2,684 results match your criteria Science Translational Medicine [Journal]


An antibody-drug conjugate directed to the ALK receptor demonstrates efficacy in preclinical models of neuroblastoma.

Sci Transl Med 2019 Mar;11(483)

Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

Enthusiasm for the use of antibody-drug conjugates (ADCs) in cancer therapy has risen over the past few years. The success of this therapeutic approach relies on the identification of cell surface antigens that are widely and selectively expressed on tumor cells. Studies have shown that native ALK protein is expressed on the surface of most neuroblastoma cells, providing an opportunity for development of immune-targeting strategies. Read More

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http://dx.doi.org/10.1126/scitranslmed.aau9732DOI Listing
March 2019
1 Read

"Inactive" ingredients in oral medications.

Sci Transl Med 2019 Mar;11(483)

Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Oral forms of medications contain "inactive" ingredients to enhance their physical properties. Using data analytics, we characterized the abundance and complexity of inactive ingredients in approved medications. A majority of medications contain ingredients that could cause adverse reactions, underscoring the need to maximize the tolerability and safety of medications and their inactive ingredients. Read More

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http://stm.sciencemag.org/lookup/doi/10.1126/scitranslmed.aa
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http://dx.doi.org/10.1126/scitranslmed.aau6753DOI Listing
March 2019
5 Reads

A gastric resident drug delivery system for prolonged gram-level dosing of tuberculosis treatment.

Sci Transl Med 2019 Mar;11(483)

Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Multigram drug depot systems for extended drug release could transform our capacity to effectively treat patients across a myriad of diseases. For example, tuberculosis (TB) requires multimonth courses of daily multigram doses for treatment. To address the challenge of prolonged dosing for regimens requiring multigram drug dosing, we developed a gastric resident system delivered through the nasogastric route that was capable of safely encapsulating and releasing grams of antibiotics over a period of weeks. Read More

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http://stm.sciencemag.org/lookup/doi/10.1126/scitranslmed.aa
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http://dx.doi.org/10.1126/scitranslmed.aau6267DOI Listing
March 2019
3 Reads

Preclinical development of an oral anti- macrolide drug for the treatment of lymphatic filariasis and onchocerciasis.

Sci Transl Med 2019 Mar;11(483)

Centre for Drugs and Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK.

There is an urgent global need for a safe macrofilaricide drug to accelerate elimination of the neglected tropical diseases onchocerciasis and lymphatic filariasis. From an anti-infective compound library, the macrolide veterinary antibiotic, tylosin A, was identified as a hit against This bacterial endosymbiont is required for filarial worm viability and fertility and is a validated target for macrofilaricidal drugs. Medicinal chemistry was undertaken to develop tylosin A analogs with improved oral bioavailability. Read More

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http://dx.doi.org/10.1126/scitranslmed.aau2086DOI Listing
March 2019
2 Reads

Noninvasive high-resolution electromyometrial imaging of uterine contractions in a translational sheep model.

Sci Transl Med 2019 Mar;11(483)

Center for Reproductive Health Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA.

In current clinical practice, uterine contractions are monitored via a tocodynamometer or an intrauterine pressure catheter, both of which provide crude information about contractions. Although electrohysterography/electromyography can measure uterine electrical activity, this method lacks spatial specificity and thus cannot accurately measure the exact location of electrical initiation and location-specific propagation patterns of uterine contractions. To comprehensively evaluate three-dimensional uterine electrical activation patterns, we describe here the development of electromyometrial imaging (EMMI) to display the three-dimensional uterine contractions at high spatial and temporal resolution. Read More

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http://dx.doi.org/10.1126/scitranslmed.aau1428DOI Listing

ZEB1 suppression sensitizes KRAS mutant cancers to MEK inhibition by an IL17RD-dependent mechanism.

