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  • Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-17
    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. We demonstrate that M7824 efficiently, specifically, and simultaneously binds PD-L1 and TGF-β. In syngeneic mouse models, M7824 suppressed tumor growth and metastasis more effectively than treatment with either an anti–PD-L1 antibody or TGF-β trap alone; furthermore, M7824 extended survival and conferred long-term protective antitumor immunity. Mechanistically, the dual anti-immunosuppressive function of M7824 resulted in activation of both the innate and adaptive immune systems, which contributed to M7824’s antitumor activity. Finally, M7824 was an effective combination partner for radiotherapy or chemotherapy in mouse models. Collectively, our preclinical data demonstrate that simultaneous blockade of the PD-L1 and TGF-β pathways by M7824 elicits potent and superior antitumor activity relative to monotherapies.

    更新日期:2018-01-18
  • Identifying DNA methylation biomarkers for non-endoscopic detection of Barrett’s esophagus
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-17
    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. We tested CCNA1 DNA methylation as a BE biomarker in cytology brushings of the distal esophagus from 173 individuals with or without BE. CCNA1 DNA methylation demonstrated an area under the curve of 0.95 for discriminating BE-related metaplasia and neoplasia cases versus normal individuals, performing identically to methylation of VIM DNA, an established BE biomarker. When combined, the resulting two biomarker panel was 95% sensitive and 91% specific. These results were replicated in an independent validation cohort of 149 individuals who were assayed using the same cutoff values for test positivity established in the training population. To progress toward non-endoscopic esophageal screening, we engineered a well-tolerated, swallowable, encapsulated balloon device able to selectively sample the distal esophagus within 5 min. In balloon samples from 86 individuals, tests of CCNA1 plus VIM DNA methylation detected BE metaplasia with 90.3% sensitivity and 91.7% specificity. Combining the balloon sampling device with molecular assays of CCNA1 plus VIM DNA methylation enables an efficient, well-tolerated, sensitive, and specific method of screening at-risk populations for BE.

    更新日期:2018-01-18
  • Inhalation of peptide-loaded nanoparticles improves heart failure
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-17
    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. Treatment of a rodent model of diabetic cardiomyopathy by inhalation of CaPs loaded with a therapeutic mimetic peptide that we previously demonstrated to improve myocardial contraction resulted in restoration of cardiac function. Translation to a porcine large animal model provides evidence that inhalation of a peptide-loaded CaP formulation is an effective method of targeted administration to the heart. Together, these results demonstrate that inhalation of biocompatible tailored peptide nanocarriers represents a pioneering approach for the pharmacological treatment of heart failure.

    更新日期:2018-01-18
  • Bacteria make their way to the brain
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-17
    Kathryn Dupnik

    Diverse bacterial species can be detected in the brains of mice with abdominal sepsis.

    更新日期:2018-01-18
  • Personalized printing for stroke prevention, hand in glove
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-17
    Kevin R. King

    3D-printed patient-specific left atrial appendage occluders overcome anatomic variability to personalize stroke prevention.

    更新日期:2018-01-18
  • Hit me with your best shot… to regenerate
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-17
    Jill K. Morris

    Intraneural ATP injection improves axonal recovery following spinal cord injury.

    更新日期:2018-01-18
  • Fighting staph: Not child’s play
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-17
    Tiffany C. Scharschmidt

    Neutralizing antibodies to Staphylococcus aureus alpha-toxin are acquired in adolescence and augmented by infection or colonization.

    更新日期:2018-01-18
  • Methicillin-resistant Staphylococcus aureus causes sustained collecting lymphatic vessel dysfunction
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-17
    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. Moreover, chronic lymphatic impairment is observed long after MRSA is cleared and inflammation is resolved. Associated with decreased collecting lymphatic vessel function was the loss and disorganization of lymphatic muscle cells (LMCs), which are critical for lymphatic contraction. In vitro, incubation with MRSA-conditioned supernatant led to LMC death. Proteomic analysis identified several accessory gene regulator (agr)–controlled MRSA exotoxins that contribute to LMC death. Infection with agr mutant MRSA resulted in sustained lymphatic function compared to animals infected with wild-type MRSA. Our findings suggest that agr is a promising target to preserve lymphatic vessel function and promote immunity during SSTIs.

    更新日期:2018-01-18
  • Engineering precision biomaterials for personalized medicine
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-17
    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.

    更新日期:2018-01-18
  • The antimicrobial peptide SAAP-148 combats drug-resistant bacteria and biofilms
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-10
    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. A single 4-hour treatment with hypromellose ointment containing SAAP-148 completely eradicated acute and established, biofilm-associated infections with methicillin-resistant Staphylococcus aureus and MDR Acinetobacter baumannii from wounded ex vivo human skin and murine skin in vivo. Together, these data demonstrate that SAAP-148 is a promising drug candidate in the battle against antibiotic-resistant bacteria that pose a great threat to human health.

    更新日期:2018-01-11
  • Rapid drug screen using 3D tumor organoids
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-10
    Kwanghun Chung

    Breast cancer organoids enable high-throughput functional drug screens to potentially guide individualized therapy.

    更新日期:2018-01-11
  • Factoring in new gene therapy treatments for hemophilia A
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-10
    Leah C. Byrne

    Delivery of a modified factor VIII gene leads to dramatic improvement of severe hemophilia A in human trials.

    更新日期:2018-01-11
  • Gold photothermal therapy: A positive for negative margins
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-10
    Miles A. Miller

    Nanoparticle-based photothermal therapy after tumor resection inhibits recurrence.

