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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Fat chance for creatine deficiency Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-13 Catherine A. Charneski
Creatine metabolism in adipose tissue is necessary to burn off extra dietary calories and helps prevent obesity.
Broadly neutralizing antibodies targeting the HIV-1 envelope V2 apex confer protection against a clade C SHIV challenge Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-06 Boris Julg, Lawrence J. Tartaglia, Brandon F. Keele, Kshitij Wagh, Amarendra Pegu, Devin Sok, Peter Abbink, Stephen D. Schmidt, Keyun Wang, Xuejun Chen, M. Gordon Joyce, Ivelin S. Georgiev, Misook Choe, Peter D. Kwong, Nicole A. Doria-Rose, Khoa Le, Mark K. Louder, Robert T. Bailer, Penny L. Moore, Bette Korber, Michael S. Seaman, Salim S. Abdool Karim, Lynn Morris, Richard A. Koup, John R. Mascola, Dennis R. Burton, Dan H. Barouch
Neutralizing antibodies to the V2 apex antigenic region of the HIV-1 envelope (Env) trimer are among the most prevalent cross-reactive antibodies elicited by natural infection. Two recently described V2-specific antibodies, PGDM1400 and CAP256-VRC26.25, have demonstrated exquisite potency and neutralization breadth against HIV-1. However, little data exist on the protective efficacy of V2-specific neutralizing antibodies. We created a novel SHIV-325c viral stock that included a clade C HIV-1 envelope and was susceptible to neutralization by both of these antibodies. Rhesus macaques received a single infusion of either antibody at three different concentrations (2, 0.4, and 0.08 mg/kg) before challenge with SHIV-325c. PGDM1400 was fully protective at the 0.4 mg/kg dose, whereas CAP256-VRC26.25-LS was fully protective even at the 0.08 mg/kg dose, which correlated with its greater in vitro neutralization potency against the challenge virus. Serum antibody concentrations required for protection were <0.75 μg/ml for CAP256-VRC26.25-LS. These data demonstrate unprecedented potency and protective efficacy of V2-specific neutralizing antibodies in nonhuman primates and validate V2 as a potential target for the prevention of HIV-1 infection in passive immunization strategies in humans.
Nondestructive tissue analysis for ex vivo and in vivo cancer diagnosis using a handheld mass spectrometry system Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-06 Jialing Zhang, John Rector, John Q. Lin, Jonathan H. Young, Marta Sans, Nitesh Katta, Noah Giese, Wendong Yu, Chandandeep Nagi, James Suliburk, Jinsong Liu, Alena Bensussan, Rachel J. DeHoog, Kyana Y. Garza, Benjamin Ludolph, Anna G. Sorace, Anum Syed, Aydin Zahedivash, Thomas E. Milner, Livia S. Eberlin
Conventional methods for histopathologic tissue diagnosis are labor- and time-intensive and can delay decision-making during diagnostic and therapeutic procedures. We report the development of an automated and biocompatible handheld mass spectrometry device for rapid and nondestructive diagnosis of human cancer tissues. The device, named MasSpec Pen, enables controlled and automated delivery of a discrete water droplet to a tissue surface for efficient extraction of biomolecules. We used the MasSpec Pen for ex vivo molecular analysis of 20 human cancer thin tissue sections and 253 human patient tissue samples including normal and cancerous tissues from breast, lung, thyroid, and ovary. The mass spectra obtained presented rich molecular profiles characterized by a variety of potential cancer biomarkers identified as metabolites, lipids, and proteins. Statistical classifiers built from the histologically validated molecular database allowed cancer prediction with high sensitivity (96.4%), specificity (96.2%), and overall accuracy (96.3%), as well as prediction of benign and malignant thyroid tumors and different histologic subtypes of lung cancer. Notably, our classifier allowed accurate diagnosis of cancer in marginal tumor regions presenting mixed histologic composition. Last, we demonstrate that the MasSpec Pen is suited for in vivo cancer diagnosis during surgery performed in tumor-bearing mouse models, without causing any observable tissue harm or stress to the animal. Our results provide evidence that the MasSpec Pen could potentially be used as a clinical and intraoperative technology for ex vivo and in vivo cancer diagnosis.
Synthetic oligosaccharides can replace animal-sourced low–molecular weight heparins Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-06 Yongmei Xu, Kasemsiri Chandarajoti, Xing Zhang, Vijayakanth Pagadala, Wenfang Dou, Debra Moorman Hoppensteadt, Erica M. Sparkenbaugh, Brian Cooley, Sharon Daily, Nigel S. Key, Diana Severynse-Stevens, Jawed Fareed, Robert J. Linhardt, Rafal Pawlinski, Jian Liu
Low–molecular weight heparin (LMWH) is used clinically to treat clotting disorders. As an animal-sourced product, LMWH is a highly heterogeneous mixture, and its anticoagulant activity is not fully reversible by protamine. Furthermore, the reliability of the LMWH supply chain is a concern for regulatory agencies. We demonstrate the synthesis of heparin dodecasaccharides (12-mers) at the gram scale. In vitro experiments demonstrate that the anticoagulant activity of the 12-mers could be reversed using protamine. One of these, labeled as 12-mer-1, reduced the size of blood clots in the mouse model of deep vein thrombosis and attenuated circulating procoagulant markers in the mouse model of sickle cell disease. An ex vivo experiment demonstrates that the anticoagulant activity of 12-mer-1 could be reversed by protamine. 12-mer-1 was also examined in a nonhuman primate model to determine its pharmacodynamic parameters. A 7-day toxicity study in a rat model showed no toxic effects. The data suggest that a synthetic homogeneous oligosaccharide can replace animal-sourced LMWHs.
