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Science Translational Medicine

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https://www.readbyqxmd.com/read/29343626/engineering-precision-biomaterials-for-personalized-medicine
#1
REVIEW
Brian A Aguado, Joseph C Grim, Adrianne M Rosales, Jana J Watson-Capps, Kristi S Anseth
As the demand for precision medicine continues to rise, the "one-size-fits-all" approach to designing medical devices and therapies is becoming increasingly outdated. Biomaterials have considerable potential for transforming precision medicine, but individual patient complexity often necessitates integrating multiple functions into a single device to successfully tailor personalized therapies. Here, we introduce an engineering strategy based on unit operations to provide a unified vocabulary and contextual framework to aid the design of biomaterial-based devices and accelerate their translation...
January 17, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29343625/methicillin-resistant-staphylococcus-aureus-causes-sustained-collecting-lymphatic-vessel-dysfunction
#2
Dennis Jones, Eelco F J Meijer, Cedric Blatter, Shan Liao, Ethel R Pereira, Echoe M Bouta, Keehoon Jung, Shan Min Chin, Peigen Huang, Lance L Munn, Benjamin J Vakoc, Michael Otto, Timothy P Padera
Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of morbidity and mortality worldwide and is a frequent cause of skin and soft tissue infections (SSTIs). Lymphedema-fluid accumulation in tissue caused by impaired lymphatic vessel function-is a strong risk factor for SSTIs. SSTIs also frequently recur in patients and sometimes lead to acquired lymphedema. However, the mechanism of how SSTIs can be both the consequence and the cause of lymphatic vessel dysfunction is not known. Intravital imaging in mice revealed an acute reduction in both lymphatic vessel contractility and lymph flow after localized MRSA infection...
January 17, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29343624/inhalation-of-peptide-loaded-nanoparticles-improves-heart-failure
#3
Michele Miragoli, Paola Ceriotti, Michele Iafisco, Marco Vacchiano, Nicolò Salvarani, Alessio Alogna, Pierluigi Carullo, Gloria Belén Ramirez-Rodríguez, Tatiana Patrício, Lorenzo Degli Esposti, Francesca Rossi, Francesca Ravanetti, Silvana Pinelli, Rossella Alinovi, Marco Erreni, Stefano Rossi, Gianluigi Condorelli, Heiner Post, Anna Tampieri, Daniele Catalucci
Peptides are highly selective and efficacious for the treatment of cardiovascular and other diseases. However, it is currently not possible to administer peptides for cardiac-targeting therapy via a noninvasive procedure, thus representing scientific and technological challenges. We demonstrate that inhalation of small (<50 nm in diameter) biocompatible and biodegradable calcium phosphate nanoparticles (CaPs) allows for rapid translocation of CaPs from the pulmonary tree to the bloodstream and to the myocardium, where their cargo is quickly released...
January 17, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29343623/identifying-dna-methylation-biomarkers-for-non-endoscopic-detection-of-barrett-s-esophagus
#4
Helen R Moinova, Thomas LaFramboise, James D Lutterbaugh, Apoorva Krishna Chandar, John Dumot, Ashley Faulx, Wendy Brock, Omar De la Cruz Cabrera, Kishore Guda, Jill S Barnholtz-Sloan, Prasad G Iyer, Marcia I Canto, Jean S Wang, Nicholas J Shaheen, Prashanti N Thota, Joseph E Willis, Amitabh Chak, Sanford D Markowitz
We report a biomarker-based non-endoscopic method for detecting Barrett's esophagus (BE) based on detecting methylated DNAs retrieved via a swallowable balloon-based esophageal sampling device. BE is the precursor of, and a major recognized risk factor for, developing esophageal adenocarcinoma. Endoscopy, the current standard for BE detection, is not cost-effective for population screening. We performed genome-wide screening to ascertain regions targeted for recurrent aberrant cytosine methylation in BE, identifying high-frequency methylation within the CCNA1 locus...