Sci Transl Med 2019 Mar;11(483)

Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors have failed to show clinical benefit in Kirsten rat sarcoma () mutant lung cancer due to various resistance mechanisms. To identify differential therapeutic sensitivities between epithelial and mesenchymal lung tumors, we performed in vivo small hairpin RNA screens, proteomic profiling, and analysis of patient tumor datasets, which revealed an inverse correlation between mitogen-activated protein kinase (MAPK) signaling dependency and a zinc finger E-box binding homeobox 1 (ZEB1)-regulated epithelial-to-mesenchymal transition. Mechanistic studies determined that MAPK signaling dependency in epithelial lung cancer cells is due to the scaffold protein interleukin-17 receptor D (IL17RD), which is directly repressed by ZEB1. Read More

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http://dx.doi.org/10.1126/scitranslmed.aaq1238DOI Listing

Activin type II receptor signaling in cardiac aging and heart failure.

Sci Transl Med 2019 Mar;11(482)

Corrigan Minehan Heart Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

Activin type II receptor (ActRII) ligands have been implicated in muscle wasting in aging and disease. However, the role of these ligands and ActRII signaling in the heart remains unclear. Here, we investigated this catabolic pathway in human aging and heart failure (HF) using circulating follistatin-like 3 (FSTL3) as a potential indicator of systemic ActRII activity. Read More

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http://dx.doi.org/10.1126/scitranslmed.aau8680DOI Listing

Structure-based design of small-molecule inhibitors of EBNA1 DNA binding blocks Epstein-Barr virus latent infection and tumor growth.

Sci Transl Med 2019 Mar;11(482)

The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.

Epstein-Barr virus (EBV) is a DNA tumor virus responsible for 1 to 2% of human cancers including subtypes of Burkitt's lymphoma, Hodgkin's lymphoma, gastric carcinoma, and nasopharyngeal carcinoma (NPC). Persistent latent infection drives EBV-associated tumorigenesis. Epstein-Barr nuclear antigen 1 (EBNA1) is the only viral protein consistently expressed in all EBV-associated tumors and is therefore an attractive target for therapeutic intervention. Read More

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http://dx.doi.org/10.1126/scitranslmed.aau5612DOI Listing
March 2019
3 Reads

Sustained B cell depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus.

Sci Transl Med 2019 Mar;11(482)

Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA.

The failure of anti-CD20 antibody (Rituximab) as therapy for lupus may be attributed to the transient and incomplete B cell depletion achieved in clinical trials. Here, using an alternative approach, we report that complete and sustained CD19 B cell depletion is a highly effective therapy in lupus models. CD8 T cells expressing CD19-targeted chimeric antigen receptors (CARs) persistently depleted CD19 B cells, eliminated autoantibody production, reversed disease manifestations in target organs, and extended life spans well beyond normal in the (NZB × NZW) F and MRL mouse models of lupus. Read More

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http://dx.doi.org/10.1126/scitranslmed.aav1648DOI Listing

Delivery of therapeutics to the inner ear: The challenge of the blood-labyrinth barrier.

Sci Transl Med 2019 Mar;11(482)

Biological Sciences, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada.

Permanent hearing loss affects more than 5% of the world's population, yet there are no nondevice therapies that can protect or restore hearing. Delivery of therapeutics to the cochlea and vestibular system of the inner ear is complicated by their inaccessible location. Drug delivery to the inner ear via the vasculature is an attractive noninvasive strategy, yet the blood-labyrinth barrier at the luminal surface of inner ear capillaries restricts entry of most blood-borne compounds into inner ear tissues. Read More

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http://dx.doi.org/10.1126/scitranslmed.aao0935DOI Listing

PAI-1 augments mucosal damage in colitis.

Sci Transl Med 2019 Mar;11(482)

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.

