Showing papers by "University of Texas Southwestern Medical Center published in 2017"
TL;DR: This work has shown that liquid–liquid phase separation driven by multivalent macromolecular interactions is an important organizing principle for biomolecular condensates and has proposed a physical framework for this organizing principle.
Abstract: In addition to membrane-bound organelles, eukaryotic cells feature various membraneless compartments, including the centrosome, the nucleolus and various granules. Many of these compartments form through liquid–liquid phase separation, and the principles, mechanisms and regulation of their assembly as well as their cellular functions are now beginning to emerge. Biomolecular condensates are micron-scale compartments in eukaryotic cells that lack surrounding membranes but function to concentrate proteins and nucleic acids. These condensates are involved in diverse processes, including RNA metabolism, ribosome biogenesis, the DNA damage response and signal transduction. Recent studies have shown that liquid–liquid phase separation driven by multivalent macromolecular interactions is an important organizing principle for biomolecular condensates. With this physical framework, it is now possible to explain how the assembly, composition, physical properties and biochemical and cellular functions of these important structures are regulated.
3,294 citations
Wayne State University1, Columbia University2, Trinity College, Dublin3, Imperial College London4, University of Glasgow5, French Institute of Health and Medical Research6, University of Western Ontario7, Children's Hospital Oakland Research Institute8, University of the Witwatersrand9, Technische Universität München10, University of Western Australia11, Sahlgrenska University Hospital12, Oregon Health & Science University13, University of Texas Southwestern Medical Center14, University of Adelaide15, Copenhagen University Hospital16, University of Copenhagen17, University Medical Center Groningen18, Helsinki University Central Hospital19, Hacettepe University20, Charité21, Saarland University22, University of Gothenburg23, University of Milan24
TL;DR: Consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD.
Abstract: Aims
To appraise the clinical and genetic evidence that low-density lipoproteins (LDLs) cause atherosclerotic cardiovascular disease (ASCVD).
2,003 citations
TL;DR: Genome-wide analyses of the clock transcriptional feedback loop have revealed a global circadian regulation of processes such as transcription factor occupancy, RNA polymerase II recruitment and initiation, nascent transcription, and chromatin remodelling.
Abstract: Circadian clocks are endogenous oscillators that control 24-hour physiological and behavioural processes in organisms. These cell-autonomous clocks are composed of a transcription-translation-based autoregulatory feedback loop. With the development of next-generation sequencing approaches, biochemical and genomic insights into circadian function have recently come into focus. Genome-wide analyses of the clock transcriptional feedback loop have revealed a global circadian regulation of processes such as transcription factor occupancy, RNA polymerase II recruitment and initiation, nascent transcription, and chromatin remodelling. The genomic targets of circadian clocks are pervasive and are intimately linked to the regulation of metabolism, cell growth and physiology.
1,538 citations
TL;DR: In this paper, the authors define pathways that are limiting for cancer progression and understand the context specificity of metabolic preferences and liabilities in malignant cells, which can guide the more effective targeting of metabolism to help patients.
1,427 citations
TL;DR: Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo.
Abstract: BackgroundThe cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. MethodsWe randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. ResultsIn all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2...
1,316 citations
Cornell University1, Paris Descartes University2, University of Massachusetts Medical School3, Spanish National Research Council4, University of Rome Tor Vergata5, Boston Children's Hospital6, University of Pittsburgh7, National University of Cuyo8, National Scientific and Technical Research Council9, Albert Einstein College of Medicine10, University of California, San Francisco11, University of New Mexico12, Goethe University Frankfurt13, University of Split14, University of Helsinki15, University of Salento16, German Cancer Research Center17, Virginia Commonwealth University18, St. Jude Children's Research Hospital19, Discovery Institute20, Harvard University21, University of Tromsø22, Hungarian Academy of Sciences23, Eötvös Loránd University24, New York University25, University of Vienna26, Babraham Institute27, University of South Australia28, Howard Hughes Medical Institute29, University of Texas Southwestern Medical Center30, University of Oviedo31, University of Graz32, National Institutes of Health33, City University of New York34, Queens College35, University of Tokyo36, University of Zurich37, Novartis38, Austrian Academy of Sciences39, University of Groningen40, University of Cambridge41, University of Padua42, University of Oxford43, University of Bern44, University of Oslo45, University of Crete46, Foundation for Research & Technology – Hellas47, Francis Crick Institute48, Osaka University49, Icahn School of Medicine at Mount Sinai50
TL;DR: A panel of leading experts in the field attempts here to define several autophagy‐related terms based on specific biochemical features to formulate recommendations that facilitate the dissemination of knowledge within and outside the field of autophagic research.
