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Science Translational Medicine

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https://www.readbyqxmd.com/read/28077684/targeting-aurora-kinase-a-and-jak2-prevents-gvhd-while-maintaining-treg-and-antitumor-ctl-function
#1
Brian C Betts, Anandharaman Veerapathran, Joseph Pidala, Hua Yang, Pedro Horna, Kelly Walton, Christopher L Cubitt, Steven Gunawan, Harshani R Lawrence, Nicholas J Lawrence, Said M Sebti, Claudio Anasetti
Graft-versus-host disease (GVHD) is a leading cause of nonrelapse mortality after allogeneic hematopoietic cell transplantation. T cell costimulation by CD28 contributes to GVHD, but prevention is incomplete when targeting CD28, downstream mammalian target of rapamycin (mTOR), or Aurora A. Likewise, interleukin-6 (IL-6)-mediated Janus kinase 2 (JAK2) signaling promotes alloreactivity, yet JAK2 inhibition does not eliminate GVHD. We provide evidence that blocking Aurora A and JAK2 in human T cells is synergistic in vitro, prevents xenogeneic GVHD, and maintains antitumor responses by cytotoxic T lymphocytes (CTLs)...
January 11, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28077683/dampening-the-effects-of-trauma-induced-inflammation
#2
Bret D Ulery
Amine-containing polymers immobilized on mesh and placed at trauma sites scavenge biomolecules that initiate a damaging immune response.
January 11, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28077682/a-weighty-problem
#3
Sarah A Stanley
Altered dopamine signaling in obesity might decrease physical activity without contributing to weight gain.
January 11, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28077681/tune-into-the-rhythm-of-your-bugs
#4
Purna Kashyap
Diurnal changes in gut microbiota localization and function alter host physiology through circadian epigenetic and transcriptional changes.
January 11, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28077680/endomicroscope-sheds-light-on-cervical-tissue
#5
Conor L Evans
A pilot study of a handheld fluorescence endomicroscope demonstrates both in vivo imaging and differentiation of normal from precancerous cervical tissue.
January 11, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28077679/crispr-cas9-gene-repair-of-hematopoietic-stem-cells-from-patients-with-x-linked-chronic-granulomatous-disease
#6
Suk See De Ravin, Linhong Li, Xiaolin Wu, Uimook Choi, Cornell Allen, Sherry Koontz, Janet Lee, Narda Theobald-Whiting, Jessica Chu, Mary Garofalo, Colin Sweeney, Lela Kardava, Susan Moir, Angelia Viley, Pachai Natarajan, Ling Su, Douglas Kuhns, Kol A Zarember, Madhusudan V Peshwa, Harry L Malech
Gene repair of CD34(+) hematopoietic stem and progenitor cells (HSPCs) may avoid problems associated with gene therapy, such as vector-related mutagenesis and dysregulated transgene expression. We used CRISPR (clustered regularly interspaced short palindromic repeat)/Cas9 (CRISPR-associated 9) to repair a mutation in the CYBB gene of CD34(+) HSPCs from patients with the immunodeficiency disorder X-linked chronic granulomatous disease (X-CGD). Sequence-confirmed repair of >20% of HSPCs from X-CGD patients restored the function of NADPH (nicotinamide adenine dinucleotide phosphate) oxidase and superoxide radical production in myeloid cells differentiated from these progenitor cells in vitro...
January 11, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28077678/disruptive-reproductive-technologies
#7
REVIEW
I Glenn Cohen, George Q Daley, Eli Y Adashi
In vitro gametogenesis raises new possibilities for reproductive and regenerative medicine as well as vexing policy challenges.
