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  • A 3D view of tumor heterogeneity
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-15
    Kwanghun Chung

    Solid tumor clearing and light-sheet microscopy improves interrogation of intratumoral heterogeneity.

    更新日期:2017-11-16
  • An antioxidant to attenuate aortic aging
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-15
    Christopher Hine

    Supplementation with the mitochondrial targeted antioxidant MitoQ for 4 weeks decreased aortic stiffness in old mice.

    更新日期:2017-11-16
  • Vascular endothelial cells take hematopoietic stem cells to school
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-15
    Brian A. Jonas

    The bone marrow vascular endothelial cell niche plays a critical role in regulating hematopoietic system aging by influencing the phenotype of hematopoietic stem cells

    更新日期:2017-11-16
  • Epilepsy clocks in
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-15
    Maria K. Lehtinen

    CircadianCLOCKgene expression is reduced in human epileptic brain tissue, and its deletion is epileptogenic in mice.

    更新日期:2017-11-16
  • A method of high-throughput functional evaluation of EGFR gene variants of unknown significance in cancer
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-15
    Shinji Kohsaka, Masaaki Nagano, Toshihide Ueno, Yoshiyuki Suehara, Takuo Hayashi, Naoko Shimada, Kazuhisa Takahashi, Kenji Suzuki, Kazuya Takamochi, Fumiyuki Takahashi, Hiroyuki Mano

    Numerous variants of unknown significance (VUS) have been identified through large-scale cancer genome projects, although their functional relevance remains uninvestigated. We developed a mixed-all-nominated-mutants-in-one (MANO) method to evaluate the transforming potential and drug sensitivity of oncogene VUS in a high-throughput manner and applied this method to 101 nonsynonymous epidermal growth factor receptor (EGFR) mutants. We discovered a number of mutations conferring resistance to EGFR tyrosine kinase inhibitors (TKIs), including gefitinib- and erlotinib-insensitive missense mutations within exon 19 and other gefitinib-resistant mutations, such as L833V, A839T, V851I, A871T, and G873E.L858R-positive tumors (12.8%) harbored compound mutations primarily in thecisallele, which decreased the gefitinib sensitivity of these tumors. The MANO method further revealed that some EGFR mutants that are highly resistant to all types of TKIs are sensitive to cetuximab. Thus, these data support the importance of examining the clinical relevance of uncommon mutations withinEGFRand of evaluating the functions of such mutations in combination. This method may become a foundation for the in vitro and in vivo assessment of variants of cancer-related genes and help customize cancer therapy for individual patients.

    更新日期:2017-11-16
  • A role for bacterial urease in gut dysbiosis and Crohn’s disease
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-15
    Josephine Ni, Ting-Chin David Shen, Eric Z. Chen, Kyle Bittinger, Aubrey Bailey, Manuela Roggiani, Alexandra Sirota-Madi, Elliot S. Friedman, Lillian Chau, Andrew Lin, Ilana Nissim, Justin Scott, Abigail Lauder, Christopher Hoffmann, Gloriany Rivas, Lindsey Albenberg, Robert N. Baldassano, Jonathan Braun, Ramnik J. Xavier, Clary B. Clish, Marc Yudkoff, Hongzhe Li, Mark Goulian, Frederic D. Bushman, James D. Lewis, Gary D. Wu

    Gut dysbiosis during inflammatory bowel disease involves alterations in the gut microbiota associated with inflammation of the host gut. We used a combination of shotgun metagenomic sequencing and metabolomics to analyze fecal samples from pediatric patients with Crohn’s disease and found an association between disease severity, gut dysbiosis, and bacterial production of free amino acids. Nitrogen flux studies using15N in mice showed that activity of bacterial urease, an enzyme that releases ammonia by hydrolysis of host urea, led to the transfer of murine host-derived nitrogen to the gut microbiota where it was used for amino acid synthesis. Inoculation of a conventional murine host (pretreated with antibiotics and polyethylene glycol) with commensalEscherichia coliengineered to express urease led to dysbiosis of the gut microbiota, resulting in a predominance of Proteobacteria species. This was associated with a worsening of immune-mediated colitis in these animals. A potential role for altered urease expression and nitrogen flux in the development of gut dysbiosis suggests that bacterial urease may be a potential therapeutic target for inflammatory bowel diseases.

    更新日期:2017-11-16
  • PD-L1 genetic overexpression or pharmacological restoration in hematopoietic stem and progenitor cells reverses autoimmune diabetes
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-15
    Moufida Ben Nasr, Sara Tezza, Francesca D’Addio, Chiara Mameli, Vera Usuelli, Anna Maestroni, Domenico Corradi, Silvana Belletti, Luca Albarello, Gabriella Becchi, Gian Paolo Fadini, Christian Schuetz, James Markmann, Clive Wasserfall, Leonard Zon, Gian Vincenzo Zuccotti, Paolo Fiorina

    Immunologically based clinical trials performed thus far have failed to cure type 1 diabetes (T1D), in part because these approaches were nonspecific. Because the disease is driven by autoreactive CD4 T cells, which destroy β cells, transplantation of hematopoietic stem and progenitor cells (HSPCs) has been recently offered as a therapy for T1D. Our transcriptomic profiling of HSPCs revealed that these cells are deficient in programmed death ligand 1 (PD-L1), an important immune checkpoint, in the T1D nonobese diabetic (NOD) mouse model. Notably, the immunoregulatory molecule PD-L1 plays a determinant role in controlling/inhibiting activated T cells and thus maintains immune tolerance. Furthermore, our genome-wide and bioinformatic analysis revealed the existence of a network of microRNAs (miRNAs) controlling PD-L1 expression, and silencing one of key altered miRNAs restored PD-L1 expression in HSPCs. We therefore sought to determine whether restoration of this defect would cure T1D as an alternative to immunosuppression. Genetically engineered or pharmacologically modulated HSPCs overexpressing PD-L1 inhibited the autoimmune response in vitro, reverted diabetes in newly hyperglycemic NOD mice in vivo, and homed to the pancreas of hyperglycemic NOD mice. The PD-L1 expression defect was confirmed in human HSPCs in T1D patients as well, and pharmacologically modulated human HSPCs also inhibited the autoimmune response in vitro. Targeting a specific immune checkpoint defect in HSPCs thus may contribute to establishing a cure for T1D.

    更新日期:2017-11-16
  • Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-15
    Antonio Galleu, Yanira Riffo-Vasquez, Cristina Trento, Cara Lomas, Luigi Dolcetti, Tik Shing Cheung, Malte von Bonin, Laura Barbieri, Krishma Halai, Sophie Ward, Ling Weng, Ronjon Chakraverty, Giovanna Lombardi, Fiona M. Watt, Kim Orchard, David I. Marks, Jane Apperley, Martin Bornhauser, Henning Walczak, Clare Bennett, Francesco Dazzi

    The immunosuppressive activity of mesenchymal stromal cells (MSCs) is well documented. However, the therapeutic benefit is completely unpredictable, thus raising concerns about MSC efficacy. One of the affecting factors is the unresolved conundrum that, despite being immunosuppressive, MSCs are undetectable after administration. Therefore, understanding the fate of infused MSCs could help predict clinical responses. Using a murine model of graft-versus-host disease (GvHD), we demonstrate that MSCs are actively induced to undergo perforin-dependent apoptosis by recipient cytotoxic cells and that this process is essential to initiate MSC-induced immunosuppression. When examining patients with GvHD who received MSCs, we found a striking parallel, whereby only those with high cytotoxic activity against MSCs responded to MSC infusion, whereas those with low activity did not. The need for recipient cytotoxic cell activity could be replaced by the infusion of apoptotic MSCs generated ex vivo. After infusion, recipient phagocytes engulf apoptotic MSCs and produce indoleamine 2,3-dioxygenase, which is ultimately necessary for effecting immunosuppression. Therefore, we propose the innovative concept that patients should be stratified for MSC treatment according to their ability to kill MSCs or that all patients could be treated with ex vivo apoptotic MSCs.