Abstract: Over the past two decades, the molecular machinery that underlies autophagic responses has been characterized with ever increasing precision in multiple model organisms. Moreover, it has become clear that autophagy and autophagy-related processes have profound implications for human pathophysiology. However, considerable confusion persists about the use of appropriate terms to indicate specific types of autophagy and some components of the autophagy machinery, which may have detrimental effects on the expansion of the field. Driven by the overt recognition of such a potential obstacle, a panel of leading experts in the field attempts here to define several autophagy-related terms based on specific biochemical features. The ultimate objective of this collaborative exchange is to formulate recommendations that facilitate the dissemination of knowledge within and outside the field of autophagy research.
1,095 citations
Memorial Sloan Kettering Cancer Center1, Cornell University2, University of Texas MD Anderson Cancer Center3, University of Colorado Denver4, Harvard University5, NewYork–Presbyterian Hospital6, Northwestern University7, Sarah Cannon Research Institute8, University of Texas Southwestern Medical Center9, City of Hope National Medical Center10, Cleveland Clinic11, University of Miami12, Stanford University13, Université Paris-Saclay14, Institut Gustave Roussy15, University of Oxford16, Celgene17, Agios Pharmaceuticals18
TL;DR: Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib, a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes.
1,084 citations
Cedars-Sinai Medical Center1, NewYork–Presbyterian Hospital2, Duke University3, University of California, Los Angeles4, University of North Carolina at Chapel Hill5, Northwestern University6, Morton Plant Hospital7, University of Texas Southwestern Medical Center8, Michigan State University9, University of Texas MD Anderson Cancer Center10, Memorial Sloan Kettering Cancer Center11
TL;DR: Findings do not support routine use of axillary lymph node dissection in this patient population based on 10-year outcomes, and overall survival for patients treated with sentinel lymph nodes dissection alone was noninferior toOverall survival for those treated with axillary node dissections.
Abstract: Importance The results of the American College of Surgeons Oncology Group Z0011 (ACOSOG Z0011) trial were first reported in 2005 with a median follow-up of 6.3 years. Longer follow-up was necessary because the majority of the patients had estrogen receptor–positive tumors that may recur later in the disease course (the ACOSOG is now part of the Alliance for Clinical Trials in Oncology). Objective To determine whether the 10-year overall survival of patients with sentinel lymph node metastases treated with breast-conserving therapy and sentinel lymph node dissection (SLND) alone without axillary lymph node dissection (ALND) is noninferior to that of women treated with axillary dissection. Design, Setting, and Participants The ACOSOG Z0011 phase 3 randomized clinical trial enrolled patients from May 1999 to December 2004 at 115 sites (both academic and community medical centers). The last date of follow-up was September 29, 2015, in the ACOSOG Z0011 (Alliance) trial. Eligible patients were women with clinical T1 or T2 invasive breast cancer, no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases. Interventions All patients had planned lumpectomy, planned tangential whole-breast irradiation, and adjuvant systemic therapy. Third-field radiation was prohibited. Main Outcomes and Measures The primary outcome was overall survival with a noninferiority hazard ratio (HR) margin of 1.3. The secondary outcome was disease-free survival. Results Among 891 women who were randomized (median age, 55 years), 856 (96%) completed the trial (446 in the SLND alone group and 445 in the ALND group). At a median follow-up of 9.3 years (interquartile range, 6.93-10.34 years), the 10-year overall survival was 86.3% in the SLND alone group and 83.6% in the ALND group (HR, 0.85 [1-sided 95% CI, 0-1.16]; noninferiorityP = .02). The 10-year disease-free survival was 80.2% in the SLND alone group and 78.2% in the ALND group (HR, 0.85 [95% CI, 0.62-1.17];P = .32). Between year 5 and year 10, 1 regional recurrence was seen in the SLND alone group vs none in the ALND group. Ten-year regional recurrence did not differ significantly between the 2 groups. Conclusions and Relevance Among women with T1 or T2 invasive primary breast cancer, no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases, 10-year overall survival for patients treated with sentinel lymph node dissection alone was noninferior to overall survival for those treated with axillary lymph node dissection. These findings do not support routine use of axillary lymph node dissection in this patient population based on 10-year outcomes. Trial Registration clinicaltrials.gov Identifier:NCT00003855
1,021 citations
TL;DR: The data indicate that tumors, including bona fide human NSCLC, can use lactate as a fuel in vivo, and directly comparing lactate and glucose metabolism in vivo indicated that lactate's contribution to the TCA cycle predominates.
