tbuckley/cabot-search huggingface dataset:
β‐Catenin regulation of farnesoid X receptor signaling and bile acid metabolism during murine cholestasis
Authors: Michael D. Thompson, Akshata Moghe, Pamela Cornuet, Rebecca Marino, Jianmin Tian, Pengcheng Wang, Xiaochao Ma, Marc Abrams, Joseph Locker, Satdarshan P. Monga, Kari Nejak‐Bowen
Journal: Hepatology (2017)

Cholestatic liver diseases result from impaired bile flow and are characterized by inflammation, atypical ductular proliferation, and fibrosis. The Wnt/β‐catenin pathway plays a role in bile duct development, yet its role in cholestatic injury remains indeterminate. Liver‐specific β‐catenin knockout mice and wild‐type littermates were subjected to cholestatic injury through bile duct ligation or short‐term exposure to 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine diet. Intriguingly, knockout mice exhibit a dramatic protection from liver injury, fibrosis, and atypical ductular proliferation, which coincides with significantly decreased total hepatic bile acids (BAs). This led to the discovery of a role for β‐catenin in regulating BA synthesis and transport through regulation of farnesoid X receptor (FXR) activation. We show that β‐catenin functions as both an inhibitor of nuclear translocation and a nuclear corepressor through formation of a physical complex with FXR. Loss of β‐catenin expedited FXR nuclear localization and FXR/retinoic X receptor alpha association, culminating in small heterodimer protein promoter occupancy and activation in response to BA or FXR agonist. Conversely, accumulation of β‐catenin sequesters FXR, thus inhibiting its activation. Finally, exogenous suppression of β‐catenin expression during cholestatic injury reduces β‐catenin/FXR complex activation of FXR to decrease total BA and alleviate hepatic injury. Conclusion: We have identified an FXR/β‐catenin interaction whose modulation through β‐catenin suppression promotes FXR activation and decreases hepatic BAs, which may provide unique therapeutic opportunities in cholestatic liver diseases. (H epatology 2018;67:955–971)
What Should Patients Be Told About Noninferiority Studies?
Authors: Jerry Menikoff
Journal: JAMA Internal Medicine (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Advances in Monte Carlo Simulation for Light Propagation in Tissue
Authors: Vijitha Periyasamy, Manojit Pramanik
Journal: IEEE Reviews in Biomedical Engineering (2017)

Monte Carlo (MC) simulation for light propagation in tissue is the gold standard for studying the light propagation in biological tissue and has been used for years. Interaction of photons with a medium is simulated based on its optical properties. New simulation geometries, tissue-light interaction methods, and recording techniques recently have been designed. Applications, such as whole mouse body simulations for fluorescence imaging, eye modeling for blood vessel imaging, skin modeling for terahertz imaging, and human head modeling for sinus imaging, have emerged. Here, we review the technical advances and recent applications of MC simulation.
Codon-Resolution Analysis Reveals a Direct and Context-Dependent Impact of Individual Synonymous Mutations on mRNA Level
Authors: Siyu Chen, Ke Li, Wenqing Cao, Jia Wang, Tong Zhao, Qing Huan, Yu-Fei Yang, Shaohuan Wu, Wenfeng Qian
Journal: Molecular Biology and Evolution (2017)

Codon usage bias (CUB) refers to the observation that synonymous codons are not used equally frequently in a genome. CUB is stronger in more highly expressed genes, a phenomenon commonly explained by stronger natural selection on translational accuracy and/or efficiency among these genes. Nevertheless, this phenomenon could also occur if CUB regulates gene expression at the mRNA level, a hypothesis that has not been tested until recently. Here, we attempt to quantify the impact of synonymous mutations on mRNA level in yeast using 3,556 synonymous variants of a heterologous gene encoding green fluorescent protein (GFP) and 523 synonymous variants of an endogenous gene TDH3. We found that mRNA level was positively correlated with CUB among these synonymous variants, demonstrating a direct role of CUB in regulating transcript concentration, likely via regulating mRNA degradation rate, as our additional experiments suggested. More importantly, we quantified the effects of individual synonymous mutations on mRNA level and found them dependent on 1) CUB and 2) mRNA secondary structure, both in proximal sequence contexts. Our study reveals the pleiotropic effects of synonymous codon usage and provides an additional explanation for the well-known correlation between CUB and gene expression level.
