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Science Translational Medicine

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https://www.readbyqxmd.com/read/28931657/neutrophil-transfer-of-mir-223-to-lung-epithelial-cells-dampens-acute-lung-injury-in-mice
#1
Viola Neudecker, Kelley S Brodsky, Eric T Clambey, Eric P Schmidt, Thomas A Packard, Bennett Davenport, Theodore J Standiford, Tingting Weng, Ashley A Fletcher, Lea Barthel, Joanne C Masterson, Glenn T Furuta, Chunyan Cai, Michael R Blackburn, Adit A Ginde, Michael W Graner, William J Janssen, Rachel L Zemans, Christopher M Evans, Ellen L Burnham, Dirk Homann, Marc Moss, Simone Kreth, Kai Zacharowski, Peter M Henson, Holger K Eltzschig
Intercellular transfer of microRNAs can mediate communication between critical effector cells. We hypothesized that transfer of neutrophil-derived microRNAs to pulmonary epithelial cells could alter mucosal gene expression during acute lung injury. Pulmonary-epithelial microRNA profiling during coculture of alveolar epithelial cells with polymorphonuclear neutrophils (PMNs) revealed a selective increase in lung epithelial cell expression of microRNA-223 (miR-223). Analysis of PMN-derived supernatants showed activation-dependent release of miR-223 and subsequent transfer to alveolar epithelial cells during coculture in vitro or after ventilator-induced acute lung injury in mice...
September 20, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28931656/single-cell-analyses-to-tailor-treatments
#2
REVIEW
Alex K Shalek, Mikael Benson
Single-cell RNA-seq could play a key role in personalized medicine by facilitating characterization of cells, pathways, and genes associated with human diseases such as cancer.
September 20, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28931655/protection-against-a-mixed-shiv-challenge-by-a-broadly-neutralizing-antibody-cocktail
#3
Boris Julg, Po-Ting Liu, Kshitij Wagh, William M Fischer, Peter Abbink, Noe B Mercado, James B Whitney, Joseph P Nkolola, Katherine McMahan, Lawrence J Tartaglia, Erica N Borducchi, Shreeya Khatiwada, Megha Kamath, Jake A LeSuer, Michael S Seaman, Stephen D Schmidt, John R Mascola, Dennis R Burton, Bette T Korber, Dan H Barouch
HIV-1 sequence diversity presents a major challenge for the clinical development of broadly neutralizing antibodies (bNAbs) for both therapy and prevention. Sequence variation in critical bNAb epitopes has been observed in most HIV-1-infected individuals and can lead to viral escape after bNAb monotherapy in humans. We show that viral sequence diversity can limit both the therapeutic and prophylactic efficacy of bNAbs in rhesus monkeys. We first demonstrate that monotherapy with the V3 glycan-dependent antibody 10-1074, but not PGT121, results in rapid selection of preexisting viral variants containing N332/S334 escape mutations and loss of therapeutic efficacy in simian-HIV (SHIV)-SF162P3-infected rhesus monkeys...
September 20, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28931654/cancer-immunotherapy-with-recombinant-poliovirus-induces-ifn-dominant-activation-of-dendritic-cells-and-tumor-antigen-specific-ctls
#4
Michael C Brown, Eda K Holl, David Boczkowski, Elena Dobrikova, Mubeen Mosaheb, Vidya Chandramohan, Darell D Bigner, Matthias Gromeier, Smita K Nair
Tumors thrive in an immunosuppressive microenvironment that impedes antitumor innate and adaptive immune responses. Thus, approaches that can overcome immunosuppression and engage antitumor immunity are needed. This study defines the adjuvant and cancer immunotherapy potential of the recombinant poliovirus/rhinovirus chimera PVSRIPO. PVSRIPO is currently in clinical trials against recurrent World Health Organization grade IV malignant glioma, a notoriously treatment-refractory cancer. Cytopathogenic infection of neoplastic cells releases the proteome and exposes pathogen- and damage-associated molecular patterns...