    更新日期:2018-01-11
  • A tropical virus that prefers cool weather
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-10
    Jonathan Miner

    Cooler temperatures exacerbate chikungunya viral arthritis.

    更新日期:2018-01-11
  • Zika–associated microcephaly: Reduce the stress and race for the treatment
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-10
    Gaia Novarino

    Inhibition of the endoplasmic reticulum stress pathway may hold the key to Zika virus–associated microcephaly treatment.

    更新日期:2018-01-11
  • Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-10
    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 = 3.3 × 10−8). These variants affected CD age of onset, disease location, LRRK2 activity, and autophagy. Bayesian network analysis of CD patient intestinal tissue further implicated LRRK2 in CD pathogenesis. Analysis of the extended LRRK2 locus in 24,570 CD cases, patients with Parkinson’s disease (PD), and healthy controls revealed extensive pleiotropy, with shared genetic effects between CD and PD in both Ashkenazi Jewish and non-Jewish cohorts. The LRRK2 N2081D CD risk allele is located in the same kinase domain as G2019S, a mutation that is the major genetic cause of familial and sporadic PD. Like the G2019S mutation, the N2081D variant was associated with increased kinase activity, whereas neither N551K nor R1398H variants on the protective haplotype altered kinase activity. We also confirmed that R1398H, but not N551K, increased guanosine triphosphate binding and hydrolyzing enzyme (GTPase) activity, thereby deactivating LRRK2. The presence of shared LRRK2 alleles in CD and PD provides refined insight into disease mechanisms and may have major implications for the treatment of these two seemingly unrelated diseases.

    更新日期:2018-01-11
  • Plasmacytoid dendritic cells promote systemic sclerosis with a key role for TLR8
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-10
    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. We demonstrate that the secretion of CXCL4 is under the control of phosphatidylinositol 3-kinase δ and is due to the aberrant presence of TLR8 on pDCs of SSc patients, which is not seen in healthy donors or in lupus pDCs, and that CXCL4 primarily acts by potentiating TLR8- but also TLR9-induced IFN production by pDCs. Depleting pDCs prevented disease in a mouse model of scleroderma and could revert fibrosis in mice with established disease. In contrast, the disease was exacerbated in mice transgenic for TLR8 with recruitment of pDCs to the fibrotic skin, whereas TLR7 only partially contributed to the inflammatory response, indicating that TLR8 is the key RNA-sensing TLR involved in the establishment of fibrosis. We conclude that the pDC is an essential cell type involved in the pathogenesis of SSc and its removal using depleting antibodies or attenuating pDC function could be a novel approach to treat SSc patients.

    更新日期:2018-01-11
  • Mechanobiologically optimized 3D titanium-mesh scaffolds enhance bone regeneration in critical segmental defects in sheep
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-10
    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. Scaffold stiffness was altered through small changes in the strut diameter only. Honeycombs were aligned to form three differently oriented channels (axial, perpendicular, and tilted) to guide the bone regeneration process. The soft scaffold (0.84 GPa stiffness) and a 3.5-fold stiffer scaffold (2.88 GPa) were tested in a critical size bone defect model in vivo in sheep. To verify that local scaffold stiffness could enhance healing, defects were stabilized with either a common locking compression plate that allowed dynamic loading of the 4-cm defect or a rigid custom-made plate that mechanically shielded the defect. Lower stress shielding led to earlier defect bridging, increased endochondral bone formation, and advanced bony regeneration of the critical size defect. This study demonstrates that mechanobiological optimization of 3D additive manufactured Ti-mesh scaffolds can enhance bone regeneration in a translational large animal study.

    更新日期:2018-01-11
  • Targeting extracellular matrix stiffness to attenuate disease: From molecular mechanisms to clinical trials
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-03
    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. Potential pharmacological interventions to overcome extracellular matrix stiffening are emerging clinically. Aside from targeting stiffening directly, alternative approaches to mitigate the effects of increased matrix stiffness aim to identify and inhibit the downstream cellular response to matrix stiffness. Therapeutic interventions that target tissue stiffening are discussed in the context of their limitations, preclinical drug development efforts, and clinical trials.

    更新日期:2018-01-04
  • Neoadjuvant oncolytic virotherapy before surgery sensitizes triple-negative breast cancer to immune checkpoint therapy
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-03
    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. Using a therapeutic model that mimics the course of treatment for women with newly diagnosed TNBC, we demonstrate that early OV treatment coupled with surgical resection provides long-term benefits. OV therapy sensitizes otherwise refractory TNBC to immune checkpoint blockade, preventing relapse in most of the treated animals. We suggest that OV therapy in combination with immune checkpoint blockade warrants testing as a neoadjuvant treatment option in the window of opportunity between TNBC diagnosis and surgical resection.

    更新日期:2018-01-04
  • A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-03
    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. Accordingly, Treginduction is improved using T cells from NFAT5 knockout (NFAT5ko) animals, whereas altering miRNA181a activity does not affect Treginduction in NFAT5ko T cells. Moreover, high costimulatory signals result in phosphoinositide 3-kinase (PI3K)–mediated NFAT5, which interferes with FoxP3+Treginduction. Blocking miRNA181a or NFAT5 increases Treginduction in murine and humanized models and reduces murine islet autoimmunity in vivo. These findings suggest targeting miRNA181a and/or NFAT5 signaling for the development of innovative personalized medicines to limit islet autoimmunity.