Queuing up for resistance testing Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-06 Kathryn Dupnik
Antibiotic resistance inEscherichia colican be assessed by real-time imaging of bacterial replication in a microfluidics system.
A tale of two amyloids Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-06 Jill K. Morris
Plasma β-amyloid drives peripheral insulin resistance, which precedes an increase in cerebral neuropathology in a novel mouse model that combines Alzheimer’s and diabetes pathologies.
Single-cell nuclei rise from the dead Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-06 Kevin R. King
High throughput, single-cell transcriptomic profiling can rapidly profile frozen mouse and human tissues.
ILCregs: The new kid in class Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-06 Tiffany C. Scharschmidt
ILCregsare a population of innate lymphoid cells that control innate intestinal inflammation through IL-10.
New class of precision antimicrobials redefines role of Clostridium difficile S-layer in virulence and viability Sci. Transl. Med. (IF 16.796) Pub Date : 2017-09-06 Joseph A. Kirk, Dana Gebhart, Anthony M. Buckley, Stephen Lok, Dean Scholl, Gillian R. Douce, Gregory R. Govoni, Robert P. Fagan
There is a medical need for antibacterial agents that do not damage the resident gut microbiota or promote the spread of antibiotic resistance. We recently described a prototypic precision bactericidal agent, Av-CD291.2, which selectively kills specificClostridium difficilestrains and prevents them from colonizing mice. We have since selected two Av-CD291.2–resistant mutants that have a surface (S)-layer–null phenotype due to distinct point mutations in theslpAgene. Using newly identified bacteriophage receptor binding proteins for targeting, we constructed a panel of Avidocin-CDs that kills diverseC. difficileisolates in an S-layer sequence-dependent manner. In addition to bacteriophage receptor recognition, characterization of the mutants also uncovered important roles for S-layer protein A (SlpA) in sporulation, resistance to innate immunity effectors, and toxin production. Surprisingly, S-layer–null mutants were found to persist in the hamster gut despite a complete attenuation of virulence. These findings suggest antimicrobials targeting virulence factors dispensable for fitness in the host force pathogens to trade virulence for viability and would have clear clinical advantages should resistance emerge. Given their exquisite specificity for the pathogen, Avidocin-CDs have substantial therapeutic potential for the treatment and prevention ofC. difficileinfections.
Rare autosomal trisomies, revealed by maternal plasma DNA sequencing, suggest increased risk of feto-placental disease Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-30 Mark D. Pertile, Meredith Halks-Miller, Nicola Flowers, Catalin Barbacioru, Sarah L. Kinnings, Darcy Vavrek, William K. Seltzer, Diana W. Bianchi
Whole-genome sequencing (WGS) of maternal plasma cell-free DNA (cfDNA) can potentially evaluate all 24 chromosomes to identify abnormalities of the placenta, fetus, or pregnant woman. Current bioinformatics algorithms typically only report on chromosomes 21, 18, 13, X, and Y; sequencing results from other chromosomes may be masked. We hypothesized that by systematically analyzing WGS data from all chromosomes, we could identify rare autosomal trisomies (RATs) to improve understanding of feto-placental biology. We analyzed two independent cohorts from clinical laboratories, both of which used a similar quality control parameter, normalized chromosome denominator quality. The entire data set included 89,817 samples. Samples flagged for analysis and classified as abnormal were 328 of 72,932 (0.45%) and 71 of 16,885 (0.42%) in cohorts 1 and 2, respectively. Clinical outcome data were available for 57 of 71 (80%) of abnormal cases in cohort 2. Visual analysis of WGS data demonstrated RATs, copy number variants, and extensive genome-wide imbalances. Trisomies 7, 15, 16, and 22 were the most frequently observed RATs in both cohorts. Cytogenetic or pregnancy outcome data were available in 52 of 60 (87%) of cases with RATs in cohort 2. Cases with RATs detected were associated with miscarriage, true fetal mosaicism, and confirmed or suspected uniparental disomy. Comparing the trisomic fraction with the fetal fraction allowed estimation of possible mosaicism. Analysis and reporting of aneuploidies in all chromosomes can clarify cases in which cfDNA findings on selected “target” chromosomes (21, 18, and 13) are discordant with the fetal karyotype and may identify pregnancies at risk of miscarriage and other complications.
