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Hamideh Parhiz, Vladimir V Shuvaev, Norbert Pardi, Makan Khoshnejad, Raisa Yu Kiseleva, Jacob S Brenner, Thomas Uhler, Steven Tuyishime, Barbara L Mui, Ying K Tam, Thomas D Madden, Michael J Hope, Drew Weissman, Vladimir R Muzykantov
Systemic administration of lipid nanoparticle (LNP)-encapsulated messenger RNA (mRNA) leads predominantly to hepatic uptake and expression. Here, we conjugated nucleoside-modified mRNA-LNPs with antibodies (Abs) specific to vascular cell adhesion molecule, PECAM-1. Systemic (intravenous) administration of Ab/LNP-mRNAs resulted in profound inhibition of hepatic uptake concomitantly with ~200-fold and 25-fold elevation of mRNA delivery and protein expression in the lungs compared to non-targeted counterparts...
October 15, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Suzana A Kahn, Xin Wang, Ryan T Nitta, Sharareh Gholamin, Johanna Theruvath, Gregor Hutter, Tej D Azad, Lina Wadi, Sara Bolin, Vijay Ramaswamy, Rogelio Esparza, Kun-Wei Liu, Michael Edwards, Fredrik J Swartling, Debashis Sahoo, Gordon Li, Robert J Wechsler-Reya, Jüri Reimand, Yoon-Jae Cho, Michael D Taylor, Irving L Weissman, Siddhartha S Mitra, Samuel H Cheshier
Medulloblastoma is the most common malignant brain tumor of childhood. Group 3 medulloblastoma, the most aggressive molecular subtype, frequently disseminates through the leptomeningeal cerebral spinal fluid (CSF) spaces in the brain and spinal cord. The mechanism of dissemination through the CSF remains poorly understood, and the molecular pathways involved in medulloblastoma metastasis and self-renewal are largely unknown. Here we show that NOTCH1 signaling pathway regulates both the initiation of metastasis and the self-renewal of medulloblastoma...
October 8, 2018: Nature Communications
Jin Liu, Ning Jiang, Amy Z Fan, Rebecca Weissman
Purpose: Identification of mental healthcare disparities through scales or questionnaires is an initial step to improve mental healthcare equity. This study was designed to investigate the performance of a single-item question relative to two psychiatric scales with multiple items in assessing mental healthcare disparities among U.S. adults using the Behavioral Risk Factor Surveillance System (BRFSS) data. Methods: The current depression (CD) and serious psychological distress (SPD) were analyzed in 2010 and 2012 with the BRFSS using two multiple-item scales in selected states...
2018: Health Equity
M Tessler, M Paul, S Halfon, B S Meyer, R Pardo, R Purtschert, K E Rehm, R Scott, M Weigand, L Weissman, S Almaraz-Calderon, M L Avila, D Baggenstos, P Collon, N Hazenshprung, Y Kashiv, D Kijel, A Kreisel, R Reifarth, D Santiago-Gonzalez, A Shor, I Silverman, R Talwar, D Veltum, R Vondrasek
The ^{36}Ar(n,γ)^{37}Ar (t_{1/2}=35  d) and ^{38}Ar(n,γ)^{39}Ar (269 yr) reactions were studied for the first time with a quasi-Maxwellian (kT∼47  keV) neutron flux for Maxwellian average cross section (MACS) measurements at stellar energies. Gas samples were irradiated at the high-intensity Soreq applied research accelerator facility-liquid-lithium target neutron source and the ^{37}Ar/^{36}Ar and ^{39}Ar/^{38}Ar ratios in the activated samples were determined by accelerator mass spectrometry at the ATLAS facility (Argonne National Laboratory)...
September 14, 2018: Physical Review Letters
Luke Gelinas, Joel S Weissman, Holly Fernandez Lynch, Avni Gupta, Ronen Rozenblum, Emily A Largent, I Glenn Cohen
A key aim of patient-centered outcomes research (PCOR) is to generate data that are important to patients by deliberately and extensively involving them in all aspects of research, from design to dissemination. However, certain elements of PCOR raise challenging and potentially novel ethical and regulatory issues for institutional review boards and oversight bodies. These challenges stem primarily from the engagement of patients in roles other than research subject, such as advisors, study personnel, and co-investigators, which gives rise to questions about appropriate levels of protection, training, and education, as well as identifying and managing conflicts of interest...
