tbuckley/cabot-search huggingface dataset:
Complex Relationships between Chromatin Accessibility, Sequence Divergence, and Gene Expression in Arabidopsis thaliana
Authors: Cristina M Alexandre, James R Urton, Ken Jean-Baptiste, John Huddleston, Michael W Dorrity, Josh T Cuperus, Alessandra M Sullivan, Felix Bemm, Dino Jolic, Andrej A Arsovski, Agnieszka Thompson, Jennifer L Nemhauser, Stan Fields, Detlef Weigel, Kerry L Bubb, Christin Queitsch
Journal: Molecular Biology and Evolution (2017)

Variation in regulatory DNA is thought to drive phenotypic variation, evolution, and disease. Prior studies of regulatory DNA and transcription factors across animal species highlighted a fundamental conundrum: Transcription factor binding domains and cognate binding sites are conserved, while regulatory DNA sequences are not. It remains unclear how conserved transcription factors and dynamic regulatory sites produce conserved expression patterns across species. Here, we explore regulatory DNA variation and its functional consequences within Arabidopsis thaliana, using chromatin accessibility to delineate regulatory DNA genome-wide. Unlike in previous cross-species comparisons, the positional homology of regulatory DNA is maintained among A. thaliana ecotypes and less nucleotide divergence has occurred. Of the ∼50,000 regulatory sites in A. thaliana, we found that 15% varied in accessibility among ecotypes. Some of these accessibility differences were associated with extensive, previously unannotated sequence variation, encompassing many deletions and ancient hypervariable alleles. Unexpectedly, for the majority of such regulatory sites, nearby gene expression was unaffected. Nevertheless, regulatory sites with high levels of sequence variation and differential chromatin accessibility were the most likely to be associated with differential gene expression. Finally, and most surprising, we found that the vast majority of differentially accessible sites show no underlying sequence variation. We argue that these surprising results highlight the necessity to consider higher-order regulatory context in evaluating regulatory variation and predicting its phenotypic consequences.
Abstract 15989: Loss of PLA2g6-dependent Store-operated Ca2+ Entry Protects Against Arterial Stiffening
Authors: Joon W Shim, Robert M Weisbrod, Francesca Seta, Victoria M Bolotina
Journal: Circulation (2016)

Introduction: Arterial stiffness is strongly associated with cardiovascular disease, but the mechanism and the role of vascular smooth muscle cell (SMC) in stiffening of the arteries in aging human...
Incidence of End-Stage Renal Disease in Patients With Type 1 Diabetes
Authors: Jaakko Helve, Reijo Sund, Martti Arffman, Valma Harjutsalo, Per-Henrik Groop, Carola Grönhagen-Riska, Patrik Finne
Journal: Diabetes Care (2017)

OBJECTIVE To investigate how risk of end-stage renal disease (ESRD) among patients with type 1 diabetes has changed over time and further how the risk is affected by age, sex, and time period of diagnosis of diabetes. RESEARCH DESIGN AND METHODS A cohort including all patients &amp;lt;30 years old diagnosed with type 1 diabetes in Finland in 1965–2011 was followed until start of renal replacement therapy, death, or end of follow-up at the end of 2013. Altogether, 29,906 patients were included. The main outcome was cumulative risk of ESRD, accounting for death as a competing risk. RESULTS The patients were followed up for a median of 20 years. During 616,403 patient-years, 1,543 ESRD cases and 4,185 deaths were recorded. The cumulative risk of ESRD was 2.2% after 20 years and 7.0% after 30 years from the diabetes diagnosis. The relative risk of ESRD was 0.13 (95% CI 0.08–0.22) among patients diagnosed in 1995–2011 compared with those diagnosed in 1965–1979. Patients &amp;lt;5 years old at the time of diagnosis had the lowest risk of ESRD after diagnosis. With the cumulative risk of ESRD estimated from time of birth, the patients aged 5–9 years at diabetes diagnosis were at highest risk. CONCLUSIONS The cumulative risk of ESRD has decreased markedly during the past five decades. This highlights the importance of modern treatment of diabetes and diabetic nephropathy.
Synthetic Cells Synthesize Therapeutic Proteins inside Tumors
Authors: Nitzan Krinsky, Maya Kaduri, Assaf Zinger, Janna Shainsky‐Roitman, Mor Goldfeder, Itai Benhar, Dov Hershkovitz, Avi Schroeder
Journal: Advanced Healthcare Materials (2017)

