and gastric pressures, quadriceps cross-section and isokinetic strength, and lean body mass. Lean body mass, quadriceps strength, and quadriceps cross-section were lower in patients with cystic fibrosis. Twitch transdiaphragmatic pressure was 23% lower and twitch gastric pressure was 22% greater in patients with cystic fibrosis than in control subjects, but diaphragm mass and abdominal muscle thickness were similar in the two groups. For any given lean body mass and quadriceps cross-section, patients with cystic fibrosis had greater diaphragm mass and abdominal muscle thickness. Diaphragm mass had greater intersubject variability in patients with cystic fibrosis than in control subjects. We conclude that diaphragm strength is decreased but abdominal muscle strength is increased in patients with cystic fibrosis. Diaphragm and abdominal muscle bulk are not affected by the general muscle wasting, which suggests that there may be a training effect of cystic fibrosis on respiratory muscles. However, the variability of diaphragm mass indicates that this beneficial response does not occur in all patients with cystic fibrosis.
Activation of the Glucocorticoid Receptor Is Associated with Poor Prognosis in Estrogen Receptor-Negative Breast Cancer
Authors: Deng Pan, Masha Kocherginsky, Suzanne D. Conzen
Journal: Cancer Research (2011)

Estrogen receptor-negative (ER(-)) breast cancers have limited treatment options and are associated with earlier relapses. Because glucocorticoid receptor (GR) signaling initiates antiapoptotic pathways in ER(-) breast cancer cells, we hypothesized that activation of these pathways might be associated with poor prognosis in ER(-) disease. Here we report findings from a genome-wide study of GR transcriptional targets in a premalignant ER(-) cell line model of early breast cancer (MCF10A-Myc) and in primary early-stage ER(-) human tumors. Chromatin immunoprecipitation with massively parallel sequencing (ChIP-seq) coupled to time-course expression profiling led us to identify epithelial-to-mesenchymal transition (EMT) pathways as an important aspect associated with GR activation. We validated these findings by carrying out a meta-analysis of primary breast tumor gene expression from 1,378 early-stage breast cancer patients with long-term clinical follow-up, confirming that high levels of GR expression significantly correlated with shorter relapse-free survival in ER(-) patients who were treated or untreated with adjuvant chemotherapy. Notably, in ER(+) breast cancer patients, high levels of GR expression in tumors were significantly associated with better outcome relative to low levels of GR expression. Gene expression analysis revealed that ER(-) tumors expressing high GR levels exhibited differential activation of EMT, cell adhesion, and inflammation pathways. Our findings suggest a direct transcriptional role for GR in determining the outcome of poor-prognosis ER(-) breast cancers.
Selective Matrix Metalloproteinase Inhibition Reduces Left Ventricular Remodeling but Does Not Inhibit Angiogenesis After Myocardial Infarction
Authors: Merry L. Lindsey, Joseph Gannon, Masanori Aikawa, Frederick J. Schoen, Elena Rabkin, Lori Lopresti-Morrow, Jamie Crawford, Shawn Black, Peter Libby, Peter G. Mitchell, Richard T. Lee
Journal: Circulation (2002)

Background — Broad inhibition of matrix metalloproteinases (MMPs) attenuates left ventricular remodeling after myocardial infarction (MI). However, it is not clear if selective MMP inhibition strategies will be effective or if MMP inhibition will impair angiogenesis after MI. Methods and Results — We used a selective MMP inhibitor (MMPi) that does not inhibit MMP-1 in rabbits, which, like humans but unlike rodents, express MMP-1 as a major collagenase. On day 1 after MI, rabbits were randomized to receive either inhibitor (n=10) or vehicle (n=8). At 4 weeks after MI, there were no differences in infarct size or collagen fractional area. However, MMPi reduced ventricular dilation. The increase in end-diastolic dimension from day 1 to week 4 was 3.1±0.5 mm for vehicle versus 1.3±0.3 mm for MMPi ( P &lt;0.01). The increase in end-systolic dimension was 2.8±0.5 mm for vehicle and 1.3±0.4 mm for MMPi ( P &lt;0.05). Furthermore, MMPi reduced infarct wall thinning; the minimal infarct thickness was 0.8±0.1 mm for vehicle and 1.6±0.3 mm for MMPi ( P &lt;0.05). Interestingly, the MMPi group had increased numbers of vessels in the subendocardial layer of the infarct; the number of capillaries was increased in the subendocardial layer (46±4 vessels/field versus 17±3 vessels/field for vehicle; P &lt;0.001), and the number of arterioles was also increased (4.0±0.8 vessels/field versus 2.0±0.4 vessels/field for vehicle; P &lt;0.05). Conclusions — MMP inhibition attenuates left ventricular remodeling even when the dominant collagenase MMP-1 is not inhibited; furthermore, this selective MMP inhibition appears to increase rather than decrease neovascularization in the subendocardium.
Clinical Features and Serum Biomarkers in HIV Immune Reconstitution Inflammatory Syndrome after Cryptococcal Meningitis: A Prospective Cohort Study
Authors: David R. Boulware, David B. Meya, Tracy L. Bergemann, Darin L. Wiesner, Joshua Rhein, Abdu Musubire, Sarah J. Lee, Andrew Kambugu, Edward N. Janoff, Paul R. Bohjanen
Journal: PLoS Medicine (2010)

David Boulware and colleagues investigate clinical features in a prospective cohort with AIDS and recent cryptococcal meningitis after initiation of antiretroviral therapy to identify biomarkers for prediction and diagnosis of CM-IRIS (cryptococcal meninigitis-related immune reconstitution inflammatory syndrome).