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https://www.readbyqxmd.com/read/28635286/utilization-of-an-active-site-mutant-receptor-for-the-identification-of-potent-and-selective-atypical-5-ht2c-receptor-agonists
#1
Joseph Carpenter, Ying Wang, Gang Wu, Jianxin Feng, Xiang-Yang Ye, Christian L Morales, Matthias Broekema, Karen A Rossi, Keith J Miller, Brian J Murphy, Ginger Yingzhe Wu, Sarah E Malmstrom, Anthony V Azzara, Philip M Sher, John M Fevig, Andrew Alt, Robert L Bertekap, Mary Jane Cullen, Timothy M Harper, Kimberly A Foster, Chiuwa Emily Luk, Qian Xiang, Mary F Grubb, Jeffrey A Robl, Dean A Wacker
Agonism of the 5-HT2C receptor represents one of the most well-studied and clinically-proven mechanisms for pharmacological weight reduction. Selectivity over the closely related 5-HT2A and 5-HT2B receptors is critical as their activation has been shown to lead to undesirable side-effects and major safety concerns. In this communication, we report the development of a new screening paradigm which utilizes an active site mutant D134A 5-HT2C receptor to identify atypical agonist structures. We additionally report the discovery and optimization of a novel class of non-basic heterocyclic amide agonists of 5-HT2C...
June 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28608424/evaluation-of-the-8th-edition-american-joint-commission-on-cancer-ajcc-staging-system-for-patients-with-intrahepatic-cholangiocarcinoma-a-surveillance-epidemiology-and-end-results-seer-analysis
#2
Yuhree Kim, Dimitrios P Moris, Xu-Feng Zhang, Fabio Bagante, Gaya Spolverato, Carl Schmidt, Mary Dilhoff, Timothy M Pawlik
BACKGROUND: The objective of this study was to assess the prognostic performance of American Joint Committee on Cancer (AJCC) 8th edition in patients with intrahepatic cholangiocarcinoma (ICC) using a cancer registry. METHODS: The Surveillance, Epidemiology, and End Results (SEER) cancer registry was queried to identify 1008 patients who underwent surgical resection of ICC during 1998-2013. Kaplan-Meier method and Cox proportional hazards regression models were used to analyze long-term survival...
June 12, 2017: Journal of Surgical Oncology
https://www.readbyqxmd.com/read/28592627/cytokines-are-markers-of-the-clostridium-difficile-induced-inflammatory-response-and-predict-disease-severity
#3
Hua Yu, Kevin Chen, Ying Sun, Mihaela Carter, Kevin W Garey, Tor C Savidge, Sridevi Devaraj, Mary Elizabeth Tessier, Erik C von Rosenvinge, Ciaran P Kelly, Marcela F Pasetti, Hanping Feng
The host immune response affects pathogen virulence in Clostridium difficile infection (CDI). Thus, cytokine responses to CDI are likely associated with disease initiation and progression. Understanding the molecular drivers of inflammation and biochemical markers of disease severity are important for developing novel therapies and predicting the disease prognosis. In this study, we investigated cytokine production in patients with CDI and evaluated the potential of cytokines to serve as biomarkers for CDI and predictors of disease severity...
June 7, 2017: Clinical and Vaccine Immunology: CVI
https://www.readbyqxmd.com/read/28540841/lung-or-heart-lung-transplant-in-pulmonary-arterial-hypertension-what-is-the-impact-of-systemic-sclerosis
#4
Shruti K Gadre, Omar A Minai, Xiao-Feng Wang, Qi Zhang, Marie Budev, Adriano R Tonelli
OBJECTIVES: Little is known about recipient characteristics and outcomes of patients with pulmonary arterial hypertension undergoing lung transplant, particularly those with systemic sclerosis-associated disease. Here, we describe the characteristics and outcomes of patients with pulmonary arterial hypertension undergoing lung transplant, focusing on systemic sclerosis-associated disease. MATERIALS AND METHODS: This retrospective study included pulmonary arterial hypertension patients undergoing lung or heart-lung transplant between July 1992 and August 2013 at a single center...