792 citations
Memorial Sloan Kettering Cancer Center1, University of California, Los Angeles2, Yale University3, Fox Chase Cancer Center4, Johns Hopkins University5, Duke University6, University of Texas Southwestern Medical Center7, University of Washington8, McMaster University9, Princess Margaret Cancer Centre10, University of Ottawa11, Bristol-Myers Squibb12
TL;DR: The primary outcome was safety and tolerability, assessed in all treated patients, and data from the latter two cohorts, which were considered potentially suitable for further clinical development, are presented.
Abstract: Summary Background Nivolumab has shown improved survival in the treatment of advanced non-small-cell lung cancer (NSCLC) previously treated with chemotherapy. We assessed the safety and activity of combination nivolumab plus ipilimumab as first-line therapy for NSCLC. Methods The open-label, phase 1, multicohort study (CheckMate 012) cohorts reported here were enrolled at eight US academic centres. Eligible patients were aged 18 years or older with histologically or cytologically confirmed recurrent stage IIIb or stage IV, chemotherapy-naive NSCLC. Patients were randomly assigned (1:1:1) by an interactive voice response system to receive nivolumab 1 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks, nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 12 weeks, or nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks until disease progression, unacceptable toxicities, or withdrawal of consent. Data from the latter two cohorts, which were considered potentially suitable for further clinical development, are presented in this report; data from the other cohort (as well as several earlier cohorts) are described in the appendix. The primary outcome was safety and tolerability, assessed in all treated patients. This ongoing study is registered with ClinicalTrials.gov, number NCT01454102. Findings Between May 15, 2014, and March 25, 2015, 78 patients were randomly assigned to receive nivolumab every 2 weeks plus ipilimumab every 12 weeks (n=38) or nivolumab every 2 weeks plus ipilimumab every 6 weeks (n=40). One patient in the ipilimumab every-6-weeks cohort was excluded before treatment; therefore 77 patients actually received treatment (38 in the ipilimumab every-12-weeks cohort; 39 in the ipilimumab every-6-weeks cohort). At data cut-off on Jan 7, 2016, 29 (76%) patients in the ipilimumab every-12-weeks cohort and 32 (82%) in the ipilimumab every-6-weeks cohort had discontinued treatment. Grade 3–4 treatment-related adverse events occurred in 14 (37%) patients in the ipilimumab every-12-weeks cohort and 13 (33%) patients in the every-6-weeks cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (three [8%] and no patients), pneumonitis (two [5%] and one [3%] patients), adrenal insufficiency (one [3%] and two [5%] patients), and colitis (one [3%] and two [5%] patients). Treatment-related serious adverse events were reported in 12 (32%) patients in the ipilimumab every-12-weeks cohort and 11 (28%) patients in the every-6-weeks cohort. Treatment-related adverse events (any grade) prompted treatment discontinuation in four (11%) patients in the every-12-weeks cohort and five (13%) patients in the every-6-weeks cohort. No treatment-related deaths occurred. Confirmed objective responses were achieved in 18 (47% [95% CI 31–64]) patients in the ipilimumab every-12-weeks cohort and 15 (38% [95% CI 23–55]) patients in the ipilimumab every-6-weeks cohort; median duration of response was not reached in either cohort, with median follow-up times of 12·8 months (IQR 9·3–15·5) in the ipilimumab every-12-weeks cohort and 11·8 months (6·7–15·9) in the ipilimumab every-6-weeks cohort. In patients with PD-L1 of 1% or greater, confirmed objective responses were achieved in 12 (57%) of 21 patients in the ipilimumab every-12-weeks cohort and 13 (57%) of 23 patients in the ipilimumab every-6-weeks cohort. Interpretation In NSCLC, first-line nivolumab plus ipilimumab had a tolerable safety profile and showed encouraging clinical activity characterised by a high response rate and durable response. To our knowledge, the results of this study are the first suggestion of improved benefit compared with anti-PD-1 monotherapy in patients with NSCLC, supporting further assessment of this combination in a phase 3 study. Funding Bristol-Myers Squibb.
784 citations
TL;DR: Three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease are observed, providing additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's Disease.