    更新日期:2018-01-04
  • Repeat doses of antibody to serum amyloid P component clear amyloid deposits in patients with systemic amyloidosis
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-03
    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. We report the safety, pharmacokinetics, and dose-response effects of up to three cycles of miridesap followed by dezamizumab in 23 adult subjects with systemic amyloidosis (ClinicalTrials.gov identifier:NCT01777243). Amyloid load was measured scintigraphically by amyloid-specific radioligand binding of123I-labeled SAP or of99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid. Organ extracellular volume was measured by equilibrium magnetic resonance imaging and liver stiffness by transient elastography. The treatment was well tolerated with the main adverse event being self-limiting early onset rashes after higher antibody doses related to whole body amyloid load. Progressive dose-related clearance of hepatic amyloid was associated with improved liver function tests.123I-SAP scintigraphy confirmed amyloid removal from the spleen and kidneys. No adverse cardiac events attributable to the intervention occurred in the six subjects with cardiac amyloidosis. Amyloid load reduction by miridesap treatment followed by dezamizumab has the potential to improve management and outcome in systemic amyloidosis.

    更新日期:2018-01-04
  • Auditory-somatosensory bimodal stimulation desynchronizes brain circuitry to reduce tinnitus in guinea pigs and humans
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-03
    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). Twenty minutes per day of LTD-inducing bimodal (but not unimodal) stimulation reduced physiological and behavioral evidence of tinnitus in the guinea pigs after 25 days. Next, we applied the same bimodal treatment to 20 human subjects with tinnitus using a double-blinded, sham-controlled, crossover study. Twenty-eight days of LTD-inducing bimodal stimulation reduced tinnitus loudness and intrusiveness. Unimodal auditory stimulation did not deliver either benefit. Bimodal auditory-somatosensory stimulation that induces LTD in the dorsal cochlear nucleus may hold promise for suppressing chronic tinnitus, which reduces quality of life for millions of tinnitus sufferers worldwide.

    更新日期:2018-01-04
  • TOR at the core of impaired regeneration
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-03
    Christopher Hine

    Repeated activation of target of rapamycin (TOR) signaling during tissue regeneration results in impaired stem cell maintenance and promotes aging.

    更新日期:2018-01-04
  • Novel drug combination unleashes apoptosis in AML
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-03
    Brian A. Jonas

    The combination of p53 activation and Bcl-2 inhibition reciprocally overcomes apoptosis resistance and leads to synergistic efficacy in acute myeloid leukemia.

    更新日期:2018-01-04
  • Adolescent obesity thwarts lifelong sleep
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-03
    Maria K. Lehtinen

    Obesity during adolescence shapes lifelong sleep circuitry via serotonin.

    更新日期:2018-01-04
  • Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade
    Sci. Transl. Med. (IF 16.796) Pub Date : 2018-01-03
    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. Oncolytic viruses (OVs) represent a promising form of cancer immunotherapy. For brain tumors, almost all studies to date have used direct intralesional injection of OV, because of the largely untested belief that intravenous administration will not deliver virus to this site. We show, in a window-of-opportunity clinical study, that intravenous infusion of oncolytic humanOrthoreovirus(referred to herein as reovirus) leads to infection of tumor cells subsequently resected as part of standard clinical care, both in high-grade glioma and in brain metastases, and increases cytotoxic T cell tumor infiltration relative to patients not treated with virus. We further show that reovirus up-regulates IFN-regulated gene expression, as well as the PD-1/PD-L1 axis in tumors, via an IFN-mediated mechanism. Finally, we show that addition of PD-1 blockade to reovirus enhances systemic therapy in a preclinical glioma model. These results support the development of combined systemic immunovirotherapy strategies for the treatment of both primary and secondary tumors in the brain.

    更新日期:2018-01-04
  • Enhanced human hematopoietic stem and progenitor cell engraftment by blocking donor T cell–mediated TNFα signaling
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-12-20
    Weijia Wang, Hisaki Fujii, Hye Jin Kim, Karin Hermans, Tatiana Usenko, Stephanie Xie, Zhi-Juan Luo, Jennifer Ma, Cristina Lo Celso, John E. Dick, Timm Schroeder, Joerg Krueger, Donna Wall, R. Maarten Egeler, Peter W. Zandstra

    Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy, but the large number of HSCs required limits its widespread use. Host conditioning and donor cell composition are known to affect HSCT outcomes. However, the specific role that the posttransplantation signaling environment plays in donor HSC fate is poorly understood. To mimic clinical HSCT, we injected human umbilical cord blood (UCB) cells at different doses and compositions into immunodeficient NOD/SCID/IL-2Rgc-null (NSG) mice. Surprisingly, higher UCB cell doses inversely correlated with stem and progenitor cell engraftment. This observation was attributable to increased donor cell–derived inflammatory signals. Donor T cell–derived tumor necrosis factor–α (TNFα) was specifically found to directly impair the survival and division of transplanted HSCs and progenitor cells. Neutralizing donor T cell–derived TNFα in vivo increased short-term stem and progenitor cell engraftment, accelerated hematopoietic recovery, and altered donor immune cell compositions. This direct effect of TNFα on transplanted cells could be decoupled from the indirect effect of alleviating graft-versus-host disease (GVHD) by interleukin-6 (IL-6) blockade. Our study demonstrates that donor immune cell–derived inflammatory signals directly influence HSC fate, and provides new clinically relevant strategies to improve engraftment efficiency during HSCT.

