tbuckley/cabot-search huggingface dataset:
Long-term balancing selection contributes to adaptation in Arabidopsis and its relatives
Authors: Qiong Wu, Ting-Shen Han, Xi Chen, Jia-Fu Chen, Yu-Pan Zou, Zi-Wen Li, Yong-Chao Xu, Ya-Long Guo
Journal: Genome biology (2017)

In contrast to positive selection, which reduces genetic variation by fixing beneficial alleles, balancing selection maintains genetic variation within a population or species and plays crucial roles in adaptation in diverse organisms. However, which genes, genome-wide, are under balancing selection and the extent to which these genes are involved in adaptation are largely unknown. We performed a genome-wide scan for genes under balancing selection across two plant species, Arabidopsis thaliana and its relative Capsella rubella, which diverged about 8 million generations ago. Among hundreds of genes with shared coding-region polymorphisms, we find evidence for long-term balancing selection in five genes: AT1G35220, AT2G16570, AT4G29360, AT5G38460, and AT5G44000. These genes are involved in the response to biotic and abiotic stress and other fundamental biochemical processes. More intriguingly, for these genes, we detected significant ecological diversification between the two haplotype groups, suggesting that balancing selection has been very important for adaptation. Our results indicate that beyond the well-known S-locus genes and resistance genes, many loci are under balancing selection. These genes are mostly correlated with resistance to stress or other fundamental functions and likely play a more important role in adaptation to diverse habitats than previously thought.
Abstract 17590: Internal Mammary Artery is Highly Sensitive to Reperfusion Injury. Direct Comparison of Free and in situ Internal Mammary Arterial Grafts and the Improvement of Current Storage Protocols
Authors: Gábor Veres, Harald Schmidt, Peter Hegedüs, Sevil Korkmaz, Tamás Radovits, Li Shiliang, Matthias Karck, Gábor Szabó
Journal: Circulation (2016)

Introduction:  The  in situ  internal mammary artery (ITA) has better long-term patency than other arterial conduit when used for coronary bypass grafting. However, patency rate of ITA used as a  free  conduit has equivalent to radial artery. The study aim was to compare directly the usage of  free  to  in situ  mammary artery and to investigate the effect of daily-used preservation solution on the endothelial function after bypass surgery.   Methods:  The ITA is harvested as  free / in situ  graft (n=6-8/group). Free grafts are stored for 1 hour in preservation solutions (Saline, Custodiol and Tiprotec). The ITA was anastomosed off-pump to the LAD (as an  in situ/free graft ) in a porcine model. Freshly harvested mammary arteries served as control. After 2 hours reperfusion the grafts were harvested. Endothelium-dependent and-independent vasorelaxations were investigated in organ bath. DNA strand breaks were assessed by TUNEL-method, mRNA expressions by quantitative real-time PCR and the expression of CD-31 by immunochemistry.   Results:  Endothelial function was severely impaired after 2h reperfusion in groups with conventional storage solutions compared to the control, whereas was partially preserved in the Tiprotec group. The  in situ  graft showed no impairement of endothelial function (maximal vasorelaxation to acetylcholine: control:87±5%,  free graft  (saline):25±3 *# ,  free graft  (Custodiol):31±4% *# ,  free graft  (Tiprotec):44±4% * ,  in situ :73±6%; p * vs. control,  # vs. Tiprotec). Endothelial integrity was also severely damaged (CD-31 positive area: control:87±2%,  free graft  (saline):62±6%,  free graft  (Custodiol):70±8%,  free graft  (Tiprotec):79±7%,  in situ : 94±2%, TUNEL positive nuclei; control:13±2%,  free graft  (saline):71±3% *# ,  free graft  (Custodiol):56±4% *# ,  free graft  (Tiprotec):38±3% * ,  in situ : 33±3%, p * vs. control,  # vs. Tiprotec). In addition, mRNA levels of Bax, Bcl-2, eNOS and caspase-3 were significantly altered in both groups.   Conclusions:  The ITA has high vulnerability against reperfusion injury.  In situ  usage of the ITA appears to be superior for the preservation of endothelial cells of bypass graft. Custodiol and saline as a preservation solution are not optimal, however Tiprotec permits better storage for  free graft .
Transcatheter Interatrial Shunt Device for the Treatment of Heart Failure With Preserved Ejection Fraction (REDUCE LAP-HF I [Reduce Elevated Left Atrial Pressure in Patients With Heart Failure])
Authors: Ted Feldman, Laura Mauri, Rami Kahwash, Sheldon Litwin, Mark J. Ricciardi, Pim van der Harst, Martin Penicka, Peter S. Fail, David M. Kaye, Mark C. Petrie, Anupam Basuray, Scott L. Hummel, Rhondalyn Forde-McLean, Christopher D. Nielsen, Scott Lilly, Joseph M. Massaro, Daniel Burkhoff, Sanjiv J. Shah
Journal: Circulation (2017)