Rewriting the genome in human embryos Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-30 Leah C. Byrne
Researchers have edited the genome of human embryos to correct dominant myocardial disease.
Nanotransfection brings progress that’s more than skin-deep Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-30 Miles A. Miller
Arrayed nanochannels efficiently transfect skin for local in vivo genetic reprogramming.
Deterring zoster Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-30 Jonathan J. Miner
Germline mutations in RNA polymerase III cause susceptibility to life-threatening varicella zoster infection.
More excitation for Rett syndrome Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-30 Gaia Novarino
D-cycloserine ameliorates breathing abnormalities and survival rate in a mouse model of Rett syndrome.
Increased adaptive immune responses and proper feedback regulation protect against clinical dengue Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-30 Etienne Simon-Lorière, Veasna Duong, Ahmed Tawfik, Sivlin Ung, Sowath Ly, Isabelle Casadémont, Matthieu Prot, Noémie Courtejoie, Kevin Bleakley, Philippe Buchy, Arnaud Tarantola, Philippe Dussart, Tineke Cantaert, Anavaj Sakuntabhai
Clinical symptoms of dengue virus (DENV) infection, the most prevalent arthropod-borne viral disease, range from classical mild dengue fever to severe, life-threatening dengue shock syndrome. However, most DENV infections cause few or no symptoms. Asymptomatic DENV-infected patients provide a unique opportunity to decipher the host immune responses leading to virus elimination without negative impact on an individual’s health. We used an integrated approach of transcriptional profiling and immunological analysis to compare a Cambodian population of strictly asymptomatic viremic individuals with clinical dengue patients. Whereas inflammatory pathways and innate immune response pathways were similar between asymptomatic individuals and clinical dengue patients, expression of proteins related to antigen presentation and subsequent T cell and B cell activation pathways was differentially regulated, independent of viral load and previous DENV infection history. Feedback mechanisms controlled the immune response in asymptomatic viremic individuals, as demonstrated by increased activation of T cell apoptosis–related pathways and FcγRIIB (Fcγ receptor IIB) signaling associated with decreased anti-DENV–specific antibody concentrations. Together, our data illustrate that symptom-free DENV infection in children is associated with increased activation of the adaptive immune compartment and proper control mechanisms, leading to elimination of viral infection without excessive immune activation, with implications for novel vaccine development strategies.
Inflammatory monocytes expressing tissue factor drive SIV and HIV coagulopathy Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-30 Melissa E. Schechter, Bruno B. Andrade, Tianyu He, George Haret Richter, Kevin W. Tosh, Benjamin B. Policicchio, Amrit Singh, Kevin D. Raehtz, Virginia Sheikh, Dongying Ma, Egidio Brocca-Cofano, Cristian Apetrei, Russel Tracy, Ruy M. Ribeiro, Alan Sher, Ivo M. B. Francischetti, Ivona Pandrea, Irini Sereti
In HIV infection, persistent inflammation despite effective antiretroviral therapy is linked to increased risk of noninfectious chronic complications such as cardiovascular and thromboembolic disease. A better understanding of inflammatory and coagulation pathways in HIV infection is needed to optimize clinical care. Markers of monocyte activation and coagulation independently predict morbidity and mortality associated with non-AIDS events. We identified a specific subset of monocytes that express tissue factor (TF), persist after virological suppression, and trigger the coagulation cascade by activating factor X. This subset of monocytes expressing TF had a distinct gene signature with up-regulated innate immune markers and evidence of robust production of multiple proinflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor–α (TNF-α), and IL-6, ex vivo and in vitro upon lipopolysaccharide stimulation. We validated our findings in a nonhuman primate model, showing that TF-expressing inflammatory monocytes were associated with simian immunodeficiency virus (SIV)–related coagulopathy in the progressive [pigtail macaques (PTMs)] but not in the nonpathogenic (African green monkeys) SIV infection model. Last, Ixolaris, an anticoagulant that inhibits the TF pathway, was tested and potently blocked functional TF activity in vitro in HIV and SIV infection without affecting monocyte responses to Toll-like receptor stimulation. Strikingly, in vivo treatment of SIV-infected PTMs with Ixolaris was associated with significant decreases in D-dimer and immune activation. These data suggest that TF-expressing monocytes are at the epicenter of inflammation and coagulation in chronic HIV and SIV infection and may represent a potential therapeutic target.