October 16, 2018: Annals of Internal Medicine
Charles K F Chan, Gunsagar S Gulati, Rahul Sinha, Justin Vincent Tompkins, Michael Lopez, Ava C Carter, Ryan C Ransom, Andreas Reinisch, Taylor Wearda, Matthew Murphy, Rachel E Brewer, Lauren S Koepke, Owen Marecic, Anoop Manjunath, Eun Young Seo, Tripp Leavitt, Wan-Jin Lu, Allison Nguyen, Stephanie D Conley, Ankit Salhotra, Thomas H Ambrosi, Mimi R Borrelli, Taylor Siebel, Karen Chan, Katharina Schallmoser, Jun Seita, Debashis Sahoo, Henry Goodnough, Julius Bishop, Michael Gardner, Ravindra Majeti, Derrick C Wan, Stuart Goodman, Irving L Weissman, Howard Y Chang, Michael T Longaker
Stem cell regulation and hierarchical organization of human skeletal progenitors remain largely unexplored. Here, we report the isolation of a self-renewing and multipotent human skeletal stem cell (hSSC) that generates progenitors of bone, cartilage, and stroma, but not fat. Self-renewing and multipotent hSSCs are present in fetal and adult bones and can also be derived from BMP2-treated human adipose stroma (B-HAS) and induced pluripotent stem cells (iPSCs). Gene expression analysis of individual hSSCs reveals overall similarity between hSSCs obtained from different sources and partially explains skewed differentiation toward cartilage in fetal and iPSC-derived hSSCs...
September 20, 2018: Cell
Linda Kimsey, Joel S Weissman, Avni Patel, Allison Drew, Tracey Koehlmoos, Jeffrey A Sparks
OBJECTIVE: To investigate factors associated with delay in initiation of initial disease-modifying antirheumatic drug (DMARD) in patients newly diagnosed with rheumatoid arthritis (RA). METHODS: We performed a retrospective cohort descriptive study using administrative data from the US military's TRICARE program (2007-2012). We identified incident RA cases using billing codes and initial DMARD receipt using prescription fill date. We quantified the time between RA presentation and initial DMARD receipt, evaluated temporal changes in delay over the study period, and investigated predictors of treatment delay (> 90 days) using logistic regression...
July 18, 2018: Seminars in Arthritis and Rheumatism
Erin A Bohula, Stephen D Wiviott, Darren K McGuire, Silvio E Inzucchi, Julia Kuder, KyungAh Im, Christina L Fanola, Arman Qamar, Conville Brown, Andrzej Budaj, Armando Garcia-Castillo, Milan Gupta, Lawrence A Leiter, Neil J Weissman, Harvey D White, Tushar Patel, Bruce Francis, Wenfeng Miao, Carlos Perdomo, Shobha Dhadda, Marc P Bonaca, Christian T Ruff, Anthony C Keech, Steven R Smith, Marc S Sabatine, Benjamin M Scirica
BACKGROUND: Lorcaserin, a selective serotonin 2C receptor agonist that modulates appetite, has proven efficacy for weight management in overweight or obese patients. The cardiovascular safety and efficacy of lorcaserin are undefined. METHODS: We randomly assigned 12,000 overweight or obese patients with atherosclerotic cardiovascular disease or multiple cardiovascular risk factors to receive either lorcaserin (10 mg twice daily) or placebo. The primary safety outcome of major cardiovascular events (a composite of cardiovascular death, myocardial infarction, or stroke) was assessed at an interim analysis to exclude a noninferiority boundary of 1...
September 20, 2018: New England Journal of Medicine
John R Weisz, Ana M Ugueto, Jenny Herren, Lauren K Marchette, Sarah Kate Bearman, Erica H Lee, Kristel Thomassin, Alisha Alleyne, Daniel M Cheron, J Lindsey Tweed, Jacqueline Hersh, Jacquelyn N Raftery-Helmer, Adam S Weissman, Amanda Jensen-Doss
OBJECTIVE: We assessed sustainability of an empirically supported, transdiagnostic youth psychotherapy program when therapist supervision was shifted from external experts to internal clinic staff. METHOD: One hundred sixty-eight youths, aged 6-15 years, 59.5% male, 85.1% Caucasian, were treated for anxiety, depression, traumatic stress, or conduct problems by clinicians employed in community mental health clinics. In Phase 1 (2.7 years), 1 group of clinicians, the Sustain group, received training in Child STEPs (a modular transdiagnostic treatment + weekly feedback on youth response) and treated clinic-referred youths, guided by weekly supervision from external STEPs experts...
