tbuckley/cabot-search huggingface dataset:
A High Frequency of Activating Extracellular Domain <i>ERBB2</i> (<i>HER2</i>) Mutation in Micropapillary Urothelial Carcinoma
Authors: Jeffrey S. Ross, Kai Wang, Laurie M. Gay, Rami N. Al-Rohil, Tipu Nazeer, Christine E. Sheehan, Timothy A. Jennings, Geoff A. Otto, Amy Donahue, Jie He, Gary Palmer, Siraj Ali, Michelle Nahas, Geneva Young, Elaine LaBrecque, Garrett Frampton, Rachel Erlich, John A. Curran, Kristina Brennan, Sean R. Downing, Roman Yelensky, Doron Lipson, Matthew Hawryluk, Vincent A. Miller, Philip J. Stephens
Journal: Clinical Cancer Research (2013)

Micropapillary urothelial carcinoma (MPUC) is a rare and aggressive form of bladder cancer. We conducted genomic analyses [next-generation sequencing (NGS)] of MPUC and non-micropapillary urothelial bladder carcinomas (non-MPUC) to characterize the genomic landscape and identify targeted treatment options.DNA was extracted from 40 μm of formalin-fixed paraffin-embedded sections from 15 MPUC and 64 non-MPUC tumors. Sequencing (NGS) was performed on hybridization-captured, adaptor ligation-based libraries to high coverage for 3,230 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. The results were evaluated for all classes of genomic alteration.Mutations in the extracellular domain of ERBB2 were identified in 6 of 15 (40%) of MPUC: S310F (four cases), S310Y (one case), and R157W (one case). All six cases of MPUC with ERBB2 mutation were negative for ERBB2 amplification and Erbb2 overexpression. In contrast, 6 of 64 (9.4%) non-MPUC harbored an ERBB2 alteration, including base substitution (three cases), amplification (two cases), and gene fusion (one case), which is higher than the 2 of 159 (1.3%) protein-changing ERBB2 mutations reported for urinary tract cancer in COSMIC. The enrichment of ERBB2 alterations in MPUC compared with non-MPUC is significant both between this series (P < 0.0084) and for all types of urinary tract cancer in COSMIC (P < 0.001).NGS of MPUC revealed a high incidence of mutation in the extracellular domain of ERBB2, a gene for which there are five approved targeted therapies. NGS can identify genomic alteration, which inform treatment options for the majority of MPUC patients.
Simulated Ischemia in Flow-Adapted Endothelial Cells Leads to Generation of Reactive Oxygen Species and Cell Signaling
Authors: Zhihua Wei, Karen Costa, Abu B. Al-Mehdi, Chandra Dodia, Vladimir Muzykantov, Aron B. Fisher
Journal: Circulation Research (1999)

Abstract —We have previously shown that increased reactive oxygen species (ROS) generation occurs with ischemia in the oxygenated lung and have hypothesized that mechanotransduction is the initiating event. In the present study, we developed an in vitro model of oxygenated ischemia by interrupting medium flow to flow-adapted bovine pulmonary artery endothelial cells in an artificial capillary system. Cellular oxygenation during the “ischemic” period was maintained by perfusing medium over the abluminal surface of porous capillaries. Cells were assessed for ROS generation, nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) binding activities, and DNA synthesis using dichlorofluorescein fluorescence by flow cytometry and spectrofluorometry, electrophoretic mobility shift assay of nuclear extracts with NF-κB–specific or AP-1–specific 32 P-labeled oligonucleotides, and 3 H-thymidine incorporation into DNA. Cells that were flow adapted for 2 to 7 days with 1 to 2 dyne/cm 2 shear stress exhibited a 1.6- to 1.9-fold increase in ROS generation during 1 hour of simulated ischemia compared with continuously perfused cells. This effect was abolished by diphenyleneiodonium chloride (DPI), indicating a role for a flavoprotein such as NADPH oxidase. The increase in ROS generation with ischemia was similar for cells from low and high passages. With ischemia, flow-adapted cells exhibited increases of 1.7-fold in nuclear NF-κB and 1.5-fold in nuclear AP-1; these changes were abolished by pretreatment with N -acetylcysteine or DPI. Ischemia for 24 hours resulted in a 1.8-fold increase of 3 H-thymidine incorporation into DNA and a significant increase of cells entering the cell cycle, as indicated by flow cytometry with propidium iodide. We conclude that flow-adapted endothelial cells generate ROS with ischemia that results in activation of NF-κB and AP-1 and an increase of DNA synthesis. This effect is not mediated by hypoxia, implicating a role for mechanotransduction in ischemia-mediated cell signaling.
Performance-Based Measures of Everyday Function in Mild Cognitive Impairment
Authors: Terry E. Goldberg, Jeremy Koppel, Lynda Keehlisen, Erica Christen, Ute Dreses-Werringloer, Concepcion Conejero-Goldberg, Marc L. Gordon, Peter Davies
Journal: American Journal of Psychiatry (2010)

