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Science Translational Medicine

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https://www.readbyqxmd.com/read/29769289/metarrestin-a-perinucleolar-compartment-inhibitor-effectively-suppresses-metastasis
#1
Kevin J Frankowski, Chen Wang, Samarjit Patnaik, Frank J Schoenen, Noel Southall, Dandan Li, Yaroslav Teper, Wei Sun, Irawati Kandela, Deqing Hu, Christopher Dextras, Zachary Knotts, Yansong Bian, John Norton, Steve Titus, Marzena A Lewandowska, Yiping Wen, Katherine I Farley, Lesley Mathews Griner, Jamey Sultan, Zhaojing Meng, Ming Zhou, Tomas Vilimas, Astin S Powers, Serguei Kozlov, Kunio Nagashima, Humair S Quadri, Min Fang, Charles Long, Ojus Khanolkar, Warren Chen, Jinsol Kang, Helen Huang, Eric Chow, Esthermanya Goldberg, Coral Feldman, Romi Xi, Hye Rim Kim, Gary Sahagian, Susan J Baserga, Andrew Mazar, Marc Ferrer, Wei Zheng, Ali Shilatifard, Jeffrey Aubé, Udo Rudloff, Juan Jose Marugan, Sui Huang
Metastasis remains a leading cause of cancer mortality due to the lack of specific inhibitors against this complex process. To identify compounds selectively targeting the metastatic state, we used the perinuclear compartment (PNC), a complex nuclear structure associated with metastatic behaviors of cancer cells, as a phenotypic marker for a high-content screen of over 140,000 structurally diverse compounds. Metarrestin, obtained through optimization of a screening hit, disassembles PNCs in multiple cancer cell lines, inhibits invasion in vitro, suppresses metastatic development in three mouse models of human cancer, and extends survival of mice in a metastatic pancreatic cancer xenograft model with no organ toxicity or discernable adverse effects...
May 16, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29769288/targeted-complement-inhibition-salvages-stressed-neurons-and-inhibits-neuroinflammation-after-stroke-in-mice
#2
Ali Alawieh, E Farris Langley, Stephen Tomlinson
Ischemic stroke results from the interruption of blood flow to the brain resulting in long-term motor and cognitive neurological deficits, and it is a leading cause of death and disability. Current interventions focus on the restoration of blood flow to limit neuronal death, but these treatments have a therapeutic window of only a few hours and do not address post-stroke cerebral inflammation. The complement system, a component of the innate immune system, is activated by natural immunoglobulin M (IgM) antibodies that recognize neoepitopes expressed in the brain after ischemic stroke...
May 16, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29769287/the-protective-role-of-macrophage-migration-inhibitory-factor-in-acute-kidney-injury-after-cardiac-surgery
#3
Christian Stoppe, Luisa Averdunk, Andreas Goetzenich, Josefin Soppert, Arnaud Marlier, Sandra Kraemer, Jil Vieten, Mark Coburn, Ana Kowark, Bong-Song Kim, Gernot Marx, Steffen Rex, Akinobu Ochi, Lin Leng, Gilbert Moeckel, Andreas Linkermann, Omar El Bounkari, Alexander Zarbock, Jürgen Bernhagen, Sonja Djudjaj, Richard Bucala, Peter Boor
Acute kidney injury (AKI) represents the most frequent complication after cardiac surgery. Macrophage migration inhibitory factor (MIF) is a stress-regulating cytokine that was shown to protect the heart from myocardial ischemia-reperfusion injury, but its role in the pathogenesis of AKI remains unknown. In an observational study, serum and urinary MIF was quantified in 60 patients scheduled for elective conventional cardiac surgery with the use of cardiopulmonary bypass. Cardiac surgery triggered an increase in MIF serum concentrations, and patients with high circulating MIF (>median) 12 hours after surgery had a significantly reduced risk of developing AKI (relative risk reduction, 72...