There is a major unmet clinical need to identify pathways in inflammatory bowel disease (IBD) to classify patient disease activity, stratify patients that will benefit from targeted therapies such as anti-tumor necrosis factor (TNF), and identify new therapeutic targets. In this study, we conducted global transcriptome analysis to identify IBD-related pathways using colon biopsies, which highlighted the coagulation gene pathway as one of the most enriched gene sets in patients with IBD. Using this gene-network analysis across 14 independent cohorts and 1800 intestinal biopsies, we found that, among the coagulation pathway genes, plasminogen activator inhibitor-1 (PAI-1) expression was highly enriched in active disease and in patients with IBD who did not respond to anti-TNF biologic therapy and that PAI-1 is a key link between the epithelium and inflammation. Read More

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http://dx.doi.org/10.1126/scitranslmed.aat0852DOI Listing
March 2019
5 Reads

Patients with autism spectrum disorders display reproducible functional connectivity alterations.

Sci Transl Med 2019 Feb;11(481)

Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.

Despite the high clinical burden, little is known about pathophysiology underlying autism spectrum disorder (ASD). Recent resting-state functional magnetic resonance imaging (rs-fMRI) studies have found atypical synchronization of brain activity in ASD. However, no consensus has been reached on the nature and clinical relevance of these alterations. Read More

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http://dx.doi.org/10.1126/scitranslmed.aat9223DOI Listing
February 2019
2 Reads

An automated hybrid bioelectronic system for autogenous restoration of sinus rhythm in atrial fibrillation.

Sci Transl Med 2019 02;11(481)

Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, 2333 ZA, Leiden, Netherlands.

Because of suboptimal therapeutic strategies, restoration of sinus rhythm in symptomatic atrial fibrillation (AF) often requires in-hospital delivery of high-voltage shocks, thereby precluding ambulatory AF termination. Continuous, rapid restoration of sinus rhythm is desired given the recurring and progressive nature of AF. Here, we present an automated hybrid bioelectronic system for shock-free termination of AF that enables the heart to act as an electric current generator for autogenous restoration of sinus rhythm. Read More

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http://dx.doi.org/10.1126/scitranslmed.aau6447DOI Listing
February 2019

Targeting the NF-κB signaling pathway in chronic tendon disease.

Sci Transl Med 2019 Feb;11(481)

Department of Orthopedic Surgery, Columbia University, 650 W 168th St, New York, NY 10032, USA.

Tendon disorders represent the most common musculoskeletal complaint for which patients seek medical attention; inflammation drives tendon degeneration before tearing and impairs healing after repair. Clinical evidence has implicated the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway as a correlate of pain-free return to function after surgical repair. However, it is currently unknown whether this response is a reaction to or a driver of pathology. Read More

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http://dx.doi.org/10.1126/scitranslmed.aav4319DOI Listing
February 2019
1 Read

Driving CAR T cell translation forward.

Sci Transl Med 2019 Feb;11(481)

Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.

Successes in CAR T cell translation have propelled their commercial launch, but expanding the impact of cancer immunotherapies remains challenging. Read More

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http://dx.doi.org/10.1126/scitranslmed.aaw2127DOI Listing
February 2019

Shaping of infant B cell receptor repertoires by environmental factors and infectious disease.

Sci Transl Med 2019 Feb;11(481)

Department of Pathology, Stanford University, Stanford, CA 94305, USA.

Antigenic exposures at epithelial sites in infancy and early childhood are thought to influence the maturation of humoral immunity and modulate the risk of developing immunoglobulin E (IgE)-mediated allergic disease. How different kinds of environmental exposures influence B cell isotype switching to IgE, IgG, or IgA, and the somatic mutation maturation of these antibody pools, is not fully understood. We sequenced antibody repertoires in longitudinal blood samples in a birth cohort from infancy through the first 3 years of life and found that, whereas IgG and IgA show linear increases in mutational maturation with age, IgM and IgD mutations are more closely tied to pathogen exposure. Read More

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http://dx.doi.org/10.1126/scitranslmed.aat2004DOI Listing
February 2019

Estimating cholera incidence with cross-sectional serology.

Sci Transl Med 2019 Feb;11(480)

Division of Infectious Diseases, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.

