tbuckley/cabot-search huggingface dataset:
Angiotensin II Promotes Development of the Renal Microcirculation through AT1 Receptors
Authors: Kirsten Madsen, Niels Marcussen, Michael Pedersen, Gitte Kjærsgaard, Carie Facemire, Thomas M. Coffman, Boye L. Jensen
Journal: Journal of the American Society of Nephrology (2010)

Pharmacologic or genetic deletion of components of the renin-angiotensin system leads to postnatal kidney injury, but the roles of these components in kidney development are unknown. To test the hypothesis that angiotensin II supports angiogenesis during postnatal kidney development, we quantified CD31(+) postglomerular microvessels, performed quantitative PCR analysis of vascular growth factor expression, and measured renal blood flow by magnetic resonance. Treating rats with the angiotensin II type 1 receptor antagonist candesartan for 2 weeks after birth reduced the total length, volume, and surface area of capillaries in both the cortex and the medulla and inhibited the organization of vasa recta bundles. In addition, angiotensin II type 1 antagonism inhibited the transcription of angiogenic growth factors vascular endothelial growth factor, angiopoietin-1, angiopoietin-2, and the angiopoietin receptor Tie-2 in cortex and medulla. Similarly, Agtr1a(-/-);Agtr1b(-/-) mouse kidneys had decreased angiopoietin-1, angiopoietin-2, and Tie-2 mRNAs at postnatal day 14. To test whether increased urinary flow leads to microvascular injury, we induced postnatal polyuria with either lithium or adrenalectomy, but these did not alter vascular endothelial growth factor expression or vasa recta organization. Compared with vehicle-treated rats, renal blood flow was significantly (approximately 20%) lower in candesartan-treated rats even 14 days after candesartan withdrawal. Taken together, these data demonstrate that angiotensin II promotes postnatal expansion of postglomerular capillaries and organization of vasa recta bundles, which are necessary for development of normal renal blood flow.
Multicenter Phase II and Translational Study of Cetuximab in Metastatic Colorectal Carcinoma Refractory to Irinotecan, Oxaliplatin, and Fluoropyrimidines
Authors: Heinz-Josef Lenz, Eric Van Cutsem, Shirin Khambata-Ford, Robert J. Mayer, Philip Gold, Philip Stella, Barry Mirtsching, Allen L. Cohn, Andrew W. Pippas, Nozar Azarnia, Zenta Tsuchihashi, David J. Mauro, Eric K. Rowinsky
Journal: Journal of Clinical Oncology (2006)

This multicenter study evaluated the antitumor activity of cetuximab, an immunoglobulin G1 antibody directed at the epidermal growth factor receptor (EGFR), in metastatic colorectal carcinoma (CRC) refractory to irinotecan, oxaliplatin, and a fluoropyrimidine. It also evaluated the safety, pharmacokinetics, immunokinetics, and biologic determinants of activity.Patients with metastatic CRC, whose tumors demonstrated EGFR immunostaining and were refractory to irinotecan, oxaliplatin, and fluoropyrimidines, were treated with cetuximab at a loading dose of 400 mg/m2 followed by 250 mg/m2 weekly. An independent review committee (IRC) reviewed responses. Blood was collected for cetuximab pharmacokinetics and to detect antibodies to cetuximab. EGFR gene sequencing of the tyrosine kinase domain and gene copy number assessments were performed.The response rates in 346 patients, as determined by the investigators and IRC, were 12.4% (95% CI, 9.1 to 16.4) and 11.6% (95% CI, 8.4 to 16.4). The median progression-free survival (PFS) and survival times were 1.4 months (95% CI, 1.4 to 2.1) and 6.6 months (95% CI, 5.6 to 7.6), respectively. An acneiform rash occurred in 82.9% of patients; grade 3 rash was observed in 4.9%. Response and survival related strongly to the severity of the rash. In contrast, clinical benefit did not relate to EGFR immunostaining. EGFR tyrosine kinase domain mutations were not identified, and EGFR gene copy number did not relate to response or PFS, but to survival (P = .03).Cetuximab is active and well tolerated in metastatic CRC refractory to irinotecan, oxaliplatin, and fluoropyrimidines. The severity of rash was related to efficacy. Neither EGFR kinase domain mutations nor EGFR gene amplification appear to be essential for response to cetuximab in this setting.
Sports injuries and illnesses during the Winter Olympic Games 2010
Authors: Lars Engebretsen, Kathrin Steffen, Juan Manuel Alonso, Mark Aubry, Jiri Dvorak, Astrid Junge, Willem Meeuwisse, Margo Mountjoy, Per Renström, Mike Wilkinson
Journal: British Journal of Sports Medicine (2010)

