tbuckley/cabot-search huggingface dataset:
Abstract 18327: Early Estrogen Replacement After Ovariectomy Limits Liver DAG and Promotes Insulin Sensitivity in a Manner That Requires Hepatic Estrogen Signaling
Authors: Lin Zhu, Owen P McGuinness, John M Stafford
Journal: Circulation (2011)

The cardiovascular effects of postmenopausal estrogen replacement have been controversial. Estrogen replacement at the time of menopause may protect from cardiovascular disease, due to improvements in the complications of obesity. We designed studies to define mechanisms by which estrogen replacement may alter the impact of high-fat feeding, when given at the time of surgical menopause by ovariectomy (OVX) in C57/B6 mice. OVX-mice had a 2-fold increase in adiposity after 5 weeks of high-fat diet feeding, compared with sham mice (sham 16.5±1.2% vs. OVX 32.4±3.1% adiposity). The weight gain and increased adiposity were prevented with subcutaneous replacement of estradiol (E2) at the time of OVX (OVX-E2 5.4±0.4% vs OVX 32.4±3.1% adiposity). We defined the impact of OVX and E2 replacement on insulin sensitivity with hyperinsulinemic-euglycemic clamp studies. For OVX mice, insulin sensitivity was reduced 25% compared with sham mice, while OVX-E2 mice had a 2.2-fold increase in insulin sensitivity (sham 694±51; OVX 519±125; OVX-E2 1584.0±197 mg•ml•[kg•min•mU]-1). Compared to OVX, after hyperinsulinemia, in the liver of OVX-E2 mice, we found: 1) increased phosphorylation of ACC (inactive form), increased protein amounts of DGAT 2 (promotes TG synthesis from DAG). This potential increase in fatty-acid oxidation, coupled with increased TG synthesis was associated with reduced liver DAG content in OVX-E2 mice (OVX 4.0±0.7 vs. OVX-E2 1.74±0.53 µg•mg-1), and increased phosphorylation of ser473-AKT (insulin-signaling activated). In order to define the requirement of liver estrogen signaling in the protective effects of E2 replacement, we performed a parallel study with OVX and E2 replacement in mice with liver estrogen receptor alpha knockout (LKO). While E2 replacement reduced adiposity in LKO mice similar to controls, E2 replacement in LKO mice failed to improve whole-body insulin resistance (746±138 mg•ml•[kg•min•mU]-1), and failed to prevent liver DAG accumulation (3.2±1.1 µg•mg-1) compared to OVX mice. This study demonstrates that estrogen replacement at the time of OVX promotes insulin sensitivity by increasing TG synthesis, thereby limiting liver DAG content, and lipotoxicity. This protective effect requires hepatic estrogen signaling.
Precisely controlled delivery of magnesium ions thru sponge-like monodisperse PLGA/nano-MgO-alginate core-shell microsphere device to enable in-situ bone regeneration
Authors: Zhengjie Lin, Jun Wu, Wei Qiao, Ying Zhao, Karen H.M. Wong, Paul K. Chu, Liming Bian, Shuilin Wu, Yufeng Zheng, Kenneth M.C. Cheung, Frankie Leung, Kelvin W.K. Yeung
Journal: Biomaterials (2018)
Optimized Dosing Schedule Based on Circadian Dynamics of Mouse Breast Cancer Stem Cells Improves the Antitumor Effects of Aldehyde Dehydrogenase Inhibitor
Authors: Naoya Matsunaga, Takashi Ogino, Yukinori Hara, Takahiro Tanaka, Satoru Koyanagi, Shigehiro Ohdo
Journal: Cancer Research (2018)

