bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endocan regulates acute lung inflammation through control of leukocyte diapedesis
Authors: Gaudet Alexandre , Portier Lucie , Prin Méline , Copin Marie-Christine , Tsicopoulos Anne , Mathieu Daniel , Lassalle Philippe , De Freitas Caires Nathalie 
Published: July 2019

Acute respiratory distress syndrome is a severe form of respiratory failure, occurring in up to 20% of patients admitted to the intensive care unit with sepsis. Dysregulated leukocyte diapedesis is a major contributor to acute respiratory distress syndrome. Endocan is a circulating proteoglycan that binds to the leukocyte integrin leukocyte functional antigen-1 and blocks its interaction with its endothelial ligand, ICAM-1. The objective of this study was to evaluate the role of endocan in the control of acute lung inflammation. In vitro, endocan inhibited human leukocyte transendothelial migration as well as ICAM-1-dependent migration but had a very mild effect on ICAM-1-dependent adhesion. Endocan also acted as an inhibitor of transendothelial migration of mouse leukocytes. The effect of systemic administration of recombinant human endocan was assessed in a model of acute lung inflammation in BALB/c mice. Treatment with endocan 1 h after intratracheal LPS challenge reduced the alveolar inflammatory response, diminished histological features of acute lung injury, and improved respiratory function. These results highlight the anti-inflammatory role of human endocan and its protective effect against acute lung injury.NEW & NOTEWORTHY We show here that endocan inhibits ICAM-1-dependent human leukocyte transendothelial migration and ICAM-1-dependent adhesion. We also found that in BALB/c mice with tracheal LPS-induced acute lung injury treatment with recombinant human endocan reduces lung inflammation, notably through reduction of neutrophilic recruitment, and restores normal lung function. These results confirm the hypothesis that human endocan may have a protective effect against acute lung inflammation.
The effect of pulmonary rehabilitation on carotid chemoreceptor activity and sensitivity in chronic obstructive pulmonary disease
Authors: Byers Bradley W. , Fuhr Desi P. , Moore Linn E. , Bhutani Mohit , Wong Eric Y. L. , Stickland Michael K. 
Published: July 2019

Recent work demonstrates that carotid chemoreceptor (CC) activity/sensitivity is elevated in patients with chronic obstructive pulmonary disease (COPD) compared with healthy controls, and this elevated chemoreception appears to contribute to increased cardiovascular risk. Exercise training has been shown to normalize CC activity/sensitivity in other populations, and therefore, the purpose of this study was to determine whether pulmonary rehabilitation (PR) can reduce CC activity/sensitivity in COPD. Forty-five COPD patients [mean FEV1 (forced expiratory volume in 1 s) = 56.6% predicted] completed PR, while 15 COPD patients (mean FEV1 = 74.6% predicted) served as non-PR controls. CC activity was determined by the reduction in ventilation while breathing transient hyperoxia ([Formula: see text] = 1.0); CC sensitivity was evaluated by the increase in ventilation relative to the drop in arterial saturation while breathing hypoxia. Dyspnea, six-minute walk and autonomic function data were also obtained. PR improved 6-minute walk distance ( P < 0.001) and dyspnea ( P = 0.04); however, there was no effect on CC activity ( P = 0.60), sensitivity ( P = 0.69), or autonomic function ( P > 0.05 for all). Subgroup analyses indicated that PR reduced CC activity in those with elevated baseline CC activity, independent of changes in autonomic function. No change in dyspnea ( P = 0.24), CC activity ( P = 0.19), sensitivity ( P = 0.80), or autonomic function ( P > 0.05 for all) was observed in the control group. Despite improvements in exercise tolerance and dyspnea, PR appears to be generally ineffective at reducing CC sensitivity in stable COPD patients; while PR reduced CC activity in those with elevated basal CC activity, the physiological significance of this is unclear. Further investigations aimed at improving CC function in COPD are needed. NEW & NOTEWORTHY While work in other chronic diseases has shown that exercise training may help normalize carotid chemoreceptor (CC) activity/sensitivity, the current study found that exercise training through pulmonary rehabilitation did not consistently reduce CC activity/sensitivity in patients with chronic obstructive pulmonary disease (COPD). These results suggest that other interventions are needed to normalize CC activity/sensitivity in COPD.
Impaired central hemodynamics in chronic obstructive pulmonary disease during submaximal exercise
Authors: Smith Joshua R. , Johnson Bruce D. , Olson Thomas P. 
Published: July 2019