The view that everyday function is preserved in mild cognitive impairment may be problematic. The objectives of this study were to determine the magnitude of impairment in everyday function in patients with mild cognitive impairment and Alzheimer's disease using a novel sensitive performance-based measure (the UCSD Performance-Based Skills Assessment; UPSA), contrast it with use of an informant-based measure (the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory; ADCS-ADL), and model the relationship between cognitive measures and the performance-based measure.Fifty cognitively normal elders, 26 patients who met criteria for amnestic mild cognitive impairment, and 22 patients who suffered from mild to moderate Alzheimer's disease were assessed on the UPSA, the ADCS-ADL, and a battery of neurocognitive tests.Patients with mild cognitive impairment had significant impairments on the UPSA but not on the ADCS-ADL. The magnitude of the effect size between the cognitively healthy and the mild cognitive impairment group for the UPSA was large (d=0.86). A strong and significant relationship was observed between cognitive performances in speed (R(2)=0.37), episodic memory (R(2)=0.10), and semantic processing (R(2)=0.03) and UPSA score using multiple regression models. The psychometric properties of the UPSA were acceptable, as were its sensitivity and specificity in contrasts between cognitively normal elders and patients with mild cognitive impairment and between the latter group and patients with Alzheimer's disease.These findings indicate that performance-based measures of function may be a sensitive tool in studies of Alzheimer's disease and mild cognitive impairment and suggest the need for a reconceptualization of the relationship between cognition and function in mild cognitive impairment so that they can be usefully aligned.
Acute renal failure in people with cystic fibrosis
Authors: K. W Southern
Journal: Thorax (2007)

Time to reflect on antibiotic strategies for CF lung infection

The putative gene in cystic fibrosis (CF) encodes a protein, cystic fibrosis transmembrane conductance regulator ( CFTR ), which has an important role in transepithelial salt transport.1 The major organ affected in CF is the lung, with remorseless and intense chronic airway infection resulting from disabled clearance of dehydrated airway surface liquid.2 Airway inflammation leading to end stage lung damage is associated with respiratory morbidity and early death. The outlook for people with CF has improved considerably with a proactive approach to treatment of airway infection as one of the cornerstones of its management. Recent data from the US CF registry suggest a continuing improvement in median predicted survival to over 35 years (http://www.cff.org/research/2006NACFC/Plenary III). With an improving outlook, perspectives have changed and expectations of people with CF and their carers have broadened. A survey of acute renal failure (ARF) in patients with CF published in this issue of Thorax ( see p 541 ) is particularly timely when reflecting on how best to achieve the goal of increased survival while balancing risks to patients.3

