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Science Translational Medicine

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https://www.readbyqxmd.com/read/28794286/combating-corruption-in-global-health
#1
REVIEW
Tim K Mackey, Jillian Kohler, Maureen Lewis, Taryn Vian
Corruption is a critical challenge to global health efforts, and combating it requires international action, advocacy, and research.
August 9, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28794285/preventing-chemotherapy-induced-myelosuppression-by-repurposing-the-flt3-inhibitor-quizartinib
#2
Samuel J Taylor, Johanna M Duyvestyn, Samantha A Dagger, Emma J Dishington, Catherine A Rinaldi, Oliver M Dovey, George S Vassiliou, Carolyn S Grove, Wallace Y Langdon
We describe an approach to inhibit chemotherapy-induced myelosuppression. We found that short-term exposure of mice to the FLT3 inhibitor quizartinib induced the transient quiescence of multipotent progenitors (MPPs). This property of quizartinib conferred marked protection to MPPs in mice receiving fluorouracil or gemcitabine. The protection resulted in the rapid recovery of bone marrow and blood cellularity, thus preventing otherwise lethal myelosuppression. A treatment strategy involving quizartinib priming that protected wild-type bone marrow progenitors, but not leukemic cells, from fluorouracil provided a more effective treatment than conventional induction therapy in mouse models of acute myeloid leukemia...
August 9, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28794284/genomic-profiling-of-er-breast-cancers-after-short-term-estrogen-suppression-reveals-alterations-associated-with-endocrine-resistance
#3
Jennifer M Giltnane, Katherine E Hutchinson, Thomas P Stricker, Luigi Formisano, Christian D Young, Monica V Estrada, Mellissa J Nixon, Liping Du, Violeta Sanchez, Paula Gonzalez Ericsson, Maria G Kuba, Melinda E Sanders, Xinmeng J Mu, Eliezer M Van Allen, Nikhil Wagle, Ingrid A Mayer, Vandana Abramson, Henry Gόmez, Monica Rizzo, Weiyi Toy, Sarat Chandarlapaty, Erica L Mayer, Jason Christiansen, Danielle Murphy, Kerry Fitzgerald, Kai Wang, Jeffrey S Ross, Vincent A Miller, Phillip J Stephens, Roman Yelensky, Levi Garraway, Yu Shyr, Ingrid Meszoely, Justin M Balko, Carlos L Arteaga
Inhibition of proliferation in estrogen receptor-positive (ER(+)) breast cancers after short-term antiestrogen therapy correlates with long-term patient outcome. We profiled 155 ER(+)/human epidermal growth factor receptor 2-negative (HER2(-)) early breast cancers from 143 patients treated with the aromatase inhibitor letrozole for 10 to 21 days before surgery. Twenty-one percent of tumors remained highly proliferative, suggesting that these tumors harbor alterations associated with intrinsic endocrine therapy resistance...
August 9, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28794283/metabolic-and-immune-effects-of-immunotherapy-with-proinsulin-peptide-in-human-new-onset-type-1-diabetes
#4
Mohammad Alhadj Ali, Yuk-Fun Liu, Sefina Arif, Danijela Tatovic, Hina Shariff, Vivienne B Gibson, Norkhairin Yusuf, Roman Baptista, Martin Eichmann, Nedyalko Petrov, Susanne Heck, Jennie H M Yang, Timothy I M Tree, Irma Pujol-Autonell, Lorraine Yeo, Lucas R Baumard, Rachel Stenson, Alex Howell, Alison Clark, Zoe Boult, Jake Powrie, Laura Adams, Florence S Wong, Stephen Luzio, Gareth Dunseath, Kate Green, Alison O'Keefe, Graham Bayly, Natasha Thorogood, Robert Andrews, Nicola Leech, Frank Joseph, Sunil Nair, Susan Seal, HoYee Cheung, Craig Beam, Robert Hills, Mark Peakman, Colin M Dayan
Immunotherapy using short immunogenic peptides of disease-related autoantigens restores immune tolerance in preclinical disease models. We studied safety and mechanistic effects of injecting human leukocyte antigen-DR4(DRB1*0401)-restricted immunodominant proinsulin peptide intradermally every 2 or 4 weeks for 6 months in newly diagnosed type 1 diabetes patients. Treatment was well tolerated with no systemic or local hypersensitivity. Placebo subjects showed a significant decline in stimulated C-peptide (measuring insulin reserve) at 3, 6, 9, and 12 months versus baseline, whereas no significant change was seen in the 4-weekly peptide group at these time points or the 2-weekly group at 3, 6, and 9 months...
