tbuckley/cabot-search huggingface dataset:
<i>EGFR</i>L858R Mutation and Polymorphisms of Genes Related to Estrogen Biosynthesis and Metabolism in Never-Smoking Female Lung Adenocarcinoma Patients
Authors: Shi-Yi Yang, Tsung-Ying Yang, Kun-Chieh Chen, Yao-Jen Li, Kuo-Hsuan Hsu, Chi-Rne Tsai, Chih-Yi Chen, Chung-Ping Hsu, Jiun-Yi Hsia, Cheng-Yen Chuang, Ying-Huang Tsai, Kuan-Yu Chen, Ming-Shyan Huang, Wu-Chou Su, Yuh-Min Chen, Chao A. Hsiung, Chen-Yang Shen, Gee-Chen Chang, Pan-Chyr Yang, Chien-Jen Chen
Journal: Clinical Cancer Research (2011)

To assess whether polymorphisms of genes related to estrogen biosynthesis and metabolism are associated with EGFR mutations.We studied 617 patients with lung adenocarcinoma, including 302 never-smoking women. On the basis of multiple candidate genes approach, the effects of polymorphisms of CYP17, CYP19A1, ERα, and COMT in association with the occurrence of EGFR mutations were evaluated using logistic regression analysis.In female never-smokers, significant associations with EGFR L858R mutation were found for the tetranucleotide (TTTA)(n) repeats in CYP19A1 (odds ratio, 2.6; 95%CI, 1.2-5.7 for 1 or 2 alleles with (TTTA)(n) repeats >7 compared with both alleles with (TTTA)(n) repeats ≤ 7), and the rs2234693 in ERα (OR, 2.1; 95% CI, 1.1-4.0 for C/T and C/C genotypes compared with T/T genotype). The C/C genotype (vs. T/T genotype) of ERα was significantly associated with EGFR L858R mutation (OR, 3.0; 95% CI, 1.1-8.1), in-frame deletion (OR, 2.9; 95% CI, 1.1-7.6) and other mutations (OR, 4.3; 95% CI, 1.3-14.0). The genotype of COMT rs4680 was significantly associated with EGFR L858R mutation in female and male never-smokers showing OR's (95% CI) of 1.8 (1.0-3.2) and 3.6 (1.1-11.3), respectively, for genotypes G/A and G/G compared with genotype A/A. The number of risk alleles of CYP17, CYP19A1, ERα, and COMT was associated with an increasing OR of EGFR L858R mutation in female never-smokers (P = 0.0002 for trend).The L858R mutation of EGFR is associated with polymorphisms of genes related to estrogen biosynthesis and metabolism in never-smoking female lung adenocarcinoma patients.
Metabolic Syndrome as a Precursor of Cardiovascular Disease and Type 2 Diabetes Mellitus
Authors: Peter W.F. Wilson, Ralph B. D’Agostino, Helen Parise, Lisa Sullivan, James B. Meigs
Journal: Circulation (2005)

Background— The incidence of cardiovascular disease (CVD), coronary heart disease (CHD), and type 2 diabetes mellitus (T2DM) has not been well defined in persons with the metabolic syndrome (at least 3 of the following: abdominal adiposity, low HDL cholesterol, high triglycerides, hypertension, and impaired fasting glucose). The objective was to investigate risk for CVD, CHD, and T2DM according to metabolic syndrome traits. Methods and Results— The study followed a cohort of 3323 middle-aged adults for the development of new CVD, CHD, and T2DM over an 8-year period. In persons without CVD or T2DM at baseline, the prevalence of the metabolic syndrome (≥3 of 5 traits) was 26.8% in men and 16.6% in women. There were 174 incident cases of CVD, 107 of CHD, and 178 of T2DM. In men, the metabolic syndrome age-adjusted relative risk (RR) and 95% CIs were RR=2.88 (95% CI 1.99 to 4.16) for CVD, RR=2.54 (95% CI 1.62 to 3.98) for CHD, and RR=6.92 (95% CI 4.47 to 10.81) for T2DM. Event rates and RRs were lower in women for CVD (RR=2.25, 95% CI 1.31 to 3.88) and CHD (RR=1.54, 95% CI 0.68 to 3.53), but they were similar for T2DM (RR=6.90, 95% CI 4.34 to 10.94). Population-attributable risk estimates associated with metabolic syndrome for CVD, CHD, and T2DM were 34%, 29%, and 62% in men and 16%, 8%, 47% in women. Conclusions— Metabolic syndrome is common and is associated with an increased risk for CVD and T2DM in both sexes. The metabolic syndrome accounts for up to one third of CVD in men and approximately half of new T2DM over 8 years of follow-up.
Why Does the Heart Beat?
Authors: Mark E. Silverman, Daniel Grove, Charles B. Upshaw
Journal: Circulation (2006)

