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  • Gene therapy delivering a paraoxonase 1 variant offers long-term prophylactic protection against nerve agents in mice
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-22
    Venkaiah Betapudi, Reena Goswami, Liliya Silayeva, Deborah M. Doctor, Nageswararao Chilukuri

    Chemical warfare nerve agents are organophosphorus chemical compounds that induce cholinergic crisis, leaving little or no time for medical intervention to prevent death. The current chemical treatment regimen may prevent death but does not prevent postexposure complications such as brain damage and permanent behavioral abnormalities. In the present study, we have demonstrated an adeno-associated virus 8 (AAV8)–mediated paraoxonase 1 variant IF-11 (PON1-IF11) gene therapy that offers asymptomatic prophylactic protection to mice against multiple lethal doses of G-type chemical warfare nerve agents, namely, tabun, sarin, cyclosarin, and soman, for up to 5 months in mice. A single injection of liver-specific adeno-associated viral particles loaded with PON1-IF11 gene resulted in expression and secretion of recombinant PON1-IF11 in milligram quantities, which has the catalytic power to break down G-type chemical warfare nerve agents into biologically inactive products in vitro and in vivo in rodents. Mice containing milligram concentrations of recombinant PON1-IF11 in their blood displayed no clinical signs of toxicity, as judged by their hematological parameters and serum chemistry profiles. Our study unfolds avenues to develop a one-time application of gene therapy to express a near-natural and circulating therapeutic PON1-IF11 protein that can potentially protect humans against G-type chemical warfare nerve agents for several weeks to months.

    更新日期:2020-01-23
  • Deep phenotyping during pregnancy for predictive and preventive medicine
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-22
    Alison G. Paquette, Leroy Hood, Nathan D. Price, Yoel Sadovsky

    Deep phenotyping during pregnancy offers an opportunity to define the antecedents of lifelong health and wellness, and to improve pregnancy outcomes.

    更新日期:2020-01-23
  • The IDH-TAU-EGFR triad defines the neovascular landscape of diffuse gliomas
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-22
    Ricardo Gargini, Berta Segura-Collar, Beatriz Herránz, Vega García-Escudero, Andrés Romero-Bravo, Felipe J. Núñez, Daniel García-Pérez, Jacqueline Gutiérrez-Guamán, Angel Ayuso-Sacido, Joan Seoane, Angel Pérez-Núñez, Juan M. Sepúlveda-Sánchez, Aurelio Hernández-Laín, María G. Castro, Ramón García-Escudero, Jesús Ávila, Pilar Sánchez-Gómez

    Gliomas that express the mutated isoforms of isocitrate dehydrogenase 1/2 (IDH1/2) have better prognosis than wild-type (wt) IDH1/2 gliomas. However, how these mutant (mut) proteins affect the tumor microenvironment is still a pending question. Here, we describe that the transcription of microtubule-associated protein TAU (MAPT), a gene that has been classically associated with neurodegenerative diseases, is epigenetically controlled by the balance between wt and mut IDH1/2 in mouse and human gliomas. In IDH1/2 mut tumors, we found high expression of TAU that decreased with tumor progression. Furthermore, MAPT was almost absent from tumors with epidermal growth factor receptor (EGFR) mutations, whereas its trancription negatively correlated with overall survival in gliomas carrying wt or amplified (amp) EGFR. We demonstrated that the overexpression of TAU, through the stabilization of microtubules, impaired the mesenchymal/pericyte-like transformation of glioma cells by blocking EGFR, nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) and the transcriptional coactivator with PDZ-binding motif (TAZ). Our data also showed that mut EGFR induced a constitutive activation of this pathway, which was no longer sensitive to TAU. By inhibiting the transdifferentiation capacity of EGFRamp/wt tumor cells, TAU protein inhibited angiogenesis and favored vascular normalization, decreasing glioma aggressiveness and increasing their sensitivity to chemotherapy.

    更新日期:2020-01-23
  • Pan-viral protection against arboviruses by activating skin macrophages at the inoculation site
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-22
    Steven R. Bryden, Marieke Pingen, Daniella A. Lefteri, Janne Miltenburg, Leen Delang, Sofie Jacobs, Rana Abdelnabi, Johan Neyts, Emilie Pondeville, Jack Major, Marietta Müller, Henna Khalid, Andrew Tuplin, Margus Varjak, Andres Merits, Julia Edgar, Gerard J. Graham, Kave Shams, Clive S. McKimmie

    Arthropod-borne viruses (arboviruses) are important human pathogens for which there are no specific antiviral medicines. The abundance of genetically distinct arbovirus species, coupled with the unpredictable nature of their outbreaks, has made the development of virus-specific treatments challenging. Instead, we have defined and targeted a key aspect of the host innate immune response to virus at the arthropod bite that is common to all arbovirus infections, potentially circumventing the need for virus-specific therapies. Using mouse models and human skin explants, we identify innate immune responses by dermal macrophages in the skin as a key determinant of disease severity. Post-exposure treatment of the inoculation site by a topical TLR7 agonist suppressed both the local and subsequent systemic course of infection with a variety of arboviruses from the Alphavirus, Flavivirus, and Orthobunyavirus genera. Clinical outcome was improved in mice after infection with a model alphavirus. In the absence of treatment, antiviral interferon expression to virus in the skin was restricted to dermal dendritic cells. In contrast, stimulating the more populous skin-resident macrophages with a TLR7 agonist elicited protective responses in key cellular targets of virus that otherwise proficiently replicated virus. By defining and targeting a key aspect of the innate immune response to virus at the mosquito bite site, we have identified a putative new strategy for limiting disease after infection with a variety of genetically distinct arboviruses.

    更新日期:2020-01-23
  • Hitting a double to treat cancer
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-22
    Asmaa El-Kenawi

    Simultaneous targeting of polyamine and methionine pathways may be a promising strategy to treat prostate cancer.

    更新日期:2020-01-23
  • Neurodevelopment and risk for ADHD and depression
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-22
    Dylan G. Gee

    Childhood brain connectivity predicts psychiatric difficulties four years later.

    更新日期:2020-01-23
  • Angling for a bug-inspired method of coating therapeutics onto microneedles
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-22
    Eoin O’Cearbhaill

    Mimicking the microstructures on the surface of European true bugs may help optimize loading of therapeutics onto transdermal microneedle patches.

    更新日期:2020-01-23
  • PI4KIIIβ is a therapeutic target in chromosome 1q–amplified lung adenocarcinoma
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-22
    Xiaochao Tan, Priyam Banerjee, Edward A. Pham, Florentine U. N. Rutaganira, Kaustabh Basu, Neus Bota-Rabassedas, Hou-Fu Guo, Caitlin L. Grzeskowiak, Xin Liu, Jiang Yu, Lei Shi, David H. Peng, B. Leticia Rodriguez, Jiaqi Zhang, Veronica Zheng, Dzifa Y. Duose, Luisa M. Solis, Barbara Mino, Maria Gabriela Raso, Carmen Behrens, Ignacio I. Wistuba, Kenneth L. Scott, Mark Smith, Khanh Nguyen, Grace Lam, Ingrid Choong, Abhijit Mazumdar, Jamal L. Hill, Don L. Gibbons, Powel H. Brown, William K. Russell, Kevan Shokat, Chad J. Creighton, Jeffrey S. Glenn, Jonathan M. Kurie

    Heightened secretion of protumorigenic effector proteins is a feature of malignant cells. Yet, the molecular underpinnings and therapeutic implications of this feature remain unclear. Here, we identify a chromosome 1q region that is frequently amplified in diverse cancer types and encodes multiple regulators of secretory vesicle biogenesis and trafficking, including the Golgi-dedicated enzyme phosphatidylinositol (PI)-4-kinase IIIβ (PI4KIIIβ). Molecular, biochemical, and cell biological studies show that PI4KIIIβ-derived PI-4-phosphate (PI4P) synthesis enhances secretion and accelerates lung adenocarcinoma progression by activating Golgi phosphoprotein 3 (GOLPH3)–dependent vesicular release from the Golgi. PI4KIIIβ-dependent secreted factors maintain 1q-amplified cancer cell survival and influence prometastatic processes in the tumor microenvironment. Disruption of this functional circuitry in 1q-amplified cancer cells with selective PI4KIIIβ antagonists induces apoptosis and suppresses tumor growth and metastasis. These results support a model in which chromosome 1q amplifications create a dependency on PI4KIIIβ-dependent secretion for cancer cell survival and tumor progression.

    更新日期:2020-01-23
  • Long-gap peripheral nerve repair through sustained release of a neurotrophic factor in nonhuman primates
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-22
    Neil B. Fadia, Jacqueline M. Bliley, Gabriella A. DiBernardo, Donald J. Crammond, Benjamin K. Schilling, Wesley N. Sivak, Alexander M. Spiess, Kia M. Washington, Matthias Waldner, Han-Tsung Liao, Isaac B. James, Danielle M. Minteer, Casey Tompkins-Rhoades, Adam R. Cottrill, Deok-Yeol Kim, Riccardo Schweizer, Debra A. Bourne, George E. Panagis, M. Asher Schusterman, Francesco M. Egro, Insiyah K. Campwala, Tyler Simpson, Douglas J. Weber, Trent Gause, Jack E. Brooker, Tvisha Josyula, Astrid A. Guevara, Alexander J. Repko, Christopher M. Mahoney, Kacey G. Marra

    Severe injuries to peripheral nerves are challenging to repair. Standard-of-care treatment for nerve gaps >2 to 3 centimeters is autografting; however, autografting can result in neuroma formation, loss of sensory function at the donor site, and increased operative time. To address the need for a synthetic nerve conduit to treat large nerve gaps, we investigated a biodegradable poly(caprolactone) (PCL) conduit with embedded double-walled polymeric microspheres encapsulating glial cell line–derived neurotrophic factor (GDNF) capable of providing a sustained release of GDNF for >50 days in a 5-centimeter nerve defect in a rhesus macaque model. The GDNF-eluting conduit (PCL/GDNF) was compared to a median nerve autograft and a PCL conduit containing empty microspheres (PCL/Empty). Functional testing demonstrated similar functional recovery between the PCL/GDNF-treated group (75.64 ± 10.28%) and the autograft-treated group (77.49 ± 19.28%); both groups were statistically improved compared to PCL/Empty-treated group (44.95 ± 26.94%). Nerve conduction velocity 1 year after surgery was increased in the PCL/GDNF-treated macaques (31.41 ± 15.34 meters/second) compared to autograft (25.45 ± 3.96 meters/second) and PCL/Empty (12.60 ± 3.89 meters/second) treatment. Histological analyses included assessment of Schwann cell presence, myelination of axons, nerve fiber density, and g-ratio. PCL/GDNF group exhibited a statistically greater average area occupied by individual Schwann cells at the distal nerve (11.60 ± 33.01 μm2) compared to autograft (4.62 ± 3.99 μm2) and PCL/Empty (4.52 ± 5.16 μm2) treatment groups. This study demonstrates the efficacious bridging of a long peripheral nerve gap in a nonhuman primate model using an acellular, biodegradable nerve conduit.