    更新日期:2017-12-21
  • A homestay for your heart
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-12-20
    Christopher M. Jewell

    Heart-injectable hydrogels containing microRNA promote cardiomyocyte proliferation in mice after myocardial infarction.

    更新日期:2017-12-21
  • Statins are skin safe, now go innovate!
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-12-20
    Hadar Lev-Tov

    Epidemiological data demonstrate no overall increased risk of skin cancer with statin use.

    更新日期:2017-12-21
  • Stress signal ACTs to hinder sleep in PTSD
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-12-20
    Vasiliki Michopoulos

    Adrenocorticotropic hormone (ACTH) modulation is associated with sleep disturbances in individuals with posttraumatic stress disorder.

    更新日期:2017-12-21
  • Personalized medicine finds the MAPK for breast cancer
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-12-20
    Monica Venere

    Whole-exome sequencing and RNA-seq on a mouse model of triple-negative breast cancer reveal actionable therapeutic targets for precision medicine guided treatment.

    更新日期:2017-12-21
  • Vaccination of dogs in an African city interrupts rabies transmission and reduces human exposure
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-12-20
    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. The modeled incidence of human rabies exposure fell to less than one person per million people per year. A phylodynamic estimation of the effective reproductive number from 29 canine rabies virus genetic sequences of the viral N-protein confirmed the results of the deterministic transmission model, implying that rabies transmission between dogs was interrupted for 9 months. However, new dog rabies cases appeared earlier than the transmission and phylodynamic models predicted. This may have been due to the continuous movement of rabies-exposed dogs into N’Djaména from outside the city. Our results show that canine rabies transmission to humans can be interrupted in an African city with currently available dog rabies vaccines, provided that the vaccination area includes larger adjacent regions, and local communities are informed and engaged.

    更新日期:2017-12-21
  • Human ESC–derived retinal epithelial cell sheets potentiate rescue of photoreceptor cell loss in rats with retinal degeneration
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-12-20
    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. We established a surgical approach to engraft this tissue-engineered product into the subretinal space of the eyes of rats with photoreceptor cell loss. We show that transplantation of the hESC-RPE cell sheets grown on a human amniotic membrane scaffold resulted in rescue of photoreceptor cell death and improved visual acuity in rats with retinal degeneration compared to hESC-RPE cells injected as a cell suspension. These results suggest that tissue-engineered hESC-RPE cell sheets produced under good manufacturing practice conditions may be a useful approach for treating diseases of retinal degeneration.

    更新日期:2017-12-21
  • A human microglia-like cellular model for assessing the effects of neurodegenerative disease gene variants
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-12-20
    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, andMETTL21B) in which the risk haplotype drives the association with both disease susceptibility and altered expression of a nearby gene (cis-eQTL). In thePILRBandLRRK2loci, the cis-eQTL was found in the MDMi cells but not in human peripheral blood monocytes, suggesting that differentiation of monocytes into microglia-like cells led to the acquisition of a cellular state that could reveal the functional consequences of certain genetic variants. We further validated the effect of risk haplotypes at the protein level forPILRBandCD33, and we confirmed that theCD33risk haplotype altered phagocytosis by the MDMi cells. We propose that increasedLRRK2gene expression by MDMi cells could be a functional outcome ofrs76904798, a single-nucleotide polymorphism in theLRKK2locus that is associated with Parkinson’s disease.

    更新日期:2017-12-21
  • Hippocampal extracellular matrix alterations contribute to cognitive impairment associated with a chronic depressive-like state in rats
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-12-20
    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. These effects were abrogated by a 3-week treatment with the antidepressant imipramine starting 8 weeks after the last defeat encounter. Next, we observed an increase in the number of perineuronal nets (PNNs) surrounding parvalbumin-expressing interneurons and a decrease in the frequency of inhibitory postsynaptic currents (IPSCs) in the hippocampal CA1 region in SDPS animals. In vivo breakdown of the hippocampus CA1 extracellular matrix by the enzyme chondroitinase ABC administered intracranially restored the number of PNNs, LTP maintenance, hippocampal inhibitory tone, and memory performance on the object place recognition test. Our data reveal a causal link between increased hippocampal extracellular matrix and the cognitive deficits associated with a chronic depressive-like state in rats exposed to SDPS.

    更新日期:2017-12-21
  • Urine lipoarabinomannan glycan in HIV-negative patients with pulmonary tuberculosis correlates with disease severity
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-12-13
    Luisa Paris, Ruben Magni, Fatima Zaidi, Robyn Araujo, Neal Saini, Michael Harpole, Jorge Coronel, Daniela E. Kirwan, Hannah Steinberg, Robert H. Gilman, Emanuel F. Petricoin, Roberto Nisini, Alessandra Luchini, Lance Liotta

    An accurate urine test for pulmonary tuberculosis (TB), affecting 9.6 million patients worldwide, is critically needed for surveillance and treatment management. Past attempts failed to reliably detect the mycobacterial glycan antigen lipoarabinomannan (LAM), a marker of active TB, in HIV-negative, pulmonary TB–infected patients’ urine (85% of 9.6 million patients). We apply a copper complex dye within a hydrogel nanocage that captures LAM with very high affinity, displacing interfering urine proteins. The technology was applied to study pretreatment urine from 48 Peruvian patients, all negative for HIV, with microbiologically confirmed active pulmonary TB. LAM was quantitatively measured in the urine with a sensitivity of >95% and a specificity of >80% (n= 101) in a concentration range of 14 to 2000 picograms per milliliter, as compared to non-TB, healthy and diseased, age-matched controls (evaluated by receiver operating characteristic analysis; area under the curve, 0.95; 95% confidence interval, 0.9005 to 0.9957). Urinary LAM was elevated in patients with a higher mycobacterial burden (n= 42), a higher proportion of weight loss (n= 37), or cough (n= 50). The technology can be configured in a variety of formats to detect a panel of previously undetectable very-low-abundance TB urinary analytes. Eight of nine patients who were smear-negative and culture-positive for TB tested positive for urinary LAM. This technology has broad implications for pulmonary TB screening, transmission control, and treatment management for HIV-negative patients.