Targeting the vascular and perivascular niches as a regenerative therapy for lung and liver fibrosis Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-30 Zhongwei Cao, Tinghong Ye, Yue Sun, Gaili Ji, Koji Shido, Yutian Chen, Lin Luo, Feifei Na, Xiaoyan Li, Zhen Huang, Jane L. Ko, Vivek Mittal, Lina Qiao, Chong Chen, Fernando J. Martinez, Shahin Rafii, Bi-Sen Ding
The regenerative capacity of lung and liver is sometimes impaired by chronic or overwhelming injury. Orthotopic transplantation of parenchymal stem cells to damaged organs might reinstate their self-repair ability. However, parenchymal cell engraftment is frequently hampered by the microenvironment in diseased recipient organs. We show that targeting both the vascular niche and perivascular fibroblasts establishes “hospitable soil” to foster the incorporation of “seed,” in this case, the engraftment of parenchymal cells in injured organs. Specifically, ectopic induction of endothelial cell (EC)–expressed paracrine/angiocrine hepatocyte growth factor (HGF) and inhibition of perivascular NOX4 [NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase 4] synergistically enabled reconstitution of mouse and human parenchymal cells in damaged organs. Reciprocally, genetic knockout ofHgfin mouse ECs (HgfiΔEC/iΔEC) aberrantly up-regulated perivascular NOX4 during liver and lung regeneration. Dysregulated HGF and NOX4 pathways subverted the function of vascular and perivascular cells from an epithelially inductive niche to a microenvironment that inhibited parenchymal reconstitution. Perivascular NOX4 induction inHgfiΔEC/iΔECmice recapitulated the phenotype of human and mouse liver and lung fibrosis. Consequently, EC-directed HGF and NOX4 inhibitor GKT137831 stimulated regenerative integration of mouse and human parenchymal cells in chronically injured lung and liver. Our data suggest that targeting dysfunctional perivascular and vascular cells in diseased organs can bypass fibrosis and enable reparative cell engraftment to reinstate lung and liver regeneration.
Subcutaneous drug delivery: An evolving enterprise Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-30 Graham B. Jones, David S. Collins, Michael W. Harrison, Nagarajan R. Thyagarajapuram, Justin M. Wright
Recent advances in subcutaneous drug delivery and device design are transforming the biopharmaceutical sector and improving patient care.
A glucagon-like peptide-1 receptor agonist reduces intracranial pressure in a rat model of hydrocephalus Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-23 Hannah F. Botfield, Maria S. Uldall, Connar S. J. Westgate, James L. Mitchell, Snorre M. Hagen, Ana Maria Gonzalez, David J. Hodson, Rigmor H. Jensen, Alexandra J. Sinclair
Current therapies for reducing raised intracranial pressure (ICP) under conditions such as idiopathic intracranial hypertension or hydrocephalus have limited efficacy and tolerability. Thus, there is a pressing need to identify alternative drugs. Glucagon-like peptide-1 receptor (GLP-1R) agonists are used to treat diabetes and promote weight loss but have also been shown to affect fluid homeostasis in the kidney. We investigated whether exendin-4, a GLP-1R agonist, is able to modulate cerebrospinal fluid (CSF) secretion at the choroid plexus and subsequently reduce ICP in rats. We used tissue sections and cell cultures to demonstrate expression of GLP-1R in the choroid plexus and its activation by exendin-4, an effect blocked by the GLP-1R antagonist exendin 9-39. Acute treatment with exendin-4 reduced Na+- and K+-dependent adenosine triphosphatase activity, a key regulator of CSF secretion, in cell cultures. Finally, we demonstrated that administration of exendin-4 to female rats with raised ICP (hydrocephalic) resulted in a GLP-1R–mediated reduction in ICP. These findings suggest that GLP-1R agonists can reduce ICP in rodents. Repurposing existing GLP-1R agonist drugs may be a useful therapeutic strategy for treating raised ICP.
A bigger and better picture of clinical samples Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-23 Kwanghun Chung
An open-top light-sheet microscope enables rapid high-resolution panoramic imaging of intact clinical samples to increase the accuracy and reproducibility of clinical histology.
Evading sepsis with exercise Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-23 Christopher Hine
Aged mice preconditioned with a running routine were resistant to acute systemic sepsis compared with non-runner.
“CHIP”s are bad for patients with solid tumors Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-23 Brian A. Jonas
In patients with nonhematologic cancers, clonal hematopoiesis is prevalent and associated with poor prognoses.
Cellular eyelashes help striatal neurons hook up Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-23 Maria K. Lehtinen
Primary cilia-based signaling provides critical infrastructure for formation of striatal neuronal networks.
An RNA interference screen identifies druggable regulators of MeCP2 stability Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-23 Laura M. Lombardi, Manar Zaghlula, Yehezkel Sztainberg, Steven A. Baker, Tiemo J. Klisch, Amy A. Tang, Eric J. Huang, Huda Y. Zoghbi
Alterations in gene dosage due to copy number variation are associated with autism spectrum disorder, intellectual disability (ID), and other psychiatric disorders. The nervous system is so acutely sensitive to the dose of methyl-CpG–binding protein 2 (MeCP2) that even a twofold change in MeCP2 protein—either increased or decreased—results in distinct disorders with overlapping features including ID, autistic behavior, and severe motor dysfunction. Rett syndrome is caused by loss-of-function mutations inMECP2, whereas duplications spanning theMECP2locus result inMECP2duplication syndrome (MDS), which accounts for ~1% of X-linked ID. Despite evidence from mouse models that restoring MeCP2 can reverse the course of disease, there are currently no U.S. Food and Drug Administration–approved therapies available to clinically modulate MeCP2 abundance. We used a forward genetic screen against all known human kinases and phosphatases to identify druggable regulators of MeCP2 stability. Two putative modulators of MeCP2, HIPK2 (homeodomain-interacting protein kinase 2) and PP2A (protein phosphatase 2A), were validated as stabilizers of MeCP2 in vivo. Further, pharmacological inhibition of PP2A in vivo reduced MeCP2 in the nervous system and rescued both overexpression and motor abnormalities in a mouse model of MDS. Our findings reveal potential therapeutic targets for treating disorders of alteredMECP2dosage.