The development of new approaches to cholera control relies on an accurate understanding of cholera epidemiology. However, most information on cholera incidence lacks laboratory confirmation and instead relies on surveillance systems reporting medically attended acute watery diarrhea. If recent infections could be identified using serological markers, cross-sectional serosurveys would offer an alternative approach to measuring incidence. Read More

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http://dx.doi.org/10.1126/scitranslmed.aau6242DOI Listing
February 2019
1 Read

The nonlesional skin surface distinguishes atopic dermatitis with food allergy as a unique endotype.

Sci Transl Med 2019 Feb;11(480)

National Jewish Health, Denver, CO 80206, USA.

Skin barrier dysfunction has been reported in both atopic dermatitis (AD) and food allergy (FA). However, only one-third of patients with AD have FA. The purpose of this study was to use a minimally invasive skin tape strip sampling method and a multiomics approach to determine whether children with AD and FA (AD +) have stratum corneum (SC) abnormalities that distinguish them from AD without FA (AD -) and nonatopic (NA) controls. Read More

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http://dx.doi.org/10.1126/scitranslmed.aav2685DOI Listing
February 2019
2 Reads

Challenges for mesenchymal stromal cell therapies.

Sci Transl Med 2019 Feb;11(480)

School of Cancer and Pharmacological Sciences, King's Health Partners Cancer Research UK Centre, King's College London, London SE1 9NH, UK.

Clinical trials of mesenchymal stromal cell therapies reveal a challenging heterogeneous landscape, including diverse therapeutic targets, patient categories, cell sources, and potential mechanisms of action. Read More

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http://dx.doi.org/10.1126/scitranslmed.aat2189DOI Listing
February 2019
1 Read

Sodium chloride is an ionic checkpoint for human T2 cells and shapes the atopic skin microenvironment.

Sci Transl Med 2019 Feb;11(480)

Institute of Virology, Technical University of Munich, 81675 Munich, Germany.

The incidence of allergic diseases has increased over the past 50 years, likely due to environmental factors. However, the nature of these factors and the mode of action by which they induce the type 2 immune deviation characteristic of atopic diseases remain unclear. It has previously been reported that dietary sodium chloride promotes the polarization of T helper 17 (T17) cells with implications for autoimmune diseases such as multiple sclerosis. Read More

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http://dx.doi.org/10.1126/scitranslmed.aau0683DOI Listing
February 2019
2 Reads

Brain metabolism modulates neuronal excitability in a mouse model of pyruvate dehydrogenase deficiency.

Sci Transl Med 2019 Feb;11(480)

Rare Brain Disorders Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Glucose is the ultimate substrate for most brain activities that use carbon, including synthesis of the neurotransmitters glutamate and γ-aminobutyric acid via mitochondrial tricarboxylic acid (TCA) cycle. Brain metabolism and neuronal excitability are thus interdependent. However, the principles that govern their relationship are not always intuitive because heritable defects of brain glucose metabolism are associated with the paradoxical coexistence, in the same individual, of episodic neuronal hyperexcitation (seizures) with reduced basal cerebral electrical activity. Read More

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http://dx.doi.org/10.1126/scitranslmed.aan0457DOI Listing
February 2019

The lymphatic border patrol outwits inflammatory cells in myocardial infarction.

Authors:
Gaetano Santulli

Sci Transl Med 2018 Jul;10(451)

Department of Medicine, Albert Einstein College of Medicine, Montefiore University Hospital, New York, NY 10461, USA. Department of Advanced Biomedical Sciences, "Federico II" University of Naples, Naples 80131, Italy.

Lymphangiogenesis modulates inflammation by clearing immune cells in the infarcted heart in a lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1)-dependent process to ameliorate cardiac dysfunction. Read More

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http://dx.doi.org/10.1126/scitranslmed.aau7379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371794PMC
July 2018
1 Read

Biology, biography, and the translational gap.

Sci Transl Med 2019 Feb;11(479)

Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.

Medicine-based evidence integrates a patient's biology and biography to improve individual medical care and to help eliminate the translational gap between research and the clinic. Read More

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http://dx.doi.org/10.1126/scitranslmed.aat7027DOI Listing
February 2019

DP antagonism reduces airway smooth muscle mass in asthma by decreasing eosinophilia and myofibroblast recruitment.