It is unknown whether central hemodynamics are impaired during exercise in chronic obstructive pulmonary disease (COPD) patients. We hypothesized that, at a similar absolute V̇o2 during exercise, COPD patients would have a lower stroke volume and cardiac output compared with healthy controls. Furthermore, we hypothesized that greater static hyperinflation [ratio of inspiratory capacity to total lung capacity (IC/TLC)] and expiratory intrathoracic pressure would be significantly related to the lower cardiac output and stroke volume responses in COPD patients. Clinically stable COPD ( n = 13; FEV1/FVC: 52 ± 13%) and controls ( n = 10) performed constant workload submaximal exercise at an absolute V̇o2 of ~1.3 L/min. During exercise, inspiratory capacity maneuvers were performed to determine operating lung volumes and cardiac output (via open-circuit acetylene rebreathe technique) and esophageal pressure were measured. At similar absolute V̇o2 during exercise ( P = 0.81), COPD had lower cardiac output than controls (COPD: 11.0 ± 1.6 vs. control: 12.2 ± 1.2 L/min, P = 0.03) due to a lower stroke volume (COPD: 107 ± 13 vs. control: 119 ± 19 mL, P = 0.04). The heart rate response during exercise was not different between groups ( P = 0.66). FEV1 (%predicted) and IC/TLC were positively related to stroke volume ( r = 0.68, P = 0.01 and r = 0.77, P < 0.01). Last, esophageal pressure-time integral during inspiration was positively related to cardiac output ( r = 0.56, P = 0.047). These data demonstrate that COPD patients have attenuated cardiac output and stroke volume responses during exercise compared with control. Furthermore, these data suggest that the COPD patients with the most severe hyperinflation and more negative inspiratory intrathoracic pressures have the most impaired central hemodynamic responses. NEW & NOTEWORTHY Chronic obstructive pulmonary disease leads to cardiac structural changes and pulmonary derangements that impact the integrative response to exercise. However, it is unknown whether these pathophysiological alterations influence the cardiac response during exercise. Herein, we demonstrate that COPD patients exhibit impaired central hemodynamics during exercise that are worsened with greater hyperinflation.
Liver- and Microbiome-derived Bile Acids Accumulate in Human Breast Tumors and Inhibit Growth and Improve Patient Survival
Authors: Tang Wei , Putluri Vasanta , Ambati Chandrashekar R. , Dorsey Tiffany H. , Putluri Nagireddy , Ambs Stefan 
Published: July 2019

