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Science Translational Medicine

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https://www.readbyqxmd.com/read/29141888/lung-cancer-associated-pulmonary-hypertension-role-of-microenvironmental-inflammation-based-on-tumor-cell-immune-cell-cross-talk
#1
Soni Savai Pullamsetti, Baktybek Kojonazarov, Samantha Storn, Henning Gall, Ylia Salazar, Janine Wolf, Andreas Weigert, Nefertiti El-Nikhely, Hossein Ardeschir Ghofrani, Gabriele A Krombach, Ludger Fink, Stefan Gattenlöhner, Ulf R Rapp, Ralph Theo Schermuly, Friedrich Grimminger, Werner Seeger, Rajkumar Savai
Dyspnea is a frequent, devastating, and poorly understood symptom of advanced lung cancer. In our cohort, among 519 patients who underwent a computed tomography scan for the diagnosis of lung cancer, 250 had a mean pulmonary artery diameter of >28 mm, indicating pulmonary hypertension (PH). In human lung cancer tissue, we consistently observed increased vascular remodeling and perivascular inflammatory cell accumulation (macrophages/lymphocytes). Vascular remodeling, PH, and perivascular inflammatory cell accumulation were mimicked in three mouse models of lung cancer (LLC1, KRas(LA2) , and cRaf-BxB)...
November 15, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29141887/apoptosis-in-mesenchymal-stromal-cells-induces-in-vivo-recipient-mediated-immunomodulation
#2
Antonio Galleu, Yanira Riffo-Vasquez, Cristina Trento, Cara Lomas, Luigi Dolcetti, Tik Shing Cheung, Malte von Bonin, Laura Barbieri, Krishma Halai, Sophie Ward, Ling Weng, Ronjon Chakraverty, Giovanna Lombardi, Fiona M Watt, Kim Orchard, David I Marks, Jane Apperley, Martin Bornhauser, Henning Walczak, Clare Bennett, Francesco Dazzi
The immunosuppressive activity of mesenchymal stromal cells (MSCs) is well documented. However, the therapeutic benefit is completely unpredictable, thus raising concerns about MSC efficacy. One of the affecting factors is the unresolved conundrum that, despite being immunosuppressive, MSCs are undetectable after administration. Therefore, understanding the fate of infused MSCs could help predict clinical responses. Using a murine model of graft-versus-host disease (GvHD), we demonstrate that MSCs are actively induced to undergo perforin-dependent apoptosis by recipient cytotoxic cells and that this process is essential to initiate MSC-induced immunosuppression...
November 15, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29141886/pd-l1-genetic-overexpression-or-pharmacological-restoration-in-hematopoietic-stem-and-progenitor-cells-reverses-autoimmune-diabetes
#3
Moufida Ben Nasr, Sara Tezza, Francesca D'Addio, Chiara Mameli, Vera Usuelli, Anna Maestroni, Domenico Corradi, Silvana Belletti, Luca Albarello, Gabriella Becchi, Gian Paolo Fadini, Christian Schuetz, James Markmann, Clive Wasserfall, Leonard Zon, Gian Vincenzo Zuccotti, Paolo Fiorina
Immunologically based clinical trials performed thus far have failed to cure type 1 diabetes (T1D), in part because these approaches were nonspecific. Because the disease is driven by autoreactive CD4 T cells, which destroy β cells, transplantation of hematopoietic stem and progenitor cells (HSPCs) has been recently offered as a therapy for T1D. Our transcriptomic profiling of HSPCs revealed that these cells are deficient in programmed death ligand 1 (PD-L1), an important immune checkpoint, in the T1D nonobese diabetic (NOD) mouse model...