January 17, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29343622/enhanced-preclinical-antitumor-activity-of-m7824-a-bifunctional-fusion-protein-simultaneously-targeting-pd-l1-and-tgf-%C3%AE
#5
Yan Lan, Dong Zhang, Chunxiao Xu, Kenneth W Hance, Bo Marelli, Jin Qi, Huakui Yu, Guozhong Qin, Aroop Sircar, Vivian M Hernández, Molly H Jenkins, Rachel E Fontana, Amit Deshpande, George Locke, Helen Sabzevari, Laszlo Radvanyi, Kin-Ming Lo
Antibodies targeting immune checkpoints are emerging as potent and viable cancer therapies, but not all patients respond to these as single agents. Concurrently targeting additional immunosuppressive pathways is a promising approach to enhance immune checkpoint blockade, and bifunctional molecules designed to target two pathways simultaneously may provide a strategic advantage over the combination of two single agents. M7824 (MSB0011359C) is a bifunctional fusion protein composed of a monoclonal antibody against programmed death ligand 1 (PD-L1) fused to the extracellular domain of human transforming growth factor-β (TGF-β) receptor II, which functions as a "trap" for all three TGF-β isoforms...
January 17, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29321260/mechanobiologically-optimized-3d-titanium-mesh-scaffolds-enhance-bone-regeneration-in-critical-segmental-defects-in-sheep
#6
Anne-Marie Pobloth, Sara Checa, Hajar Razi, Ansgar Petersen, James C Weaver, Katharina Schmidt-Bleek, Markus Windolf, Andras Á Tatai, Claudia P Roth, Klaus-Dieter Schaser, Georg N Duda, Philipp Schwabe
Three-dimensional (3D) titanium-mesh scaffolds offer many advantages over autologous bone grafting for the regeneration of challenging large segmental bone defects. Our study supports the hypothesis that endogenous bone defect regeneration can be promoted by mechanobiologically optimized Ti-mesh scaffolds. Using finite element techniques, two mechanically distinct Ti-mesh scaffolds were designed in a honeycomb-like configuration to minimize stress shielding while ensuring resistance against mechanical failure...
January 10, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29321259/plasmacytoid-dendritic-cells-promote-systemic-sclerosis-with-a-key-role-for-tlr8
#7
Marie Dominique Ah Kioon, Claudio Tripodo, David Fernandez, Kyriakos A Kirou, Robert F Spiera, Mary K Crow, Jessica K Gordon, Franck J Barrat
Systemic sclerosis (SSc) is a multisystem life-threatening fibrosing disorder that lacks effective treatment. The link between the inflammation observed in organs such as the skin and profibrotic mechanisms is not well understood. The plasmacytoid dendritic cell (pDC) is a key cell type mediating Toll-like receptor (TLR)-induced inflammation in autoimmune disease patients, including lupus and skin diseases with interface dermatitis. However, the role of pDCs in fibrosis is less clear. We show that pDCs infiltrate the skin of SSc patients and are chronically activated, leading to secretion of interferon-α (IFN-α) and CXCL4, which are both hallmarks of the disease...
January 10, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29321258/functional-variants-in-the-lrrk2-gene-confer-shared-effects-on-risk-for-crohn-s-disease-and-parkinson-s-disease
#8
Ken Y Hui, Heriberto Fernandez-Hernandez, Jianzhong Hu, Adam Schaffner, Nathan Pankratz, Nai-Yun Hsu, Ling-Shiang Chuang, Shai Carmi, Nicole Villaverde, Xianting Li, Manual Rivas, Adam P Levine, Xiuliang Bao, Philippe R Labrias, Talin Haritunians, Darren Ruane, Kyle Gettler, Ernie Chen, Dalin Li, Elena R Schiff, Nikolas Pontikos, Nir Barzilai, Steven R Brant, Susan Bressman, Adam S Cheifetz, Lorraine N Clark, Mark J Daly, Robert J Desnick, Richard H Duerr, Seymour Katz, Todd Lencz, Richard H Myers, Harry Ostrer, Laurie Ozelius, Haydeh Payami, Yakov Peter, John D Rioux, Anthony W Segal, William K Scott, Mark S Silverberg, Jeffery M Vance, Iban Ubarretxena-Belandia, Tatiana Foroud, Gil Atzmon, Itsik Pe'er, Yiannis Ioannou, Dermot P B McGovern, Zhenyu Yue, Eric E Schadt, Judy H Cho, Inga Peter
Crohn's disease (CD), a form of inflammatory bowel disease, has a higher prevalence in Ashkenazi Jewish than in non-Jewish European populations. To define the role of nonsynonymous mutations, we performed exome sequencing of Ashkenazi Jewish patients with CD, followed by array-based genotyping and association analysis in 2066 CD cases and 3633 healthy controls. We detected association signals in the LRRK2 gene that conferred risk for CD (N2081D variant, P = 9.5 × 10-10) or protection from CD (N551K variant, tagging R1398H-associated haplotype, P = 3...