CTGFの局所サイレンシングのためのナノ層化siRNAデリバリープラットフォームは第3度熱傷における皮膚瘢痕収縮を減少させる【Powered by NICT】
Authors: A Castleberry Steven, Golberg Alexander, Sharkh Malak Abu, Khan Saiqa, D Almquist Benjamin, G Austen William, L Yarmush Martin, T Hammond Paula
Journal: Biomaterials (2016)
Outcomes of Adult Patients with Relapsed/Refractory Burkitt or Burkitt-like Leukemia/Lymphoma
Authors: Nicholas J. Short, Elias J. Jabbour, Heidi Ko, Farhad Ravandi, Deborah A Thomas, Guillermo Garcia-Manero, Rita B. Khouri, Jorge E. Cortes, William G. Wierda, Srdan Verstovsek, Zeev Estrov, Alessandra Ferrajoli, Philip A Thompson, Sherry Pierce, Hagop M. Kantarjian
Journal: Blood (2016)
The potential role and rationale for treatment of heart failure with sodium–glucose co‐transporter 2 inhibitors
Authors: Javed Butler, Carine E. Hamo, Gerasimos Filippatos, Stuart J. Pocock, Richard A. Bernstein, Martina Brueckmann, Alfred K. Cheung, Jyothis T. George, Jennifer B. Green, James L. Januzzi, Sanjay Kaul, Carolyn S.P. Lam, Gregory Y.H. Lip, Nikolaus Marx, Peter A. McCullough, Cyrus R. Mehta, Piotr Ponikowski, Julio Rosenstock, Naveed Sattar, Afshin Salsali, Benjamin M. Scirica, Sanjiv J. Shah, Hiroyuki Tsutsui, Subodh Verma, Christoph Wanner, Hans‐Juergan Woerle, Faiez Zannad, Stefan D. Anker
Journal: European Journal of Heart Failure (2017)
Synergistic antitumor effects of combination treatment with metronomic doxorubicin and VEGF-targeting RNAi nanoparticles
Authors: Gijung Kwak, Sung Duk Jo, Dongkyu Kim, Hyosuk Kim, Myung Goo Kim, Kwangmeyung Kim, Ick Chan Kwon, Sun Hwa Kim
Journal: Journal of Controlled Release (2017)
Long noncoding RNA ZEB1-AS1 epigenetically regulates the expressions of ZEB1 and downstream molecules in prostate cancer
Authors: Wenjing Su, Miao Xu, Xueqin Chen, Ni Chen, Jing Gong, Ling Nie, Ling Li, Xinglan Li, Mengni Zhang, Qiao Zhou
Journal: Molecular Cancer (2017)

Emerging studies show that long noncoding RNAs (lncRNAs) play important roles in carcinogenesis and cancer progression. The lncRNA ZEB1 antisense 1 (ZEB1-AS1) derives from the promoter region of ZEB1 and we still know little about its expressions, roles and mechanisms.RACE was used to obtain the sequence of ZEB1-AS1. RNA interference was used to decrease ZEB1-AS1 expression. Adenovirus expression vector was used to increase ZEB1-AS1 expression. CHIP and RIP were used to detect the epigenetic mechanisms by which ZEB1-AS1 regulated ZEB1. CCK8 assay, wound healing assay and transwell assay were used to measure proliferation and migration of prostate cancer cells.In this study, in prostate cancer cells, we found that RNAi-mediated downregulation of ZEB1-AS1 induced significant ZEB1 inhibition while artificial overexpression of ZEB1-AS1 rescued ZEB1 expression, which means that ZEB1-AS1 promotes ZEB1 expression. Also, ZEB1-AS1 indirectly inhibited miR200c, the well-known target of ZEB1, and upregulated miR200c's target BMI1. Mechanistically, ZEB1-AS1 bound and recruited histone methyltransferase MLL1 to the promoter region of ZEB1, induced H3K4me3 modification therein, and activated ZEB1 transcription. Biologically, ZEB1-AS1 promoted proliferation and migration of prostate cancer cells.Collectively, ZEB1-AS1 functions as an oncogene in prostate cancer via epigenetically activating ZEB1 and indirectly regulating downstream molecules of ZEB1.
