tbuckley/cabot-search huggingface dataset:
Neurodevelopmental defects after steroid treatment of premature lung disease
Authors: K E Johnson
Journal: Thorax (2004)

▴ Yeh TF, Lin YJ, Lin HC, et al. Outcomes at school age after postnatal dexamethsaone therapy for lung disease of prematurity. N Engl J Med2004;350:1304–13. [OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4] There has been much controversy in recent years regarding the early use of postnatal corticosteroids to treat preterm infants with respiratory distress syndrome (RDS). Short term respiratory benefits must be weighed against the potential for detrimental neurodevelopmental effects. This … [1]: {openurl}?query=rft.jtitle%253DNew%2BEngland%2BJournal%2Bof%2BMedicine%26rft.stitle%253DNEJM%26rft.issn%253D0028-4793%26rft.aulast%253DYeh%26rft.auinit1%253DT.%2BF.%26rft.volume%253D350%26rft.issue%253D13%26rft.spage%253D1304%26rft.epage%253D1313%26rft.atitle%253DOutcomes%2Bat%2BSchool%2BAge%2Bafter%2BPostnatal%2BDexamethasone%2BTherapy%2Bfor%2BLung%2BDisease%2Bof%2BPrematurity%26rft_id%253Dinfo%253Adoi%252F10.1056%252FNEJMoa032089%26rft_id%253Dinfo%253Apmid%252F15044641%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1056/NEJMoa032089&link_type=DOI [3]: /lookup/external-ref?access_num=15044641&link_type=MED&atom=%2Fthoraxjnl%2F59%2F6%2F464.atom [4]: /lookup/external-ref?access_num=000220393900008&link_type=ISI
Enhancing Poxvirus Oncolytic Effects through Increased Spread and Immune Evasion
Authors: David H. Kirn, Yaohe Wang, Wenchung Liang, Christopher H. Contag, Stephen H. Thorne
Journal: Cancer Research (2008)

Abstract The antitumoral effects of oncolytic viruses have generally been limited by inefficient spread of the viruses within infected tumors and by inefficient systemic delivery, particularly in preimmunized hosts. Tumor-selective poxviruses have biological characteristics that may overcome these limitations. Nevertheless, physical barriers within the tumor microenvironment, including the extracellular matrix, can still limit intratumoral spread, and neutralizing antibodies can impede systemic delivery. To counter these limitations, we sought to take advantage of a naturally occurring poxvirus form known as extracellular enveloped virus (EEV). The EEV is shrouded by a host cell–derived lipid bilayer containing anticomplement proteins and is typically released from infected cells early during the infection cycle. Therefore, the EEV form evolved for rapid systemic spread within the host and for evasion of immune-mediated clearance. We compared the oncolytic potential of low versus high EEV-producing strains of vaccinia. EEV-enhanced vaccinia strains displayed improved spread within tumors after systemic delivery, resulting in significantly improved antitumor effects. The EEV-enhanced strains also displayed a greater ability to spread between injected and noninjected distant tumors through the blood and, importantly, displayed reduced clearance by neutralizing antibody. Safety was unaffected. The incorporation of EEV-enhancing mutations into next generation oncolytic vaccinia strains may improve the potency of these viruses without sacrificing safety. [Cancer Res 2008;68(7):2071–5]
Acute and Prolonged Effects of Sildenafil on Brachial Artery Flow-Mediated Dilatation in Type 2 Diabetes
Authors: Vivian Fonseca
Journal: Diabetes Care (2003)

We appreciate the comments of Drs. Khaodhiar and Veves (1). We agree that in order to dissect the action of sildenafil on the endothelial cell and the vascular smooth muscle cell it is necessary to perform measurements that evaluate both endothelium-dependent and endothelium-independent vasodilatation. However, the latter requires …
An unexpected cause of muscle pain in diabetes
Authors: L Silberstein
Journal: Annals of the Rheumatic Diseases (2001)

Diabetic muscle infarction is a rare condition which may present to a rheumatologist. It was first reported in 1965. Two illustrative cases are described here and the mechanisms of pathogenesis discussed. Analysis of the published data, results of the muscle biopsies, and a technetium-99m sestamibi scan suggest that the condition, which occurs against a background of diabetic microangiopathy, can be triggered by an ischaemic event and causes extensive muscle necrosis through hypoxia-reperfusion injury and compartment syndrome.
Phenotypic and Genotypic Expression of Self-incompatibility Haplotypes in Arabidopsis lyrata Suggests Unique Origin of Alleles in Different Dominance Classes
Authors: Nadia L. Prigoda, Annette Nassuth, Barbara K. Mable
Journal: Molecular Biology and Evolution (2005)