There are several reasons why people with CF are at risk of ARF. The salt transport defect makes people with CF prone to salt loss and consequently fluid imbalance and dehydration.4,5 The impact of CFTR dysfunction on pancreatic function and architecture results in significant hypoinsulinaemia (CF-related diabetes) in a significant proportion of older patients with CF, again posing a challenge to fluid balance and the long-term possibility of diabetic kidney disease.6,7 Finally, as a cohort, these patients are exposed to industrial quantities of potentially nephrotoxic chemotherapeutic agents (in our CF centre some children have received a cumulative intravenous dose of over 300 g of the aminoglycoside tobramycin). Given cumulative exposure to potentially …
Bacteria-Induced Gap Junctions in Tumors Favor Antigen Cross-Presentation and Antitumor Immunity
Authors: Fabiana Saccheri, Chiara Pozzi, Francesca Avogadri, Sara Barozzi, Mario Faretta, Paola Fusi, Maria Rescigno
Journal: Science Translational Medicine (2010)

Bacterial infection induces extra gap junctions in tumors, through which tumor antigens travel to antigen-presenting cells, triggering an effective antitumor immune response.
The Urinary Metabolite Profile of the Dietary Carcinogen 2-Amino-1-Methyl-6-Phenylimidazo[4,5-<i>b</i>]Pyridine Is Predictive of Colon DNA Adducts after a Low-Dose Exposure in Humans
Authors: Michael A. Malfatti, Karen H. Dingley, Susan Nowell-Kadlubar, Esther A. Ubick, Nisha Mulakken, David Nelson, Nicholas P. Lang, James S. Felton, Kenneth W. Turteltaub
Journal: Cancer Research (2006)

Abstract Epidemiologic evidence indicates that exposure to heterocyclic amines in the diet is an important risk factor for the development of colon cancer. Well-done cooked meats contain significant levels of heterocyclic amines, which have been shown to cause cancer in laboratory animals. To better understand the mechanisms of heterocyclic amine bioactivation in humans, the most mass abundant heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), was used to assess the relationship between PhIP metabolism and DNA adduct formation. Ten human volunteers where administered a dietary relevant dose of [14C]PhIP 48 to 72 hours before surgery to remove colon tumors. Urine was collected for 24 hours after dosing for metabolite analysis, and DNA was extracted from colon tissue and analyzed by accelerator mass spectrometry for DNA adducts. All 10 subjects were phenotyped for cytochrome P4501A2 (CYP1A2), N-acetyltransferase 2, and sulfotransferase 1A1 enzyme activity. Twelve PhIP metabolites were detected in the urine samples. The most abundant metabolite in all volunteers was N-hydroxy-PhIP-N2-glucuronide. Metabolite levels varied significantly between the volunteers. Interindividual differences in colon DNA adducts levels were observed between each individual. The data showed that individuals with a rapid CYP1A2 phenotype and high levels of urinary N-hydroxy-PhIP-N2-glucuronide had the lowest level of colon PhIP-DNA adducts. This suggests that glucuronidation plays a significant role in detoxifying N-hydroxy-PhIP. The levels of urinary N-hydroxy-PhIP-N2-glucuronide were negatively correlated to colon DNA adduct levels. Although it is difficult to make definite conclusions from a small data set, the results from this pilot study have encouraged further investigations using a much larger study group. (Cancer Res 2006; 66(21): 10541-7)
Randomized Trial of Early Phacoemulsification versus Peripheral Iridotomy to Prevent Intraocular Pressure Rise after Acute Primary Angle Closure
Authors: Dennis S.C. Lam, Dexter Y.L. Leung, Clement C.Y. Tham, Felix C.H. Li, Yolanda Y.Y. Kwong, Thomas Y.H. Chiu, Dorothy S.P. Fan
Journal: Ophthalmology (2008)
Haemodynamic response to dynamic exercise after heart-lung transplantation
Authors: JL Vachiery, G Niset, M Antoine, JL LeClerc, S Degre, M Estenne
Journal: European Respiratory Journal (1999)