AbstractPurpose:Metabolomics is a discovery tool for novel associations of metabolites with disease. Here, we interrogated the metabolome of human breast tumors to describe metabolites whose accumulation affects tumor biology.Experimental Design:We applied large-scale metabolomics followed by absolute quantification and machine learning-based feature selection using LASSO to identify metabolites that show a robust association with tumor biology and disease outcome. Key observations were validated with the analysis of an independent dataset and cell culture experiments.Results:LASSO-based feature selection revealed an association of tumor glycochenodeoxycholate levels with improved breast cancer survival, which was confirmed using a Cox proportional hazards model. Absolute quantification of four bile acids, including glycochenodeoxycholate and microbiome-derived deoxycholate, corroborated the accumulation of bile acids in breast tumors. Levels of glycochenodeoxycholate and other bile acids showed an inverse association with the proliferation score in tumors and the expression of cell-cycle and G2–M checkpoint genes, which was corroborated with cell culture experiments. Moreover, tumor levels of these bile acids markedly correlated with metabolites in the steroid metabolism pathway and increased expression of key genes in this pathway, suggesting that bile acids may interfere with hormonal pathways in the breast. Finally, a proteome analysis identified the complement and coagulation cascade as being upregulated in glycochenodeoxycholate-high tumors.Conclusions:We describe the unexpected accumulation of liver- and microbiome-derived bile acids in breast tumors. Tumors with increased bile acids show decreased proliferation, thus fall into a good prognosis category, and exhibit significant changes in steroid metabolism.
Clinical and Genome-Wide Analysis of Serum Platinum Levels after Cisplatin-Based Chemotherapy
Authors: Trendowski Matthew R. , El-Charif Omar , Ratain Mark J. , Monahan Patrick , Mu Zepeng , Wheeler Heather E. , Dinh Paul C. , Feldman Darren R. , Ardeshir-Rouhani-Fard Shirin , Hamilton Robert J. , Vaughn David J. , Fung Chunkit , Kollmannsberger Christian , Mushiroda Taisei , Kubo Michiaki , Hannigan Robyn , Strathmann Frederick , Einhorn Lawrence H. , Fossa Sophie D. , Travis Lois B. , Dolan M. Eileen 
Published: July 2019

Abstract

Purpose:
Serum platinum is measurable for years after completion of cisplatin-based chemotherapy (CBC). We report the largest investigation of serum platinum levels to date of 1,010 testicular cancer survivors (TCS) assessed 1–35 years after CBC and evaluate genetic contributions to these levels.

Experimental Design:
Eligible TCS given 300 or 400 (±15) mg/m2 cisplatin underwent extensive audiometric testing, clinical examination, completed questionnaires, and had crude serum platinum levels measured. Associations between serum platinum and various risk factors and toxicities were assessed after fitting a biexponential model adjusted for follow-up time and cumulative cisplatin dose. A genome-wide association study (GWAS) was performed using the serum platinum residuals of the dose and time-adjusted model.

Results:
Serum platinum levels exceeded the reference range for approximately 31 years, with a strong inverse relationship with creatinine clearance at follow-up (age-adjusted P = 2.13 × 10−3). We observed a significant, positive association between residual platinum values and luteinizing hormone (age-adjusted P = 6.58 × 10−3). Patients with high residual platinum levels experienced greater Raynaud phenomenon than those with medium or low levels (age-adjusted ORhigh/low = 1.46; P = 0.04), as well as a higher likelihood of developing tinnitus (age-adjusted ORhigh/low = 1.68, P = 0.07). GWAS identified one single-nucleotide polymorphism (SNP) meeting genome-wide significance, rs1377817 (P = 4.6 × 10−8, a SNP intronic to MYH14).

Conclusions:
This study indicates that residual platinum values are correlated with several cisplatin-related toxicities. One genetic variant is associated with these levels.
Eμ-TCL1xMyc: A Novel Mouse Model for Concurrent CLL and B-Cell Lymphoma
Authors: Lucas Fabienne , Rogers Kerry A. , Harrington Bonnie K. , Pan Alexander , Yu Lianbo , Breitbach Justin , Bundschuh Ralf , Goettl Virginia M. , Hing Zachary A. , Kanga Parviz , Mantel Rose , Sampath Deepa , Smith Lisa L. , Wasmuth Ronni , White Danielle K. , Yan Pearlly , Byrd John C. , Lapalombella Rosa , Woyach Jennifer A. 
Published: July 2019

