tbuckley/cabot-search huggingface dataset:
Abstract 15581: Absence of Intestinal Microbiota Increases Beta-cyclodextrin Stimulated Reverse Cholesterol Transport
Authors: Rima H Mistry, Henkjan J Verkade, Uwe J Tietge
Journal: Circulation (2016)

Background:  Atherosclerotic cardiovascular disease (CVD) represents the highest cause of mortality worldwide. Currently drug treatment with statins is the main stay of therapy to prevent heart attacks and stroke. However, despite the vast use of statins, the incidence of CVD events decreased at best by only 30%. Therefore, additional therapeutic strategies are warranted. Dietary intervention appears hereby particularly attractive, since it is easy and increases adherence to the treatment.   Aim:  The aim of the present study was to characterize the impact of dietary s-cyclodextrin (sCD, 10%), a cyclic oligosaccharide, on sterol metabolism and reverse cholesterol transport (RCT) in conventional as well as germ-free mice. Germ-free mice were included to establish whether fermentation products of sCD by the intestinal microbiota contribute to the biological effects of this non-digestible carbohydrate.   Method and Results:  In conventional sCD-fed C57BL/6 wild-type mice plasma cholesterol levels decreased significantly (-40%, p    Conclusion:  In summary, this study demonstrates that sCD lowers plasma cholesterol levels and increases fecal cholesterol excretion from a RCT-relevant pool independent of bacterial metabolism in the intestine. The metabolic effects of dietary sCD are expected to translate into cardiovascular health benefits.
Targeting senescent cholangiocytes and activated fibroblasts with B‐cell lymphoma‐extra large inhibitors ameliorates fibrosis in multidrug resistance 2 gene knockout (Mdr2−/− ) mice
Authors: Anja Moncsek, Mohammed S. Al‐Suraih, Christy E. Trussoni, Steven P. O'Hara, Patrick L. Splinter, Camille Zuber, Eleonora Patsenker, Piero V. Valli, Christian D. Fingas, Achim Weber, Yi Zhu, Tamar Tchkonia, James L. Kirkland, Gregory J. Gores, Beat Müllhaupt, Nicholas F. LaRusso, Joachim C. Mertens
Journal: Hepatology (2017)

Cholangiocyte senescence has been linked to primary sclerosing cholangitis (PSC). Persistent secretion of growth factors by senescent cholangiocytes leads to the activation of stromal fibroblasts (ASFs), which are drivers of fibrosis. The activated phenotype of ASFs is characterized by an increased sensitivity to apoptotic stimuli. Here, we examined the mechanisms of apoptotic priming in ASFs and explored a combined targeting strategy to deplete senescent cholangiocytes and ASFs from fibrotic tissue to ameliorate liver fibrosis. Using a coculture system, we determined that senescent cholangiocytes promoted quiescent mesenchymal cell activation in a platelet-derived growth factor (PDGF)-dependent manner. We also identified B-cell lymphoma-extra large (Bcl-xL) as a key survival factor in PDGF-activated human and mouse fibroblasts. Bcl-xL was also up-regulated in senescent cholangiocytes. In vitro, inhibition of Bcl-xL by the small molecule Bcl-2 homology domain 3 mimetic, A-1331852, or Bcl-xL-specific small interfering RNA induced apoptosis in PDGF-activated fibroblasts, but not in quiescent fibroblasts. Likewise, inhibition of Bcl-xL reduced the survival and increased apoptosis of senescent cholangiocytes, compared to nonsenescent cells. Treatment of multidrug resistance 2 gene knockout (Mdr2-/- ) mice with A-1331852 resulted in an 80% decrease in senescent cholangiocytes, a reduction of fibrosis-inducing growth factors and cytokines, decrease of α-smooth muscle actin-positive ASFs, and finally in a significant reduction of liver fibrosis.Bcl-xL is a key survival factor in ASFs as well as in senescent cholangiocytes. Treatment with the Bcl-xL-specific inhibitor, A-1331852, reduces liver fibrosis, possibly by a dual effect on activated fibroblasts and senescent cholangiocytes. This mechanism represents an attractive therapeutic strategy in biliary fibrosis. (Hepatology 2018;67:247-259).
Inspiratory muscle training does not improve clinical outcomes in 3-week COPD rehabilitation: results from a randomised controlled trial
Authors: Konrad Schultz, Danijel Jelusic, Michael Wittmann, Benjamin Krämer, Veronika Huber, Sebastian Fuchs, Nicola Lehbert, Silke Wingart, Dragan Stojanovic, Oliver Göhl, Harma J. Alma, Corina de Jong, Thys van der Molen, Hermann Faller, Michael Schuler
Journal: European Respiratory Journal (2018)