The purpose of this study was to investigate the haemodynamic response to dynamic exercise after heart-lung transplantation (HLT). Nine stable HLT recipients (6 males) were studied 12-55 months after transplantation. While sitting on a cycle ergometer, they first underwent a maximal symptom-limited exercise test (power increment was 10 W x min(-1)) to determine the maximal tolerable workload. On the next day, they performed a second exercise test at 0, 40, 60 and 80% of their predetermined maximal workload (mean+/-sD: 108+/-20 W). Stage duration was 6 min. Respiratory, gas exchange, and haemodynamic measurements were performed at rest, during the last minute of each stage, and after recovery. Haemodynamic variables at rest were within normal limits except heart rate (HR) which was greater and stroke volume index (SVI) which was lower than normal. Peak oxygen consumption was 61+/-8% of predicted. HR showed an initial slow increase followed by a steeper rise, and a delayed return to baseline during the recovery period. SVI and cardiac index (CI) increased at the onset of exercise but did not change significantly at 40-80% of the maximal workload. Pulmonary capillary wedge pressure increased from 4+/-2 mmHg at rest to 14+/-3 mmHg at maximal exercise. It is concluded that during dynamic exercise, heart-lung transplantation recipients demonstrate a chronotropic incompetence, a reduced increase in cardiac index and stroke volume index, and an excessive rise in left ventricular filling pressures. These alterations may contribute to the persistent exercise limitation.
Oral Ivermectin versus Malathion Lotion for Difficult-to-Treat Head Lice
Authors: Olivier Chosidow, Bruno Giraudeau, Jeremy Cottrell, Arezki Izri, Robert Hofmann, Stephen G. Mann, Ian Burgess
Journal: New England Journal of Medicine (2010)

Head-lice infestation is prevalent worldwide, especially in children 3 to 11 years old. Topical insecticides (i.e., pyrethroids and malathion) used as a lotion, applied twice at an interval of 7 to 11 days, are typically used for treatment. Resistance of lice to insecticides, particularly pyrethroids, results in treatment failure. The efficacy of alternative agents is controversial.We conducted a multicenter, cluster-randomized, double-blind, double-dummy, controlled trial comparing oral ivermectin (at a dose of 400 microg per kilogram of body weight) with 0.5% malathion lotion, each given on days 1 and 8, for patients with live lice not eradicated by topical insecticide used 2 to 6 weeks before enrollment. The cluster was defined as the household. Infestation was confirmed and monitored by means of fine-toothed combing. Patients were at least 2 years of age and weighed at least 15 kg; all were treated at the study sites. The primary end point was the absence of head lice on day 15.A total of 812 patients from 376 households were randomly assigned to receive either ivermectin or malathion. In the intention-to-treat population, 95.2% of patients receiving ivermectin were lice-free on day 15, as compared with 85.0% of those receiving malathion (absolute difference, 10.2 percentage points; 95% confidence interval [CI], 4.6 to 15.7; P<0.001). In the per-protocol population, 97.1% of patients in the ivermectin group were lice-free on day 15, as compared with 89.8% of those in the malathion group (absolute difference, 7.3 percentage points; 95% CI, 2.8 to 11.8; P=0.002). There were no significant differences in the frequencies of adverse events between the two treatment groups.For difficult-to-treat head-lice infestation, oral ivermectin, given twice at a 7-day interval, had superior efficacy as compared with topical 0.5% malathion lotion, a finding that suggests that it could be an alternative treatment. (ClinicalTrials.gov number, NCT00819520.)
Comparison of serial electrocardiographic and vectorcardiographic changes during recovery from status asthmaticus.
Authors: J R Bateman, D Siegler, D Wagstaff, S W Clarke
Journal: Thorax (1980)