AbstractPurpose:Aberrant Myc expression is a major factor in the pathogenesis of aggressive lymphoma, and these lymphomas, while clinically heterogeneous, often are resistant to currently available treatments and have poor survival. Myc expression can also be seen in aggressive lymphomas that are observed in the context of CLL, and we sought to develop a mouse model that could be used to study therapeutic strategies for aggressive lymphoma in the context of CLL.Experimental Design:We crossed the Eμ-TCL1 mouse model with the Eμ-Myc mouse model to investigate the clinical phenotype associated with B-cell–restricted expression of these oncogenes. The resulting malignancy was then extensively characterized, from both a clinical and biologic perspective.Results:Eμ-TCL1xMyc mice uniformly developed highly aggressive lymphoid disease with histologically, immunophenotypically, and molecularly distinct concurrent CLL and B-cell lymphoma, leading to a significantly reduced lifespan. Injection of cells from diseased Eμ-TCL1xMyc into WT mice established a disease similar to that in the double-transgenic mice. Both Eμ-TCL1xMyc mice and mice with disease after adoptive transfer failed to respond to ibrutinib. Effective and durable disease control was, however, observed by selective inhibition of nuclear export protein exportin-1 (XPO1) using a compound currently in clinical development for relapsed/refractory malignancies, including CLL and lymphoma.Conclusions:The Eμ-TCL1xMyc mouse is a new preclinical tool for testing experimental drugs for aggressive B-cell lymphoma, including in the context of CLL.
Aberrant Expression of ERG Promotes Resistance to Combined PI3K and AR Pathway Inhibition through Maintenance of AR Target Genes
Authors: Mao Ninghui , Gao Dong , Hu Wenhuo , Hieronymus Haley , Wang Shangqian , Lee Young Sun , Lee Cindy , Choi Danielle , Gopalan Anuradha , Chen Yu , Carver Brett S. 
Published: July 2019

Abstract
On the basis of our previous work defining the molecular rationale for combined targeting of the PI3K and AR pathways in PTEN loss prostate cancer, the first clinical trial was recently reported demonstrating a significant benefit for combination therapy in patients with metastatic prostate cancer. In this phase II trial, loss of PTEN was a biomarker predictive of response to combined AKT and AR inhibition. Given that PTEN loss prostate cancers are significantly enriched for ERG genomic rearrangements, we evaluated how the aberrant expression of ERG may impact response to PI3K/AR-targeted therapy. Here, we show that overexpression of ERG in the setting of Pten loss promotes resistance to combined PI3K and AR pathway inhibition with associated maintenance of AR target gene expression. Importantly, following AR knockout in the setting of ERG overexpression, there is maintenance of a subset of AR lineage–specific target genes, making AR dispensable in this context. This has important clinical implications as even in the setting of the androgen-regulated TMPRSS2:ERG genomic rearrangement, ERG expression is never abolished following AR inhibition and may allow for cell survival following AR (lineage)–targeted therapies.
Entre o legado musical e a redescoberta da escuta na pós-modernidade
Authors: Nicoletti Daniela Amaral Rodrigues , Berg Silvia 
Published: July 2019