The highly divergent alleles of the SRK gene in outcrossing Arabidopsis lyrata have provided important insights into the evolutionary history of self-incompatibility (SI) alleles and serve as an ideal model for studies of the evolutionary and molecular interactions between alleles in cell-cell recognition systems in general. One tantalizing question is how new specificities arise in systems that require coordination between male and female components. Allelic recruitment via gene conversion has been proposed as one possibility, based on the division of DNA sequences at the SRK locus into two distinctive groups: (1) sequences whose relationships are not well resolved and display the long branch lengths expected for a gene under balancing selection (Class A); and (2) sequences falling into a well-supported group with shorter branch lengths (Class B) that are closely related to an unlinked paralogous locus. The purpose of this study was to determine if differences in phenotype (site of expression assayed using allele-specific reverse transcription–polymerase chain reaction) or function (dominance relationships assayed through controlled pollinations) accompany the sequence-based classification. Expression of Class A alleles was restricted to floral tissues, as predicted for genes involved in the SI response. In contrast, Class B alleles, despite being tightly linked to the SI phenotype, were unexpectedly expressed in both leaves and floral tissues; the same pattern found for a related unlinked paralogous sequence. Whereas Class A included haplotypes in three different dominance classes, all Class B haplotypes were found to be recessive to all except one Class A haplotype. In addition, mapping of expression and dominance patterns onto an S-domain–based genealogy suggested that allelic dominance may be determined more by evolutionary history than by frequency-dependent selection for lowered dominance as some theories suggest. The possibility that interlocus gene conversion might have contributed to allelic diversity is discussed.
Durable Therapeutic Efficacy Utilizing Combinatorial Blockade against IDO, CTLA-4, and PD-L1 in Mice with Brain Tumors
Authors: Derek A. Wainwright, Alan L. Chang, Mahua Dey, Irina V. Balyasnikova, Chung Kwon Kim, Alex Tobias, Yu Cheng, Julius W. Kim, Jian Qiao, Lingjiao Zhang, Yu Han, Maciej S. Lesniak
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Glioblastoma (GBM) is the most common form of malignant glioma in adults. Although protected by both the blood–brain and blood–tumor barriers, GBMs are actively infiltrated by T cells. Previous work has shown that IDO, CTLA-4, and PD-L1 are dominant molecular participants in the suppression of GBM immunity. This includes IDO-mediated regulatory T-cell (Treg; CD4+CD25+FoxP3+) accumulation, the interaction of T-cell–expressed, CTLA-4, with dendritic cell-expressed, CD80, as well as the interaction of tumor- and/or macrophage-expressed, PD-L1, with T-cell–expressed, PD-1. The individual inhibition of each pathway has been shown to increase survival in the context of experimental GBM. However, the impact of simultaneously targeting all three pathways in brain tumors has been left unanswered. Experimental Design and Results: In this report, we demonstrate that, when dually challenged, IDO-deficient tumors provide a selectively competitive survival advantage against IDO-competent tumors. Next, we provide novel observations regarding tryptophan catabolic enzyme expression, before showing that the therapeutic inhibition of IDO, CTLA-4, and PD-L1 in a mouse model of well-established glioma maximally decreases tumor-infiltrating Tregs, coincident with a significant increase in T-cell–mediated long-term survival. In fact, 100% of mice bearing intracranial tumors were long-term survivors following triple combination therapy. The expression and/or frequency of T cell expressed CD44, CTLA-4, PD-1, and IFN-γ depended on timing after immunotherapeutic administration. Conclusions: Collectively, these data provide strong preclinical evidence that combinatorially targeting immunosuppression in malignant glioma is a strategy that has high potential value for future clinical trials in patients with GBM. Clin Cancer Res; 20(20); 5290–301. ©2014 AACR.
Down-regulation of OPA1 alters mouse mitochondrial morphology, PTP function, and cardiac adaptation to pressure overload
Authors: Jerome Piquereau, Fanny Caffin, Marta Novotova, Alexandre Prola, Anne Garnier, Philippe Mateo, Dominique Fortin, Le Ha Huynh, Valérie Nicolas, Marcel V. Alavi, Catherine Brenner, Renée Ventura-Clapier, Vladimir Veksler, Frédéric Joubert
Journal: Cardiovascular Research (2012)