The value of inspiratory muscle training (IMT) in pulmonary rehabilitation in chronic obstructive pulmonary disease (COPD) is unclear. The RIMTCORE (Routine Inspiratory Muscle Training within COPD Rehabilitation) randomised controlled trial examined the effectiveness of IMT added to pulmonary rehabilitation. In total, 611 COPD patients (Global Initiative for Chronic Obstructive Lung Disease stage II–IV) received a 3-week inpatient pulmonary rehabilitation, of which 602 patients were included in the intention-to-treat analyses. The intervention group (n=300) received highly intensive IMT and the control group (n=302) received sham IMT. The primary outcome was maximal inspiratory pressure ( P Imax ). The secondary outcomes were 6-min walk distance, dyspnoea, quality of life and lung function. Outcomes were assessed pre- and post-pulmonary rehabilitation. ANCOVA was used. The intervention group showed higher effects in P Imax (p&lt;0.001) and forced inspiratory volume in 1 s (p=0.013). All other outcomes in both study groups improved significantly, but without further between-group differences. Sex and pulmonary rehabilitation admission shortly after hospitalisation modified quality of life effects. IMT as an add-on to a 3-week pulmonary rehabilitation improves inspiratory muscle strength, but does not provide additional benefits in terms of exercise capacity, quality of life or dyspnoea. A general recommendation for COPD patients to add IMT to a 3-week pulmonary rehabilitation cannot be made.
Sex-specific gene and pathway modeling of inherited glioma risk
Authors: Quinn T Ostrom, Warren Coleman, William Huang, Joshua B Rubin, Justin D Lathia, Michael E Berens, Gil Speyer, Peter Liao, Margaret R Wrensch, Jeanette E Eckel-Passow, Georgina Armstrong, Terri Rice, John K Wiencke, Lucie S McCoy, Helen M Hansen, Christopher I Amos, Jonine L Bernstein, Elizabeth B Claus, Richard S Houlston, Dora Il’yasova, Robert B Jenkins, Christoffer Johansen, Daniel H Lachance, Rose K Lai, Ryan T Merrell, Sara H Olson, Siegal Sadetzki, Joellen M Schildkraut, Sanjay Shete, Ulrika Andersson, Preetha Rajaraman, Stephen J Chanock, Martha S Linet, Zhaoming Wang, Meredith Yeager, M Berger, P Bracci, S Chang, J Clarke, A Molinaro, A Perry, M Pezmecki, M Prados, I Smirnov, T Tihan, K Walsh, J Wiemels, S Zheng, Laura E Beane Freeman, Stella Koutros, Demetrius Albanes, Kala Visvanathan, Victoria L Stevens, Roger Henriksson, Dominique S Michaud, Maria Feychting, Anders Ahlbom, Graham G Giles Roger Milne, Roberta McKean-Cowdin, Loic Le Marchand, Meir Stampfer, Avima M Ruder, Tania Carreon, Goran Hallmans, Anne Zeleniuch-Jacquotte, J Michael Gaziano, Howard D Sesso, Mark P Purdue, Emily White, Ulrike Peters, Julie Buring, Beatrice Melin, Melissa L Bondy, Jill S Barnholtz-Sloan
Journal: Neuro-Oncology (2018)

To date, genome-wide association studies (GWAS) have identified 25 risk variants for glioma, explaining 30% of heritable risk. Most histologies occur with significantly higher incidence in males, and this difference is not explained by currently known risk factors. A previous GWAS identified sex-specific glioma risk variants, and this analysis aims to further elucidate risk variation by sex using gene- and pathway-based approaches. Results from the Glioma International Case-Control Study were used as a testing set, and results from 3 GWAS were combined via meta-analysis and used as a validation set. Using summary statistics for nominally significant autosomal SNPs (P < 0.01 in a previous meta-analysis) and nominally significant X-chromosome SNPs (P < 0.01), 3 algorithms (Pascal, BimBam, and GATES) were used to generate gene scores, and Pascal was used to generate pathway scores. Results were considered statistically significant in the discovery set when P < 3.3 × 10−6 and in the validation set when P < 0.001 in 2 of 3 algorithms. Twenty-five genes within 5 regions and 19 genes within 6 regions reached statistical significance in at least 2 of 3 algorithms in males and females, respectively. EGFR was significantly associated with all glioma and glioblastoma in males only and a female-specific association in TERT, all of which remained nominally significant after conditioning on known risk loci. There were nominal associations with the BioCarta telomeres pathway in both males and females. These results provide additional evidence that there may be differences by sex in genetic risk for glioma. Additional analyses may further elucidate the biological processes through which this risk is conferred.
Abstract 20724: Efficacy and Cost-Effectiveness of Wearable Cardioverter Defibrillator as a Lifesaving-Bridge Therapy for Decision in High Risk Patients of Sudden Arrhythmic Death : 3-Year Follow-Up Result
Authors: Yusuke Kondo, Marehiko Ueda, Yoshio Kobayashi
Journal: Circulation (2016)