January 10, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29321257/the-antimicrobial-peptide-saap-148-combats-drug-resistant-bacteria-and-biofilms
#9
Anna de Breij, Martijn Riool, Robert A Cordfunke, Nermina Malanovic, Leonie de Boer, Roman I Koning, Elisabeth Ravensbergen, Marnix Franken, Tobias van der Heijde, Bouke K Boekema, Paulus H S Kwakman, Niels Kamp, Abdelouahab El Ghalbzouri, Karl Lohner, Sebastian A J Zaat, Jan W Drijfhout, Peter H Nibbering
Development of novel antimicrobial agents is a top priority in the fight against multidrug-resistant (MDR) and persistent bacteria. We developed a panel of synthetic antimicrobial and antibiofilm peptides (SAAPs) with enhanced antimicrobial activities compared to the parent peptide, human antimicrobial peptide LL-37. Our lead peptide SAAP-148 was more efficient in killing bacteria under physiological conditions in vitro than many known preclinical- and clinical-phase antimicrobial peptides. SAAP-148 killed MDR pathogens without inducing resistance, prevented biofilm formation, and eliminated established biofilms and persister cells...
January 10, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29298869/intravenous-delivery-of-oncolytic-reovirus-to-brain-tumor-patients-immunologically-primes-for-subsequent-checkpoint-blockade
#10
Adel Samson, Karen J Scott, David Taggart, Emma J West, Erica Wilson, Gerard J Nuovo, Simon Thomson, Robert Corns, Ryan K Mathew, Martin J Fuller, Timothy J Kottke, Jill M Thompson, Elizabeth J Ilett, Julia V Cockle, Philip van Hille, Gnanamurthy Sivakumar, Euan S Polson, Samantha J Turnbull, Elizabeth S Appleton, Gemma Migneco, Ailsa S Rose, Matthew C Coffey, Deborah A Beirne, Fiona J Collinson, Christy Ralph, D Alan Anthoney, Christopher J Twelves, Andrew J Furness, Sergio A Quezada, Heiko Wurdak, Fiona Errington-Mais, Hardev Pandha, Kevin J Harrington, Peter J Selby, Richard G Vile, Stephen D Griffin, Lucy F Stead, Susan C Short, Alan A Melcher
Immune checkpoint inhibitors, including those targeting programmed cell death protein 1 (PD-1), are reshaping cancer therapeutic strategies. Evidence suggests, however, that tumor response and patient survival are determined by tumor programmed death ligand 1 (PD-L1) expression. We hypothesized that preconditioning of the tumor immune microenvironment using targeted, virus-mediated interferon (IFN) stimulation would up-regulate tumor PD-L1 protein expression and increase cytotoxic T cell infiltration, improving the efficacy of subsequent checkpoint blockade...
January 3, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29298868/auditory-somatosensory-bimodal-stimulation-desynchronizes-brain-circuitry-to-reduce-tinnitus-in-guinea-pigs-and-humans
#11
Kendra L Marks, David T Martel, Calvin Wu, Gregory J Basura, Larry E Roberts, Kara C Schvartz-Leyzac, Susan E Shore
The dorsal cochlear nucleus is the first site of multisensory convergence in mammalian auditory pathways. Principal output neurons, the fusiform cells, integrate auditory nerve inputs from the cochlea with somatosensory inputs from the head and neck. In previous work, we developed a guinea pig model of tinnitus induced by noise exposure and showed that the fusiform cells in these animals exhibited increased spontaneous activity and cross-unit synchrony, which are physiological correlates of tinnitus. We delivered repeated bimodal auditory-somatosensory stimulation to the dorsal cochlear nucleus of guinea pigs with tinnitus, choosing a stimulus interval known to induce long-term depression (LTD)...