    更新日期:2017-12-15
  • Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-12-13
    David Lagares, Alba Santos, Paula E. Grasberger, Fei Liu, Clemens K. Probst, Rod A. Rahimi, Norihiko Sakai, Tobias Kuehl, Jeremy Ryan, Patrick Bhola, Joan Montero, Mohit Kapoor, Murray Baron, Xaralabos Varelas, Daniel J. Tschumperlin, Anthony Letai, Andrew M. Tager

    Persistent myofibroblast activation distinguishes pathological fibrosis from physiological wound healing, suggesting that therapies selectively inducing myofibroblast apoptosis could prevent progression and potentially reverse established fibrosis in diseases such as scleroderma, a heterogeneous autoimmune disease characterized by multiorgan fibrosis. We demonstrate that fibroblast-to-myofibroblast differentiation driven by matrix stiffness increases the mitochondrial priming (proximity to the apoptotic threshold) of these activated cells. Mitochondria in activated myofibroblasts, but not quiescent fibroblasts, are primed by death signals such as the proapoptotic BH3-only protein BIM, which creates a requirement for tonic expression of the antiapoptotic protein BCL-XLto sequester BIM and ensure myofibroblast survival. Myofibroblasts become particularly susceptible to apoptosis induced by “BH3 mimetic” drugs inhibiting BCL-XLsuch as ABT-263. ABT-263 displaces BCL-XLbinding to BIM, allowing BIM to activate apoptosis on stiffness-primed myofibroblasts. Therapeutic blockade of BCL-XLwith ABT-263 (navitoclax) effectively treats established fibrosis in a mouse model of scleroderma dermal fibrosis by inducing myofibroblast apoptosis. Using a BH3 profiling assay to assess mitochondrial priming in dermal fibroblasts derived from patients with scleroderma, we demonstrate that the extent of apoptosis induced by BH3 mimetic drugs correlates with the extent of their mitochondrial priming, indicating that BH3 profiling could predict apoptotic responses of fibroblasts to BH3 mimetic drugs in patients with scleroderma. Together, our findings elucidate the potential efficacy of targeting myofibroblast antiapoptotic proteins with BH3 mimetic drugs in scleroderma and other fibrotic diseases.

    更新日期:2017-12-15
  • Durability and correlates of vaccine protection against Zika virus in rhesus monkeys
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-12-13
    Peter Abbink, Rafael A. Larocca, Kittipos Visitsunthorn, Michael Boyd, Rafael A. De La Barrera, Gregory D. Gromowski, Marinela Kirilova, Rebecca Peterson, Zhenfeng Li, Ovini Nanayakkara, Ramya Nityanandam, Noe B. Mercado, Erica N. Borducchi, Abishek Chandrashekar, David Jetton, Shanell Mojta, Priya Gandhi, Jake LeSuer, Shreeya Khatiwada, Mark G. Lewis, Kayvon Modjarrad, Richard G. Jarman, Kenneth H. Eckels, Stephen J. Thomas, Nelson L. Michael, Dan H. Barouch

    An effective Zika virus (ZIKV) vaccine will require long-term durable protection. Several ZIKV vaccine candidates have demonstrated protective efficacy in nonhuman primates, but these studies have typically involved ZIKV challenge shortly after vaccination at peak immunity. We show that a single immunization with an adenovirus vector–based vaccine, as well as two immunizations with a purified inactivated virus vaccine, afforded robust protection against ZIKV challenge in rhesus monkeys at 1 year after vaccination. In contrast, two immunizations with an optimized DNA vaccine, which provided complete protection at peak immunity, resulted in reduced protective efficacy at 1 year that was associated with declining neutralizing antibody titers to subprotective levels. These data define a microneutralization log titer of 2.0 to 2.1 as the threshold required for durable protection against ZIKV challenge in this model. Moreover, our findings demonstrate that protection against ZIKV challenge in rhesus monkeys is possible for at least 1 year with a single-shot vaccine.

    更新日期:2017-12-15
  • A diet pill for critical illness weakness?
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-12-13
    Huimahn Alex Choi

    The serotoninergic drug Lorcaserin rescued motor neuron electrophysiological abnormalities in an animal model of critical illness–induced weakness.

    更新日期:2017-12-15
  • Running interference on hemorrhagic fever
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-12-13
    Jeffrey Haspel

    A siRNA-based therapy for Marburg viruses shows promise.

    更新日期:2017-12-15
  • Myc heals all (tumor) wounds
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-12-13
    Kristopher Sarosiek

    The activation of Myc in Ras-driven lung adenomas causes profound immune/stromal remodeling to support tumor growth.

    更新日期:2017-12-15
  • NRF2 much of a good thing
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-12-13
    Ashley H. Shoemaker

    Chronic hyperglycemia induces hypertension and renal injury through nuclear factor erythroid 2–related factor 2 (NRF2)–stimulation of the renin-angiotensin system.