Abstract: We identified rare coding variants associated with Alzheimer's disease in a three-stage case–control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10−4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10−8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10−10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10−10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10−14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein–protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
TL;DR: Data that provide new mechanistic explanations for the success or failure of radiotherapy are highlighted, and how the combination of immune-modulation and radiation could tip the balance of the host immune response to promote cure is postulated.
Abstract: Investigations into the interaction between radiotherapy and the host immune system have uncovered new mechanisms that can potentially be exploited to improve the efficacy of radiotherapy. Radiation promotes the release of danger signals and chemokines that recruit inflammatory cells into the tumour microenvironment, including antigen-presenting cells that activate cytotoxic T-cell function. By contrast, radiation can attract immunosuppressive cells into the tumour microenvironment. In rare circumstances, the antitumour effect of radiotherapy has been observed outside of the radiation field, known as the abscopal effect. This phenomenon is proposed to have an immune origin and indicates that local radiotherapy elicits systemic effects. Herein, we highlight data that provide new mechanistic explanations for the success or failure of radiotherapy, and postulate how the combination of immune-modulation and radiation could tip the balance of the host immune response to promote cure. We use the concept of radiation- induced tumour equilibrium (RITE) as a starting point to discuss the mechanistic influence of immune-checkpoint therapies on radiotherapy efficacy.
TL;DR: The growing field of ncRNA — including microRNA, intronic RNA, repetitive RNA and long non-coding RNA — is discussed and the potential and challenges in their therapeutic exploitation are assessed.
Abstract: Most of the human genome encodes RNAs that do not code for proteins. These non-coding RNAs (ncRNAs) may affect normal gene expression and disease progression, making them a new class of targets for drug discovery. Because their mechanisms of action are often novel, developing drugs to target ncRNAs will involve equally novel challenges. However, many potential problems may already have been solved during the development of technologies to target mRNA. Here, we discuss the growing field of ncRNA - including microRNA, intronic RNA, repetitive RNA and long non-coding RNA - and assess the potential and challenges in their therapeutic exploitation.
TL;DR: It is proposed that, under SAM-limiting conditions, METTL16 occupancy on hp1 increases due to inefficient enzymatic turnover, which promotes MAT2A splicing, which suggests that the conserved U6 snRNA methyltransferase evolved an additional function in vertebrates to regulate SAM homeostasis.
TL;DR: MRX34 treatment with dexamethasone premedication was associated with acceptable safety and showed evidence of antitumor activity in a subset of patients with refractory advanced solid tumors.
Abstract: Purpose Naturally occurring tumor suppressor microRNA-34a (miR-34a) downregulates the expression of >30 oncogenes across multiple oncogenic pathways, as well as genes involved in tumor immune evasion, but is lost or under-expressed in many malignancies. This first-in-human, phase I study assessed the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical activity of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumors. Patients and Methods Adult patients with solid tumors refractory to standard treatment were enrolled in a standard 3 + 3 dose escalation trial. MRX34 was given intravenously twice weekly (BIW) for three weeks in 4-week cycles. Results Forty-seven patients with various solid tumors, including hepatocellular carcinoma (HCC; n = 14), were enrolled. Median age was 60 years, median prior therapies was 4 (range, 1–12), and most were Caucasian (68%) and male (57%). Most common adverse events (AEs) included fever (all grade %/G3%: 64/2), fatigue (57/13), back pain (57/11), nausea (49/2), diarrhea (40/11), anorexia (36/4), and vomiting (34/4). Laboratory abnormalities included lymphopenia (G3%/G4%: 23/9), neutropenia (13/11), thrombocytopenia (17/0), increased AST (19/4), hyperglycemia (13/2), and hyponatremia (19/2). Dexamethasone premedication was required to manage infusion-related AEs. The MTD for non-HCC patients was 110 mg/m2, with two patients experiencing dose-limiting toxicities of G3 hypoxia and enteritis at 124 mg/m2. The half-life was >24 h, and Cmax and AUC increased with increasing dose. One patient with HCC achieved a prolonged confirmed PR lasting 48 weeks, and four patients experienced SD lasting ≥4 cycles. Conclusion MRX34 treatment with dexamethasone premedication was associated with acceptable safety and showed evidence of antitumor activity in a subset of patients with refractory advanced solid tumors. The MTD for the BIW schedule was 110 mg/m2 for non-HCC and 93 mg/m2 for HCC patients. Additional dose schedules of MRX34 have been explored to improve tolerability.