May 22, 2017: Experimental and Clinical Transplantation
https://www.readbyqxmd.com/read/28533371/blue-fluorescent-amino-acid-for-biological-spectroscopy-and-microscopy
#5
Mary Rose Hilaire, Ismail A Ahmed, Chun-Wei Lin, Hyunil Jo, William F DeGrado, Feng Gai
Many fluorescent proteins are currently available for biological spectroscopy and imaging measurements, allowing a wide range of biochemical and biophysical processes and interactions to be studied at various length scales. However, in applications where a small fluorescence reporter is required or desirable, the choice of fluorophores is rather limited. As such, continued effort has been devoted to the development of amino acid-based fluorophores that do not require a specific environment and additional time to mature and have a large fluorescence quantum yield, long fluorescence lifetime, good photostability, and an emission spectrum in the visible region...
June 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28533151/low-rates-of-androgen-deprivation-therapy-use-with-salvage-radiation-therapy-in-patients-with-prostate-cancer-after-radical-prostatectomy
#6
David D Yang, Vinayak Muralidhar, Brandon A Mahal, Michelle D Nezolosky, Shelby A Labe, Marie E Vastola, Ninjin Boldbaatar, Martin T King, Neil E Martin, Peter F Orio, Tni K Choueiri, Quoc-Dien Trinh, Robert B Den, Daniel E Spratt, Karen E Hoffman, Felix Y Feng, Paul L Nguyen
OBJECTIVE: The RTOG 9601 and GETUG-AFU 16 randomized controlled trials demonstrated that the addition of androgen deprivation therapy (ADT) to salvage radiation therapy (SRT) improves progression-free and, for RTOG 9601, overall survival. We examined national trends in the use of ADT with SRT. MATERIALS AND METHODS: Of the 484,009 patients in the National Cancer Database from 2004 to 2012 with localized or locally advanced prostate cancer treated with radical prostatectomy (RP), 4,200 men received SRT (≥6mo after surgery)...
May 19, 2017: Urologic Oncology
https://www.readbyqxmd.com/read/28514685/virus-like-particles-identify-an-hiv-v1v2-apex-binding-neutralizing-antibody-that-lacks-a-protruding-loop
#7
Evan M Cale, Jason Gorman, Nathan A Radakovich, Ema T Crooks, Keiko Osawa, Tommy Tong, Jiaqi Li, Raju Nagarajan, Gabriel Ozorowski, David R Ambrozak, Mangai Asokan, Robert T Bailer, Anthony K Bennici, Xuejun Chen, Nicole A Doria-Rose, Aliaksandr Druz, Yu Feng, M Gordon Joyce, Mark K Louder, Sijy O'Dell, Courtney Oliver, Marie Pancera, Mark Connors, Thomas J Hope, Thomas B Kepler, Richard T Wyatt, Andrew B Ward, Ivelin S Georgiev, Peter D Kwong, John R Mascola, James M Binley
Most HIV-1-specific neutralizing antibodies isolated to date exhibit unusual characteristics that complicate their elicitation. Neutralizing antibodies that target the V1V2 apex of the HIV-1 envelope (Env) trimer feature unusually long protruding loops, which enable them to penetrate the HIV-1 glycan shield. As antibodies with loops of requisite length are created through uncommon recombination events, an alternative mode of apex binding has been sought. Here, we isolated a lineage of Env apex-directed neutralizing antibodies, N90-VRC38...
May 16, 2017: Immunity
https://www.readbyqxmd.com/read/28497786/tunable-and-low-loss-correlated-plasmons-in-mott-like-insulating-oxides
#8
Teguh Citra Asmara, Dongyang Wan, Yongliang Zhao, Muhammad Aziz Majidi, Christopher T Nelson, Mary C Scott, Yao Cai, Bixing Yan, Daniel Schmidt, Ming Yang, Tao Zhu, Paolo E Trevisanutto, Mallikarjuna R Motapothula, Yuan Ping Feng, Mark B H Breese, Matthew Sherburne, Mark Asta, Andrew Minor, T Venkatesan, Andrivo Rusydi
Plasmonics has attracted tremendous interests for its ability to confine light into subwavelength dimensions, creating novel devices with unprecedented functionalities. New plasmonic materials are actively being searched, especially those with tunable plasmons and low loss in the visible-ultraviolet range. Such plasmons commonly occur in metals, but many metals have high plasmonic loss in the optical range, a main issue in current plasmonic research. Here, we discover an anomalous form of tunable correlated plasmons in a Mott-like insulating oxide from the Sr1-xNb1-yO3+δ family...