Abstract Synthetic cells, artificial cell‐like particles, capable of autonomously synthesizing RNA and proteins based on a DNA template, are emerging platforms for studying cellular functions and for revealing the origins‐of‐life. Here, it is shown for the first time that artificial lipid‐based vesicles, containing the molecular machinery necessary for transcription and translation, can be used to synthesize anticancer proteins inside tumors. The synthetic cells are engineered as stand‐alone systems, sourcing nutrients from their biological microenvironment to trigger protein synthesis. When pre‐loaded with template DNA, amino acids and energy‐supplying molecules, up to 2 × 10 7 copies of green fluorescent protein are synthesized in each synthetic cell. A variety of proteins, having molecular weights reaching 66 kDa and with diagnostic and therapeutic activities, are synthesized inside the particles. Incubating synthetic cells, encoded to secrete Pseudomonas exotoxin A (PE) with 4T1 breast cancer cells in culture, resulted in killing of most of the malignant cells. In mice bearing 4T1 tumors, histological evaluation of the tumor tissue after a local injection of PE‐producing particles indicates robust apoptosis. Synthetic cells are new platforms for synthesizing therapeutic proteins on‐demand in diseased tissues.
Tumor Microenvironment‐Enabled Nanotherapy
Authors: Liying Wang, Minfeng Huo, Yu Chen, Jianlin Shi
Journal: Advanced Healthcare Materials (2017)

Cancer is now one of the world's leading threats to human health. With the development of oncology in both biology and biomedicine, it has been demonstrated that abnormal physiochemical conditions and dysregulated biosynthetic intermediates in tumor microenvironment (TME) play a pivotal role in enabling tumor cells to defend or evade the damage by traditional clinical tumor therapeutics including surgery, chemotherapy, radiotherapy, etc. The fast advances of TME-enabled theranostic nanomedicine have offered promising perspectives, strategies, and approaches for combating cancer based on the novel concept of TME-enabled nanotherapy. In this comprehensive review, the origins of TME (e.g., enhanced permeability and retention effect, overexpressed biosynthetic intermediates, mild acidic nature, redox potentials, hypoxia) are initially introduced and discussed, followed by detailed discussion and overview on the state-of-the-art progresses in TME-enabled antitumor nanotherapies (e.g., chemo/chemodynamic therapy, photodynamic therapy, radiotherapy). Finally, the obstacles and challenges of future development on TME-enabled nanotherapies for further clinical translation are outlooked.
Association of Informal Clinical Integration of Physicians With Cardiac Surgery Payments
Authors: Russell J. Funk, Jason Owen-Smith, Samuel A. Kaufman, Brahmajee K. Nallamothu, John M. Hollingsworth
Journal: JAMA Surgery (2017)

To reduce inefficiency and waste associated with care fragmentation, many current programs target greater clinical integration among physicians. However, these programs have led to only modest Medicare spending reductions. Most programs focus on formal integration, which often bears little resemblance to actual physician interaction patterns.To examine how physician interaction patterns vary between health systems and to assess whether variation in informal integration is associated with care delivery payments.National Medicare data from January 1, 2008, through December 31, 2011, identified 253 545 Medicare beneficiaries (aged ≥66 years) from 1186 health systems where Medicare beneficiaries underwent coronary artery bypass grafting (CABG) procedures. Interactions were mapped between all physicians who treated these patients-including primary care physicians and surgical and medical specialists-within a health system during their surgical episode. The level of informal integration was measured in these networks of interacting physicians. Multivariate regression models were fitted to evaluate associations between payments for each surgical episode made on a beneficiary's behalf and the level of informal integration in the health system where the patient was treated.The informal integration level of a health system.Price-standardized total surgical episode and component payments.The total 253 545 study participants included 175 520 men (69.2%; mean [SD] age, 74.51 [5.75] years) and 78 024 women (34.3%; 75.67 [5.91] years). One beneficiary of the 253 545 participants did not have sex information. The low level of informal clinical integration included 84 598 patients (33.4%; mean [SD] age, 75.00 [5.93] years); medium level, 84 442 (33.30%; 74.94 [5.87] years); and high level, 84 505 (33.34%; 74.66 [5.72] years) (P < .001). Informal integration levels varied across health systems. After adjusting for patient, health-system, and community factors, higher levels of informal integration were associated with significantly lower total episode and component payments (β coefficients for informal integration were -365.87 [95% CI, -451.08 to -280.67] for total episode payments, -182.63 [-239.80 to -125.46] for index hospitalization, -43.13 [-55.53 to -30.72] for physician services, -74.48 [-103.45 to -45.51] for hospital readmissions, and -62.04 [-88.00 to -36.07] for postacute care; P < .001 for each association). When beneficiaries were treated in health systems with higher informal integration, the greatest savings of lower estimated payments were from hospital readmissions (13.0%) and postacute care services (5.8%).Informal integration is associated with lower spending. Although most programs that seek to promote clinical integration are focused on health systems' formal structures, policy makers may also want to address informal integration.
Human Mesenchymal Stem Cells Promote M2 Macrophage Polarization In Both In Vivo And In Vitro Models Of ARDS
Authors: A.D. Krasnodembskaya, T. Morrison, J.E. Gotts, C. O'Kane, D.F. McAuley, M.A. Matthay
Journal: American Journal of Respiratory and Critical Care Medicine (2014)
Annals Story Slam - A Son of Health Disparity
Authors: Kevin A. Jenkins
Journal: Annals of Internal Medicine (2017)