Identification of high-risk sports, including their most common and severe injuries and illnesses, will facilitate the identification of sports and athletes at risk at an early stage.To analyse the frequencies and characteristics of injuries and illnesses during the XXI Winter Olympic Games in Vancouver 2010.All National Olympic Committees' (NOC) head physicians were asked to report daily the occurrence (or non-occurrence) of newly sustained injuries and illnesses on a standardised reporting form. In addition, the medical centres at the Vancouver and Whistler Olympic clinics reported daily on all athletes treated for injuries and illnesses.Physicians covering 2567 athletes (1045 females, 1522 males) from 82 NOCs participated in the study. The reported 287 injuries and 185 illnesses resulted in an incidence of 111.8 injuries and 72.1 illnesses per 1000 registered athletes. In relation to the number of registered athletes, the risk of sustaining an injury was highest for bobsleigh, ice hockey, short track, alpine freestyle and snowboard cross (15-35% of registered athletes were affected in each sport). The injury risk was lowest for the Nordic skiing events (biathlon, cross country skiing, ski jumping, Nordic combined), luge, curling, speed skating and freestyle moguls (less than 5% of registered athletes). Head/cervical spine and knee were the most common injury locations. Injuries were evenly distributed between training (54.0%) and competition (46.0%; p=0.18), and 22.6% of the injuries resulted in an absence from training or competition. In skeleton, figure and speed skating, curling, snowboard cross and biathlon, every 10th athlete suffered from at least one illness. In 113 illnesses (62.8%), the respiratory system was affected.At least 11% of the athletes incurred an injury during the games, and 7% of the athletes an illness. The incidence of injuries and illnesses varied substantially between sports. Analyses of injury mechanisms in high-risk Olympic winter sports are essential to better direct injury-prevention strategies.
Aspirin Resistance in Diabetic Patients
Authors: Giovanni de Gaetano
Journal: Diabetes Care (2004)

The results of the 5th and final year, Fiscal Year 2003, are included in Table 1.We obviously did not come close to realizing this ambitious goal.In my 1998 Presidential Address, I compared the ADA to a large ship in which a new course first required a change of direction (which would occur slowly) before proceeding toward and hopefully reaching a new port.It's obvious that we have not reached that port, and realistically speaking, we probably never will.However, I would be remiss if I didn't point out the following.In each of the previous years, the increase in funding for Research Awards and Grants was much less than
Genetic association study for RSV bronchiolitis in infancy at the 5q31 cytokine cluster
Authors: J T Forton, K Rowlands, K Rockett, N Hanchard, M Herbert, D P Kwiatkowski, J Hull
Journal: Thorax (2009)

<h3>Background:</h3> The pathophysiological basis of severe respiratory syncytial virus (RSV) bronchiolitis in infancy is poorly understood and has hindered vaccine development. Studies implicate the cell-mediated immune response in the pathogenesis of the disease. A recent twin study estimated a heritable contribution of 22% to RSV bronchiolitis. Genetic epidemiology provides a new approach to identifying important immune determinants of disease severity. <h3>Methods:</h3> A comprehensive high-density gene-region association study for severe RSV bronchiolitis in infancy at 5q31 across 11 genes including the Th2-cytokine cluster was performed. A haplotype tagging approach was used to analyse genetic variation at 113 single nucleotide polymorphisms (SNPs) in 780 independent cases and 1045 controls. The study had sufficient power to detect small effects, perform extensive haplotype analysis and analyse both a principal phenotype and a refined age-limited phenotype enriched for first-exposure RSV infection. <h3>Results:</h3> SNP associations were found at <i>IL4</i> and a highly significant risk haplotype was identified across <i>IL13</i><i>CNS-1</i> and <i>IL4</i> (odds ratio 1.69, p&lt;0.0001), present in both case-control and family-based analyses. All associations were strongest for a phenotype limited to &lt;6 months of age, implicating this locus in primary RSV disease. The same risk haplotype has previously been shown to be associated with increased <i>IL13</i> expression. <h3>Conclusions:</h3> A haplotype at <i>IL13–1L4</i>, which is associated with increased <i>IL13</i> production, confers an increased risk of severe primary RSV bronchiolitis in early infancy. This study, together with previous studies implicating the same locus in atopic sensitisation, suggests that primary RSV bronchiolitis and atopy share a genetic contribution at the <i>IL13–IL4</i> locus.
Transcriptional and Posttranscriptional Down-Regulation of the Imprinted Tumor Suppressor Gene <i>ARHI</i> (<i>DRAS3</i>) in Ovarian Cancer
Authors: Zhen Lu, Robert Z. Luo, Hongqi Peng, Daniel G. Rosen, E. Neely Atkinson, Carla Warneke, Maosheng Huang, Arata Nishmoto, Jinsong Liu, Warren S-L. Liao, Yinhua Yu, Robert C. Bast
Journal: Clinical Cancer Research (2006)