Sex-specific transcriptional signatures in human depression
Authors: Benoit Labonté, Olivia Engmann, Immanuel Purushothaman, Caroline Menard, Junshi Wang, Chunfeng Tan, Joseph R Scarpa, Gregory Moy, Yong-Hwee E Loh, Michael Cahill, Zachary S Lorsch, Peter J Hamilton, Erin S Calipari, Georgia E Hodes, Orna Issler, Hope Kronman, Madeline Pfau, Aleksandar L J Obradovic, Yan Dong, Rachael L Neve, Scott Russo, Andrew Kasarskis, Carol Tamminga, Naguib Mechawar, Gustavo Turecki, Bin Zhang, Li Shen, Eric J Nestler
Journal: Nature Medicine (2017)
Alternative splicing discriminates molecular subtypes and has prognostic impact in diffuse large B-cell lymphoma
Authors: S-K Leivonen, M Taskinen, A Cervera, M-L Karjalainen-Lindsberg, J Delabie, H Holte, R Lehtonen, S Hautaniemi, S Leppä
Journal: Blood Cancer Journal (2017)

Abstract Effect of alternative splicing (AS) on diffuse large B-cell lymphoma (DLBCL) pathogenesis and survival has not been systematically addressed. Here, we compared differentially expressed genes and exons in association with survival after chemoimmunotherapy, and between germinal center B-cell like (GCB) and activated B-cell like (ABC) DLBCLs. Genome-wide exon array-based screen was performed from samples of 38 clinically high-risk patients who were treated in a Nordic phase II study with dose-dense chemoimmunotherapy and central nervous system prophylaxis. The exon expression profile separated the patients according to molecular subgroups and survival better than the gene expression profile. Pathway analyses revealed enrichment of AS genes in inflammation and adhesion-related processes, and in signal transduction, such as phosphatidylinositol signaling system and adenosine triphosphate binding cassette transporters. Altogether, 49% of AS-related exons were protein coding, and domain prediction showed 28% of such exons to include a functional domain, such as transmembrane helix domain or phosphorylation sites. Validation in an independent cohort of 92 DLBCL samples subjected to RNA-sequencing confirmed differential exon usage of selected genes and association of AS with molecular subtypes and survival. The results indicate that AS events are able to discriminate GCB and ABC DLBCLs and have prognostic impact in DLBCL.
