tbuckley/cabot-search huggingface dataset:
Human Papillomavirus Infections and Upper Aero-Digestive Tract Cancers: The ARCAGE Study
Authors: Devasena Anantharaman, Tarik Gheit, Tim Waterboer, Behnoush Abedi-Ardekani, Christine Carreira, Sandrine McKay-Chopin, Valerie Gaborieau, Manuela Marron, Pagona Lagiou, Wolfgang Ahrens, Ivana Holcátová, Franco Merletti, Kristina Kjaerheim, Renato Talamini, Lorenzo Simonato, Xavier Castellsague, Tatiana V. Macfarlane, Anne-Marie Biggs, Nalin Thakker, Ariana Znaor, Peter Thomson, Cristina Canova, David I. Conway, Claire M. Healy, Massimo Tommasino, Michael Pawlita, Paul Brennan
Journal: JNCI Journal of the National Cancer Institute (2013)

Human papillomavirus (HPV) is causally implicated in a subset of cancers of the upper aero-digestive tract (UADT).Associations between type-specific HPV antibodies were examined among 1496 UADT cancer case subjects and 1425 control subjects by estimating odds ratios (ORs) in logistic regression analyses adjusted for potential confounders. The agreement between serology and tumor markers of HPV infection, including presence of HPV DNA and p16 expression, were examined in a subset of tumors.HPV16 L1 seropositivity was associated with increased risk of oral cavity and oropharyngeal cancer (OR = 1.94, 95% confidence interval [CI] = 1.03 to 3.65; OR = 8.60, 95% CI = 5.21 to 14.20, respectively). HPV16 E6 antibodies were present in 30.2% of oropharyngeal case subjects and only 0.8% of control subjects (OR = 132.0, 95% CI = 65.29 to 266.86). Combined seropositivity to HPV16 E6 and E7 was rare (n = 1 of 1425 control subjects). An agreement of 67% was observed between HPV16 E6 serology and the corresponding presence of an HPV-related cancer: four of six HPV DNA-positive/p16-overexpressing tumors were HPV16 E6 antibody positive. An HPV16 independent association was observed for HPV18 and oropharyngeal cancer (OR = 8.14, 95% CI = 2.21 to 29.99 for HPV18 E6 seropositivity) and HPV6 and laryngeal cancer (OR = 3.25, 95% CI = 1.46 to 7.24 for HPV6 E7 seropositivity).These results confirm an important role for HPV16 infection in oropharyngeal cancer. HPV16 E6 antibodies are strongly associated with HPV16-related oropharyngeal cancers. Continuing efforts are needed to consider both HPV serology and p16 staining as biomarkers relevant to the etiology and natural history of HPV16-related oropharyngeal tumors. These results also support a marginal role for HPV18 in oropharyngeal cancer and HPV6 in laryngeal cancer.
Predictive genetic testing for the identification of high-risk groups: a simulation study on the impact of predictive ability
Authors: Raluca Mihaescu, Ramal Moonesinghe, Muin J Khoury, A Janssens
Journal: Genome Medicine (2011)

Genetic risk models could potentially be useful in identifying high-risk groups for the prevention of complex diseases. We investigated the performance of this risk stratification strategy by examining epidemiological parameters that impact the predictive ability of risk models. We assessed sensitivity, specificity, and positive and negative predictive value for all possible risk thresholds that can define high-risk groups and investigated how these measures depend on the frequency of disease in the population, the frequency of the high-risk group, and the discriminative accuracy of the risk model, as assessed by the area under the receiver-operating characteristic curve (AUC). In a simulation study, we modeled genetic risk scores of 50 genes with equal odds ratios and genotype frequencies, and varied the odds ratios and the disease frequency across scenarios. We also performed a simulation of age-related macular degeneration risk prediction based on published odds ratios and frequencies for six genetic risk variants. We show that when the frequency of the high-risk group was lower than the disease frequency, positive predictive value increased with the AUC but sensitivity remained low. When the frequency of the high-risk group was higher than the disease frequency, sensitivity was high but positive predictive value remained low. When both frequencies were equal, both positive predictive value and sensitivity increased with increasing AUC, but higher AUC was needed to maximize both measures. The performance of risk stratification is strongly determined by the frequency of the high-risk group relative to the frequency of disease in the population. The identification of high-risk groups with appreciable combinations of sensitivity and positive predictive value requires higher AUC.
Tissue Plasminogen Activator: The Biochemistry and Pharmacology of Variants Produced by Mutagenesis
Authors: D L Higgins, W F Bennett
Journal: The Annual Review of Pharmacology and Toxicology (1990)