National Institutes of Health1, University of Texas Southwestern Medical Center2, University of Alabama at Birmingham3, Ohio State University4, Primary Children's Hospital5, University of Florida6, University of New Mexico7, New York University8, University of Virginia9, Seattle Cancer Care Alliance10, University of California, San Francisco11, University of Pennsylvania12
TL;DR: Using integrated genomic analysis of 264 T-ALL cases, 106 putative driver genes are identified and new mechanisms of coding and noncoding alteration are described, which suggests that different signaling pathways have distinct roles according to maturational stage.
Abstract: Genetic alterations that activate NOTCH1 signaling and T cell transcription factors, coupled with inactivation of the INK4/ARF tumor suppressors, are hallmarks of T-lineage acute lymphoblastic leukemia (T-ALL), but detailed genome-wide sequencing of large T-ALL cohorts has not been carried out. Using integrated genomic analysis of 264 T-ALL cases, we identified 106 putative driver genes, half of which had not previously been described in childhood T-ALL (for example, CCND3, CTCF, MYB, SMARCA4, ZFP36L2 and MYCN). We describe new mechanisms of coding and noncoding alteration and identify ten recurrently altered pathways, with associations between mutated genes and pathways, and stage or subtype of T-ALL. For example, NRAS/FLT3 mutations were associated with immature T-ALL, JAK3/STAT5B mutations in HOXA1 deregulated ALL, PTPN2 mutations in TLX1 deregulated T-ALL, and PIK3R1/PTEN mutations in TAL1 deregulated ALL, which suggests that different signaling pathways have distinct roles according to maturational stage. This genomic landscape provides a logical framework for the development of faithful genetic models and new therapeutic approaches.
TL;DR: The therapeutic potential of autophagy modulators is discussed, the obstacles that have limited their development are analysed and strategies that may unlock the full therapeutic potential in the clinic are proposed.
Abstract: Autophagy is central to the maintenance of organismal homeostasis in both physiological and pathological situations Accordingly, alterations in autophagy have been linked to clinically relevant conditions as diverse as cancer, neurodegeneration and cardiac disorders Throughout the past decade, autophagy has attracted considerable attention as a target for the development of novel therapeutics However, such efforts have not yet generated clinically viable interventions In this Review, we discuss the therapeutic potential of autophagy modulators, analyse the obstacles that have limited their development and propose strategies that may unlock the full therapeutic potential of autophagy modulation in the clinic
TL;DR: It is shown that cGAS mediates cellular senescence and retards immortalization, a cytosolic DNA sensor that activates innate immunity, which is distinct from, and complementary to, the role ofcGAS in activating antitumor immunity.
Abstract: Cellular senescence is a natural barrier to tumorigenesis and it contributes to the antitumor effects of several therapies, including radiation and chemotherapeutic drugs. Senescence also plays an important role in aging, fibrosis, and tissue repair. The DNA damage response is a key event leading to senescence, which is characterized by the senescence-associated secretory phenotype (SASP) that includes expression of inflammatory cytokines. Here we show that cGMP-AMP (cGAMP) synthase (cGAS), a cytosolic DNA sensor that activates innate immunity, is essential for senescence. Deletion of cGAS accelerated the spontaneous immortalization of mouse embryonic fibroblasts. cGAS deletion also abrogated SASP induced by spontaneous immortalization or DNA damaging agents, including radiation and etoposide. cGAS is localized in the cytoplasm of nondividing cells but enters the nucleus and associates with chromatin DNA during mitosis in proliferating cells. DNA damage leads to accumulation of damaged DNA in cytoplasmic foci that contain cGAS. In human lung adenocarcinoma patients, low expression of cGAS is correlated with poor survival. These results indicate that cGAS mediates cellular senescence and retards immortalization. This is distinct from, and complementary to, the role of cGAS in activating antitumor immunity.
TL;DR: This data indicates that pre-emptive surgery is a viable option for the treatment of deep vein thrombosis in women with pre-operative indications and this work’s results support this view.