Sci Transl Med 2019 Feb;11(479)

University of Leicester, Leicester LE3 9QP, UK.

Increased airway smooth muscle mass, a feature of airway remodeling in asthma, is the strongest predictor of airflow limitation and contributes to asthma-associated morbidity and mortality. No current drug therapy for asthma is known to affect airway smooth muscle mass. Although there is increasing evidence that prostaglandin D type 2 receptor (DP) is expressed in airway structural and inflammatory cells, few studies have addressed the expression and function of DP in airway smooth muscle cells. Read More

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http://dx.doi.org/10.1126/scitranslmed.aao6451DOI Listing
February 2019
1 Read

Platelet decoys inhibit thrombosis and prevent metastatic tumor formation in preclinical models.

Sci Transl Med 2019 Feb;11(479)

Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.

Platelets are crucial for normal hemostasis; however, their hyperactivation also contributes to many potentially lethal pathologies including myocardial infarction, stroke, and cancer. We hypothesized that modified platelets lacking their aggregation and activation capacity could act as reversible inhibitors of platelet activation cascades. Here, we describe the development of detergent-extracted human modified platelets (platelet decoys) that retained platelet binding functions but were incapable of functional activation and aggregation. Read More

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http://dx.doi.org/10.1126/scitranslmed.aau5898DOI Listing
February 2019
11 Reads

Human tumor-associated monocytes/macrophages and their regulation of T cell responses in early-stage lung cancer.

Sci Transl Med 2019 Feb;11(479)

Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104, USA.

Data from mouse tumor models suggest that tumor-associated monocyte/macrophage lineage cells (MMLCs) dampen antitumor immune responses. However, given the fundamental differences between mice and humans in tumor evolution, genetic heterogeneity, and immunity, the function of MMLCs might be different in human tumors, especially during early stages of disease. Here, we studied MMLCs in early-stage human lung tumors and found that they consist of a mixture of classical tissue monocytes and tumor-associated macrophages (TAMs). Read More

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http://dx.doi.org/10.1126/scitranslmed.aat1500DOI Listing
February 2019
1 Read

IDH1-R132H acts as a tumor suppressor in glioma via epigenetic up-regulation of the DNA damage response.

Sci Transl Med 2019 Feb;11(479)

Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Patients with glioma whose tumors carry a mutation in isocitrate dehydrogenase 1 (IDH1) are younger at diagnosis and live longer. mutations co-occur with other molecular lesions, such as 1p/19q codeletion, inactivating mutations in the tumor suppressor protein 53 ) gene, and loss-of-function mutations in alpha thalassemia/mental retardation syndrome X-linked gene (). All adult low-grade gliomas (LGGs) harboring ATRX loss also express the IDH1 mutation. Read More

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http://dx.doi.org/10.1126/scitranslmed.aaq1427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400220PMC
February 2019
1 Read

Tissue-specific regulation of p53 by PKM2 is redox dependent and provides a therapeutic target for anthracycline-induced cardiotoxicity.

Sci Transl Med 2019 Feb;11(478)

Department of Medicine, University of Alberta, Edmonton, Alberta T6G 2J7, Canada.

Chemotherapy-induced cardiotoxicity (CIC) is a common clinical problem that compromises effective anticancer therapies. Many chemotherapeutics (including anthracyclines, such as doxorubicin) induce the proapoptotic transcription factor p53 in the tumor and nonspecifically in the heart, promoting heart failure. Although inhibition of p53 shows benefit in preclinical heart failure models, it would not be an attractive adjuvant therapy for CIC, because it would prevent tumor regression. Read More

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http://dx.doi.org/10.1126/scitranslmed.aau8866DOI Listing
February 2019

Suppressing fatty acid uptake has therapeutic effects in preclinical models of prostate cancer.

Sci Transl Med 2019 Feb;11(478)

Monash Partners Comprehensive Cancer Consortium, Monash Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Group, Department of Physiology, Monash University, Clayton, VIC 3800, Australia.