In nonrandomized, open-label studies, a transcatheter interatrial shunt device (IASD, Corvia Medical) was associated with lower pulmonary capillary wedge pressure (PCWP), fewer symptoms, and greater quality of life and exercise capacity in patients with heart failure (HF) and midrange or preserved ejection fraction (EF ≥40%). We conducted the first randomized sham-controlled trial to evaluate the IASD in HF with EF ≥40%.REDUCE LAP-HF I (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) was a phase 2, randomized, parallel-group, blinded multicenter trial in patients with New York Heart Association class III or ambulatory class IV HF, EF ≥40%, exercise PCWP ≥25 mm Hg, and PCWP-right atrial pressure gradient ≥5 mm Hg. Participants were randomized (1:1) to the IASD versus a sham procedure (femoral venous access with intracardiac echocardiography but no IASD placement). The participants and investigators assessing the participants during follow-up were blinded to treatment assignment. The primary effectiveness end point was exercise PCWP at 1 month. The primary safety end point was major adverse cardiac, cerebrovascular, and renal events at 1 month. PCWP during exercise was compared between treatment groups using a mixed-effects repeated measures model analysis of covariance that included data from all available stages of exercise.A total of 94 patients were enrolled, of whom 44 met inclusion/exclusion criteria and were randomized to the IASD (n=22) and control (n=22) groups. Mean age was 70±9 years, and 50% were female. At 1 month, the IASD resulted in a greater reduction in PCWP compared with sham control (P=0.028 accounting for all stages of exercise). Peak PCWP decreased by 3.5±6.4 mm Hg in the treatment group versus 0.5±5.0 mm Hg in the control group (P=0.14). There were no peri-procedural or 1-month major adverse cardiac, cerebrovascular, and renal events in the IASD group and 1 event (worsening renal function) in the control group (P=1.0).In patients with HF and EF ≥40%, IASD treatment reduces PCWP during exercise. Whether this mechanistic effect will translate into sustained improvements in symptoms and outcomes requires further evaluation.URL: https://clinicaltrials.gov. Unique identifier: NCT02600234.
Surgical Enlargement of the Aortic Root Does Not Increase the Operative Risk of Aortic Valve Replacement
Authors: Rodolfo V. Rocha, Cedric Manlhiot, Christopher M. Feindel, Terrence M. Yau, Brigitte Mueller, Tirone E. David, Maral Ouzounian
Journal: Circulation (2017)

