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Science Translational Medicine

Sharlene N Flesher, Jennifer L Collinger, Stephen T Foldes, Jeffrey M Weiss, John E Downey, Elizabeth C Tyler-Kabara, Sliman J Bensmaia, Andrew B Schwartz, Michael L Boninger, Robert A Gaunt
Intracortical microstimulation of the somatosensory cortex offers the potential for creating a sensory neuroprosthesis to restore tactile sensation. Whereas animal studies have suggested that both cutaneous and proprioceptive percepts can be evoked using this approach, the perceptual quality of the stimuli cannot be measured in these experiments. We show that microstimulation within the hand area of the somatosensory cortex of a person with long-term spinal cord injury evokes tactile sensations perceived as originating from locations on the hand and that cortical stimulation sites are organized according to expected somatotopic principles...
October 13, 2016: Science Translational Medicine
Michael M Lipp, Richard Batycky, Jerome Moore, Mika Leinonen, Martin I Freed
Inhaled drugs offer advantages, such as rapid onset of action, but require formulations and delivery systems that reproducibly and conveniently administer the drug. CVT-301 is a powder formulation of levodopa delivered by a breath-actuated inhaler that has been developed for treating OFF episodes (motor fluctuations between doses of standard oral levodopa) in patients with Parkinson's disease (PD). We present preclinical, phase 1, and phase 2 results for CVT-301. In dogs insufflated with a levodopa powder, plasma levodopa peaked in all animals 2...
October 12, 2016: Science Translational Medicine
Nuh N Rahbari, Dmitriy Kedrin, Joao Incio, Hao Liu, William W Ho, Hadi T Nia, Christina M Edrich, Keehoon Jung, Julien Daubriac, Ivy Chen, Takahiro Heishi, John D Martin, Yuhui Huang, Nir Maimon, Christoph Reissfelder, Jurgen Weitz, Yves Boucher, Jeffrey W Clark, Alan J Grodzinsky, Dan G Duda, Rakesh K Jain, Dai Fukumura
The survival benefit of anti-vascular endothelial growth factor (VEGF) therapy in metastatic colorectal cancer (mCRC) patients is limited to a few months because of acquired resistance. We show that anti-VEGF therapy induced remodeling of the extracellular matrix with subsequent alteration of the physical properties of colorectal liver metastases. Preoperative treatment with bevacizumab in patients with colorectal liver metastases increased hyaluronic acid (HA) deposition within the tumors. Moreover, in two syngeneic mouse models of CRC metastasis in the liver, we show that anti-VEGF therapy markedly increased the expression of HA and sulfated glycosaminoglycans (sGAGs), without significantly changing collagen deposition...
October 12, 2016: Science Translational Medicine
Mark A DeWitt, Wendy Magis, Nicolas L Bray, Tianjiao Wang, Jennifer R Berman, Fabrizia Urbinati, Seok-Jin Heo, Therese Mitros, Denise P Muñoz, Dario Boffelli, Donald B Kohn, Mark C Walters, Dana Carroll, David I K Martin, Jacob E Corn
Genetic diseases of blood cells are prime candidates for treatment through ex vivo gene editing of CD34(+) hematopoietic stem/progenitor cells (HSPCs), and a variety of technologies have been proposed to treat these disorders. Sickle cell disease (SCD) is a recessive genetic disorder caused by a single-nucleotide polymorphism in the β-globin gene (HBB). Sickle hemoglobin damages erythrocytes, causing vasoocclusion, severe pain, progressive organ damage, and premature death. We optimize design and delivery parameters of a ribonucleoprotein (RNP) complex comprising Cas9 protein and unmodified single guide RNA, together with a single-stranded DNA oligonucleotide donor (ssODN), to enable efficient replacement of the SCD mutation in human HSPCs...
October 12, 2016: Science Translational Medicine
Josalyn L Cho, Morris F Ling, David C Adams, Lucas Faustino, Sabina A Islam, Roshi Afshar, Jason W Griffith, Robert S Harris, Aylwin Ng, Giorgia Radicioni, Amina A Ford, Andre K Han, Ramnik Xavier, William W Kwok, Richard Boucher, James J Moon, Daniel L Hamilos, Mehmet Kesimer, Melissa J Suter, Benjamin D Medoff, Andrew D Luster
Despite systemic sensitization, not all allergic individuals develop asthma symptoms upon airborne allergen exposure. Determination of the factors that lead to the asthma phenotype in allergic individuals could guide treatment and identify novel therapeutic targets. We used segmental allergen challenge of allergic asthmatics (AA) and allergic nonasthmatic controls (AC) to determine whether there are differences in the airway immune response or airway structural cells that could drive the development of asthma...