Abstract Although malignant phenotypes of triple-negative breast cancer (TNBC) are subject to circadian alterations, the role of cancer stem cells (CSC) in defining this circadian change remains unclear. CSC are often characterized by high aldehyde dehydrogenase (ALDH) activity, which is associated with the malignancy of cancer cells and is used for identification and isolation of CSC. Here, we show that the population of ALDH-positive cells in a mouse 4T1 breast tumor model exhibits pronounced circadian alterations. Alterations in the number of ALDH-positive cells were generated by time-dependent increases and decreases in the expression of Aldh3a1. Importantly, circadian clock genes were rhythmically expressed in ALDH-negative cells, but not in ALDH-positive cells. Circadian expression of Aldh3a1 in ALDH-positive cells was dependent on the time-dependent release of Wingless-type mmtv integration site family 10a (WNT10a) from ALDH-negative cells. Furthermore, antitumor and antimetastatic effects of ALDH inhibitor N,N-diethylaminobenzaldehyde were enhanced by administration at the time of day when ALDH activity was increased in 4T1 tumor cells. Our findings reveal a new role for the circadian clock within the tumor microenvironment in regulating the circadian dynamics of CSC. These results should enable the development of novel therapeutic strategies for treatment of TNBC with ALDH inhibitors. Significance: This seminal report reveals that circadian dynamics of CSC are regulated by the tumor microenvironment and provides a proof of principle of its implication for chronotherapy in TNBC. Cancer Res; 78(13); 3698–708. ©2018 AACR.
Commentary: Future Directions and Research Priorities for Food Mutagens
Authors: F. J. de Serres, E. Zeiger, F. T. Hatch
Journal: Environmental Health Perspectives (1986)

This symposium on formation of mutagens during cooking and heat processing of foods has covered the current status of the research effort and the significant findings to date. In order to provide an opportunity for discussion of additional research perceived as needed, future directions that should be addressed, and steps leading toward assessment of possible human health effects, a workshop attended by many ofthe symposium participants was held on the following day, December 19, 1984, at the Halekulani Hotel in Honolulu. This workshop was sponsored by the U.S.-Japan Environ? mental Panel on Mutagenesis and Carcinogenesis, and was co-chaired by Dr. F. J. de Serres, Associate Di? rector of the National Institute of Environmental Health Sciences, and Dr. T. Sugimura, President ofthe National Cancer Center of Japan.
Toll‐Like Receptor 9 Deficiency Breaks Tolerance to RNA‐Associated Antigens and Up‐Regulates Toll‐Like Receptor 7 Protein in <i>Sle1</i> Mice
Authors: Teja Celhar, Hiroko Yasuga, Hui Yin Lee, Olga Zharkova, Shubhita Tripathi, Susannah I. Thornhill, Hao K. Lu, Bijin Au, Lina H. K. Lim, Thomas P. Thamboo, Shizuo Akira, Edward K. Wakeland, John E. Connolly, Anna‐Marie Fairhurst
Journal: Arthritis & Rheumatology (2018)

Toll-like receptors (TLRs) 7 and 9 are important innate signaling molecules with opposing roles in the development and progression of systemic lupus erythematosus (SLE). While multiple studies support the notion of a dependency on TLR-7 for disease development, genetic ablation of TLR-9 results in severe disease with glomerulonephritis (GN) by a largely unknown mechanism. This study was undertaken to examine the suppressive role of TLR-9 in the development of severe lupus in a mouse model.We crossed Sle1 lupus-prone mice with TLR-9-deficient mice to generate Sle1TLR-9-/- mice. Mice ages 4.5-6.5 months were evaluated for severe autoimmunity by assessing splenomegaly, GN, immune cell populations, autoantibody and total Ig profiles, kidney dendritic cell (DC) function, and TLR-7 protein expression. Mice ages 8-10 weeks were used for functional B cell studies, Ig profiling, and determination of TLR-7 expression.Sle1TLR-9-/- mice developed severe disease similar to TLR-9-deficient MRL and Nba2 models. Sle1TLR-9-/- mouse B cells produced more class-switched antibodies, and the autoantibody repertoire was skewed toward RNA-containing antigens. GN in these mice was associated with DC infiltration, and purified Sle1TLR-9-/- mouse renal DCs were more efficient at TLR-7-dependent antigen presentation and expressed higher levels of TLR-7 protein. Importantly, this increase in TLR-7 expression occurred prior to disease development, indicating a role in the initiation stages of tissue destruction.The increase in TLR-7-reactive immune complexes, and the concomitant enhanced expression of their receptor, promotes inflammation and disease in Sle1TLR9-/- mice.
MIPSS70+ Version 2.0: Mutation and Karyotype-Enhanced International Prognostic Scoring System for Primary Myelofibrosis
Authors: Ayalew Tefferi, Paola Guglielmelli, Terra L. Lasho, Naseema Gangat, Rhett P. Ketterling, Animesh Pardanani, Alessandro M. Vannucchi
Journal: Journal of Clinical Oncology (2018)
Association of vitamin D with risk of type 2 diabetes: A Mendelian randomisation study in European and Chinese adults
Authors: Ling Lu, Derrick A. Bennett, Iona Y. Millwood, Sarah Parish, Mark I. McCarthy, Anubha Mahajan, Xu Lin, Fiona Bragg, Yu Guo, Michael V. Holmes, Shoaib Afzal, Børge G. Nordestgaard, Zheng Bian, Michael Hill, Robin G. Walters, Liming Li, Zhengming Chen, Robert Clarke
Journal: PLoS Medicine (2018)