    更新日期:2020-01-23
  • Cerebellar oscillations driven by synaptic pruning deficits of cerebellar climbing fibers contribute to tremor pathophysiology
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-15
    Ming-Kai Pan, Yong-Shi Li, Shi-Bing Wong, Chun-Lun Ni, Yi-Mei Wang, Wen-Chuan Liu, Liang-Yin Lu, Jye-Chang Lee, Etty P. Cortes, Jean-Paul G. Vonsattel, Qian Sun, Elan D. Louis, Phyllis L. Faust, Sheng-Han Kuo

    Essential tremor (ET) is one of the most common movement disorders and the prototypical disorder for abnormal rhythmic movements. However, the pathophysiology of tremor generation in ET remains unclear. Here, we used autoptic cerebral tissue from patients with ET, clinical data, and mouse models to report that synaptic pruning deficits of climbing fiber (CF)–to–Purkinje cell (PC) synapses, which are related to glutamate receptor delta 2 (GluRδ2) protein insufficiency, cause excessive cerebellar oscillations and might be responsible for tremor. The CF-PC synaptic pruning deficits were correlated with the reduction in GluRδ2 expression in the postmortem ET cerebellum. Mice with GluRδ2 insufficiency and CF-PC synaptic pruning deficits develop ET-like tremor that can be suppressed with viral rescue of GluRδ2 protein. Step-by-step optogenetic or pharmacological inhibition of neuronal firing, axonal activity, or synaptic vesicle release confirmed that the activity of the excessive CF-to-PC synapses is required for tremor generation. In vivo electrophysiology in mice showed that excessive cerebellar oscillatory activity is CF dependent and necessary for tremor and optogenetic-driven PC synchronization was sufficient to generate tremor in wild-type animals. Human validation by cerebellar electroencephalography confirmed that excessive cerebellar oscillations also exist in patients with ET. Our findings identify a pathophysiologic contribution to tremor at molecular (GluRδ2), structural (CF-to-PC synapses), physiological (cerebellar oscillations), and behavioral levels (kinetic tremor) that might have clinical applications for treating ET.

    更新日期:2020-01-16
  • Weighing in on asthma
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-15
    Patrick M. Brunner

    Immune activation and microbiota alterations are accentuated in obese asthmatics.

    更新日期:2020-01-16
  • The “cancer flu shot”?
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-15
    Anand D. Jeyasekharan

    Direct injection of an influenza vaccine into tumors in mice increases immune infiltration and prolongs survival.

    更新日期:2020-01-16
  • Organoid optimization: Engineering a better cell therapy to treat type 1 diabetes
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-15
    Jessica D. Weaver

    Islet organoids reaggregated in endothelialized collagen constructs improve engraftment and function in the subcutaneous space in diabetic mice.

    更新日期:2020-01-16
  • Human umbilical cord perivascular cells improve human pancreatic islet transplant function by increasing vascularization
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-15
    Shareen Forbes, Andrew R. Bond, Kayleigh L. Thirlwell, Paul Burgoyne, Kay Samuel, June Noble, Gary Borthwick, David Colligan, Neil W. A. McGowan, Philip Starkey Lewis, Alasdair R. Fraser, Joanne C. Mountford, Roderick N. Carter, Nicholas M. Morton, Marc L. Turner, Gerard J. Graham, John D. M. Campbell

    Islet transplantation is an efficacious therapy for type 1 diabetes; however, islets from multiple donor pancreata are required, and a gradual attrition in transplant function is seen. Here, we manufactured human umbilical cord perivascular mesenchymal stromal cells (HUCPVCs) to Good Manufacturing Practice (GMP) standards. HUCPVCs showed a stable phenotype while undergoing rapid ex vivo expansion at passage 2 (p2) to passage 4 (p4) and produced proregenerative factors, strongly suppressing T cell responses in the resting state and in response to inflammation. Transplanting an islet equivalent (IEQ):HUCPVC ratio of 1:30 under the kidney capsule in diabetic NSG mice demonstrated the fastest return to normoglycemia by 3 days after transplant: Superior glycemic control was seen at both early (2.7 weeks) and later stages (7, 12, and 16 weeks) versus ratios of 1:0, 1:10, and 1:50, respectively. Syngeneic islet transplantation in immunocompetent mice using the clinically relevant hepatic portal route with a marginal islet mass showed that mice transplanted with an IEQ:HUCPVC ratio of 1:150 had superior glycemic control versus ratios of 1:0, 1:90, and 1:210 up to 6 weeks after transplant. Immunodeficient mice transplanted with human islets (IEQ:HUCPVC ratio of 1:150) exhibited better glycemic control for 7 weeks after transplant versus islet transplant alone, and islets transplanted via the hepatic portal vein in an allogeneic mouse model using a curative islet mass demonstrated delayed rejection of islets when cotransplanted with HUCPVCs (IEQ:HUCPVC ratio of 1:150). The immunosuppressive and proregenerative properties of HUCPVCs demonstrated long-term positive effects on graft function in vivo, indicating that they may improve long-term human islet allotransplantation outcomes.

    更新日期:2020-01-16
  • Engraftment of rare, pathogenic donor hematopoietic mutations in unrelated hematopoietic stem cell transplantation
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-15
    Wing Hing Wong, Sima Bhatt, Kathryn Trinkaus, Iskra Pusic, Kevin Elliott, Nitin Mahajan, Fei Wan, Galen E. Switzer, Dennis L. Confer, John DiPersio, Michael A. Pulsipher, Nirali N. Shah, Jennifer Sees, Amelia Bystry, Jamie R. Blundell, Bronwen E. Shaw, Todd E. Druley

    Clonal hematopoiesis is associated with various age-related morbidities. Error-corrected sequencing (ECS) of human blood samples, with a limit of detection of ≥0.0001, has demonstrated that nearly every healthy individual >50 years old harbors rare hematopoietic clones below the detection limit of standard high-throughput sequencing. If these rare mutations confer survival or proliferation advantages, then the clone(s) could expand after a selective pressure such as chemotherapy, radiotherapy, or chronic immunosuppression. Given these observations and the lack of quantitative data regarding clonal hematopoiesis in adolescents and young adults, who are more likely to serve as unrelated hematopoietic stem cell donors, we completed this pilot study to determine whether younger adults harbored hematopoietic clones with pathogenic mutations, how often those clones were transferred to recipients, and what happened to these clones over time after transplantation. We performed ECS on 125 blood and marrow samples from 25 matched unrelated donors and recipients. Clonal mutations, with a median variant allele frequency of 0.00247, were found in 11 donors (44%; median, 36 years old). Of the mutated clones, 84.2% of mutations were predicted to be molecularly pathogenic and 100% engrafted in recipients. Recipients also demonstrated de novo clonal expansion within the first 100 days after hematopoietic stem cell transplant (HSCT). Given this pilot demonstration that rare, pathogenic clonal mutations are far more prevalent in younger adults than previously appreciated, and they engraft in recipients and persist over time, larger studies with longer follow-up are necessary to correlate clonal engraftment with post-HSCT morbidity.

    更新日期:2020-01-16
  • β-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-15
    Fang Zhang, Mary Gannon, Yunjia Chen, Shun Yan, Sixue Zhang, Wendy Feng, Jiahui Tao, Bingdong Sha, Zhenghui Liu, Takashi Saito, Takaomi Saido, C. Dirk Keene, Kai Jiao, Erik D. Roberson, Huaxi Xu, Qin Wang

    The brain noradrenergic system is critical for normal cognition and is affected at early stages in Alzheimer’s disease (AD). Here, we reveal a previously unappreciated direct role of norepinephrine signaling in connecting β-amyloid (Aβ) and tau, two key pathological components of AD pathogenesis. Our results show that Aβ oligomers bind to an allosteric site on α2A adrenergic receptor (α2AAR) to redirect norepinephrine-elicited signaling to glycogen synthase kinase 3β (GSK3β) activation and tau hyperphosphorylation. This norepinephrine-dependent mechanism sensitizes pathological GSK3β/tau activation in response to nanomolar accumulations of extracellular Aβ, which is 50- to 100-fold lower than the amount required to activate GSK3β by Aβ alone. The significance of our findings is supported by in vivo evidence in two mouse models, human tissue sample analysis, and longitudinal clinical data. Our study provides translational insights into mechanisms underlying Aβ proteotoxicity, which might have strong implications for the interpretation of Aβ clearance trial results and future drug design and for understanding the selective vulnerability of noradrenergic neurons in AD.

    更新日期:2020-01-16
  • Intratumoral expression of IL-7 and IL-12 using an oncolytic virus increases systemic sensitivity to immune checkpoint blockade
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-15
    Shinsuke Nakao, Yukinori Arai, Mamoru Tasaki, Midori Yamashita, Ryuji Murakami, Tatsuya Kawase, Nobuaki Amino, Motomu Nakatake, Hajime Kurosaki, Masamichi Mori, Masahiro Takeuchi, Takafumi Nakamura

    The immune status of the tumor microenvironment is a key indicator in determining the antitumor effectiveness of immunotherapies. Data support the role of activation and expansion of tumor-infiltrating lymphocytes (TILs) in increasing the benefit of immunotherapies in patients with solid tumors. We found that intratumoral injection of a tumor-selective oncolytic vaccinia virus encoding interleukin-7 (IL-7) and IL-12 into tumor-bearing immunocompetent mice activated the inflammatory immune status of previously poorly immunogenic tumors and resulted in complete tumor regression, even in distant tumor deposits. Mice achieving complete tumor regression resisted rechallenge with the same tumor cells, suggesting establishment of long-term tumor-specific immune memory. Combining this virotherapy with anti–programmed cell death-1 (PD-1) or anti–cytotoxic T lymphocyte antigen 4 (CTLA4) antibody further increased the antitumor activity as compared to virotherapy alone, in tumor models unresponsive to either of the checkpoint inhibitor monotherapies. These findings suggest that administration of an oncolytic vaccinia virus carrying genes encoding for IL-7 and IL-12 has antitumor activity in both directly injected and distant noninjected tumors through immune status changes rendering tumors sensitive to immune checkpoint blockade. The benefit of intratumoral IL-7 and IL-12 expression was also observed in humanized mice bearing human cancer cells. These data support further investigation in patients with non-inflamed solid tumors.