The optic atrophy 1 (OPA1) protein is an essential protein involved in the fusion of the mitochondrial inner membrane. Despite its high level of expression, the role of OPA1 in the heart is largely unknown. We investigated the role of this protein in Opa1+/− mice, having a 50% reduction in OPA1 protein expression in cardiac tissue. In mutant mice, cardiac function assessed by echocardiography was not significantly different from that of the Opa1+/+. Electron and fluorescence microscopy revealed altered morphology of the Opa1+/− mice mitochondrial network; unexpectedly, mitochondria were larger with the presence of clusters of fused mitochondria and altered cristae. In permeabilized mutant ventricular fibres, mitochondrial functional properties were maintained, but direct energy channelling between mitochondria and myofilaments was weakened. Importantly, the mitochondrial permeability transition pore (PTP) opening in isolated permeabilized cardiomyocytes and in isolated mitochondria was significantly less sensitive to mitochondrial calcium accumulation. Finally, 6 weeks after transversal aortic constriction, Opa1+/− hearts demonstrated hypertrophy almost two-fold higher (P< 0.01) than in wild-type mice with altered ejection fraction (decrease in 43 vs. 22% in Opa1+/+ mice, P< 0.05). These results suggest that, in adult cardiomyocytes, OPA1 plays an important role in mitochondrial morphology and PTP functioning. These properties may be critical for cardiac function under conditions of chronic pressure overload.
Mediastinal Lymph Node Clearance After Docetaxel-Cisplatin Neoadjuvant Chemotherapy Is Prognostic of Survival in Patients With Stage IIIA pN2 Non–Small-Cell Lung Cancer: A Multicenter Phase II Trial
Authors: Daniel C. Betticher, Shu-Fang Hsu Schmitz, Martin Tötsch, Eva Hansen, Christine Joss, Christian von Briel, Ralph A. Schmid, Miklos Pless, James Habicht, Arnaud D. Roth, Anastase Spiliopoulos, Rolf Stahel, Walter Weder, Roger Stupp, Fritz Egli, Markus Furrer, Hanspeter Honegger, Martin Wernli, Thomas Cerny, Hans-Beat Ris
Journal: Journal of Clinical Oncology (2003)

Purpose: A multicenter, phase II trial investigated the efficacy and toxicity of neoadjuvant docetaxel-cisplatin in locally advanced non–small-cell lung cancer (NSCLC) and examined prognostic factors for patients not benefiting from surgery. Patients and Methods: Ninety patients with previously untreated, potentially operable stage IIIA (mediastinoscopically pN2) NSCLC received three cycles of docetaxel 85 mg/m 2 day 1 plus cisplatin 40 mg/m 2 days 1 and 2, with subsequent surgical resection. Results: Administered dose-intensities were docetaxel 85 mg/m 2 /3 weeks (range, 53 to 96) and cisplatin 95 mg/m 2 /3 weeks (range, 0 to 104). The 265 cycles were well tolerated, and the overall response rate was 66% (95% confidence interval [CI], 55% to 75%). Seventy-five patients underwent tumor resection with positive resection margin and involvement of the uppermost mediastinal lymph node in 16% and 35% of patients, respectively (perioperative mortality, 3%; morbidity, 17%). Pathologic complete response occurred in 19% of patients with tumor resection. In patients with tumor resection, downstaging to N0–1 at surgery was prognostic and significantly prolonged event-free survival (EFS) and overall survival (OS; P = .0001). At median follow-up of 32 months, the median EFS and OS were 14.8 months (range, 2.4 to 53.4) and 33 months (range, 2.4 to 53.4), respectively. Local relapse occurred in 27% of patients with tumor resection, with distant metastases in 37%. Multivariate analyses identified mediastinal clearance (hazard ratio, 0.22; P = .0003) and complete resection (hazard ratio, 0.26; P = .0006) as strongly prognostic for increased survival. Conclusion: Neoadjuvant docetaxel-cisplatin is effective and tolerable in stage IIIA pN2 NSCLC. Resection is recommended only for patients with mediastinal downstaging after chemotherapy.
Bone loss in very early inflammatory back pain in undifferentiated spondyloarthropathy: a 1-year observational study
Authors: G. Haugeberg, A. N. Bennett, D. McGonagle, P. Emery, H. Marzo-Ortega
Journal: Annals of the Rheumatic Diseases (2010)