October 5, 2016: Science Translational Medicine
David C Adams, Lida P Hariri, Alyssa J Miller, Yan Wang, Josalyn L Cho, Martin Villiger, Jasmin A Holz, Margit V Szabari, Daniel L Hamilos, R Scott Harris, Jason W Griffith, Brett E Bouma, Andrew D Luster, Benjamin D Medoff, Melissa J Suter
The inability to visualize airway smooth muscle (ASM) cells in vivo is a major obstacle in understanding their role in normal physiology and diseases. At present, there is no imaging modality available to assess ASM in vivo. Confocal endomicroscopy lacks the penetration depth and field of view, and conventional optical coherence tomography (OCT) does not have sufficient contrast to differentiate ASM from surrounding tissues. We have developed a birefringence microscopy platform that leverages the micro-organization of tissue to add further dimension to traditional OCT...
October 5, 2016: Science Translational Medicine
Roy Malka, David M Nathan, John M Higgins
The amount of glycated hemoglobin (HbA1c) in diabetic patients' blood provides the best estimate of the average blood glucose concentration over the preceding 2 to 3 months. It is therefore essential for disease management and is the best predictor of disease complications. Nevertheless, substantial unexplained glucose-independent variation in HbA1c makes its reflection of average glucose inaccurate and limits the precision of medical care for diabetics. The true average glucose concentration of a nondiabetic and a poorly controlled diabetic may differ by less than 15 mg/dl, but patients with identical HbA1c values may have true average glucose concentrations that differ by more than 60 mg/dl...
October 5, 2016: Science Translational Medicine
Stephen S Y Lam, Eric S K Ho, Bai-Liang He, Wui-Wing Wong, Chae-Yin Cher, Nelson K L Ng, Cheuk-Him Man, Harinder Gill, Alice M S Cheung, Ho-Wan Ip, Chi-Chiu So, Jerome Tamburini, Chi Wai Eric So, Dona N Ho, Chun-Hang Au, Tsun-Leung Chan, Edmond S K Ma, Raymond Liang, Yok-Lam Kwong, Anskar Y H Leung
An in vitro drug-screening platform on patient samples was developed and validated to design personalized treatment for relapsed/refractory acute myeloid leukemia (AML). Unbiased clustering and correlation showed that homoharringtonine (HHT), also known as omacetaxine mepesuccinate, exhibited preferential antileukemia effect against AML carrying internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD). It worked synergistically with FLT3 inhibitors to suppress leukemia growth in vitro and in xenograft mouse models...
October 5, 2016: Science Translational Medicine
Sarah J Higgins, Lisa A Purcell, Karlee L Silver, Vanessa Tran, Valerie Crowley, Michael Hawkes, Andrea L Conroy, Robert O Opoka, John G Hay, Susan E Quaggin, Gavin Thurston, W Conrad Liles, Kevin C Kain
Cerebral malaria is a leading cause of global morbidity and mortality. Interventions targeting the underlying pathophysiology of cerebral malaria may improve outcomes compared to treatment with antimalarials alone. Microvascular leak plays an important role in the pathogenesis of cerebral malaria. The angiopoietin (Ang)-Tie-2 system is a critical regulator of vascular function. We show that Ang-1 expression and soluble Tie-2 expression were associated with disease severity and outcome in a prospective study of Ugandan children with severe malaria and in a preclinical murine model of experimental cerebral malaria...
September 28, 2016: Science Translational Medicine
Adam E Jakus, Alexandra L Rutz, Sumanas W Jordan, Abhishek Kannan, Sean M Mitchell, Chawon Yun, Katie D Koube, Sung C Yoo, Herbert E Whiteley, Claus-Peter Richter, Robert D Galiano, Wellington K Hsu, Stuart R Stock, Erin L Hsu, Ramille N Shah
Despite substantial attention given to the development of osteoregenerative biomaterials, severe deficiencies remain in current products. These limitations include an inability to adequately, rapidly, and reproducibly regenerate new bone; high costs and limited manufacturing capacity; and lack of surgical ease of handling. To address these shortcomings, we generated a new, synthetic osteoregenerative biomaterial, hyperelastic "bone" (HB). HB, which is composed of 90 weight % (wt %) hydroxyapatite and 10 wt % polycaprolactone or poly(lactic-co-glycolic acid), could be rapidly three-dimensionally (3D) printed (up to 275 cm(3)/hour) from room temperature extruded liquid inks...