    更新日期:2017-11-16
  • Lung cancer–associated pulmonary hypertension: Role of microenvironmental inflammation based on tumor cell–immune cell cross-talk
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-15
    Soni Savai Pullamsetti, Baktybek Kojonazarov, Samantha Storn, Henning Gall, Ylia Salazar, Janine Wolf, Andreas Weigert, Nefertiti El-Nikhely, Hossein Ardeschir Ghofrani, Gabriele A. Krombach, Ludger Fink, Stefan Gattenlöhner, Ulf R. Rapp, Ralph Theo Schermuly, Friedrich Grimminger, Werner Seeger, Rajkumar Savai

    Dyspnea is a frequent, devastating, and poorly understood symptom of advanced lung cancer. In our cohort, among 519 patients who underwent a computed tomography scan for the diagnosis of lung cancer, 250 had a mean pulmonary artery diameter of >28 mm, indicating pulmonary hypertension (PH). In human lung cancer tissue, we consistently observed increased vascular remodeling and perivascular inflammatory cell accumulation (macrophages/lymphocytes). Vascular remodeling, PH, and perivascular inflammatory cell accumulation were mimicked in three mouse models of lung cancer (LLC1,KRasLA2, andcRaf-BxB). In contrast,NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJimmunodeficient xenograft and dominant-negative IKK2 mutant triple transgenic (Sftpc-rtTA/Tet-O-Ikk2DN) mice did not develop PH. Coculturing human lung cancer cells with macrophages and lymphocytes strongly up-regulated cytokine release, provoking enhanced migration, apoptosis resistance, and phosphodiesterase 5 (PDE5)–mediated up-regulation of human lung vascular cells, which are typical features of PH. The PDE5 inhibitor sildenafil largely suppressed PH in the LLC1 model. We conclude that lung cancer–associated PH represents a distinct PH category; targeting inflammation in the microenvironment and PDE5 offers a potential therapeutic option.

    更新日期:2017-11-16
  • Matrix-binding checkpoint immunotherapies enhance antitumor efficacy and reduce adverse events
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-08
    Jun Ishihara, Kazuto Fukunaga, Ako Ishihara, Hans M. Larsson, Lambert Potin, Peyman Hosseinchi, Gabriele Galliverti, Melody A. Swartz, Jeffrey A. Hubbell

    Immune checkpoint blockade exhibits considerable antitumor activity, but previous studies have reported instances of severe treatment-related adverse events. We sought to explore local immune checkpoint blockade, with an antibody (Ab) form that would be retained intra- or peritumorally, limiting systemic exposure. To accomplish this, we conjugated the checkpoint blockade Abs to an extracellular matrix (ECM)–super-affinity peptide derived from placenta growth factor–2 (PlGF-2123–144). We show enhanced tissue retention and lower Ab concentrations in blood plasma after PlGF-2123–144conjugation, reducing systemic side effects such as the risk of autoimmune diabetes. Peritumoral injections of PlGF-2123–144–anti-CTLA4 (cytotoxic T lymphocyte antigen 4) and PlGF-2123–144–anti–PD-L1 (programmed death ligand 1) Abs delayed tumor growth and prolonged survival compared to the unmodified Abs in genetically engineered murine tumor models of melanoma and breast cancer. The PlGF-2123–144–Abs increased tumor-infiltrating activated CD8+and CD4+T cells, resulting in a delay of distant tumor growth as well. This simple and translatable approach of engineered ECM-binding Abs may present a viable and safer approach in checkpoint blockade.

    更新日期:2017-11-10
  • Getting in touch with your inner stomach
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-08
    Christopher M. Jewell

    An ingestible and mechanically flexible piezoelectric device enables sensing of changes in the GI tract of pigs.

    更新日期:2017-11-10
  • Topical valsartan increases the healing pressure on wounds
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-08
    Hadar Lev-Tov

    Topical valsartan may help heal wounds in people with diabetes.

    更新日期:2017-11-10
  • Stress CRasHes into fertility command center
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-08
    Vasiliki Michopoulos

    Corticotropin-releasing hormone alters activity of gonadotropin-releasing hormone neurons in an estradiol-dependent manner.

    更新日期:2017-11-10
  • Serving cancer its last meal
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-08
    Monica Venere

    Abolishment of just one of the pathways activated by mTORC1 creates a metabolic imbalance that drives cancer cell death.

    更新日期:2017-11-10
  • Circadian actin dynamics drive rhythmic fibroblast mobilization during wound healing
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-08
    Nathaniel P. Hoyle, Estere Seinkmane, Marrit Putker, Kevin A. Feeney, Toke P. Krogager, Johanna E. Chesham, Liam K. Bray, Justyn M. Thomas, Ken Dunn, John Blaikley, John S. O’Neill

    Fibroblasts are primary cellular protagonists of wound healing. They also exhibit circadian timekeeping, which imparts an approximately 24-hour rhythm to their biological function. We interrogated the functional consequences of the cell-autonomous clockwork in fibroblasts using a proteome-wide screen for rhythmically expressed proteins. We observed temporal coordination of actin regulators that drives cell-intrinsic rhythms in actin dynamics. In consequence, the cellular clock modulates the efficiency of actin-dependent processes such as cell migration and adhesion, which ultimately affect the efficacy of wound healing. Accordingly, skin wounds incurred during a mouse’s active phase exhibited increased fibroblast invasion in vivo and ex vivo, as well as in cultured fibroblasts and keratinocytes. Our experimental results correlate with the observation that the time of injury significantly affects healing after burns in humans, with daytime wounds healing ~60% faster than nighttime wounds. We suggest that circadian regulation of the cytoskeleton influences wound-healing efficacy from the cellular to the organismal scale.

    更新日期:2017-11-10
  • Stress hormones promote EGFR inhibitor resistance in NSCLC: Implications for combinations with β-blockers
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-08
    Monique B. Nilsson, Huiying Sun, Lixia Diao, Pan Tong, Diane Liu, Lerong Li, Youhong Fan, Alissa Poteete, Seung-Oe Lim, Kathryn Howells, Vincent Haddad, Daniel Gomez, Hai Tran, Guillermo Armaiz Pena, Lecia V. Sequist, James C. Yang, Jing Wang, Edward S. Kim, Roy Herbst, J. Jack Lee, Waun Ki Hong, Ignacio Wistuba, Mien-Chie Hung, Anil K. Sood, John V. Heymach

    Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance mediated by T790M-independent mechanisms remains a major challenge in the treatment of non–small cell lung cancer (NSCLC). We identified a targetable mechanism of EGFR inhibitor resistance whereby stress hormones activate β2-adrenergic receptors (β2-ARs) on NSCLC cells, which cooperatively signal with mutant EGFR, resulting in the inactivation of the tumor suppressor, liver kinase B1 (LKB1), and subsequently induce interleukin-6 (IL-6) expression. We show that stress and β2-AR activation promote tumor growth and EGFR inhibitor resistance, which can be abrogated with β-blockers or IL-6 inhibition. IL-6 was associated with a worse outcome in EGFR TKI–treated NSCLC patients, and β-blocker use was associated with lower IL-6 concentrations and improved benefit from EGFR inhibitors. These findings provide evidence that chronic stress hormones promote EGFR TKI resistance via β2-AR signaling by an LKB1/CREB (cyclic adenosine 3′,5′-monophosphate response element–binding protein)/IL-6–dependent mechanism and suggest that combinations of β-blockers with EGFR TKIs merit further investigation as a strategy to abrogate resistance.

    更新日期:2017-11-10
  • RNA binding proteins and the pathological cascade in ALS/FTD neurodegeneration
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-08
    Daisuke Ito, Mami Hatano, Norihiro Suzuki

    Advanced genetic approaches have accelerated the identification of causative genes linked to the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Most of the disease-related proteins encoded by these genes form aggregates in the cellular machineries that regulate RNA and protein quality control in cells. Cross-talk among the signaling pathways governing these machineries leads to pathological cascades mediated by the accumulation of mutant RNA binding proteins. We outline the molecular basis of ALS and FTD pathogenesis and discuss the prospects for therapeutic strategies to treat these diseases.