September 20, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28931653/combined-ox40l-and-mtor-blockade-controls-effector-t-cell-activation-while-preserving-treg-reconstitution-after-transplant
#5
Victor Tkachev, Scott N Furlan, Benjamin Watkins, Daniel J Hunt, Hengqi Betty Zheng, Angela Panoskaltsis-Mortari, Kayla Betz, Melanie Brown, John B Schell, Katie Zeleski, Alison Yu, Ian Kirby, Sarah Cooley, Jeffrey S Miller, Bruce R Blazar, Duncan Casson, Phil Bland-Ward, Leslie S Kean
A critical question facing the field of transplantation is how to control effector T cell (Teff) activation while preserving regulatory T cell (Treg) function. Standard calcineurin inhibitor-based strategies can partially control Teffs, but breakthrough activation still occurs, and these agents are antagonistic to Treg function. Conversely, mechanistic target of rapamycin (mTOR) inhibition with sirolimus is more Treg-compatible but is inadequate to fully control Teff activation. In contrast, blockade of OX40L signaling has the capacity to partially control Teff activation despite maintaining Treg function...
September 20, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28931652/responsive-monitoring-of-mitochondrial-redox-states-in-heart-muscle-predicts-impending-cardiac-arrest
#6
Dorothy A Perry, Joshua W Salvin, Padraic Romfh, Peili Chen, Kalyani Krishnamurthy, Lindsay M Thomson, Brian D Polizzotti, Francis X McGowan, Daryoosh Vakhshoori, John N Kheir
Assessing the adequacy of oxygen delivery to tissues is vital, particularly in the fields of intensive care medicine and surgery. As oxygen delivery to a cell becomes deficient, changes in mitochondrial redox state precede changes in cellular function. We describe a technique for the continuous monitoring of the mitochondrial redox state on the epicardial surface using resonance Raman spectroscopy. We quantify the reduced fraction of specific electron transport chain cytochromes, a metric we name the resonance Raman reduced mitochondrial ratio (3RMR)...
September 20, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28904227/peptide-probes-detect-misfolded-transthyretin-oligomers-in-plasma-of-hereditary-amyloidosis-patients
#7
Joseph D Schonhoft, Cecilia Monteiro, Lars Plate, Yvonne S Eisele, John M Kelly, Daniel Boland, Christopher G Parker, Benjamin F Cravatt, Sergio Teruya, Stephen Helmke, Mathew Maurer, John Berk, Yoshiki Sekijima, Marta Novais, Teresa Coelho, Evan T Powers, Jeffery W Kelly
Increasing evidence supports the hypothesis that soluble misfolded protein assemblies contribute to the degeneration of postmitotic tissue in amyloid diseases. However, there is a dearth of reliable nonantibody-based probes for selectively detecting oligomeric aggregate structures circulating in plasma or deposited in tissues, making it difficult to scrutinize this hypothesis in patients. Hence, understanding the structure-proteotoxicity relationships driving amyloid diseases remains challenging, hampering the development of early diagnostic and novel treatment strategies...
September 13, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28904226/tumor-lymphangiogenesis-promotes-t-cell-infiltration-and-potentiates-immunotherapy-in-melanoma
#8
Manuel Fankhauser, Maria A S Broggi, Lambert Potin, Natacha Bordry, Laura Jeanbart, Amanda W Lund, Elodie Da Costa, Sylvie Hauert, Marcela Rincon-Restrepo, Christopher Tremblay, Elena Cabello, Krisztian Homicsko, Olivier Michielin, Douglas Hanahan, Daniel E Speiser, Melody A Swartz
In melanoma, vascular endothelial growth factor-C (VEGF-C) expression and consequent lymphangiogenesis correlate with metastasis and poor prognosis. VEGF-C also promotes tumor immunosuppression, suggesting that lymphangiogenesis inhibitors may be clinically useful in combination with immunotherapy. We addressed this concept in mouse melanoma models with VEGF receptor-3 (VEGFR-3)-blocking antibodies and unexpectedly found that VEGF-C signaling enhanced rather than suppressed the response to immunotherapy. We further found that this effect was mediated by VEGF-C-induced CCL21 and tumor infiltration of naïve T cells before immunotherapy because CCR7 blockade reversed the potentiating effects of VEGF-C...