May 16, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29769286/targeted-inhibition-of-histone-h3k27-demethylation-is-effective-in-high-risk-neuroblastoma
#4
Timothy L Lochmann, Krista M Powell, Jungoh Ham, Konstantinos V Floros, Daniel A R Heisey, Richard I J Kurupi, Marissa L Calbert, Maninderjit S Ghotra, Patricia Greninger, Mikhail Dozmorov, Madhu Gowda, Andrew J Souers, C Patrick Reynolds, Cyril H Benes, Anthony C Faber
High-risk neuroblastoma is often distinguished by amplification of MYCN and loss of differentiation potential. We performed high-throughput drug screening of epigenetic-targeted therapies across a large and diverse tumor cell line panel and uncovered the hypersensitivity of neuroblastoma cells to GSK-J4, a small-molecule dual inhibitor of lysine 27 of histone 3 (H3K27) demethylases ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), and histone demethylase Jumonji D3 (JMJD3). Mechanistically, GSK-J4 induced neuroblastoma differentiation and endoplasmic reticulum (ER) stress, with accompanying up-regulation of p53 up-regulated modulator of apoptosis (PUMA) and induction of cell death...
May 16, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29769285/the-broad-socioeconomic-benefits-of-vaccination
#5
REVIEW
David E Bloom, Victoria Y Fan, J P Sevilla
Evaluating vaccination programs according to their broad socioeconomic benefits, beyond their health benefits, will help to address the twin problems of vaccine underutilization and weak incentives for vaccine innovation.
May 16, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29743351/survival-of-syngeneic-and-allogeneic-ipsc-derived-neural-precursors-after-spinal-grafting-in-minipigs
#6
Jan Strnadel, Cassiano Carromeu, Cedric Bardy, Michael Navarro, Oleksandr Platoshyn, Andreas N Glud, Silvia Marsala, Jozef Kafka, Atsushi Miyanohara, Tomohisa Kato, Takahiro Tadokoro, Michael P Hefferan, Kota Kamizato, Tetsuya Yoshizumi, Stefan Juhas, Jana Juhasova, Chak-Sum Ho, Taba Kheradmand, PeiXi Chen, Dasa Bohaciakova, Marian Hruska-Plochan, Andrew J Todd, Shawn P Driscoll, Thomas D Glenn, Samuel L Pfaff, Jiri Klima, Joseph Ciacci, Eric Curtis, Fred H Gage, Jack Bui, Kazuhiko Yamada, Alysson R Muotri, Martin Marsala
The use of autologous (or syngeneic) cells derived from induced pluripotent stem cells (iPSCs) holds great promise for future clinical use in a wide range of diseases and injuries. It is expected that cell replacement therapies using autologous cells would forego the need for immunosuppression, otherwise required in allogeneic transplantations. However, recent studies have shown the unexpected immune rejection of undifferentiated autologous mouse iPSCs after transplantation. Whether similar immunogenic properties are maintained in iPSC-derived lineage-committed cells (such as neural precursors) is relatively unknown...
May 9, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29743350/high-throughput-sequencing-of-the-t-cell-receptor-%C3%AE-gene-identifies-aggressive-early-stage-mycosis-fungoides
#7
Adele de Masson, John T O'Malley, Christopher P Elco, Sarah S Garcia, Sherrie J Divito, Elizabeth L Lowry, Marianne Tawa, David C Fisher, Phillip M Devlin, Jessica E Teague, Nicole R Leboeuf, Ilan R Kirsch, Harlan Robins, Rachael A Clark, Thomas S Kupper
Mycosis fungoides (MF), the most common cutaneous T cell lymphoma (CTCL) is a malignancy of skin-tropic memory T cells. Most MF cases present as early stage (stage I A/B, limited to the skin), and these patients typically have a chronic, indolent clinical course. However, a small subset of early-stage cases develop progressive and fatal disease. Because outcomes can be so different, early identification of this high-risk population is an urgent unmet clinical need. We evaluated the use of next-generation high-throughput DNA sequencing of the T cell receptor β gene ( TCRB ) in lesional skin biopsies to predict progression and survival in a discovery cohort of 208 patients with CTCL (177 with MF) from a 15-year longitudinal observational clinical study...