November 15, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29141885/a-role-for-bacterial-urease-in-gut-dysbiosis-and-crohn-s-disease
#4
Josephine Ni, Ting-Chin David Shen, Eric Z Chen, Kyle Bittinger, Aubrey Bailey, Manuela Roggiani, Alexandra Sirota-Madi, Elliot S Friedman, Lillian Chau, Andrew Lin, Ilana Nissim, Justin Scott, Abigail Lauder, Christopher Hoffmann, Gloriany Rivas, Lindsey Albenberg, Robert N Baldassano, Jonathan Braun, Ramnik J Xavier, Clary B Clish, Marc Yudkoff, Hongzhe Li, Mark Goulian, Frederic D Bushman, James D Lewis, Gary D Wu
Gut dysbiosis during inflammatory bowel disease involves alterations in the gut microbiota associated with inflammation of the host gut. We used a combination of shotgun metagenomic sequencing and metabolomics to analyze fecal samples from pediatric patients with Crohn's disease and found an association between disease severity, gut dysbiosis, and bacterial production of free amino acids. Nitrogen flux studies using (15)N in mice showed that activity of bacterial urease, an enzyme that releases ammonia by hydrolysis of host urea, led to the transfer of murine host-derived nitrogen to the gut microbiota where it was used for amino acid synthesis...
November 15, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29141884/a-method-of-high-throughput-functional-evaluation-of-egfr-gene-variants-of-unknown-significance-in-cancer
#5
Shinji Kohsaka, Masaaki Nagano, Toshihide Ueno, Yoshiyuki Suehara, Takuo Hayashi, Naoko Shimada, Kazuhisa Takahashi, Kenji Suzuki, Kazuya Takamochi, Fumiyuki Takahashi, Hiroyuki Mano
Numerous variants of unknown significance (VUS) have been identified through large-scale cancer genome projects, although their functional relevance remains uninvestigated. We developed a mixed-all-nominated-mutants-in-one (MANO) method to evaluate the transforming potential and drug sensitivity of oncogene VUS in a high-throughput manner and applied this method to 101 nonsynonymous epidermal growth factor receptor (EGFR) mutants. We discovered a number of mutations conferring resistance to EGFR tyrosine kinase inhibitors (TKIs), including gefitinib- and erlotinib-insensitive missense mutations within exon 19 and other gefitinib-resistant mutations, such as L833V, A839T, V851I, A871T, and G873E...
November 15, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29118264/accumulation-of-5-oxoproline-in-myocardial-dysfunction-and-the-protective-effects-of-oplah
#6
Atze van der Pol, Andres Gil, Herman H W Silljé, Jasper Tromp, Ekaterina S Ovchinnikova, Inge Vreeswijk-Baudoin, Martijn Hoes, Ibrahim J Domian, Bart van de Sluis, Jan M van Deursen, Adriaan A Voors, Dirk J van Veldhuisen, Wiek H van Gilst, Eugene Berezikov, Pim van der Harst, Rudolf A de Boer, Rainer Bischoff, Peter van der Meer
In response to heart failure (HF), the heart reacts by repressing adult genes and expressing fetal genes, thereby returning to a more fetal-like gene profile. To identify genes involved in this process, we carried out transcriptional analysis on murine hearts at different stages of development and on hearts from adult mice with HF. Our screen identified Oplah, encoding for 5-oxoprolinase, a member of the γ-glutamyl cycle that functions by scavenging 5-oxoproline. OPLAH depletion occurred as a result of cardiac injury, leading to elevated 5-oxoproline and oxidative stress, whereas OPLAH overexpression improved cardiac function after ischemic injury...
November 8, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29118263/rna-binding-proteins-and-the-pathological-cascade-in-als-ftd-neurodegeneration
#7
REVIEW
Daisuke Ito, Mami Hatano, Norihiro Suzuki
Advanced genetic approaches have accelerated the identification of causative genes linked to the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Most of the disease-related proteins encoded by these genes form aggregates in the cellular machineries that regulate RNA and protein quality control in cells. Cross-talk among the signaling pathways governing these machineries leads to pathological cascades mediated by the accumulation of mutant RNA binding proteins...