Due to the massive data sets available for drug candidates, modern drug discovery has advanced to the big data era. Central to this shift is the development of artificial intelligence approaches to implementing innovative modeling based on the dynamic, ...Read More
Molecular evolution of mammalian aquaporin-2: further evidence that elephant shrew and aardvark join the paenungulate clade
Authors: O. Madsen, P. M. Deen, G. Pesole, C. Saccone, W. W. de Jong
Journal: Molecular Biology and Evolution (1997)

A 328-bp sequence from exon 1 of the gene for aquaporin-2 (AQP2) was compared in 12 mammalian species, representing as many eutherian orders. This sequence encodes the N-terminal half of this kidney-specific water channel protein. Most amino acid replacements, as well as an insertion, have occurred in extracellular loops connecting the transmembrane helices, in agreement with a lower functional importance of these loops. Phylogenetic analyses were performed with parsimony, distance, and maximum-likelihood methods. The AQP2 data set, alone as well as in combination with previously published alpha A-crystallin protein sequences, strongly supports a clade consisting of elephant, hyrax, aardvark, and elephant shrew, reaching bootstrap values of 99%. This finding fully agrees with the only other presently available sequence data sets that include these taxa, those of von Willebrand factor and interphotoreceptor retinoid-binding protein, and suggests that this extended paenungulate clade is one of the most conspicuous superordinal groupings in eutherian phylogeny. Some support was obtained for an artiodactyl/perissodactyl clade, while the grouping of pholidotes with edentates was contradicted.
Heat Shock Protein 90-Sheltered Overexpression of Insulin-Like Growth Factor 1 Receptor Contributes to Malignancy of Thymic Epithelial Tumors
Authors: Marco Breinig, Philipp Mayer, Andreas Harjung, Benjamin Goeppert, Mona Malz, Roland Penzel, Olaf Neumann, Arndt Hartmann, Hendrik Dienemann, Giuseppe Giaccone, Peter Schirmacher, Michael André Kern, Gabriela Chiosis, Ralf Joachim Rieker
Journal: Clinical Cancer Research (2011)

The underlying molecular mechanisms of thymic epithelial malignancies (TEMs) are poorly understood. Consequently, there is a lack of efficacious targeted therapies and patient prognosis remains dismal, particularly for advanced TEMs. We sought to investigate protumorigenic mechanism relevant to this understudied cancer.Recently established cell lines derived from thymic epithelial tumors were used as a model system. The antitumor activity of specific heat shock protein 90 (Hsp90) inhibitors was investigated by an analysis of cell viability, cell cycle, and apoptosis using MTT-assays and flow cytometry. Western blotting was used to investigate the altered expression of Hsp90 clients. Pharmacological inhibitors against select Hsp90 clients, as well as RNAi, were employed to test the relevance of each client independently. Tissue microarray analysis was performed to match the in vitro findings with observations obtained from patient-derived samples.Hsp90 inhibition significantly reduces cell viability of thymic carcinoma cells, induces cell cycle arrest and apoptosis, and blocks invasiveness. Hsp90 inhibition triggers the degradation of multiple oncogenic clients, for example insulin-like growth factor 1 receptor (IGF-1R), CDK4, and the inactivation of PI3K/Akt and RAF/Erk signaling. Mechanistically, the IGF/IGF-1R-signaling axis contributes to the establishment of the antiapoptotic phenotype of thymic cancer cells. Finally, IGF-1R is overexpressed in advanced TEMs.We have unraveled a novel protumorigenic mechanism in TEMs, namely Hsp90-capacitated overexpression of IGF-1R, which confers apoptosis evasion in malignant thymic epithelial cells. Our data indicate that Hsp90 inhibition, which simultaneously blocks multiple cancer hallmarks, represents a therapeutic strategy in TEMs that may merit evaluation in clinical trials.
Enhanced Ca<sup>2 +</sup>Mobilization in Airway Smooth Muscle Contributes to Airway Hyperresponsiveness in an Inbred Strain of Rat
Authors: FLORENCE C. TAO, BARBARA TOLLOCZKO, DAVID H. EIDELMAN, JAMES G. MARTIN
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