Bone loss in patients with inflammatory back pain (IBP) suspicious of early undifferentiated spondyloarthropathy is poorly defined. The aim of this study was to examine changes in bone mineral density (BMD) at the hip, lumbar spine and hand in patients with early IBP and to look for possible biomarkers associated with this change.In 30 patients with early IBP, clinical data were collected and BMD assessed using dual energy x-ray absorptiometry at baseline, 6 and 12 months. Further imaging performed included MRI of the sacroiliac joints (SIJs) and spine at baseline and x-rays of the SIJs at baseline and after 8 years.After 12 months no significant reduction in hip, spine and hand BMD was seen at the group level. However, hip bone loss was found to be associated with raised baseline C-reactive protein levels, baseline MRI bone marrow oedema of the SIJs and the presence of radiographic sacroiliitis after 8 years. No association was found with change in spine and hand BMD.Systemic bone loss in the hip is an early feature of the inflammatory disease process in patients with IBP in undifferentiated spondyloarthropathy and is related to disease activity. These data highlight the importance of aggressive intervention in the early stages of disease in undifferentiated spondyloarthropathy.
A comparison of hormonal profiles between breast cancer and benign breast disease: a case–control study
Authors: P. Lagiou, E. Samoli, A. Lagiou, P. Zourna, A. Barbouni, C. Georgila, A. Tsikkinis, D. Vassilarou, P. Minaki, C. Sfikas, E. Spanos, D. Trichopoulos
Journal: Annals of Oncology (2013)
Importance of P-Cadherin, β-Catenin, and Wnt5a/Frizzled for Progression of Melanocytic Tumors and Prognosis in Cutaneous Melanoma
Authors: Ingeborg M. Bachmann, Oddbjørn Straume, Hanne E. Puntervoll, May Britt Kalvenes, Lars A. Akslen
Journal: Clinical Cancer Research (2005)

Abstract Purpose: It has been proposed that melanoma cells shift from E-cadherin to N-cadherin expression during tumor development, and recent gene profiling has shown increased expression of Wnt5a/Frizzled in aggressive melanomas possibly by interactions with β-catenin. We therefore wanted to investigate the role of cadherin subtypes, β-catenin, and Wnt5a/Frizzled in melanocytic tumors, with focus on prognosis in nodular melanomas. Experimental Design: The immunohistochemical expression of E-cadherin, N-cadherin, P-cadherin, β-catenin, and Wnt5a/Frizzled was examined using tissue microarrays of 312 melanocytic tumors. Results: Cytoplasmic expression of P-cadherin was associated with increasing tumor thickness (P = 0.005) and level of invasion (P = 0.019), whereas membranous staining was associated with thinner (P = 0.012) and more superficial (P = 0.018) tumors. Increased cytoplasmic P-cadherin was associated with reduced survival (P = 0.047). Lack of nuclear β-catenin expression was related to increased tumor thickness (P = 0.002) and poor patient survival in univariate (P = 0.0072) and multivariate (P = 0.004) analyses. Membranous expression of N-cadherin was significantly increased from primary tumors to metastatic lesions, whereas E-cadherin staining tended to be decreased. Wnt5a and its receptor Frizzled were highly coexpressed, and nuclear expression of both markers was significantly reduced from benign nevi to melanomas, with a shift from nuclear to cytoplasmic expression in malignant tumors. In addition, Wnt5a expression was significantly associated with nuclear β-catenin expression. Conclusions: Alterations in the expression and subcellular localization of cell adhesion markers are important in the development and progression of melanocytic tumors, and strong cytoplasmic P-cadherin expression and loss of nuclear β-catenin staining were associated with aggressive melanoma behavior and reduced patient survival.
Effects of two types of training on pulmonary and cardiac responses to moderate exercise in patients with COPD
Authors: L Puente-Maestu, M Sánz, P Sánz, J.m Ruíz de Oña, J.l Rodríguez-Hermosa, B.j Whipp
Journal: European Respiratory Journal (2000)