May 9, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29743349/the-root-problem-of-heart-valve-engineering
#8
REVIEW
Jonathan T Butcher
Acellular heart valve grafts optimized through computational modeling recellularize and function in sheep for up to 1 year (Emmert et al. , this issue).
May 9, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29743348/humidity-regulated-clca2-protects-the-epidermis-from-hyperosmotic-stress
#9
Kristin Seltmann, Michael Meyer, Jitka Sulcova, Tobias Kockmann, Ulrike Wehkamp, Stephan Weidinger, Ulrich Auf dem Keller, Sabine Werner
Low environmental humidity aggravates symptoms of the inflammatory skin disease atopic dermatitis (AD). Using mice that develop AD-like signs, we show that an increase in environmental humidity rescues their cutaneous inflammation and associated epidermal abnormalities. Quantitative proteomics analysis of epidermal lysates of mice kept at low or high humidity identified humidity-regulated proteins, including chloride channel accessory 3A2 (CLCA3A2), a protein with previously unknown function in the skin. The epidermis of patients with AD, organotypic skin cultures under dry conditions, and cultured keratinocytes exposed to hyperosmotic stress showed up-regulation of the nonorthologous human homolog CLCA2...
May 9, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29743347/computational-modeling-guides-tissue-engineered-heart-valve-design-for-long-term-in-vivo-performance-in-a-translational-sheep-model
#10
Maximilian Y Emmert, Boris A Schmitt, Sandra Loerakker, Bart Sanders, Hendrik Spriestersbach, Emanuela S Fioretta, Leon Bruder, Kerstin Brakmann, Sarah E Motta, Valentina Lintas, Petra E Dijkman, Laura Frese, Felix Berger, Frank P T Baaijens, Simon P Hoerstrup
Valvular heart disease is a major cause of morbidity and mortality worldwide. Current heart valve prostheses have considerable clinical limitations due to their artificial, nonliving nature without regenerative capacity. To overcome these limitations, heart valve tissue engineering (TE) aiming to develop living, native-like heart valves with self-repair, remodeling, and regeneration capacity has been suggested as next-generation technology. A major roadblock to clinically relevant, safe, and robust TE solutions has been the high complexity and variability inherent to bioengineering approaches that rely on cell-driven tissue remodeling...
May 9, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29743346/pgd2-dp2-receptor-activation-promotes-severe-viral-bronchiolitis-by-suppressing-ifn-%C3%AE-production
#11
Rhiannon B Werder, Jason P Lynch, Jennifer C Simpson, Vivian Zhang, Nick H Hodge, Matthew Poh, Elizabeth Forbes-Blom, Christina Kulis, Mark L Smythe, John W Upham, Kirsten Spann, Mark L Everard, Simon Phipps
Prostaglandin D2 (PGD2) signals through PGD2 receptor 2 (DP2, also known as CRTH2) on type 2 effector cells to promote asthma pathogenesis; however, little is known about its role during respiratory syncytial virus (RSV) bronchiolitis, a major risk factor for asthma development. We show that RSV infection up-regulated hematopoietic prostaglandin D synthase expression and increased PGD2 release by cultured human primary airway epithelial cells (AECs). Moreover, PGD2 production was elevated in nasopharyngeal samples from young infants hospitalized with RSV bronchiolitis compared to healthy controls...
May 9, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29720452/arginine-vasopressin-in-cerebrospinal-fluid-is-a-marker-of-sociality-in-nonhuman-primates
#12
Karen J Parker, Joseph P Garner, Ozge Oztan, Erna R Tarara, Jiang Li, Valentina Sclafani, Laura A Del Rosso, Katie Chun, Sean W Berquist, Michael G Chez, Sonia Partap, Antonio Y Hardan, Elliott H Sherr, John P Capitanio
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by core social impairments. ASD remains poorly understood because of the difficulty in studying disease biology directly in patients and the reliance on mouse models that lack clinically relevant, complex social cognition abilities. We use ethological observations in rhesus macaques to identify male monkeys with naturally occurring low sociality. These monkeys showed differences in specific neuropeptide and kinase signaling pathways compared to socially competent male monkeys...