Abstract Purpose: ARHI expression is lost or markedly down-regulated in the majority of ovarian cancers. The mechanism by which ARHI is down-regulated in ovarian cancers is still not clear. Our previous reports indicated that ARHI promoter activity was reduced in ovarian cancer cells, due in part to the effects of negative regulatory transcription factor(s). Experimental Design and Results: We now show that E2F1 and E2F4, but not E2F2, E2F3, or E2F5, bind to the ARHI promoter and repress its activity in ovarian cancer cells. Consistent with this observation, immunochemical staining of cell lines and of 364 samples of ovarian cancer tissue show that the expression of E2F1 and E2F4 proteins is much higher in ovarian cancer cells than in normal ovarian epithelial cells, and that increased expression of E2Fs was negatively correlated with ARHI expression (P &amp;lt; 0.05). Mutation of the putative E2F binding site in the ARHI promoter reversed this inhibitory effect and significantly increased ARHI promoter activity. In addition to the effects of transcriptional regulation, ARHI mRNA also exhibited a significantly reduced half-life in ovarian cancer cells when compared with that in normal ovarian epithelial cells (P &amp;lt; 0.01), suggesting posttranscriptional regulation of ARHI expression. ARHI mRNA contains AU-rich elements (ARE) in the 3′-untranslated region. We have found that these AREs interact with HuR, an ARE-binding protein that stabilizes bound mRNAs, possibly contributing to the rapid turnover of ARHI mRNA. Finally, reduced HuR ARE binding activity was observed in ovarian cancer cells when compared with normal ovarian surface epithelium. Conclusions: Taken together, our data suggest that ARHI expression is regulated at both the transcriptional and the posttranscriptional levels, contributing to the dramatic decrease in ARHI expression in ovarian cancers.
P Wave Analysis in 2464 Orthogonal Electrocardiograms from Normal Subjects and Patients with Atrial Overload
Authors: KYOZO ISHIKAWA, P. MANOHAR KINI, HUBERT V. PIPBERGER
Journal: Circulation (1973)

The purpose of this study was to establish limits of normal for P wave measurements, and to propose criteria for routine electrocardiographic readings and for multivariate analysis to recognize left atrial overload (LAO) and right atrial overload (RAO) in the orthogonal electrocardiogram (ECG). Frank ECG's were obtained from 2464 subjects, including 580 normals, 164 patients with mitral valve disease (MVD) forming the LAO group, and 623 with chronic lung disease (CLD) as the RAO sample. Each group was divided into training and test sets. Using a digital computer, 120 different P wave measurements were computed for each ECG to find optimal discriminators between normal (N), LAO, and RAO. In the training set of MVD, using three scalar measurements, LAO was recognized in 57% with 3% false positives. These criteria diagnosed LAO in 70% of the test cases of MVD. Four discriminators identified RAO in 30% and 37% of training and test cases of CLD with 11% false positives. A set of 15 measurements obtained by multivariate analysis was used in a classification in which the three groups, N, LAO, and RAO were considered simultaneously. Ninety-four percent N, 74% LAO, and 45% RAO in the training sets, and 95%, 71%, and 24% in N, LAO, and RAO test sets were correctly identified. An attempt was made to correlate the rate of recognition of LAO with the degree of LAO estimated by cardiac catheterization. Data reported in the present study can serve as standard for P wave analysis in the Frank ECG.
Cryptogenic fibrosing alveolitis/idiopathic pulmonary fibrosis
Authors: R.M. du Bois, A.U. Wells
Journal: European Respiratory Journal (2001)