Web Exclusives19 December 2017Annals Story Slam - A Son of Health DisparityFREEKevin A. Jenkins, MDKevin A. Jenkins, MDUniversity of Pennsylvania and Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (K.A.J.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/W17-0074 SectionsAboutVisual Abstract ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Video. Annals Story Slam - A Son of Health Disparity "A Son of Health Disparity," by Dr. Kevin A. Jenkins (Duration 6:45)Building on the popular Annals feature “On Being a Doctor,” storytellers share stories about the experience of doctoring on video.For more videos from and information on Annals Story Slam, visit go.annals.org/StorySlam. Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: University of Pennsylvania and Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (K.A.J.)Current Author Address: Kevin A. Jenkins, MD; e-mail, [email protected]edu. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 19 December 2017Volume 167, Issue 12Page: SS1KeywordsHealth disparities ePublished: 19 December 2017 Issue Published: 19 December 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.Loading ...
CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials
Authors: G. Goss, C.-M. Tsai, F.A. Shepherd, M.-J. Ahn, L. Bazhenova, L. Crinò, F. de Marinis, E. Felip, A. Morabito, R. Hodge, M. Cantarini, M. Johnson, T. Mitsudomi, P.A. Jänne, J.C.-H. Yang
Journal: Annals of Oncology (2017)
Comparison of Different Diastolic Resting Indexes to iFR
Authors: Marcel van't Veer, Nico H.J. Pijls, Barry Hennigan, Stuart Watkins, Ziad A. Ali, Bernard De Bruyne, Frederik M. Zimmermann, Lokien X. van Nunen, Emanuele Barbato, Colin Berry, Keith G. Oldroyd
Journal: Journal of the American College of Cardiology (2017)

Pressure measurement for the duration of the wave-free period (WFP) is considered essential for resting-state physiological assessment of coronary stenosis severity using the instantaneous wave-free ratio (iFR).The aim of this study was to compare other diastolic resting indexes to iFR.In the population of the VERIFY2 (Pd/Pa vs iFR in an Unselected Population Referred for Invasive Angiography) study, iFR calculated by proprietary software (Volcano Harvest, Volcano Corporation, Rancho Cordova, California) was compared with the ratio of resting distal coronary pressure and aortic pressure during the complete duration of diastole (dPR), 25% to 75% of diastole (dPR25-75), and midpoint of diastole (dPRmid), along with Matlab calculated iFR (iFRmatlab) and iFR-like indexes shortening the length of the WFP by 50 and 100 ms (iFR-50ms and iFR-100ms), respectively. Mutual differences, Spearman correlations, area under the curve values from receiver-operating characteristic analyses, and diagnostic performance with respect to iFR and fractional flow reserve (FFR) were calculated for all indexes.Median iFR in 197 patients with 257 vessels was 0.91 with an interquartile range of 0.87 to 0.95. The mutual differences (± SD) with iFR were 0.006 ± 0.011 (dPR), 0.001 ± 0.007 (dPR25-75), 0.001 ± 0.008 (dPRmid), 0.005 ± 0.009 (iFRmatlab), 0.003 ± 0.008 (iFR-50ms), and 0.001 ± 0.009 (iFR-100ms). Correlations for all indexes with iFR were >0.99 (p < 0.001 for all). Area under the curve values for predicting iFR were >0.99 for all indexes as well. Diagnostic accuracy compared with FFR was 76% to 77% for all indexes including iFR.All diastolic resting indexes tested were identical to iFR, both numerically and with respect to their agreement with FFR. A numerically equal value to iFR can be determined without restriction to the WFP. Cutoff values, guidelines, and clinical recommendations for iFR can therefore be extended to these other indexes. (Pd/Pa vs iFR in an Unselected Population Referred for Invasive Angiography [VERIFY2]; NCT02377310).
Abstract 292: The Role of the ATF6 Branch of the ER Stress Response in the Endocrine Heart
Authors: Erik A Blackwood, Christopher C Glembotski
Journal: Circulation Research (2016)