Serial electrocardiographs (ECG) and vectorcardiographs (VCG) have been performed on 10 patients admitted to hospital in status asthmaticus on 12 separate occasions. The VCG was more efficient than the ECG in the detection of right atrial and ventricular enlargement. Both investigations were equally reliable in recording changes in frontal plane P wave axis. The mean frontal plane P wave axis fell from +60 degrees (range +35 degrees to +90 degrees) on the day of admission to +43 degrees (range +30 degrees to +60 degrees) at the time of discharge. The mean FEV1 expressed as a percentage of predicted values increased from 48% (range 25% to 81%) to 87% (range 44% to 123%). In direct contrast to previous studies the presence of an abnormally vertical frontal plane P wave axis (&gt; 60 degrees) was related to the severity of airway obstruction (p &lt; 0.01).
Aldosterone Inactivates the Endothelin-B Receptor via a Cysteinyl Thiol Redox Switch to Decrease Pulmonary Endothelial Nitric Oxide Levels and Modulate Pulmonary Arterial Hypertension
Authors: Bradley A. Maron, Ying-Yi Zhang, Kevin White, Stephen Y. Chan, Diane E. Handy, Christopher E. Mahoney, Joseph Loscalzo, Jane A. Leopold
Journal: Circulation (2012)

Pulmonary arterial hypertension (PAH) is characterized, in part, by decreased endothelial nitric oxide (NO(·)) production and elevated levels of endothelin-1. Endothelin-1 is known to stimulate endothelial nitric oxide synthase (eNOS) via the endothelin-B receptor (ET(B)), suggesting that this signaling pathway is perturbed in PAH. Endothelin-1 also stimulates adrenal aldosterone synthesis; in systemic blood vessels, hyperaldosteronism induces vascular dysfunction by increasing endothelial reactive oxygen species generation and decreasing NO(·) levels. We hypothesized that aldosterone modulates PAH by disrupting ET(B)-eNOS signaling through a mechanism involving increased pulmonary endothelial oxidant stress.In rats with PAH, elevated endothelin-1 levels were associated with elevated aldosterone levels in plasma and lung tissue and decreased lung NO(·) metabolites in the absence of left-sided heart failure. In human pulmonary artery endothelial cells, endothelin-1 increased aldosterone levels via peroxisome proliferator-activated receptor gamma coactivator-1α/steroidogenesis factor-1-dependent upregulation of aldosterone synthase. Aldosterone also increased reactive oxygen species production, which oxidatively modified cysteinyl thiols in the eNOS-activating region of ET(B) to decrease endothelin-1-stimulated eNOS activity. Substitution of ET(B)-Cys405 with alanine improved ET(B)-dependent NO(·) synthesis under conditions of oxidant stress, confirming that Cys405 is a redox-sensitive thiol that is necessary for ET(B)-eNOS signaling. In human pulmonary artery endothelial cells, mineralocorticoid receptor antagonism with spironolactone decreased aldosterone-mediated reactive oxygen species generation and restored ET(B)-dependent NO(·) production. Spironolactone or eplerenone prevented or reversed pulmonary vascular remodeling and improved cardiopulmonary hemodynamics in 2 animal models of PAH in vivo.Our findings demonstrate that aldosterone modulates an ET(B) cysteinyl thiol redox switch to decrease pulmonary endothelium-derived NO(·) and promote PAH.
Evidence for Longitudinal and Transverse Fiber Conduction in Human Pulmonary Veins
Authors: Javier E. Sanchez, Vance J. Plumb, Andrew E. Epstein, G. Neal Kay
Journal: Circulation (2003)