    更新日期:2020-01-16
  • Stromal cell protein kinase C-β inhibition enhances chemosensitivity in B cell malignancies and overcomes drug resistance
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-15
    Eugene Park, Jingyu Chen, Andrew Moore, Maurizio Mangolini, Antonella Santoro, Joseph R. Boyd, Hilde Schjerven, Veronika Ecker, Maike Buchner, James C. Williamson, Paul J. Lehner, Luca Gasparoli, Owen Williams, Johannes Bloehdorn, Stephan Stilgenbauer, Michael Leitges, Alexander Egle, Marc Schmidt-Supprian, Seth Frietze, Ingo Ringshausen

    Overcoming drug resistance remains a key challenge to cure patients with acute and chronic B cell malignancies. Here, we describe a stromal cell–autonomous signaling pathway, which contributes to drug resistance of malignant B cells. We show that protein kinase C (PKC)–β–dependent signals from bone marrow–derived stromal cells markedly decrease the efficacy of cytotoxic therapies. Conversely, small-molecule PKC-β inhibitors antagonize prosurvival signals from stromal cells and sensitize tumor cells to targeted and nontargeted chemotherapy, resulting in enhanced cytotoxicity and prolonged survival in vivo. Mechanistically, stromal PKC-β controls the expression of adhesion and matrix proteins, required for activation of phosphoinositide 3-kinases (PI3Ks) and the extracellular signal–regulated kinase (ERK)–mediated stabilization of B cell lymphoma–extra large (BCL-XL) in tumor cells. Central to the stroma-mediated drug resistance is the PKC-β–dependent activation of transcription factor EB, regulating lysosome biogenesis and plasma membrane integrity. Stroma-directed therapies, enabled by direct inhibition of PKC-β, enhance the effectiveness of many antileukemic therapies.

    更新日期:2020-01-16
  • Bystanders get in the game
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-08
    Heather D. Hickman

    Tissue-resident memory T cells respond in a nonspecific manner to reduce bacteria in the lungs of mice.

    更新日期:2020-01-09
  • Microglial sex affects Alzheimer’s disease
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-08
    Josh Neman

    Sex-specific microglial microRNAs impact tau pathogenesis.

    更新日期:2020-01-09
  • A potential gut punch to gastric cancer
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-08
    Vikramaditya G. Yadav

    Combination chemotherapies that also inhibit the proline isomerase Pin1 may overcome the notorious drug resistance of gastric cancer.

    更新日期:2020-01-09
  • GDNF rescues the fate of neural progenitor grafts by attenuating Notch signals in the injured spinal cord in rodents
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-08
    Mohamad Khazaei, Christopher S. Ahuja, Hiroaki Nakashima, Narihito Nagoshi, Lijun Li, Jian Wang, Jonathon Chio, Anna Badner, David Seligman, Ayaka Ichise, Shinsuke Shibata, Michael G. Fehlings

    Neural progenitor cell (NPC) transplantation is a promising strategy for the treatment of spinal cord injury (SCI). In this study, we show that injury-induced Notch activation in the spinal cord microenvironment biases the fate of transplanted NPCs toward astrocytes in rodents. In a screen for potential clinically relevant factors to modulate Notch signaling, we identified glial cell–derived neurotrophic factor (GDNF). GDNF attenuates Notch signaling by mediating delta-like 1 homolog (DLK1) expression, which is independent of GDNF’s effect on cell survival. When transplanted into a rodent model of cervical SCI, GDNF-expressing human-induced pluripotent stem cell–derived NPCs (hiPSC-NPCs) demonstrated higher differentiation toward a neuronal fate compared to control cells. In addition, expression of GDNF promoted endogenous tissue sparing and enhanced electrical integration of transplanted cells, which collectively resulted in improved neurobehavioral recovery. CRISPR-induced knockouts of the DLK1 gene in GDNF-expressing hiPSC-NPCs attenuated the effect on functional recovery, demonstrating that this effect is partially mediated through DLK1 expression. These results represent a mechanistically driven optimization of hiPSC-NPC therapy to redirect transplanted cells toward a neuronal fate and enhance their integration.

    更新日期:2020-01-09
  • Thrombin contributes to cancer immune evasion via proteolysis of platelet-bound GARP to activate LTGF-β
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-08
    Alessandra Metelli, Bill X. Wu, Brian Riesenberg, Silvia Guglietta, John D. Huck, Catherine Mills, Anqi Li, Saleh Rachidi, Carsten Krieg, Mark P. Rubinstein, Daniel T. Gewirth, Shaoli Sun, Michael B. Lilly, Amy H. Wahlquist, David P. Carbone, Yiping Yang, Bei Liu, Zihai Li

    Cancer-associated thrombocytosis and high concentrations of circulating transforming growth factor–β1 (TGF-β1) are frequently observed in patients with progressive cancers. Using genetic and pharmacological approaches, we show a direct link between thrombin catalytic activity and release of mature TGF-β1 from platelets. We found that thrombin cleaves glycoprotein A repetitions predominant (GARP), a cell surface docking receptor for latent TGF-β1 (LTGF-β1) on platelets, resulting in liberation of active TGF-β1 from the GARP–LTGF-β1 complex. Furthermore, systemic inhibition of thrombin obliterates TGF-β1 maturation in platelet releasate and rewires the tumor microenvironment toward favorable antitumor immunity, which translates into efficient cancer control either alone or in combination with programmed cell death 1–based immune checkpoint blockade therapy. Last, we demonstrate that soluble GARP and GARP–LTGF-β1 complex are present in the circulation of patients with cancer. Together, our data reveal a mechanism of cancer immune evasion that involves thrombin-mediated GARP cleavage and the subsequent TGF-β1 release from platelets. We propose that blockade of GARP cleavage is a valuable therapeutic strategy to overcome cancer’s resistance to immunotherapy.

    更新日期:2020-01-09
  • Pancreatitis is an FGF21-deficient state that is corrected by replacement therapy
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-08
    Genaro Hernandez, Ting Luo, Tanveer A. Javed, Li Wen, Michael A. Kalwat, Kevin Vale, Farah Ammouri, Sohail Z. Husain, Steven A. Kliewer, David J. Mangelsdorf

    The exocrine pancreas expresses the highest concentrations of fibroblast growth factor 21 (FGF21) in the body, where it maintains acinar cell proteostasis. Here, we showed in both mice and humans that acute and chronic pancreatitis is associated with a loss of FGF21 expression due to activation of the integrated stress response (ISR) pathway. Mechanistically, we found that activation of the ISR in cultured acinar cells and mouse pancreata induced the expression of ATF3, a transcriptional repressor that directly bound to specific sites on the Fgf21 promoter and resulted in loss of FGF21 expression. These ATF3 binding sites are conserved in the human FGF21 promoter. Consistent with the mouse studies, we also observed the reciprocal expression of ATF3 and FGF21 in the pancreata of human patients with pancreatitis. Using three different mouse models of pancreatitis, we showed that pharmacologic replacement of FGF21 mitigated the ISR and resolved pancreatitis. Likewise, inhibition of the ISR with an inhibitor of the PKR-like endoplasmic reticulum kinase (PERK) also restored FGF21 expression and alleviated pancreatitis. These findings highlight the importance of FGF21 in preserving exocrine pancreas function and suggest its therapeutic use for prevention and treatment of pancreatitis.

    更新日期:2020-01-09
  • Nucleoside-modified mRNA vaccination partially overcomes maternal antibody inhibition of de novo immune responses in mice
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-08
    Elinor Willis, Norbert Pardi, Kaela Parkhouse, Barbara L. Mui, Ying K. Tam, Drew Weissman, Scott E. Hensley

    Maternal antibodies provide short-term protection to infants against many infections. However, they can inhibit de novo antibody responses in infants elicited by infections or vaccination, leading to increased long-term susceptibility to infectious diseases. Thus, there is a need to develop vaccines that are able to elicit protective immune responses in the presence of antigen-specific maternal antibodies. Here, we used a mouse model to demonstrate that influenza virus–specific maternal antibodies inhibited de novo antibody responses in mouse pups elicited by influenza virus infection or administration of conventional influenza vaccines. We found that a recently developed influenza vaccine, nucleoside-modified mRNA encapsulated in lipid nanoparticles (mRNA-LNP), partially overcame this inhibition by maternal antibodies. The mRNA-LNP influenza vaccine established long-lived germinal centers in the mouse pups and elicited stronger antibody responses than did a conventional influenza vaccine approved for use in humans. Vaccination with mRNA-LNP vaccines may offer a promising strategy for generating robust immune responses in infants in the presence of maternal antibodies.