Rationale: Atrial natriuretic peptide (ANP) is stored in the heart in large dense core granules of atrial myocytes as a biologically inactive precursor, pro-ANP. Hemodynamic stress and atrial stretch stimulate coordinate secretion and proteolytic cleavage of pro-ANP to its bioactive form, ANP, which promotes renal salt excretion and vasodilation, which, together contribute to decreasing blood pressure. While the ATF6 branch of the ER stress response has been studied in ventricular tissue mouse models of myocardial ischemia and pathological hypertrophy, roles for ATF6 and ER stress on the endocrine function of atrial myocytes have not been studied. Objective/Methods: To address this gap in our knowledge, we knocked down ATF6 in primary cultured neonatal rat atrial myocytes (NRAMs) using a chemical inhibitor of the proteolytic cleavage site enabling ATF6 activation and siRNA and measured ANP expression and secretion basally and in response to alpha- adrenergic agonist stimulation using phenylephrine. We also compared the ANP secretion from wild- type mice and ATF6 knockout mice in an ex vivo Langendorff model of the isolated perfused heart. Results: ATF6 knockdown in NRAMs significantly impaired basal and phenylephrine-stimulated ANP secretion. ATF6 knockout mice displayed lower levels of ANP in atrial tissue at baseline as well as after phenylephrine treatment. Similarly, in the ex vivo isolated perfused heart model, less ANP was detected in effluent of ATF6 knockout hearts compared to wild-type hearts. Conclusions: The ATF6 branch of the ER stress response is necessary for efficient co-secretional processing of pro-ANP to ANP and for agonist-stimulated ANP secretion from atrial myocytes. As ANP is secreted in a regulated manner in response to a stimulus and pro-ANP is synthesized and packaged through the classical secretory pathway, we posit that ATF6 is required for adequate expression, folding, trafficking, processing and secretion of biologically active ANP from the endocrine heart.
The association between nonalcoholic fatty liver disease and metabolic comorbidities
Authors: Qian Zhao, Xinyue Tang, Jiansheng Wu
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. To the Editor: We read with great interest the research by Allen et al.1 They investigated the trends in nonalcoholic fatty liver disease (NAFLD) incidence and the impact of NAFLD on incident metabolic comorbidities, cardiovascular events, and mortality from a community cohort of all adults diagnosed with NAFLD in Olmsted County during 1997‐2014 using the Rochester Epidemiology Project database. However, there are some key points worthy of discussion. Firstly, the current study examined the temporal associations between rates of NAFLD and the frequency of abdominal ultrasound testing in all Olmsted County residents during the study time frame. Abdominal B‐mode ultrasonography may underestimate the true prevalence of NAFLD as ultrasound examinations of the liver are relatively insensitive in cases where the hepatic lipid content is <30%.2 Therefore, to enhance the diagnosis rate of NAFLD, laboratory tests and FibroScan examinations should be included, and liver biopsies should be performed when necessary. Secondly, in this context, the NAFLD incidence increase was highest (7‐fold) in young adults, aged 18‐39 years; and the steeper increase in NAFLD diagnosis in young adults compared to other age groups is alarming. In addition, studies have revealed that NAFLD is currently the most common liver abnormality in children aged 2‐19 years, with a prevalence as high as 38% in obese children.3 Because this study is only focused on the incidence of NAFLD in adults, the incidence of NAFLD in children and teenagers was not investigated. Thirdly, this study reported that the prevalence of obesity among NAFLD subjects remained constant at 68% during the study period. Interestingly, studies4 have indicated that 7.6%‐25.6% of NAFLD patients have a normal body mass index, and their condition is known as "nonobese NAFLD," which is consistent with the proportion of nonobese NAFLD patients in this study (approximately 32%). Therefore, the absence of obesity and weight gain that has not yet resulted in obesity (especially in individuals aged 20 years and older) are also key predictive factors in the onset of NAFLD and the subsequent induction of metabolic syndrome. Therefore, segregation of the patient population for discussion in this study is recommended.
Microglial Ramification, Surveillance, and Interleukin-1β Release Are Regulated by the Two-Pore Domain K+ Channel THIK-1
Authors: Christian Madry, Vasiliki Kyrargyri, I. Lorena Arancibia-Cárcamo, Renaud Jolivet, Shinichi Kohsaka, Robert M. Bryan, David Attwell
Journal: Neuron (2017)