November 8, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29118262/stress-hormones-promote-egfr-inhibitor-resistance-in-nsclc-implications-for-combinations-with-%C3%AE-blockers
#8
Monique B Nilsson, Huiying Sun, Lixia Diao, Pan Tong, Diane Liu, Lerong Li, Youhong Fan, Alissa Poteete, Seung-Oe Lim, Kathryn Howells, Vincent Haddad, Daniel Gomez, Hai Tran, Guillermo Armaiz Pena, Lecia V Sequist, James C Yang, Jing Wang, Edward S Kim, Roy Herbst, J Jack Lee, Waun Ki Hong, Ignacio Wistuba, Mien-Chie Hung, Anil K Sood, John V Heymach
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance mediated by T790M-independent mechanisms remains a major challenge in the treatment of non-small cell lung cancer (NSCLC). We identified a targetable mechanism of EGFR inhibitor resistance whereby stress hormones activate β2-adrenergic receptors (β2-ARs) on NSCLC cells, which cooperatively signal with mutant EGFR, resulting in the inactivation of the tumor suppressor, liver kinase B1 (LKB1), and subsequently induce interleukin-6 (IL-6) expression...
November 8, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29118261/erratum-for-the-research-article-dysbiosis-of-the-gut-microbiota-is-associated-with-hiv-disease-progression-and-tryptophan-catabolism-by-i-vujkovic-cvijin-r-m-dunham-s-iwai-m-c-maher-r-g-albright-m-j-broadhurst-r-d-hernandez-m-m-lederman-y-huang-m-somsouk-s
#9
https://www.readbyqxmd.com/read/29118260/circadian-actin-dynamics-drive-rhythmic-fibroblast-mobilization-during-wound-healing
#10
Nathaniel P Hoyle, Estere Seinkmane, Marrit Putker, Kevin A Feeney, Toke P Krogager, Johanna E Chesham, Liam K Bray, Justyn M Thomas, Ken Dunn, John Blaikley, John S O'Neill
Fibroblasts are primary cellular protagonists of wound healing. They also exhibit circadian timekeeping, which imparts an approximately 24-hour rhythm to their biological function. We interrogated the functional consequences of the cell-autonomous clockwork in fibroblasts using a proteome-wide screen for rhythmically expressed proteins. We observed temporal coordination of actin regulators that drives cell-intrinsic rhythms in actin dynamics. In consequence, the cellular clock modulates the efficiency of actin-dependent processes such as cell migration and adhesion, which ultimately affect the efficacy of wound healing...
November 8, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29118259/matrix-binding-checkpoint-immunotherapies-enhance-antitumor-efficacy-and-reduce-adverse-events
#11
Jun Ishihara, Kazuto Fukunaga, Ako Ishihara, Hans M Larsson, Lambert Potin, Peyman Hosseinchi, Gabriele Galliverti, Melody A Swartz, Jeffrey A Hubbell
Immune checkpoint blockade exhibits considerable antitumor activity, but previous studies have reported instances of severe treatment-related adverse events. We sought to explore local immune checkpoint blockade, with an antibody (Ab) form that would be retained intra- or peritumorally, limiting systemic exposure. To accomplish this, we conjugated the checkpoint blockade Abs to an extracellular matrix (ECM)-super-affinity peptide derived from placenta growth factor-2 (PlGF-2123-144). We show enhanced tissue retention and lower Ab concentrations in blood plasma after PlGF-2123-144 conjugation, reducing systemic side effects such as the risk of autoimmune diabetes...
November 8, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29093183/therapeutic-targeting-of-pgbd5-induced-dna-repair-dependency-in-pediatric-solid-tumors
#12
Anton G Henssen, Casie Reed, Eileen Jiang, Heathcliff Dorado Garcia, Jennifer von Stebut, Ian C MacArthur, Patrick Hundsdoerfer, Jun Hyun Kim, Elisa de Stanchina, Yasumichi Kuwahara, Hajime Hosoi, Neil J Ganem, Filemon Dela Cruz, Andrew L Kung, Johannes H Schulte, John H Petrini, Alex Kentsis
Despite intense efforts, the cure rates of childhood and adult solid tumors are not satisfactory. Resistance to intensive chemotherapy is common, and targets for molecular therapies are largely undefined. We have found that the majority of childhood solid tumors, including rhabdoid tumors, neuroblastoma, medulloblastoma, and Ewing sarcoma, express an active DNA transposase, PGBD5, that can promote site-specific genomic rearrangements in human cells. Using functional genetic approaches, we discovered that mouse and human cells deficient in nonhomologous end joining (NHEJ) DNA repair cannot tolerate the expression of PGBD5...
