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Nature Medicine

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https://www.readbyqxmd.com/read/30323331/precision-identification-of-diverse-bloodstream-pathogens-in-the-gut-microbiome
#1
Fiona B Tamburini, Tessa M Andermann, Ekaterina Tkachenko, Fiona Senchyna, Niaz Banaei, Ami S Bhatt
A comprehensive evaluation of every patient with a bloodstream infection includes an attempt to identify the infectious source. Pathogens can originate from various places, such as the gut microbiota, skin and the external environment. Identifying the definitive origin of an infection would enable precise interventions focused on management of the source1,2 . Unfortunately, hospital infection control practices are often informed by assumptions about the source of various specific pathogens; if these assumptions are incorrect, they lead to interventions that do not decrease pathogen exposure3 ...
October 15, 2018: Nature Medicine
https://www.readbyqxmd.com/read/30297912/systemic-messenger-rna-as-an-etiological-treatment-for-acute-intermittent-porphyria
#2
Lei Jiang, Pedro Berraondo, Daniel Jericó, Lin T Guey, Ana Sampedro, Andrea Frassetto, Kerry E Benenato, Kristine Burke, Eva Santamaría, Manuel Alegre, Álvaro Pejenaute, Mayur Kalariya, William Butcher, Ji-Sun Park, Xuling Zhu, Staci Sabnis, E Sathyajith Kumarasinghe, Timothy Salerno, Matthew Kenney, Christine M Lukacs, Matías A Ávila, Paolo G V Martini, Antonio Fontanellas
Acute intermittent porphyria (AIP) results from haploinsufficiency of porphobilinogen deaminase (PBGD), the third enzyme in the heme biosynthesis pathway. Patients with AIP have neurovisceral attacks associated with increased hepatic heme demand. Phenobarbital-challenged mice with AIP recapitulate the biochemical and clinical characteristics of patients with AIP, including hepatic overproduction of the potentially neurotoxic porphyrin precursors. Here we show that intravenous administration of human PBGD (hPBGD) mRNA (encoded by the gene HMBS) encapsulated in lipid nanoparticles induces dose-dependent protein expression in mouse hepatocytes, rapidly normalizing urine porphyrin precursor excretion in ongoing attacks...
October 8, 2018: Nature Medicine
https://www.readbyqxmd.com/read/30297911/neoadjuvant-versus-adjuvant-ipilimumab-plus-nivolumab-in-macroscopic-stage-iii-melanoma
#3
Christian U Blank, Elisa A Rozeman, Lorenzo F Fanchi, Karolina Sikorska, Bart van de Wiel, Pia Kvistborg, Oscar Krijgsman, Marlous van den Braber, Daisy Philips, Annegien Broeks, Johannes V van Thienen, Henk A Mallo, Sandra Adriaansz, Sylvia Ter Meulen, Loes M Pronk, Lindsay G Grijpink-Ongering, Annemarie Bruining, Rachel M Gittelman, Sarah Warren, Harm van Tinteren, Daniel S Peeper, John B A G Haanen, Alexander C J van Akkooi, Ton N Schumacher
Adjuvant ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) both improve relapse-free survival of stage III melanoma patients1,2 . In stage IV disease, the combination of ipilimumab + nivolumab is superior to ipilimumab alone and also appears to be more effective than nivolumab monotherapy3 . Preclinical work suggests that neoadjuvant application of checkpoint inhibitors may be superior to adjuvant therapy4 . To address this question and to test feasibility, 20 patients with palpable stage III melanoma were 1:1 randomized to receive ipilimumab 3 mg kg-1 and nivolumab 1 mg kg-1 , as either four courses after surgery (adjuvant arm) or two courses before surgery and two courses postsurgery (neoadjuvant arm)...
October 8, 2018: Nature Medicine
https://www.readbyqxmd.com/read/30297910/wireless-bioresorbable-electronic-system-enables-sustained-nonpharmacological-neuroregenerative-therapy
#4
Jahyun Koo, Matthew R MacEwan, Seung-Kyun Kang, Sang Min Won, Manu Stephen, Paul Gamble, Zhaoqian Xie, Ying Yan, Yu-Yu Chen, Jiho Shin, Nathan Birenbaum, Sangjin Chung, Sung Bong Kim, Jawad Khalifeh, Daniel V Harburg, Kelsey Bean, Michael Paskett, Jeonghyun Kim, Zohny S Zohny, Seung Min Lee, Ruoyao Zhang, Kaijing Luo, Bowen Ji, Anthony Banks, Hyuck Mo Lee, Younggang Huang, Wilson Z Ray, John A Rogers
Peripheral nerve injuries represent a significant problem in public health, constituting 2-5% of all trauma cases1 . For severe nerve injuries, even advanced forms of clinical intervention often lead to incomplete and unsatisfactory motor and/or sensory function2 . Numerous studies report the potential of pharmacological approaches (for example, growth factors, immunosuppressants) to accelerate and enhance nerve regeneration in rodent models3-10 . Unfortunately, few have had a positive impact in clinical practice...