    更新日期:2020-01-09
  • HDAC inhibition improves cardiopulmonary function in a feline model of diastolic dysfunction
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-08
    Markus Wallner, Deborah M. Eaton, Remus M. Berretta, Laura Liesinger, Matthias Schittmayer, Juergen Gindlhuber, Jichuan Wu, Mark Y. Jeong, Ying H. Lin, Giulia Borghetti, Sandy T. Baker, Huaqing Zhao, Jessica Pfleger, Sandra Blass, Peter P. Rainer, Dirk von Lewinski, Heiko Bugger, Sadia Mohsin, Wolfgang F. Graier, Andreas Zirlik, Timothy A. McKinsey, Ruth Birner-Gruenberger, Marla R. Wolfson, Steven R. Houser

    Heart failure with preserved ejection fraction (HFpEF) is a major health problem without effective therapies. This study assessed the effects of histone deacetylase (HDAC) inhibition on cardiopulmonary structure, function, and metabolism in a large mammalian model of pressure overload recapitulating features of diastolic dysfunction common to human HFpEF. Male domestic short-hair felines (n = 31, aged 2 months) underwent a sham procedure (n = 10) or loose aortic banding (n = 21), resulting in slow-progressive pressure overload. Two months after banding, animals were treated daily with suberoylanilide hydroxamic acid (b + SAHA, 10 mg/kg, n = 8), a Food and Drug Administration–approved pan-HDAC inhibitor, or vehicle (b + veh, n = 8) for 2 months. Echocardiography at 4 months after banding revealed that b + SAHA animals had significantly reduced left ventricular hypertrophy (LVH) (P < 0.0001) and left atrium size (P < 0.0001) versus b + veh animals. Left ventricular (LV) end-diastolic pressure and mean pulmonary arterial pressure were significantly reduced in b + SAHA (P < 0.01) versus b + veh. SAHA increased myofibril relaxation ex vivo, which correlated with in vivo improvements of LV relaxation. Furthermore, SAHA treatment preserved lung structure, compliance, blood oxygenation, and reduced perivascular fluid cuffs around extra-alveolar vessels, suggesting attenuated alveolar capillary stress failure. Acetylation proteomics revealed that SAHA altered lysine acetylation of mitochondrial metabolic enzymes. These results suggest that acetylation defects in hypertrophic stress can be reversed by HDAC inhibitors, with implications for improving cardiac structure and function in patients.

    更新日期:2020-01-09
  • A class of costimulatory CD28-bispecific antibodies that enhance the antitumor activity of CD3-bispecific antibodies
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-08
    Dimitris Skokos, Janelle C. Waite, Lauric Haber, Alison Crawford, Aynur Hermann, Erica Ullman, Rabih Slim, Stephen Godin, Dharani Ajithdoss, Xuan Ye, Bei Wang, Qi Wu, Ilyssa Ramos, Arpita Pawashe, Lauren Canova, Kristin Vazzana, Priyanka Ram, Evan Herlihy, Hassan Ahmed, Erin Oswald, Jacquelynn Golubov, Patrick Poon, Lauren Havel, Danica Chiu, Miguel Lazo, Kathleen Provoncha, Kevin Yu, Julie Kim, Jacqueline J. Warsaw, Nicole Stokes Oristian, Chia-Jen Siao, Drew Dudgeon, Tammy Huang, Terra Potocky, Joel Martin, Douglas MacDonald, Adelekan Oyejide, Ashique Rafique, William Poueymirou, Jessica R. Kirshner, Eric Smith, William Olson, John Lin, Gavin Thurston, Matthew A. Sleeman, Andrew J. Murphy, George D. Yancopoulos

    T cell activation is initiated upon binding of the T cell receptor (TCR)/CD3 complex to peptide–major histocompatibility complexes (“signal 1”); activation is enhanced by engagement of a second “costimulatory” receptor, such as the CD28 receptor on T cells binding to its cognate ligand(s) on the target cell (“signal 2”). CD3-based bispecific antibodies act by replacing conventional signal 1, linking T cells to tumor cells by binding a tumor-specific antigen (TSA) with one arm of the bispecific and bridging to TCR/CD3 with the other. Although some of these so-called TSAxCD3 bispecifics have demonstrated promising antitumor efficacy in patients with cancer, their activity remains to be optimized. Here, we introduce a class of bispecific antibodies that mimic signal 2 by bridging TSA to the costimulatory CD28 receptor on T cells. We term these TSAxCD28 bispecifics and describe two such bispecific antibodies: one specific for ovarian and the other for prostate cancer antigens. Unlike CD28 superagonists, which broadly activate T cells and resulted in profound toxicity in early clinical trials, these TSAxCD28 bispecifics show limited activity and no toxicity when used alone in genetically humanized immunocompetent mouse models or in primates. However, when combined with TSAxCD3 bispecifics, they enhance the artificial synapse between a T cell and its target cell, potentiate T cell activation, and markedly improve antitumor activity of CD3 bispecifics in a variety of xenogeneic and syngeneic tumor models. Combining this class of CD28-costimulatory bispecific antibodies with the emerging class of TSAxCD3 bispecifics may provide well-tolerated, off-the-shelf antibody therapies with robust antitumor efficacy.

    更新日期:2020-01-09
  • Platelet-derived growth factor-AB improves scar mechanics and vascularity after myocardial infarction
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-01
    Sujitha Thavapalachandran, Stuart M. Grieve, Robert D. Hume, Thi Yen Loan Le, Kalyan Raguram, James E. Hudson, Jim Pouliopoulos, Gemma A. Figtree, Rafael P. Dye, Anthony M. Barry, Paula Brown, Juntang Lu, Sean Coffey, Scott H. Kesteven, Richard J. Mills, Fairooj N. Rashid, Elena Taran, Pramesh Kovoor, Liza Thomas, Alan Robert Denniss, Eddy Kizana, Naisana S. Asli, Munira Xaymardan, Michael P. Feneley, Robert M. Graham, Richard P. Harvey, James J. H. Chong

    Therapies that target scar formation after myocardial infarction (MI) could prevent ensuing heart failure or death from ventricular arrhythmias. We have previously shown that recombinant human platelet-derived growth factor-AB (rhPDGF-AB) improves cardiac function in a rodent model of MI. To progress clinical translation, we evaluated rhPDGF-AB treatment in a clinically relevant porcine model of myocardial ischemia-reperfusion. Thirty-six pigs were randomized to sham procedure or balloon occlusion of the proximal left anterior descending coronary artery with 7-day intravenous infusion of rhPDGF-AB or vehicle. One month after MI, rhPDGF-AB improved survival by 40% compared with vehicle, and cardiac magnetic resonance imaging showed left ventricular (LV) ejection fraction improved by 11.5%, driven by reduced LV end-systolic volumes. Pressure volume loop analyses revealed improved myocardial contractility and energetics after rhPDGF-AB treatment with minimal effect on ventricular compliance. rhPDGF-AB enhanced angiogenesis and increased scar anisotropy (high fiber alignment) without affecting overall scar size or stiffness. rhPDGF-AB reduced inducible ventricular tachycardia by decreasing heterogeneity of the ventricular scar that provides a substrate for reentrant circuits. In summary, we demonstrated that rhPDGF-AB promotes post-MI cardiac wound repair by altering the mechanics of the infarct scar, resulting in robust cardiac functional improvement, decreased ventricular arrhythmias, and improved survival. Our findings suggest a strong translational potential for rhPDGF-AB as an adjunct to current MI treatment and possibly to modulate scar in other organs.

    更新日期:2020-01-02
  • Drilling down in the fight against bacterial superbugs
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-01
    Megan L. McCain

    Light-activated molecular nanomachines can resensitize antibiotic-resistant bacteria to antibiotics by drilling holes in their cell wall.

    更新日期:2020-01-02
  • Seizing control of fragile X Syndrome
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-01
    Emily K. Osterweil

    Loss of Fmr1 in glutamatergic neurons of the inferior colliculus is responsible for audiogenic seizures in the fragile X syndrome mouse model.

    更新日期:2020-01-02
  • Doubling down on tumor suppressor deletion
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-01
    Adam G. Sowalsky

    Codeletion of BRCA2 and RB1 increases prostate cancer sensitivity to PARP inhibitor therapy.

    更新日期:2020-01-02
  • Helminth infections drive heterogeneity in human type 2 and regulatory cells
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-01
    Karin de Ruiter, Simon P. Jochems, Dicky L. Tahapary, Koen A. Stam, Marion König, Vincent van Unen, Sandra Laban, Thomas Höllt, Moustapha Mbow, Boudewijn P. F. Lelieveldt, Frits Koning, Erliyani Sartono, Johannes W. A. Smit, Taniawati Supali, Maria Yazdanbakhsh

    Helminth infections induce strong type 2 and regulatory responses, but the degree of heterogeneity of such cells is not well characterized. Using mass cytometry, we profiled these cells in Europeans and Indonesians not exposed to helminths and in Indonesians residing in rural areas infected with soil-transmitted helminths. To assign immune alteration to helminth infection, the profiling was performed before and 1 year after deworming. Very distinct signatures were found in Europeans and Indonesians, showing expanded frequencies of T helper 2 cells, particularly CD161+ cells and ILC2s in helminth-infected Indonesians, which was confirmed functionally through analysis of cytokine-producing cells. Besides ILC2s and CD4+ T cells, CD8+ T cells and γδ T cells in Indonesians produced type 2 cytokines. Regulatory T cells were also expanded in Indonesians, but only those expressing CTLA-4, and some coexpressed CD38, HLA-DR, ICOS, or CD161. CD11c+ B cells were found to be the main IL-10 producers among B cells in Indonesians, a subset that was almost absent in Europeans. A number of the distinct immune profiles were driven by helminths as the profiles reverted after clearance of helminth infections. Moreover, Indonesians with no helminth infections residing in an urban area showed immune profiles that resembled Europeans rather than rural Indonesians, which excludes a major role for ethnicity. Detailed insight into the human type 2 and regulatory networks could provide opportunities to target these cells for more precise interventions.

    更新日期:2020-01-02
  • Prospective longitudinal atrophy in Alzheimer’s disease correlates with the intensity and topography of baseline tau-PET
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-01
    Renaud La Joie, Adrienne V. Visani, Suzanne L. Baker, Jesse A. Brown, Viktoriya Bourakova, Jungho Cha, Kiran Chaudhary, Lauren Edwards, Leonardo Iaccarino, Mustafa Janabi, Orit H. Lesman-Segev, Zachary A. Miller, David C. Perry, James P. O’Neil, Julie Pham, Julio C. Rojas, Howard J. Rosen, William W. Seeley, Richard M. Tsai, Bruce L. Miller, William J. Jagust, Gil D. Rabinovici

    β-Amyloid plaques and tau-containing neurofibrillary tangles are the two neuropathological hallmarks of Alzheimer’s disease (AD) and are thought to play crucial roles in a neurodegenerative cascade leading to dementia. Both lesions can now be visualized in vivo using positron emission tomography (PET) radiotracers, opening new opportunities to study disease mechanisms and improve patients’ diagnostic and prognostic evaluation. In a group of 32 patients at early symptomatic AD stages, we tested whether β-amyloid and tau-PET could predict subsequent brain atrophy measured using longitudinal magnetic resonance imaging acquired at the time of PET and 15 months later. Quantitative analyses showed that the global intensity of tau-PET, but not β-amyloid–PET, signal predicted the rate of subsequent atrophy, independent of baseline cortical thickness. Additional investigations demonstrated that the specific distribution of tau-PET signal was a strong indicator of the topography of future atrophy at the single patient level and that the relationship between baseline tau-PET and subsequent atrophy was particularly strong in younger patients. These data support disease models in which tau pathology is a major driver of local neurodegeneration and highlight the relevance of tau-PET as a precision medicine tool to help predict individual patient’s progression and design future clinical trials.

