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Science Translational Medicine

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https://www.readbyqxmd.com/read/29997252/erratum-for-the-research-article-a-human-disease-model-of-drug-toxicity-induced-pulmonary-edema-in-allung-on-a-chip-microdevice-by-d-huh-d-c-leslie-b-d-matthews-j-p-fraser-s-jurek-g-a-hamilton-k-s-thorneloe-m-a-mcalexander-d-e-ingber
#1
https://www.readbyqxmd.com/read/29997251/modeling-of-patient-virus-titers-suggests-that-availability-of-a-vaccine-could-reduce-hepatitis-c-virus-transmission-among-injecting-drug-users
#2
Marian Major, Alexander Gutfraind, Louis Shekhtman, Qingwen Cui, Alla Kachko, Scott J Cotler, Behzad Hajarizadeh, Rachel Sacks-Davis, Kimberly Page, Basmattee Boodram, Harel Dahari
The major route of hepatitis C virus (HCV) transmission in the United States is injection drug use. We hypothesized that if an HCV vaccine were available, vaccination could affect HCV transmission among people who inject drugs by reducing HCV titers after viral exposure without necessarily achieving sterilizing immunity. To investigate this possibility, we developed a mathematical model to determine transmission probabilities relative to the HCV RNA titers of needle/syringe-sharing donors. We simulated sharing of two types of syringes fitted with needles that retain either large or small amounts of fluid after expulsion...
July 11, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29997250/crispr-enhanced-engineering-of-therapy-sensitive-cancer-cells-for-self-targeting-of-primary-and-metastatic-tumors
#3
Clemens Reinshagen, Deepak Bhere, Sung Hugh Choi, Stefan Hutten, Irina Nesterenko, Hiroaki Wakimoto, Eloi Le Roux, Alia Rizvi, Wanlu Du, Charles Minicucci, Khalid Shah
Tumor cells engineered to express therapeutic agents have shown promise to treat cancer. However, their potential to target cell surface receptors specific to the tumor site and their posttreatment fate have not been explored. We created therapeutic tumor cells expressing ligands specific to primary and recurrent tumor sites (receptor self-targeted tumor cells) and extensively characterized two different approaches using (i) therapy-resistant cancer cells, engineered with secretable death receptor-targeting ligands for "off-the-shelf" therapy in primary tumor settings, and (ii) therapy-sensitive cancer cells, which were CRISPR-engineered to knock out therapy-specific cell surface receptors before engineering with receptor self-targeted ligands and reapplied in autologous models of recurrent or metastatic disease...
July 11, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29997249/torc1-inhibition-enhances-immune-function-and-reduces-infections-in-the-elderly
#4
Joan B Mannick, Melody Morris, Hans-Ulrich P Hockey, Guglielmo Roma, Martin Beibel, Kenneth Kulmatycki, Mollie Watkins, Tea Shavlakadze, Weihua Zhou, Dean Quinn, David J Glass, Lloyd B Klickstein
Inhibition of the mechanistic target of rapamycin (mTOR) protein kinase extends life span and ameliorates aging-related pathologies including declining immune function in model organisms. The objective of this phase 2a randomized, placebo-controlled clinical trial was to determine whether low-dose mTOR inhibitor therapy enhanced immune function and decreased infection rates in 264 elderly subjects given the study drugs for 6 weeks. A low-dose combination of a catalytic (BEZ235) plus an allosteric (RAD001) mTOR inhibitor that selectively inhibits target of rapamycin complex 1 (TORC1) downstream of mTOR was safe and was associated with a significant ( P = 0...