Introduction: The wearable cardioverter-defibrillator (WCD) is an external defibrillator that automatically detects and treats ventricular tachyarrhythmias without the need for assistance from a by...
Oral Arsenic Plus Retinoic Acid Versus Intravenous Arsenic Plus Retinoic Acid for Non-High Risk Acute Promyelocytic Leukemia: A Multicenter Randomized Controlled Trials
Authors: Honghu Zhu, Depei Wu, Xi Zhang, Lin LIU, Jun Ma, Zonghong Shao, Hanyun Ren, Jianda Hu, Kailin Xu, Jing-Wen Wang, Yongping Song, Mei-Yun Fang, Xiao-Jun Huang
Journal: Blood (2017)
Mitoxantrone in Combination with Clofarabine (MITCL) in Children, Adolescents and Young Adults with Refractory/Relapsed Acute Leukemia
Authors: Jessica C. Hochberg, Javier Oesterheld, Allyson M. Flower, Liana Klejmont, Gregory Hemenway, Lauren Harrison, Qiuhu Shi, Mitchell S. Cairo
Journal: Blood (2017)
Randomized Maintenance Therapy with Azacitidine (Vidaza) in Older Patients (>= 60 years of age) with Acute Myeloid Leukemia (AML) and Refractory Anemia with Excess of Blasts (RAEB, RAEB-t). Results of the HOVON97 Phase III Randomized Multicentre Study (EudraCT 2008-001290-15)
Authors: Geert Huls, Dana Chitu, Violaine Havelange, Mojca Jongen-Lavrencic, Arjen van de Loosdrecht, Bart J. Biemond, Harm Sinnege, Beata Hodossy, Carlos Graux, Marinus van Marwijk Kooij, Okke de Weerdt, Dimitri Breems, Saskia Klein, Jurgen Kuball, Gert J. Ossenkoppele, Bob Lowenberg, Edo Vellenga
Journal: Blood (2017)
Synergistic Binding of bHLH Transcription Factors to the Promoter of the Maize NADP-ME Gene Used in C4 Photosynthesis Is Based on an Ancient Code Found in the Ancestral C3 State
Authors: Ana Rita Borba, Tânia S Serra, Alicja Górska, Paulo Gouveia, André M Cordeiro, Ivan Reyna-Llorens, Jana Kneřová, Pedro M Barros, Isabel A Abreu, Maria Margarida Oliveira, Julian M Hibberd, Nelson J M Saibo
Journal: Molecular Biology and Evolution (2018)

C4 photosynthesis has evolved repeatedly from the ancestral C3 state to generate a carbon concentrating mechanism that increases photosynthetic efficiency. This specialized form of photosynthesis is particularly common in the PACMAD clade of grasses, and is used by many of the world's most productive crops. The C4 cycle is accomplished through cell-type-specific accumulation of enzymes but cis-elements and transcription factors controlling C4 photosynthesis remain largely unknown. Using the NADP-Malic Enzyme (NADP-ME) gene as a model we tested whether mechanisms impacting on transcription in C4 plants evolved from ancestral components found in C3 species. Two basic Helix-Loop-Helix (bHLH) transcription factors, ZmbHLH128 and ZmbHLH129, were shown to bind the C4NADP-ME promoter from maize. These proteins form heterodimers and ZmbHLH129 impairs trans-activation by ZmbHLH128. Electrophoretic mobility shift assays indicate that a pair of cis-elements separated by a seven base pair spacer synergistically bind either ZmbHLH128 or ZmbHLH129. This pair of cis-elements is found in both C3 and C4 Panicoid grass species of the PACMAD clade. Our analysis is consistent with this cis-element pair originating from a single motif present in the ancestral C3 state. We conclude that C4 photosynthesis has co-opted an ancient C3 regulatory code built on G-box recognition by bHLH to regulate the NADP-ME gene. More broadly, our findings also contribute to the understanding of gene regulatory networks controlling C4 photosynthesis.
Inhibition of Endothelial Notch Signaling Impairs Fatty Acid Transport and Leads to Metabolic and Vascular Remodeling of the Adult Heart
Authors: Markus Jabs, Adam J. Rose, Lorenz H. Lehmann, Jacqueline Taylor, Iris Moll, Tjeerd P. Sijmonsma, Stefanie E. Herberich, Sven W. Sauer, Gernot Poschet, Giuseppina Federico, Carolin Mogler, Eva-Maria Weis, Hellmut G. Augustin, Minhong Yan, Norbert Gretz, Roland M. Schmid, Ralf H. Adams, Hermann-Joseph Gröne, Rüdiger Hell, Jürgen G. Okun, Johannes Backs, Peter P. Nawroth, Stephan Herzig, Andreas Fischer
Journal: Circulation (2018)