September 2018: Journal of Consulting and Clinical Psychology
Michael J Mack, William T Abraham, JoAnn Lindenfeld, Steven F Bolling, Ted E Feldman, Paul A Grayburn, Samir R Kapadia, Patrick M McCarthy, D Scott Lim, James E Udelson, Michael R Zile, James S Gammie, A Marc Gillinov, Donald D Glower, David A Heimansohn, Rakesh M Suri, Jeffrey T Ellis, Yu Shu, Saibal Kar, Neil J Weissman, Gregg W Stone
BACKGROUND: Patients with heart failure (HF) and symptomatic secondary mitral regurgitation (SMR) have a poor prognosis, with morbidity and mortality directly correlated with MR severity. Correction of isolated SMR with surgery is not well established in this population, and medical management remains the preferred approach in most patients. The Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) trial was designed to determine whether transcatheter mitral valve (MV) repair with the MitraClip device is safe and effective in patients with symptomatic HF and clinically significant SMR...
August 1, 2018: American Heart Journal
Rebecca T Hahn, Philippe Pibarot, Jonathon Leipsic, Philipp Blanke, Pamela S Douglas, Neil J Weissman, Samir Kapadia, Vinod H Thourani, Howard C Herrmann, Tamim Nazif, Thomas McAndrew, John G Webb, Martin B Leon, Susheel Kodali
OBJECTIVES: The purpose of this study was to understand the effects of balloon post-dilatation on outcomes following transcatheter aortic valve replacement with the SAPIEN 3 valve. BACKGROUND: Hemodynamics and outcomes with balloon post-dilatation for the SAPIEN 3 valve have not been previously reported. METHODS: The effects of balloon post-dilatation (BPD) in 1,661 intermediate (S3i cohort) and high surgical risk (S3HR cohort) patients with aortic stenosis enrolled in the PARTNER (Placement of Aortic Transcatheter Valves) 2, SAPIEN 3 observational study on outcomes, as well as procedural complications, were assessed...
September 10, 2018: JACC. Cardiovascular Interventions
Elizabeth A Whitcomb, Yien Che Tsai, Johnvesly Basappa, Ke Liu, Aurélie K Le Feuvre, Allan M Weissman, Allen Taylor
Ubiquitinylation drives many cellular processes by targeting proteins for proteasomal degradation. Ubiquitin conjugation enzymes promote ubiquitinylation and, thus, degradation of protein substrates. Ubiquitinylation is a well-known posttranslational modification controlling cell-cycle transitions and levels or/and activation levels of ubiquitin-conjugating enzymes change during development and cell cycle. Progression through the cell cycle is tightly controlled by CDK inhibitors such as p27Kip1 . Here we show that, in contrast to promoting its degradation, the ubiquitin-conjugating enzyme UBCH7/UBE2L3 specifically protects p27Kip1 from degradation...
August 16, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Jie Yang, Mengru Zhang, Hongshik Ahn, Qing Zhang, Tony B Jin, Ien Li, Matthew Nemesure, Nandita Joshi, Haoran Jiang, Jeffrey M Miller, Robert Todd Ogden, Eva Petkova, Matthew S Milak, Mary Elizabeth Sublette, Gregory M Sullivan, Madhukar H Trivedi, Myrna Weissman, Patrick J McGrath, Maurizio Fava, Benji T Kurian, Diego A Pizzagalli, Crystal M Cooper, Melvin McInnis, Maria A Oquendo, Joseph John Mann, Ramin V Parsey, Christine DeLorenzo
This study aimed to identify biomarkers of major depressive disorder (MDD), by relating neuroimage-derived measures to binary (MDD/control), ordinal (severe MDD/mild MDD/control), or continuous (depression severity) outcomes. To address MDD heterogeneity, factors (severity of psychic depression, motivation, anxiety, psychosis, and sleep disturbance) were also used as outcomes. A multisite, multimodal imaging (diffusion MRI [dMRI] and structural MRI [sMRI]) cohort (52 controls and 147 MDD patients) and several modeling techniques-penalized logistic regression, random forest, and support vector machine (SVM)-were used...
November 2018: Human Brain Mapping
Mingye Feng, Kristopher D Marjon, Fangfang Zhu, Rachel Weissman-Tsukamoto, Aaron Levett, Katie Sullivan, Kevin S Kao, Maxim Markovic, Paul A Bump, Hannah M Jackson, Timothy S Choi, Jing Chen, Allison M Banuelos, Jie Liu, Phung Gip, Lei Cheng, Denong Wang, Irving L Weissman
Macrophage-mediated programmed cell removal (PrCR) is a process essential for the clearance of unwanted (damaged, dysfunctional, aged, or harmful) cells. The detection and recognition of appropriate target cells by macrophages is a critical step for successful PrCR, but its molecular mechanisms have not been delineated. Here using the models of tissue turnover, cancer immunosurveillance, and hematopoietic stem cells, we show that unwanted cells such as aging neutrophils and living cancer cells are susceptible to "labeling" by secreted calreticulin (CRT) from macrophages, enabling their clearance through PrCR...
