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Science Translational Medicine

Yuxuan Wang, Lu Li, Christopher Douville, Joshua D Cohen, Ting-Tai Yen, Isaac Kinde, Karin Sundfelt, Susanne K Kjær, Ralph H Hruban, Ie-Ming Shih, Tian-Li Wang, Robert J Kurman, Simeon Springer, Janine Ptak, Maria Popoli, Joy Schaefer, Natalie Silliman, Lisa Dobbyn, Edward J Tanner, Ana Angarita, Maria Lycke, Kirsten Jochumsen, Bahman Afsari, Ludmila Danilova, Douglas A Levine, Kris Jardon, Xing Zeng, Jocelyne Arseneau, Lili Fu, Luis A Diaz, Rachel Karchin, Cristian Tomasetti, Kenneth W Kinzler, Bert Vogelstein, Amanda N Fader, Lucy Gilbert, Nickolas Papadopoulos
We report the detection of endometrial and ovarian cancers based on genetic analyses of DNA recovered from the fluids obtained during a routine Papanicolaou (Pap) test. The new test, called PapSEEK, incorporates assays for mutations in 18 genes as well as an assay for aneuploidy. In Pap brush samples from 382 endometrial cancer patients, 81% [95% confidence interval (CI), 77 to 85%] were positive, including 78% of patients with early-stage disease. The sensitivity in 245 ovarian cancer patients was 33% (95% CI, 27 to 39%), including 34% of patients with early-stage disease...
March 21, 2018: Science Translational Medicine
Mikhail Volkov, Jacqueline Dekkers, Bruno G Loos, Sergio Bizzarro, Thomas W J Huizinga, Helle A Praetorius, René E M Toes, Diane van der Woude
The link between rheumatoid arthritis and exposure to a bacterial toxin was not found in a population of rheumatoid arthritis patients from Netherlands.
March 21, 2018: Science Translational Medicine
Joseph A Lewnard, Yonatan H Grad
After decades of declining mumps incidence amid widespread vaccination, the United States and other developed countries have experienced a resurgence in mumps cases over the last decade. Outbreaks affecting vaccinated individuals and communities with high vaccine coverage have prompted concerns about the effectiveness of the live attenuated vaccine currently in use. It is unclear whether immune protection wanes or whether the vaccine protects inadequately against currently circulating mumps virus lineages. Synthesizing data from six studies of mumps vaccine effectiveness, we estimated that vaccine-derived immune protection against mumps wanes on average 27 years (95% confidence interval, 16 to 51 years) after vaccination...
March 21, 2018: Science Translational Medicine
Jean Publicover, Anuj Gaggar, Jillian M Jespersen, Ugur Halac, Audra J Johnson, Amanda Goodsell, Lia Avanesyan, Stephen L Nishimura, Meghan Holdorf, Keith G Mansfield, Joyce Bousquet Judge, Arya Koshti, Michael Croft, Adil E Wakil, Philip Rosenthal, Eric Pai, Stewart Cooper, Jody L Baron
Depending on age of acquisition, hepatitis B virus (HBV) can induce a cell-mediated immune response that results in either cure or progressive liver injury. In adult-acquired infection, HBV antigens are usually cleared, whereas in infancy-acquired infection, they persist. Individuals infected during infancy therefore represent the majority of patients chronically infected with HBV (CHB). A therapy that can promote viral antigen clearance in most CHB patients has not been developed and would represent a major health care advance and cost mitigator...
March 21, 2018: Science Translational Medicine
Maximilian F Konig, Jon T Giles, Ricardo P Teles, Niki M Moutsopoulos, Felipe Andrade
Antibodies to leukotoxin A are markers that link Aggregatibacter actinomycetemcomitans -associated periodontitis and rheumatoid arthritis.
March 21, 2018: Science Translational Medicine
Chun Gwon Park, Christina A Hartl, Daniela Schmid, Ellese M Carmona, Hye-Jung Kim, Michael S Goldberg
Cancer immunotherapy can confer durable benefit, but the percentage of patients who respond to this approach remains modest. The ability to concentrate immunostimulatory compounds at the site of disease can overcome local immune tolerance and reduce systemic toxicity. Surgical resection of tumors may improve the efficacy of immunotherapy by removing the concentrated immunosuppressive microenvironment; however, it also removes tumor-specific leukocytes as well as tumor antigens that may be important to establishing antitumor immunity...