October 8, 2018: Nature Medicine
https://www.readbyqxmd.com/read/30297909/neoadjuvant-immune-checkpoint-blockade-in-high-risk-resectable-melanoma
#5
Rodabe N Amaria, Sangeetha M Reddy, Hussein A Tawbi, Michael A Davies, Merrick I Ross, Isabella C Glitza, Janice N Cormier, Carol Lewis, Wen-Jen Hwu, Ehab Hanna, Adi Diab, Michael K Wong, Richard Royal, Neil Gross, Randal Weber, Stephen Y Lai, Richard Ehlers, Jorge Blando, Denái R Milton, Scott Woodman, Robin Kageyama, Danny K Wells, Patrick Hwu, Sapna P Patel, Anthony Lucci, Amy Hessel, Jeffrey E Lee, Jeffrey Gershenwald, Lauren Simpson, Elizabeth M Burton, Liberty Posada, Lauren Haydu, Linghua Wang, Shaojun Zhang, Alexander J Lazar, Courtney W Hudgens, Vancheswaran Gopalakrishnan, Alexandre Reuben, Miles C Andrews, Christine N Spencer, Victor Prieto, Padmanee Sharma, James Allison, Michael T Tetzlaff, Jennifer A Wargo
Preclinical studies suggest that treatment with neoadjuvant immune checkpoint blockade is associated with enhanced survival and antigen-specific T cell responses compared with adjuvant treatment1 ; however, optimal regimens have not been defined. Here we report results from a randomized phase 2 study of neoadjuvant nivolumab versus combined ipilimumab with nivolumab in 23 patients with high-risk resectable melanoma ( NCT02519322 ). RECIST overall response rates (ORR), pathologic complete response rates (pCR), treatment-related adverse events (trAEs) and immune correlates of response were assessed...
October 8, 2018: Nature Medicine
https://www.readbyqxmd.com/read/30297908/structure-guided-combination-therapy-to-potently-improve-the-function-of-mutant-cftrs
#6
Guido Veit, Haijin Xu, Elise Dreano, Radu G Avramescu, Miklos Bagdany, Lenore K Beitel, Ariel Roldan, Mark A Hancock, Cecilia Lay, Wei Li, Katelin Morin, Sandra Gao, Puiying A Mak, Edward Ainscow, Anthony P Orth, Peter McNamara, Aleksander Edelman, Saul Frenkiel, Elias Matouk, Isabelle Sermet-Gaudelus, William G Barnes, Gergely L Lukacs
Available corrector drugs are unable to effectively rescue the folding defects of CFTR-ΔF508 (or CFTR-F508del), the most common disease-causing mutation of the cystic fibrosis transmembrane conductance regulator, a plasma membrane (PM) anion channel, and thus to substantially ameliorate clinical phenotypes of cystic fibrosis (CF). To overcome the corrector efficacy ceiling, here we show that compounds targeting distinct structural defects of CFTR can synergistically rescue mutant expression and function at the PM...
October 8, 2018: Nature Medicine
https://www.readbyqxmd.com/read/30291359/publisher-correction-clinical-activity-and-molecular-correlates-of-response-to-atezolizumab-alone-or-in-combination-with-bevacizumab-versus-sunitinib-in-renal-cell-carcinoma
#7
David F McDermott, Mahrukh A Huseni, Michael B Atkins, Robert J Motzer, Brian I Rini, Bernard Escudier, Lawrence Fong, Richard W Joseph, Sumanta K Pal, James A Reeves, Mario Sznol, John Hainsworth, W Kimryn Rathmell, Walter M Stadler, Thomas Hutson, Martin E Gore, Alain Ravaud, Sergio Bracarda, Cristina Suárez, Riccardo Danielli, Viktor Gruenwald, Toni K Choueiri, Dorothee Nickles, Suchit Jhunjhunwala, Elisabeth Piault-Louis, Alpa Thobhani, Jiaheng Qiu, Daniel S Chen, Priti S Hegde, Christina Schiff, Gregg D Fine, Thomas Powles
In the version of this article originally published, there was an error in Fig. 2n. The top line of the HR comparison chart originally was Atezo + bev vs sun. It should have been Atezo + bev vs atezo. The error has been corrected in the HTML and PDF versions of this article.