Targeting VCP enhances anticancer activity of oncolytic virus M1 in hepatocellular carcinoma Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-23 Haipeng Zhang, Kai Li, Yuan Lin, Fan Xing, Xiao Xiao, Jing Cai, Wenbo Zhu, Jiankai Liang, Yaqian Tan, Liwu Fu, Fang Wang, Wei Yin, Bingzheng Lu, Pengxin Qiu, Xingwen Su, Shoufang Gong, Xuetao Bai, Jun Hu, Guangmei Yan
Oncolytic virotherapy is rapidly progressing through clinical evaluation. However, the therapeutic efficacy of oncolytic viruses in humans has been less than expected from preclinical studies. We describe an anticancer drug screen for compounds that enhance M1 oncolytic virus activity in hepatocellular carcinoma (HCC). An inhibitor of the valosin-containing protein (VCP) was identified as the top sensitizer, selectively increasing potency of the oncolytic virus up to 3600-fold. Further investigation revealed that VCP inhibitors cooperated with M1 virus–suppressed inositol-requiring enzyme 1α (IRE1α)–X-box binding protein 1 (XBP1) pathway and triggered irresolvable endoplasmic reticulum (ER) stress, subsequently promoting robust apoptosis in HCC. We show that VCP inhibitor improved the oncolytic efficacy of M1 virus in several mouse models of HCC and primary HCC tissues. Finally, this combinatorial therapeutic strategy was well tolerated in nonhuman primates. Our study identifies combined VCP inhibition and oncolytic virus as a potential treatment for HCC and demonstrates promising therapeutic potential.
A lower-extremity exoskeleton improves knee extension in children with crouch gait from cerebral palsy Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-23 Zachary F. Lerner, Diane L. Damiano, Thomas C. Bulea
The ability to walk contributes considerably to physical health and overall well-being, particularly in children with motor disability, and is therefore prioritized as a rehabilitation goal. However, half of ambulatory children with cerebral palsy (CP), the most prevalent childhood movement disorder, cease to walk in adulthood. Robotic gait trainers have shown positive outcomes in initial studies, but these clinic-based systems are limited to short-term programs of insufficient length to maintain improved function in a lifelong disability such as CP. Sophisticated wearable exoskeletons are now available, but their utility in treating childhood movement disorders remains unknown. We evaluated an exoskeleton for the treatment of crouch (or flexed-knee) gait, one of the most debilitating pathologies in CP. We show that the exoskeleton reduced crouch in a cohort of ambulatory children with CP during overground walking. The exoskeleton was safe and well tolerated, and all children were able to walk independently with the device. Rather than guiding the lower limbs, the exoskeleton dynamically changed the posture by introducing bursts of knee extension assistance during discrete portions of the walking cycle, a perturbation that resulted in maintained or increased knee extensor muscle activity during exoskeleton use. Six of seven participants exhibited postural improvements equivalent to outcomes reported from invasive orthopedic surgery. We also demonstrate that improvements in crouch increased over the course of our multiweek exploratory trial. Together, these results provide evidence supporting the use of wearable exoskeletons as a treatment strategy to improve walking in children with CP.
Loss of dual leucine zipper kinase signaling is protective in animal models of neurodegenerative disease Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-16 Claire E. Le Pichon, William J. Meilandt, Sara Dominguez, Hilda Solanoy, Han Lin, Hai Ngu, Alvin Gogineni, Arundhati Sengupta Ghosh, Zhiyu Jiang, Seung-Hye Lee, Janice Maloney, Vineela D. Gandham, Christine D. Pozniak, Bei Wang, Sebum Lee, Michael Siu, Snahel Patel, Zora Modrusan, Xingrong Liu, York Rudhard, Miriam Baca, Amy Gustafson, Josh Kaminker, Richard A. D. Carano, Eric J. Huang, Oded Foreman, Robby Weimer, Kimberly Scearce-Levie, Joseph W. Lewcock
Hallmarks of chronic neurodegenerative disease include progressive synaptic loss and neuronal cell death, yet the cellular pathways that underlie these processes remain largely undefined. We provide evidence that dual leucine zipper kinase (DLK) is an essential regulator of the progressive neurodegeneration that occurs in amyotrophic lateral sclerosis and Alzheimer’s disease. We demonstrate that DLK/c-Jun N-terminal kinase signaling was increased in mouse models and human patients with these disorders and that genetic deletion of DLK protected against axon degeneration, neuronal loss, and functional decline in vivo. Furthermore, pharmacological inhibition of DLK activity was sufficient to attenuate the neuronal stress response and to provide functional benefit even in the presence of ongoing disease. These findings demonstrate that pathological activation of DLK is a conserved mechanism that regulates neurodegeneration and suggest that DLK inhibition may be a potential approach to treat multiple neurodegenerative diseases.