The mechanisms underlying airway hyperresponsiveness are still unknown but increased contractility of airway smooth muscle may play a role. This study sought to demonstrate a relationship between in vivo airway responsiveness and a number of measures of airway smooth muscle responsiveness ex vivo, including intracellular Ca2 + signaling, by comparing three inbred strains of rat with different degrees of airways responsiveness to methacholine. Lewis, ACI, and Fisher strains of rat were characterized for their pulmonary responses to 5-hydroxytryptamine (5HT) in vivo and Fisher rats were found to be hyperresponsive to 5HT compared with ACI and Lewis rats. The responsiveness of the airways from these strains of rat ex vivo revealed that intraparenchymal airways from Fisher rats significantly narrowed to a greater degree and at a faster rate to 5HT than Lewis rat airways, consistent with their differences in vivo. Intraparenchymal ACI airways, however, narrowed to the same degree as Fisher airways but took longer to do so at a high concentration of 5HT. 5HT caused concentration-dependent increases in intracellular Ca2 + in airway smooth muscle cells from all three strains of rat, but Fisher and ACI displayed higher responses than Lewis airway smooth muscle. Our results demonstrate that the degree of intracellular Ca2 + mobilization by 5HT in airway smooth muscle parallels the rate and degree of intraparenchymal airway narrowing and suggest that the degree of intracellular Ca2 + mobilization plays a role in determining airway smooth muscle contractility.
TCT-692 Left atrial appendage closure: Single-center experience with the 4th generation Watchman device
Authors: Maik Gonzaga, Stefan C. Bertog, Annkathrin Braut, Janine Bauer, Patrick Boehm, Ilona Hofmann, Laura Vaskelyte, Horst Sievert
Journal: Journal of the American College of Cardiology (2013)
Distribution of Coronary Artery Stenosis After Radiation for Breast Cancer
Authors: Greger Nilsson, Lars Holmberg, Hans Garmo, Olov Duvernoy, Iwar Sjögren, Bo Lagerqvist, Carl Blomqvist
Journal: Journal of Clinical Oncology (2011)

To study distribution of coronary artery stenosis among patients with breast cancer (BC) and to assess correlation between radiotherapy (RT) and location of stenosis.A Swedish BC cohort diagnosed from 1970 to 2003 was linked to registers of coronary angiography from 1990 to 2004, which yielded 199 patients. Stenoses of the coronary arteries were graded from 0 to 5, where 0 indicated a normal vessel and 5 indicated occlusion. Two hotspot areas for radiation were defined: proximal right coronary artery (prox RCA), mid and distal left anterior descending artery and distal diagonal (mdLAD + dD). RT regimens were categorized as high or low risk of irradiating the hotspot areas. Left breast/chest wall was considered high risk for mdLAD + dD; left internal mammary chain (IMC), high risk for prox RCA and mdLAD + dD from 1970 to 1995 and thereafter solely for mdLAD + dD; and right IMC, high risk for prox RCA. Other RT targets and no RT were considered low risk. Results were expressed in odds ratios (ORs) and 95% CIs.For irradiated left- versus right-sided BC, the OR for grade 3 to 5 stenosis in mdLAD + dD was 4.38 (95% CI, 1.64 to 11.7), and for grade 4 to 5 stenosis, the OR was 7.22 (95% CI, 1.64 to 31.8). For high-risk RT versus low-risk or no RT, the OR for grade 3 to 5 stenosis in hotspot areas was 1.90 (95% CI, 1.11 to 3.24).An increase of stenosis in mdLAD + dD in irradiated left-sided BC and an association between high-risk RT and stenosis in hotspot areas for radiation indicate a direct link between radiation and location of coronary stenoses.
A Phase Ib and Pharmacokinetic Trial of Patupilone Combined with Carboplatin in Patients with Advanced Cancer
Authors: Martin Forster, Stan Kaye, Amit Oza, Ivo Sklenar, Anandhi Johri, Wing Cheung, Sara Zaknoen, Martin Gore
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Patupilone is a microtubule-targeting chemotherapeutic agent with clinical activity in a broad range of taxane-sensitive/resistant tumor types. The present phase Ib study examined the safety/tolerability and pharmacokinetics of patupilone in combination with carboplatin in patients with advanced solid tumors. Experimental Design: Patients with advanced cancer received patupilone via a 5- to 10-min i.v. infusion at doses of 3.6 to 6.0 mg/m2 q3w, immediately followed by carboplatin area under the curve (AUC) 5 or 6 mg/mL/min. Results: Of the 37 patients enrolled, the majority previously received taxanes (81%) and/or platinum-containing drugs (97.3%). The maximum tolerated dose (MTD) of patupilone with carboplatin AUC 6 was 4.8 mg/m2; additional patients were enrolled to consolidate experience at this dose. Of the 22 patients who received the MTD, the most common nonhematologic adverse events were fatigue in six (27.3%) and diarrhea, nausea, vomiting, abdominal pain, and neuropathy in one each (4.5%; all grade 3); hematologic toxicities included two patients (9.1%) with grade 3 neutropenia. The pharmacokinetics of patupilone were similar to those in a previous study of patupilone monotherapy. Of the 26 patients with recurrent platinum-sensitive ovarian cancer, tumor response was assessable by response evaluation criteria in solid tumors in 17; 1 patient (6%) achieved a complete response, and 10 (59%) achieved a partial response. Conclusions: The combination of patupilone 4.8 mg/m2/carboplatin AUC 6 was well tolerated and showed antitumor activity similar to established regimens in patients with recurrent platinum-sensitive ovarian cancer. The optimal dose for this regimen is currently being further refined in phase II trials.
MODIFICATION OF AN IMPROVED ANAEROBE JAR
Authors: J. Howard Brown
Journal: The Journal of Experimental Medicine (1922)