January 3, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29298867/repeat-doses-of-antibody-to-serum-amyloid-p-component-clear-amyloid-deposits-in-patients-with-systemic-amyloidosis
#12
Duncan B Richards, Louise M Cookson, Sharon V Barton, Lia Liefaard, Thirusha Lane, David F Hutt, James M Ritter, Marianna Fontana, James C Moon, Julian D Gillmore, Ashutosh Wechalekar, Philip N Hawkins, Mark B Pepys
Systemic amyloidosis is a fatal disorder caused by pathological extracellular deposits of amyloid fibrils that are always coated with the normal plasma protein, serum amyloid P component (SAP). The small-molecule drug, miridesap, [(R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC)] depletes circulating SAP but leaves some SAP in amyloid deposits. This residual SAP is a specific target for dezamizumab, a fully humanized monoclonal IgG1 anti-SAP antibody that triggers immunotherapeutic clearance of amyloid...
January 3, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29298866/a-mirna181a-nfat5-axis-links-impaired-t-cell-tolerance-induction-with-autoimmune-type-1-diabetes
#13
Isabelle Serr, Martin G Scherm, Adam M Zahm, Jonathan Schug, Victoria K Flynn, Markus Hippich, Stefanie Kälin, Maike Becker, Peter Achenbach, Alexei Nikolaev, Katharina Gerlach, Nicole Liebsch, Brigitta Loretz, Claus-Michael Lehr, Benedikt Kirchner, Melanie Spornraft, Bettina Haase, James Segars, Christoph Küper, Ralf Palmisano, Ari Waisman, Richard A Willis, Wan-Uk Kim, Benno Weigmann, Klaus H Kaestner, Anette-Gabriele Ziegler, Carolin Daniel
Molecular checkpoints that trigger the onset of islet autoimmunity or progression to human type 1 diabetes (T1D) are incompletely understood. Using T cells from children at an early stage of islet autoimmunity without clinical T1D, we find that a microRNA181a (miRNA181a)-mediated increase in signal strength of stimulation and costimulation links nuclear factor of activated T cells 5 (NFAT5) with impaired tolerance induction and autoimmune activation. We show that enhancing miRNA181a activity increases NFAT5 expression while inhibiting FOXP3+ regulatory T cell (Treg) induction in vitro...
January 3, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29298865/neoadjuvant-oncolytic-virotherapy-before-surgery-sensitizes-triple-negative-breast-cancer-to-immune-checkpoint-therapy
#14
Marie-Claude Bourgeois-Daigneault, Dominic Guy Roy, Amelia Sadie Aitken, Nader El Sayes, Nikolas Tim Martin, Oliver Varette, Theresa Falls, Lauren Elizabeth St-Germain, Adrian Pelin, Brian Dennis Lichty, David Francis Stojdl, Guy Ungerechts, Jean-Simon Diallo, John Cameron Bell
Triple-negative breast cancer (TNBC) is an aggressive disease for which treatment options are limited and associated with severe toxicities. Immunotherapeutic approaches like immune checkpoint inhibitors (ICIs) are a potential strategy, but clinical trials have demonstrated limited success in this patient cohort. Clinical studies using ICIs have revealed that patients with preexisting anticancer immunity are the most responsive. Given that oncolytic viruses (OVs) induce antitumor immunity, we investigated their use as an ICI-sensitizing approach...
January 3, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29298864/targeting-extracellular-matrix-stiffness-to-attenuate-disease-from-molecular-mechanisms-to-clinical-trials
#15
REVIEW
Marsha C Lampi, Cynthia A Reinhart-King
Tissues stiffen during aging and during the pathological progression of cancer, fibrosis, and cardiovascular disease. Extracellular matrix stiffness is emerging as a prominent mechanical cue that precedes disease and drives its progression by altering cellular behaviors. Targeting extracellular matrix mechanics, by preventing or reversing tissue stiffening or interrupting the cellular response, is a therapeutic approach with clinical potential. Major drivers of changes to the mechanical properties of the extracellular matrix include phenotypically converted myofibroblasts, transforming growth factor β (TGFβ), and matrix cross-linking...
January 3, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29263233/hippocampal-extracellular-matrix-alterations-contribute-to-cognitive-impairment-associated-with-a-chronic-depressive-like-state-in-rats
#16
Danai Riga, Ioannis Kramvis, Maija K Koskinen, Pieter van Bokhoven, Johanneke E van der Harst, Tim S Heistek, A Jaap Timmerman, Pim van Nierop, Roel C van der Schors, Anton W Pieneman, Anouk de Weger, Yvar van Mourik, Anton N M Schoffelmeer, Huib D Mansvelder, Rhiannon M Meredith, Witte J G Hoogendijk, August B Smit, Sabine Spijker
Patients with depression often suffer from cognitive impairments that contribute to disease burden. We used social defeat-induced persistent stress (SDPS) to induce a depressive-like state in rats and then studied long-lasting memory deficits in the absence of acute stressors in these animals. The SDPS rat model showed reduced short-term object location memory and maintenance of long-term potentiation (LTP) in CA1 pyramidal neurons of the dorsal hippocampus. SDPS animals displayed increased expression of synaptic chondroitin sulfate proteoglycans in the dorsal hippocampus...