November 1, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29093182/a-completely-biological-off-the-shelf-arteriovenous-graft-that-recellularizes-in-baboons
#13
Zeeshan H Syedain, Melanie L Graham, Ty B Dunn, Timothy O'Brien, Sandra L Johnson, Robert J Schumacher, Robert T Tranquillo
Prosthetic arteriovenous grafts (AVGs) conventionally used for hemodialysis are associated with inferior primary patency rates and increased risk of infection compared with autogenous vein grafts. We tissue-engineered an AVG grown from neonatal human dermal fibroblasts entrapped in bovine fibrin gel that is then decellularized. This graft is both "off-the-shelf" (nonliving) and completely biological. Grafts that are 6 mm in diameter and about 15 cm in length were evaluated in a baboon model of hemodialysis access in an axillary-cephalic or axillary-brachial upper arm AVG construction procedure...
November 1, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29093181/a-precision-therapy-against-cancers-driven-by-kit-pdgfra-mutations
#14
Erica K Evans, Alexandra K Gardino, Joseph L Kim, Brian L Hodous, Adam Shutes, Alison Davis, Xing Julia Zhu, Oleg Schmidt-Kittler, Doug Wilson, Kevin Wilson, Lucian DiPietro, Yulian Zhang, Natasja Brooijmans, Timothy P LaBranche, Agnieszka Wozniak, Yemarshet K Gebreyohannes, Patrick Schöffski, Michael C Heinrich, Daniel J DeAngelo, Stephen Miller, Beni Wolf, Nancy Kohl, Timothy Guzi, Nicholas Lydon, Andy Boral, Christoph Lengauer
Targeting oncogenic kinase drivers with small-molecule inhibitors can have marked therapeutic benefit, especially when administered to an appropriate genomically defined patient population. Cancer genomics and mechanistic studies have revealed that heterogeneous mutations within a single kinase can result in various mechanisms of kinase activation. Therapeutic benefit to patients can best be optimized through an in-depth understanding of the disease-driving mutations combined with the ability to match these insights to tailored highly selective drugs...
November 1, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29093180/the-fcrn-inhibitor-rozanolixizumab-reduces-human-serum-igg-concentration-a-randomized-phase-1-study
#15
Peter Kiessling, Rocio Lledo-Garcia, Shikiko Watanabe, Grant Langdon, Diep Tran, Muhammad Bari, Louis Christodoulou, Emma Jones, Graham Price, Bryan Smith, Frank Brennan, Ian White, Stephen Jolles
Pathogenic immunoglobulin G (IgG) autoantibodies characterize some human autoimmune diseases; their high concentration and long half-life are dependent on recycling by the neonatal Fc receptor (FcRn). Inhibition of FcRn is an attractive new treatment concept for IgG-mediated autoimmune diseases. Rozanolixizumab (UCB7665; CA170_01519.g57 IgG4P) is an anti-human FcRn monoclonal antibody. In cynomolgus monkeys, rozanolixizumab reduced IgG (maximum 75 to 90% by about day 10), was well tolerated, and did not increase risk of infection...
November 1, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29093179/a-distinct-hematopoietic-stem-cell-population-for-rapid-multilineage-engraftment-in-nonhuman-primates
#16
Stefan Radtke, Jennifer E Adair, Morgan A Giese, Yan-Yi Chan, Zachary K Norgaard, Mark Enstrom, Kevin G Haworth, Lauren E Schefter, Hans-Peter Kiem
Hematopoietic reconstitution after bone marrow transplantation is thought to be driven by committed multipotent progenitor cells followed by long-term engrafting hematopoietic stem cells (HSCs). We observed a population of early-engrafting cells displaying HSC-like behavior, which persisted long-term in vivo in an autologous myeloablative transplant model in nonhuman primates. To identify this population, we characterized the phenotype and function of defined nonhuman primate hematopoietic stem and progenitor cell (HSPC) subsets and compared these to human HSPCs...