    更新日期:2020-01-02
  • A dual-action peptide-containing hydrogel targets wound infection and inflammation
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-01
    Manoj Puthia, Marta Butrym, Jitka Petrlova, Ann-Charlotte Strömdahl, Madelene Å. Andersson, Sven Kjellström, Artur Schmidtchen

    There is a clinical need for improved wound treatments that prevent both infection and excessive inflammation. TCP-25, a thrombin-derived peptide, is antibacterial and scavenges pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide, thereby preventing CD14 interaction and Toll-like receptor dimerization, leading to reduced downstream immune activation. Here, we describe the development of a hydrogel formulation that was functionalized with TCP-25 to target bacteria and associated PAMP-induced inflammation. In vitro studies determined the polymer prerequisites for such TCP-25–mediated dual action, favoring the use of noncharged hydrophilic hydrogels, which enabled peptide conformational changes and LPS binding. The TCP-25–functionalized hydrogels killed Gram-positive Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa bacteria in vitro, as well as in experimental mouse models of subcutaneous infection. The TCP-25 hydrogel also mediated reduction of LPS-induced local inflammatory responses, as demonstrated by analysis of local cytokine production and in vivo bioimaging using nuclear factor κB (NF-κB) reporter mice. In porcine partial thickness wound models, TCP-25 prevented infection with S. aureus and reduced concentrations of proinflammatory cytokines. Proteolytic fragmentation of TCP-25 in vitro yielded a series of bioactive TCP fragments that were identical or similar to those present in wounds in vivo. Together, the results demonstrate the therapeutic potential of TCP-25 hydrogel, a wound treatment based on the body’s peptide defense, for prevention of both bacterial infection and the accompanying inflammation.

    更新日期:2020-01-02
  • Physiological consequences of transient hyperleptinemia during discrete developmental periods on body weight in mice
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-01
    Alicja A. Skowronski, Charles A. LeDuc, Kylie S. Foo, Yossef Goffer, Lisa C. Burnett, Dieter Egli, Rudolph L. Leibel

    Leptin plays a role in central nervous system developmental programs and intercurrent physiological processes related to body fat regulation. The timing and neuromolecular mechanisms for these effects are relevant to the prevention and treatment of obesity. Factors implicated in a body weight “set point” including dietary fat, circulating leptin, and other adipokines tend to covary with adiposity and are difficult to disarticulate experimentally. To dissociate leptin effects from adiposity and diet, we created a transgenic mouse in which leptin expression is regulated by doxycycline exposure. Using this system, we investigated the physiological consequences of developmentally-timed transient hyperleptinemia on subsequent adiposity. We evaluated physiological effects of leptin elevation during adulthood (9 to 29 weeks old), “adolescence” (3 to 8 weeks old), and the immediate postnatal period [postnatal days 0 to 22 (P0 to P22)] on long-term adiposity and susceptibility to gain weight on high-fat diet (HFD) fed ad libitum. We found that inducing chronic hyperleptinemia in adult or “adolescent” mice did not alter body weight when excess leptin was discontinued, and upon later exposure to HFD, weight gain did not differ from controls. However, transient elevation of circulating leptin from P0 to P22 increased weight and fat gain in response to HFD, indicating greater susceptibility to obesity as adults. Thus, transient plasma leptin elevations—mimicking one aspect of transient adiposity—increased later susceptibility to diet-induced obesity, although these effects were restricted to a critical developmental (P0 to P22) time window. These findings may have clinical implications for weight management in infancy.

    更新日期:2020-01-02
  • Circulating tumor DNA methylation profiles enable early diagnosis, prognosis prediction, and screening for colorectal cancer
    Sci. Transl. Med. (IF 17.161) Pub Date : 2020-01-01
    Huiyan Luo, Qi Zhao, Wei Wei, Lianghong Zheng, Shaohua Yi, Gen Li, Wenqiu Wang, Hui Sheng, Hengying Pu, Haiyu Mo, Zhixiang Zuo, Zexian Liu, Chaofeng Li, Chuanbo Xie, Zhaolei Zeng, Weimin Li, Xiaoke Hao, Yuying Liu, Sumei Cao, Wanli Liu, Sarah Gibson, Kang Zhang, Guoliang Xu, Rui-hua Xu

    Circulating tumor DNA (ctDNA) has emerged as a useful diagnostic and prognostic biomarker in many cancers. Here, we conducted a study to investigate the potential use of ctDNA methylation markers for the diagnosis and prognostication of colorectal cancer (CRC) and used a prospective cohort to validate their effectiveness in screening patients at high risk of CRC. We first identified CRC-specific methylation signatures by comparing CRC tissues to normal blood leukocytes. Then, we applied a machine learning algorithm to develop a predictive diagnostic and a prognostic model using cell-free DNA (cfDNA) samples from a cohort of 801 patients with CRC and 1021 normal controls. The obtained diagnostic prediction model discriminated patients with CRC from normal controls with high accuracy (area under curve = 0.96). The prognostic prediction model also effectively predicted the prognosis and survival of patients with CRC (P < 0.001). In addition, we generated a ctDNA-based molecular classification of CRC using an unsupervised clustering method and obtained two subgroups of patients with CRC with significantly different overall survival (P = 0.011 in validation cohort). Last, we found that a single ctDNA methylation marker, cg10673833, could yield high sensitivity (89.7%) and specificity (86.8%) for detection of CRC and precancerous lesions in a high-risk population of 1493 participants in a prospective cohort study. Together, our findings showed the value of ctDNA methylation markers in the diagnosis, surveillance, and prognosis of CRC.

    更新日期:2020-01-02
  • Synthetic mRNA nanoparticle-mediated restoration of p53 tumor suppressor sensitizes p53-deficient cancers to mTOR inhibition
    Sci. Transl. Med. (IF 17.161) Pub Date : 2019-12-18
    Na Kong, Wei Tao, Xiang Ling, Junqing Wang, Yuling Xiao, Sanjun Shi, Xiaoyuan Ji, Aram Shajii, Silvia Tian Gan, Na Yoon Kim, Dan G. Duda, Tian Xie, Omid C. Farokhzad, Jinjun Shi

    Loss of function in tumor suppressor genes is commonly associated with the onset/progression of cancer and treatment resistance. The p53 tumor suppressor gene, a master regulator of diverse cellular pathways, is frequently altered in various cancers, for example, in ~36% of hepatocellular carcinomas (HCCs) and ~68% of non–small cell lung cancers (NSCLCs). Current methods for restoration of p53 expression, including small molecules and DNA therapies, have yielded progressive success, but each has formidable drawbacks. Here, a redox-responsive nanoparticle (NP) platform is engineered for effective delivery of p53-encoding synthetic messenger RNA (mRNA). We demonstrate that the synthetic p53-mRNA NPs markedly delay the growth of p53-null HCC and NSCLC cells by inducing cell cycle arrest and apoptosis. We also reveal that p53 restoration markedly improves the sensitivity of these tumor cells to everolimus, a mammalian target of rapamycin (mTOR) inhibitor that failed to show clinical benefits in advanced HCC and NSCLC. Moreover, cotargeting of tumor-suppressing p53 and tumorigenic mTOR signaling pathways results in marked antitumor effects in vitro and in multiple animal models of HCC and NSCLC. Our findings indicate that restoration of tumor suppressors by the synthetic mRNA NP delivery strategy could be combined together with other therapies for potent combinatorial cancer treatment.

    更新日期:2019-12-19
  • Advances in clinical MRI technology
    Sci. Transl. Med. (IF 17.161) Pub Date : 2019-12-18
    Mukesh G. Harisinghani, Aileen O’Shea, Ralph Weissleder

    Advances in MRI technologies have the potential to detect, characterize, and monitor a wide variety of diseases.

    更新日期:2019-12-19
  • DNA vaccination before conception protects Zika virus–exposed pregnant macaques against prolonged viremia and improves fetal outcomes
    Sci. Transl. Med. (IF 17.161) Pub Date : 2019-12-18
    Koen K. A. Van Rompay, Rebekah I. Keesler, Amir Ardeshir, Jennifer Watanabe, Jodie Usachenko, Anil Singapuri, Christina Cruzen, Eliza Bliss-Moreau, Ashley M. Murphy, JoAnn L. Yee, Helen Webster, Maria Dennis, Tulika Singh, Holly Heimsath, Danilo Lemos, Jackson Stuart, Kaitlyn M. Morabito, Bryant M. Foreman, Katherine E. Burgomaster, Amy T. Noe, Kimberly A. Dowd, Erin Ball, Kevin Woolard, Pietro Presicce, Suhas G. Kallapur, Sallie R. Permar, Kathryn E. Foulds, Lark L. Coffey, Theodore C. Pierson, Barney S. Graham

    Zika virus (ZIKV) infection of pregnant women is associated with congenital Zika syndrome (CZS) and no vaccine is available, although several are being tested in clinical trials. We tested the efficacy of ZIKV DNA vaccine VRC5283 in a rhesus macaque model of congenital ZIKV infection. Most animal vaccine experiments have a set pathogen exposure several weeks or months after vaccination. In the real world, people encounter pathogens years or decades after vaccination, or may be repeatedly exposed if the virus is endemic. To more accurately mimic how this vaccine would be used, we immunized macaques before conception and then exposed them repeatedly to ZIKV during early and mid-gestation. In comparison to unimmunized animals, vaccinated animals had a significant reduction in peak magnitude and duration of maternal viremia, early fetal loss, fetal infection, and placental and fetal brain pathology. Vaccine-induced neutralizing antibody titers on the day of first ZIKV exposure were negatively associated with the magnitude of maternal viremia, and the absence of prolonged viremia was associated with better fetal outcomes. These data support further clinical development of ZIKV vaccine strategies to protect against negative fetal outcomes.