October 5, 2018: Nature Medicine
https://www.readbyqxmd.com/read/30291358/author-correction-mitotalen-reduces-mutant-mtdna-load-and-restores-trna-ala-levels-in-a-mouse-model-of-heteroplasmic-mtdna-mutation
#8
Sandra R Bacman, Johanna H K Kauppila, Claudia V Pereira, Nadee Nissanka, Maria Miranda, Milena Pinto, Sion L Williams, Nils-Göran Larsson, James B Stewart, Carlos T Moraes
In the version of this article originally published, there was an error in Fig. 1a. The m.5024C>T mutation, shown as a green T, was displaced by one base. The error has been corrected in the print, HTML and PDF versions of this article.
October 5, 2018: Nature Medicine
https://www.readbyqxmd.com/read/30275570/dynamics-of-genetically-engineered-hematopoietic-stem-and-progenitor-cells-after-autologous-transplantation-in-humans
#9
Serena Scala, Luca Basso-Ricci, Francesca Dionisio, Danilo Pellin, Stefania Giannelli, Federica Andrea Salerio, Lorena Leonardelli, Maria Pia Cicalese, Francesca Ferrua, Alessandro Aiuti, Luca Biasco
Hematopoietic stem and progenitor cells (HSPC) are endowed with the role of generating and maintaining lifelong the extremely diverse pool of blood cells1 . Clinically, transplantation of human HSPC from an allogeneic healthy donor or infusion of autologous gene-corrected HSPC can effectively replenish defective blood cell production caused by congenital or acquired disorders2-9 . However, due to methodological and ethical constraints that have limited the study of human HSPC primarily to in vitro assays10 or xenotransplantation models11,12 , the in vivo activity of HSPC has to date remained relatively unexplored in humans13-16 ...
October 1, 2018: Nature Medicine
https://www.readbyqxmd.com/read/30275569/genetic-mechanisms-of-target-antigen-loss-in-car19-therapy-of-acute-lymphoblastic-leukemia
#10
Elena J Orlando, Xia Han, Catherine Tribouley, Patricia A Wood, Rebecca J Leary, Markus Riester, John E Levine, Muna Qayed, Stephan A Grupp, Michael Boyer, Barbara De Moerloose, Eneida R Nemecek, Henrique Bittencourt, Hidefumi Hiramatsu, Jochen Buechner, Stella M Davies, Michael R Verneris, Kevin Nguyen, Jennifer L Brogdon, Hans Bitter, Michael Morrissey, Piotr Pierog, Serafino Pantano, Jeffrey A Engelman, Wendy Winckler
We identified genetic mutations in CD19 and loss of heterozygosity at the time of CD19- relapse to chimeric antigen receptor (CAR) therapy. The mutations are present in the vast majority of resistant tumor cells and are predicted to lead to a truncated protein with a nonfunctional or absent transmembrane domain and consequently to a loss of surface antigen. This irreversible loss of CD19 advocates for an alternative targeting or combination CAR approach.
October 1, 2018: Nature Medicine
https://www.readbyqxmd.com/read/30275568/induction-of-resistance-to-chimeric-antigen-receptor-t-cell-therapy-by-transduction-of-a-single-leukemic-b-cell
#11
Marco Ruella, Jun Xu, David M Barrett, Joseph A Fraietta, Tyler J Reich, David E Ambrose, Michael Klichinsky, Olga Shestova, Prachi R Patel, Irina Kulikovskaya, Farzana Nazimuddin, Vijay G Bhoj, Elena J Orlando, Terry J Fry, Hans Bitter, Shannon L Maude, Bruce L Levine, Christopher L Nobles, Frederic D Bushman, Regina M Young, John Scholler, Saar I Gill, Carl H June, Stephan A Grupp, Simon F Lacey, J Joseph Melenhorst
We report a patient relapsing 9 months after CD19-targeted CAR T cell (CTL019) infusion with CD19- leukemia that aberrantly expressed the anti-CD19 CAR. The CAR gene was unintentionally introduced into a single leukemic B cell during T cell manufacturing, and its product bound in cis to the CD19 epitope on the surface of leukemic cells, masking it from recognition by and conferring resistance to CTL019.
October 1, 2018: Nature Medicine
https://www.readbyqxmd.com/read/30275567/the-influence-of-ethnicity-and-geography-on-human-gut-microbiome-composition
#12
Christopher A Gaulke, Thomas J Sharpton
No abstract text is available yet for this article.