November 1, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29070701/longitudinal-genomic-surveillance-of-mrsa-in-the-uk-reveals-transmission-patterns-in-hospitals-and-the-community
#17
Francesc Coll, Ewan M Harrison, Michelle S Toleman, Sandra Reuter, Kathy E Raven, Beth Blane, Beverley Palmer, A Ruth M Kappeler, Nicholas M Brown, M Estée Török, Julian Parkhill, Sharon J Peacock
Genome sequencing has provided snapshots of the transmission of methicillin-resistant Staphylococcus aureus (MRSA) during suspected outbreaks in isolated hospital wards. Scale-up to populations is now required to establish the full potential of this technology for surveillance. We prospectively identified all individuals over a 12-month period who had at least one MRSA-positive sample processed by a routine diagnostic microbiology laboratory in the East of England, which received samples from three hospitals and 75 general practitioner (GP) practices...
October 25, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29070700/evolution-informed-forecasting-of-seasonal-influenza-a-h3n2
#18
Xiangjun Du, Aaron A King, Robert J Woods, Mercedes Pascual
Interpandemic or seasonal influenza A, currently subtypes H3N2 and H1N1, exacts an enormous annual burden both in terms of human health and economic impact. Incidence prediction ahead of season remains a challenge largely because of the virus' antigenic evolution. We propose a forecasting approach that incorporates evolutionary change into a mechanistic epidemiological model. The proposed models are simple enough that their parameters can be estimated from retrospective surveillance data. These models link amino acid sequences of hemagglutinin epitopes with a transmission model for seasonal H3N2 influenza, also informed by H1N1 levels...
October 25, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29070699/inhibition-of-pyruvate-dehydrogenase-kinase-improves-pulmonary-arterial-hypertension-in-genetically-susceptible-patients
#19
Evangelos D Michelakis, Vikram Gurtu, Linda Webster, Gareth Barnes, Geoffrey Watson, Luke Howard, John Cupitt, Ian Paterson, Richard B Thompson, Kelvin Chow, Declan P O'Regan, Lan Zhao, John Wharton, David G Kiely, Adam Kinnaird, Aristeidis E Boukouris, Chris White, Jayan Nagendran, Darren H Freed, Stephen J Wort, J Simon R Gibbs, Martin R Wilkins
Pulmonary arterial hypertension (PAH) is a progressive vascular disease with a high mortality rate. It is characterized by an occlusive vascular remodeling due to a pro-proliferative and antiapoptotic environment in the wall of resistance pulmonary arteries (PAs). Proliferating cells exhibit a cancer-like metabolic switch where mitochondrial glucose oxidation is suppressed, whereas glycolysis is up-regulated as the major source of adenosine triphosphate production. This multifactorial mitochondrial suppression leads to inhibition of apoptosis and downstream signaling promoting proliferation...
October 25, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29070698/transplantation-of-wild-type-mouse-hematopoietic-stem-and-progenitor-cells-ameliorates-deficits-in-a-mouse-model-of-friedreich-s-ataxia
#20
Celine J Rocca, Spencer M Goodman, Jennifer N Dulin, Joseph H Haquang, Ilya Gertsman, Jordan Blondelle, Janell L M Smith, Charles J Heyser, Stephanie Cherqui
Friedreich's ataxia (FRDA) is an incurable autosomal recessive neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin due to an intronic GAA-repeat expansion in the FXN gene. We report the therapeutic efficacy of transplanting wild-type mouse hematopoietic stem and progenitor cells (HSPCs) into the YG8R mouse model of FRDA. In the HSPC-transplanted YG8R mice, development of muscle weakness and locomotor deficits was abrogated as was degeneration of large sensory neurons in the dorsal root ganglia (DRGs) and mitochondrial capacity was improved in brain, skeletal muscle, and heart...
October 25, 2017: Science Translational Medicine
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