September 13, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28904225/endothelial-aplnr-regulates-tissue-fatty-acid-uptake-and-is-essential-for-apelin-s-glucose-lowering-effects
#9
Cheol Hwangbo, Jingxia Wu, Irinna Papangeli, Takaomi Adachi, Bikram Sharma, Saejeong Park, Lina Zhao, Hyekyung Ju, Gwang-Woong Go, Guoliang Cui, Mohammed Inayathullah, Judith K Job, Jayakumar Rajadas, Stephanie L Kwei, Ming O Li, Alan R Morrison, Thomas Quertermous, Arya Mani, Kristy Red-Horse, Hyung J Chun
Treatment of type 2 diabetes mellitus continues to pose an important clinical challenge, with most existing therapies lacking demonstrable ability to improve cardiovascular outcomes. The atheroprotective peptide apelin (APLN) enhances glucose utilization and improves insulin sensitivity. However, the mechanism of these effects remains poorly defined. We demonstrate that the expression of APLNR (APJ/AGTRL1), the only known receptor for apelin, is predominantly restricted to the endothelial cells (ECs) of multiple adult metabolic organs, including skeletal muscle and adipose tissue...
September 13, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28904224/targeted-inhibition-of-gq-signaling-induces-airway-relaxation-in-mouse-models-of-asthma
#10
Michaela Matthey, Richard Roberts, Alexander Seidinger, Annika Simon, Ralf Schröder, Markus Kuschak, Suvi Annala, Gabriele M König, Christa E Müller, Ian P Hall, Evi Kostenis, Bernd K Fleischmann, Daniela Wenzel
Obstructive lung diseases are common causes of disability and death worldwide. A hallmark feature is aberrant activation of Gq protein-dependent signaling cascades. Currently, drugs targeting single G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors (GPCRs) are used to reduce airway tone. However, therapeutic efficacy is often limited, because various GPCRs contribute to bronchoconstriction, and chronic exposure to receptor-activating medications results in desensitization. We therefore hypothesized that pharmacological Gq inhibition could serve as a central mechanism to achieve efficient therapeutic bronchorelaxation...
September 13, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28878013/new-class-of-precision-antimicrobials-redefines-role-of-clostridium-difficile-s-layer-in-virulence-and-viability
#11
Joseph A Kirk, Dana Gebhart, Anthony M Buckley, Stephen Lok, Dean Scholl, Gillian R Douce, Gregory R Govoni, Robert P Fagan
There is a medical need for antibacterial agents that do not damage the resident gut microbiota or promote the spread of antibiotic resistance. We recently described a prototypic precision bactericidal agent, Av-CD291.2, which selectively kills specific Clostridium difficile strains and prevents them from colonizing mice. We have since selected two Av-CD291.2-resistant mutants that have a surface (S)-layer-null phenotype due to distinct point mutations in the slpA gene. Using newly identified bacteriophage receptor binding proteins for targeting, we constructed a panel of Avidocin-CDs that kills diverse C...
September 6, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28878012/synthetic-oligosaccharides-can-replace-animal-sourced-low-molecular-weight-heparins
#12
Yongmei Xu, Kasemsiri Chandarajoti, Xing Zhang, Vijayakanth Pagadala, Wenfang Dou, Debra Moorman Hoppensteadt, Erica M Sparkenbaugh, Brian Cooley, Sharon Daily, Nigel S Key, Diana Severynse-Stevens, Jawed Fareed, Robert J Linhardt, Rafal Pawlinski, Jian Liu
Low-molecular weight heparin (LMWH) is used clinically to treat clotting disorders. As an animal-sourced product, LMWH is a highly heterogeneous mixture, and its anticoagulant activity is not fully reversible by protamine. Furthermore, the reliability of the LMWH supply chain is a concern for regulatory agencies. We demonstrate the synthesis of heparin dodecasaccharides (12-mers) at the gram scale. In vitro experiments demonstrate that the anticoagulant activity of the 12-mers could be reversed using protamine...