Metabolism alterations are hallmarks of cancer, but the involvement of lipid metabolism in disease progression is unclear. We investigated the role of lipid metabolism in prostate cancer using tissue from patients with prostate cancer and patient-derived xenograft mouse models. We showed that fatty acid uptake was increased in human prostate cancer and that these fatty acids were directed toward biomass production. Read More

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http://dx.doi.org/10.1126/scitranslmed.aau5758DOI Listing
February 2019
1 Read

Modulation of the sigma-1 receptor-IRE1 pathway is beneficial in preclinical models of inflammation and sepsis.

Sci Transl Med 2019 Feb;11(478)

Center for Brain Immunology and Glia, Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.

Sepsis is an often deadly complication of infection in which systemic inflammation damages the vasculature, leading to tissue hypoperfusion and multiple organ failure. Currently, the standard of care for sepsis is predominantly supportive, with few therapeutic options available. Because of increased sepsis incidence worldwide, there is an urgent need for discovery of novel therapeutic targets and development of new treatments. Read More

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http://dx.doi.org/10.1126/scitranslmed.aau5266DOI Listing
February 2019
1 Read

Clinical implications of tumor-intrinsic mechanisms regulating PD-L1.

Sci Transl Med 2019 Feb;11(478)

Department of Hematology and Oncology, Freiburg University Medical Center, 79106 Freiburg, Germany.

Treatment with immune checkpoint inhibitors targeting programmed death receptor-1 (PD-1) or programmed death ligand-1 (PD-L1) is effective in many cancer types. Tumors harboring specific mutations modulate antitumor immune responses through the PD-1/PD-L1 axis, and this should be taken into account when designing rational combinatory treatments. Read More

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http://dx.doi.org/10.1126/scitranslmed.aav4810DOI Listing
February 2019
15 Reads

Recurrent group A tonsillitis is an immunosusceptibility disease involving antibody deficiency and aberrant T cells.

Sci Transl Med 2019 Feb;11(478)

Division of Vaccine Discovery, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA.

"Strep throat" is highly prevalent among children, yet it is unknown why only some children develop recurrent tonsillitis (RT), a common indication for tonsillectomy. To gain insights into this classic childhood disease, we performed phenotypic, genotypic, and functional studies on pediatric group A (GAS) RT and non-RT tonsils from two independent cohorts. GAS RT tonsils had smaller germinal centers, with an underrepresentation of GAS-specific CD4 germinal center T follicular helper (GC-T) cells. Read More

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http://dx.doi.org/10.1126/scitranslmed.aau3776DOI Listing
February 2019
3 Reads

Durable anticancer immunity from intratumoral administration of IL-23, IL-36γ, and OX40L mRNAs.

Sci Transl Med 2019 Jan;11(477)

Moderna Inc., 200 Technology Square, Cambridge, MA 02139, USA.

Many solid cancers contain dysfunctional immune microenvironments. Immune system modulators that initiate responses to foreign pathogens could be promising candidates for reigniting productive responses toward tumors. Interleukin-1 (IL-1) and IL-12 cytokine family members cooperate at barrier tissues after microbial invasion, in human inflammatory diseases, and in antitumoral immunity. Read More

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http://dx.doi.org/10.1126/scitranslmed.aat9143DOI Listing
January 2019
19 Reads

A biologic scaffold-associated type 2 immune microenvironment inhibits tumor formation and synergizes with checkpoint immunotherapy.

Sci Transl Med 2019 Jan;11(477)

Translational Tissue Engineering Center, Baltimore, MD 21231, USA.

Biomaterials in regenerative medicine are designed to mimic and modulate tissue environments to promote repair. Biologic scaffolds (derived from decellularized tissue extracellular matrix) promote a wound-healing (proregenerative) immune phenotype and are used clinically to treat tissue loss, including in the context of tumor resection. It is unknown whether a biomaterial microenvironment that encourages tissue formation may also promote tumor development. Read More

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http://dx.doi.org/10.1126/scitranslmed.aat7973DOI Listing
January 2019
15.843 Impact Factor

Dynamics of circulating TNF during adalimumab treatment using a drug-tolerant TNF assay.