Why does the heart beat? This question--known as the myogenic versus neurogenic theory--dominated cardiac research in the 19th century. In 1839, Jan Evangelista Purkinje discovered gelatinous fibers in the ventricular subendocardium that he thought were muscular. Walter Gaskell, in 1886, demonstrated specialized muscle fibers joining the atria and ventricles that caused "block" when cut and found that the sinus venosus was the area of first excitation of the heart. By examining serial embryologic sections, Wilhelm His, Jr, showed that a connective tissue sheet became a bundle connecting the upper and lower cardiac chambers, the bundle of His. Sunao Tawara traced the atrioventricular (AV) bundle of His backward to find a compact node of fibers at the base of the atrial septum and forward where it connected with the bundles of cells discovered by Purkinje in 1839. Tawara concluded that this "AV connecting system" originated in the AV node, penetrated the septum as the His bundle, and then divided into left and right bundle branches that terminated in the Purkinje fibers. Martin Flack and Arthur Keith studied the conduction system of a mole and found a structure in the sinoauricular junction that histologically resembled the AV node. They felt that this was where "the dominating rhythm of the heart normally begins" and named it the sinoauricular node in 1907. The ECG of Einthoven soon brought a new understanding to the complex electrical system that makes the heart beat. In 2006 and 2007, we celebrate the 100th anniversaries of the publication of the exciting discovery of the AV and sinus nodes, truly landmarks in our understanding of cardiac structure and physiology.
Personalizing carbamazepine therapy
Authors: Taisei Mushiroda, Yusuke Nakamura
Journal: Genome Medicine (2011)

The anticonvulsant carbamazepine has a high incidence of cutaneous adverse drug reactions. A recent prospective clinical trial in Taiwan has indicated that HLA-B*1502 screening will reduce the incidence of life-threatening adverse reactions to carbamazepine, while a genome-wide association study has identified the HLA-A*3101 allele as a genetic risk factor for the full spectrum of carbamazepine-induced cutaneous adverse drug reactions in a European population. These studies should aid future decision-making for personalized use of carbamazepine treatment.
Executive Summary: Heart Disease and Stroke Statistics—2010 Update
Authors: Donald Lloyd-Jones, Robert J. Adams, Todd M. Brown, Mercedes Carnethon, Shifan Dai, Giovanni De Simone, T. Bruce Ferguson, Earl Ford, Karen Furie, Cathleen Gillespie, Alan Go, Kurt Greenlund, Nancy Haase, Susan Hailpern, P. Michael Ho, Virginia Howard, Brett Kissela, Steven Kittner, Daniel Lackland, Lynda Lisabeth, Ariane Marelli, Mary M. McDermott, James Meigs, Dariush Mozaffarian, Michael Mussolino, Graham Nichol, Véronique L. Roger, Wayne Rosamond, Ralph Sacco, Paul Sorlie, Randall Stafford, Thomas Thom, Sylvia Wasserthiel-Smoller, Nathan D. Wong, Judith Wylie-Rosett
Journal: Circulation (2010)
Ageing is associated with deterioration of calcium homeostasis in isolated human right atrial myocytes
Authors: Adela Herraiz-Martínez, Jesus Álvarez-García, Anna Llach, Cristina E. Molina, Jacqueline Fernandes, Andreu Ferrero-Gregori, Cristina Rodríguez, Alexander Vallmitjana, Raúl Benítez, Josep M. Padró, José Martínez-González, Juan Cinca, Leif Hove-Madsen
Journal: Cardiovascular Research (2015)