January 11, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28077677/pharmacological-rescue-of-diabetic-skeletal-stem-cell-niches
#8
Ruth Tevlin, Eun Young Seo, Owen Marecic, Adrian McArdle, Xinming Tong, Bryan Zimdahl, Andrey Malkovskiy, Rahul Sinha, Gunsagar Gulati, Xiyan Li, Taylor Wearda, Rachel Morganti, Michael Lopez, Ryan C Ransom, Christopher R Duldulao, Melanie Rodrigues, Allison Nguyen, Michael Januszyk, Zeshaan Maan, Kevin Paik, Kshemendra-Senarath Yapa, Jayakumar Rajadas, Derrick C Wan, Geoffrey C Gurtner, Michael Snyder, Philip A Beachy, Fan Yang, Stuart B Goodman, Irving L Weissman, Charles K F Chan, Michael T Longaker
Diabetes mellitus (DM) is a metabolic disease frequently associated with impaired bone healing. Despite its increasing prevalence worldwide, the molecular etiology of DM-linked skeletal complications remains poorly defined. Using advanced stem cell characterization techniques, we analyzed intrinsic and extrinsic determinants of mouse skeletal stem cell (mSSC) function to identify specific mSSC niche-related abnormalities that could impair skeletal repair in diabetic (Db) mice. We discovered that high serum concentrations of tumor necrosis factor-α directly repressed the expression of Indian hedgehog (Ihh) in mSSCs and in their downstream skeletogenic progenitors in Db mice...
January 11, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28077676/a-ptk7-targeted-antibody-drug-conjugate-reduces-tumor-initiating-cells-and-induces-sustained-tumor-regressions
#9
Marc Damelin, Alexander Bankovich, Jeffrey Bernstein, Justin Lucas, Liang Chen, Samuel Williams, Albert Park, Jorge Aguilar, Elana Ernstoff, Manoj Charati, Russell Dushin, Monette Aujay, Christina Lee, Hanna Ramoth, Milly Milton, Johannes Hampl, Sasha Lazetic, Virginia Pulito, Edward Rosfjord, Yongliang Sun, Lindsay King, Frank Barletta, Alison Betts, Magali Guffroy, Hadi Falahatpisheh, Christopher J O'Donnell, Robert Stull, Marybeth Pysz, Paul Escarpe, David Liu, Orit Foord, Hans Peter Gerber, Puja Sapra, Scott J Dylla
Disease relapse after treatment is common in triple-negative breast cancer (TNBC), ovarian cancer (OVCA), and non-small cell lung cancer (NSCLC). Therapies that target tumor-initiating cells (TICs) should improve patient survival by eliminating the cells that can drive tumor recurrence and metastasis. We demonstrate that protein tyrosine kinase 7 (PTK7), a highly conserved but catalytically inactive receptor tyrosine kinase in the Wnt signaling pathway, is enriched on TICs in low-passage TNBC, OVCA, and NSCLC patient-derived xenografts (PDXs)...
January 11, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28077675/post-hoc-assessment-of-the-immunogenicity-of-bioengineered-factor-viia-demonstrates-the-use-of-preclinical-tools
#10
Kasper Lamberth, Stine Louise Reedtz-Runge, Jonathan Simon, Ksenia Klementyeva, Gouri Shankar Pandey, Søren Berg Padkjær, Véronique Pascal, Ileana R León, Charlotte Nini Gudme, Søren Buus, Zuben E Sauna
Immunogenicity is an important consideration in the licensure of a therapeutic protein because the development of neutralizing anti-drug antibodies (ADAs) can affect both safety and efficacy. Neoantigens introduced by bioengineering of a protein drug are a particular cause for concern. The development of a bioengineered recombinant factor VIIa (rFVIIa) analog was discontinued after phase 3 trials because of the development of ADAs. The unmodified parent molecule (rFVIIa), on the other hand, has been successfully used as a drug for more than two decades with no reports of immunogenicity in congenital hemophilia patients with inhibitors...
January 11, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28053159/complete-attenuation-of-genetically-engineered-plasmodium-falciparum-sporozoites-in-human-subjects
#11
James G Kublin, Sebastian A Mikolajczak, Brandon K Sack, Matt E Fishbaugher, Annette Seilie, Lisa Shelton, Tracie VonGoedert, Melike Firat, Sara Magee, Emma Fritzen, Will Betz, Heather S Kain, Dorender A Dankwa, Ryan W J Steel, Ashley M Vaughan, D Noah Sather, Sean C Murphy, Stefan H I Kappe
Immunization of humans with whole sporozoites confers complete, sterilizing immunity against malaria infection. However, achieving consistent safety while maintaining immunogenicity of whole parasite vaccines remains a formidable challenge. We generated a genetically attenuated Plasmodium falciparum (Pf) malaria parasite by deleting three genes expressed in the pre-erythrocytic stage (Pf p52(-)/p36(-)/sap1(-)). We then tested the safety and immunogenicity of the genetically engineered (Pf GAP3KO) sporozoites in human volunteers...