Background Observational studies have reported that higher plasma 25-hydroxyvitamin D (25[OH]D) concentrations are associated with lower risks of diabetes, but it is unclear if these associations are causal. The aim of this study was to test the relevance of 25(OH)D for type 2 diabetes using genetically instrumented differences in plasma 25(OH)D concentrations. Methods and findings Data were available on four 25(OH)D single nucleotide polymorphisms (SNPs; n = 82,464), plasma 25(OH)D concentrations (n = 13,565), and cases with diabetes (n = 5,565) in the China Kadoorie Biobank (CKB). The effects on risk of diabetes were assessed by a genetic score using two 25(OH)D synthesis SNPs (DHCR7-rs12785878 and CYP2R1-rs10741657), with and without the addition of SNPs affecting the transport (GC/DBP-rs2282679) and catabolism (CYP24A1-rs6013897) of 25(OH)D. The CKB results were combined in a meta-analysis of 10 studies for the 2 synthesis SNPs (n = 58,312 cases) and 7 studies for all 4 SNPs (n = 32,796 cases). Mean (SD) 25(OH)D concentration was 62 (20) nmol/l in CKB, and the per allele effects of genetic scores on 25(OH)D were 2.87 (SE 0.39) for the synthesis SNPs and 3.54 (SE 0.32) for all SNPs. A 25-nmol/l higher biochemically measured 25(OH)D was associated with a 9% (95% CI: 0%–18%) lower risk of diabetes in CKB. In a meta-analysis of all studies, a 25-nmol/l higher genetically instrumented 25(OH)D concentration was associated with a 14% (95% CI: 3%–23%) lower risk of diabetes (p = 0.01) using the 2 synthesis SNPs. An equivalent difference in 25(OH)D using a genetic score with 4 SNPs was not significantly associated with diabetes (odds ratio 8%, 95% CI: −1% to 16%, lower risk, p = 0.07), but had some evidence of pleiotropy. A limitation of the meta-analysis was the access only to study level rather than individual level data. Conclusions The concordant risks of diabetes for biochemically measured and genetically instrumented differences in 25(OH)D using synthesis SNPs provide evidence for a causal effect of higher 25(OH)D for prevention of diabetes.
Picking the right tools for the job: opening up the statistical toolkit to build a compelling case in sport and exercise medicine research
Authors: Johann Windt, Rasmus Oestergaard Nielsen, Bruno D Zumbo
Journal: British Journal of Sports Medicine (2018)

P values have been the subject of debate for decades. Many researchers tend to think—or at least describe—their study outcomes to be either true or false based solely on p values.1 While a recent British Journal of Sports Medicine editorial provided a primer for sports medicine researchers to correctly understand p values,2 we aim to extend this discussion by reminding researchers to adopt a thoughtful approach to the entire statistical analysis process, using the relevant tools to build their case.

Scientific reasoning can be viewed as building a case for the existence (or non-existence) of phenomena. For sports medicine researchers, their specific goals may include the case for or against a treatment’s effectiveness, the risk of injury associated with certain risk factors, or the ability to predict a certain outcome given a set of criteria.