May 2, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29720451/tlr7-agonists-induce-transient-viremia-and-reduce-the-viral-reservoir-in-siv-infected-rhesus-macaques-on-antiretroviral-therapy
#13
So-Yon Lim, Christa E Osuna, Peter T Hraber, Joe Hesselgesser, Jeffrey M Gerold, Tiffany L Barnes, Srisowmya Sanisetty, Michael S Seaman, Mark G Lewis, Romas Geleziunas, Michael D Miller, Tomas Cihlar, William A Lee, Alison L Hill, James B Whitney
Antiretroviral therapy (ART) can halt HIV-1 replication but fails to target the long-lived latent viral reservoir. Several pharmacological compounds have been evaluated for their ability to reverse HIV-1 latency, but none has demonstrably reduced the latent HIV-1 reservoir or affected viral rebound after the interruption of ART. We evaluated orally administered selective Toll-like receptor 7 (TLR7) agonists GS-986 and GS-9620 for their ability to induce transient viremia in rhesus macaques infected with simian immunodeficiency virus (SIV) and treated with suppressive ART...
May 2, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29720450/er-stress-in-prostate-cancer-a-therapeutically-exploitable-vulnerability
#14
REVIEW
Christopher Logothetis, Ana Aparicio, Timothy C Thompson
Cooperative oncogenic effects resulting from the loss of PTEN and overexpression of MYC overcome the deleterious effects of endoplasmic reticulum stress not only to promote the growth of aggressive prostate cancer but also to expose a new therapy target for this disease (Nguyen et al , this issue).
May 2, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29720449/development-of-a-stress-response-therapy-targeting-aggressive-prostate-cancer
#15
Hao G Nguyen, Crystal S Conn, Yae Kye, Lingru Xue, Craig M Forester, Janet E Cowan, Andrew C Hsieh, John T Cunningham, Charles Truillet, Feven Tameire, Michael J Evans, Christopher P Evans, Joy C Yang, Byron Hann, Constantinos Koumenis, Peter Walter, Peter R Carroll, Davide Ruggero
Oncogenic lesions up-regulate bioenergetically demanding cellular processes, such as protein synthesis, to drive cancer cell growth and continued proliferation. However, the hijacking of these key processes by oncogenic pathways imposes onerous cell stress that must be mitigated by adaptive responses for cell survival. The mechanism by which these adaptive responses are established, their functional consequences for tumor development, and their implications for therapeutic interventions remain largely unknown...
May 2, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29720448/microbial-ecology-perturbation-in-human-iga-deficiency
#16
Jehane Fadlallah, Hela El Kafsi, Delphine Sterlin, Catherine Juste, Christophe Parizot, Karim Dorgham, Gaëlle Autaa, Doriane Gouas, Mathieu Almeida, Patricia Lepage, Nicolas Pons, Emmanuelle Le Chatelier, Florence Levenez, Sean Kennedy, Nathalie Galleron, Jean-Paul Pais de Barros, Marion Malphettes, Lionel Galicier, David Boutboul, Alexis Mathian, Makoto Miyara, Eric Oksenhendler, Zahir Amoura, Joel Doré, Claire Fieschi, S Dusko Ehrlich, Martin Larsen, Guy Gorochov
Paradoxically, loss of immunoglobulin A (IgA), one of the most abundant antibodies, does not irrevocably lead to severe infections in humans but rather is associated with relatively mild respiratory infections, atopy, and autoimmunity. IgA might therefore also play covert roles, not uniquely associated with control of pathogens. We show that human IgA deficiency is not associated with massive quantitative perturbations of gut microbial ecology. Metagenomic analysis highlights an expected pathobiont expansion but a less expected depletion in some typically beneficial symbionts...