Sci Transl Med 2019 Jan;11(477)

Department of Immunopathology, Sanquin Research, 1066 CX Amsterdam, Netherlands, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands.

Patients with rheumatoid arthritis (RA) can be successfully treated with tumor necrosis factor (TNF) inhibitors, including the monoclonal antibody adalimumab. Once in remission, a proportion of patients can successfully discontinue treatment, indicating that blocking TNF is no longer required for disease control. To explore the dynamics of circulating TNF during adalimumab treatment, we developed a competition enzyme-linked immunosorbent assay that can quantify TNF in the presence of large amounts of TNF inhibitor, i. Read More

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http://stm.sciencemag.org/lookup/doi/10.1126/scitranslmed.aa
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http://dx.doi.org/10.1126/scitranslmed.aat3356DOI Listing
January 2019
12 Reads

Transforming medicine with the microbiome.

Sci Transl Med 2019 Jan;11(477)

Immunology Department, Weizmann Institute of Science, Rehovot 7610001, Israel.

Advances in microbiome research are spurring the development of new therapeutics for a variety of diseases, but translational challenges remain. Read More

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http://dx.doi.org/10.1126/scitranslmed.aaw1815DOI Listing
January 2019

Inhibition of polyamine synthesis and uptake reduces tumor progression and prolongs survival in mouse models of neuroblastoma.

Sci Transl Med 2019 Jan;11(477)

Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia.

Amplification of the oncogene is associated with an aggressive phenotype and poor outcome in childhood neuroblastoma. Polyamines are highly regulated essential cations that are frequently elevated in cancer cells, and the rate-limiting enzyme in polyamine synthesis, ornithine decarboxylase 1 (ODC1), is a direct transcriptional target of MYCN. Treatment of neuroblastoma cells with the ODC1 inhibitor difluoromethylornithine (DFMO), although a promising therapeutic strategy, is only partially effective at impeding neuroblastoma cell growth due to activation of compensatory mechanisms resulting in increased polyamine uptake from the surrounding microenvironment. Read More

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http://dx.doi.org/10.1126/scitranslmed.aau1099DOI Listing
January 2019
15.843 Impact Factor

Therapeutic targeting of the RB1 pathway in retinoblastoma with the oncolytic adenovirus VCN-01.

Sci Transl Med 2019 Jan;11(476)

Institut de Recerca Sant Joan de Deu, Barcelona 08950, Spain.

Retinoblastoma is a pediatric solid tumor of the retina activated upon homozygous inactivation of the tumor suppressor VCN-01 is an oncolytic adenovirus designed to replicate selectively in tumor cells with high abundance of free E2F-1, a consequence of a dysfunctional RB1 pathway. Thus, we reasoned that VCN-01 could provide targeted therapeutic activity against even chemoresistant retinoblastoma. In vitro, VCN-01 effectively killed patient-derived retinoblastoma models. Read More

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http://dx.doi.org/10.1126/scitranslmed.aat9321DOI Listing
January 2019
1 Read

Cyclin G1 and TASCC regulate kidney epithelial cell G-M arrest and fibrotic maladaptive repair.

Sci Transl Med 2019 Jan;11(476)

Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.

Fibrosis contributes to the progression of chronic kidney disease (CKD). Severe acute kidney injury can lead to CKD through proximal tubular cell (PTC) cycle arrest in the G-M phase, with secretion of profibrotic factors. Here, we show that epithelial cells in the G-M phase form target of rapamycin (TOR)-autophagy spatial coupling compartments (TASCCs), which promote profibrotic secretion similar to the senescence-associated secretory phenotype. Read More

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http://dx.doi.org/10.1126/scitranslmed.aav4754DOI Listing
January 2019
9 Reads
15.843 Impact Factor

Rapamycin and Alzheimer's disease: Time for a clinical trial?