    更新日期:2017-11-10
  • Accumulation of 5-oxoproline in myocardial dysfunction and the protective effects of OPLAH
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-11-08
    Atze van der Pol, Andres Gil, Herman H. W. Silljé, Jasper Tromp, Ekaterina S. Ovchinnikova, Inge Vreeswijk-Baudoin, Martijn Hoes, Ibrahim J. Domian, Bart van de Sluis, Jan M. van Deursen, Adriaan A. Voors, Dirk J. van Veldhuisen, Wiek H. van Gilst, Eugene Berezikov, Pim van der Harst, Rudolf A. de Boer, Rainer Bischoff, Peter van der Meer

    In response to heart failure (HF), the heart reacts by repressing adult genes and expressing fetal genes, thereby returning to a more fetal-like gene profile. To identify genes involved in this process, we carried out transcriptional analysis on murine hearts at different stages of development and on hearts from adult mice with HF. Our screen identifiedOplah, encoding for 5-oxoprolinase, a member of the γ-glutamyl cycle that functions by scavenging 5-oxoproline. OPLAH depletion occurred as a result of cardiac injury, leading to elevated 5-oxoproline and oxidative stress, whereas OPLAH overexpression improved cardiac function after ischemic injury. In HF patients, we observed elevated plasma 5-oxoproline, which was associated with a worse clinical outcome. Understanding and modulating fetal-like genes in the failing heart may lead to potential diagnostic, prognostic, and therapeutic options in HF.

    更新日期:2017-11-10
  • Preclinical modeling highlights the therapeutic potential of hematopoietic stem cell gene editing for correction of SCID-X1
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-10-11
    Giulia Schiroli, Samuele Ferrari, Anthony Conway, Aurelien Jacob, Valentina Capo, Luisa Albano, Tiziana Plati, Maria C. Castiello, Francesca Sanvito, Andrew R. Gennery, Chiara Bovolenta, Rahul Palchaudhuri, David T. Scadden, Michael C. Holmes, Anna Villa, Giovanni Sitia, Angelo Lombardo, Pietro Genovese, Luigi Naldini

    Targeted genome editing in hematopoietic stem/progenitor cells (HSPCs) is an attractive strategy for treating immunohematological diseases. However, the limited efficiency of homology-directed editing in primitive HSPCs constrains the yield of corrected cells and might affect the feasibility and safety of clinical translation. These concerns need to be addressed in stringent preclinical models and overcome by developing more efficient editing methods. We generated a humanized X-linked severe combined immunodeficiency (SCID-X1) mouse model and evaluated the efficacy and safety of hematopoietic reconstitution from limited input of functional HSPCs, establishing thresholds for full correction upon different types of conditioning. Unexpectedly, conditioning before HSPC infusion was required to protect the mice from lymphoma developing when transplanting small numbers of progenitors. We then designed a one-size-fits-allIL2RG(interleukin-2 receptor common γ-chain) gene correction strategy and, using the same reagents suitable for correction of human HSPC, validated the edited human gene in the disease model in vivo, providing evidence of targeted gene editing in mouse HSPCs and demonstrating the functionality of theIL2RG-edited lymphoid progeny. Finally, we optimized editing reagents and protocol for human HSPCs and attained the threshold ofIL2RGediting in long-term repopulating cells predicted to safely rescue the disease, using clinically relevant HSPC sources and highly specific zinc finger nucleases or CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein 9). Overall, our work establishes the rationale and guiding principles for clinical translation of SCID-X1 gene editing and provides a framework for developing gene correction for other diseases.

    更新日期:2017-10-12
  • An analysis of IL-36 signature genes and individuals with IL1RL2 knockout mutations validates IL-36 as a psoriasis therapeutic target
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-10-11
    Satveer K. Mahil, Marika Catapano, Paola Di Meglio, Nick Dand, Helena Ahlfors, Ian M. Carr, Catherine H. Smith, Richard C. Trembath, Mark Peakman, John Wright, Francesca D. Ciccarelli, Jonathan N. Barker, Francesca Capon

    Interleukin (IL)–36α, IL-36β, and IL-36γ are innate mediators of acute epithelial inflammation. We sought to demonstrate that these cytokines are also required for the pathogenesis of plaque psoriasis, a common and chronic skin disorder, caused by abnormal T helper 17 (TH17) cell activation. To investigate this possibility, we first defined the genes that are induced by IL-36 cytokines in primary human keratinocytes. This enabled us to demonstrate a significant IL-36 signature among the transcripts that are up-regulated in plaque psoriasis and the susceptibility loci associated with the disease in genome-wide studies. Next, we investigated the impact of in vivo and ex vivo IL-36 receptor blockade using a neutralizing antibody or a recombinant antagonist. Both inhibitors had marked anti-inflammatory effects on psoriatic skin, demonstrated by statistically significant reductions in IL-17 expression, keratinocyte activation, and leukocyte infiltration. Finally, we explored the potential safety profile associated with IL-36 blockade by phenotyping 12 individuals carrying knockout mutations of the IL-36 receptor gene. We found that normal immune function was broadly preserved in these individuals, suggesting that IL-36 signaling inhibition would not substantially compromise host defenses. These observations, which integrate the results of transcriptomics and model system analysis, pave the way for early-stage clinical trials of IL-36 antagonists.

    更新日期:2017-10-12
  • High-density lipoprotein delivered after myocardial infarction increases cardiac glucose uptake and function in mice
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-10-11
    Sarah E. Heywood, Adele L. Richart, Darren C. Henstridge, Karen Alt, Helen Kiriazis, Claire Zammit, Andrew L. Carey, Helene L. Kammoun, Lea M. Delbridge, Medini Reddy, Yi-Ching Chen, Xiao-Jun Du, Christoph E. Hagemeyer, Mark A. Febbraio, Andrew L. Siebel, Bronwyn A. Kingwell

    Protecting the heart after an acute coronary syndrome is a key therapeutic goal to support cardiac recovery and prevent progression to heart failure. A potential strategy is to target cardiac glucose metabolism at the early stages after ischemia when glycolysis is critical for myocyte survival. Building on our discovery that high-density lipoprotein (HDL) modulates skeletal muscle glucose metabolism, we now demonstrate that a single dose of reconstituted HDL (rHDL) delivered after myocardial ischemia increases cardiac glucose uptake, reduces infarct size, and improves cardiac remodeling in association with enhanced functional recovery in mice. These findings applied equally to metabolically normal and insulin-resistant mice. We further establish direct effects of HDL on cardiomyocyte glucose uptake, glycolysis, and glucose oxidation via the Akt signaling pathway within 15 min of reperfusion. These data support the use of infusible HDL preparations for management of acute coronary syndromes in the setting of primary percutaneous interventions.

    更新日期:2017-10-12
  • Functional ultrasound imaging of brain activity in human newborns
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-10-11
    Charlie Demene, Jérome Baranger, Miguel Bernal, Catherine Delanoe, Stéphane Auvin, Valérie Biran, Marianne Alison, Jérome Mairesse, Elisabeth Harribaud, Mathieu Pernot, Mickael Tanter, Olivier Baud

    Functional neuroimaging modalities are crucial for understanding brain function, but their clinical use is challenging. Recently, the use of ultrasonic plane waves transmitted at ultrafast frame rates was shown to allow for the spatiotemporal identification of brain activation through neurovascular coupling in rodents. Using a customized flexible and noninvasive headmount, we demonstrate in human neonates that real-time functional ultrasound imaging (fUSI) is feasible by combining simultaneous continuous video–electroencephalography (EEG) recording and ultrafast Doppler (UfD) imaging of the brain microvasculature. fUSI detected very small cerebral blood volume variations in the brains of neonates that closely correlated with two different sleep states defined by EEG recordings. fUSI was also used to assess brain activity in two neonates with congenital abnormal cortical development enabling elucidation of the dynamics of neonatal seizures with high spatiotemporal resolution (200 μm for UfD and 1 ms for EEG). fUSI was then applied to track how waves of vascular changes were propagated during interictal periods and to determine the ictal foci of the seizures. Imaging the human brain with fUSI enables high-resolution identification of brain activation through neurovascular coupling and may provide new insights into seizure analysis and the monitoring of brain function.