Background— Segmental ostial ablation of the pulmonary veins (PVs) allows for successful control of paroxysmal atrial fibrillation in many patients. We hypothesized that mapping of the left atrial-PV junction with a 64-electrode basket catheter would allow characterization of conduction patterns that would identify sites where ablation is required to electrically isolate the PV. Methods and Results— A 64-electrode basket catheter was used to map the PVs of 50 patients undergoing PV isolation procedures for the treatment of atrial fibrillation. Activation along each spline was classified as reflecting either longitudinal, transverse, or no activation. A longitudinal activation pattern recorded along a spline during sinus rhythm in right-sided PV and during CS pacing in left-sided PV before the delivery of any RF energy application had a sensitivity and specificity for a required ostial ablation site of 83% and 82%, respectively. When longitudinal activation along the spline was present during preablation recordings in both sinus rhythm and CS pacing, the sensitivity and specificity were 92% and 90%, respectively. A longitudinal activation pattern after the first RF application that produced a change in PV activation sequence had a sensitivity and specificity for sites where further ablation was required of 91% and 94%, respectively. Conclusions— Mapping of PV activation with a 64-electrode basket catheter allows characterization of conduction patterns that predict requirement for ablation. The presence of a longitudinal activation pattern is a strong predictor of ostial sites where ablative energy is required to electrically isolate the PV.
Is Mohs micrographic surgery more effective than wide local excision for treatment of dermatofibrosarcoma protuberans in reducing risk of local recurrence? A Critically Appraised Topic
Authors: R.N. Matin, K.M. Acland, H.C. Williams
Journal: British Journal of Dermatology (2012)

Journal Article Is Mohs micrographic surgery more effective than wide local excision for treatment of dermatofibrosarcoma protuberans in reducing risk of local recurrence? A Critically Appraised Topic Get access R.N. Matin, R.N. Matin Department of Dermatology, Amersham Hospital, Buckinghamshire Hospitals NHS Trust, Amersham HA7 0JD, U.KCentre of Evidence Based Medicine, Queen’s Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, U.K E‐mail: rnhmatin@doctors.org.uk Search for other works by this author on: Oxford Academic Google Scholar K.M. Acland, K.M. Acland Department of Dermatology, Amersham Hospital, Buckinghamshire Hospitals NHS Trust, Amersham HA7 0JD, U.K Search for other works by this author on: Oxford Academic Google Scholar H.C. Williams H.C. Williams Centre of Evidence Based Medicine, Queen’s Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, U.K Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 167, Issue 1, 1 July 2012, Pages 6–9, https://doi.org/10.1111/j.1365-2133.2012.11054.x Published: 01 July 2012
Extragastric MALT lymphoma
Authors: A C Wotherspoon
Journal: Gut (2002)

A case of mucosa associated lymphoid tissue (MALT) lymphoma of the oesophagus, diagnosed and treated by endoscopic mucosal resection

A pproximately 40% of all non-Hodgkin's lymphomas occur in extranodal locations. The majority are of the diffuse large B cell type but extranodal marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT lymphoma) is the commonest extranodal small B cell non-Hodgkin's lymphoma. Approximately 37% of extranodal lymphomas occur in the gastrointestinal tract and oesophagus.1 The commonest site is the stomach (23% of extranodal lymphomas) followed by the small intestine (7.5%) and the colorectum (5.5%).1 Primary lymphoma of the oesophagus is very rare accounting for only three cases in a series of 1467 reported by Freeman and colleagues.1 The majority of lymphomas that have been reported in the literature date from before the advent of current knowledge about MALT lymphoma, its pathogenesis, molecular genetics, and treatment but in this issue of Gut , Hosaka and colleagues2 describe in detail a case of primary oesophageal lymphoma, diagnosed and treated by endoscopic mucosal resection [see 281] . Their case illustrates several interesting …
SIMULTANEOUS ASSESSMENT OF ENDOTHELIAL FUNCTION AND MORPHOLOGY IN BRACHIAL ARTERY USING A NEW SEMI-AUTOMATIC ULTRASOUND SYSTEM
Authors: Tomokazu Iguchi, Yasuhiko Takemoto, Kenei Shimada, Kenji Matsumoto, Yasukatsu Izumi, Yasuhiro Nakamura, Akihisa Hanatani, Minoru Yoshiyama
Journal: Journal of the American College of Cardiology (2013)