Direct detection of early-stage cancers using circulating tumor DNA Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-16 Jillian Phallen, Mark Sausen, Vilmos Adleff, Alessandro Leal, Carolyn Hruban, James White, Valsamo Anagnostou, Jacob Fiksel, Stephen Cristiano, Eniko Papp, Savannah Speir, Thomas Reinert, Mai-Britt Worm Orntoft, Brian D. Woodward, Derek Murphy, Sonya Parpart-Li, David Riley, Monica Nesselbush, Naomi Sengamalay, Andrew Georgiadis, Qing Kay Li, Mogens Rørbæk Madsen, Frank Viborg Mortensen, Joost Huiskens, Cornelis Punt, Nicole van Grieken, Remond Fijneman, Gerrit Meijer, Hatim Husain, Robert B. Scharpf, Luis A. Diaz, Siân Jones, Sam Angiuoli, Torben Ørntoft, Hans Jørgen Nielsen, Claus Lindbjerg Andersen, Victor E. Velculescu
Early detection and intervention are likely to be the most effective means for reducing morbidity and mortality of human cancer. However, development of methods for noninvasive detection of early-stage tumors has remained a challenge. We have developed an approach called targeted error correction sequencing (TEC-Seq) that allows ultrasensitive direct evaluation of sequence changes in circulating cell-free DNA using massively parallel sequencing. We have used this approach to examine 58 cancer-related genes encompassing 81 kb. Analysis of plasma from 44 healthy individuals identified genomic changes related to clonal hematopoiesis in 16% of asymptomatic individuals but no alterations in driver genes related to solid cancers. Evaluation of 200 patients with colorectal, breast, lung, or ovarian cancer detected somatic mutations in the plasma of 71, 59, 59, and 68%, respectively, of patients with stage I or II disease. Analyses of mutations in the circulation revealed high concordance with alterations in the tumors of these patients. In patients with resectable colorectal cancers, higher amounts of preoperative circulating tumor DNA were associated with disease recurrence and decreased overall survival. These analyses provide a broadly applicable approach for noninvasive detection of early-stage tumors that may be useful for screening and management of patients with cancer.
Metabolic differentiation of early Lyme disease from southern tick–associated rash illness (STARI) Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-16 Claudia R. Molins, Laura V. Ashton, Gary P. Wormser, Barbara G. Andre, Ann M. Hess, Mark J. Delorey, Mark A. Pilgard, Barbara J. Johnson, Kristofor Webb, M. Nurul Islam, Adoracion Pegalajar-Jurado, Irida Molla, Mollie W. Jewett, John T. Belisle
Lyme disease, the most commonly reported vector-borne disease in the United States, results from infection withBorrelia burgdorferi.Early clinical diagnosis of this disease is largely based on the presence of an erythematous skin lesion for individuals in high-risk regions. This, however, can be confused with other illnesses including southern tick−associated rash illness (STARI), an illness that lacks a defined etiological agent or laboratory diagnostic test, and is coprevalent with Lyme disease in portions of the eastern United States. By applying an unbiased metabolomics approach with sera retrospectively obtained from well-characterized patients, we defined biochemical and diagnostic differences between early Lyme disease and STARI. Specifically, a metabolic biosignature consisting of 261 molecular features (MFs) revealed that alteredN-acyl ethanolamine and primary fatty acid amide metabolism discriminated early Lyme disease from STARI. Development of classification models with the 261-MF biosignature and testing against validation samples differentiated early Lyme disease from STARI with an accuracy of 85 to 98%. These findings revealed metabolic dissimilarity between early Lyme disease and STARI, and provide a powerful and new approach to inform patient management by objectively distinguishing early Lyme disease from an illness with nearly identical symptoms.
Resistance is futile Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-16 Christopher M. Jewell
Combining tandem peptides that localize toxins to bacterial membranes with scaffolds that target these payloads to the lungs combats drug resistant bacteria without off-target effects.
Wounds getting the royal treatment Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-16 Hadar Lev-Tov
Insect defensin-1 improves wound healing by inducing production of matrix metalloproteinase-9.
Painful marks of childhood abuse Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-16 Vasiliki Michopoulos
Adverse childhood experiences epigenetically regulate expression of kappa opioid receptors.