O presente artigo propõe-se primeiramente a examinar o argumento de Seth Kim-Cohen sobre a existência de um divisor de águas nas artes em meados do século XX a que atribui a origem de uma “virada epistemológica e ontológica” cultural profunda – situada, na música, no ano de 1948. Kim-Cohen aponta nessa data a confluência de três eventos decisivos para isso: o início das experimentações sonoras do engenheiro Pierre Schaeffer, nos estúdios da ORTF (Office de Radiodiffusion Télévision Française) e a primeira composição silenciosa de John Cage – lançando os princípios da música concreta e da aleatoriedade na música, como alternativa ao paradigma da música ocidental erudita. O terceiro evento assinalado por Kim-Cohen refere-se às gravações elétricas pioneiras de Muddy Water, em que a tecnologia, usada tanto na gravação como na reprodução sonora, por um lado amplifica e modifica o som acústico, por outro interfere na relação presença/ausência, dada pela interação entre os próprios músicos na performance musical, entre músicos e ouvintes, entre produção sonora e espaço acústico, além de tornar possível, a ampla circulação e utilização de músicas.
Sob essa perspectiva, o artigo busca compreender os possíveis efeitos da introdução de tecnologias na produção e reprodução sonora, no século XX sobre a escuta na pós-modernidade e, de outro lado, sobre a composição musical, em particular, sobre a poética do compositor Luciano Berio, enquanto pensamento musical e estético. A escolha desse compositor entre tantos se justifica primeiramente pelo interesse na maneira como mostra articular muitas das questões que se apresentaram à sua geração, especialmente no que concerne à relação entre legado, ruptura e inovação, entre som-em-si e os significados implícitos em suas escolhas, entre o seu itinerário pessoal e a consciência do seu tempo, entre expressão pessoal e o sentimento de responsabilidade histórica, entre a representação da nacionalidade e a alteridade.
Inhibition of VEGF (Vascular Endothelial Growth Factor)-A or its Receptor Activity Suppresses Experimental Aneurysm Progression in the Aortic Elastase Infusion Model
Authors: Xu Baohui , Iida Yasunori , Glover Keith J. , Ge Yingbin , Wang Yan , Xuan Haojun , Hu Xiaolei , Tanaka Hiroki , Wang Wei , Fujimura Naoki , Miyata Masaaki , Shoji Takahiro , Guo Jia , Zheng Xiaoya , Gerritsen Mary , Kuo Calvin , Michie Sara A. , Dalman Ronald L. 
Published: July 2019

Objective:
We examined the pathogenic significance of VEGF (vascular endothelial growth factor)-A in experimental abdominal aortic aneurysms (AAAs) and the translational value of pharmacological VEGF-A or its receptor inhibition in aneurysm suppression.

Approaches and Results:
AAAs were created in male C57BL/6J mice via intra-aortic elastase infusion. Soluble VEGFR (VEGF receptor)-2 extracellular ligand-binding domain (delivered in Ad [adenovirus]-VEGFR-2), anti–VEGF-A mAb (monoclonal antibody), and sunitinib were used to sequester VEGF-A, neutralize VEGF-A, and inhibit receptor tyrosine kinase activity, respectively. Influences on AAAs were assessed using ultrasonography and histopathology. In vitro transwell migration and quantitative reverse transcription polymerase chain reaction assays were used to assess myeloid cell chemotaxis and mRNA expression, respectively. Abundant VEGF-A mRNA and VEGF-A–positive cells were present in aneurysmal aortae. Sequestration of VEGF-A by Ad-VEGFR-2 prevented AAA formation, with attenuation of medial elastolysis and smooth muscle depletion, mural angiogenesis and monocyte/macrophage infiltration. Treatment with anti–VEGF-A mAb prevented AAA formation without affecting further progression of established AAAs. Sunitinib therapy substantially mitigated both AAA formation and further progression of established AAAs, attenuated aneurysmal aortic MMP2 (matrix metalloproteinase) and MMP9 protein expression, inhibited inflammatory monocyte and neutrophil chemotaxis to VEGF-A, and reduced MMP2, MMP9, and VEGF-A mRNA expression in macrophages and smooth muscle cells in vitro. Additionally, sunitinib treatment reduced circulating monocytes in aneurysmal mice.

Conclusions:
VEGF-A and its receptors contribute to experimental AAA formation by suppressing mural angiogenesis, MMP and VEGF-A production, myeloid cell chemotaxis, and circulating monocytes. Pharmacological inhibition of receptor tyrosine kinases by sunitinib or related compounds may provide novel opportunities for clinical aneurysm suppression.
Hepatic Forkhead Box Protein A3 Regulates ApoA-I (Apolipoprotein A-I) Expression, Cholesterol Efflux, and Atherogenesis
Authors: Li Yuanyuan , Xu Yanyong , Jadhav Kavita , Zhu Yingdong , Yin Liya , Zhang Yanqiao 
Published: July 2019

Objective:
To determine the role of hepatic FOXA3 (forkhead box A3) in lipid metabolism and atherosclerosis.