July 11, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29997248/optogenetic-stimulation-of-cochlear-neurons-activates-the-auditory-pathway-and-restores-auditory-driven-behavior-in-deaf-adult-gerbils
#5
Christian Wrobel, Alexander Dieter, Antoine Huet, Daniel Keppeler, Carlos J Duque-Afonso, Christian Vogl, Gerhard Hoch, Marcus Jeschke, Tobias Moser
Cochlear implants partially restore hearing via direct electrical stimulation of spiral ganglion neurons (SGNs). However, spread of excitation from each electrode limits spectral coding. We explored the use of optogenetics to deliver spatially restricted and cell-specific excitation in the cochlea of adult Mongolian gerbils. Adeno-associated virus carrying the gene encoding the light-sensitive calcium translocating channelrhodopsin (CatCh) was injected into the cochlea of adult gerbils. SGNs in all cochlea turns showed stable and long-lasting CatCh expression, and electrophysiological recording from single SGNs showed that light stimulation up to few hundred Hertz induced neuronal firing...
July 11, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29973407/reversal-of-endothelial-dysfunction-reduces-white-matter-vulnerability-in-cerebral-small-vessel-disease-in-rats
#6
Rikesh M Rajani, Sophie Quick, Silvie R Ruigrok, Delyth Graham, Sarah E Harris, Benjamin F J Verhaaren, Myriam Fornage, Sudha Seshadri, Santosh S Atanur, Anna F Dominiczak, Colin Smith, Joanna M Wardlaw, Anna Williams
Dementia is a major social and economic problem for our aging population. One of the most common of dementia in the elderly is cerebral small vessel disease (SVD). Magnetic resonance scans of SVD patients typically show white matter abnormalities, but we do not understand the mechanistic pathological link between blood vessels and white matter myelin damage. Hypertension is suggested as the cause of sporadic SVD, but a recent alternative hypothesis invokes dysfunction of the blood-brain barrier as the primary cause...
July 4, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29973406/mek-inhibition-induces-myog-and-remodels-super-enhancers-in-ras-driven-rhabdomyosarcoma
#7
Marielle E Yohe, Berkley E Gryder, Jack F Shern, Young K Song, Hsien-Chao Chou, Sivasish Sindiri, Arnulfo Mendoza, Rajesh Patidar, Xiaohu Zhang, Rajarashi Guha, Donna Butcher, Kristine A Isanogle, Christina M Robinson, Xiaoling Luo, Jin-Qiu Chen, Ashley Walton, Parirokh Awasthi, Elijah F Edmondson, Simone Difilippantonio, Jun S Wei, Keji Zhao, Marc Ferrer, Craig J Thomas, Javed Khan
The RAS isoforms are frequently mutated in many types of human cancers, including PAX3/PAX7 fusion-negative rhabdomyosarcoma. Pediatric RMS arises from skeletal muscle progenitor cells that have failed to differentiate normally. The role of mutant RAS in this differentiation blockade is incompletely understood. We demonstrate that oncogenic RAS, acting through the RAF-MEK [mitogen-activated protein kinase (MAPK) kinase]-ERK (extracellular signal-regulated kinase) MAPK effector pathway, inhibits myogenic differentiation in rhabdomyosarcoma by repressing the expression of the prodifferentiation myogenic transcription factor, MYOG...
July 4, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29973405/-bcl3-expression-promotes-resistance-to-alkylating-chemotherapy-in-gliomas
#8
Longtao Wu, Giovanna M Bernal, Kirk E Cahill, Peter Pytel, Carrie A Fitzpatrick, Heather Mashek, Ralph R Weichselbaum, Bakhtiar Yamini
The response of patients with gliomas to alkylating chemotherapy is heterogeneous. However, there are currently no universally accepted predictors of patient response to these agents. We identify the nuclear factor κB (NF-κB) co-regulator B cell CLL/lymphoma 3 (BCL-3) as an independent predictor of response to temozolomide (TMZ) treatment. In glioma patients with tumors that have a methylated O 6 -methylguanine DNA methyltransferase ( MGMT ) promoter, high BCL-3 expression was associated with a poor response to TMZ...