As with any building process, a number of steps are required. In this analogy, the process should include the following: designing the blueprint (preregistering studies where possible and outlining planned analyses), laying a foundation of sound data collection (appropriate sampling strategy, blinding where possible, ensuring measurement validity/reliability), understanding the flooring and roofing of study power (effect size, sample size and others), and painting the internal/external validity of the study. The entire process takes …
Abstract 10630: Active Myocardial TGF-β Level is Significantly Increased in End-Stage Human Heart Failure
Authors: Shaukat Khan, Joyce Jennifer, Kenneth Margulies, Takeshi Tsuda
Journal: Circulation (2011)

Persistent TGF-β activation is thought to be involved in progressive ventricular remodeling and TGF-β inhibition has been considered as a potential treatment to prevent the progression of heart failure. However, there has been no direct evidence of increased active TGF-β levels in the diseased human myocardium. Thus, we assessed the hypothesis that increased active TGF-β is seen in the myocardium of end-stage heart failure. We examined the molecular and biochemical profiles of human myocardial tissues from non failing donors (NF; n = 10), patients with ischemic cardiomyopathy (ICM; n = 10) and non-ischemic cardiomyopathy (NICM; n = 10) obtained at the time of heart transplant. We studied mRNA levels by real-time RT-PCR, protein levels by immunoblots, and active TGF-β levels by bioassay using cultured mink lung epithelial cells transfected with plasminogen activator inhibitor (PAI)-1 promoter-luciferase construct. Using this assay, active TGF-β levels were measured in the protein extracts from myocardial tissues. Data were shown as mean ±SD. The patients9 ages were NF 49± 20, ICM 57± 5, and NICM 52 ±10. Pre-transplant LVEF was NF 67 ±7%, ICM 21 ±14%, and NICM 14 ±6%. There was no significant difference in Collagen I, Collagen III, or TGF-β1 mRNA levels among the 3 groups. Although TGF-β1 protein levels by immunoblots were not significantly different in 3 groups, there was a pronounced increase in free TGF-β levels (Figure) and in phosphorylation of Smad2 in ICM and NICM compared with NF [NF 1.0 ±0.16; ICM 2.44 ±0.47 (p
Sofosbuvir plus ribavirin and sofosbuvir plus daclatasvir-based regimens are suboptimal in genotype 2 patients: real-life experience
Authors: C. Hezode, V. De Ledinghen, G. Haour, J.-P. Bronowicki, F. Zoulim, D. Larrey, M. Sophie, T. Albert, M. Patrick, D. Samuel, O. Chazouillères, C. Stephane, D. Celine, F. Helene, J.-M. Pawlotsky, C. Fabrice, P. Stanislas
Journal: Journal of Hepatology (2018)
Virological and clinical characterization of a hepatitis A outbreak in Barcelona involving primarily men who have sex with men
Authors: S. Rodríguez-Tajes, E. Perpiñan, B. Caballol, S. Lens, Z. Mariño, J. Costa, A. Vilella, S.P. del Pulgar, X. Forns, G. Koutsoudakis
Journal: Journal of Hepatology (2018)
Abstract 17726: Left Ventricular Global Longitudinal Strain Predicts All-cause Mortality in Patients With Isolated Mitral Regurgitation
Authors: Daniel K Pu, Anthony A Holmes, Ningxin Wan, Cynthia Taub
Journal: Circulation (2016)

Introduction:  Strain echocardiography (echo) is increasingly recognized as an effective technique for predicting patient survival in a wide spectrum of diseases. We sought to evaluate the effectiveness of 2D speckle-tracking echo in predicting all-cause mortality in patients with isolated mitral regurgitation (MR).   Methods:  Transthoracic echo examinations were retrieved for patients with mild to severe MR from 2010-2012. After excluding patients with previous CABG, other valvular lesions, valve replacement, congenital heart disease, or incomplete echos, conventional and strain echocardiographic parameters were obtained in 80 patients.   Results:  Over mean follow up of 1020 ± 617 days, a total of 33 (41%) patients died. Patients had a mean age of 70 ± 15 years. Thirty (38%) had severe MR. Patients who died had significantly worse global longitudinal strain (GLS) (12.6±3.5% versus 15.8±4.2%; p   Conclusion:  Left ventricular GLS is an independent predictor of all-cause mortality in patients with isolated mitral regurgitation. This can help further risk stratify patients in addition to conventional 2D-echocargraphy parameters such as LVEF and LVESD.
Residual Inflammatory Risk on Treatment With PCSK9 Inhibition and Statin Therapy
Authors: Aruna D. Pradhan, Aaron W. Aday, Lynda M. Rose, Paul M Ridker
Journal: Circulation (2018)