September 6, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28878011/nondestructive-tissue-analysis-for-ex-vivo-and-in-vivo-cancer-diagnosis-using-a-handheld-mass-spectrometry-system
#13
Jialing Zhang, John Rector, John Q Lin, Jonathan H Young, Marta Sans, Nitesh Katta, Noah Giese, Wendong Yu, Chandandeep Nagi, James Suliburk, Jinsong Liu, Alena Bensussan, Rachel J DeHoog, Kyana Y Garza, Benjamin Ludolph, Anna G Sorace, Anum Syed, Aydin Zahedivash, Thomas E Milner, Livia S Eberlin
Conventional methods for histopathologic tissue diagnosis are labor- and time-intensive and can delay decision-making during diagnostic and therapeutic procedures. We report the development of an automated and biocompatible handheld mass spectrometry device for rapid and nondestructive diagnosis of human cancer tissues. The device, named MasSpec Pen, enables controlled and automated delivery of a discrete water droplet to a tissue surface for efficient extraction of biomolecules. We used the MasSpec Pen for ex vivo molecular analysis of 20 human cancer thin tissue sections and 253 human patient tissue samples including normal and cancerous tissues from breast, lung, thyroid, and ovary...
September 6, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28878010/broadly-neutralizing-antibodies-targeting-the-hiv-1-envelope-v2-apex-confer-protection-against-a-clade-c-shiv-challenge
#14
Boris Julg, Lawrence J Tartaglia, Brandon F Keele, Kshitij Wagh, Amarendra Pegu, Devin Sok, Peter Abbink, Stephen D Schmidt, Keyun Wang, Xuejun Chen, M Gordon Joyce, Ivelin S Georgiev, Misook Choe, Peter D Kwong, Nicole A Doria-Rose, Khoa Le, Mark K Louder, Robert T Bailer, Penny L Moore, Bette Korber, Michael S Seaman, Salim S Abdool Karim, Lynn Morris, Richard A Koup, John R Mascola, Dennis R Burton, Dan H Barouch
Neutralizing antibodies to the V2 apex antigenic region of the HIV-1 envelope (Env) trimer are among the most prevalent cross-reactive antibodies elicited by natural infection. Two recently described V2-specific antibodies, PGDM1400 and CAP256-VRC26.25, have demonstrated exquisite potency and neutralization breadth against HIV-1. However, little data exist on the protective efficacy of V2-specific neutralizing antibodies. We created a novel SHIV-325c viral stock that included a clade C HIV-1 envelope and was susceptible to neutralization by both of these antibodies...
September 6, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28855399/subcutaneous-drug-delivery-an-evolving-enterprise
#15
REVIEW
Graham B Jones, David S Collins, Michael W Harrison, Nagarajan R Thyagarajapuram, Justin M Wright
Recent advances in subcutaneous drug delivery and device design are transforming the biopharmaceutical sector and improving patient care.
August 30, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28855398/targeting-the-vascular-and-perivascular-niches-as-a-regenerative-therapy-for-lung-and-liver-fibrosis
#16
Zhongwei Cao, Tinghong Ye, Yue Sun, Gaili Ji, Koji Shido, Yutian Chen, Lin Luo, Feifei Na, Xiaoyan Li, Zhen Huang, Jane L Ko, Vivek Mittal, Lina Qiao, Chong Chen, Fernando J Martinez, Shahin Rafii, Bi-Sen Ding
The regenerative capacity of lung and liver is sometimes impaired by chronic or overwhelming injury. Orthotopic transplantation of parenchymal stem cells to damaged organs might reinstate their self-repair ability. However, parenchymal cell engraftment is frequently hampered by the microenvironment in diseased recipient organs. We show that targeting both the vascular niche and perivascular fibroblasts establishes "hospitable soil" to foster the incorporation of "seed," in this case, the engraftment of parenchymal cells in injured organs...