Cryptogenic fibrosing alveolitis (CFA), synonymous with idiopathic pulmonary fibrosis (IPF), remains a life-threatening disease: 50% of patients die within 5 yrs. Historically, many diseases that are now considered to be quite distinct have been “labelled” as CFA. More recently, high-resolution computed tomography and new appreciation of the histopathological patterns of idiopathic interstitial pneumonias have enabled disease variants to be defined according to their different responses to therapy and survival. CFA is believed to be induced by an external agent, although it is not clear whether CFA represents the final common outcome of numerous pathogenetic mechanisms or has a single cause. In addition, there are currently no prospective double-blind, placebo-controlled trials of treatment showing superiority of one drug regimen over another. This review attempts to dissect the different patterns of cryptogenic fibrosing alveolitis, illustrate the major features of each, and refine the clinico-radiological-pathological descriptors that together define cryptogenic fibrosing alveolitis as it is understood today.
Human Heart Generates Complement Proteins That Are Upregulated and Activated After Myocardial Infarction
Authors: Koji Yasojima, Claudia Schwab, Edith G. McGeer, Patrick L. McGeer
Journal: Circulation Research (1998)

Abstract —In human heart, we detected mRNAs and proteins for C1q, C1r, C1s, C2, C3, C4, C5, C6, C7, C8, and C9 with the use of reverse transcriptase–polymerase chain reaction, Western blotting, and immunohistochemical techniques. We found an upregulation of both mRNAs and proteins in areas of recent and old myocardial infarctions. In both situations, the classical complement pathway was activated, with C4d, C3d, and the membrane attack complex (C5b-9) being deposited on damaged cardiac myocytes. These activated complement components were also identified on Western blots of infarcted tissue. Complement mRNAs in infarcted heart tissue were higher than those in liver, and liver complement mRNAs were not upregulated in cases with infarcted hearts. Our results establish that (1) complement proteins are endogenously produced by human heart; (2) the classical complement pathway is fully activated after myocardial infarction; (3) complement activation is directly involved in myocardial damage after ischemic insults; and (4) damage from complement activation may be chronically sustained. These data suggest that inhibition of the complement system should be effective in treating myocardial infarction.
Inhibition of microRNA-29b reduces murine abdominal aortic aneurysm development
Authors: Lars Maegdefessel, Junya Azuma, Ryuji Toh, Denis R. Merk, Alicia Deng, Jocelyn T. Chin, Uwe Raaz, Anke M. Schoelmerich, Azad Raiesdana, Nicholas J. Leeper, Michael V. McConnell, Ronald L. Dalman, Joshua M. Spin, Philip S. Tsao
Journal: Journal of Clinical Investigation (2012)

MicroRNAs (miRs) regulate gene expression at the posttranscriptional level and play crucial roles in vascular integrity. As such, they may have a role in modifying abdominal aortic aneurysm (AAA) expansion, the pathophysiological mechanisms of which remain incompletely explored. Here, we investigate the role of miRs in 2 murine models of experimental AAA: the porcine pancreatic elastase (PPE) infusion model in C57BL/6 mice and the AngII infusion model in Apoe-/- mice. AAA development was accompanied by decreased aortic expression of miR-29b, along with increased expression of known miR-29b targets, Col1a1, Col3a1, Col5a1, and Eln, in both models. In vivo administration of locked nucleic acid anti-miR-29b greatly increased collagen expression, leading to an early fibrotic response in the abdominal aortic wall and resulting in a significant reduction in AAA progression over time in both models. In contrast, overexpression of miR-29b using a lentiviral vector led to augmented AAA expansion and significant increase of aortic rupture rate. Cell culture studies identified aortic fibroblasts as the likely vascular cell type mediating the profibrotic effects of miR-29b modulation. A similar pattern of reduced miR-29b expression and increased target gene expression was observed in human AAA tissue samples compared with that in organ donor controls. These data suggest that therapeutic manipulation of miR-29b and its target genes holds promise for limiting AAA disease progression and protecting from rupture.
Platelets aggregation in obstructive sleep apnoea before and after CPAP treatment measured with the optical aggregometry
Authors: Maria Wilczynska, Keir Lewis, Matthew Lawrence, Sophie Stanford, Phillip Evans
Journal: European Respiratory Journal (2013)

Introduction: Platelets play an important role in atherothrombosis therefore OSA related increased cardiovascular risk could be partially explained by defective platelets function.

Aim: To investigate the effects of OSA and continuous positive airway pressure (CPAP) on platelet aggregability.

Methods: 12 subjects with untreated OSAS: 11 males, (mean±SD) BMI 36.62±6.6 kg/m2, age 54.8±12.1 years, 4% Dip-rate (DR) 43.8±26 events/hour, Epworth Sleepiness score 14.5±5.2. Platelet aggregation was assessed in vitro on whole blood samples, before and after 40.3±14.7 days of treatment with CPAP. ADP (ADP), arachidonic acid (ASPI) and collagen (COL) induced platelet aggregability was measured with the optical aggregometry. Patients on anticoagulation were excluded.