December 20, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29263232/a-human-microglia-like-cellular-model-for-assessing-the-effects-of-neurodegenerative-disease-gene-variants
#17
Katie J Ryan, Charles C White, Kruti Patel, Jishu Xu, Marta Olah, Joseph M Replogle, Michael Frangieh, Maria Cimpean, Phoebe Winn, Allison McHenry, Belinda J Kaskow, Gail Chan, Nicole Cuerdon, David A Bennett, Justin D Boyd, Jaime Imitola, Wassim Elyaman, Philip L De Jager, Elizabeth M Bradshaw
Microglia are emerging as a key cell type in neurodegenerative diseases, yet human microglia are challenging to study in vitro. We developed an in vitro cell model system composed of human monocyte-derived microglia-like (MDMi) cells that recapitulated key aspects of microglia phenotype and function. We then used this model system to perform an expression quantitative trait locus (eQTL) study examining 94 genes from loci associated with Alzheimer's disease, Parkinson's disease, and multiple sclerosis. We found six loci (CD33, PILRB, NUP160, LRRK2, RGS1, and METTL21B) in which the risk haplotype drives the association with both disease susceptibility and altered expression of a nearby gene (cis-eQTL)...
December 20, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29263231/human-esc-derived-retinal-epithelial-cell-sheets-potentiate-rescue-of-photoreceptor-cell-loss-in-rats-with-retinal-degeneration
#18
Karim Ben M'Barek, Walter Habeler, Alexandra Plancheron, Mohamed Jarraya, Florian Regent, Angélique Terray, Ying Yang, Laure Chatrousse, Sophie Domingues, Yolande Masson, José-Alain Sahel, Marc Peschanski, Olivier Goureau, Christelle Monville
Replacing defective retinal pigment epithelial (RPE) cells with those derived from human embryonic stem cells (hESCs) or human-induced pluripotent stem cells (hiPSCs) is a potential strategy for treating retinal degenerative diseases. Early clinical trials have demonstrated that hESC-derived or hiPSC-derived RPE cells can be delivered safely as a suspension to the human eye. The next step is transplantation of hESC/hiPSC-derived RPE cells as cell sheets that are more physiological. We have developed a tissue-engineered product consisting of hESC-derived RPE cells grown as sheets on human amniotic membrane as a biocompatible substrate...
December 20, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29263230/vaccination-of-dogs-in-an-african-city-interrupts-rabies-transmission-and-reduces-human-exposure
#19
Jakob Zinsstag, Monique Lechenne, Mirjam Laager, Rolande Mindekem, Service Naïssengar, Assandi Oussiguéré, Kebkiba Bidjeh, Germain Rives, Julie Tessier, Seraphin Madjaninan, Mahamat Ouagal, Daugla D Moto, Idriss O Alfaroukh, Yvonne Muthiani, Abdallah Traoré, Jan Hattendorf, Anthony Lepelletier, Lauriane Kergoat, Hervé Bourhy, Laurent Dacheux, Tanja Stadler, Nakul Chitnis
Despite the existence of effective rabies vaccines for dogs, dog-transmitted human rabies persists and has reemerged in Africa. Two consecutive dog vaccination campaigns took place in Chad in 2012 and 2013 (coverage of 71% in both years) in the capital city of N'Djaména, as previously published. We developed a deterministic model of dog-human rabies transmission fitted to weekly incidence data of rabid dogs and exposed human cases in N'Djaména. Our analysis showed that the effective reproductive number, that is, the number of new dogs infected by a rabid dog, fell to below one through November 2014...
December 20, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29263229/erratum-for-the-research-article-the-synthetic-diazonamide-dz-2384-has-distinct-effects-on-microtubule-curvature-and-dynamics-without-neurotoxicity-by-m-wieczorek-j-tcherkezian-c-bernier-a-e-prota-s-chaaban-y-rolland-c-godbout-m-a-hancock-j-c-arezzo-o-ocal
#20
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