March 21, 2018: Science Translational Medicine
Xiaoxing Kou, Xingtian Xu, Chider Chen, Maria Laura Sanmillan, Tao Cai, Yanheng Zhou, Claudio Giraudo, Anh Le, Songtao Shi
Mesenchymal stem cells (MSCs) are capable of secreting exosomes, extracellular vesicles, and cytokines to regulate cell and tissue homeostasis. However, it is unknown whether MSCs use a specific exocytotic fusion mechanism to secrete exosomes and cytokines. We show that Fas binds with Fas-associated phosphatase-1 (Fap-1) and caveolin-1 (Cav-1) to activate a common soluble N -ethylmaleimide-sensitive factor (NSF) attachment protein receptor (SNARE)-mediated membrane fusion mechanism to release small extracellular vesicles (sEVs) in MSCs...
March 14, 2018: Science Translational Medicine
Paul D Marasco, Jacqueline S Hebert, Jon W Sensinger, Courtney E Shell, Jonathon S Schofield, Zachary C Thumser, Raviraj Nataraj, Dylan T Beckler, Michael R Dawson, Dan H Blustein, Satinder Gill, Brett D Mensh, Rafael Granja-Vazquez, Madeline D Newcomb, Jason P Carey, Beth M Orzell
To effortlessly complete an intentional movement, the brain needs feedback from the body regarding the movement's progress. This largely nonconscious kinesthetic sense helps the brain to learn relationships between motor commands and outcomes to correct movement errors. Prosthetic systems for restoring function have predominantly focused on controlling motorized joint movement. Without the kinesthetic sense, however, these devices do not become intuitively controllable. We report a method for endowing human amputees with a kinesthetic perception of dexterous robotic hands...
March 14, 2018: Science Translational Medicine
James E Cassat, Jessica L Moore, Kevin J Wilson, Zach Stark, Boone M Prentice, Raf Van de Plas, William J Perry, Yaofang Zhang, John Virostko, Daniel C Colvin, Kristie L Rose, Audra M Judd, Michelle L Reyzer, Jeffrey M Spraggins, Caroline M Grunenwald, John C Gore, Richard M Caprioli, Eric P Skaar
Diseases are characterized by distinct changes in tissue molecular distribution. Molecular analysis of intact tissues traditionally requires preexisting knowledge of, and reagents for, the targets of interest. Conversely, label-free discovery of disease-associated tissue analytes requires destructive processing for downstream identification platforms. Tissue-based analyses therefore sacrifice discovery to gain spatial distribution of known targets or sacrifice tissue architecture for discovery of unknown targets...
March 14, 2018: Science Translational Medicine
Stefan Roth, Vikramjeet Singh, Steffen Tiedt, Lisa Schindler, Georg Huber, Arie Geerlof, Daniel J Antoine, Antoine Anfray, Cyrille Orset, Maxime Gauberti, Antoine Fournier, Lesca M Holdt, Helena Erlandsson Harris, Britta Engelhardt, Marco E Bianchi, Denis Vivien, Christof Haffner, Jürgen Bernhagen, Martin Dichgans, Arthur Liesz
Stroke induces a multiphasic systemic immune response, but the consequences of this response on atherosclerosis-a major source of recurrent vascular events-have not been thoroughly investigated. We show that stroke exacerbates atheroprogression via alarmin-mediated propagation of vascular inflammation. The prototypic brain-released alarmin high-mobility group box 1 protein induced monocyte and endothelial activation via the receptor for advanced glycation end products (RAGE)-signaling cascade and increased plaque load and vulnerability...