Results: All subjects treated with CPAP achieved good control of obstructive events (4% DR 7.7±10.6 events/hour). On average CPAP was used for 4±1.7 hrs per night. CPAP treatment did not affect platelets function. There were no statistically significant changes in platelets aggregation when stimulated with the agonists and all measurements were within normal range.

View this table:

Platelets aggregation pre and post CPAP treatment in response to agonists.





Platelets aggregation before and after CPAP treatment was independent from age, BMI, gender, 4%DR and mean overnight Sa02.

Conclusions: Despite improvement in obstructive events and good compliance, CPAP treatment does not influence platelets function in severe OSAS. Longer follow-up might be required to reveal benefits of CPAP on platelets function.
Relationships between nasal potential difference and respiratory function in adults with cystic fibrosis
Authors: I Fajac, D Hubert, T Bienvenu, B Richaud-Thiriez, R Matran, JC Kaplan, J Dall'Ava-Santucci, DJ Dusser
Journal: European Respiratory Journal (1998)

This study investigated the relations between nasal transepithelial electric potential difference (PD) and the phenotype and genotype of cystic fibrosis (CF) adult patients. Basal nasal PD was measured in 95 adult CF patients who were classified into three groups of nasal PD (expressed as absolute values) according to the 10th and the 90th percentiles (28.3 and 49.2 mV, respectively), which defined group 1 (nasal PD < or =28.3 mV), group 2 (nasal PD 28.3-49.2 mV) and group 3 (nasal PD > or =49.2 mV). Patients from group 1 had a higher forced vital capacity (FVC) than patients from groups 2 and 3 (76.5+/-22.4 versus 57.4+/-21.2 and 55.7+/-21.1% predicted, respectively, p<0.05) and a higher forced expiratory volume in one second (FEV1) (69.3+/-24.0 versus 42.5+/-22.4 and 42.2+/-21.4% pred, respectively, p<0.01). Among patients with severe mutations (deltaF508 homozygotes, or one deltaF508 mutation plus another "severe" mutation, or two "severe" mutations), patients from group 1 had a higher FVC, FEV1 and arterial oxygen tension than patients from groups 2 and 3 (p<0.05 for each comparison). The results show that in adult cystic fibrosis patients a normal basal nasal potential difference is related to milder respiratory disease, irrespective of the severity of the genotype.
Assessment of Chk1 Phosphorylation as a Pharmacodynamic Biomarker of Chk1 Inhibition
Authors: Leslie A. Parsels, Yushen Qian, Daria M. Tanska, Marisa Gross, Lili Zhao, Maria C. Hassan, Sankari Arumugarajah, Joshua D. Parsels, Linda Hylander-Gans, Diane M. Simeone, Deborah Morosini, Jeffrey L. Brown, Sonya D. Zabludoff, Jonathan Maybaum, Theodore S. Lawrence, Meredith A. Morgan
Journal: Clinical Cancer Research (2011)

Chk1 inhibitors, such as AZD7762, are in clinical development in combination with cytotoxic agents for the treatment of solid tumors, including pancreatic cancers. To maximize the likelihood of their clinical success, it is essential to optimize drug scheduling as well as pharmacodynamic biomarkers in preclinical models.We tested multiple schedules of administration of gemcitabine and AZD7762 on the survival of pancreatic cancer cells. Potential pharmacodynamic biomarkers including pChk1, pChk2, pHistone H3, and caspase-3 were evaluated in vitro, followed by assessment of promising candidate biomarkers in vivo. We then went on to determine the contributions of PP2A and DNA damage to the mechanism(s) of induction of the identified biomarker, pS345 Chk1.AZD7762 given during and after or after gemcitabine administration produced maximum chemosensitization. In vivo, AZD7762 significantly inhibited the growth of pancreatic tumor xenografts in response to gemcitabine. Of the biomarkers assessed, pS345 Chk1 was most consistently increased in response to gemcitabine and AZD7762 in tumors and normal tissues (hair follicles). pS345 Chk1 induction in response to gemcitabine and AZD7762 occurred in the presence of PP2A inhibition and in association with elevated γH2AX, suggesting that DNA damage is an underlying mechanism.AZD7762 sensitizes pancreatic cancer cells and tumors to gemcitabine in association with induction of pS345 Chk1. Together these data support the clinical investigation of AZD7762 with gemcitabine in pancreatic cancer under a dosing schedule in which gemcitabine is administered concurrent with or before AZD7762 and in conjunction with skin biopsies to measure pS345 Chk1.