In the filtrates of typhus-infected tissues of guinea pigs can be occasionally found a substance which produces in these animals thermic reactions, lesions characteristic of experimental typhus, and, still less frequently, inimunity to later injections of active virus. The general indications are that this substance is not a living organism.
Heritability of upper airway dimensions derived using acoustic pharyngometry
Authors: S. R. Patel, J. M. Frame, E. K. Larkin, S. Redline
Journal: European Respiratory Journal (2008)

Acoustic pharyngometry represents a simple, quick noninvasive method of measuring upper airway dimensions, which are predictive of sleep apnoea risk. The aim of the present study was to assess the genetic basis of upper airway size as determined using pharyngometry. Participants in the Cleveland Family Study aged &gt;14 yrs underwent three acoustic pharyngometric measurements. Variance component models adjusted for age and sex were used to estimate the heritability of pharyngometry-derived airway measures. A total of 568 out of 655 (87%) subjects provided pharyngometric curves of sufficient quality. Although African-Americans tended to show narrower airways compared with white subjects, heritability patterns were similar in these two groups. The minimum cross-sectional area exhibited a heritability of 0.34 in white subjects and 0.39 in African-Americans, suggesting that 30–40% of the total variance in this measure is explained by shared familial factors. Estimates were unchanged after adjustment for body mass index or neck circumference. In contrast, oropharyngeal length did not show significant heritability in either ethnic group. The minimum cross-sectional area of the oropharynx is a highly heritable trait, suggesting the presence of an underlying genetic basis. These findings demonstrate the potential utility of acoustic pharyngometry in dissecting the genetic basis of sleep apnoea.
Sildenafil Prevents Rebound Pulmonary Hypertension after Withdrawal of Nitric Oxide in Children
Authors: Poongundran Namachivayam, Ulf Theilen, Warwick W. Butt, Sian M. Cooper, Daniel J. Penny, Lara S. Shekerdemian
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Rebound pulmonary hypertension (PHT) can complicate the weaning of nitric oxide (NO), and is in part related to transient depletion of intrinsic cyclic guanosine monophosphate. Rebound is characterized by increased pulmonary arterial (PA) pressure, cardiopulmonary instability, and in some cases, the need to continue NO beyond the intended period of use. There is anecdotal evidence that sildenafil, a phosphodiesterase-5 inhibitor, may prevent recurrence of rebound.We investigated the role of sildenafil in preventing rebound (an increase in PA pressure of 20% or greater, or failure to discontinue NO) in patients in whom previous attempts had not been made to wean from NO.Thirty ventilated infants and children, receiving 10 ppm or greater inhaled NO, were randomized to receive 0.4 mg/kg of sildenafil, or placebo, 1 h before discontinuing NO. Twenty-nine patients completed the study.PA pressures and blood gases were measured before the study drug, and 1 and 4 h after stopping NO.Rebound occurred in 10 of 14 placebo patients, and 0 of 15 sildenafil patients (p < 0.001). PA pressure increased by 25% (14-67) in placebo patients, and by 1%(-9-5) in sildenafil patients (p < 0.001). Four placebo patients could not be weaned from NO due to severe cardiovascular instability, whereas all sildenafil patients were weaned (p = 0.042). Duration of ventilation after study was 98.0 (47.0-223.5) h for placebo patients and 28.2 (15.7-54.6) h for sildenafil patients (p = 0.024).A single dose of sildenafil prevented rebound after withdrawal of NO, and reduced the duration of mechanical ventilation. Prophylaxis with sildenafil should be considered when weaning patients from inhaled NO.
The conduction system in double outlet right ventricle with subpulmonic ventricular septal defect and related hearts (the Taussig-Bing group).
Authors: S Bharati, M Lev
Journal: Circulation (1976)