September 28, 2016: Science Translational Medicine
Ismail Çimen, Begüm Kocatürk, Seda Koyuncu, Özlem Tufanlı, Umut I Onat, Asli D Yıldırım, Onur Apaydın, Şeyma Demirsoy, Zaliha G Aykut, Uyen T Nguyen, Steven M Watkins, Gökhan S Hotamışlıgil, Ebru Erbay
De novo lipogenesis (DNL), the conversion of glucose and other substrates to lipids, is often associated with ectopic lipid accumulation, metabolic stress, and insulin resistance, especially in the liver. However, organ-specific DNL can also generate distinct lipids with beneficial metabolic bioactivity, prompting a great interest in their use for the treatment of metabolic diseases. Palmitoleate (PAO), one such bioactive lipid, regulates lipid metabolism in liver and improves glucose utilization in skeletal muscle when it is generated de novo from the obese adipose tissue...
September 28, 2016: Science Translational Medicine
Maximilian Muenchhoff, Emily Adland, Owen Karimanzira, Carol Crowther, Matthew Pace, Anna Csala, Ellen Leitman, Angeline Moonsamy, Callum McGregor, Jacob Hurst, Andreas Groll, Masahiko Mori, Smruti Sinmyee, Christina Thobakgale, Gareth Tudor-Williams, Andrew J Prendergast, Henrik Kloverpris, Julia Roider, Alasdair Leslie, Delane Shingadia, Thea Brits, Samantha Daniels, John Frater, Christian B Willberg, Bruce D Walker, Thumbi Ndung'u, Pieter Jooste, Penny L Moore, Lynn Morris, Philip Goulder
Disease-free infection in HIV-infected adults is associated with human leukocyte antigen-mediated suppression of viremia, whereas in the sooty mangabey and other healthy natural hosts of simian immunodeficiency virus (SIV), viral replication continues unabated. To better understand factors preventing HIV disease, we investigated pediatric infection, where AIDS typically develops more rapidly than in adults. Among 170 nonprogressing antiretroviral therapy-naïve children aged >5 years maintaining normal-for-age CD4 T cell counts, immune activation levels were low despite high viremia (median, 26,000 copies/ml)...
September 28, 2016: Science Translational Medicine
Ann Chahroudi, Guido Silvestri
A subset of HIV-infected children shows an unusually benign course of infection that recapitulates key immunological aspects of the natural SIV infection of sooty mangabeys (Muenchhoff et al.).
September 28, 2016: Science Translational Medicine
Binh An Diep, Vien T M Le, Cedric Badiou, Hoan N Le, Marcos Gabriel Pinheiro, Au H Duong, Xing Wang, Etyene Castro Dip, Fábio Aguiar-Alves, Li Basuino, Helene Marbach, Thuy T Mai, Marie N Sarda, Osamu Kajikawa, Gustavo Matute-Bello, Christine Tkaczyk, Jean-Philippe Rasigade, Bret R Sellman, Henry F Chambers, Gerard Lina
New therapeutic approaches are urgently needed to improve survival outcomes for patients with necrotizing pneumonia caused by Staphylococcus aureus One such approach is adjunctive treatment with intravenous immunoglobulin (IVIG), but clinical practice guidelines offer conflicting recommendations. In a preclinical rabbit model, prophylaxis with IVIG conferred protection against necrotizing pneumonia caused by five different epidemic strains of community-associated methicillin-resistant S. aureus (MRSA) as well as a widespread strain of hospital-associated MRSA...