July 4, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29973404/the-human-naive-b-cell-repertoire-contains-distinct-subclasses-for-a-germline-targeting-hiv-1-vaccine-immunogen
#9
Colin Havenar-Daughton, Anita Sarkar, Daniel W Kulp, Laura Toy, Xiaozhen Hu, Isaiah Deresa, Oleksandr Kalyuzhniy, Kirti Kaushik, Amit A Upadhyay, Sergey Menis, Elise Landais, Liwei Cao, Jolene K Diedrich, Sonu Kumar, Torben Schiffner, Samantha M Reiss, Grégory Seumois, John R Yates, James C Paulson, Steven E Bosinger, Ian A Wilson, William R Schief, Shane Crotty
Traditional vaccine development to prevent some of the worst current pandemic diseases has been unsuccessful so far. Germline-targeting immunogens have potential to prime protective antibodies (Abs) via more targeted immune responses. Success of germline-targeting vaccines in humans will depend on the composition of the human naive B cell repertoire, including the frequencies and affinities of epitope-specific B cells. However, the human naive B cell repertoire remains largely undefined. Assessment of antigen-specific human naive B cells among hundreds of millions of B cells from multiple donors may be used as pre-phase 1 ex vivo human testing to potentially forecast B cell and Ab responses to new vaccine designs...
July 4, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29950446/preclinical-assessment-of-antiviral-combination-therapy-in-a-genetically-humanized-mouse-model-for-hepatitis-delta-virus-infection
#10
Benjamin Y Winer, Elham Shirvani-Dastgerdi, Yaron Bram, Julie Sellau, Benjamin E Low, Heath Johnson, Tiffany Huang, Gabriela Hrebikova, Brigitte Heller, Yael Sharon, Katja Giersch, Sherif Gerges, Kathleen Seneca, Mihai-Alexandru Pais, Angela S Frankel, Luis Chiriboga, John Cullen, Ronald G Nahass, Marc Lutgehetmann, Jared E Toettcher, Michael V Wiles, Robert E Schwartz, Alexander Ploss
Chronic delta hepatitis, caused by hepatitis delta virus (HDV), is the most severe form of viral hepatitis, affecting at least 20 million hepatitis B virus (HBV)-infected patients worldwide. HDV/HBV co- or superinfections are major drivers for hepatocarcinogenesis. Antiviral treatments exist only for HBV and can only suppress but not cure infection. Development of more effective therapies has been impeded by the scarcity of suitable small-animal models. We created a transgenic (tg) mouse model for HDV expressing the functional receptor for HBV and HDV, the human sodium taurocholate cotransporting peptide NTCP...
June 27, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29950445/targeting-the-xpo1-dependent-nuclear-export-of-e2f7-reverses-anthracycline-resistance-in-head-and-neck-squamous-cell-carcinomas
#11
Natalia Saenz-Ponce, Rachael Pillay, Lilia Merida de Long, Trinayan Kashyap, Christian Argueta, Yosef Landesman, Mehlika Hazar-Rethinam, Samuel Boros, Benedict Panizza, Maarten Jacquemyn, Dirk Daelemans, Orla M Gannon, Nicholas A Saunders
Patient mortality rates have remained stubbornly high (40%) for the past 35 years in head and neck squamous cell carcinoma (HNSCC) due to inherent or acquired drug resistance. Thus, a critical issue in advanced SCC is to identify and target the mechanisms that contribute to therapy resistance. We report that the transcriptional inhibitor, E2F7, is mislocalized to the cytoplasm in >80% of human HNSCCs, whereas the transcriptional activator, E2F1, retains localization to the nucleus in SCC. This results in an imbalance in the control of E2F-dependent targets such as SPHK1 , which is derepressed and drives resistance to anthracyclines in HNSCC...
June 27, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29950444/opiates-increase-the-number-of-hypocretin-producing-cells-in-human-and-mouse-brain-and-reverse-cataplexy-in-a-mouse-model-of-narcolepsy
#12
Thomas C Thannickal, Joshi John, Ling Shan, Dick F Swaab, Ming-Fung Wu, Lalini Ramanathan, Ronald McGregor, Keng-Tee Chew, Marcia Cornford, Akihiro Yamanaka, Ayumu Inutsuka, Rolf Fronczek, Gert Jan Lammers, Paul F Worley, Jerome M Siegel
The changes in brain function that perpetuate opiate addiction are unclear. In our studies of human narcolepsy, a disease caused by loss of immunohistochemically detected hypocretin (orexin) neurons, we encountered a control brain (from an apparently neurologically normal individual) with 50% more hypocretin neurons than other control human brains that we had studied. We discovered that this individual was a heroin addict. Studying five postmortem brains from heroin addicts, we report that the brain tissue had, on average, 54% more immunohistochemically detected neurons producing hypocretin than did control brains from neurologically normal subjects...