Ageing-related cardiac disorders such as heart failure and atrial fibrillation often present with intracellular calcium homeostasis dysfunction. However, knowledge of the intrinsic effects of ageing on cellular calcium handling in the human heart is sparse. Therefore, this study aimed to analyse how ageing affects key mechanisms that regulate intracellular calcium in human atrial myocytes. Whole membrane currents and intracellular calcium transients were measured in isolated human right atrial myocytes from 80 patients with normal left atrial dimensions and no history of atrial fibrillation. Patients were categorized as young (<55 years, n = 21), middle aged (55–74 years, n = 42), and old (≥75 years, n = 17). Protein levels were determined by western blot. Ageing was associated with the following electrophysiological changes: (i) a 3.2-fold decrease in the calcium transient (P < 0.01); (ii) reduction of the L-type calcium current (ICa) amplitude (2.4 ± 0.3 pA/pF vs. 1.4 ± 0.2 pA/pF, P < 0.01); (iii) lower levels of L-type calcium channel alpha-subunit (P < 0.05); (iv) lower rates of both fast (14.5 ± 0.9 ms vs. 20.9 ± 1.9, P < 0.01) and slow (73 ± 3 vs. 120 ± 12 ms, P < 0.001) ICa inactivation; and (v) a decrease in the sarcoplasmic reticulum calcium content (10.1 ± 0.8 vs. 6.4 ± 0.6 amol/pF, P < 0.005) associated with a significant decrease in both SERCA2 (P < 0.05) and calsequestrin-2 (P < 0.05) protein levels. In contrast, ageing did not affect spontaneous sarcoplasmic reticulum calcium release. Ageing is associated with depression of SR calcium content, L-type calcium current, and calcium transient amplitude that may favour a progressive decline in right atrial contractile function with age.
Amylin Compared with Calcitonin Gene-Related Peptide: Structure, Biology, and Relevance to Metabolic Disease
Authors: GARTH J. S. COOPER
Journal: Endocrine Reviews (1994)

ISLETβ-cells play a central role in the regulation of most cells in the body through secretion of insulin. These cells are now known to secrete a second hormone-like protein, amylin, also known as islet or insulinoma amyloid polypeptide (IAPP) (1–4) as well as numerous other compounds (5) in response to stimuli that elicit insulin release (6–9). Amylin is structurally similar to calcitonin gene-related peptide (CGRP) (1, 2), a widely distributed neuropeptide (10) and potent vasodilator (11–13). It is the major protein in islet amyloid (1, 3), extracellular accumulation of which occurs in most patients with non-insulin-dependent diabetes mellitus (NIDDM) (14) and increases in extent with duration in this disease (15). Amylin and CGRP produce similar biological effects in many tissues. Their actions in skeletal muscle and liver stimulate glycogen breakdown and oppose the actions of insulin (16–22), perhaps through evoked alterations in the activity of enzymes including glycogen phosphorylase (23–25) and glycogen synthase (23, 25).
Increased morbidity associated with chronic infection by an epidemic Pseudomonas aeruginosa strain in CF patients
Authors: M Al-Aloul
Journal: Thorax (2004)