    更新日期:2017-12-15
  • Thorase variants are associated with defects in glutamatergic neurotransmission that can be rescued by Perampanel
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-12-13
    George K. E. Umanah, Marco Pignatelli, Xiling Yin, Rong Chen, Joshua Crawford, Stewart Neifert, Leslie Scarffe, Adam A. Behensky, Noah Guiberson, Melissa Chang, Erica Ma, Jin Wan Kim, Cibele C. Castro, Xiaobo Mao, Li Chen, Shaida A. Andrabi, Mikhail V. Pletnikov, Ann E. Pulver, Dimitrios Avramopoulos, Antonello Bonci, David Valle, Ted M. Dawson, Valina L. Dawson

    The AAA+ adenosine triphosphatase (ATPase) Thorase plays a critical role in controlling synaptic plasticity by regulating the expression of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Bidirectional sequencing of exons ofATAD1, the gene encoding Thorase, in a cohort of patients with schizophrenia and healthy controls revealed rare Thorase variants. These variants caused defects in glutamatergic signaling by impairing AMPAR internalization and recycling in mouse primary cortical neurons. This contributed to increased surface expression of the AMPAR subunit GluA2 and enhanced synaptic transmission. Heterozygous Thorase-deficient mice engineered to express these Thorase variants showed altered synaptic transmission and several behavioral deficits compared to heterozygous Thorase-deficient mice expressing wild-type Thorase. These behavioral impairments were rescued by the competitive AMPAR antagonist Perampanel, a U.S. Food and Drug Administration–approved drug. These findings suggest that Perampanel may be useful for treating disorders involving compromised AMPAR-mediated glutamatergic neurotransmission.

    更新日期:2017-12-15
  • Effect of population viral load on prospective HIV incidence in a hyperendemic rural African community
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-12-13
    Frank Tanser, Alain Vandormael, Diego Cuadros, Andrew N. Phillips, Tulio de Oliveira, Andrew Tomita, Till Bärnighausen, Deenan Pillay

    Monitoring HIV population viral load (PVL) has been advocated as an important means of inferring HIV transmission potential and predicting the future rate of new HIV infections (HIV incidence) in a particular community. However, the relationship between PVL measures and directly measured HIV incidence has not been quantified in any setting and, most importantly, in a hyperendemic sub-Saharan African setting. We assessed this relationship using one of Africa’s largest population-based prospective population cohorts in rural KwaZulu-Natal, South Africa in which we followed 8732 HIV-uninfected participants between 2011 and 2015. Despite clear evidence of spatial clustering of high viral loads in some communities, our results demonstrate that PVL metrics derived from aggregation of viral load data only from the HIV-positive members of a particular community did not predict HIV incidence in this typical hyperendemic, rural African population. Only once we used modified PVL measures, which combined viral load information with the underlying spatial variation in the proportion of the population infected (HIV prevalence), did we find a consistently strong relationship with future risk of HIV acquisition. For example, every 1% increase in the overall proportion of a population having detectable virus (PDVP) was independently associated with a 6.3% increase in an individual’s risk of HIV acquisition (P= 0.001). In hyperendemic African populations, these modified PVL indices could play a key role in targeting and monitoring interventions in the most vulnerable communities where the future rate of new HIV infections is likely to be highest.

    更新日期:2017-12-15
  • Clinical trial design: The nobility of randomization
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-12-06
    Nelson L. Michael

    A clinical trial evaluating HIV vaccine therapy teaches us much about optimal design (Snelleret al., this issue).

    更新日期:2017-12-06
  • PPARδ activation by bexarotene promotes neuroprotection by restoring bioenergetic and quality control homeostasis
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-12-06
    Audrey S. Dickey, Dafne N. Sanchez, Martin Arreola, Kunal R. Sampat, Weiwei Fan, Nicolas Arbez, Sergey Akimov, Michael J. Van Kanegan, Kohta Ohnishi, Stephen K. Gilmore-Hall, April L. Flores, Janice M. Nguyen, Nicole Lomas, Cynthia L. Hsu, Donald C. Lo, Christopher A. Ross, Eliezer Masliah, Ronald M. Evans, Albert R. La Spada

    Neurons must maintain protein and mitochondrial quality control for optimal function, an energetically expensive process. The peroxisome proliferator–activated receptors (PPARs) are ligand-activated transcription factors that promote mitochondrial biogenesis and oxidative metabolism. We recently determined that transcriptional dysregulation of PPARδ contributes to Huntington’s disease (HD), a progressive neurodegenerative disorder resulting from a CAG-polyglutamine repeat expansion in the huntingtin gene. We documented that the PPARδ agonist KD3010 is an effective therapy for HD in a mouse model. PPARδ forms a heterodimer with the retinoid X receptor (RXR), and RXR agonists are capable of promoting PPARδ activation. One compound with potent RXR agonist activity is the U.S. Food and Drug Administration–approved drug bexarotene. We tested the therapeutic potential of bexarotene in HD and found that bexarotene was neuroprotective in cellular models of HD, including medium spiny-like neurons generated from induced pluripotent stem cells (iPSCs) derived from patients with HD. To evaluate bexarotene as a treatment for HD, we treated the N171-82Q mouse model with the drug and found that bexarotene improved motor function, reduced neurodegeneration, and increased survival. To determine the basis for PPARδ neuroprotection, we evaluated metabolic function and noted markedly impaired oxidative metabolism in HD neurons, which was rescued by bexarotene or KD3010. We examined mitochondrial and protein quality control in cellular models of HD and observed that treatment with a PPARδ agonist promoted cellular quality control. By boosting cellular activities that are dysfunctional in HD, PPARδ activation may have therapeutic applications in HD and potentially other neurodegenerative diseases.