March 14, 2018: Science Translational Medicine
Joao Incio, Jennifer A Ligibel, Daniel T McManus, Priya Suboj, Keehoon Jung, Kosuke Kawaguchi, Matthias Pinter, Suboj Babykutty, Shan M Chin, Trupti D Vardam, Yuhui Huang, Nuh N Rahbari, Sylvie Roberge, Dannie Wang, Igor L Gomes-Santos, Stefan B Puchner, Christopher L Schlett, Udo Hoffmman, Marek Ancukiewicz, Sara M Tolaney, Ian E Krop, Dan G Duda, Yves Boucher, Dai Fukumura, Rakesh K Jain
Anti-vascular endothelial growth factor (VEGF) therapy has failed to improve survival in patients with breast cancer (BC). Potential mechanisms of resistance to anti-VEGF therapy include the up-regulation of alternative angiogenic and proinflammatory factors. Obesity is associated with hypoxic adipose tissues, including those in the breast, resulting in increased production of some of the aforementioned factors. Hence, we hypothesized that obesity could contribute to anti-VEGF therapy's lack of efficacy. We found that BC patients with obesity harbored increased systemic concentrations of interleukin-6 (IL-6) and/or fibroblast growth factor 2 (FGF-2), and their tumor vasculature was less sensitive to anti-VEGF treatment...
March 14, 2018: Science Translational Medicine
Xilin Sun, Zunyu Xiao, Gongyan Chen, Zhaoguo Han, Yang Liu, Chongqing Zhang, Yingying Sun, Yan Song, Kai Wang, Fang Fang, Xiance Wang, Yanhong Lin, Lili Xu, Liming Shao, Jin Li, Zhen Cheng, Sanjiv Sam Gambhir, Baozhong Shen
Tumor heterogeneity and changes in epidermal growth factor receptor (EGFR) mutation status over time challenge the design of effective EGFR tyrosine kinase inhibitor (TKI) treatment strategies for non-small cell lung cancer (NSCLC). Therefore, there is an urgent need to develop techniques for comprehensive tumor EGFR profiling in real time, particularly in lung cancer precision medicine trials. We report a positron emission tomography (PET) tracer, N -(3-chloro-4-fluorophenyl)-7-(2-(2-(2-(2-18 F-fluoroethoxy) ethoxy) ethoxy) ethoxy)-6-methoxyquinazolin-4-amine (18 F-MPG), with high specificity to activating EGFR mutant kinase...
March 7, 2018: Science Translational Medicine
Anand Chandrasekhar, Chang-Sei Kim, Mohammed Naji, Keerthana Natarajan, Jin-Oh Hahn, Ramakrishna Mukkamala
High blood pressure (BP) is a major cardiovascular risk factor that is treatable, yet hypertension awareness and control rates are low. Ubiquitous BP monitoring technology could improve hypertension management, but existing devices require an inflatable cuff and are not compatible with such anytime, anywhere measurement of BP. We extended the oscillometric principle, which is used by most automatic cuff devices, to develop a cuff-less BP monitoring device using a smartphone. As the user presses her/his finger against the smartphone, the external pressure of the underlying artery is steadily increased while the phone measures the applied pressure and resulting variable-amplitude blood volume oscillations...
March 7, 2018: Science Translational Medicine
Florence F Wagner, Lina Benajiba, Arthur J Campbell, Michel Weïwer, Joshua R Sacher, Jennifer P Gale, Linda Ross, Alexandre Puissant, Gabriela Alexe, Amy Conway, Morgan Back, Yana Pikman, Ilene Galinsky, Daniel J DeAngelo, Richard M Stone, Taner Kaya, Xi Shi, Matthew B Robers, Thomas Machleidt, Jennifer Wilkinson, Olivier Hermine, Andrew Kung, Adam J Stein, Damodharan Lakshminarasimhan, Michael T Hemann, Edward Scolnick, Yan-Ling Zhang, Jen Q Pan, Kimberly Stegmaier, Edward B Holson
Glycogen synthase kinase 3 (GSK3), a key regulatory kinase in the wingless-type MMTV integration site family (WNT) pathway, is a therapeutic target of interest in many diseases. Although dual GSK3α/β inhibitors have entered clinical trials, none has successfully translated to clinical application. Mechanism-based toxicities, driven in part by the inhibition of both GSK3 paralogs and subsequent β-catenin stabilization, are a concern in the translation of this target class because mutations and overexpression of β-catenin are associated with many cancers...