Abstract: Disclosures outside the scope of this work: Dr. Minei receiv grant support from Irrespet Corp. AtoxBio. Dr. Laronga rec sation for lectures from Genomic Health Inc. and royalties Date. Dr. Jensen is a consultant and paid speaker for Ethico ceives honoraria from CareFusion for their Speaker’s Progr from Irrimax Corp. for consulting and Research Funding honoraria from Surgical Inc. for consultation. Dr. Itani for a multi-institutional study for Sanofi-Pastuer and the Committee Chair. Dr. Dellinger is on the Advisory B Melinta, and Therevance and a grant recipient from Moti trial of iclaprim vs. vancomycin for treatment of skin and so tions. The remaining authors declare no conflicts. Presented at the Surgical Infection Society, Palm Beach, FL
TL;DR: A minimalist nanovaccine by a simple physical mixture of an antigen with a synthetic polymeric nanoparticle, PC7A NP, which generated a strong cytotoxic T cell response with low systemic cytokine expression is reported, suggesting generation of long-term antitumor memory.
Abstract: The generation of tumour-specific T cells is critically important for cancer immunotherapy. A major challenge in achieving a robust T-cell response is the spatiotemporal orchestration of antigen cross-presentation in antigen-presenting cells with innate stimulation. Here, we report a minimalist nanovaccine, comprising a simple physical mixture of an antigen and a synthetic polymeric nanoparticle, PC7A NP, which generates a strong cytotoxic T-cell response with low systemic cytokine expression. Mechanistically, the PC7A NP achieves efficient cytosolic delivery of tumour antigens to antigen-presenting cells in draining lymph nodes, leading to increased surface presentation while simultaneously activating type I interferon-stimulated genes. This effect is dependent on stimulator of interferon genes (STING), but not the Toll-like receptor or the mitochondrial antiviral-signalling protein (MAVS) pathway. The nanovaccine led to potent tumour growth inhibition in melanoma, colon cancer and human papilloma virus-E6/E7 tumour models. The combination of the PC7A nanovaccine and an anti-PD-1 antibody showed great synergy, with 100% survival over 60 days in a TC-1 tumour model. Rechallenging of these tumour-free animals with TC-1 cells led to complete inhibition of tumour growth, suggesting the generation of long-term antitumour memory. The STING-activating nanovaccine offers a simple, safe and robust strategy in boosting anti-tumour immunity for cancer immunotherapy.
University of Toronto1, Tulane University2, Ohio State University3, Hannover Medical School4, University of Texas Southwestern Medical Center5, Washington University in St. Louis6, University of California, San Francisco7, Laval University8, Boston Children's Hospital9, University of Hamburg10, University of Pennsylvania11, Sheba Medical Center12, University of Padua13, University of Pittsburgh14, Oregon Health & Science University15, Medical College of Wisconsin16, University of New South Wales17, Medical University of South Carolina18, University of Manitoba19, Tel Aviv University20, Tel Aviv Sourasky Medical Center21, Saint George Hospital22, University of Wisconsin-Madison23
TL;DR: An extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations, uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load.
TL;DR: Solid-state nuclear magnetic resonance methods are used to characterize the molecular structure of self-assembling fibrils formed by the LC domain of the fused in sarcoma (FUS) RNA-binding protein, offering a structural basis for understanding LC domain self-assembly, phase separation, and regulation by post-translational modification.
Cleveland Clinic1, University of Adelaide2, Eli Lilly and Company3, University of New South Wales4, University of Edinburgh5, Beth Israel Deaconess Medical Center6, Sorbonne7, Columbia University8, St. Michael's Hospital9, University of Texas Southwestern Medical Center10, University of São Paulo11, Harbin Medical University12, St. Michael's GAA, Sligo13
TL;DR: Treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high‐risk vascular disease, and had favorable effects on established lipid biomarkers.
Abstract: BackgroundThe cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease MethodsIn a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy The primary efficacy end point was the first occurrence of any component of the composite of death from car
TL;DR: Chronic social defeat stress induces loss of protein claudin-5, leading to abnormalities in blood vessel morphology, increased blood brain barrier permeability, infiltration of immune signals and depression-like behaviors.
Abstract: Studies suggest that heightened peripheral inflammation contributes to the pathogenesis of major depressive disorder. We investigated the effect of chronic social defeat stress, a mouse model of depression, on blood–brain barrier (BBB) permeability and infiltration of peripheral immune signals. We found reduced expression of the endothelial cell tight junction protein claudin-5 (Cldn5) and abnormal blood vessel morphology in nucleus accumbens (NAc) of stress-susceptible but not resilient mice. CLDN5 expression was also decreased in NAc of depressed patients. Cldn5 downregulation was sufficient to induce depression-like behaviors following subthreshold social stress whereas chronic antidepressant treatment rescued Cldn5 loss and promoted resilience. Reduced BBB integrity in NAc of stress-susceptible or mice injected with adeno-associated virus expressing shRNA against Cldn5 caused infiltration of the peripheral cytokine interleukin-6 (IL-6) into brain parenchyma and subsequent expression of depression-like behaviors. These findings suggest that chronic social stress alters BBB integrity through loss of tight junction protein Cldn5, promoting peripheral IL-6 passage across the BBB and depression. Chronic social defeat stress induces loss of protein claudin-5, leading to abnormalities in blood vessel morphology, increased blood brain barrier permeability, infiltration of immune signals and depression-like behaviors.