Background: Nutrients are transported through endothelial cells before being metabolized in muscle cells. However, little is known about the regulation of endothelial transport processes. Notch signaling is a critical regulator of metabolism and angiogenesis during development. Here, we studied how genetic and pharmacological manipulation of endothelial Notch signaling in adult mice affects endothelial fatty acid transport, cardiac angiogenesis, and heart function. Methods: Endothelial-specific Notch inhibition was achieved by conditional genetic inactivation of Rbp-jκ in adult mice to analyze fatty acid metabolism and heart function. Wild-type mice were treated with neutralizing antibodies against the Notch ligand Delta-like 4. Fatty acid transport was studied in cultured endothelial cells and transgenic mice. Results: Treatment of wild-type mice with Delta-like 4 neutralizing antibodies for 8 weeks impaired fractional shortening and ejection fraction in the majority of mice. Inhibition of Notch signaling specifically in the endothelium of adult mice by genetic ablation of Rbp-jκ caused heart hypertrophy and failure. Impaired heart function was preceded by alterations in fatty acid metabolism and an increase in cardiac blood vessel density. Endothelial Notch signaling controlled the expression of endothelial lipase, Angptl4, CD36, and Fabp4, which are all needed for fatty acid transport across the vessel wall. In endothelial-specific Rbp-jκ–mutant mice, lipase activity and transendothelial transport of long-chain fatty acids to muscle cells were impaired. In turn, lipids accumulated in the plasma and liver. The attenuated supply of cardiomyocytes with long-chain fatty acids was accompanied by higher glucose uptake, increased concentration of glycolysis intermediates, and mTOR-S6K signaling. Treatment with the mTOR inhibitor rapamycin or displacing glucose as cardiac substrate by feeding a ketogenic diet prolonged the survival of endothelial-specific Rbp-jκ–deficient mice. Conclusions: This study identifies Notch signaling as a novel regulator of fatty acid transport across the endothelium and as an essential repressor of angiogenesis in the adult heart. The data imply that the endothelium controls cardiomyocyte metabolism and function.
Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management
Authors: David J Birnkrant, Katharine Bushby, Carla M Bann, Benjamin A Alman, Susan D Apkon, Angela Blackwell, Laura E Case, Linda Cripe, Stasia Hadjiyannakis, Aaron K Olson, Daniel W Sheehan, Julie Bolen, David R Weber, Leanne M Ward
Journal: The Lancet Neurology (2018)
E-Cadherin/ROS1 Inhibitor Synthetic Lethality in Breast Cancer
Authors: Ilirjana Bajrami, Rebecca Marlow, Marieke van de Ven, Rachel Brough, Helen N. Pemberton, Jessica Frankum, Feifei Song, Rumana Rafiq, Asha Konde, Dragomir B. Krastev, Malini Menon, James Campbell, Aditi Gulati, Rahul Kumar, Stephen J. Pettitt, Mark D. Gurden, Marta Llorca Cardenosa, Irene Chong, Patrycja Gazinska, Fredrik Wallberg, Elinor J. Sawyer, Lesley-Ann Martin, Mitch Dowsett, Spiros Linardopoulos, Rachael Natrajan, Colm J. Ryan, Patrick W.B. Derksen, Jos Jonkers, Andrew N.J. Tutt, Alan Ashworth, Christopher J. Lord
Journal: Cancer Discovery (2018)