Approach and Results:

Hepatic FOXA3 expression was reduced in diabetic or high fat diet-fed mice or patients with nonalcoholic steatohepatitis. We then used adenoviruses to overexpress or knock down hepatic FOXA3 expression. Overexpression of FOXA3 in the liver increased hepatic ApoA-I (apolipoprotein A-I) expression, plasma HDL-C (high-density lipoprotein cholesterol) level, macrophage cholesterol efflux, and macrophage reverse cholesterol transport. In contrast, knockdown of hepatic FOXA3 expression had opposite effects. We further showed that FOXA3 directly bound to the promoter of the
Apoa1
gene to regulate its transcription. Finally, AAV8 (adeno-associated virus serotype 8)-mediated overexpression of human FOXA3 in the hepatocytes of
Apoe
−/−
(apolipoprotein E-deficient) mice raised plasma HDL-C levels and significantly reduced atherosclerotic lesions.

Conclusions:
Hepatocyte FOXA3 protects against atherosclerosis by inducing ApoA-I and macrophage reverse cholesterol transport.
SGLT-2 (Sodium-Glucose Cotransporter 2) Inhibition Reduces Ang II (Angiotensin II)–Induced Dissecting Abdominal Aortic Aneurysm in ApoE (Apolipoprotein E) Knockout Mice
Authors: Ortega Rebeca , Collado Aida , Selles Francisca , Gonzalez-Navarro Herminia , Sanz Maria-Jesus , Real José T. , Piqueras Laura 
Published: July 2019

Objective:

Abdominal aortic aneurysm (AAA) is a pathological condition of permanent vessel dilatation that predisposes to the potentially fatal consequence of aortic rupture. SGLT-2 (sodium-glucose cotransporter 2) inhibitors have emerged as powerful pharmacological tools for type 2 diabetes mellitus treatment. Beyond their glucose-lowering effects, recent studies have shown that SGLT-2 inhibitors reduce cardiovascular events and have beneficial effects on several vascular diseases such as atherosclerosis; however, the potential effects of SGLT-2 inhibition on AAA remain unknown. This study evaluates the effect of oral chronic treatment with empagliflozin—an SGLT-2 inhibitor—on dissecting AAA induced by Ang II (angiotensin II) infusion in apoE (apolipoprotein E)
−/
−
mice.

Approach and Results:

Empagliflozin treatment significantly reduced the Ang II–induced increase in maximal suprarenal aortic diameter in apoE
−/
−
mice independently of blood pressure effects. Immunohistochemistry analysis revealed that empagliflozin diminished Ang II–induced elastin degradation, neovessel formation, and macrophage infiltration at the AAA lesion. Furthermore, Ang II infusion resulted in a marked increase in the expression of chemokines (CCL-2 [chemokine (C-C motif) ligand 2] and CCL-5 [chemokine (C-C motif) ligand 5]), VEGF (vascular endothelial growth factor), and MMP (matrix metalloproteinase)-2 and MMP-9 in suprarenal aortic walls of apoE
−/
−
mice, and all were reduced by empagliflozin cotreatment. Western blot analysis revealed that p38 MAPK (p38 mitogen-activated protein kinase) and NF-κB (nuclear factor-κB) activation was also reduced in the suprarenal aortas of apoE
−/
−
mice cotreated with empagliflozin. Finally, in vitro studies in human aortic endothelial cells and macrophages showed that empagliflozin inhibited leukocyte-endothelial cell interactions and release of proinflammatory chemokines.

Conclusions:
Pharmacological inhibition of SGLT-2 by empagliflozin inhibits AAA formation. SGLT-2 inhibition might represent a novel promising therapeutic strategy to prevent AAA progression.