May 12, 2017: Nature Communications
https://www.readbyqxmd.com/read/28490495/exclusion-of-alternative-exon-33-of-cav1-2-calcium-channels-in-heart-is-proarrhythmogenic
#9
Guang Li, Juejin Wang, Ping Liao, Peter Bartels, Hengyu Zhang, Dejie Yu, Mui Cheng Liang, Kian Keong Poh, Chye Yun Yu, Fengli Jiang, Tan Fong Yong, Yuk Peng Wong, Zhenyu Hu, Hua Huang, Guangqin Zhang, Mary Joyce Galupo, Jin-Song Bian, Sathivel Ponniah, Scott Lee Trasti, Kelvin See, Roger Foo, Uta C Hoppe, Stefan Herzig, Tuck Wah Soong
Alternative splicing changes the CaV1.2 calcium channel electrophysiological property, but the in vivo significance of such altered channel function is lacking. Structure-function studies of heterologously expressed CaV1.2 channels could not recapitulate channel function in the native milieu of the cardiomyocyte. To address this gap in knowledge, we investigated the role of alternative exon 33 of the CaV1.2 calcium channel in heart function. Exclusion of exon 33 in CaV1.2 channels has been reported to shift the activation potential -10...
May 23, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28469254/immune-checkpoint-protein-vista-critically-regulates-the-il-23-il-17-inflammatory-axis
#10
Na Li, Wenwen Xu, Ying Yuan, Natarajan Ayithan, Yasutomo Imai, Xuesong Wu, Halli Miller, Michael Olson, Yunfeng Feng, Yina H Huang, Mary Jo Turk, Samuel T Hwang, Subramaniam Malarkannan, Li Wang
V-domain Immunoglobulin Suppressor of T cell Activation (VISTA) is an inhibitory immune-checkpoint molecule that suppresses CD4(+) and CD8(+) T cell activation when expressed on antigen-presenting cells. Vsir (-/-) mice developed loss of peripheral tolerance and multi-organ chronic inflammatory phenotypes. Vsir (-/-) CD4(+) and CD8(+) T cells were hyper-responsive towards self- and foreign antigens. Whether or not VISTA regulates innate immunity is unknown. Using a murine model of psoriasis induced by TLR7 agonist imiquimod (IMQ), we show that VISTA deficiency exacerbated psoriasiform inflammation...
May 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28463152/national-trends-and-predictors-of-androgen-deprivation-therapy-use-in-low-risk-prostate-cancer
#11
David D Yang, Vinayak Muralidhar, Brandon A Mahal, Shelby A Labe, Michelle D Nezolosky, Marie E Vastola, Martin T King, Neil E Martin, Peter F Orio, Toni K Choueiri, Quoc-Dien Trinh, Daniel E Spratt, Karen E Hoffman, Felix Y Feng, Paul L Nguyen
PURPOSE: Androgen deprivation therapy (ADT) is not recommended for low-risk prostate cancer because of its lack of benefit and potential for harm. We evaluated the incidence and predictors of ADT use in low-risk disease. METHODS AND MATERIALS: Using the National Cancer Database, we identified 197,957 patients with low-risk prostate cancer (Gleason score of 3 + 3 = 6, prostate-specific antigen level <10 ng/mL, and cT1-T2a) diagnosed from 2004 to 2012 with complete demographic and treatment information...
June 1, 2017: International Journal of Radiation Oncology, Biology, Physics
https://www.readbyqxmd.com/read/28452714/the-mbd7-complex-promotes-expression-of-methylated-transgenes-without-significantly-altering-their-methylation-status
#12
Dongming Li, Ana Marie S Palanca, So Youn Won, Lei Gao, Ying Feng, Ajay A Vashisht, Li Liu, Yuanyuan Zhao, Xigang Liu, Xiuyun Wu, Shaofang Li, Brandon Le, Yun Ju Kim, Guodong Yang, Shengben Li, Jinyuan Liu, James A Wohlschlegel, Hongwei Guo, Beixin Mo, Xuemei Chen, Julie A Law
DNA methylation is associated with gene silencing in eukaryotic organisms. Although pathways controlling the establishment, maintenance and removal of DNA methylation are known, relatively little is understood about how DNA methylation influences gene expression. Here we identified a METHYL-CpG-BINDING DOMAIN 7 (MBD7) complex in Arabidopsis thaliana that suppresses the transcriptional silencing of two LUCIFERASE (LUC) reporters via a mechanism that is largely downstream of DNA methylation. Although mutations in components of the MBD7 complex resulted in modest increases in DNA methylation concomitant with decreased LUC expression, we found that these hyper-methylation and gene expression phenotypes can be genetically uncoupled...