    更新日期:2017-10-12
  • Check twice, cut once—Improved CRISPR-Cas9 genome editing accuracy
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-10-11
    Leah C. Byrne

    Based on observations of the mechanism underlying target discrimination, researchers have developed highly accurate variants of CRISPR-Cas9.

    更新日期:2017-10-12
  • Less is more for anticancer therapy combinations
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-10-11
    Miles A. Miller

    Withdrawal of MAPK inhibition sensitizes cancer cells to DNA repair–targeting drugs.

    更新日期:2017-10-12
  • Lurking culprits
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-10-11
    Jonathan J. Miner

    IL-17–producing T cells persist in resolved psoriatic skin lesions.

    更新日期:2017-10-12
  • The science of love in ASD and ADHD
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-10-11
    Gaia Novarino

    Genetic variations in the oxytocin receptor gene affect patients with ASD and ADHD differently.

    更新日期:2017-10-12
  • Rapid pathogen-specific phenotypic antibiotic susceptibility testing using digital LAMP quantification in clinical samples
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-10-04
    Nathan G. Schoepp, Travis S. Schlappi, Matthew S. Curtis, Slava S. Butkovich, Shelley Miller, Romney M. Humphries, Rustem F. Ismagilov

    Rapid antimicrobial susceptibility testing (AST) is urgently needed for informing treatment decisions and preventing the spread of antimicrobial resistance resulting from the misuse and overuse of antibiotics. To date, no phenotypic AST exists that can be performed within a single patient visit (30 min) directly from clinical samples. We show that AST results can be obtained by using digital nucleic acid quantification to measure the phenotypic response ofEscherichia colipresent within clinical urine samples exposed to an antibiotic for 15 min. We performed this rapid AST using our ultrafast (~7 min) digital real-time loop-mediated isothermal amplification (dLAMP) assay [area under the curve (AUC), 0.96] and compared the results to a commercial (~2 hours) digital polymerase chain reaction assay (AUC, 0.98). The rapid dLAMP assay can be used with SlipChip microfluidic devices to determine the phenotypic antibiotic susceptibility ofE. colidirectly from clinical urine samples in less than 30 min. With further development for additional pathogens, antibiotics, and sample types, rapid digital AST (dAST) could enable rapid clinical decision-making, improve management of infectious diseases, and facilitate antimicrobial stewardship.

    更新日期:2017-10-04
  • An anti–glypican 3/CD3 bispecific T cell–redirecting antibody for treatment of solid tumors
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-10-04
    Takahiro Ishiguro, Yuji Sano, Shun-ichiro Komatsu, Mika Kamata-Sakurai, Akihisa Kaneko, Yasuko Kinoshita, Hirotake Shiraiwa, Yumiko Azuma, Toshiaki Tsunenari, Yoko Kayukawa, Yukiko Sonobe, Natsuki Ono, Kiyoaki Sakata, Toshihiko Fujii, Yoko Miyazaki, Mizuho Noguchi, Mika Endo, Asako Harada, Werner Frings, Etsuko Fujii, Eitaro Nanba, Atsushi Narita, Akihisa Sakamoto, Tetsuya Wakabayashi, Hiroko Konishi, Hiroaki Segawa, Tomoyuki Igawa, Takashi Tsushima, Hironori Mutoh, Yukari Nishito, Mina Takahashi, Lorraine Stewart, Ehab ElGabry, Yoshiki Kawabe, Masaki Ishigai, Shuichi Chiba, Masahiro Aoki, Kunihiro Hattori, Junichi Nezu

    Cancer care is being revolutionized by immunotherapies such as immune checkpoint inhibitors, engineered T cell transfer, and cell vaccines. The bispecific T cell–redirecting antibody (TRAB) is one such promising immunotherapy, which can redirect T cells to tumor cells by engaging CD3 on a T cell and an antigen on a tumor cell. Because T cells can be redirected to tumor cells regardless of the specificity of T cell receptors, TRAB is considered efficacious for less immunogenic tumors lacking enough neoantigens. Its clinical efficacy has been exemplified by blinatumomab, a bispecific T cell engager targeting CD19 and CD3, which has shown marked clinical responses against hematological malignancies. However, the success of TRAB in solid tumors has been hampered by the lack of a target molecule with sufficient tumor selectivity to avoid “on-target off-tumor” toxicity. Glypican 3 (GPC3) is a highly tumor-specific antigen that is expressed during fetal development but is strictly suppressed in normal adult tissues. We developed ERY974, a whole humanized immunoglobulin G–structured TRAB harboring a common light chain, which bispecifically binds to GPC3 and CD3. Using a mouse model with reconstituted human immune cells, we revealed that ERY974 is highly effective in killing various types of tumors that have GPC3 expression comparable to that in clinical tumors. ERY974 also induced a robust antitumor efficacy even against tumors with nonimmunogenic features, which are difficult to treat by inhibiting immune checkpoints such as PD-1 (programmed cell death protein–1) and CTLA-4 (cytotoxic T lymphocyte–associated protein–4). Immune monitoring revealed that ERY974 converted the poorly inflamed tumor microenvironment to a highly inflamed microenvironment. Toxicology studies in cynomolgus monkeys showed transient cytokine elevation, but this was manageable and reversible. No organ toxicity was evident. These data provide a rationale for clinical testing of ERY974 for the treatment of patients with GPC3-positive solid tumors.

    更新日期:2017-10-04
  • Targeting the renin-angiotensin system to improve cancer treatment: Implications for immunotherapy
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-10-04
    Matthias Pinter, Rakesh K. Jain

    Renin-angiotensin system (RAS) inhibitors (RASi)—widely prescribed for the treatment of cardiovascular diseases—have considerable potential in oncology. The RAS plays a crucial role in cancer biology and affects tumor growth and dissemination directly and indirectly by remodeling the tumor microenvironment. We review clinical data on the benefit of RASi in primary and metastatic tumors and propose that, by activating immunostimulatory pathways, these inhibitors can enhance immunotherapy of cancer.

    更新日期:2017-10-04
  • Engineering a highly elastic human protein–based sealant for surgical applications
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-10-04
    Nasim Annabi, Yi-Nan Zhang, Alexander Assmann, Ehsan Shirzaei Sani, George Cheng, Antonio D. Lassaletta, Andrea Vegh, Bijan Dehghani, Guillermo U. Ruiz-Esparza, Xichi Wang, Sidhu Gangadharan, Anthony S. Weiss, Ali Khademhosseini

    Surgical sealants have been used for sealing or reconnecting ruptured tissues but often have low adhesion, inappropriate mechanical strength, cytotoxicity concerns, and poor performance in biological environments. To address these challenges, we engineered a biocompatible and highly elastic hydrogel sealant with tunable adhesion properties by photocrosslinking the recombinant human protein tropoelastin. The subcutaneous implantation of the methacryloyl-substituted tropoelastin (MeTro) sealant in rodents demonstrated low toxicity and controlled degradation. All animals survived surgical procedures with adequate blood circulation by using MeTro in an incisional model of artery sealing in rats, and animals showed normal breathing and lung function in a model of surgically induced rat lung leakage. In vivo experiments in a porcine model demonstrated complete sealing of severely leaking lung tissue in the absence of sutures or staples, with no clinical or sonographic signs of pneumothorax during 14 days of follow-up. The engineered MeTro sealant has high potential for clinical applications because of superior adhesion and mechanical properties compared to commercially available sealants, as well as opportunity for further optimization of the degradation rate to fit desired surgical applications on different tissues.