TL;DR: It is demonstrated that the endogenous regenerative properties of the adult mammalian heart can be reactivated by exposure to gradual systemic hypoxaemia, and the potential therapeutic role of hypoxia in regenerative medicine is highlighted.
Abstract: The adult mammalian heart is incapable of regeneration following cardiomyocyte loss, which underpins the lasting and severe effects of cardiomyopathy Recently, it has become clear that the mammalian heart is not a post-mitotic organ For example, the neonatal heart is capable of regenerating lost myocardium, and the adult heart is capable of modest self-renewal In both of these scenarios, cardiomyocyte renewal occurs via the proliferation of pre-existing cardiomyocytes, and is regulated by aerobic-respiration-mediated oxidative DNA damage Therefore, we reasoned that inhibiting aerobic respiration by inducing systemic hypoxaemia would alleviate oxidative DNA damage, thereby inducing cardiomyocyte proliferation in adult mammals Here we report that, in mice, gradual exposure to severe systemic hypoxaemia, in which inspired oxygen is gradually decreased by 1% and maintained at 7% for 2 weeks, results in inhibition of oxidative metabolism, decreased reactive oxygen species production and oxidative DNA damage, and reactivation of cardiomyocyte mitosis Notably, we find that exposure to hypoxaemia 1 week after induction of myocardial infarction induces a robust regenerative response with decreased myocardial fibrosis and improvement of left ventricular systolic function Genetic fate-mapping analysis confirms that the newly formed myocardium is derived from pre-existing cardiomyocytes These results demonstrate that the endogenous regenerative properties of the adult mammalian heart can be reactivated by exposure to gradual systemic hypoxaemia, and highlight the potential therapeutic role of hypoxia in regenerative medicine
TL;DR: Over the past 5 years, there has been a worldwide resurgence of studies on SCLC, including comprehensive molecular analyses, the development of relevant genetically engineered mouse models and the establishment of patient-derived xenografts, which have led to the discovery of new potential therapeutic vulnerabilities for SCLc and therefore to new clinical trials.
Abstract: Small-cell lung cancer (SCLC) is a deadly tumour accounting for approximately 15% of lung cancers and is pathologically, molecularly, biologically and clinically very different from other lung cancers. While the majority of tumours express a neuroendocrine programme (integrating neural and endocrine properties), an important subset of tumours have low or absent expression of this programme. The probable initiating molecular events are inactivation of TP53 and RB1, as well as frequent disruption of several signalling networks, including Notch signalling. SCLC, when diagnosed, is usually widely metastatic and initially responds to cytotoxic therapy but nearly always rapidly relapses with resistance to further therapies. There were no important therapeutic clinical advances for 30 years, leading SCLC to be designated a 'recalcitrant cancer'. Scientific studies are hampered by a lack of tissue availability. However, over the past 5 years, there has been a worldwide resurgence of studies on SCLC, including comprehensive molecular analyses, the development of relevant genetically engineered mouse models and the establishment of patient-derived xenografts. These studies have led to the discovery of new potential therapeutic vulnerabilities for SCLC and therefore to new clinical trials. Thus, while the past has been bleak, the future offers greater promise.
University of Texas MD Anderson Cancer Center1, Johns Hopkins University2, University of Texas Southwestern Medical Center3, Mayo Clinic4, State University of New York Upstate Medical University5, University of Alabama at Birmingham6, Washington University in St. Louis7, Texas Oncology8, University of Pittsburgh9, Christiana Care Health System10, Baptist Health11, Ottawa Hospital Research Institute12
TL;DR: IMRT was associated with lower rates of severe pneumonitis and cardiac doses in NRG Oncology clinical trial RTOG 0617, which supports routine use of IMRT for locally advanced NSCLC.