Sci Transl Med 2019 Jan;11(476)

Department of Cellular and Integrative Physiology, Barshop Institute for Longevity and Aging Studies and Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health San Antonio, San Antonio, TX 78229, USA.

The drug rapamycin has beneficial effects in a number of animal models of neurodegeneration and aging including mouse models of Alzheimer's disease. Despite its compelling preclinical record, no clinical trials have tested rapamycin or other mTOR inhibitors in patients with Alzheimer's disease. We argue that such clinical trials should be undertaken. Read More

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http://dx.doi.org/10.1126/scitranslmed.aar4289DOI Listing
January 2019
3 Reads

A recombinant human protein targeting HER2 overcomes drug resistance in HER2-positive breast cancer.

Sci Transl Med 2019 Jan;11(476)

Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.

Resistance to current human epidermal growth factor receptor 2 (HER2) inhibitors, such as trastuzumab (Ttzm), is a major unresolved clinical problem in HER2-positive breast cancer (HER2-BC). Because HER2 remains overexpressed in drug-resistant HER2-BC cells, we investigated whether PEPD can overcome the resistance. PEPD is a recombinant enzymatically inactive mutant of human peptidase D, which strongly inhibits HER2 in cancer cells by binding to its extracellular domain. Read More

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http://dx.doi.org/10.1126/scitranslmed.aav1620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409101PMC
January 2019
3 Reads

Hypertrophic cardiomyopathy mutations in dysregulate myosin.

Sci Transl Med 2019 Jan;11(476)

Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

The mechanisms by which truncating mutations in (encoding cardiac myosin-binding protein C; cMyBPC) or myosin missense mutations cause hypercontractility and poor relaxation in hypertrophic cardiomyopathy (HCM) are incompletely understood. Using genetic and biochemical approaches, we explored how depletion of cMyBPC altered sarcomere function. We demonstrated that stepwise loss of cMyBPC resulted in reciprocal augmentation of myosin contractility. Read More

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http://stm.sciencemag.org/lookup/doi/10.1126/scitranslmed.aa
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http://dx.doi.org/10.1126/scitranslmed.aat1199DOI Listing
January 2019
16 Reads

An engineered Nissle improves hyperammonemia and survival in mice and shows dose-dependent exposure in healthy humans.

Sci Transl Med 2019 Jan;11(475)

Synlogic Inc., 301 Binney Street, Cambridge, MA 02142, USA.

The intestine is a major source of systemic ammonia (NH); thus, capturing part of gut NH may mitigate disease symptoms in conditions of hyperammonemia such as urea cycle disorders and hepatic encephalopathy. As an approach to the lowering of blood ammonia arising from the intestine, we engineered the orally delivered probiotic Nissle 1917 to create strain SYNB1020 that converts NH to l-arginine (l-arg). We up-regulated arginine biosynthesis in SYNB1020 by deleting a negative regulator of l-arg biosynthesis and inserting a feedback-resistant l-arg biosynthetic enzyme. Read More

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http://dx.doi.org/10.1126/scitranslmed.aau7975DOI Listing
January 2019
4 Reads

Clinical-grade stem cell-derived retinal pigment epithelium patch rescues retinal degeneration in rodents and pigs.

Sci Transl Med 2019 Jan;11(475)

Unit on Ocular and Stem Cell Translational Research, National Eye Institute, NIH, Bethesda, MD 20892, USA.

Considerable progress has been made in testing stem cell-derived retinal pigment epithelium (RPE) as a potential therapy for age-related macular degeneration (AMD). However, the recent reports of oncogenic mutations in induced pluripotent stem cells (iPSCs) underlie the need for robust manufacturing and functional validation of clinical-grade iPSC-derived RPE before transplantation. Here, we developed oncogenic mutation-free clinical-grade iPSCs from three AMD patients and differentiated them into clinical-grade iPSC-RPE patches on biodegradable scaffolds. Read More

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http://dx.doi.org/10.1126/scitranslmed.aat5580DOI Listing
January 2019
1 Read
15.843 Impact Factor