    更新日期:2019-12-19
  • Elite control of HIV is associated with distinct functional and transcriptional signatures in lymphoid tissue CD8+ T cells
    Sci. Transl. Med. (IF 17.161) Pub Date : 2019-12-18
    Son Nguyen, Claire Deleage, Samuel Darko, Amy Ransier, Duc P. Truong, Divyansh Agarwal, Alberto Sada Japp, Vincent H. Wu, Leticia Kuri-Cervantes, Mohamed Abdel-Mohsen, Perla M. Del Rio Estrada, Yuria Ablanedo-Terrazas, Emma Gostick, James A. Hoxie, Nancy R. Zhang, Ali Naji, Gustavo Reyes-Terán, Jacob D. Estes, David A. Price, Daniel C. Douek, Steven G. Deeks, Marcus Buggert, Michael R. Betts

    The functional properties of circulating CD8+ T cells have been associated with immune control of HIV. However, viral replication occurs predominantly in secondary lymphoid tissues, such as lymph nodes (LNs). We used an integrated single-cell approach to characterize effective HIV-specific CD8+ T cell responses in the LNs of elite controllers (ECs), defined as individuals who suppress viral replication in the absence of antiretroviral therapy (ART). Higher frequencies of total memory and follicle-homing HIV-specific CD8+ T cells were detected in the LNs of ECs compared with the LNs of chronic progressors (CPs) who were not receiving ART. Moreover, HIV-specific CD8+ T cells potently suppressed viral replication without demonstrable cytolytic activity in the LNs of ECs, which harbored substantially lower amounts of CD4+ T cell–associated HIV DNA and RNA compared with the LNs of CPs. Single-cell RNA sequencing analyses further revealed a distinct transcriptional signature among HIV-specific CD8+ T cells from the LNs of ECs, typified by the down-regulation of inhibitory receptors and cytolytic molecules and the up-regulation of multiple cytokines, predicted secreted factors, and components of the protein translation machinery. Collectively, these results provide a mechanistic framework to expedite the identification of novel antiviral factors, highlighting a potential role for the localized deployment of noncytolytic functions as a determinant of immune efficacy against HIV.

    更新日期:2019-12-19
  • Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology
    Sci. Transl. Med. (IF 17.161) Pub Date : 2019-12-18
    Irit Reichenstein, Chen Eitan, Sandra Diaz-Garcia, Guy Haim, Iddo Magen, Aviad Siany, Mariah L. Hoye, Natali Rivkin, Tsviya Olender, Beata Toth, Revital Ravid, Amitai D. Mandelbaum, Eran Yanowski, Jing Liang, Jeffrey K. Rymer, Rivka Levy, Gilad Beck, Elena Ainbinder, Sali M. K. Farhan, Kimberly A. Lennox, Nicole M. Bode, Mark A. Behlke, Thomas Möller, Smita Saxena, Cristiane A. M. Moreno, Giancarlo Costaguta, Kristel R. van Eijk, Hemali Phatnani, Ammar Al-Chalabi, A. Nazli Başak, Leonard H. van den Berg, Orla Hardiman, John E. Landers, Jesus S. Mora, Karen E. Morrison, Pamela J. Shaw, Jan H. Veldink, Samuel L. Pfaff, Ofer Yizhar, Christina Gross, Robert H. Brown, John M. Ravits, Matthew B. Harms, Timothy M. Miller, Eran Hornstein

    Motor neuron–specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic lateral sclerosis (ALS) motor neurons, miR-218 is down-regulated and its mRNA targets are reciprocally up-regulated (derepressed). We further identify the potassium channel Kv10.1 as a new miR-218 direct target that controls neuronal activity. In addition, we screened thousands of ALS genomes and identified six rare variants in the human miR-218-2 sequence. miR-218 gene variants fail to regulate neuron activity, suggesting the importance of this small endogenous RNA for neuronal robustness. The underlying mechanisms involve inhibition of miR-218 biogenesis and reduced processing by DICER. Therefore, miR-218 activity in motor neurons may be susceptible to failure in human ALS, suggesting that miR-218 may be a potential therapeutic target in motor neuron disease.

    更新日期:2019-12-19
  • Activity of the poly(A) binding protein MSUT2 determines susceptibility to pathological tau in the mammalian brain
    Sci. Transl. Med. (IF 17.161) Pub Date : 2019-12-18
    Jeanna M. Wheeler, Pamela McMillan, Timothy J. Strovas, Nicole F. Liachko, Alexandre Amlie-Wolf, Rebecca L. Kow, Ronald L. Klein, Patricia Szot, Linda Robinson, Chris Guthrie, Aleen Saxton, Nicholas M. Kanaan, Murray Raskind, Elaine Peskind, John Q. Trojanowski, Virginia M. Y. Lee, Li-San Wang, C. Dirk Keene, Thomas Bird, Gerard D. Schellenberg, Brian Kraemer

    Brain lesions composed of pathological tau help to drive neurodegeneration in Alzheimer’s disease (AD) and related tauopathies. Here, we identified the mammalian suppressor of tauopathy 2 (MSUT2) gene as a modifier of susceptibility to tau toxicity in two mouse models of tauopathy. Transgenic PS19 mice overexpressing tau, a model of AD, and lacking the Msut2 gene exhibited decreased learning and memory deficits, reduced neurodegeneration, and reduced accumulation of pathological tau compared to PS19 tau transgenic mice expressing Msut2. Conversely, Msut2 overexpression in 4RTauTg2652 tau transgenic mice increased pathological tau deposition and promoted the neuroinflammatory response to pathological tau. MSUT2 is a poly(A) RNA binding protein that antagonizes the canonical nuclear poly(A) binding protein PABPN1. In individuals with AD, MSUT2 abundance in postmortem brain tissue predicted an earlier age of disease onset. Postmortem AD brain tissue samples with normal amounts of MSUT2 showed elevated neuroinflammation associated with tau pathology. We observed co-depletion of MSUT2 and PABPN1 in postmortem brain samples from a subset of AD cases with higher tau burden and increased neuronal loss. This suggested that MSUT2 and PABPN1 may act together in a macromolecular complex bound to poly(A) RNA. Although MSUT2 and PABPN1 had opposing effects on both tau aggregation and poly(A) RNA tail length, we found that increased poly(A) tail length did not ameliorate tauopathy, implicating other functions of the MSUT2/PABPN1 complex in tau proteostasis. Our findings implicate poly(A) RNA binding proteins both as modulators of pathological tau toxicity in AD and as potential molecular targets for interventions to slow neurodegeneration in tauopathies.

    更新日期:2019-12-19
  • Biocompatible near-infrared quantum dots delivered to the skin by microneedle patches record vaccination
    Sci. Transl. Med. (IF 17.161) Pub Date : 2019-12-18
    Kevin J. McHugh, Lihong Jing, Sean Y. Severt, Mache Cruz, Morteza Sarmadi, Hapuarachchige Surangi N. Jayawardena, Collin F. Perkinson, Fridrik Larusson, Sviatlana Rose, Stephanie Tomasic, Tyler Graf, Stephany Y. Tzeng, James L. Sugarman, Daniel Vlasic, Matthew Peters, Nels Peterson, Lowell Wood, Wen Tang, Jihyeon Yeom, Joe Collins, Philip A. Welkhoff, Ari Karchin, Megan Tse, Mingyuan Gao, Moungi G. Bawendi, Robert Langer, Ana Jaklenec

    Accurate medical recordkeeping is a major challenge in many low-resource settings where well-maintained centralized databases do not exist, contributing to 1.5 million vaccine-preventable deaths annually. Here, we present an approach to encode medical history on a patient using the spatial distribution of biocompatible, near-infrared quantum dots (NIR QDs) in the dermis. QDs are invisible to the naked eye yet detectable when exposed to NIR light. QDs with a copper indium selenide core and aluminum-doped zinc sulfide shell were tuned to emit in the NIR spectrum by controlling stoichiometry and shelling time. The formulation showing the greatest resistance to photobleaching after simulated sunlight exposure (5-year equivalence) through pigmented human skin was encapsulated in microparticles for use in vivo. In parallel, microneedle geometry was optimized in silico and validated ex vivo using porcine and synthetic human skin. QD-containing microparticles were then embedded in dissolvable microneedles and administered to rats with or without a vaccine. Longitudinal in vivo imaging using a smartphone adapted to detect NIR light demonstrated that microneedle-delivered QD patterns remained bright and could be accurately identified using a machine learning algorithm 9 months after application. In addition, codelivery with inactivated poliovirus vaccine produced neutralizing antibody titers above the threshold considered protective. These findings suggest that intradermal QDs can be used to reliably encode information and can be delivered with a vaccine, which may be particularly valuable in the developing world and open up new avenues for decentralized data storage and biosensing.

    更新日期:2019-12-19
  • Feeling the α-synuclein strain
    Sci. Transl. Med. (IF 17.161) Pub Date : 2019-12-18
    Cathryn Haigh

    α-synuclein strains may be responsible for the differing disease etiologies of the α-Synucleinopathies.

    更新日期:2019-12-19
  • A new hope for neuroblastoma treatment?
    Sci. Transl. Med. (IF 17.161) Pub Date : 2019-12-18
    Joan Montero

    Combined ALK and PIM1 inhibition may treat high-risk neuroblastomas.

    更新日期:2019-12-19
  • Targeting NASH with OxPL neutralization
    Sci. Transl. Med. (IF 17.161) Pub Date : 2019-12-18
    Lale Ozcan

    Accumulation of oxidized phospholipids (OxPLs) contribute to NASH development.