October 1, 2018: Nature Medicine
https://www.readbyqxmd.com/read/30275566/renal-compartment-specific-genetic-variation-analyses-identify-new-pathways-in-chronic-kidney-disease
#13
Chengxiang Qiu, Shizheng Huang, Jihwan Park, YoSon Park, Yi-An Ko, Matthew J Seasock, Joshua S Bryer, Xiang-Xi Xu, Wen-Chao Song, Matthew Palmer, Jon Hill, Paolo Guarnieri, Julie Hawkins, Carine M Boustany-Kari, Steven S Pullen, Christopher D Brown, Katalin Susztak
Chronic kidney disease (CKD), a condition in which the kidneys are unable to clear waste products, affects 700 million people globally. Genome-wide association studies (GWASs) have identified sequence variants for CKD; however, the biological basis of these GWAS results remains poorly understood. To address this issue, we created an expression quantitative trait loci (eQTL) atlas for the glomerular and tubular compartments of the human kidney. Through integrating the CKD GWAS with eQTL, single-cell RNA sequencing and regulatory region maps, we identified novel genes for CKD...
October 1, 2018: Nature Medicine
https://www.readbyqxmd.com/read/30258217/safety-and-antiviral-activity-of-combination-hiv-1-broadly-neutralizing-antibodies-in-viremic-individuals
#14
Yotam Bar-On, Henning Gruell, Till Schoofs, Joy A Pai, Lilian Nogueira, Allison L Butler, Katrina Millard, Clara Lehmann, Isabelle Suárez, Thiago Y Oliveira, Theodora Karagounis, Yehuda Z Cohen, Christoph Wyen, Stefan Scholten, Lisa Handl, Shiraz Belblidia, Juan P Dizon, Jörg J Vehreschild, Maggi Witmer-Pack, Irina Shimeliovich, Kanika Jain, Kerstin Fiddike, Kelly E Seaton, Nicole L Yates, Jill Horowitz, Roy M Gulick, Nico Pfeifer, Georgia D Tomaras, Michael S Seaman, Gerd Fätkenheuer, Marina Caskey, Florian Klein, Michel C Nussenzweig
Monotherapy of HIV-1 infection with single antiretroviral agents is ineffective because error-prone HIV-1 replication leads to the production of drug-resistant viral variants1,2 . Combinations of drugs can establish long-term control, however, antiretroviral therapy (ART) requires daily dosing, can cause side effects and does not eradicate the infection3,4 . Although anti-HIV-1 antibodies constitute a potential alternative to ART5,6 , treatment of viremic individuals with a single antibody also results in emergence of resistant viral variants7-9 ...
September 26, 2018: Nature Medicine
https://www.readbyqxmd.com/read/30250144/author-correction-regional-variation-limits-applications-of-healthy-gut-microbiome-reference-ranges-and-disease-models
#15
Yan He, Wei Wu, Hui-Min Zheng, Pan Li, Daniel McDonald, Hua-Fang Sheng, Mu-Xuan Chen, Zi-Hui Chen, Gui-Yuan Ji, Zhong-Dai-Xi Zheng, Prabhakar Mujagond, Xiao-Jiao Chen, Zu-Hua Rong, Peng Chen, Li-Yi Lyu, Xian Wang, Chong-Bin Wu, Nan Yu, Yan-Jun Xu, Jia Yin, Jeroen Raes, Rob Knight, Wen-Jun Ma, Hong-Wei Zhou
In the version of this article originally published, in the sentence "Applying the same approach to obesity (Fig. 2b), MetS (Fig. 2c) and fatty liver (Fig. 2d) yielded similar results," two figure panels were cited incorrectly. The data for obesity are in Fig. 2c, and the data for MetS are in Fig. 2b. The sentence has been updated with the correct citations in the print, PDF and HTML versions of the article.
September 24, 2018: Nature Medicine
https://www.readbyqxmd.com/read/30250143/mitotalen-reduces-mutant-mtdna-load-and-restores-trna-ala-levels-in-a-mouse-model-of-heteroplasmic-mtdna-mutation
#16
Sandra R Bacman, Johanna H K Kauppila, Claudia V Pereira, Nadee Nissanka, Maria Miranda, Milena Pinto, Sion L Williams, Nils-Göran Larsson, James B Stewart, Carlos T Moraes
Mutations in the mitochondrial DNA (mtDNA) are responsible for several metabolic disorders, commonly involving muscle and the central nervous system1 . Because of the critical role of mtDNA in oxidative phosphorylation, the majority of pathogenic mtDNA mutations are heteroplasmic, co-existing with wild-type molecules1 . Using a mouse model with a heteroplasmic mtDNA mutation2 , we tested whether mitochondrial-targeted TALENs (mitoTALENs)3,4 could reduce the mutant mtDNA load in muscle and heart. AAV9-mitoTALEN was administered via intramuscular, intravenous, and intraperitoneal injections...