<b>Background:</b> Chronic pulmonary infection with transmissible <i>Pseudomonas aeruginosa</i> strains in individuals with cystic fibrosis (CF) has been reported, raising issues of cross infection and patient segregation. The first such strain to be described (the Liverpool epidemic strain, LES) is now widespread in many UK CF centres. However, whether such infection carries a worse prognosis is unknown. To address this, the clinical course of a group of CF patients chronically infected by LES was compared with that in patients harbouring unique strains. <b>Methods:</b> Using <i>P aeruginosa</i> strain genotyping, two cohorts of CF patients attending the Liverpool CF service were identified who were LES positive or negative in 1998 and remained so until 2002. From these, two groups of 12 patients were matched in 1998 for age, spirometric parameters, and nutritional state and their clinical course was followed for 5 years. Patients chronically infected with <i>Burkholderia cepacia</i> were excluded. <b>Results:</b> Patients chronically infected with LES had a greater annual loss of lung function than those not chronically infected by LES (mean difference between groups −4.4% (95% CI −8.1 to −0.9; p&lt;0.02)), and by 2002 their percentage predicted forced expiratory volume in 1 second (FEV<sub>1</sub>) was worse (mean 65.0% <i>v</i> 82.6%, p&lt;0.03). Their nutritional state also deteriorated over the study period (mean difference between groups in body mass index −0.7 (95% CI −1.2 to −0.2; p&lt;0.01)), such that by 2002 they were malnourished compared with LES negative patients (mean BMI 19.4 <i>v</i> 22.7, p&lt;0.02). <b>Conclusions:</b> Chronic infection with the Liverpool epidemic <i>P aeruginosa</i> strain in CF patients confers a worse prognosis than infection with unique strains alone, confirming the need for patient segregation. Since this strain is common in many CF units, strain identification in all CF centres is essential. This can only be carried out using genomic typing methods.
Clinical outcome in 22 patients with rheumatoid arthritis treated with B lymphocyte depletion
Authors: M J Leandro
Journal: Annals of the Rheumatic Diseases (2002)

<b>Objectives:</b> To obtain evidence for dose response and to extend evidence of safety and efficacy for B lymphocyte depletion in rheumatoid arthritis. <b>Methods:</b> Twenty two patients with rheumatoid arthritis received a total of 29 treatments with five different combinations of rituximab (RTX), cyclophosphamide (CP), and/or high dose prednisolone (PR) on an open basis as follows; cohort I: RTX 1400 mg/m<sup>2</sup>, CP 750×2+PR; cohort II: RTX 300–700 mg/m<sup>2</sup>, −CP±PR); cohort III: RTX 600–700 mg/m<sup>2</sup>, CP 750×2+PR; cohort IV: RTX 1200 mg/m<sup>2</sup>, CP 750×2−PR; cohort V: RTX 500 mg/m<sup>2</sup>, CP 750×2+PR. American College of Rheumatology (ACR) criteria of improvement at six months were chosen as the primary outcome measure. Disease activity scores and total duration of improvement and of B cytopenia were also recorded. <b>Results:</b> No major adverse events attributable to treatment were seen. ACR grades of improvement at six months were as follows: cohort I: ACR70×3, ACR50×2; cohort II: ACR20×1, ACR0×3; cohort III: ACR70×6, ACR50×2, ACR20×2; cohort IV: ACR70×2, ACR50×2, ACR20×1, ACR0×1; cohort V: ACR0×4. <b>Conclusions:</b> B lymphocyte depletion in rheumatoid arthritis has so far proved to be safe and associated with major improvement with protocols including RTX 600 mg/m<sup>2</sup> or more and CP, but not with more limited protocols. These observations provide an initial basis for the design of formal trials of B cell depletion and other B cell directed treatments, including a phase II controlled trial now in progress.
Mineralocorticoid receptor is involved in rat and human ocular chorioretinopathy
Authors: Min Zhao, Isabelle Célérier, Elodie Bousquet, Jean-Claude Jeanny, Laurent Jonet, Michèle Savoldelli, Olivier Offret, Antoine Curan, Nicolette Farman, Frédéric Jaisser, Francine Behar-Cohen
Journal: Journal of Clinical Investigation (2012)