Aberrant regulation of histone deacetlyase 2 suppresses systemic cell-cycle regulatory circuit in human hepatocellular cacrcinoma
Authors: Ji Heon Noh, Jung Woo Eun, So Yeon Ryu, Jung Kyu Kim, Kwang Hwa Jung, Sug Hyung Lee, Won Sang Park, Nam Jin Yoo, Jung Young Lee, Suk Woo Nam
Journal: Cancer Research (2007)

4563    The recruitment of histone acetyltransferases and histone deacetylases (HDACs) is considered as a key element in the dynamic regulation of many genes playing important roles in cellular proliferation and differentiation during normal development and carcinogenesis. Recent studies suggested that inappropriate activation of Wnt-signaling pathway induces HDAC2 expression depending on c-Myc, and the consequent activation of HDAC2 is required for the acquisition of neoplastic property in colorectal cancer. In addition, accumulating evidences reported that HDAC2 over-expression was found in many different types of cancers. We also reported large-scale dominant expression profiles relate to multi-steps hepatocarcinogenesis, and were noted continuous increasing expression pattern of HDAC2 from hepatic dysplasia to overt cancer. In contrast with colon cancer, we observed that silencing of    s    -catenin, c-myc and cyclin D1    genes by using RNA interference did not stimulate transcriptional activation of  HDAC2  genes indicating that aberrant regulation of HDAC2 is independent to Wnt-pathway in HCC. However, we found that silencing of  HDAC2  gene arrested cell-growth, and enhanced cellular apoptosis in Hep3b liver cancer cells. To identify down-stream effectors of HDAC2 in cell-cycle regulation, we analyzed dominant expression profiles of 3,084 genetic elements in our previous report and depicted tentative cell-cycle circuit regulated by HDAC2 in liver cancer cells. We finally validated this schematic by which confirmation of regulatory elements of cell-cycle in the condition of targeted-disruption of HDAC2 on Hep3b cells. In conclusion, we found that the aberrant expression of HDAC2 suppressed negative cell cycle regulators  leading to the transcriptional activation of cyclin dependent kinases, and this, in turn, activated down stream of E2F/DP-1 target genes. This suggests that aberrant regulation of HDAC2 plays a pivotal role in the liver cancer progression through the systemic activation of cell-cycle circuit, and these findings provide a particularly relevant potential target in liver cancer.
Plausibility criteria for putative pathophysiological mechanisms in functional gastrointestinal disorders: a consensus of experts
Authors: Jan Tack, Maura Corsetti, Michael Camilleri, Eamonn MM Quigley, Magnus Simren, Hidekazu Suzuki, Nicholas J Talley, Hans Tornblom, Lukas Van Oudenhove
Journal: Gut (2017)

The functional gastrointestinal disorders (FGIDs) are extremely common conditions associated with a considerable personal, social and health economic burden. Managing FGIDs in clinical practice is challenging because of the uncertainty of symptom-based diagnosis, the high frequency of overlap between these conditions and the limited efficacy of available therapies. It has often been argued that successful drug development and management of FGIDs requires knowledge of the underlying pathophysiology. Numerous and highly variable candidate pathophysiological mechanisms have been implicated in the generation of FGID symptoms, but there is no current consensus on how to best define the relevance of these disturbances.A group of international experts on FGIDs developed plausibility criteria that should be fulfilled by relevant pathophysiological mechanisms in FGIDs.Five criteria are proposed: (1) the presence of the abnormality in a subset of patients, (2) temporal association between proposed mechanism and symptom(s), (3) correlation between the level of impairment of the mechanism and symptom(s), (4) induction of the symptom(s) by provoking the pathophysiological abnormality in healthy subjects and (5) treatment response by a therapy specifically correcting the underlying disorder or congruent natural history of symptoms and dysfunction in the absence of specific therapy. Based on strength of evidence for these five criteria according to the Grading of Recommendations Assessment, Development and Evaluation system, a plausibility score can be calculated for each mechanism.Evaluation of the strength of evidence for candidate pathophysiological abnormalities fulfilling these five plausibility criteria will help to identify the most relevant mechanisms to target for novel diagnostic approaches and for the development of new therapies.