The combination of statin therapy and PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition markedly lowers low-density lipoprotein cholesterol (LDL-C) and reduces cardiovascular event rates. Whether residual inflammatory risk as measured by on-treatment high sensitivity C-reactive protein (hsCRP) remains an important clinical issue in such patients is uncertain.We evaluated residual inflammatory risk among 9738 patients participating in the SPIRE-1 and SPIRE-2 cardiovascular outcomes trials (Studies of PCSK9 Inhibition and the Reduction in Vascular Events), who were receiving both statin therapy and bococizumab, according to on-treatment levels of hsCRP (hsCRPOT) and LDL-COT measured 14 weeks after drug initiation. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death.At 14 weeks, the mean percentage change in LDL-C among statin-treated patients who additionally received bococizumab was -60.5% (95% confidence interval [CI], -61.2 to -59.8; P<0.001; median change, -65.4%) as compared to 6.6% (95% CI, -1.0 to 14.1; P=0.09; median change, 0.0%) for hsCRP. Incidence rates for future cardiovascular events for patients treated with both statin therapy and bococizumab according to hsCRPOT <1, 1 to 3, and >3 mg/L were 1.96, 2.50, and 3.59 events per 100 person-years, respectively, corresponding to multivariable adjusted hazard ratios of 1.0, 1.16 (95% CI, 0.81-1.66), and 1.62 (95% CI, 1.14-2.30) (P-trend=0.001) after adjustment for traditional cardiovascular risk factors and LDL-COT. Comparable adjusted hazard ratios for LDL-COT (<30, 30-50, >50 mg/dL) were 1.0, 0.87, and 1.21, respectively (P-trend=0.16). Relative risk reductions with bococizumab were similar across hsCRPOT groups (P-interaction=0.87).In this post hoc analysis of the SPIRE trials of bococizumab in a stable outpatient population, evidence of residual inflammatory risk persisted among patients treated with both statin therapy and proprotein convertase subtilisin-kexin type 9 inhibition.URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01975376, NCT01975389.
ARO-AAT, a subcutaneous RNAi-based therapeutic for alpha-1 antitrypsin-related liver disease, demonstrates liver exposure-response and efficacy in preclinical studies
Authors: C. Wooddell, K. Blomenkamp, H. Chen, J. Griffin, R. Zhu, Q. Chu, H. Hamilton, J. Hegge, D. Christianson, Z. Li, J. Teckman, B. Given
Journal: Journal of Hepatology (2018)
Platinum-Based Nanovectors Engineered with Immuno-Modulating Adjuvant for Inhibiting Tumor growth and Promoting Immunity
Authors: Lisha Liu, Qinjun Chen, Chunhui Ruan, Xinli Chen, Yu Zhang, Xi He, Yujie Zhang, Yifei Lu, Qin Guo, Tao Sun, Hao Wang, Chen Jiang
Journal: Theranostics (2018)