January 4, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28053158/a-bioengineered-living-cell-construct-activates-an-acute-wound-healing-response-in-venous-leg-ulcers
#12
Rivka C Stone, Olivera Stojadinovic, Ashley M Rosa, Horacio A Ramirez, Evangelos Badiavas, Miroslav Blumenberg, Marjana Tomic-Canic
Chronic nonhealing venous leg ulcers (VLUs) are widespread and debilitating, with high morbidity and associated costs; about $15 billion is spent annually on the care of VLUs in the United States. Despite this, there is a paucity of treatments for VLUs because of the lack of pathophysiologic insight into ulcer development as well as the lack of knowledge regarding biologic actions of existing VLU-targeted therapies. The bioengineered bilayered living cellular construct (BLCC) skin substitute is a U.S. Food and Drug Administration-approved biologic treatment for healing VLUs...
January 4, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28053157/blockade-of-protease-activated-receptor-4-par4-provides-robust-antithrombotic-activity-with-low-bleeding
#13
Pancras C Wong, Dietmar Seiffert, J Eileen Bird, Carol A Watson, Jeffrey S Bostwick, Mary Giancarli, Nick Allegretto, Ji Hua, David Harden, Jocelyne Guay, Mario Callejo, Michael M Miller, R Michael Lawrence, Jacques Banville, Julia Guy, Brad D Maxwell, E Scott Priestley, Anne Marinier, Ruth R Wexler, Michel Bouvier, David A Gordon, William A Schumacher, Jing Yang
Antiplatelet agents are proven efficacious treatments for cardiovascular and cerebrovascular diseases. However, the existing drugs are compromised by unwanted and sometimes life-threatening bleeding that limits drug usage or dosage. There is a substantial unmet medical need for an antiplatelet drug with strong efficacy and low bleeding risk. Thrombin is a potent platelet agonist that directly induces platelet activation via the G protein (heterotrimeric guanine nucleotide-binding protein)-coupled protease-activated receptors PAR1 and PAR4...
January 4, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28053156/targeted-clinical-control-of-trauma-patient-coagulation-through-a-thrombin-dynamics-model
#14
Amor A Menezes, Ryan F Vilardi, Adam P Arkin, Mitchell J Cohen
We present a methodology for personalizing the clinical treatment of severely injured patients with acute traumatic coagulopathy (ATC), an endogenous biological response of impaired coagulation that occurs early after trauma and shock and that is associated with increased bleeding, morbidity, and mortality. Despite biological characterization of ATC, it is not easily or rapidly diagnosed, not always captured by slow laboratory testing, and not accurately represented by coagulation models. This lack of knowledge, combined with the inherent time pressures of trauma treatment, forces surgeons to treat ATC patients according to empirical resuscitation protocols...
January 4, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28053155/a-case-of-mistaken-identity
#15
Alex K Shalek
No abstract text is available yet for this article.
January 4, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28053154/interfering-with-hiv-therapy
#16
Amanda W Lund
No abstract text is available yet for this article.
January 4, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28053153/fear-memory-erasure-through-neuronal-transplantation
#17
Amit Etkin
No abstract text is available yet for this article.
January 4, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28053152/unleashing-the-wrath-of-ras
#18
Himisha Beltran
No abstract text is available yet for this article.
January 4, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28053151/optimized-temporal-pattern-of-brain-stimulation-designed-by-computational-evolution
#19
David T Brocker, Brandon D Swan, Rosa Q So, Dennis A Turner, Robert E Gross, Warren M Grill
Brain stimulation is a promising therapy for several neurological disorders, including Parkinson's disease. Stimulation parameters are selected empirically and are limited to the frequency and intensity of stimulation. We varied the temporal pattern of deep brain stimulation to ameliorate symptoms in a parkinsonian animal model and in humans with Parkinson's disease. We used model-based computational evolution to optimize the stimulation pattern. The optimized pattern produced symptom relief comparable to that from standard high-frequency stimulation (a constant rate of 130 or 185 Hz) and outperformed frequency-matched standard stimulation in a parkinsonian rat model and in patients...
January 4, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28053150/the-study-is-open-participants-are-now-recruiting-investigators
#20
EDITORIAL
Sharon F Terry
Two U.S. national initiatives have stated emphatically that people will be, not patients, but partners in clinical research.
January 4, 2017: Science Translational Medicine
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