Central serous chorioretinopathy (CSCR) is a vision-threatening eye disease with no validated treatment and unknown pathogeny. In CSCR, dilation and leakage of choroid vessels underneath the retina cause subretinal fluid accumulation and retinal detachment. Because glucocorticoids induce and aggravate CSCR and are known to bind to the mineralocorticoid receptor (MR), CSCR may be related to inappropriate MR activation. Our aim was to assess the effect of MR activation on rat choroidal vasculature and translate the results to CSCR patients. Intravitreous injection of the glucocorticoid corticosterone in rat eyes induced choroidal enlargement. Aldosterone, a specific MR activator, elicited the same effect, producing choroid vessel dilation -and leakage. We identified an underlying mechanism of this effect: aldosterone upregulated the endothelial vasodilatory K channel KCa2.3. Its blockade prevented aldosterone-induced thickening. To translate these findings, we treated 2 patients with chronic nonresolved CSCR with oral eplerenone, a specific MR antagonist, for 5 weeks, and observed impressive and rapid resolution of retinal detachment and choroidal vasodilation as well as improved visual acuity. The benefit was maintained 5 months after eplerenone withdrawal. Our results identify MR signaling as a pathway controlling choroidal vascular bed relaxation and provide a pathogenic link with human CSCR, which suggests that blockade of MR could be used therapeutically to reverse choroid vasculopathy.
Henoch-Scho[Combining Diaeresis]nlein Purpura in Adults
Authors: Evangéline Pillebout, Eric Thervet, Gary Hill, Corinne Alberti, Philippe Vanhille, Dominique Nochy
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Henoch-Scho[Combining Diaeresis]nlein Purpura nephritis (HSPN) has been extensively studied in children but, its natural history in adults is much less known. A cohort of 250 adults suffering HSP was retrospectively analyzed for a median follow-up period of 14.8 yr. All patients had biopsies consistent with HSP (predominant IgA mesangial deposits) associated with purpura, bowel angina, and/or abdominal pain. At presentation, palpable purpura was present in 96% of patients, and arthritis was reported in 61%, and gastrointestinal involvement in 48%. Thirty-two percent of the patients showed renal insufficiency (Creatinine clearance [CrCl] &lt;50 ml/min), usually associated with proteinuria (99%) and/or hematuria (93%). Endocapillary glomerulonephritis was the most frequent lesion on renal biopsy (61%). At the end of follow-up, patient survival was only 74%. The first cause of death was carcinoma (most of them of respiratory or digestive tract). Regarding renal function, 11% of patients reached end-stage renal failure, 13% exhibited severe renal failure (CrCl &lt;30 ml/min), and 14% moderate renal insufficiency (CrCl &lt;50 ml/min). Clinical remission defined as the absence of proteinuria, hematuria, and a normal renal function was achieved in only 20%. This is a retrospective study; therefore, it is not possible to demonstrate any steroid and/or cyclophosphamide efficacy in diminishing the incidence of renal insufficiency. Multivariate analysis demonstrated that renal function impairment and proteinuria level at presentation and, on renal biopsy, the degree of interstitial fibrosis, percentage of sclerotic glomeruli, and presence of glomeruli with fibrinoid necrosis were associated with a poor renal prognosis. The data indicate that clinical presentation of HSPN in adults is severe and its outcome relatively poor, worse than in children. Identification of clinical and histologic prognostic factors may permit the design of appropriate therapeutic prospective studies.
Impairment of endothelium-dependent pulmonary vasodilation in patients with primary pulmonary hypertension.
Authors: S. J. Brett, J. Simon, R. Gibbs, J. R. Pepper, T. W. Evans
Journal: Thorax (1996)