    更新日期:2017-10-04
  • Delaying methylation drift with diet
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-10-04
    Christopher Hine

    Aging related DNA methylation drift is delayed by a calorically restricted diet.

    更新日期:2017-10-04
  • Just say NO to leaky bone marrow vasculature in AML
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-10-04
    Brian A. Jonas

    Inhibition of nitric oxide (NO) production improved treatment response and normalized NO-mediated alterations in bone marrow vascular architecture and function in acute myeloid leukemia.

    更新日期:2017-10-04
  • Going with your gut in multiple sclerosis
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-10-04
    Maria K. Lehtinen

    The gut microbiome plays a key role in the pathogenesis of multiple sclerosis.

    更新日期:2017-10-04
  • Neutralizing human monoclonal antibodies prevent Zika virus infection in macaques
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-10-04
    Diogo M. Magnani, Thomas F. Rogers, Nathan Beutler, Michael J. Ricciardi, Varian K. Bailey, Lucas Gonzalez-Nieto, Bryan Briney, Devin Sok, Khoa Le, Alexander Strubel, Martin J. Gutman, Núria Pedreño-Lopez, Nathan D. Grubaugh, Cassia G. T. Silveira, Helen S. Maxwell, Aline Domingues, Mauricio A. Martins, David E. Lee, Erica E. Okwuazi, Sherrie Jean, Elizabeth A. Strobert, Ann Chahroudi, Guido Silvestri, Thomas H. Vanderford, Esper G. Kallas, Ronald C. Desrosiers, Myrna C. Bonaldo, Stephen S. Whitehead, Dennis R. Burton, David I. Watkins

    Therapies to prevent maternal Zika virus (ZIKV) infection and its subsequent fetal developmental complications are urgently required. We isolated three potent ZIKV-neutralizing monoclonal antibodies (nmAbs) from the plasmablasts of a ZIKV-infected patient—SMZAb1, SMZAb2, and SMZAb5—directed against two different domains of the virus. We engineered these nmAbs with Fc LALA mutations that abrogate Fcγ receptor binding, thus eliminating potential therapy-mediated antibody-dependent enhancement. We administered a cocktail of these three nmAbs to nonhuman primates 1 day before challenge with ZIKV and demonstrated that the nmAbs completely prevented viremia in serum after challenge. Given that numerous antibodies have exceptional safety profiles in humans, the cocktail described here could be rapidly developed to protect uninfected pregnant women and their fetuses.

    更新日期:2017-10-04
  • RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-27
    Christine I. Wooddell, Man-Fung Yuen, Henry Lik-Yuen Chan, Robert G. Gish, Stephen A. Locarnini, Deborah Chavez, Carlo Ferrari, Bruce D. Given, James Hamilton, Steven B. Kanner, Ching-Lung Lai, Johnson Y. N. Lau, Thomas Schluep, Zhao Xu, Robert E. Lanford, David L. Lewis

    Chronic hepatitis B virus (HBV) infection is a major health concern worldwide, frequently leading to liver cirrhosis, liver failure, and hepatocellular carcinoma. Evidence suggests that high viral antigen load may play a role in chronicity. Production of viral proteins is thought to depend on transcription of viral covalently closed circular DNA (cccDNA). In a human clinical trial with an RNA interference (RNAi)–based therapeutic targeting HBV transcripts, ARC-520, HBV S antigen (HBsAg) was strongly reduced in treatment-naïve patients positive for HBV e antigen (HBeAg) but was reduced significantly less in patients who were HBeAg-negative or had received long-term therapy with nucleos(t)ide viral replication inhibitors (NUCs). HBeAg positivity is associated with greater disease risk that may be moderately reduced upon HBeAg loss. The molecular basis for this unexpected differential response was investigated in chimpanzees chronically infected with HBV. Several lines of evidence demonstrated that HBsAg was expressed not only from the episomal cccDNA minichromosome but also from transcripts arising from HBV DNA integrated into the host genome, which was the dominant source in HBeAg-negative chimpanzees. Many of the integrants detected in chimpanzees lacked target sites for the small interfering RNAs in ARC-520, explaining the reduced response in HBeAg-negative chimpanzees and, by extension, in HBeAg-negative patients. Our results uncover a heretofore underrecognized source of HBsAg that may represent a strategy adopted by HBV to maintain chronicity in the presence of host immunosurveillance. These results could alter trial design and endpoint expectations of new therapies for chronic HBV.

    更新日期:2017-09-28
  • Rapid antigen tests for dengue virus serotypes and Zika virus in patient serum
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-27
    Irene Bosch, Helena de Puig, Megan Hiley, Marc Carré-Camps, Federico Perdomo-Celis, Carlos F. Narváez, Doris M. Salgado, Dewahar Senthoor, Madeline O’Grady, Elizabeth Phillips, Ann Durbin, Diana Fandos, Hikaru Miyazaki, Chun-Wan Yen, Margarita Gélvez-Ramírez, Rajas V. Warke, Lucas S. Ribeiro, Mauro M. Teixeira, Roque P. Almeida, José E. Muñóz-Medina, Juan E. Ludert, Mauricio L. Nogueira, Tatiana E. Colombo, Ana C. B. Terzian, Patricia T. Bozza, Andrea S. Calheiros, Yasmine R. Vieira, Giselle Barbosa-Lima, Alexandre Vizzoni, José Cerbino-Neto, Fernando A. Bozza, Thiago M. L. Souza, Monique R. O. Trugilho, Ana M. B. de Filippis, Patricia C. de Sequeira, Ernesto T. A. Marques, Tereza Magalhaes, Francisco J. Díaz, Berta N. Restrepo, Katerine Marín, Salim Mattar, Daniel Olson, Edwin J. Asturias, Mark Lucera, Mohit Singla, Guruprasad R. Medigeshi, Norma de Bosch, Justina Tam, Jose Gómez-Márquez, Charles Clavet, Luis Villar, Kimberly Hamad-Schifferli, Lee Gehrke

    The recent Zika virus (ZIKV) outbreak demonstrates that cost-effective clinical diagnostics are urgently needed to detect and distinguish viral infections to improve patient care. Unlike dengue virus (DENV), ZIKV infections during pregnancy correlate with severe birth defects, including microcephaly and neurological disorders. Because ZIKV and DENV are related flaviviruses, their homologous proteins and nucleic acids can cause cross-reactions and false-positive results in molecular, antigenic, and serologic diagnostics. We report the characterization of monoclonal antibody pairs that have been translated into rapid immunochromatography tests to specifically detect the viral nonstructural 1 (NS1) protein antigen and distinguish the four DENV serotypes (DENV1–4) and ZIKV without cross-reaction. To complement visual test analysis and remove user subjectivity in reading test results, we used image processing and data analysis for data capture and test result quantification. Using a 30-μl serum sample, the sensitivity and specificity values of the DENV1–4 tests and the pan-DENV test, which detects all four dengue serotypes, ranged from 0.76 to 1.00. Sensitivity/specificity for the ZIKV rapid test was 0.81/0.86, respectively, using a 150-μl serum input. Serum ZIKV NS1 protein concentrations were about 10-fold lower than corresponding DENV NS1 concentrations in infected patients; moreover, ZIKV NS1 protein was not detected in polymerase chain reaction–positive patient urine samples. Our rapid immunochromatography approach and reagents have immediate application in differential clinical diagnosis of acute ZIKV and DENV cases, and the platform can be applied toward developing rapid antigen diagnostics for emerging viruses.