    更新日期:2019-12-19
  • Impaired hemostatic activity of healthy transfused platelets in inherited and acquired platelet disorders: Mechanisms and implications
    Sci. Transl. Med. (IF 17.161) Pub Date : 2019-12-11
    Robert H. Lee, Raymond Piatt, Ankita Dhenge, María L. Lozano, Verónica Palma-Barqueros, José Rivera, Wolfgang Bergmeier

    Platelet transfusions can fail to prevent bleeding in patients with inherited platelet function disorders (IPDs), such as Glanzmann’s thrombasthenia (GT; integrin αIIbβ3 dysfunction), Bernard-Soulier syndrome [BSS; glycoprotein (GP) Ib/V/IX dysfunction], and the more recently identified nonsyndromic RASGRP2 variants. Here, we used IPD mouse models and real-time imaging of hemostatic plug formation to investigate whether dysfunctional platelets impair the hemostatic function of healthy donor [wild-type (WT)] platelets. In Rasgrp2−/− mice or mice with platelet-specific deficiency in the integrin adaptor protein TALIN1 (“GT-like”), WT platelet transfusion was ineffective unless the ratio between mutant and WT platelets was ~2:1. In contrast, thrombocytopenic mice or mice lacking the extracellular domain of GPIbα (“BSS-like”) required very few transfused WT platelets to normalize hemostasis. Both Rasgrp2−/− and GT-like, but not BSS-like, platelets effectively localized to the injury site. Mechanistic studies identified at least two mechanisms of interference by dysfunctional platelets in IPDs: (i) delayed adhesion of WT donor platelets due to reduced access to GPIbα ligands exposed at sites of vascular injury and (ii) impaired consolidation of the hemostatic plug. We also investigated the hemostatic activity of transfused platelets in the setting of dual antiplatelet therapy (DAPT), an acquired platelet function disorder (APD). “DAPT” platelets did not prolong the time to initial hemostasis, but plugs were unstable and frequent rebleeding was observed. Thus, we propose that the endogenous platelet count and the ratio of transfused versus endogenous platelets should be considered when treating select IPD and APD patients with platelet transfusions.

    更新日期:2019-12-11
  • PD-1H (VISTA)–mediated suppression of autoimmunity in systemic and cutaneous lupus erythematosus
    Sci. Transl. Med. (IF 17.161) Pub Date : 2019-12-11
    Xue Han, Matthew D. Vesely, Wendy Yang, Miguel F. Sanmamed, Ti Badri, Jude Alawa, Francesc López-Giráldez, Patricia Gaule, Sang Won Lee, Jian-Ping Zhang, Xinxin Nie, Ala Nassar, Agedi Boto, Dallas B. Flies, Linghua Zheng, Tae Kon Kim, Gilbert W. Moeckel, Jennifer M. McNiff, Lieping Chen

    Systemic lupus erythematosus (SLE) and discoid lupus erythematosus (DLE) of the skin are autoimmune diseases characterized by inappropriate immune responses against self-proteins; the key elements that determine disease pathogenesis and progression are largely unknown. Here, we show that mice lacking immune inhibitory receptor VISTA or programmed death-1 homolog (PD-1H KO) on a BALB/c background spontaneously develop cutaneous and systemic autoimmune diseases resembling human lupus. Cutaneous lupus lesions of PD-1H KO mice have clustering of plasmacytoid dendritic cells (pDCs) similar to human DLE. Using mass cytometry, we identified proinflammatory neutrophils as critical early immune infiltrating cells within cutaneous lupus lesions of PD-1H KO mice. We also found that PD-1H is highly expressed on immune cells in human SLE, DLE lesions, and cutaneous lesions of MRL/lpr mice. A PD-1H agonistic monoclonal antibody in MRL/lpr mice reduces cutaneous disease, autoantibodies, inflammatory cytokines, chemokines, and immune cell expansion. Furthermore, PD-1H on both T cells and myeloid cells including neutrophils and pDCs could transmit inhibitory signals, resulting in reduced activation and function, establishing PD-1H as an inhibitory receptor on T cells and myeloid cells. On the basis of these findings, we propose that PD-1H is a critical element in the pathogenesis and progression of lupus, and PD-1H activation could be effective for treatment of systemic and cutaneous lupus.

    更新日期:2019-12-11
  • Hair eruption initiates and commensal skin microbiota aggravate adverse events of anti-EGFR therapy
    Sci. Transl. Med. (IF 17.161) Pub Date : 2019-12-11
    Jörg Klufa, Thomas Bauer, Buck Hanson, Craig Herbold, Philipp Starkl, Beate Lichtenberger, Dagmar Srutkova, Daniel Schulz, Igor Vujic, Thomas Mohr, Klemens Rappersberger, Bernd Bodenmiller, Hana Kozakova, Sylvia Knapp, Alexander Loy, Maria Sibilia

    Epidermal growth factor receptor (EGFR)–targeted anticancer therapy induces stigmatizing skin toxicities affecting patients’ quality of life and therapy adherence. The lack of mechanistic details underlying these adverse events hampers their management. We found that EGFR/ERK signaling is required in LRIG1-positive stem cells during de novo hair eruption to secure barrier integrity and prevent the invasion of commensal microbiota and inflammatory skin disease. EGFR-deficient epidermis is permissive for microbiota outgrowth and displays an atopic-like TH2-dominated signature. The opening of the follicular ostia during hair eruption allows invasion of commensal microbiota into the hair follicle, initiating an additional TH1 and TH17 response culminating in chronic folliculitis. Restoration of epidermal ERK signaling via prophylactic FGF7 treatment or transgenic SOS expression rescues the barrier defect in the absence of EGFR, highlighting a therapeutic anchor point. These data reveal that commensal skin microbiota provoke atopic-like inflammatory skin diseases by invading into the follicular opening of erupting hair.

    更新日期:2019-12-11
  • Caveolin-1–derived peptide limits development of pulmonary fibrosis
    Sci. Transl. Med. (IF 17.161) Pub Date : 2019-12-11
    Amarnath Satheesh Marudamuthu, Yashodhar Prabhakar Bhandary, Liang Fan, Vijay Radhakrishnan, BreAnne MacKenzie, Esther Maier, Shwetha Kumari Shetty, M.R. Nagaraja, Venkadesaperumal Gopu, Nivedita Tiwari, Yajie Zhang, Alan B. Watts, Robert O. Williams, Gerald J Criner, Sudhir Bolla, Nathaniel Marchetti, Steven Idell, Sreerama Shetty

    Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease with a median 5-year survival of ~20%. Current U.S. Food and Drug Administration–approved pharmacotherapies slow progression of IPF, providing hope that even more effective treatments can be developed. Alveolar epithelial progenitor type II cell (AEC) apoptosis and proliferation, and accumulation of activated myofibroblasts or fibrotic lung fibroblasts (fLfs) contribute to the progression of IPF. Full-length caveolin-1 scaffolding domain peptide (CSP; amino acids 82 to 101 of Cav1: DGIWKASFTTFTVTKYWFYR) inhibits AEC apoptosis and fLf activation and expansion and attenuates PF in bleomycin (BLM)–induced lung injury in mice. Like full-length CSP, a seven–amino acid deletion fragment of CSP, CSP7 (FTTFTVT), demonstrated antifibrotic effects in murine models of lung fibrosis. When CSP7 was administered during the fibrotic phase in three preclinical models [single-dose BLM, repeated-dose BLM, and adenovirus expressing constitutively active transforming growth factor–β1 (Ad-TGF-β1)–induced established PF], CSP7 reduced extracellular matrix (ECM) markers characteristic of PF, increased AEC survival, and improved lung function. CSP7 is amenable to both systemic (intraperitoneal) or direct lung delivery in a nebulized or dry powder form. Furthermore, CSP7 treatment of end-stage human IPF lung tissue explants attenuated ECM production and promoted AEC survival. Ames testing for mutagenicity and in vitro human peripheral blood lymphocyte and in vivo mouse micronucleus transformation assays indicated that CSP7 is not carcinogenic. Together, these findings support the further development of CSP7 as an antifibrotic treatment for patients with IPF or other interstitial lung diseases.

    更新日期:2019-12-11
  • Distinct neural mechanisms for the prosocial and rewarding properties of MDMA
    Sci. Transl. Med. (IF 17.161) Pub Date : 2019-12-11
    Boris D. Heifets, Juliana S. Salgado, Madison D. Taylor, Paul Hoerbelt, Daniel F. Cardozo Pinto, Elizabeth E. Steinberg, Jessica J. Walsh, Ji Y. Sze, Robert C. Malenka

    The extensively abused recreational drug (±)3,4-methylenedioxymethamphetamine (MDMA) has shown promise as an adjunct to psychotherapy for treatment-resistant psychiatric disease. It is unknown, however, whether the mechanisms underlying its prosocial therapeutic effects and abuse potential are distinct. We modeled both the prosocial and nonsocial drug reward of MDMA in mice and investigated the mechanism of these processes using brain region–specific pharmacology, transgenic manipulations, electrophysiology, and in vivo calcium imaging. We demonstrate in mice that MDMA acting at the serotonin transporter within the nucleus accumbens is necessary and sufficient for MDMA’s prosocial effect. MDMA’s acute rewarding properties, in contrast, require dopaminergic signaling. MDMA’s prosocial effect requires 5-HT1b receptor activation and is mimicked by d-fenfluramine, a selective serotonin-releasing compound. By dissociating the mechanisms of MDMA’s prosocial effects from its addictive properties, we provide evidence for a conserved neuronal pathway, which can be leveraged to develop novel therapeutics with limited abuse liability.

    更新日期:2019-12-11
  • A recombinant platform for flavivirus vaccines and diagnostics using chimeras of a new insect-specific virus
    Sci. Transl. Med. (IF 17.161) Pub Date : 2019-12-11
    Jody Hobson-Peters, Jessica J. Harrison, Daniel Watterson, Jessamine E. Hazlewood, Laura J. Vet, Natalee D. Newton, David Warrilow, Agathe M. G. Colmant, Carmel Taylor, Bixing Huang, Thisun B. H. Piyasena, Weng Kong Chow, Yin Xiang Setoh, Bing Tang, Eri Nakayama, Kexin Yan, Alberto A. Amarilla, Sarah Wheatley, Peter R. Moore, Mitchell Finger, Nina Kurucz, Naphak Modhiran, Paul R. Young, Alexander A. Khromykh, Helle Bielefeldt-Ohmann, Andreas Suhrbier, Roy A. Hall

    Flaviviruses such as dengue, yellow fever, Zika, West Nile, and Japanese encephalitis virus present substantial global health burdens. New vaccines are being sought to address safety and manufacturing issues associated with current live attenuated vaccines. Here, we describe a new insect-specific flavivirus, Binjari virus, which was found to be remarkably tolerant for exchange of its structural protein genes (prME) with those of the aforementioned pathogenic vertebrate-infecting flaviviruses (VIFs). Chimeric BinJ/VIF-prME viruses remained replication defective in vertebrate cells but replicated with high efficiency in mosquito cells. Cryo–electron microscopy and monoclonal antibody binding studies illustrated that the chimeric BinJ/VIF-prME virus particles were structurally and immunologically similar to their parental VIFs. Pilot manufacturing in C6/36 cells suggests that high yields can be reached up to 109.5 cell culture infectious dose/ml or ≈7 mg/liter. BinJ/VIF-prME viruses showed utility in diagnostic (microsphere immunoassays and ELISAs using panels of human and equine sera) and vaccine applications (illustrating protection against Zika virus challenge in murine IFNAR−/− mouse models). BinJ/VIF-prME viruses thus represent a versatile, noninfectious (for vertebrate cells), high-yield technology for generating chimeric flavivirus particles with low biocontainment requirements.