Background: Surgical aortic root enlargement (ARE) during aortic valve replacement (AVR) allows for larger prosthesis implantation and may be an important adjunct to surgical AVR in the transcatheter valve-in-valve era. The incremental operative risk of adding ARE to AVR has not been established. We aimed to evaluate the early outcomes of patients undergoing AVR with or without ARE. Methods: From January 1990 to August 2014, 7039 patients underwent AVR (AVR+ARE, n=1854; AVR, n=5185) at a single institution. Patients with aortic dissection and active endocarditis were excluded. Mean age was 65±14 years and 63% were male. Logistic regression and propensity score matching were used to adjust for unbalanced variables in group comparisons. Results: Patients undergoing AVR+ARE were more likely to be female (46% versus 34%, P &lt;0.001) and had higher rates of previous cardiac surgery (18% versus 12%, P &lt;0.001), chronic obstructive pulmonary disease (5% versus 3%, P =0.004), urgent/emergent status (6% versus 4%, P =0.01), and worse New York Heart Association status ( P &lt;0.001). Most patients received bioprosthetic valves (AVR+ARE: 73.4% versus AVR: 73.3%, P =0.98) and also underwent concomitant cardiac procedures (AVR+ARE: 68% versus AVR: 67%, P =0.31). Mean prosthesis size implanted was slightly smaller in patients requiring AVR+ARE versus AVR (23.4±2.1 versus 24.1±2.3, P &lt;0.001). In-hospital mortality was higher after AVR+ARE (4.3% versus 3.0%, P =0.008), although when the cohort was restricted to patients undergoing isolated aortic valve replacement with or without root enlargement, mortality was not statistically different (AVR+ARE: 1.7% versus AVR: 1.1%, P =0.29). After adjustment for baseline characteristics, AVR+ARE was not associated with an increased risk of in-hospital mortality when compared with AVR (odds ratio, 1.03; 95% confidence interval, 0.75–1.41; P =0.85). Furthermore, AVR+ARE was not associated with an increased risk of postoperative adverse events. Results were similar if propensity matching was used instead of multivariable adjustments for baseline characteristics. Conclusions: In the largest analysis to date, ARE was not associated with increased risk of mortality or adverse events. Surgical ARE is a safe adjunct to AVR in the modern era.
Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas
Authors: Jelena Todoric, Laura Antonucci, Giuseppe Di Caro, Ning Li, Xuefeng Wu, Nikki K. Lytle, Debanjan Dhar, Sourav Banerjee, Johan B. Fagman, Cecille D. Browne, Atsushi Umemura, Mark A. Valasek, Hannes Kessler, David Tarin, Michael Goggins, Tannishtha Reya, Maria Diaz-Meco, Jorge Moscat, Michael Karin
Journal: Cancer Cell (2017)
Poor agreement in questionnaire‐based diagnostic criteria for adult atopic dermatitis is a challenge when examining cardiovascular comorbidity
Authors: Y. M. F. Andersen, A. Egeberg, C. R. Hamann, L. Skov, G. H. Gislason, T. Skaaby, A. Linneberg, J. P. Thyssen
Journal: Allergy (2017)

The association between atopic dermatitis (AD) and cardio-metabolic risk factors is not yet established. Furthermore, no validated questionnaire-based method of identifying adults with AD is currently available.To assess the cardio-metabolic risk in adults with a history of AD using 3 different questionnaire-based diagnostic criteria.We utilized data from a general population study including questionnaire data and objective measurements of 9656 Danish adults. To identify adults with a history of AD, we used a question regarding physician-diagnosed AD and 2 versions of the UK Working Party Diagnostic Criteria. Associations between AD status and cardio-metabolic endpoints were estimated using survey weighted logistic and linear regression analysis.We identified 462 (4.8%) adults with self-reported physician-diagnosed AD, whereas 903 (9.4%) and 226 (2.3%) had AD according to the UK Working Party Criteria when at least 2 and 3of 4 minor criteria were fulfilled. The populations were not comparable in terms of occurrence of cardio-metabolic risk factors. For example, the prevalence of obesity was lower in participants with physician-diagnosed AD but overall higher in UK 2/4 and UK 3/4.Due to the heterogeneity in the captured study populations in terms of the studied outcomes and absence of a gold standard, no conclusions regarding the cardio-metabolic risk in adults with AD in a general population could be made. This study serves as an example of the challenges that are often encountered in questionnaire-based epidemiologic studies and highlights the need of better definitions for this patient group.
Vitamin C Sensitizes Melanoma to BET Inhibitors
Authors: Sushmita Mustafi, Vladimir Camarena, Claude-Henry Volmar, Tyler C. Huff, David W. Sant, Shaun P. Brothers, Zhao-Jun Liu, Claes Wahlestedt, Gaofeng Wang
Journal: Cancer Research (2017)