August 9, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28794282/partial-efficacy-of-a-broadly-neutralizing-antibody-against-cell-associated-shiv-infection
#5
Matthew S Parsons, Sarah B Lloyd, Wen Shi Lee, Anne B Kristensen, Thakshila Amarasena, Rob J Center, Brandon F Keele, Jeffrey D Lifson, Celia C LaBranche, David Montefiori, Bruce D Wines, P Mark Hogarth, Kristine M Swiderek, Vanessa Venturi, Miles P Davenport, Stephen J Kent
Broadly neutralizing antibodies (BnAbs) protect macaques from cell-free simian/human immunodeficiency virus (SHIV) challenge, but their efficacy against cell-associated SHIV is unclear. Virus in cell-associated format is highly infectious, present in transmission-competent bodily fluids, and potentially capable of evading antibody-mediated neutralization. The PGT121 BnAb, which recognizes an epitope consisting of the V3 loop and envelope glycans, mediates antibody-dependent cellular cytotoxicity and neutralization of cell-to-cell HIV-1 transmission...
August 9, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28768807/folamirs-ligand-targeted-vehicle-free-delivery-of-micrornas-for-the-treatment-of-cancer
#6
Esteban A Orellana, Srinivasarao Tenneti, Loganathan Rangasamy, L Tiffany Lyle, Philip S Low, Andrea L Kasinski
MicroRNAs are small RNAs that negatively regulate gene expression posttranscriptionally. Because changes in microRNA expression can promote or maintain disease states, microRNA-based therapeutics are being evaluated extensively. Unfortunately, the therapeutic potential of microRNA replacement is limited by deficient delivery vehicles. In this work, microRNAs are delivered in the absence of a protective vehicle. The method relies on direct attachment of microRNAs to folate (FolamiR), which mediates delivery of the conjugated microRNA into cells that overexpress the folate receptor...
August 2, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28768806/a-phenotypically-and-functionally-distinct-human-th2-cell-subpopulation-is-associated-with-allergic-disorders
#7
Erik Wambre, Veronique Bajzik, Jonathan H DeLong, Kimberly O'Brien, Quynh-Anh Nguyen, Cate Speake, Vivian H Gersuk, Hannah A DeBerg, Elizabeth Whalen, Chester Ni, Mary Farrington, David Jeong, David Robinson, Peter S Linsley, Brian P Vickery, William W Kwok
Allergen-specific type 2 helper T (TH2) cells play a central role in initiating and orchestrating the allergic and asthmatic inflammatory response pathways. One major factor limiting the use of such atopic disease-causing T cells as both therapeutic targets and clinically useful biomarkers is the lack of an accepted methodology to identify and differentiate these cells from overall nonpathogenic TH2 cell types. We have described a subset of human memory TH2 cells confined to atopic individuals that includes all allergen-specific TH2 cells...
August 2, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28768805/response-to-comment-on-using-geospatial-mapping-to-design-hiv-elimination-strategies-for-sub-saharan-africa
#8
LETTER
Justin T Okano, Brian J Coburn, Sally Blower
Detailed geospatial mapping of a generalized HIV epidemic in sub-Saharan Africa shows that implementing the Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 strategy could potentially exacerbate urban-rural health care disparities.
August 2, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28768804/synergistic-action-of-the-mcl-1-inhibitor-s63845-with-current-therapies-in-preclinical-models-of-triple-negative-and-her2-amplified-breast-cancer
#9
Delphine Merino, James R Whittle, François Vaillant, Antonin Serrano, Jia-Nan Gong, Goknur Giner, Ana Leticia Maragno, Maïa Chanrion, Emilie Schneider, Bhupinder Pal, Xiang Li, Grant Dewson, Julius Gräsel, Kevin Liu, Najoua Lalaoui, David Segal, Marco J Herold, David C S Huang, Gordon K Smyth, Olivier Geneste, Guillaume Lessene, Jane E Visvader, Geoffrey J Lindeman
The development of BH3 mimetics, which antagonize prosurvival proteins of the BCL-2 family, represents a potential breakthrough in cancer therapy. Targeting the prosurvival member MCL-1 has been an area of intense interest because it is frequently deregulated in cancer. In breast cancer, MCL-1 is often amplified, and high expression predicts poor patient outcome. We tested the MCL-1 inhibitor S63845 in breast cancer cell lines and patient-derived xenografts with high expression of MCL-1. S63845 displayed synergistic activity with docetaxel in triple-negative breast cancer and with trastuzumab or lapatinib in HER2-amplified breast cancer...