    更新日期:2017-12-06
  • A reversible thermoresponsive sealant for temporary closure of ocular trauma
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-12-06
    Niki Bayat, Yi Zhang, Paulo Falabella, Roby Menefee, John J. Whalen, Mark S. Humayun, Mark E. Thompson

    Open globe injuries are full-thickness injuries sustained to the eye wall (cornea or sclera), which cause immediate drops in intraocular pressure that may lead to retinal detachment and permanent vision loss if not treated rapidly after injury. The current standard of care for open globe injuries consists of suturing the margins closed, but the technique can be time-consuming, requires specialized training and equipment, and can lead to patient discomfort, abrasion, and infection from eye rubbing. We engineered an injectable, thermoresponsive sealant (TRS) and a custom tool to occlude open globe injuries. The smart hydrogel sealant consists of physically cross-linkedN-isopropylacrylamide copolymerized with butylacrylate. At low temperatures, it can be injected as a liquid, and when raised to body temperature, a heat-induced gelation converts the hydrogel into a solidified occlusion. The sealant can be repositioned or removed without causing additional trauma via exposure to cold water. In vitro and ex vivo assessments of mechanical adhesion to eye tissue revealed maintenance of intraocular pressure that is five times greater than the physiological range with reversible seal strength comparable to cyanoacrylate (super glue). In vivo assessment in a rabbit model of ocular trauma demonstrated ease of use for TRS deployment, statistically significant improvement in wound sealing, and no evidence of neurotoxicity, retinal tissue degradation, or significant chronic inflammatory response after 30 days of exposure. Given the advantages of body heat–induced gelation, rapid reversible occlusion, and in vivo safety and efficacy, shape-adaptable TRSs have translational potential as smart wound sealants for temporary occlusion of surgical incisions or traumatic injuries.

    更新日期:2017-12-06
  • Who’s afraid of the big bad pathogen?
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-12-06
    Stephanie A. Christenson

    Bacterial predation byAcinetobacter baylyisubstantially increases cross-species horizontal gene transfer, leading to rapid acquisition of antimicrobial resistance genes.

    更新日期:2017-12-06
  • Brain leak, mind bleak
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-12-06
    Kafui Dzirasa

    Stress-induced changes in blood-brain barrier permeability contribute to depression pathology.

    更新日期:2017-12-06
  • Breaking free from the NETs
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-12-06
    Benjamin Levi

    Neutrophil extracellular traps exacerbate ischemia reperfusion injury associated with neonatal midgut volvulus and serve as a therapeutic target.

    更新日期:2017-12-06
  • Taking control of a volatile situation
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-12-06
    Jennifer A. Philips

    A 3D microscale model of the human bronchiole reveals volatile-mediated communication betweenAspergillus,Pseudomonas, and host.

    更新日期:2017-12-06
  • A degradation fragment of type X collagen is a real-time marker for bone growth velocity
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-12-06
    Ryan F. Coghlan, Jon A. Oberdorf, Susan Sienko, Michael D. Aiona, Bruce A. Boston, Kara J. Connelly, Chelsea Bahney, Jeremie LaRouche, Sarah M. Almubarak, Daniel T. Coleman, Irute Girkontaite, Klaus von der Mark, Gregory P. Lunstrum, William A. Horton

    Despite its importance as a key parameter of child health and development, growth velocity is difficult to determine in real time because skeletal growth is slow and clinical tools to accurately detect very small increments of growth do not exist. We report discovery of a marker for skeletal growth in infants and children. The intact trimeric noncollagenous 1 (NC1) domain of type X collagen, the marker we designated as CXM for Collagen X Marker, is a degradation by-product of endochondral ossification that is released into the circulation in proportion to overall growth plate activity. This marker corresponds to the rate of linear bone growth at time of measurement. Serum concentrations of CXM plotted against age show a pattern similar to well-established height growth velocity curves and correlate with height growth velocity calculated from incremental height measurements in this study. The CXM marker is stable once collected and can be accurately assayed in serum, plasma, and dried blood spots. CXM testing may be useful for monitoring growth in the pediatric population, especially responses of infants and children with genetic and acquired growth disorders to interventions that target the underlying growth disturbances. The utility of CXM may potentially extend to managing other conditions such as fracture healing, scoliosis, arthritis, or cancer.

    更新日期:2017-12-06
  • BCAS1 expression defines a population of early myelinating oligodendrocytes in multiple sclerosis lesions
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-12-06
    Maryam K. Fard, Franziska van der Meer, Paula Sánchez, Ludovico Cantuti-Castelvetri, Sunit Mandad, Sarah Jäkel, Eugenio F. Fornasiero, Sebastian Schmitt, Marc Ehrlich, Laura Starost, Tanja Kuhlmann, Christina Sergiou, Verena Schultz, Claudia Wrzos, Wolfgang Brück, Henning Urlaub, Leda Dimou, Christine Stadelmann, Mikael Simons

    Investigations into brain function and disease depend on the precise classification of neural cell types. Cells of the oligodendrocyte lineage differ greatly in their morphology, but accurate identification has thus far only been possible for oligodendrocyte progenitor cells and mature oligodendrocytes in humans. We find that breast carcinoma amplified sequence 1 (BCAS1) expression identifies an oligodendroglial subpopulation in the mouse and human brain. These cells are newly formed, myelinating oligodendrocytes that segregate from oligodendrocyte progenitor cells and mature oligodendrocytes and mark regions of active myelin formation in development and in the adult. We find that BCAS1+oligodendrocytes are restricted to the fetal and early postnatal human white matter but remain in the cortical gray matter until old age. BCAS1+oligodendrocytes are reformed after experimental demyelination and found in a proportion of chronic white matter lesions of patients with multiple sclerosis (MS) even in a subset of patients with advanced disease. Our work identifies a means to map ongoing myelin formation in health and disease and presents a potential cellular target for remyelination therapies in MS.