September 21, 2016: Science Translational Medicine
Rizwan Romee, Maximillian Rosario, Melissa M Berrien-Elliott, Julia A Wagner, Brea A Jewell, Timothy Schappe, Jeffrey W Leong, Sara Abdel-Latif, Stephanie E Schneider, Sarah Willey, Carly C Neal, Liyang Yu, Stephen T Oh, Yi-Shan Lee, Arend Mulder, Frans Claas, Megan A Cooper, Todd A Fehniger
Natural killer (NK) cells are an emerging cellular immunotherapy for patients with acute myeloid leukemia (AML); however, the best approach to maximize NK cell antileukemia potential is unclear. Cytokine-induced memory-like NK cells differentiate after a brief preactivation with interleukin-12 (IL-12), IL-15, and IL-18 and exhibit enhanced responses to cytokine or activating receptor restimulation for weeks to months after preactivation. We hypothesized that memory-like NK cells exhibit enhanced antileukemia functionality...
September 21, 2016: Science Translational Medicine
Anuradha Rao, Astrid Kosters, Jamie E Mells, Wujuan Zhang, Kenneth D R Setchell, Angelica M Amanso, Grace M Wynn, Tianlei Xu, Brad T Keller, Hong Yin, Sophia Banton, Dean P Jones, Hao Wu, Paul A Dawson, Saul J Karpen
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world, and safe and effective therapies are needed. Bile acids (BAs) and their receptors [including the nuclear receptor for BAs, farnesoid X receptor (FXR)] play integral roles in regulating whole-body metabolism and hepatic lipid homeostasis. We hypothesized that interruption of the enterohepatic BA circulation using a luminally restricted apical sodium-dependent BA transporter (ASBT) inhibitor (ASBTi; SC-435) would modify signaling in the gut-liver axis and reduce steatohepatitis in high-fat diet (HFD)-fed mice...
September 21, 2016: Science Translational Medicine
Nelomi Anandagoda, Graham M Lord
Investment in national infrastructure is critical for growth in early-phase translational research and experimental medicine.
September 21, 2016: Science Translational Medicine
Corine Ngufor, Raphael N'Guessan, Josias Fagbohoun, Damien Todjinou, Abibath Odjo, David Malone, Hanafy Ismail, Martin Akogbeto, Mark Rowland
Olyset Duo is a new long-lasting insecticidal net treated with permethrin (a pyrethroid) and pyriproxyfen, an insect growth regulator that disrupts the maturation of oocytes in mosquitoes exposed to the net. We tested the Olyset Duo net against pyrethroid-resistant Anopheles gambiae mosquitoes, which transmit malaria parasites, in laboratory bioassays and in a trial in Benin using experimental huts that closely resemble local habitations. Host-seeking mosquitoes that entered to feed were free to contact the occupied nets and were collected the next morning from exit traps...
September 14, 2016: Science Translational Medicine
Rong Yang, Vishakha Sabharwal, Obiajulu S Okonkwo, Nadya Shlykova, Rong Tong, Lily Yun Lin, Weiping Wang, Shutao Guo, John J Rosowski, Stephen I Pelton, Daniel S Kohane
Otitis media is the most common reason U.S. children receive antibiotics. The requisite 7- to 10-day course of oral antibiotics can be challenging to deliver in children, entails potential systemic toxicity, and encourages selection of antimicrobial-resistant bacteria. We developed a drug delivery system that, when applied once to the tympanic membrane through the external auditory canal, delivers an entire course of antimicrobial therapy to the middle ear. A pentablock copolymer poloxamer 407-polybutylphosphoester (P407-PBP) was designed to flow easily during application and then to form a mechanically strong hydrogel on the tympanic membrane...
September 14, 2016: Science Translational Medicine
Christian Hundhausen, Alena Roth, Elizabeth Whalen, Janice Chen, Anya Schneider, S Alice Long, Shan Wei, Rebecca Rawlings, MacKenzie Kinsman, Stephen P Evanko, Thomas N Wight, Carla J Greenbaum, Karen Cerosaletti, Jane H Buckner
Interleukin-6 (IL-6) is a key pathogenic cytokine in multiple autoimmune diseases including rheumatoid arthritis and multiple sclerosis, suggesting that dysregulation of the IL-6 pathway may be a common feature of autoimmunity. The role of IL-6 in type 1 diabetes (T1D) is not well understood. We show that signal transducer and activator of transcription 3 (STAT3) and STAT1 responses to IL-6 are significantly enhanced in CD4 and CD8 T cells from individuals with T1D compared to healthy controls. The effect is IL-6-specific because it is not seen with IL-10 or IL-27 stimulation, two cytokines that signal via STAT3...
September 14, 2016: Science Translational Medicine
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