June 27, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29950443/integrated-pathogen-load-and-dual-transcriptome-analysis-of-systemic-host-pathogen-interactions-in-severe-malaria
#13
Hyun Jae Lee, Athina Georgiadou, Michael Walther, Davis Nwakanma, Lindsay B Stewart, Michael Levin, Thomas D Otto, David J Conway, Lachlan J Coin, Aubrey J Cunnington
The pathogenesis of infectious diseases depends on the interaction of host and pathogen. In Plasmodium falciparum malaria, host and parasite processes can be assessed by dual RNA sequencing of blood from infected patients. We performed dual transcriptome analyses on samples from 46 malaria-infected Gambian children to reveal mechanisms driving the systemic pathophysiology of severe malaria. Integrating these transcriptomic data with estimates of parasite load and detailed clinical information allowed consideration of potentially confounding effects due to differing leukocyte proportions in blood, parasite developmental stage, and whole-body pathogen load...
June 27, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29925637/interrogation-of-nonconserved-human-adipose-lincrnas-identifies-a-regulatory-role-of-linc-adal-in-adipocyte-metabolism
#14
Xuan Zhang, Chenyi Xue, Jennie Lin, Jane F Ferguson, Amber Weiner, Wen Liu, Yumiao Han, Christine Hinkle, Wenjun Li, Hongfeng Jiang, Sager Gosai, Melanie Hachet, Benjamin A Garcia, Brian D Gregory, Raymond E Soccio, John B Hogenesch, Patrick Seale, Mingyao Li, Muredach P Reilly
Long intergenic noncoding RNAs (lincRNAs) have emerged as important modulators of cellular functions. Most lincRNAs are not conserved among mammals, raising the fundamental question of whether nonconserved adipose-expressed lincRNAs are functional. To address this, we performed deep RNA sequencing of gluteal subcutaneous adipose tissue from 25 healthy humans. We identified 1001 putative lincRNAs expressed in all samples through de novo reconstruction of noncoding transcriptomes and integration with existing lincRNA annotations...
June 20, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29925636/the-erbb-network-facilitates-kras-driven-lung-tumorigenesis
#15
Björn Kruspig, Tiziana Monteverde, Sarah Neidler, Andreas Hock, Emma Kerr, Colin Nixon, William Clark, Ann Hedley, Sarah Laing, Seth B Coffelt, John Le Quesne, Craig Dick, Karen Vousden, Carla P Martins, Daniel J Murphy
KRAS is the most frequently mutated driver oncogene in human adenocarcinoma of the lung. There are presently no clinically proven strategies for treatment of KRAS-driven lung cancer. Activating mutations in KRAS are thought to confer independence from upstream signaling; however, recent data suggest that this independence may not be absolute. We show that initiation and progression of KRAS-driven lung tumors require input from ERBB family receptor tyrosine kinases (RTKs): Multiple ERBB RTKs are expressed and active from the earliest stages of KRAS-driven lung tumor development, and treatment with a multi-ERBB inhibitor suppresses formation of KRASG12D -driven lung tumors...