Prostate cancer loses when androgen receptor can’t stick the landing Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-16 Monica Venere
A small-molecule inhibitor blocks the interaction of the androgen receptor with DNA to target drug-resistant prostate cancer.
mGlu7 potentiation rescues cognitive, social, and respiratory phenotypes in a mouse model of Rett syndrome Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-16 Rocco G. Gogliotti, Rebecca K. Senter, Nicole M. Fisher, Jeffrey Adams, Rocio Zamorano, Adam G. Walker, Anna L. Blobaum, Darren W. Engers, Corey R. Hopkin, J. Scott Daniels, Carrie K. Jones, Craig W. Lindsley, Zixiu Xiang, P. Jeffrey Conn, Colleen M. Niswender
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in themethyl-CpG binding protein 2(MECP2) gene. The cognitive impairments seen in mouse models of RTT correlate with deficits in long-term potentiation (LTP) at Schaffer collateral (SC)–CA1 synapses in the hippocampus. Metabotropic glutamate receptor 7 (mGlu7) is the predominant mGlu receptor expressed presynaptically at SC-CA1 synapses in adult mice, and its activation on GABAergic interneurons is necessary for induction of LTP. We demonstrate that pathogenic mutations inMECP2reduce mGlu7protein expression in brain tissue from RTT patients and in MECP2-deficient mouse models. In rodents, this reduction impairs mGlu7-mediated control of synaptic transmission. We show that positive allosteric modulation of mGlu7activity restores LTP and improves contextual fear learning, novel object recognition, and social memory. Furthermore, mGlu7positive allosteric modulation decreases apneas inMecp2+/−mice, suggesting that mGlu7may be a potential therapeutic target for multiple aspects of the RTT phenotype.
Partial efficacy of a broadly neutralizing antibody against cell-associated SHIV infection Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-09 Matthew S. Parsons, Sarah B. Lloyd, Wen Shi Lee, Anne B. Kristensen, Thakshila Amarasena, Rob J. Center, Brandon F. Keele, Jeffrey D. Lifson, Celia C. LaBranche, David Montefiori, Bruce D. Wines, P. Mark Hogarth, Kristine M. Swiderek, Vanessa Venturi, Miles P. Davenport, Stephen J. Kent
Broadly neutralizing antibodies (BnAbs) protect macaques from cell-free simian/human immunodeficiency virus (SHIV) challenge, but their efficacy against cell-associated SHIV is unclear. Virus in cell-associated format is highly infectious, present in transmission-competent bodily fluids, and potentially capable of evading antibody-mediated neutralization. The PGT121 BnAb, which recognizes an epitope consisting of the V3 loop and envelope glycans, mediates antibody-dependent cellular cytotoxicity and neutralization of cell-to-cell HIV-1 transmission. To evaluate whether a BnAb can prevent infection after cell-associated viral challenge, we infused pigtail macaques with PGT121 or an isotype control and challenged animals 1 hour later intravenously with SHIVSF162P3-infected splenocytes. All five controls had high viremia 1 week after challenge. Three of six PGT121-infused animals were completely protected, two of six animals had a 1-week delay in onset of high viremia, and one animal had a 7-week delay in onset of viremia. The infused antibody had decayed on average to 2.0 μg/ml by 1 week after infusion and was well below 1 μg/ml (range, <0.1 to 0.8 μg/ml) by 8 weeks. The animals with a 1-week delay before high viremia had relatively lower plasma concentrations of PGT121. Transfer of 22 million peripheral blood mononuclear cells (PBMCs) stored at weeks 1 to 4 from the animal with the 7-week delayed onset of viremia into uninfected macaques did not initiate infection. Our results show that HIV-1–specific neutralizing antibodies have partial efficacy against cell-associated virus exposure in macaques. We conclude that sustaining high concentrations of bioavailable BnAb is important for protecting against cell-associated virus.
Imaging covert consciousness Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-09 Huimahn Alex Choi
Imaging and electroencephalography help to detect covert consciousness after acute brain injury.
Mind your bedtime: The circadian clock and mTOR in an orphan brain disease Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-09 Jeffrey Haspel
Circadian disturbances that accompany tuberous sclerosis Complex are explored in mouse models.
Meta-screen for cancer dependencies Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-09 Kristopher Sarosiek
Systematic identification of gene dependencies in cancer cells teaches us some lessons.
I scream, you scream, we all scream for irisin Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-09 Ashley Shoemaker
Skeletal muscle may communicate with pancreatic beta cells through irisin, a muscle-derived hormone that promotes beta cell survival and insulin release.
Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-09 Mohammad Alhadj Ali, Yuk-Fun Liu, Sefina Arif, Danijela Tatovic, Hina Shariff, Vivienne B. Gibson, Norkhairin Yusuf, Roman Baptista, Martin Eichmann, Nedyalko Petrov, Susanne Heck, Jennie H. M. Yang, Timothy I. M. Tree, Irma Pujol-Autonell, Lorraine Yeo, Lucas R. Baumard, Rachel Stenson, Alex Howell, Alison Clark, Zoe Boult, Jake Powrie, Laura Adams, Florence S. Wong, Stephen Luzio, Gareth Dunseath, Kate Green, Alison O’Keefe, Graham Bayly, Natasha Thorogood, Robert Andrews, Nicola Leech, Frank Joseph, Sunil Nair, Susan Seal, HoYee Cheung, Craig Beam, Robert Hills, Mark Peakman, Colin M. Dayan
Immunotherapy using short immunogenic peptides of disease-related autoantigens restores immune tolerance in preclinical disease models. We studied safety and mechanistic effects of injecting human leukocyte antigen–DR4(DRB1*0401)–restricted immunodominant proinsulin peptide intradermally every 2 or 4 weeks for 6 months in newly diagnosed type 1 diabetes patients. Treatment was well tolerated with no systemic or local hypersensitivity. Placebo subjects showed a significant decline in stimulated C-peptide (measuring insulin reserve) at 3, 6, 9, and 12 months versus baseline, whereas no significant change was seen in the 4-weekly peptide group at these time points or the 2-weekly group at 3, 6, and 9 months. The placebo group’s daily insulin use increased by 50% over 12 months but remained unchanged in the intervention groups. C-peptide retention in treated subjects was associated with proinsulin-stimulated interleukin-10 production, increased FoxP3 expression by regulatory T cells, low baseline levels of activated β cell–specific CD8 T cells, and favorable β cell stress markers (proinsulin/C-peptide ratio). Thus, proinsulin peptide immunotherapy is safe, does not accelerate decline in β cell function, and is associated with antigen-specific and nonspecific immune modulation.
Genomic profiling of ER+ breast cancers after short-term estrogen suppression reveals alterations associated with endocrine resistance Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-09 Jennifer M. Giltnane, Katherine E. Hutchinson, Thomas P. Stricker, Luigi Formisano, Christian D. Young, Monica V. Estrada, Mellissa J. Nixon, Liping Du, Violeta Sanchez, Paula Gonzalez Ericsson, Maria G. Kuba, Melinda E. Sanders, Xinmeng J. Mu, Eliezer M. Van Allen, Nikhil Wagle, Ingrid A. Mayer, Vandana Abramson, Henry Gόmez, Monica Rizzo, Weiyi Toy, Sarat Chandarlapaty, Erica L. Mayer, Jason Christiansen, Danielle Murphy, Kerry Fitzgerald, Kai Wang, Jeffrey S. Ross, Vincent A. Miller, Phillip J. Stephens, Roman Yelensky, Levi Garraway, Yu Shyr, Ingrid Meszoely, Justin M. Balko, Carlos L. Arteaga
Inhibition of proliferation in estrogen receptor–positive (ER+) breast cancers after short-term antiestrogen therapy correlates with long-term patient outcome. We profiled 155 ER+/human epidermal growth factor receptor 2–negative (HER2–) early breast cancers from 143 patients treated with the aromatase inhibitor letrozole for 10 to 21 days before surgery. Twenty-one percent of tumors remained highly proliferative, suggesting that these tumors harbor alterations associated with intrinsic endocrine therapy resistance. Whole-exome sequencing revealed a correlation between 8p11-12 and 11q13 gene amplifications, including FGFR1 and CCND1, respectively, and high Ki67. We corroborated these findings in a separate cohort of serial pretreatment, postneoadjuvant chemotherapy, and recurrent ER+ tumors. Combined inhibition of FGFR1 and CDK4/6 reversed antiestrogen resistance in ER+ FGFR1/CCND1 coamplified CAMA1 breast cancer cells. RNA sequencing of letrozole-treated tumors revealed the existence of intrachromosomal ESR1 fusion transcripts and increased expression of gene signatures indicative of enhanced E2F-mediated transcription and cell cycle processes in cancers with high Ki67. These data suggest that short-term preoperative estrogen deprivation followed by genomic profiling can be used to identify druggable alterations that may cause intrinsic endocrine therapy resistance.
Preventing chemotherapy-induced myelosuppression by repurposing the FLT3 inhibitor quizartinib Sci. Transl. Med. (IF 16.796) Pub Date : 2017-08-09 Samuel J. Taylor, Johanna M. Duyvestyn, Samantha A. Dagger, Emma J. Dishington, Catherine A. Rinaldi, Oliver M. Dovey, George S. Vassiliou, Carolyn S. Grove, Wallace Y. Langdon
We describe an approach to inhibit chemotherapy-induced myelosuppression. We found that short-term exposure of mice to the FLT3 inhibitor quizartinib induced the transient quiescence of multipotent progenitors (MPPs). This property of quizartinib conferred marked protection to MPPs in mice receiving fluorouracil or gemcitabine. The protection resulted in the rapid recovery of bone marrow and blood cellularity, thus preventing otherwise lethal myelosuppression. A treatment strategy involving quizartinib priming that protected wild-type bone marrow progenitors, but not leukemic cells, from fluorouracil provided a more effective treatment than conventional induction therapy in mouse models of acute myeloid leukemia. This strategy has the potential to be extended for use in other cancers where FLT3 inhibition does not adversely affect the effectiveness of chemotherapy. Thus, the addition of quizartinib to cancer treatment regimens could markedly improve cancer patient survival and quality of life.
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