August 2, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28768803/modulation-of-prefrontal-cortex-excitation-inhibition-balance-rescues-social-behavior-in-cntnap2-deficient-mice
#10
Aslihan Selimbeyoglu, Christina K Kim, Masatoshi Inoue, Soo Yeun Lee, Alice S O Hong, Isaac Kauvar, Charu Ramakrishnan, Lief E Fenno, Thomas J Davidson, Matthew Wright, Karl Deisseroth
Alterations in the balance between neuronal excitation and inhibition (E:I balance) have been implicated in the neural circuit activity-based processes that contribute to autism phenotypes. We investigated whether acutely reducing E:I balance in mouse brain could correct deficits in social behavior. We used mice lacking the CNTNAP2 gene, which has been implicated in autism, and achieved a temporally precise reduction in E:I balance in the medial prefrontal cortex (mPFC) either by optogenetically increasing the excitability of inhibitory parvalbumin (PV) neurons or decreasing the excitability of excitatory pyramidal neurons...
August 2, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28768802/comment-on-using-geospatial-mapping-to-design-hiv-elimination-strategies-for-sub-saharan-africa
#11
LETTER
Christopher Fontaine, Mary Mahy, José-Antonio Izazola, Peter D Ghys
A recent study showed how geospatial mapping can be used to improve Lesotho's HIV treatment program to achieve the 90-90-90 targets set by the United Nations but incorrectly describes "treatment as prevention" as the UN's strategy for a successful national AIDS response.
August 2, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28768801/pinning-allergies-on-pathogenic-th2-cells
#12
REVIEW
David J Cousins
A new proinflammatory subtype of antigen-specific TH2 cell that expresses CD161 emerges as the pathogenic cell type in allergic disease and is deleted during allergen-specific immunotherapy (Wambre et al, this issue).
August 2, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28747517/a-soft-robotic-exosuit-improves-walking-in-patients-after-stroke
#13
Louis N Awad, Jaehyun Bae, Kathleen O'Donnell, Stefano M M De Rossi, Kathryn Hendron, Lizeth H Sloot, Pawel Kudzia, Stephen Allen, Kenneth G Holt, Terry D Ellis, Conor J Walsh
Stroke-induced hemiparetic gait is characteristically slow and metabolically expensive. Passive assistive devices such as ankle-foot orthoses are often prescribed to increase function and independence after stroke; however, walking remains highly impaired despite-and perhaps because of-their use. We sought to determine whether a soft wearable robot (exosuit) designed to supplement the paretic limb's residual ability to generate both forward propulsion and ground clearance could facilitate more normal walking after stroke...
July 26, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28747516/redundant-and-diverse-intranodal-pacemakers-and-conduction-pathways-protect-the-human-sinoatrial-node-from-failure
#14
Ning Li, Brian J Hansen, Thomas A Csepe, Jichao Zhao, Anthony J Ignozzi, Lidiya V Sul, Stanislav O Zakharkin, Anuradha Kalyanasundaram, Jonathan P Davis, Brandon J Biesiadecki, Ahmet Kilic, Paul M L Janssen, Peter J Mohler, Raul Weiss, John D Hummel, Vadim V Fedorov
The human sinoatrial node (SAN) efficiently maintains heart rhythm even under adverse conditions. However, the specific mechanisms involved in the human SAN's ability to prevent rhythm failure, also referred to as its robustness, are unknown. Challenges exist because the three-dimensional (3D) intramural structure of the human SAN differs from well-studied animal models, and clinical electrode recordings are limited to only surface atrial activation. Hence, to innovate the translational study of human SAN structural and functional robustness, we integrated intramural optical mapping, 3D histology reconstruction, and molecular mapping of the ex vivo human heart...