    更新日期:2017-12-06
  • A randomized controlled safety/efficacy trial of therapeutic vaccination in HIV-infected individuals who initiated antiretroviral therapy early in infection
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-12-06
    Michael C. Sneller, J. Shawn Justement, Kathleen R. Gittens, Mary E. Petrone, Katherine E. Clarridge, Michael A. Proschan, Richard Kwan, Victoria Shi, Jana Blazkova, Eric W. Refsland, Daryl E. Morris, Kristen W. Cohen, M. Juliana McElrath, Rong Xu, Michael A. Egan, John H. Eldridge, Erika Benko, Colin Kovacs, Susan Moir, Tae-Wook Chun, Anthony S. Fauci

    Despite substantial clinical benefits, complete eradication of HIV has not been possible using antiretroviral therapy (ART) alone. Strategies that can either eliminate persistent viral reservoirs or boost host immunity to prevent rebound of virus from these reservoirs after discontinuation of ART are needed; one possibility is therapeutic vaccination. We report the results of a randomized, placebo-controlled trial of a therapeutic vaccine regimen in patients in whom ART was initiated during the early stage of HIV infection and whose immune system was anticipated to be relatively intact. The objectives of our study were to determine whether the vaccine was safe and could induce an immune response that would maintain suppression of plasma viremia after discontinuation of ART. Vaccinations were well tolerated with no serious adverse events but produced only modest augmentation of existing HIV-specific CD4+T cell responses, with little augmentation of CD8+T cell responses. Compared with placebo, the vaccination regimen had no significant effect on the kinetics or magnitude of viral rebound after interruption of ART and no impact on the size of the HIV reservoir in the CD4+T cell compartment. Notably, 26% of subjects in the placebo arm exhibited sustained suppression of viremia (<400 copies/ml) after treatment interruption, a rate of spontaneous suppression higher than previously reported. Our findings regarding the degree and kinetics of plasma viral rebound after ART interruption have potentially important implications for the design of future trials testing interventions aimed at achieving ART-free control of HIV infection.

    更新日期:2017-12-06
  • Vasopressin stimulates the proliferation and differentiation of red blood cell precursors and improves recovery from anemia
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-29
    Balázs Mayer, Krisztián Németh, Miklós Krepuska, Vamsee D. Myneni, Dragan Maric, John F. Tisdale, Matthew M. Hsieh, Naoya Uchida, Heon-Jin Lee, Michael J. Nemeth, Kenn Holmbeck, Constance Tom Noguchi, Heather Rogers, Soumyadeep Dey, Arne Hansen, Jeffrey Hong, Ian Chow, Sharon Key, Ildikó Szalayova, Jerome Pagani, Károly Markó, Ian McClain-Caldwell, Lynn Vitale-Cross, W. Scott Young, Michael J. Brownstein, Éva Mezey

    Arginine vasopressin (AVP) made by hypothalamic neurons is released into the circulation to stimulate water resorption by the kidneys and restore water balance after blood loss. Patients who lack this antidiuretic hormone suffer from central diabetes insipidus. We observed that many of these patients were anemic and asked whether AVP might play a role in red blood cell (RBC) production. We found that all three AVP receptors are expressed in human and mouse hematopoietic stem and progenitor cells. The AVPR1B appears to play the most important role in regulating erythropoiesis in both human and mouse cells. AVP increases phosphorylation of signal transducer and activator of transcription 5, as erythropoietin (EPO) does. After sublethal irradiation, AVP-deficient Brattleboro rats showed delayed recovery of RBC numbers compared to control rats. In mouse models of anemia (induced by bleeding, irradiation, or increased destruction of circulating RBCs), AVP increased the number of circulating RBCs independently of EPO. In these models, AVP appears to jump-start peripheral blood cell replenishment until EPO can take over. We suggest that specific AVPR1B agonists might be used to induce fast RBC production after bleeding, drug toxicity, or chemotherapy.

    更新日期:2017-11-30
  • To grow or not to grow: Postantibiotic effect is the question
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-29
    Kathryn Dupnik

    Temporary inhibition ofEscherichia coligrowth in vitro after antibiotic administration is proportional to total antibiotic quantity.

    更新日期:2017-11-30
  • A scar-y movie, starring IL-11
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-29
    Kevin R. King

    IL-11 is found to be a critical mediator of TGFβ1-induced scarring and fibrosis in the heart and kidney.

    更新日期:2017-11-30
  • Feel the burn to improve cognition
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-29
    Jill K. Morris

    Increased brain lactate uptake is related to improved executive function following high-intensity interval exercise.

    更新日期:2017-11-30
  • S. aureus induces IL-36 to start the itch
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-29
    Tiffany C. Scharschmidt

    Epicutaneous exposure toStaphylococcus aureusphenol-soluble modulin alpha peptides facilitates IL-36–dependent skin inflammation.

    更新日期:2017-11-30
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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