Abstract Bromodomain and extraterminal inhibitors (BETi) are promising cancer therapies, yet prominent side effects of BETi at effective doses have been reported in phase I clinical trials. Here, we screened a panel of small molecules targeting epigenetic modulators against human metastatic melanoma cells. Cells were pretreated with or without ascorbate (vitamin C), which promotes DNA demethylation and subsequently changes the sensitivity to drugs. Top hits were structurally unrelated BETi, including JQ1, I-BET151, CPI-203, and BI-2536. Ascorbate enhanced the efficacy of BETi by decreasing acetylation of histone H4, but not H3, while exerting no effect on the expression of BRD proteins. Histone acetyltransferase 1 (HAT1), which catalyzes H4K5ac and H4K12ac, was downregulated by ascorbate mainly via the TET-mediated DNA hydroxymethylation pathway. Loss of H4ac, especially H4K5ac and H4K12ac, disrupted the interaction between BRD4 and H4 by which ascorbate and BETi blocked the binding of BRD4 to acetylated histones. Cotreatment with ascorbate and JQ1 induced apoptosis and inhibited proliferation of cultured melanoma cells. Ascorbate deficiency as modeled in Gulo−/− mice diminished the treatment outcome of JQ1 for melanoma tumorgraft. In contrast, ascorbate supplementation lowered the effective dose of JQ1 needed to successfully inhibit melanoma tumors in mice. On the basis of our findings, future clinical trials with BETi should consider ascorbate levels in patients. Furthermore, ascorbate supplementation might help reduce the severe side effects that arise from BETi therapy by reducing the dosage necessary for treatment. Significance: This study shows that ascorbate can enhance the efficacy of BET inhibitors, providing a possible clinical solution to challenges arising in phase I trials from the dose-dependent side effects of this class of epigenetic therapy. Cancer Res; 78(2); 572–83. ©2017 AACR.
Histidine-rich Modification of a Scorpion-derived Peptide Improves Bioavailability and Inhibitory Activity against HSV-1
Authors: Zhengyang Zeng, Runhong Zhang, Wei Hong, Yuting Cheng, Huijuan Wang, Yange Lang, Zhenglin Ji, Yingliang Wu, Wenxin Li, Youli Xie, Zhijian Cao
Journal: Theranostics (2017)

Rationale: HSV is one of the most widespread human viral pathogens. HSV-1 infects a large portion of the human population and causes severe diseases. The current clinical treatment for HSV-1 is based on nucleoside analogues, the use of which is limited due to drug resistance, side effects and poor bioavailability. AMPs have been identified as potential antiviral agents that may overcome these limitations. Therefore, we screened anti-HSV-1 peptides from a scorpion-derived AMP library and engineered one candidate into a histidine-rich peptide with significantly improved antiviral activity and development potential. Methods: A venomous gland cDNA library was constructed from the scorpion Euscorpiops validus in the Yunnan Province of China. Six putative AMPs were characterized from this cDNA library, and the synthesized peptides were screened via plaque-forming assays to determine their virucidal potential. Time of addition experiments according to the infection progress of HSV-1 were used to identify the modes of action for peptides of interest. The histidine-rich modification was designed based on structural analysis of peptides by a helical wheel model and CD spectroscopy. Peptide cellular uptake and distribution were measured by flow cytometry and confocal microscopy, respectively. Results: The peptide Eval418 was found to have high clearance activity in an HSV-1 plaque reduction assay. Eval418 exhibited dose-dependent and time-dependent inactivation of HSV-1 and dose-dependent inhibition of HSV-1 attachment to host cells. However, Eval418 scarcely suppressed an established HSV-1 infection due to poor cellular uptake. We further designed and modified Eval418 into four histidine-rich derivative peptides with enhanced antiviral activities and lower cytotoxicities. All of the derivative peptides suppressed established HSV-1 infections. One of these peptides, Eval418-FH5, not only had strong viral inactivation activity and enhanced attachment inhibitory activity but also had high inhibitory activity against intracellular HSV-1, which was consistent with its improved intracellular uptake and distribution as confirmed by confocal microscopy and flow cytometry. Conclusion: We successfully identified an anti-HSV-1 peptide, Eval418, from a scorpion venom peptide library and designed a histidine-rich Eval418 derivative with significantly improved potential for further development as an anti-HSV-1 drug. This successful modification can provide a design strategy to improve the bioavailability, cellular distribution and antiviral activity of peptide agents.
Enhancing palliative care patient access to outpatient and outreach counseling services.
Authors: Diana Guzman, Eduardo Bruera, Janet L. Williams, John M Najera, Monica Raznahan, Sujin Ann-Yi, Cindy L. Carmack
Journal: Journal of Clinical Oncology (2017)