BACKGROUND: Pulmonary vascular tone may be modulated by endothelium-derived vasoactive mediators. Endothelial dysfunction is thought to occur in primary pulmonary hypertension. The aim of this study was to evaluate the vascular responses of patients with severe primary pulmonary hypertension to endothelium-dependent vasodilators (for example, substance P) and non-endothelium-dependent vaasodilators (for example, adenosine). METHODS: Six patients with primary pulmonary hypertension (mean (SE) systolic, diastolic, and pulmonary artery pressures 91.1 (7), 45.2 (3), and 62 (4.2) mm Hg, respectively, and baseline total pulmonary vascular resistance (TPVR) 1949 (164) dynes.s.cm-5) underwent sequential infusions of substance P (5-100 pmol/min) and adenosine (5-50 micrograms/kg/min) in random order. Pulmonary and systemic haemodynamics were monitored by indwelling radial and pulmonary arterial catheters. RESULTS: Substance P caused a marked fall in systemic vascular resistance (SVR) but minimal pulmonary vasodilation (mean maximal percentage change from baseline in TPVR:SVR ratio 27.85 (6.5)%, p &lt; 0.01). Adenosine caused TPVR to fall, but resulted in no change in SVR (mean maximum percentage change from baseline in TPVR:SVR ratio -9.85 (3.5)%, p &lt; 0.05). CONCLUSION: Endothelium-dependent vasodilation is deficient in the pulmonary circulation of patients with primary pulmonary hypertension and may contribute to the abnormalities of pulmonary vascular tone and reactivity seen in that condition.
On the Weighted-Average Relationship Between Plasma Glucose and HbA1c
Authors: Oliver J. Gibson, Patrick E. McSharry, Lionel Tarassenko
Journal: Diabetes Care (2006)

HbA1c (A1C) is widely used to assess glycemic control in clinical and research settings, but the precise relationship between A1C and preceding self-monitored plasma glucose measurements is recognized to be complex. It has been reported that measuring plasma glucose levels in the 120 days before an A1C measurement has a nonuniform effect on the result depending on the time that has elapsed between the glucose level and subsequent A1C measurement (1). Tahara and Shima (2) attempted to model this weighted-average …
Allogeneic Stem-Cell Transplantation Using a Reduced-Intensity Conditioning Regimen Has the Capacity to Produce Durable Remissions and Long-Term Disease-Free Survival in Patients With High-Risk Acute Myeloid Leukemia and Myelodysplasia
Authors: Sudhir Tauro, Charles Craddock, Karl Peggs, Gulnaz Begum, Premini Mahendra, Gordon Cook, Judith Marsh, Donald Milligan, Anthony Goldstone, Ann Hunter, Asim Khwaja, Raj Chopra, Timothy Littlewood, Andrew Peniket, Anne Parker, Graham Jackson, Geoff Hale, Mark Cook, Nigel Russell, Stephen Mackinnon
Journal: Journal of Clinical Oncology (2005)

Purpose The toxicity of allogeneic stem-cell transplantation can be substantially reduced using a reduced-intensity conditioning (RIC) regimen. This has increased the proportion of patients with myeloid malignancies eligible for allogeneic transplantation. However, the capacity of RIC allografts to produce durable remissions in patients with acute myeloid leukemia (AML) and myelodysplasia (MDS) has not yet been defined, and consequently, the role of RIC allografts in the management of these diseases remains conjectural. Patients and Methods Seventy-six patients with high-risk AML or MDS received an allograft using a fludarabine/melphalan RIC regimen incorporating alemtuzumab. The median age of the cohort was 52 years (range, 18 to 71 years). Results The 100-day transplantation-related mortality rate was 9%, and no patient developed greater than grade 2 graft-versus-host disease. With a median follow-up of 36 months (range, 13 to 70 months), 27 patients were alive and in remission, with 3-year actuarial overall survival (OS) and disease-free survival (DFS) rates of 41% and 37%, respectively. The 3-year OS and DFS rates of patients with AML in complete remission at the time of transplantation were 48% and 42%, respectively. Disease relapse was the most common cause of treatment failure and occurred at a median time of 6 months after transplantation. All but one patient destined to relapse did so within 24 months of transplantation. Conclusion The extended follow-up in this series identifies a high risk of early disease relapse but provides evidence that RIC allografts can produce sustained DFS in a significant number of patients with AML who would be ineligible for allogeneic transplantation with myeloablative conditioning.