The effects of two 8-week programmes of exercise reconditioning on the time constants (tau) of the pulmonary gas exchange, ventilatory and heart rate responses to moderate intensity exercise in patients with chronic obstructive pulmonary disease (COPD) were studied. Thirty-five subjects (mean+/-SD 64+/-5 yrs; forced expiratory volume in one second (FEV1) 1.09+/-0.17 L; 41+/-6.2% predicted) were randomly assigned either to supervised (s) training on a treadmill, 4 days x week(-1) (group S; n=21) or self-monitored (SM) walking 3 or 4 km in 1 h 4 days x week(-l) (group SM; n=20). The different levels of supervision resulted in a different estimated intensity of training (35+/-10 W in the SM group and 70+/-22 W in the S group). The kinetics were evaluated with a constant-load exercise test on a cycle-ergometer at a work rate corresponding to 80% the highest oxygen consumption (V'O2) that can be achieved without blood lactic acidosis (V'O2,LAT) or 50% of V'O2,max, if maximum oxygen consumption V'O2,LAT was not found. Mean endurance time at a work rate equivalent to 70% of the pretraining V'O2,max increased by 493+/-281 s in the S group and 254+/-283 s in the SM group (p<0.001). Mean tauV'O2 decreased from 83+/-17 s to 67+/-11 s (p<0.0001) in the S group and from 84+/-12 to 79+/-16 (p=0.04) in the SM group. Mean tau for carbon dioxide output minute ventilation and heart rate were also speeded after training, again more markedly in the S group. In the S group there was a significant correlation between the decrease in tauV'O2 and the increase in endurance time (r=-0.56, SEM=0.21). It is concluded that training speeds the kinetic response of oxygen consumption, carbon dioxide production, minute ventilation and heart rate to moderate exercise and that the effect is greater after supervised, more intense training.
Betaine acts on a ligand-gated ion channel in the nervous system of the nematode C. elegans
Authors: Aude S Peden, Patrick Mac, You-Jun Fei, Cecilia Castro, Guoliang Jiang, Kenneth J Murfitt, Eric A Miska, Julian L Griffin, Vadivel Ganapathy, Erik M Jorgensen
Journal: Nature Neuroscience (2013)
Evolutionary Transition from Pathogenicity to Commensalism: Global Regulator Mutations Mediate Fitness Gains through Virulence Attenuation
Authors: Gunther Jansen, Lena L Crummenerl, Felix Gilbert, Timm Mohr, Roxana Pfefferkorn, Robert Thänert, Philip Rosenstiel, Hinrich Schulenburg
Journal: Molecular Biology and Evolution (2015)

Symbiotic interactions are indispensable for metazoan function, but their origin and evolution remain elusive. We use a controlled evolution experiment to demonstrate the emergence of novel commensal interactions between Pseudomonas aeruginosa, an initially pathogenic bacterium, and a metazoan host, Caenorhabditis elegans. We show that commensalism evolves through loss of virulence, because it provides bacteria with a double fitness advantage: Increased within-host fitness and a larger host population to infect. Commensalism arises irrespective of host immune status, as the adaptive path in immunocompromised C. elegans knockouts does not differ from that in wild type. Dissection of temporal dynamics of genomic adaptation for 125 bacterial populations reveals highly parallel evolution of incipient commensalism across independent biological replicates. Adaptation is mainly achieved through frame shift mutations in the global regulator lasR and nonsynonymous point mutations in the polymerase gene rpoB that arise early in evolution. Genetic knockouts of lasR not only corroborate its role in virulence attenuation but also show that further mutations are necessary for the fully commensal phenotype. The evolutionary transition from pathogenicity to commensalism as we observe here is facilitated by mutations in global regulators such as lasR, because few genetic changes cause pleiotropic effects across the genome with large phenotypic effects. Finally, we found that nucleotide diversity increased more quickly in bacteria adapting to immunocompromised hosts than in those adapting to immunocompetent hosts. Nevertheless, the outcome of evolution was comparable across host types. Commensalism can thus evolve independently of host immune state solely as a side-effect of bacterial adaptation to novel hosts.
Response to Comment on: Lipsky et al. Developing and Validating a Risk Score for Lower-Extremity Amputation in Patients Hospitalized for a Diabetic Foot Infection. Diabetes Care 2011;34:1695-1700
Authors: Benjamin A. Lipsky, John A. Weigelt, Richard S. Johannes, Karen G. Derby, Xiaowu Sun, Ying P. Tabak
Journal: Diabetes Care (2011)

We thank Drs. Aragon-Sanchez and Lazaro-Martinez (1) for their insightful comments and questions about our article (2). As we noted, we used virtually the same database of patients as we did for a previously published article (3) in which we investigated mortality, length of stay, and cost associated with skin and soft tissue infections (of both the foot and other anatomic sites) in persons with diabetes. Because some patients had multiple codes for infections, we devised a hierarchy based on associated mortality risk to ensure that patients were counted only once and were classified into the highest mortality risk group.

In our current article concerning a lower-extremity amputation (LEA) risk score (2 …