MRE11 Promotes Tumorigenesis by Facilitating Resistance to Oncogene-Induced Replication Stress
Authors: Elizabeth Spehalski, Kayla M. Capper, Cheryl J. Smith, Mary J. Morgan, Maria Dinkelmann, Jeffrey Buis, JoAnn M. Sekiguchi, David O. Ferguson
Journal: Cancer Research (2017)

Abstract Hypomorphic mutations in the genes encoding the MRE11/RAD50/NBS1 (MRN) DNA repair complex lead to cancer-prone syndromes. MRN binds DNA double-strand breaks, where it functions in repair and triggers cell-cycle checkpoints via activation of the ataxia-telangiectasia mutated kinase. To gain understanding of MRN in cancer, we engineered mice with B lymphocytes lacking MRN, or harboring MRN in which MRE11 lacks nuclease activities. Both forms of MRN deficiency led to hallmarks of cancer, including oncogenic translocations involving c-Myc and the immunoglobulin locus. These preneoplastic B lymphocytes did not progress to detectable B lineage lymphoma, even in the absence of p53. Moreover, Mre11 deficiencies prevented tumorigenesis in a mouse model strongly predisposed to spontaneous B-cell lymphomas. Our findings indicate that MRN cannot be considered a standard tumor suppressor and instead imply that nuclease activities of MRE11 are required for oncogenesis. Inhibition of MRE11 nuclease activity increased DNA damage and selectively induced apoptosis in cells overexpressing oncogenes, suggesting MRE11 serves an important role in countering oncogene-induced replication stress. Thus, MRE11 may offer a target for cancer therapeutic development. More broadly, our work supports the idea that subtle enhancements of endogenous genome instability can exceed the tolerance of cancer cells and be exploited for therapeutic ends. Cancer Res; 77(19); 5327–38. ©2017 AACR.
Moving Towards Precision Urologic Oncology: Targeting Enzalutamide-resistant Prostate Cancer and Mutated Forms of the Androgen Receptor Using the Novel Inhibitor Darolutamide (ODM-201)
Authors: Hendrik Borgmann, Nada Lallous, Deniz Ozistanbullu, Eliana Beraldi, Naman Paul, Kush Dalal, Ladan Fazli, Axel Haferkamp, Pascale Lejeune, Artem Cherkasov, Martin E. Gleave
Journal: European Urology (2017)
Abstract 305: Nebivolol Confers Mitochondria-Targeted Cardioprotection in Isoproterenol-Induced Acute Stressor State
Authors: Sumeet S Vaikunth, Karl T Weber, Syamal K Bhattacharya
Journal: Circulation Research (2012)

Introduction: Isoproterenol-induced acute stressor state simulates injury from burns or trauma, and results in Ca 2+ overloading and oxidative stress in diverse tissues, including cardiac myocytes and their subsarcolemmal mitochondria (SSM), overwhelming endogenous Zn 2+ -based antioxidant defenses. We hypothesized that pretreatment with nebivolol (Nebi), having dual beta-1 antagonistic and novel beta-3 receptor agonistic properties, would prevent Ca 2+ overloading and oxidative stress and upregulate Zn 2+ -based antioxidant defenses, thus enhancing its overall cardioprotective potential in acute stressor state. Methods: Eight-week-old male Sprague-Dawley rats received a single subcutaneous dose of isoproterenol (1 mg/kg) and compared to those treated with Nebi (10 mg/kg by gavage) for 10 days prior to isoproterenol. SSM were harvested from cardiac tissue at sacrifice. Total Ca 2+ , Zn 2+ and 8-isoprostane levels in tissue, and mitochondrial permeability transition pore (mPTP) opening, free [Ca 2+ ] m and H 2 O 2 production in SSM were monitored. Untreated, age-/sex-matched rats served as controls; each group had six rats and data shown as mean±SEM. Results: Compared to controls, isoproterenol rats revealed: (1) Significantly (*p&lt;0.05) increased cardiac tissue Ca 2+ (8.2±0.8 vs. 13.7±1.0*, nEq/mg fat-free dry tissue (FFDT)), which was abrogated ( # p&lt;0.05) by Nebi (8.9±0.4 # ); (2) Reduced cardiac Zn 2+ (82.8±2.4 vs. 78.5±1.0*, ng/mg FFDT), but restored by Nebi (82.4±0.6 # ); (3) Two-fold rise in cardiac 8-isoprostane (111.4±13.7 vs. 232.1±17.2*, pmoles/mg protein), and negated by Nebi (122.3+14.5 # ); (4) Greater opening propensity for mPTP that diminished by Nebi; (5) Elevated [Ca 2+ ] m (88.8±2.5 vs. 161.5±1.0*, nM), but normalized by Nebi (93.3±2.7 # ); and (6) Increased H 2 O 2 production by SSM (97.4±5.3 vs. 142.8±7.0*, pmoles/mg protein/min), and nullified by Nebi (106.8±9.0 # ). Conclusions : Cardioprotection conferred by Nebi, a unique beta-blocker, prevented Ca 2+ overloading and oxidative stress in cardiac tissue and SSM, while simultaneously augmenting antioxidant capacity and promoting mPTP stability. Therapeutic potential of Nebi in patients with acute stressor states remains a provocative possibility that deserves to be explored.