September 24, 2018: Nature Medicine
https://www.readbyqxmd.com/read/30250142/genome-editing-in-mitochondria-corrects-a-pathogenic-mtdna-mutation-in-vivo
#17
Payam A Gammage, Carlo Viscomi, Marie-Lune Simard, Ana S H Costa, Edoardo Gaude, Christopher A Powell, Lindsey Van Haute, Beverly J McCann, Pedro Rebelo-Guiomar, Raffaele Cerutti, Lei Zhang, Edward J Rebar, Massimo Zeviani, Christian Frezza, James B Stewart, Michal Minczuk
Mutations of the mitochondrial genome (mtDNA) underlie a substantial portion of mitochondrial disease burden. These disorders are currently incurable and effectively untreatable, with heterogeneous penetrance, presentation and prognosis. To address the lack of effective treatment for these disorders, we exploited a recently developed mouse model that recapitulates common molecular features of heteroplasmic mtDNA disease in cardiac tissue: the m.5024C>T tRNAAla mouse. Through application of a programmable nuclease therapy approach, using systemically administered, mitochondrially targeted zinc-finger nucleases (mtZFN) delivered by adeno-associated virus, we induced specific elimination of mutant mtDNA across the heart, coupled to a reversion of molecular and biochemical phenotypes...
September 24, 2018: Nature Medicine
https://www.readbyqxmd.com/read/30250141/meeting-brain-computer-interface-user-performance-expectations-using-a-deep-neural-network-decoding-framework
#18
Michael A Schwemmer, Nicholas D Skomrock, Per B Sederberg, Jordyn E Ting, Gaurav Sharma, Marcia A Bockbrader, David A Friedenberg
Brain-computer interface (BCI) neurotechnology has the potential to reduce disability associated with paralysis by translating neural activity into control of assistive devices1-9 . Surveys of potential end-users have identified key BCI system features10-14 , including high accuracy, minimal daily setup, rapid response times, and multifunctionality. These performance characteristics are primarily influenced by the BCI's neural decoding algorithm1,15 , which is trained to associate neural activation patterns with intended user actions...
September 24, 2018: Nature Medicine
https://www.readbyqxmd.com/read/30250140/neuromodulation-of-lumbosacral-spinal-networks-enables-independent-stepping-after-complete-paraplegia
#19
Megan L Gill, Peter J Grahn, Jonathan S Calvert, Margaux B Linde, Igor A Lavrov, Jeffrey A Strommen, Lisa A Beck, Dimitry G Sayenko, Meegan G Van Straaten, Dina I Drubach, Daniel D Veith, Andrew R Thoreson, Cesar Lopez, Yury P Gerasimenko, V Reggie Edgerton, Kendall H Lee, Kristin D Zhao
Spinal sensorimotor networks that are functionally disconnected from the brain because of spinal cord injury (SCI) can be facilitated via epidural electrical stimulation (EES) to restore robust, coordinated motor activity in humans with paralysis1-3 . Previously, we reported a clinical case of complete sensorimotor paralysis of the lower extremities in which EES restored the ability to stand and the ability to control step-like activity while side-lying or suspended vertically in a body-weight support system (BWS)4 ...
September 24, 2018: Nature Medicine
https://www.readbyqxmd.com/read/30224757/classification-and-mutation-prediction-from-non-small-cell-lung-cancer-histopathology-images-using-deep-learning
#20
Nicolas Coudray, Paolo Santiago Ocampo, Theodore Sakellaropoulos, Navneet Narula, Matija Snuderl, David Fenyö, Andre L Moreira, Narges Razavian, Aristotelis Tsirigos
Visual inspection of histopathology slides is one of the main methods used by pathologists to assess the stage, type and subtype of lung tumors. Adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) are the most prevalent subtypes of lung cancer, and their distinction requires visual inspection by an experienced pathologist. In this study, we trained a deep convolutional neural network (inception v3) on whole-slide images obtained from The Cancer Genome Atlas to accurately and automatically classify them into LUAD, LUSC or normal lung tissue...
September 17, 2018: Nature Medicine
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