Abstract: PurposeAlthough intensity-modulated radiation therapy (IMRT) is increasingly used to treat locally advanced non–small-cell lung cancer (NSCLC), IMRT and three-dimensional conformal external beam radiation therapy (3D-CRT) have not been compared prospectively. This study compares 3D-CRT and IMRT outcomes for locally advanced NSCLC in a large prospective clinical trial.Patients and MethodsA secondary analysis was performed to compare IMRT with 3D-CRT in NRG Oncology clinical trial RTOG 0617, in which patients received concurrent chemotherapy of carboplatin and paclitaxel with or without cetuximab, and 60- versus 74-Gy radiation doses. Comparisons included 2-year overall survival (OS), progression-free survival, local failure, distant metastasis, and selected Common Terminology Criteria for Adverse Events (version 3) ≥ grade 3 toxicities.ResultsThe median follow-up was 21.3 months. Of 482 patients, 53% were treated with 3D-CRT and 47% with IMRT. The IMRT group had larger planning treatment volumes (median, 4...
TL;DR: The majority of recent publications that used data from the NIS, the majority did not adhere to required practices, and further research is needed to identify strategies to improve the quality of research using the N IS and assess whether there are similar problems with use of other publicly available data sets.
Abstract: Importance Publicly available data sets hold much potential, but their unique design may require specific analytic approaches. Objective To determine adherence to appropriate research practices for a frequently used large public database, the National Inpatient Sample (NIS) of the Agency for Healthcare Research and Quality (AHRQ). Design, Setting, and Participants In this observational study of the 1082 studies published using the NIS from January 2015 through December 2016, a representative sample of 120 studies was systematically evaluated for adherence to practices required by AHRQ for the design and conduct of research using the NIS. Exposures None. Main Outcomes and Measures All studies were evaluated on 7 required research practices based on AHRQ’s recommendations and compiled under 3 domains: (1) data interpretation (interpreting data as hospitalization records rather than unique patients); (2) research design (avoiding use in performing state-, hospital-, and physician-level assessments where inappropriate; not using nonspecific administrative secondary diagnosis codes to study in-hospital events); and (3) data analysis (accounting for complex survey design of the NIS and changes in data structure over time). Results Of 120 published studies, 85% (n = 102) did not adhere to 1 or more required practices and 62% (n = 74) did not adhere to 2 or more required practices. An estimated 925 (95% CI, 852-998) NIS publications did not adhere to 1 or more required practices and 696 (95% CI, 596-796) NIS publications did not adhere to 2 or more required practices. A total of 79 sampled studies (68.3% [95% CI, 59.3%-77.3%]) among the 1082 NIS studies screened for eligibility did not account for the effects of sampling error, clustering, and stratification; 62 (54.4% [95% CI, 44.7%-64.0%]) extrapolated nonspecific secondary diagnoses to infer in-hospital events; 45 (40.4% [95% CI, 30.9%-50.0%]) miscategorized hospitalizations as individual patients; 10 (7.1% [95% CI, 2.1%-12.1%]) performed state-level analyses; and 3 (2.9% [95% CI, 0.0%-6.2%]) reported physician-level volume estimates. Of 27 studies (weighted; 218 studies [95% CI, 134-303]) spanning periods of major changes in the data structure of the NIS, 21 (79.7% [95% CI, 62.5%-97.0%]) did not account for the changes. Among the 24 studies published in journals with an impact factor of 10 or greater, 16 (67%) did not adhere to 1 or more practices, and 9 (38%) did not adhere to 2 or more practices. Conclusions and Relevance In this study of 120 recent publications that used data from the NIS, the majority did not adhere to required practices. Further research is needed to identify strategies to improve the quality of research using the NIS and assess whether there are similar problems with use of other publicly available data sets.
TL;DR: The inner mitochondrial membrane protein, PHB2, is identified as a crucial mitophagy receptor involved in targeting mitochondria for autophagic degradation and a function of prohibitin 2 that may underlie its roles in physiology, aging, and disease is demonstrated.
The Catholic University of America1, University of Central Florida2, UCL Institute of Child Health3, University of Cologne4, Columbia University Medical Center5, Harvard University6, French Institute of Health and Medical Research7, University of Utah8, Children's Hospital of Philadelphia9, University of Wisconsin-Madison10, Boston Children's Hospital11, University of Freiburg12, University of Texas Southwestern Medical Center13, Johns Hopkins University14, Newcastle University15, Karolinska Institutet16
TL;DR: The methods used to achieve these recommendations are presented, and an update on diagnosis, rehabilitation, orthopedic and spinal management; and nutritional, swallowing and gastrointestinal management are presented.