    更新日期:2017-09-28
  • Human pluripotent stem cell–derived erythropoietin-producing cells ameliorate renal anemia in mice
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-27
    Hirofumi Hitomi, Tomoko Kasahara, Naoko Katagiri, Azusa Hoshina, Shin-Ichi Mae, Maki Kotaka, Takafumi Toyohara, Asadur Rahman, Daisuke Nakano, Akira Niwa, Megumu K. Saito, Tatsutoshi Nakahata, Akira Nishiyama, Kenji Osafune

    The production of erythropoietin (EPO) by the kidneys, a principal hormone for the hematopoietic system, is reduced in patients with chronic kidney disease (CKD), eventually resulting in severe anemia. Although recombinant human EPO treatment improves anemia in patients with CKD, returning to full red blood cell production without fluctuations does not always occur. We established a method to generate EPO-producing cells from human induced pluripotent stem cells (hiPSCs) by modifying previously reported hepatic differentiation protocols. These cells showed increased EPO expression and secretion in response to low oxygen conditions, prolyl hydroxylase domain–containing enzyme inhibitors, and insulin-like growth factor 1. The EPO protein secreted from hiPSC-derived EPO-producing (hiPSC-EPO) cells induced the erythropoietic differentiation of human umbilical cord blood progenitor cells in vitro. Furthermore, transplantation of hiPSC-EPO cells into mice with CKD induced by adenine treatment improved renal anemia. Thus, hiPSC-EPO cells may be a useful tool for clarifying the mechanisms of EPO production and may be useful as a therapeutic strategy for treating renal anemia.

    更新日期:2017-09-28
  • Neutrophil macroaggregates promote widespread pulmonary thrombosis after gut ischemia
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-27
    Yuping Yuan, Imala Alwis, Mike C. L. Wu, Zane Kaplan, Katrina Ashworth, David Bark, Alan Pham, James Mcfadyen, Simone M. Schoenwaelder, Emma C. Josefsson, Benjamin T. Kile, Shaun P. Jackson

    Gut ischemia is common in critically ill patients, promoting thrombosis and inflammation in distant organs. The mechanisms linking hemodynamic changes in the gut to remote organ thrombosis remain ill-defined. We demonstrate that gut ischemia in the mouse induces a distinct pulmonary thrombotic disorder triggered by neutrophil macroaggregates. These neutrophil aggregates lead to widespread occlusion of pulmonary arteries, veins, and the microvasculature. A similar pulmonary neutrophil-rich thrombotic response occurred in humans with the acute respiratory distress syndrome. Intravital microscopy during gut ischemia-reperfusion injury revealed that rolling neutrophils extract large membrane fragments from remnant dying platelets in multiple organs. These platelet fragments bridge adjacent neutrophils to facilitate macroaggregation. Platelet-specific deletion of cyclophilin D, a mitochondrial regulator of cell necrosis, prevented neutrophil macroaggregation and pulmonary thrombosis. Our studies demonstrate the existence of a distinct pulmonary thrombotic disorder triggered by dying platelets and neutrophil macroaggregates. Therapeutic targeting of platelet death pathways may reduce pulmonary thrombosis in critically ill patients.

    更新日期:2017-09-28
  • Hyperpolarization-activated cyclic nucleotide–gated 2 (HCN2) ion channels drive pain in mouse models of diabetic neuropathy
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-27
    Christoforos Tsantoulas, Sergio Laínez, Sara Wong, Ishita Mehta, Bruno Vilar, Peter A. McNaughton

    Diabetic patients frequently suffer from continuous pain that is poorly treated by currently available analgesics. We used mouse models of type 1 and type 2 diabetes to investigate a possible role for the hyperpolarization-activated cyclic nucleotide–gated 2 (HCN2) ion channels as drivers of diabetic pain. Blocking or genetically deleting HCN2 channels in small nociceptive neurons suppressed diabetes-associated mechanical allodynia and prevented neuronal activation of second-order neurons in the spinal cord in mice. In addition, we found that intracellular cyclic adenosine monophosphate (cAMP), a positive HCN2 modulator, is increased in somatosensory neurons in an animal model of painful diabetes. We propose that the increased intracellular cAMP drives diabetes-associated pain by facilitating HCN2 activation and consequently promoting repetitive firing in primary nociceptive nerve fibers. Our results suggest that HCN2 may be an analgesic target in the treatment of painful diabetic neuropathy.

    更新日期:2017-09-28
  • A game of thrones and broken bones
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-27
    Christopher M. Jewell

    Repair of cranial bone trauma with degradable magnesium implants could reduce complications and eliminate the need for implant removal.

    更新日期:2017-09-28
  • Genomics are CReePing up on inflammation in PTSD
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-27
    Vasiliki Michopoulos

    Posttraumatic stress disorder is linked to increased blood and genetic and epigenetic markers of C-reactive protein.

    更新日期:2017-09-28
  • Foe becomes friend as Zika joins the fight against cancer
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-27
    Monica Venere

    Zika virus preferentially targets cancer stem cells in glioblastoma, resulting in reduced tumor growth.

    更新日期:2017-09-28
  • Responsive monitoring of mitochondrial redox states in heart muscle predicts impending cardiac arrest
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-20
    Dorothy A. Perry, Joshua W. Salvin, Padraic Romfh, Peili Chen, Kalyani Krishnamurthy, Lindsay M. Thomson, Brian D. Polizzotti, Francis X. McGowan, Daryoosh Vakhshoori, John N. Kheir

    Assessing the adequacy of oxygen delivery to tissues is vital, particularly in the fields of intensive care medicine and surgery. As oxygen delivery to a cell becomes deficient, changes in mitochondrial redox state precede changes in cellular function. We describe a technique for the continuous monitoring of the mitochondrial redox state on the epicardial surface using resonance Raman spectroscopy. We quantify the reduced fraction of specific electron transport chain cytochromes, a metric we name the resonance Raman reduced mitochondrial ratio (3RMR). As oxygen deficiency worsens, heme moieties within the electron transport chain become progressively more reduced, leading to an increase in 3RMR. Myocardial 3RMR increased from baseline values of 18.1 ± 5.9 to 44.0 ± 16.9% (P= 0.0039) after inferior vena cava occlusion in rodents (n= 8). To demonstrate the diagnostic power of this measurement, 3RMR was continuously measured in rodents (n= 31) ventilated with 5 to 8% inspired oxygen for 30 min. A 3RMR value exceeding 40% at 10 min predicted subsequent cardiac arrest with 95% sensitivity and 100% specificity [area under the curve (AUC), 0.98], outperforming all current measures, including contractility (AUC, 0.51) and ejection fraction (AUC, 0.39). 3RMR correlated with indices of intracellular redox state and energy production. This technique may permit the real-time identification of critical defects in organ-specific oxygen delivery.

    更新日期:2017-09-21
  • Combined OX40L and mTOR blockade controls effector T cell activation while preserving Treg reconstitution after transplant
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-20
    Victor Tkachev, Scott N. Furlan, Benjamin Watkins, Daniel J. Hunt, Hengqi Betty Zheng, Angela Panoskaltsis-Mortari, Kayla Betz, Melanie Brown, John B. Schell, Katie Zeleski, Alison Yu, Ian Kirby, Sarah Cooley, Jeffrey S. Miller, Bruce R. Blazar, Duncan Casson, Phil Bland-Ward, Leslie S. Kean

    A critical question facing the field of transplantation is how to control effector T cell (Teff) activation while preserving regulatory T cell (Treg) function. Standard calcineurin inhibitor–based strategies can partially control Teffs, but breakthrough activation still occurs, and these agents are antagonistic to Tregfunction. Conversely, mechanistic target of rapamycin (mTOR) inhibition with sirolimus is more Treg-compatible but is inadequate to fully control Teffactivation. In contrast, blockade of OX40L signaling has the capacity to partially control Teffactivation despite maintaining Tregfunction. We used the nonhuman primate graft-versus-host disease (GVHD) model to probe the efficacy of combinatorial immunomodulation with sirolimus and the OX40L-blocking antibody KY1005. Our results demonstrate significant biologic activity of KY1005 alone (prolonging median GVHD-free survival from 8 to 19.5 days), as well as marked, synergistic control of GVHD with KY1005 + sirolimus (median survival time, >100 days;P< 0.01 compared to all other regimens), which was associated with potent control of both TH/TC1 (T helper cell 1/cytotoxic T cell 1) and TH/TC17 activation. Combined administration also maintained Tregreconstitution [resulting in an enhanced Treg/Teffratio (40% over baseline) in the KY1005/sirolimus cohort compared to a 2.9-fold decrease in the unprophylaxed GVHD cohort]. This unique immunologic signature resulted in transplant recipients that were able to control GVHD for the length of analysis and to down-regulate donor/recipient alloreactivity despite maintaining anti–third-party responses. These data indicate that combined OX40L blockade and sirolimus represents a promising strategy to induce immune balance after transplant and is an important candidate regimen for clinical translation.