April 28, 2017: ELife
https://www.readbyqxmd.com/read/28423296/eltrombopag-added-to-standard-immunosuppression-for-aplastic-anemia
#13
Danielle M Townsley, Phillip Scheinberg, Thomas Winkler, Ronan Desmond, Bogdan Dumitriu, Olga Rios, Barbara Weinstein, Janet Valdez, Jennifer Lotter, Xingmin Feng, Marie Desierto, Harshraj Leuva, Margaret Bevans, Colin Wu, Andre Larochelle, Katherine R Calvo, Cynthia E Dunbar, Neal S Young
BACKGROUND: Acquired aplastic anemia results from immune-mediated destruction of bone marrow. Immunosuppressive therapies are effective, but reduced numbers of residual stem cells may limit their efficacy. In patients with aplastic anemia that was refractory to immunosuppression, eltrombopag, a synthetic thrombopoietin-receptor agonist, led to clinically significant increases in blood counts in almost half the patients. We combined standard immunosuppressive therapy with eltrombopag in previously untreated patients with severe aplastic anemia...
April 20, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28414301/striatopallidal-dysfunction-underlies-repetitive-behavior-in-shank3-deficient-model-of-autism
#14
Wenting Wang, Chenchen Li, Qian Chen, Marie-Sophie van der Goes, James Hawrot, Annie Y Yao, Xian Gao, Congyi Lu, Ying Zang, Qiangge Zhang, Katherine Lyman, Dongqing Wang, Baolin Guo, Shengxi Wu, Charles R Gerfen, Zhanyan Fu, Guoping Feng
The postsynaptic scaffolding protein SH3 and multiple ankyrin repeat domains 3 (SHANK3) is critical for the development and function of glutamatergic synapses. Disruption of the SHANK3-encoding gene has been strongly implicated as a monogenic cause of autism, and Shank3 mutant mice show repetitive grooming and social interaction deficits. Although basal ganglia dysfunction has been proposed to underlie repetitive behaviors, few studies have provided direct evidence to support this notion and the exact cellular mechanisms remain largely unknown...
May 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28403174/exercise-in-vivo-marks-human-myotubes-in-vitro-training-induced-increase-in-lipid-metabolism
#15
Jenny Lund, Arild C Rustan, Nils G Løvsletten, Jonathan M Mudry, Torgrim M Langleite, Yuan Z Feng, Camilla Stensrud, Mari G Brubak, Christian A Drevon, Kåre I Birkeland, Kristoffer J Kolnes, Egil I Johansen, Daniel S Tangen, Hans K Stadheim, Hanne L Gulseth, Anna Krook, Eili T Kase, Jørgen Jensen, G Hege Thoresen
BACKGROUND AND AIMS: Physical activity has preventive as well as therapeutic benefits for overweight subjects. In this study we aimed to examine effects of in vivo exercise on in vitro metabolic adaptations by studying energy metabolism in cultured myotubes isolated from biopsies taken before and after 12 weeks of extensive endurance and strength training, from healthy sedentary normal weight and overweight men. METHODS: Healthy sedentary men, aged 40-62 years, with normal weight (body mass index (BMI) < 25 kg/m2) or overweight (BMI ≥ 25 kg/m2) were included...
2017: PloS One
https://www.readbyqxmd.com/read/28399408/eradication-of-tumors-through-simultaneous-ablation-of-cd276-b7-h3-positive-tumor-cells-and-tumor-vasculature
#16
Steven Seaman, Zhongyu Zhu, Saurabh Saha, Xiaoyan M Zhang, Mi Young Yang, Mary Beth Hilton, Karen Morris, Christopher Szot, Holly Morris, Deborah A Swing, Lino Tessarollo, Sean W Smith, Sylvia Degrado, Dmitry Borkin, Nareshkumar Jain, Julia Scheiermann, Yang Feng, Yanping Wang, Jinyu Li, Dean Welsch, Gary DeCrescenzo, Amit Chaudhary, Enrique Zudaire, Kimberly D Klarmann, Jonathan R Keller, Dimiter S Dimitrov, Brad St Croix
Targeting the tumor vasculature with antibody-drug conjugates (ADCs) is a promising anti-cancer strategy that in order to be realized must overcome several obstacles, including identification of suitable targets and optimal warheads. Here, we demonstrate that the cell-surface protein CD276/B7-H3 is broadly overexpressed by multiple tumor types on both cancer cells and tumor-infiltrating blood vessels, making it a potentially ideal dual-compartment therapeutic target. In preclinical studies CD276 ADCs armed with a conventional MMAE warhead destroyed CD276-positive cancer cells, but were ineffective against tumor vasculature...