July 26, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28747515/erratum-for-the-research-article-targeting-kras-dependent-tumors-with-azd4785-a-high-affinity-therapeutic-antisense-oligonucleotide-inhibitor-of-kras-by-s-j-ross-a-s-revenko-l-l-hanson-r-ellston-a-staniszewska-n-whalley-s-k-pandey-m-revill-c-rooney-l-k-buckett
#15
https://www.readbyqxmd.com/read/28747514/mechanoresponsive-stem-cells-to-target-cancer-metastases-through-biophysical-cues
#16
Linan Liu, Shirley X Zhang, Wenbin Liao, Henry P Farhoodi, Chi W Wong, Claire C Chen, Aude I Ségaliny, Jenu V Chacko, Lily P Nguyen, Mengrou Lu, George Polovin, Egest J Pone, Timothy L Downing, Devon A Lawson, Michelle A Digman, Weian Zhao
Despite decades of effort, little progress has been made to improve the treatment of cancer metastases. To leverage the central role of the mechanoenvironment in cancer metastasis, we present a mechanoresponsive cell system (MRCS) to selectively identify and treat cancer metastases by targeting the specific biophysical cues in the tumor niche in vivo. Our MRCS uses mechanosensitive promoter-driven mesenchymal stem cell (MSC)-based vectors, which selectively home to and target cancer metastases in response to specific mechanical cues to deliver therapeutics to effectively kill cancer cells, as demonstrated in a metastatic breast cancer mouse model...
July 26, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28747513/repression-of-bet-activity-sensitizes-homologous-recombination-proficient-cancers-to-parp-inhibition
#17
Lu Yang, Youyou Zhang, Weiwei Shan, Zhongyi Hu, Jiao Yuan, Jingjiang Pi, Yueying Wang, Lingling Fan, Zhaoqing Tang, Chunsheng Li, Xiaowen Hu, Janos L Tanyi, Yi Fan, Qihong Huang, Kathleen Montone, Chi V Dang, Lin Zhang
Strategies to enhance response to poly(adenosine diphosphate-ribose) polymerase inhibitor (PARPi) in primary and acquired homologous recombination (HR)-proficient tumors would be a major advance in cancer care. We used a drug synergy screen that combined a PARPi, olaparib, with 20 well-characterized epigenetic drugs and identified bromodomain and extraterminal domain inhibitors (BETis; JQ1, I-BET762, and OTX015) as drugs that acted synergistically with olaparib in HR-proficient cancer cells. Functional assays demonstrated that repressed BET activity reduces HR and thus enhances PARPi-induced DNA damage in cancer cells...
July 26, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28747512/charting-the-unknown-unknowns-of-cancer-progression
#18
REVIEW
Hani Goodarzi
Integrated computational and experimental strategies reveal previously unknown regulatory programs underlying metastatic disease.
July 26, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28724577/in-situ-expansion-of-engineered-human-liver-tissue-in-a-mouse-model-of-chronic-liver-disease
#19
Kelly R Stevens, Margaret A Scull, Vyas Ramanan, Chelsea L Fortin, Ritika R Chaturvedi, Kristin A Knouse, Jing W Xiao, Canny Fung, Teodelinda Mirabella, Amanda X Chen, Margaret G McCue, Michael T Yang, Heather E Fleming, Kwanghun Chung, Ype P de Jong, Christopher S Chen, Charles M Rice, Sangeeta N Bhatia
Control of both tissue architecture and scale is a fundamental translational roadblock in tissue engineering. An experimental framework that enables investigation into how architecture and scaling may be coupled is needed. We fabricated a structurally organized engineered tissue unit that expanded in response to regenerative cues after implantation into mice with liver injury. Specifically, we found that tissues containing patterned human primary hepatocytes, endothelial cells, and stromal cells in a degradable hydrogel expanded more than 50-fold over the course of 11 weeks in mice with injured livers...
July 19, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28724576/erratum-for-the-research-article-neoadjuvant-chemotherapy-induces-breast-cancer-metastasis-through-a-tmem-mediated-mechanism-by-g-s-karagiannis-j-m-pastoriza-y-wang-a-s-harney-d-entenberg-j-pignatelli-v-p-sharma-e-a-xue-e-cheng-t-m-d-alfonso-j-g-jones-j-anampa
#20
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journal
42361
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