184 Background: MD Anderson’s interdisciplinary out-patient clinic, palliative care team includes mental health professionals who provide psychological care, including 3 full time Master’s level counselors. Counseling sessions are offered during the patient’s clinic appointments. To increase opportunity and access for additional counseling, patients are offered follow-up counseling through an outreach program which includes videoconferencing or telephone sessions. The data presented represents almost 2 years of our Master’s level clinicians’ practices. Methods: Retrospective chart review of 2041 consecutive patients (3606 total contacts) seen for psychology counseling services in the Supportive Care Center between 6/2015 and 3/2017. Results: Counselors saw 2041 consecutive patients (52% of the patients seen at the out-patient Supportive Care Center). Most patients only had 1 session in clinic (63%); almost 1/3 received 2-5 sessions (33.9%). Median time for the follow-up visit was 30.5 days. Approximately 25% (N = 511) were offered outreach services; 79% (N = 405) of those offered received these services. Median number of outreach sessions received was 1 (57%); 2-5 (38%); 6-9 (4%) and 10+ (1%). Sessions lasted 10-15 minutes (58%); 20-35 minutes (31%); and 40+ minutes (11%). Patient preferred mode of outreach included telephone (93%), Facetime (5.0%), and videoconferencing (2%). In total, 798 outreach sessions were provided representing 18% of total counseling sessions offered. Conclusions: The out-patient palliative care service is able to offer psychological assessment and counseling to more than half of the patients they serviced due to the addition of 3 Master’s level counselors embedded in the clinic. Follow-up counseling for these patients can be challenged for those residing in rural areas, with limited resources and/or transportation problems, and with physical limitations that make travel difficult. Our outreach program has successfully enhanced access to services to patients who otherwise may have had limited to no follow-up psychosocial care.
Mejoras en la vigilancia de la tuberculosis
Authors: J M Watson
Journal: Eurosurveillance (2000)

En 1996, una declaracion de consenso en materia de vigilancia de la tuberculosis en Europa recomendaba la recogida de datos de todos los casos locales de tuberculosis (1). La declaracion, ratificada por la Union Internacional de Lucha contra la Tuberculosis y Enfermedades Pulmonares (International Union Against Tuberculosis and Lung Disease), la Organizacion Mundial de la Salud y representantes de los paises europeos, aconsejaba utilizar un conjunto de datos comunes y recoger y analizar datos individualizados en los niveles local, regional y nacional (1). Paralelamente, se establecio un plan financiado por la Union Europea para comparar y analizar estos datos estandarizados (EuroTB). Los resultados de esta colaboracion ya han sido publicados (2,3).
Cardiac safety of bedaquiline: a systematic and critical analysis of the evidence
Authors: Emanuele Pontali, Giovanni Sotgiu, Simon Tiberi, Lia D'Ambrosio, Rosella Centis, Giovanni B. Migliori
Journal: European Respiratory Journal (2017)