Microglia exhibit two modes of motility: they constantly extend and retract their processes to survey the brain, but they also send out targeted processes to envelop sites of tissue damage. We now show that these motility modes differ mechanistically. We identify the two-pore domain channel THIK-1 as the main K+ channel expressed in microglia in situ. THIK-1 is tonically active, and its activity is potentiated by P2Y12 receptors. Inhibiting THIK-1 function pharmacologically or by gene knockout depolarizes microglia, which decreases microglial ramification and thus reduces surveillance, whereas blocking P2Y12 receptors does not affect membrane potential, ramification, or surveillance. In contrast, process outgrowth to damaged tissue requires P2Y12 receptor activation but is unaffected by blocking THIK-1. Block of THIK-1 function also inhibits release of the pro-inflammatory cytokine interleukin-1β from activated microglia, consistent with K+ loss being needed for inflammasome assembly. Thus, microglial immune surveillance and cytokine release require THIK-1 channel activity.
Abstract 16832: Oxidized LDL and Adiponectin Interact and Regulate the Other’s Respective Functions
Authors: Akemi Kakino, Yoshiko Fujita, Tatsuya Sawamura
Journal: Circulation (2016)

Background: Adiponectin (AN) has anti-diabetic, anti-inflammatory, and anti-atherogenic properties. While the anti-diabetic role of AN has been well defined through the study of its receptors, Adip...
TLK286, a novel glutathione analog prodrug, is synergistic with carboplatin and paclitaxel as a triplet in human cancer cells
Authors: Jiandong Jiang, Yan Lin Wang, Yan Li, Premkumar Reddy, James F. Holland
Journal: Cancer Research (2005)

4991  TLK286 is a glutathione analog cancer prodrug which can be activated by GST P1-1, an enzyme often over-expressed in ovarian, non-small cell lung, breast, colorectal, pancreatic cancers and lymphoma. The activation of TLK286 releases two electrophilic fragments, a phosphorodiamidate and a glutathione analog vinyl sulfone that subsequently induce apoptosis. TLK286 has shown significant antitumor activity as a single agent in ovarian, non-small cell lung, breast and colon cancers and has non-overlapping toxicity and non-cross-resistance to standard anticancer agents. To support the continued development of TLK286 in combination regimens, we have tested TLK286 in combination with platinum and taxane based drugs in vitro. In OVCAR3 ovarian and A549 lung cancer cells, the combination of TLK286 with either paclitaxel or carboplatin showed marked enhancement of cytotoxicity when compared to the standard agents alone. Furthermore, in OVCAR3 cells that were made 30-fold resistant to paclitaxel, the combination of TLK286 and paclitaxel showed enhanced cytotoxicity, suggesting that TLK286 was capable of restoring sensitivity to paclitaxel. In OVCAR3 cells, the addition of TLK286 to the combination of carboplatin and paclitaxel resulted in significant synergy as evidenced by the increased cytotoxicity of the triplet compared to the sum of TLK286 and the carboplatin-paclitaxel doublet combination. These data confirm that TLK286 is a promising candidate for triplet combination therapy and provides support for an ongoing multicenter Phase 2 study using carboplatin, paclitaxel and TLK286 in frontline non-small cell lung cancer patients.
Abstract 20913: Fluid Retention in Elderly Women, Independent of Cardiac and Renal Function in the Community-Based Population
Authors: Takuya Hasegawa, Masanori Asakura, Mari Sakamoto, Hiroshi Asanuma, Makoto Amaki, Hiroyuki Takahama, Yasuo Sugano, Hideaki Kanzaki, Satoshi Yasuda, Hisao Ogawa, Toshihisa Anzai, Masafumi Kitakaze
Journal: Circulation (2016)

Background: Elderly women is considered to have a higher risk of heart failure with preserved ejection fraction (HFpEF), main pathophysiology of which is a congestion and diuretic-effectiveness in ...