March 7, 2018: Science Translational Medicine
Chloe R McDonald, Lindsay S Cahill, Joel R Gamble, Robyn Elphinstone, Lisa M Gazdzinski, Kathleen J Y Zhong, Adrienne C Philson, Mwayiwawo Madanitsa, Linda Kalilani-Phiri, Victor Mwapasa, Feiko O Ter Kuile, John G Sled, Andrea L Conroy, Kevin C Kain
Reducing adverse birth outcomes due to malaria in pregnancy (MIP) is a global health priority. However, there are few safe and effective interventions. l-Arginine is an essential amino acid in pregnancy and an immediate precursor in the biosynthesis of nitric oxide (NO), but there are limited data on the impact of MIP on NO biogenesis. We hypothesized that hypoarginemia contributes to the pathophysiology of MIP and that l-arginine supplementation would improve birth outcomes. In a prospective study of pregnant Malawian women, we show that MIP was associated with lower concentrations of l-arginine and higher concentrations of endogenous inhibitors of NO biosynthesis, asymmetric and symmetric dimethylarginine, which were associated with adverse birth outcomes...
March 7, 2018: Science Translational Medicine
Devon K Taylor, Nanette Mittereder, Ellen Kuta, Tracy Delaney, Timothy Burwell, Karma Dacosta, Weiguang Zhao, Lily I Cheng, Charles Brown, Anmarie Boutrin, Xiang Guo, Wendy I White, Jie Zhu, Huifang Dong, Michael A Bowen, Jia Lin, Changshou Gao, Li Yu, Madhu Ramaswamy, Marie-Claude Gaudreau, Rob Woods, Ronald Herbst, Gianluca Carlesso
Systemic sclerosis (SSc) is a debilitating inflammatory and fibrotic disease that affects the skin and internal organs. Although the pathophysiology of SSc remains poorly characterized, mononuclear cells, mainly macrophages and T cells, have been implicated in inflammation and fibrosis. Inducible costimulator (ICOS), which is expressed on a subset of memory T helper (TH ) and T follicular helper (TFH ) cells, has been shown to be increased in SSc and associated with disease pathology. However, the identity of the relevant ICOS+ T cells and their contribution to inflammation and fibrosis in SSc are still unknown...
March 7, 2018: Science Translational Medicine
James G Beeson, Michelle J L Scoullar, Philippe Boeuf
Decreased l-arginine and nitric oxide bioavailability in pregnant women with malaria contributes to low birth weight, suggesting that l-arginine supplementation could be a potential treatment (McDonald et al ).
March 7, 2018: Science Translational Medicine
Steven A Yukl, Philipp Kaiser, Peggy Kim, Sushama Telwatte, Sunil K Joshi, Mai Vu, Harry Lampiris, Joseph K Wong
Latently infected CD4+ T cells are the main barrier to complete clearance of HIV infection, but it is unclear what mechanisms govern latent HIV infection in vivo. To address this question, we developed a new panel of reverse transcription droplet digital polymerase chain reaction (RT-ddPCR) assays specific for different HIV transcripts that define distinct blocks to transcription. We applied this panel of assays to CD4+ T cells freshly isolated from HIV-infected patients on suppressive antiretroviral therapy (ART) to quantify the degree to which different mechanisms inhibit HIV transcription...
February 28, 2018: Science Translational Medicine
Mireille Kamariza, Peyton Shieh, Christopher S Ealand, Julian S Peters, Brian Chu, Frances P Rodriguez-Rivera, Mohammed R Babu Sait, William V Treuren, Neil Martinson, Rainer Kalscheuer, Bavesh D Kana, Carolyn R Bertozzi
Tuberculosis (TB) is the leading cause of death from an infectious bacterial disease. Poor diagnostic tools to detect active disease plague TB control programs and affect patient care. Accurate detection of live Mycobacterium tuberculosis (Mtb), the causative agent of TB, could improve TB diagnosis and patient treatment. We report that mycobacteria and other corynebacteria can be specifically detected with a fluorogenic trehalose analog. We designed a 4- N,N -dimethylamino-1,8-naphthalimide-conjugated trehalose (DMN-Tre) probe that undergoes >700-fold increase in fluorescence intensity when transitioned from aqueous to hydrophobic environments...
February 28, 2018: Science Translational Medicine
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