Association of Lithium in Drinking Water With the Incidence of Dementia
Authors: Lars Vedel Kessing, Thomas Alexander Gerds, Nikoline Nygård Knudsen, Lisbeth Flindt Jørgensen, Søren Munch Kristiansen, Denitza Voutchkova, Vibeke Ernstsen, Jörg Schullehner, Birgitte Hansen, Per Kragh Andersen, Annette Kjær Ersbøll
Journal: JAMA Psychiatry (2017)

<h3>Importance</h3> Results from animal and human studies suggest that lithium in therapeutic doses may improve learning and memory and modify the risk of developing dementia. Additional preliminary studies suggest that subtherapeutic levels, including microlevels of lithium, may influence human cognition. <h3>Objective</h3> To investigate whether the incidence of dementia in the general population covaries with long-term exposure to microlevels of lithium in drinking water. <h3>Design, Setting, and Participants</h3> This Danish nationwide, population-based, nested case-control study examined longitudinal, individual geographic data on municipality of residence and data from drinking water measurements combined with time-specific data from all patients aged 50 to 90 years with a hospital contact with a diagnosis of dementia from January 1, 1970, through December 31, 2013, and 10 age- and sex-matched control individuals from the Danish population. The mean lithium exposure in drinking water since 1986 was estimated for all study individuals. Data analysis was performed from January 1, 1995, through December 31, 2013. <h3>Main Outcomes and Measures</h3> A diagnosis of dementia in a hospital inpatient or outpatient contact. Diagnoses of Alzheimer disease and vascular dementia were secondary outcome measures. In primary analyses, distribution of lithium exposure was compared between patients with dementia and controls. <h3>Results</h3> A total of 73 731 patients with dementia and 733 653 controls (median age, 80.3 years; interquartile range, 74.9-84.6 years; 44 760 female [60.7%] and 28 971 male [39.3%]) were included in the study. Lithium exposure was statistically significantly different between patients with a diagnosis of dementia (median, 11.5 µg/L; interquartile range, 6.5-14.9 µg/L) and controls (median, 12.2 µg/L; interquartile range, 7.3-16.0 µg/L;<i>P</i> &lt; .001). A nonlinear association was observed. Compared with individuals exposed to 2.0 to 5.0 µg/L, the incidence rate ratio (IRR) of dementia was decreased in those exposed to more than 15.0 µg/L (IRR, 0.83; 95% CI, 0.81-0.85;<i>P</i> &lt; .001) and 10.1 to 15.0 µg/L (IRR, 0.98; 95% CI, 0.96-1.01;<i>P</i> = .17) and increased with 5.1 to 10.0 µg/L (IRR, 1.22; 95% CI, 1.19-1.25;<i>P</i> &lt; .001). Similar patterns were found with Alzheimer disease and vascular dementia as outcomes. <h3>Conclusions and Relevance</h3> Long-term increased lithium exposure in drinking water may be associated with a lower incidence of dementia in a nonlinear way; however, confounding from other factors associated with municipality of residence cannot be excluded.
高齢マウスの脳における過よう素酸‐Schiff試薬か粒エピトープを含むアミロイド凝集体変性構造へのから【Powered by NICT】
Authors: Manich Gemma, Cabezon Itsaso, Auge Elisabet, Pelegri Carme, Vilaplana Jordi
Journal: Ageing Research Reviews (2016)