The Taussig-Bind group of hearts is that group in which the aorta emerges completely from the right ventricle, unrelated to the position of the ventricular septal defect (VSD), while the pulmonary trunk emerges at varying degrees from the right ventricle related to the location of the VSD. Several types of surgical procedures involve the VSD in these hearts. The conduction systems in six of these hearts were therefore studied. The atrioventricular (A-V) bundle lies in the inferior (posterior) wall of the defect on the left side beneath the summit of the ventricular septum. In some cases, the bundle may be proximal to the defect, thus lying intramuscularly, and only the right and left bundle branches are related to the defect. The pattern od development of the atrioventricular (A-V) node, bundle and bundle branches is related primarily to the development of the endocardial cushions and posterior ventricular septum, and not to that of the absorption of the bulbus.
Psoriatic arthritis: update on pathophysiology, assessment and management
Authors: P. J. Mease
Journal: Annals of the Rheumatic Diseases (2011)

Psoriatic arthritis (PsA) is classified as a spondyloarthropathy and characterised by synovitis, enthesitis, dactylitis and spondylitis usually manifesting as skin and nail psoriasis. Our understanding about the PsA disease state, its genetics, pathophysiology and comorbidities, as well as the ability to assess and treat the disease, has advanced as a result of significant collaborative efforts by rheumatologists and dermatologists in the development of classification criteria, outcome measures to assess the various clinical domains, and treatment trials with agents also used for diseases such as rheumatoid arthritis (RA) and psoriasis. Biological agents, especially the antitumour necrosis factors, have demonstrated significant efficacy and reasonable safety in all clinical domains of the disease, resulting in amelioration of clinical symptoms, inhibition of structural damage and improvement of function and quality of life. Although there is considerable overlap with RA, there are some differences in pathophysiology and approach to assessment and management that are important to consider. This paper reviews these subjects, with an emphasis on recent data.
Dysregulation of Regional Endogenous Opioid Function in Borderline Personality Disorder
Authors: Alan R. Prossin, Tiffany M. Love, Robert A. Koeppe, Jon-Kar Zubieta, Kenneth R. Silk
Journal: American Journal of Psychiatry (2010)

Objective Borderline personality disorder is characterized by a lack of effective regulation of emotional responses. The authors investigated the role of the endogenous opioid system and μ-opioid receptors in emotion regulation in borderline personality disorder. Method Mu-opioid receptor availability in vivo (nondisplaceable binding potential, or BPND) was measured with positron emission tomography and the selective radiotracer [11C]carfentanil during neutral and sustained sadness states in 18 unmedicated female patients with borderline personality disorder and 14 healthy female comparison subjects. Results Patients showed greater regional μ-opioid BPND than did comparison subjects at baseline (neutral state) bilaterally in the orbitofrontal cortex, caudate, and nucleus accumbens and in the left amygdala, but lower BPND in the posterior thalamus. Sadness induction was associated with greater reductions in BPND (endogenous opioid system activation) in the patient group than in the comparison group in the pregenual anterior cingulate, left orbitofrontal cortex, left ventral pallidum, left amygdala, and left inferior temporal cortex. Patients showed evidence of endogenous opioid system deactivation in the left nucleus accumbens, the hypothalamus, and the right hippocampus/parahippocampus relative to comparison subjects. Correlations of baseline measures with the Dissociative Experiences Scale and endogenous opioid system activation with the Barratt Impulsiveness Scale did not remain significant after correction for multiple comparisons. Conclusions Differences exist between patients with borderline personality disorder and comparison subjects in baseline in vivo μ-opioid receptor concentrations and in the endogenous opioid system response to a negative emotional challenge that can be related to some of the clinical characteristics of patients with borderline personality disorder. The regional network involved is implicated in the representation and regulation of emotion and stress responses.
Serum concentration of visfatin in obese women
Authors: Barbara Zahorska-Markiewicz, Magdalena Olszanecka-Glinianowicz, Joanna Janowska, Piotr Kocełak, Elżbieta Semik-Grabarczyk, Michał Holecki, Piotr Dąbrowski, Anna Skorupa
Journal: Metabolism (2007)