Although there is ample evidence that the chemotherapeutic drugs trigger an immune response, the efficient tumor rejection or regression is not guaranteed probably due to the massive immunosuppression within the tumor microenvironment. Thus, a rational delivery platform that overcomes immunosuppression is needed to maximally achieve both cytotoxic and immune-modulatory functions of chemotherapeutics. Accumulating evidence suggests that platinum-based drugs might be suitable for this application. Methods: The dendrigraft polylysine (DGL) with its uniform size and multifunctional groups was employed as the polymeric core and conjugated with platinum-based compounds as therapeutics and WKYMVm peptide (Wpep) as a targeting ligand to construct the novel delivery platform Wpep-DGL/Pt. A series of in vitro and in vivo analyses, including physical and chemical characterizations, targeting property, biosafety, and antitumor efficacy of Wpep-DGL/Pt were systematically carried out. Results: Wpep-DGL/Pt showed potent antitumor efficacy in MDA-MB-231 cells tumor-bearing nude mice with a deficient immune system, demonstrating targeted delivery of chemotherapeutics and the resultant cytotoxicity. Furthermore, in immunocompetent mice bearing 4T1 cells tumors, Wpep-DGL/Pt activated immune cells and induced cell death proving their dual function of chemotherapeutic and immunomodulatory efficacy. Conclusion: This work represents a novel approach for cancer immunotherapy by integrating nanotechnology and platinum-based therapeutics which not only efficiently exerts the chemotherapeutic cytotoxic effect on tumor cell but also restores immune response of immunological cells within the tumor microenvironment.
Combination of an FXR agonist and an ACC inhibitor increases anti-fibrotic efficacy in rodent models of NASH
Authors: J. Bates, D. Hollenback, A. Zagorska, G. Budas, J. Liles, H. Liu, K. Liu, S. Kusam, R. Brockett, D. Newstrom, I. Mikaelian, T. Wang, A. Ray, D. Breckenridge
Journal: Journal of Hepatology (2018)
Oxidatively Modified Protein‐Disulfide Isomerase–Associated 3 Promotes Dyskerin Pseudouridine Synthase 1–Mediated Malignancy and Survival of Hepatocellular Carcinoma Cells
Authors: Eunkyong Ko, Jong‐Seo Kim, Soomi Ju, Hyun‐Wook Seo, Yeonji Chang, Jung‐Ah Kang, Sung‐Gyoo Park, Guhung Jung
Journal: Hepatology (2018)

Dyskerin pseudouridine synthase 1 ( DKC1 ) is a conserved gene encoding the RNA‐binding protein dyskerin, which is an essential component of the telomerase holoenzyme. DKC1 up‐regulation is frequently observed in many different human cancers including hepatocellular carcinoma (HCC); however, its regulatory mechanisms remain unclear. Thus, we investigated the regulatory mechanism of DKC1 in HCC progression. We found that protein‐disulfide isomerase‐associated 3 (PDIA3) interacted with the DKC1 regulatory DNA in HCC cells but not in HCC cells with elevated reactive oxygen species (ROS) levels, using liquid chromatographic–tandem mass spectrometric analysis after isolating the DKC1 regulatory region binding proteins. PDIA3 repressed DKC1 expression in HCC cells by recognizing the G‐quadruplex DNA at the DKC1 location. However, oxidative modification of PDIA3 induced by ROS redistributed this protein into the cytosolic regions, which stimulated DKC1 expression. We also identified Met338 in PDIA3 as the oxidatively modified residue and validated the effect of oxidative modification using an ectopic expression system, a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR‐associated 9 knock‐in system, and a xenograft mouse model. We observed that oxidatively modified PDIA3 promoted DKC1‐mediated malignancy and survival of HCC cells in vitro and in vivo . HCC tissues showed a positive association with ROS, cytoplasmic PDIA3, and nuclear DKC1 levels. HCC patients with high PDIA3 protein and DKC1 mRNA levels also displayed reduced recurrence‐free survival rates. Cumulatively, the results showed that cytoplasmic PDIA3 activity could be essential in raising DKC1 expression in HCC progression and predicting poor prognoses in HCC patients. Conclusion: Our study indicates that the elevated ROS levels in HCC modulate cytoplasmic PDIA3 levels, resulting in HCC cell survival through DKC1 up‐regulation.
Sustained efficacy of adjuvant immunotherapy with cytokineinduced killer cells for hepatocellular carcinoma: an extended 5-year follow-up
Authors: J.-H. Lee, J.H. Lee, Y.-S. Lim, J.E. Yeon, T.-J. Song, S. Yu, K.M. Kim, Y.J. Kim, J.W. Lee, J.-H. Yoon
Journal: Journal of Hepatology (2018)