June 20, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29925635/afatinib-restrains-k-ras-driven-lung-tumorigenesis
#16
Herwig P Moll, Klemens Pranz, Monica Musteanu, Beatrice Grabner, Natascha Hruschka, Julian Mohrherr, Petra Aigner, Patricia Stiedl, Luka Brcic, Viktoria Laszlo, Daniel Schramek, Richard Moriggl, Robert Eferl, Judit Moldvay, Katalin Dezso, Pedro P Lopez-Casas, Dagmar Stoiber, Manuel Hidalgo, Josef Penninger, Maria Sibilia, Balázs Győrffy, Mariano Barbacid, Balázs Dome, Helmut Popper, Emilio Casanova
On the basis of clinical trials using first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), it became a doctrine that V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ( K-RAS ) mutations drive resistance to EGFR inhibition in non-small cell lung cancer (NSCLC). Conversely, we provide evidence that EGFR signaling is engaged in K-RAS-driven lung tumorigenesis in humans and in mice. Specifically, genetic mouse models revealed that deletion of Egfr quenches mutant K-RAS activity and transiently reduces tumor growth...
June 20, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29925634/tissue-engineering-toward-temporomandibular-joint-disc-regeneration
#17
Natalia Vapniarsky, Le W Huwe, Boaz Arzi, Meghan K Houghton, Mark E Wong, James W Wilson, David C Hatcher, Jerry C Hu, Kyriacos A Athanasiou
Treatments for temporomandibular joint (TMJ) disc thinning and perforation, conditions prevalent in TMJ pathologies, are palliative but not reparative. To address this, scaffold-free tissue-engineered implants were created using allogeneic, passaged costal chondrocytes. A combination of compressive and bioactive stimulation regimens produced implants with mechanical properties akin to those of the native disc. Efficacy in repairing disc thinning was examined in minipigs. Compared to empty controls, treatment with tissue-engineered implants restored disc integrity by inducing 4...
June 20, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29899025/curbing-cholera
#18
REVIEW
Robert H Hall
Colonization of the gut by virulent Vibrio cholerae is suppressed by probiotic-like activity of a live cholera vaccine candidate and Lactococcus lactis in two animal models (Hubbard et al. and Mao et al. , this issue).
June 13, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29899024/a-live-vaccine-rapidly-protects-against-cholera-in-an-infant-rabbit-model
#19
Troy P Hubbard, Gabriel Billings, Tobias Dörr, Brandon Sit, Alyson R Warr, Carole J Kuehl, Minsik Kim, Fernanda Delgado, John J Mekalanos, Joseph A Lewnard, Matthew K Waldor
Outbreaks of cholera, a rapidly fatal diarrheal disease, often spread explosively. The efficacy of reactive vaccination campaigns-deploying Vibrio cholerae vaccines during epidemics-is partially limited by the time required for vaccine recipients to develop adaptive immunity. We created HaitiV, a live attenuated cholera vaccine candidate, by deleting diarrheagenic factors from a recent clinical isolate of V. cholerae and incorporating safeguards against vaccine reversion. We demonstrate that administration of HaitiV 24 hours before lethal challenge with wild-type V...
June 13, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29899023/nedd9-targets-col3a1-to-promote-endothelial-fibrosis-and-pulmonary-arterial-hypertension
#20
Andriy O Samokhin, Thomas Stephens, Bradley M Wertheim, Rui-Sheng Wang, Sara O Vargas, Lai-Ming Yung, Minwei Cao, Marcel Brown, Elena Arons, Paul B Dieffenbach, Jason G Fewell, Majed Matar, Frederick P Bowman, Kathleen J Haley, George A Alba, Stefano M Marino, Rahul Kumar, Ivan O Rosas, Aaron B Waxman, William M Oldham, Dinesh Khanna, Brian B Graham, Sachiko Seo, Vadim N Gladyshev, Paul B Yu, Laura E Fredenburgh, Joseph Loscalzo, Jane A Leopold, Bradley A Maron
Germline mutations involving small mothers against decapentaplegic-transforming growth factor-β (SMAD-TGF-β) signaling are an important but rare cause of pulmonary arterial hypertension (PAH), which is a disease characterized, in part, by vascular fibrosis and hyperaldosteronism (ALDO). We developed and analyzed a fibrosis protein-protein network (fibrosome) in silico, which predicted that the SMAD3 target neural precursor cell expressed developmentally down-regulated 9 (NEDD9) is a critical ALDO-regulated node underpinning pathogenic vascular fibrosis...
June 13, 2018: Science Translational Medicine
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