August 30, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28855397/inflammatory-monocytes-expressing-tissue-factor-drive-siv-and-hiv-coagulopathy
#17
Melissa E Schechter, Bruno B Andrade, Tianyu He, George Haret Richter, Kevin W Tosh, Benjamin B Policicchio, Amrit Singh, Kevin D Raehtz, Virginia Sheikh, Dongying Ma, Egidio Brocca-Cofano, Cristian Apetrei, Russel Tracy, Ruy M Ribeiro, Alan Sher, Ivo M B Francischetti, Ivona Pandrea, Irini Sereti
In HIV infection, persistent inflammation despite effective antiretroviral therapy is linked to increased risk of noninfectious chronic complications such as cardiovascular and thromboembolic disease. A better understanding of inflammatory and coagulation pathways in HIV infection is needed to optimize clinical care. Markers of monocyte activation and coagulation independently predict morbidity and mortality associated with non-AIDS events. We identified a specific subset of monocytes that express tissue factor (TF), persist after virological suppression, and trigger the coagulation cascade by activating factor X...
August 30, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28855396/increased-adaptive-immune-responses-and-proper-feedback-regulation-protect-against-clinical-dengue
#18
Etienne Simon-Lorière, Veasna Duong, Ahmed Tawfik, Sivlin Ung, Sowath Ly, Isabelle Casadémont, Matthieu Prot, Noémie Courtejoie, Kevin Bleakley, Philippe Buchy, Arnaud Tarantola, Philippe Dussart, Tineke Cantaert, Anavaj Sakuntabhai
Clinical symptoms of dengue virus (DENV) infection, the most prevalent arthropod-borne viral disease, range from classical mild dengue fever to severe, life-threatening dengue shock syndrome. However, most DENV infections cause few or no symptoms. Asymptomatic DENV-infected patients provide a unique opportunity to decipher the host immune responses leading to virus elimination without negative impact on an individual's health. We used an integrated approach of transcriptional profiling and immunological analysis to compare a Cambodian population of strictly asymptomatic viremic individuals with clinical dengue patients...
August 30, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28855395/rare-autosomal-trisomies-revealed-by-maternal-plasma-dna-sequencing-suggest-increased-risk-of-feto-placental-disease
#19
Mark D Pertile, Meredith Halks-Miller, Nicola Flowers, Catalin Barbacioru, Sarah L Kinnings, Darcy Vavrek, William K Seltzer, Diana W Bianchi
Whole-genome sequencing (WGS) of maternal plasma cell-free DNA (cfDNA) can potentially evaluate all 24 chromosomes to identify abnormalities of the placenta, fetus, or pregnant woman. Current bioinformatics algorithms typically only report on chromosomes 21, 18, 13, X, and Y; sequencing results from other chromosomes may be masked. We hypothesized that by systematically analyzing WGS data from all chromosomes, we could identify rare autosomal trisomies (RATs) to improve understanding of feto-placental biology...
August 30, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28835518/a-lower-extremity-exoskeleton-improves-knee-extension-in-children-with-crouch-gait-from-cerebral-palsy
#20
Zachary F Lerner, Diane L Damiano, Thomas C Bulea
The ability to walk contributes considerably to physical health and overall well-being, particularly in children with motor disability, and is therefore prioritized as a rehabilitation goal. However, half of ambulatory children with cerebral palsy (CP), the most prevalent childhood movement disorder, cease to walk in adulthood. Robotic gait trainers have shown positive outcomes in initial studies, but these clinic-based systems are limited to short-term programs of insufficient length to maintain improved function in a lifelong disability such as CP...
August 23, 2017: Science Translational Medicine
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