    更新日期:2019-12-11
  • A gut reaction to exercise
    Sci. Transl. Med. (IF 17.161) Pub Date : 2019-12-11
    Annie Curtis

    Alterations in gut microbiome composition and function predict those who respond favorably to exercise in metabolic control.

    更新日期:2019-12-11
  • Mass-producing wearable sensors: No sweat
    Sci. Transl. Med. (IF 17.161) Pub Date : 2019-12-11
    Li-Hsin Han

    Laser engraving can mass-produce cost-efficient, wearable sensors that monitor vital signs and sweat, detecting biomarkers linked to chronic diseases.

    更新日期:2019-12-11
  • Tumor mutations are not alone in the plasma
    Sci. Transl. Med. (IF 17.161) Pub Date : 2019-12-11
    Kamila Naxerova

    Most cell-free DNA mutations in cancer patients originate in hematopoietic clones.

    更新日期:2019-12-11
  • Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer
    Sci. Transl. Med. (IF 17.161) Pub Date : 2019-12-04
    Yanjing Li, Yiping He, William Butler, Lingfan Xu, Yan Chang, Kefeng Lei, Hong Zhang, Yinglu Zhou, Allen C. Gao, Qingfu Zhang, Daniel G. Taylor, Donghui Cheng, Suzette Farber-Katz, Rachid Karam, Tyler Landrith, Bing Li, Sitao Wu, Vickie Hsuan, Qing Yang, Hailiang Hu, Xufeng Chen, Melissa Flowers, Shannon J. McCall, John K. Lee, Bryan A. Smith, Jung Wook Park, Andrew S. Goldstein, Owen N. Witte, Qianben Wang, Matthew B. Rettig, Andrew J. Armstrong, Qing Cheng, Jiaoti Huang

    Hormonal therapy targeting androgen receptor (AR) is initially effective to treat prostate cancer (PCa), but it eventually fails. It has been hypothesized that cellular heterogeneity of PCa, consisting of AR+ luminal tumor cells and AR− neuroendocrine (NE) tumor cells, may contribute to therapy failure. Here, we describe the successful purification of NE cells from primary fresh human prostate adenocarcinoma based on the cell surface receptor C-X-C motif chemokine receptor 2 (CXCR2). Functional studies revealed CXCR2 to be a driver of the NE phenotype, including loss of AR expression, lineage plasticity, and resistance to hormonal therapy. CXCR2-driven NE cells were critical for the tumor microenvironment by providing a survival niche for the AR+ luminal cells. We demonstrate that the combination of CXCR2 inhibition and AR targeting is an effective treatment strategy in mouse xenograft models. Such a strategy has the potential to overcome therapy resistance caused by tumor cell heterogeneity.

    更新日期:2019-12-05
  • In vitro selection predicts malaria parasite resistance to dihydroorotate dehydrogenase inhibitors in a mouse infection model
    Sci. Transl. Med. (IF 17.161) Pub Date : 2019-12-04
    Rebecca E. K. Mandt, Maria Jose Lafuente-Monasterio, Tomoyo Sakata-Kato, Madeline R. Luth, Delfina Segura, Alba Pablos-Tanarro, Sara Viera, Noemi Magan, Sabine Ottilie, Elizabeth A. Winzeler, Amanda K. Lukens, Francisco Javier Gamo, Dyann F. Wirth

    Resistance has developed in Plasmodium malaria parasites to every antimalarial drug in clinical use, prompting the need to characterize the pathways mediating resistance. Here, we report a framework for assessing development of resistance of Plasmodium falciparum to new antimalarial therapeutics. We investigated development of resistance by P. falciparum to the dihydroorotate dehydrogenase (DHODH) inhibitors DSM265 and DSM267 in tissue culture and in a mouse model of P. falciparum infection. We found that resistance to these drugs arose rapidly both in vitro and in vivo. We identified 13 point mutations mediating resistance in the parasite DHODH in vitro that overlapped with the DHODH mutations that arose in the mouse infection model. Mutations in DHODH conferred increased resistance (ranging from 2- to ~400-fold) to DHODH inhibitors in P. falciparum in vitro and in vivo. We further demonstrated that the drug-resistant parasites carrying the C276Y mutation had mitochondrial energetics comparable to the wild-type parasite and also retained their fitness in competitive growth experiments. Our data suggest that in vitro selection of drug-resistant P. falciparum can predict development of resistance in a mouse model of malaria infection.

    更新日期:2019-12-05
  • A once-a-month oral contraceptive
    Sci. Transl. Med. (IF 17.161) Pub Date : 2019-12-04
    Ameya R. Kirtane, Tiffany Hua, Alison Hayward, Ambika Bajpayee, Aniket Wahane, Aaron Lopes, Taylor Bensel, Lihong Ma, Frank Z. Stanczyk, Sierra Brooks, Declan Gwynne, Jacob Wainer, Joy Collins, Siddartha M. Tamang, Robert Langer, Giovanni Traverso

    Poor patient adherence to oral contraceptives is the predominant cause of failure of these therapies, leading to unplanned pregnancies that can negatively affect female health worldwide. To improve patient adherence, we developed an oral contraceptive that is administered once a month. Here, we describe the design and report in vivo characterization of a levonorgestrel-releasing gastric resident dosage form in pigs.

    更新日期:2019-12-05
  • Blood-brain barrier dysfunction in aging induces hyperactivation of TGFβ signaling and chronic yet reversible neural dysfunction
    Sci. Transl. Med. (IF 17.161) Pub Date : 2019-12-04
    Vladimir V. Senatorov, Aaron R. Friedman, Dan Z. Milikovsky, Jonathan Ofer, Rotem Saar-Ashkenazy, Adiel Charbash, Naznin Jahan, Gregory Chin, Eszter Mihaly, Jessica M. Lin, Harrison J. Ramsay, Ariana Moghbel, Marcela K. Preininger, Chelsy R. Eddings, Helen V. Harrison, Rishi Patel, Yishuo Shen, Hana Ghanim, Huanjie Sheng, Ronel Veksler, Peter H. Sudmant, Albert Becker, Barry Hart, Michael A. Rogawski, Andrew Dillin, Alon Friedman, Daniela Kaufer

    Aging involves a decline in neural function that contributes to cognitive impairment and disease. However, the mechanisms underlying the transition from a young-and-healthy to aged-and-dysfunctional brain are not well understood. Here, we report breakdown of the vascular blood-brain barrier (BBB) in aging humans and rodents, which begins as early as middle age and progresses to the end of the life span. Gain-of-function and loss-of-function manipulations show that this BBB dysfunction triggers hyperactivation of transforming growth factor–β (TGFβ) signaling in astrocytes, which is necessary and sufficient to cause neural dysfunction and age-related pathology in rodents. Specifically, infusion of the serum protein albumin into the young rodent brain (mimicking BBB leakiness) induced astrocytic TGFβ signaling and an aged brain phenotype including aberrant electrocorticographic activity, vulnerability to seizures, and cognitive impairment. Furthermore, conditional genetic knockdown of astrocytic TGFβ receptors or pharmacological inhibition of TGFβ signaling reversed these symptomatic outcomes in aged mice. Last, we found that this same signaling pathway is activated in aging human subjects with BBB dysfunction. Our study identifies dysfunction in the neurovascular unit as one of the earliest triggers of neurological aging and demonstrates that the aging brain may retain considerable latent capacity, which can be revitalized by therapeutic inhibition of TGFβ signaling.

    更新日期:2019-12-05
  • The human tissue-resident CCR5+ T cell compartment maintains protective and functional properties during inflammation
    Sci. Transl. Med. (IF 17.161) Pub Date : 2019-12-04
    Amanda S. Woodward Davis, Hayley N. Roozen, Matthew J. Dufort, Hannah A. DeBerg, Martha A. Delaney, Florian Mair, Jami R. Erickson, Chloe K. Slichter, Julia D. Berkson, Alexis M. Klock, Matthias Mack, Yu Lwo, Alexander Ko, Rhonda M. Brand, Ian McGowan, Peter S. Linsley, Douglas R. Dixon, Martin Prlic

    CCR5 is thought to play a central role in orchestrating migration of cells in response to inflammation. CCR5 antagonists can reduce inflammatory disease processes, which has led to an increased interest in using CCR5 antagonists in a wide range of inflammation-driven diseases. Paradoxically, these antagonists appear to function without negatively affecting host immunity at barrier sites. We reasoned that the resolution to this paradox may lie in the CCR5+ T cell populations that permanently reside in tissues. We used a single-cell analysis approach to examine the human CCR5+ T cell compartment in the blood, healthy, and inflamed mucosal tissues to resolve these seemingly contradictory observations. We found that 65% of the CD4 tissue-resident memory T (TRM) cell compartment expressed CCR5. These CCR5+ TRM cells were enriched in and near the epithelial layer and not only limited to TH1-type cells but also contained a large TH17-producing and a stable regulatory T cell population. The CCR5+ TRM compartment was stably maintained even in inflamed tissues including the preservation of TH17 and regulatory T cell populations. Further, using tissues from the CHARM-03 clinical trial, we found that CCR5+ TRM are preserved in human mucosal tissue during treatment with the CCR5 antagonist Maraviroc. Our data suggest that the human CCR5+ TRM compartment is functionally and spatially equipped to maintain barrier immunity even in the absence of CCR5-mediated, de novo T cell recruitment from the periphery.

    更新日期:2019-12-05
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