August 10, 2018: Nature Communications
Ofira Zloto, Irina S Barequet, Alon Weissman, Orit Ezra Nimni, Yoav Berger, Noa Avni-Zauberman
PURPOSE: To examine the clinical characteristics, treatments, and prognosis of all cases of infectious keratitis resistant to conventional therapy and treated by photo-activated chromophore for keratitis corneal cross-linking (PACK-CXL) in one institution between 2012 and 2016. METHODS: A database search of patients who underwent PACK-CXL (ultraviolet-A for 10 minutes for irradiance of 9 mW/cm2 ) for infectious keratitis unresponsive to medical treatment at a tertiary care hospital was conducted...
August 1, 2018: Journal of Refractive Surgery
Nicholas T Ingolia, Jeffrey A Hussmann, Jonathan S Weissman
The translation of messenger RNA (mRNA) into protein and the folding of the resulting protein into an active form are prerequisites for virtually every cellular process and represent the single largest investment of energy by cells. Ribosome profiling-based approaches have revolutionized our ability to monitor every step of protein synthesis in vivo, allowing one to measure the rate of protein synthesis across the proteome, annotate the protein coding capacity of genomes, monitor localized protein synthesis, and explore cotranslational folding and targeting...
July 23, 2018: Cold Spring Harbor Perspectives in Biology
Max A Horlbeck, Albert Xu, Min Wang, Neal K Bennett, Chong Y Park, Derek Bogdanoff, Britt Adamson, Eric D Chow, Martin Kampmann, Tim R Peterson, Ken Nakamura, Michael A Fischbach, Jonathan S Weissman, Luke A Gilbert
Seminal yeast studies have established the value of comprehensively mapping genetic interactions (GIs) for inferring gene function. Efforts in human cells using focused gene sets underscore the utility of this approach, but the feasibility of generating large-scale, diverse human GI maps remains unresolved. We developed a CRISPR interference platform for large-scale quantitative mapping of human GIs. We systematically perturbed 222,784 gene pairs in two cancer cell lines. The resultant maps cluster functionally related genes, assigning function to poorly characterized genes, including TMEM261, a new electron transport chain component...
August 9, 2018: Cell
Theodore L Roth, Cristina Puig-Saus, Ruby Yu, Eric Shifrut, Julia Carnevale, P Jonathan Li, Joseph Hiatt, Justin Saco, Paige Krystofinski, Han Li, Victoria Tobin, David N Nguyen, Michael R Lee, Amy L Putnam, Andrea L Ferris, Jeff W Chen, Jean-Nicolas Schickel, Laurence Pellerin, David Carmody, Gorka Alkorta-Aranburu, Daniela Del Gaudio, Hiroyuki Matsumoto, Montse Morell, Ying Mao, Min Cho, Rolen M Quadros, Channabasavaiah B Gurumurthy, Baz Smith, Michael Haugwitz, Stephen H Hughes, Jonathan S Weissman, Kathrin Schumann, Jonathan H Esensten, Andrew P May, Alan Ashworth, Gary M Kupfer, Siri Atma W Greeley, Rosa Bacchetta, Eric Meffre, Maria Grazia Roncarolo, Neil Romberg, Kevan C Herold, Antoni Ribas, Manuel D Leonetti, Alexander Marson
Decades of work have aimed to genetically reprogram T cells for therapeutic purposes1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4 . The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6 . Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function...
July 2018: Nature
Joshua M Liao, Judy A Shea, Arlene Weissman, Amol S Navathe
We surveyed a national sample of internal medicine physicians in March-May 2017 to explore their beliefs about the newly implemented Merit-based Incentive Payment System (MIPS). Respondents believed that their efforts in the four focus areas identified in the survey would ultimately improve the value of care. When informed that those areas represented the four MIPS domains, the majority remained positive about the likely impact on value. However, expectations varied by physicians' characteristics and sense of control over the desired outcomes, and many respondents believed that unintended consequences could occur...
July 2018: Health Affairs
Weihan Li, Voytek Okreglak, Jirka Peschek, Philipp Kimmig, Meghan Zubradt, Jonathan S Weissman, Peter Walter
The endoplasmic reticulum (ER) protein folding capacity is balanced with the protein folding burden to prevent accumulation of un- or misfolded proteins. The ER membrane-resident kinase/RNase Ire1 maintains ER protein homeostasis through two fundamentally distinct processes. First, Ire1 can initiate a transcriptional response through a non-conventional mRNA splicing reaction to increase the ER folding capacity. Second, Ire1 can decrease the ER folding burden through selective mRNA decay. In Saccharomyces cerevisiae and Schizosaccharomyces pombe, the two Ire1 functions have been evolutionarily separated...
July 9, 2018: ELife
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