    更新日期:2017-09-21
  • Cancer immunotherapy with recombinant poliovirus induces IFN-dominant activation of dendritic cells and tumor antigen–specific CTLs
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-20
    Michael C. Brown, Eda K. Holl, David Boczkowski, Elena Dobrikova, Mubeen Mosaheb, Vidya Chandramohan, Darell D. Bigner, Matthias Gromeier, Smita K. Nair

    Tumors thrive in an immunosuppressive microenvironment that impedes antitumor innate and adaptive immune responses. Thus, approaches that can overcome immunosuppression and engage antitumor immunity are needed. This study defines the adjuvant and cancer immunotherapy potential of the recombinant poliovirus/rhinovirus chimera PVSRIPO. PVSRIPO is currently in clinical trials against recurrent World Health Organization grade IV malignant glioma, a notoriously treatment-refractory cancer. Cytopathogenic infection of neoplastic cells releases the proteome and exposes pathogen- and damage-associated molecular patterns. At the same time, sublethal infection of antigen-presenting cells, such as dendritic cells and macrophages, yields potent, sustained type I interferon-dominant activation in an immunosuppressed microenvironment and promotes the development of tumor antigen–specific T cell responses in vitro and antitumor immunity in vivo. PVSRIPO’s immune adjuvancy stimulates canonical innate anti-pathogen inflammatory responses within the tumor microenvironment that culminate in dendritic cell and T cell infiltration. Our findings provide mechanistic evidence that PVSRIPO functions as a potent intratumor immune adjuvant that generates tumor antigen–specific cytotoxic T lymphocyte responses.

    更新日期:2017-09-21
  • Protection against a mixed SHIV challenge by a broadly neutralizing antibody cocktail
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-20
    Boris Julg, Po-Ting Liu, Kshitij Wagh, William M. Fischer, Peter Abbink, Noe B. Mercado, James B. Whitney, Joseph P. Nkolola, Katherine McMahan, Lawrence J. Tartaglia, Erica N. Borducchi, Shreeya Khatiwada, Megha Kamath, Jake A. LeSuer, Michael S. Seaman, Stephen D. Schmidt, John R. Mascola, Dennis R. Burton, Bette T. Korber, Dan H. Barouch

    HIV-1 sequence diversity presents a major challenge for the clinical development of broadly neutralizing antibodies (bNAbs) for both therapy and prevention. Sequence variation in critical bNAb epitopes has been observed in most HIV-1–infected individuals and can lead to viral escape after bNAb monotherapy in humans. We show that viral sequence diversity can limit both the therapeutic and prophylactic efficacy of bNAbs in rhesus monkeys. We first demonstrate that monotherapy with the V3 glycan-dependent antibody 10-1074, but not PGT121, results in rapid selection of preexisting viral variants containing N332/S334 escape mutations and loss of therapeutic efficacy in simian-HIV (SHIV)–SF162P3–infected rhesus monkeys. We then show that the V3 glycan-dependent antibody PGT121 alone and the V2 glycan-dependent antibody PGDM1400 alone both fail to protect against a mixed challenge with SHIV-SF162P3 and SHIV-325c. In contrast, the combination of both bNAbs provides 100% protection against this mixed SHIV challenge. These data reveal that single bNAbs efficiently select resistant viruses from a diverse challenge swarm to establish infection, demonstrating the importance of bNAb cocktails for HIV-1 prevention.

    更新日期:2017-09-21
  • Single-cell analyses to tailor treatments
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-20
    Alex K. Shalek, Mikael Benson

    Single-cell RNA-seq could play a key role in personalized medicine by facilitating characterization of cells, pathways, and genes associated with human diseases such as cancer.

    更新日期:2017-09-21
  • Neutrophil transfer of miR-223 to lung epithelial cells dampens acute lung injury in mice
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-20
    Viola Neudecker, Kelley S. Brodsky, Eric T. Clambey, Eric P. Schmidt, Thomas A. Packard, Bennett Davenport, Theodore J. Standiford, Tingting Weng, Ashley A. Fletcher, Lea Barthel, Joanne C. Masterson, Glenn T. Furuta, Chunyan Cai, Michael R. Blackburn, Adit A. Ginde, Michael W. Graner, William J. Janssen, Rachel L. Zemans, Christopher M. Evans, Ellen L. Burnham, Dirk Homann, Marc Moss, Simone Kreth, Kai Zacharowski, Peter M. Henson, Holger K. Eltzschig

    Intercellular transfer of microRNAs can mediate communication between critical effector cells. We hypothesized that transfer of neutrophil-derived microRNAs to pulmonary epithelial cells could alter mucosal gene expression during acute lung injury. Pulmonary-epithelial microRNA profiling during coculture of alveolar epithelial cells with polymorphonuclear neutrophils (PMNs) revealed a selective increase in lung epithelial cell expression of microRNA-223 (miR-223). Analysis of PMN-derived supernatants showed activation-dependent release ofmiR-223and subsequent transfer to alveolar epithelial cells during coculture in vitro or after ventilator-induced acute lung injury in mice. Genetic studies indicated thatmiR-223deficiency was associated with severe lung inflammation, whereas pulmonary overexpression ofmiR-223in mice resulted in protection during acute lung injury induced by mechanical ventilation or by infection withStaphylococcus aureus. Studies of putativemiR-223gene targets implicated repression of poly(adenosine diphosphate–ribose) polymerase–1 (PARP-1) in themiR-223–dependent attenuation of lung inflammation. Together, these findings suggest that intercellular transfer ofmiR-223from neutrophils to pulmonary epithelial cells may dampen acute lung injury through repression of PARP-1.

    更新日期:2017-09-21
  • Cerebral ischemia comes in waves
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-20
    Huimahn Alex Choi

    Subarachnoid blood induces spreading depolarizations, which are associated with cortical infractions.

    更新日期:2017-09-21
  • Education isn’t everything (for infant immunity)
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-20
    Jeffrey Haspel

    A deficit in tissue-resident memory T cell production helps explain virus susceptibility in early life.

    更新日期:2017-09-21
  • Blocking cell death to enhance cell death
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-20
    Kristopher Sarosiek

    Inhibiting caspase activation during apoptosis may enhance the ability of the immune system to target cancer cells.

    更新日期:2017-09-21
  • Learning from cancer to promote weight loss
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-20
    Ashley Shoemaker

    Growth differentiation factor 15 suppresses appetite and promotes weight loss by activating a receptor expressed in two brain regions.