The treatment of multidrug-resistant (MDR) or extensively drug-resistant (XDR) tuberculosis (TB) remains a challenge for clinicians for several reasons, including the large number of drugs required, the cost, the tolerability of single drugs and their combinations, and the effectiveness and long treatment duration [1–6]. Therefore, fresh attention has recently been paid to new and repurposed anti-TB drugs [4, 5, 7–18]. Bedaquiline is well tolerated: evidence indicates a minority of patients discontinue use due to QT extension <http://ow.ly/9NRT30fNv4y>
Frequencies and expression levels of programmed death ligand 1 (PD-L1) in circulating tumor RNA (ctRNA) in various cancer types
Authors: T. Ishiba, K. Danenberg, J. Usher, T. Nakagawa, G. Oda, H. Uetake, N. Hoshino, Y. Nishioka, T. Kawano
Journal: Annals of Oncology (2017)
P1.05-043 Survival Following Surgical Resection of Lung Adenocarcinoma Stratified According to Morphological Sub-Type
Authors: Haval Balata, Timothy Edwards, Charlene Tennyson, Philip Foden, Anshuman Chaturvedi, Philip Crosbie, Richard Booton, Matthew Evison
Journal: Journal of Thoracic Oncology (2017)
Clinical implementation of the universal tumor screening with the mismatch repair (MMR) proteins on decision impact of adjuvant chemotherapy in patients with resected stage II/III colorectal cancer (CRC)
Authors: Y. Yamamoto, Y. Tsukada, H. Bando, T. Sasaki, Y. Nishizawa, M. Kojima, T. Kuwata, M. Ito, T. Yoshino
Journal: Annals of Oncology (2017)
P3.02c-036 Management of Early Disease Progression during Treatment of Advanced Non-Small Cell Lung Cancer with Nivolumab
Authors: Carlo Genova, Giovanni Rossi, Erika Rijavec, Giulia Barletta, Federica Biello, Claudia Maggioni, Simone Mennella, Maria Giovanna Dal Bello, Roberta Distefano, Giuseppe Cittadini, Franco Merlo, Carlo Genova
Journal: Journal of Thoracic Oncology (2017)
Tamm-Horsfall Protein Regulates Mononuclear Phagocytes in the Kidney
Authors: Radmila Micanovic, Shehnaz Khan, Danielle Janosevic, Maya E. Lee, Takashi Hato, Edward F. Srour, Seth Winfree, Joydeep Ghosh, Yan Tong, Susan E. Rice, Pierre C. Dagher, Xue-Ru Wu, Tarek M. El-Achkar
Journal: Journal of the American Society of Nephrology (2017)

Tamm-Horsfall protein (THP), also known as uromodulin, is a kidney-specific protein produced by cells of the thick ascending limb of the loop of Henle. Although predominantly secreted apically into the urine, where it becomes highly polymerized, THP is also released basolaterally, toward the interstitium and circulation, to inhibit tubular inflammatory signaling. Whether, through this latter route, THP can also regulate the function of renal interstitial mononuclear phagocytes (MPCs) remains unclear, however. Here, we show that THP is primarily in a monomeric form in human serum. Compared with wild-type mice, THP-/- mice had markedly fewer MPCs in the kidney. A nonpolymerizing, truncated form of THP stimulated the proliferation of human macrophage cells in culture and partially restored the number of kidney MPCs when administered to THP-/- mice. Furthermore, resident renal MPCs had impaired phagocytic activity in the absence of THP. After ischemia-reperfusion injury, THP-/- mice, compared with wild-type mice, exhibited aggravated injury and an impaired transition of renal macrophages toward an M2 healing phenotype. However, treatment of THP-/- mice with truncated THP after ischemia-reperfusion injury mitigated the worsening of AKI. Taken together, our data suggest that interstitial THP positively regulates mononuclear phagocyte number, plasticity, and phagocytic activity. In addition to the effect of THP on the epithelium and granulopoiesis, this new immunomodulatory role could explain the protection conferred by THP during AKI.