April 10, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28384226/inhibition-of-prenylated-kras-in-a-lipid-environment
#17
Johanna M Jansen, Charles Wartchow, Wolfgang Jahnke, Susan Fong, Tiffany Tsang, Keith Pfister, Tatiana Zavorotinskaya, Dirksen Bussiere, Jan Marie Cheng, Kenneth Crawford, Yumin Dai, Jeffrey Dove, Eric Fang, Yun Feng, Jean-Michel Florent, John Fuller, Alvar D Gossert, Mohammad Hekmat-Nejad, Chrystèle Henry, Julia Klopp, William P Lenahan, Andreas Lingel, Sylvia Ma, Arndt Meyer, Yuji Mishina, Jamie Narberes, Gwynn Pardee, Savithri Ramurthy, Sebastien Rieffel, Darrin Stuart, Sharadha Subramanian, Laura Tandeske, Stephania Widger, Armin Widmer, Aurelie Winterhalter, Isabel Zaror, Stephen Hardy
RAS mutations lead to a constitutively active oncogenic protein that signals through multiple effector pathways. In this chemical biology study, we describe a novel coupled biochemical assay that measures activation of the effector BRAF by prenylated KRASG12V in a lipid-dependent manner. Using this assay, we discovered compounds that block biochemical and cellular functions of KRASG12V with low single-digit micromolar potency. We characterized the structural basis for inhibition using NMR methods and showed that the compounds stabilized the inactive conformation of KRASG12V...
2017: PloS One
https://www.readbyqxmd.com/read/28367502/an-overdetermined-system-of-transform-equations-in-support-of-robust-dce-mri-registration-with-outlier-rejection
#18
Adam Johansson, James Balter, Mary Feng, Yue Cao
Quantitative hepatic perfusion parameters derived by fitting dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) of liver to a pharmacokinetic model are prone to errors if the dynamic images are not corrected for respiratory motion by image registration. The contrast-induced intensity variations in pre- and postcontrast phases pose challenges for the accuracy of image registration. We propose an overdetermined system of transformation equations between the image volumes in the DCE-MRI series to achieve robust alignment...
September 2016: Tomography: a Journal for Imaging Research
https://www.readbyqxmd.com/read/28334750/ctc1-mediated-c-strand-fill-in-is-an-essential-step-in-telomere-length-maintenance
#19
Xuyang Feng, Shih-Jui Hsu, Christopher Kasbek, Mary Chaiken, Carolyn M Price
To prevent progressive telomere shortening as a result of conventional DNA replication, new telomeric DNA must be added onto the chromosome end. The de novo DNA synthesis involves elongation of the G-rich strand of the telomere by telomerase. In human cells, the CST complex (CTC1-STN1-TEN1) also functions in telomere replication. CST first aids in duplication of the telomeric dsDNA. Then after telomerase has extended the G-rich strand, CST facilitates fill-in synthesis of the complementary C-strand. Here, we analyze telomere structure after disruption of human CTC1 and demonstrate that functional CST is essential for telomere length maintenance due to its role in mediating C-strand fill-in...
May 5, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28334037/ang1-treatment-reduces-muscle-pathology-and-prevents-a-decline-in-perfusion-in-dmd-mice
#20
Kelly M Gutpell, Nikola Tasevski, Boaz Wong, William Thomas Hrinivich, Feng Su, Jennifer Hadway, Lise Desjardins, Ting-Yim Lee, Lisa Marie Hoffman
Vascular endothelial growth factor (VEGF) and other pro-angiogenic growth factors have been investigated to enhance muscle tissue perfusion and repair in Duchenne muscular dystrophy (DMD). Current understanding is limited by a lack of functional data following in vivo delivery of these growth factors. We previously used dynamic contrast-enhanced computed tomography to monitor disease progression in murine models of DMD, but no study to date has utilized this imaging technique to assess vascular therapy in a preclinical model of DMD...
2017: PloS One
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