    更新日期:2017-09-21
  • Targeted inhibition of Gq signaling induces airway relaxation in mouse models of asthma
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-13
    Michaela Matthey, Richard Roberts, Alexander Seidinger, Annika Simon, Ralf Schröder, Markus Kuschak, Suvi Annala, Gabriele M. König, Christa E. Müller, Ian P. Hall, Evi Kostenis, Bernd K. Fleischmann, Daniela Wenzel

    Obstructive lung diseases are common causes of disability and death worldwide. A hallmark feature is aberrant activation of Gqprotein–dependent signaling cascades. Currently, drugs targeting single G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptors (GPCRs) are used to reduce airway tone. However, therapeutic efficacy is often limited, because various GPCRs contribute to bronchoconstriction, and chronic exposure to receptor-activating medications results in desensitization. We therefore hypothesized that pharmacological Gqinhibition could serve as a central mechanism to achieve efficient therapeutic bronchorelaxation. We found that the compound FR900359 (FR), a membrane-permeable inhibitor of Gq, was effective in silencing Gqsignaling in murine and human airway smooth muscle cells. Moreover, FR both prevented bronchoconstrictor responses and triggered sustained airway relaxation in mouse, pig, and human airway tissue ex vivo. Inhalation of FR in healthy wild-type mice resulted in high local concentrations of the compound in the lungs and prevented airway constriction without acute effects on blood pressure and heart rate. FR administration also protected against airway hyperreactivity in murine models of allergen sensitization using ovalbumin and house dust mite as allergens. Our findings establish FR as a selective Gqinhibitor when applied locally to the airways of mice in vivo and suggest that pharmacological blockade of Gqproteins may be a useful therapeutic strategy to achieve bronchorelaxation in asthmatic lung disease.

    更新日期:2017-09-14
  • Endothelial APLNR regulates tissue fatty acid uptake and is essential for apelin’s glucose-lowering effects
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-13
    Cheol Hwangbo, Jingxia Wu, Irinna Papangeli, Takaomi Adachi, Bikram Sharma, Saejeong Park, Lina Zhao, Hyekyung Ju, Gwang-woong Go, Guoliang Cui, Mohammed Inayathullah, Judith K. Job, Jayakumar Rajadas, Stephanie L. Kwei, Ming O. Li, Alan R. Morrison, Thomas Quertermous, Arya Mani, Kristy Red-Horse, Hyung J. Chun

    Treatment of type 2 diabetes mellitus continues to pose an important clinical challenge, with most existing therapies lacking demonstrable ability to improve cardiovascular outcomes. The atheroprotective peptide apelin (APLN) enhances glucose utilization and improves insulin sensitivity. However, the mechanism of these effects remains poorly defined. We demonstrate that the expression of APLNR (APJ/AGTRL1), the only known receptor for apelin, is predominantly restricted to the endothelial cells (ECs) of multiple adult metabolic organs, including skeletal muscle and adipose tissue. Conditional endothelial-specific deletion ofAplnr(AplnrECKO) resulted in markedly impaired glucose utilization and abrogation of apelin-induced glucose lowering. Furthermore, we identified inactivation of Forkhead box protein O1 (FOXO1) and inhibition of endothelial expression of fatty acid (FA) binding protein 4 (FABP4) as key downstream signaling targets of apelin/APLNR signaling. Both theApln−/−andAplnrECKOmice demonstrated increased endothelial FABP4 expression and excess tissue FA accumulation, whereas concurrent endothelialFoxo1deletion or pharmacologic FABP4 inhibition rescued the excess FA accumulation phenotype of theApln−/−mice. The impaired glucose utilization in theAplnrECKOmice was associated with excess FA accumulation in the skeletal muscle. Treatment of these mice with an FABP4 inhibitor abrogated these metabolic phenotypes. These findings provide mechanistic insights that could greatly expand the therapeutic repertoire for type 2 diabetes and related metabolic disorders.

    更新日期:2017-09-14
  • Tumor lymphangiogenesis promotes T cell infiltration and potentiates immunotherapy in melanoma
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-13
    Manuel Fankhauser, Maria A. S. Broggi, Lambert Potin, Natacha Bordry, Laura Jeanbart, Amanda W. Lund, Elodie Da Costa, Sylvie Hauert, Marcela Rincon-Restrepo, Christopher Tremblay, Elena Cabello, Krisztian Homicsko, Olivier Michielin, Douglas Hanahan, Daniel E. Speiser, Melody A. Swartz

    In melanoma, vascular endothelial growth factor–C (VEGF-C) expression and consequent lymphangiogenesis correlate with metastasis and poor prognosis. VEGF-C also promotes tumor immunosuppression, suggesting that lymphangiogenesis inhibitors may be clinically useful in combination with immunotherapy. We addressed this concept in mouse melanoma models with VEGF receptor–3 (VEGFR-3)–blocking antibodies and unexpectedly found that VEGF-C signaling enhanced rather than suppressed the response to immunotherapy. We further found that this effect was mediated by VEGF-C–induced CCL21 and tumor infiltration of naïve T cells before immunotherapy because CCR7 blockade reversed the potentiating effects of VEGF-C. In human metastatic melanoma, gene expression of VEGF-C strongly correlated with CCL21 and T cell inflammation, and serum VEGF-C concentrations associated with both T cell activation and expansion after peptide vaccination and clinical response to checkpoint blockade. We propose that VEGF-C potentiates immunotherapy by attracting naïve T cells, which are locally activated upon immunotherapy-induced tumor cell killing, and that serum VEGF-C may serve as a predictive biomarker for immunotherapy response.

    更新日期:2017-09-14
  • Do not cross to avoid an exacerbation
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-13
    Stephanie A. Christenson

    Reducing IgE with Omalizumab in children with asthma improves the plasmacytoid dendritic cell interferon response to virus in vitro.

    更新日期:2017-09-14
  • In the mood for food
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-13
    Kafui Dzirasa

    A neuronal subpopulation in the central amygdala promotes food consumption.

    更新日期:2017-09-14
  • Problems with mast transit
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-13
    Benjamin Levi

    Mast cell inhibition prevents heterotopic ossification in a model of fibrodysplasia ossificans progressiva.

    更新日期:2017-09-14
  • NLRP3, keep it down so we can hear
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-13
    Jennifer A. Philips

    A gain-of-function mutation inNLRP3is associated with cochlear inflammation and hearing loss.

    更新日期:2017-09-14
  • Peptide probes detect misfolded transthyretin oligomers in plasma of hereditary amyloidosis patients
    Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-13
    Joseph D. Schonhoft, Cecilia Monteiro, Lars Plate, Yvonne S. Eisele, John M. Kelly, Daniel Boland, Christopher G. Parker, Benjamin F. Cravatt, Sergio Teruya, Stephen Helmke, Mathew Maurer, John Berk, Yoshiki Sekijima, Marta Novais, Teresa Coelho, Evan T. Powers, Jeffery W. Kelly

    Increasing evidence supports the hypothesis that soluble misfolded protein assemblies contribute to the degeneration of postmitotic tissue in amyloid diseases. However, there is a dearth of reliable nonantibody-based probes for selectively detecting oligomeric aggregate structures circulating in plasma or deposited in tissues, making it difficult to scrutinize this hypothesis in patients. Hence, understanding the structure-proteotoxicity relationships driving amyloid diseases remains challenging, hampering the development of early diagnostic and novel treatment strategies. We report peptide-based probes that selectively label misfolded transthyretin (TTR) oligomers circulating in the plasma of TTR hereditary amyloidosis patients exhibiting a predominant neuropathic phenotype. These probes revealed that there are much fewer misfolded TTR oligomers in healthy controls, in asymptomatic carriers of mutations linked to amyloid polyneuropathy, and in patients with TTR-associated cardiomyopathies. The absence of misfolded TTR oligomers in the plasma of cardiomyopathy patients suggests that the tissue tropism observed in the TTR amyloidoses is structure-based. Misfolded oligomers decrease in TTR amyloid polyneuropathy patients treated with disease-modifying therapies (tafamidis or liver transplant–mediated gene therapy). In a subset of TTR amyloid polyneuropathy patients, the probes also detected a circulating TTR fragment that disappeared after tafamidis treatment. Proteomic analysis of the isolated TTR oligomers revealed a specific patient-associated signature composed of proteins that likely associate with the circulating TTR oligomers. Quantification of plasma oligomer concentrations using peptide probes could become an early diagnostic strategy, a response-to-therapy biomarker, and a useful tool for understanding structure-proteotoxicity relationships in the TTR amyloidoses.

    更新日期:2017-09-14
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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