Abstract The cell adhesion glycoprotein E-cadherin (CDH1) is commonly inactivated in breast tumors. Precision medicine approaches that exploit this characteristic are not available. Using perturbation screens in breast tumor cells with CRISPR/Cas9-engineered CDH1 mutations, we identified synthetic lethality between E-cadherin deficiency and inhibition of the tyrosine kinase ROS1. Data from large-scale genetic screens in molecularly diverse breast tumor cell lines established that the E-cadherin/ROS1 synthetic lethality was not only robust in the face of considerable molecular heterogeneity but was also elicited with clinical ROS1 inhibitors, including foretinib and crizotinib. ROS1 inhibitors induced mitotic abnormalities and multinucleation in E-cadherin–defective cells, phenotypes associated with a defect in cytokinesis and aberrant p120 catenin phosphorylation and localization. In vivo, ROS1 inhibitors produced profound antitumor effects in multiple models of E-cadherin–defective breast cancer. These data therefore provide the preclinical rationale for assessing ROS1 inhibitors, such as the licensed drug crizotinib, in appropriately stratified patients. Significance: E-cadherin defects are common in breast cancer but are currently not targeted with a precision medicine approach. Our preclinical data indicate that licensed ROS1 inhibitors, including crizotinib, should be repurposed to target E-cadherin–defective breast cancers, thus providing the rationale for the assessment of these agents in molecularly stratified phase II clinical trials. Cancer Discov; 8(4); 498–515. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 371
Pulmonary melioidosis with laryngeal involvement: an unusual site of infection
Authors: Chew Lip Ng, Xuandao Liu, Nicholas Jin Hong Tan, Vyas Malur Narayan Prasad, Pyng Lee
Journal: Thorax (2018)

A 42-year-old Malay man presented with cough productive of yellowish sputum, hoarseness and intermittent daily fever associated with chills and rigours for 3 weeks. Apart from previous pulmonary TB in 1994 for which treatment was complete, there were no other comorbidities. The patient was an active cigarette smoker of 20 pack-years, and worked as an outdoor project coordinator frequently in contact with soil during field surveys in gardens. Chest radiograph showed right perihilar consolidation (figure 1A). CT thorax showed mass-like consolidation of the right upper lobe with extensive mediastinal lymphadenopathy (figure 1B). White cell count was 8.8 (range 3.4–11.0×109/L) with neutrophilia 72.2%; blood, sputum and urine for bacterial cultures, as well as sputum for acid fast bacilli smears and TB PCR assay, were negative. Random blood sugar level was 23.0 mmol/L (range 4.0–7.8 mmol/L) and glycated haemoglobin level was 12.1%. Bronchoscopy showed mobile …
Abstract P200: Neighborhood Disadvantage and Poor Social Conditions Influence Cardiovascular Disease Incidence in African American Adults: A Prospective Analysis in the Jackson Heart Study
Authors: Sharrelle Barber, DeMarc A Hickson, Xu Wang, Mario Sims, Cheryl Nelson, Ana Diez-Roux
Journal: Circulation (2016)

Introduction: Racial residential segregation results in increased exposure to adverse neighborhood environments in African Americans; however the impact of economic and social neighborhood conditions on CVD incidence has not been examined in large, socioeconomically diverse African American samples. Hypothesis: Neighborhood disadvantage and poor social conditions (i.e. violence, physical disorder, and low social cohesion) will be associated with increased risk of developing CVD. Methods: The study included 4,096 African American women and men ages 21-93 from the Jackson Heart Study. Census tracts served as proxies for neighborhoods. Neighborhood disadvantage was assessed using 8 indicators from the 2000 US Census. Neighborhood-level social conditions including social cohesion, violence, and physical disorder were assed using self-reported, validated scales. Multivariable cox-proportional hazards models were used to calculate gender-stratified adjusted hazard ratios and 95% confidence intervals. Results: A total of 232 incident cases of CVD occurred during a median follow-up of 8.38 years. Age-adjusted incidence rates generally increased as neighborhood economic and social conditions worsened for both women and men. Among African American women, each standard deviation increase in neighborhood disadvantage was associated with a 25% increased risk of developing CVD after adjustment for socio-demographic characteristics (HR: 1.25, 95% CI: 1.05-1.49). Risk of developing CVD also increased as levels of neighborhood violence and physical disorder increased after socio-demographic adjustment (HR: 1.13, 95% CI: 1.00-1.28 and HR: 1.20, 95% CI: 1.02-1.40, respectively). No statistically significant associations were observed among African American men in multivariable-adjusted models. Conclusion: In conclusion, worse neighborhood economic and social conditions contributed to increased risk of developing CVD among African American women in our sample. Policies and interventions directly addressing these issues may alleviate the burden of CVD in this group.
Old Drugs with New Tricks: Rituximab in Combination with Albumin-Bound paclitaxel and Pegylated Liposomal Doxorubicin in the Treatment of Relapsed/Refractory Diffuse Large B Cell Lymphoma
Authors: Liang Wang, Hua Wang, Xiao-qin Chen, Wei-da Wang, Zhongjun Xia
Journal: Blood (2017)