May 2, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29695457/a-digital-microfluidic-system-for-serological-immunoassays-in-remote-settings
#17
Alphonsus H C Ng, Ryan Fobel, Christian Fobel, Julian Lamanna, Darius G Rackus, Aimee Summers, Christopher Dixon, Michael D M Dryden, Charis Lam, Man Ho, Nooman S Mufti, Victor Lee, Mohd Afiq Mohd Asri, Edward A Sykes, M Dean Chamberlain, Rachael Joseph, Maurice Ope, Heather M Scobie, Alaine Knipes, Paul A Rota, Nina Marano, Paul M Chege, Mary Njuguna, Rosemary Nzunza, Ngina Kisangau, John Kiogora, Michael Karuingi, John Wagacha Burton, Peter Borus, Eugene Lam, Aaron R Wheeler
Serosurveys are useful for assessing population susceptibility to vaccine-preventable disease outbreaks. Although at-risk populations in remote areas could benefit from this type of information, they face several logistical barriers to implementation, such as lack of access to centralized laboratories, cold storage, and transport of samples. We describe a potential solution: a compact and portable, field-deployable, point-of-care system relying on digital microfluidics that can rapidly test a small volume of capillary blood for disease-specific antibodies...
April 25, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29695456/human-fetal-immune-cells-fight-back
#18
REVIEW
Claire A Chougnet
Immune dysregulation begins in utero, influenced by inflammation, maternal microchimerism, and the activation of fetal immune responses (Frascoli et al , this issue).
April 25, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29695455/alloreactive-fetal-t-cells-promote-uterine-contractility-in-preterm-labor-via-ifn-%C3%AE-and-tnf-%C3%AE
#19
Michela Frascoli, Lacy Coniglio, Russell Witt, Cerine Jeanty, Shannon Fleck-Derderian, Dana E Myers, Tzong-Hae Lee, Sheila Keating, Michael P Busch, Philip J Norris, Qizhi Tang, Giovanna Cruz, Lisa F Barcellos, Nardhy Gomez-Lopez, Roberto Romero, Tippi C MacKenzie
Healthy pregnancy is the most successful form of graft tolerance, whereas preterm labor (PTL) may represent a breakdown in maternal-fetal tolerance. Although maternal immune responses have been implicated in pregnancy complications, fetal immune responses against maternal antigens are often not considered. To examine the fetal immune system in the relevant clinical setting, we analyzed maternal and cord blood in patients with PTL and healthy term controls. We report here that the cord blood of preterm infants has higher amounts of inflammatory cytokines and a greater activation of dendritic cells...
April 25, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29695454/targeting-protein-biotinylation-enhances-tuberculosis-chemotherapy
#20
Divya Tiwari, Sae Woong Park, Maram M Essawy, Surendra Dawadi, Alan Mason, Madhumitha Nandakumar, Matthew Zimmerman, Marizel Mina, Hsin Pin Ho, Curtis A Engelhart, Thomas Ioerger, James C Sacchettini, Kyu Rhee, Sabine Ehrt, Courtney C Aldrich, Véronique Dartois, Dirk Schnappinger
Successful drug treatment for tuberculosis (TB) depends on the unique contributions of its component drugs. Drug resistance poses a threat to the efficacy of individual drugs and the regimens to which they contribute. Biologically and chemically validated targets capable of replacing individual components of current TB chemotherapy are a major unmet need in TB drug development. We demonstrate that chemical inhibition of the bacterial biotin protein ligase (BPL) with the inhibitor Bio-AMS (5'-[ N -(d-biotinoyl)sulfamoyl]amino-5'-deoxyadenosine) killed Mycobacterium tuberculosis ( Mtb ), the bacterial pathogen causing TB...
April 25, 2018: Science Translational Medicine
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