Background: Prehospital plasma improves survival in severely injured trauma patients at risk for hemorrhagic shock and transported by air ambulance. We hypothesized that prehospital plasma would be associated with a reduction in immune imbalance and endothelial damage. Methods: We collected blood samples from 405 trauma patients enrolled in the Prehospital Air MedicalPlasma (PAMPer) trial upon hospital admission (0 hours) and 24 hours post admission across 6 U.S. sites(9 level-one trauma centers) with air medical transport services. We assayed samples for 21 inflammatory mediators and 7 markers of endothelial damage. We performed hierarchical clustering analysis (HCA) on principal components of these biomarkers of the immune response and endothelial injury. Regression analysis was used to control for known differences across study arms near the time of randomization and to assess any association with prehospital plasma administration. Results: HCA based on inflammatory mediator and endothelial damage marker concentrations distinguished two patient clusters, each with different injury patterns and outcomes. Patients in cluster A had greater injury severity and incidence of blunt trauma, traumatic brain injury, and mortality. Cluster A patients that received prehospital plasma as compared to standard care fluid resuscitation showed improved 30-day survival. Prehospital plasma did not improve survival in cluster B patients. In an adjusted analysis of themost seriously injured patients (ISS>30), plasma was associated with a an increase in circulating levels of adiponectin, IL-1β, IL-17A, IL-23, and IL-17E upon admission. One day following admission, prehospital plasmas was associated with a reduction in syndecan-1, TM, VEGF, IL-6, IP-10, MCP-1, and TNF-α, and an increase in IL-33, IL-21, IL-23, and IL-17E. Conclusion: This is the first human study to suggest that prehospital plasma may ameliorate the endotheliopathy of trauma and modulate an imbalance between pro-inflammatory (e.g. IL-6, TNF-α, and MCP-1) and protective (e.g. IL-33 and IL-17E) mediators. These effects of early plasma administration may contribute to improved survival in severely injured patients. Trial Registration: ClinicalTrials.gov NCT01818427 Funding: National Institutes of Health T32; U.S. Army Medical Research and Materiel Command W81XWH-12-2-0023; National Institutes of Health R35; National Institutes of Health 1R35GM119526-01; the Office of the Assistant Secretary of Defense for Health Affairs, through the Defense Medical Research and Development Program W81XWH-18-2-0051 and W81XWH-15-PRORP-OCRCA. Opinions, interpretations, conclusions and recommendations are those of the authors and not necessarily endorsed by the Department of Defense.
Danielle S. Gruen, Joshua B. Brown, Francis X. Guyette, Yoram Vodovotz, Par I. Johansson, Jakob Stensballe, Derek A. Barclay, Jinling Yin, Brian J. Daley, Richard S. Miller, Brian G. Harbrecht, Jeffrey A. Claridge, Herb A. Phelan, Matthew D. Neal, Brian Zuckerbraun, Timothy R. Billiar, Jason L. Sperry
Background: Specific features of the tumor microenvironment (TME) may provide useful prognostic information. We conducted a systematic investigation of the cellular composition and prognostic landscape of TME in gastric cancer. Methods: We evaluated the prognostic significance of major stromal and immune cells within TME. We proposed a composite TME-based risk score and tested it in six independent cohorts of 1,678 patients with gene expression or immunohistochemistry measurements. Further, we devised a new patient classification system based on TME characteristics. Results: We identified natural killer cells, fibroblasts, and endothelial cells as the most robust prognostic markers. The TME risk score combining these cell types was an independent prognostic factor when adjusted for clinicopathologic variables (gene expression: HR [95% CI]: 1.42 [1.22–1.66]; immunohistochemistry: 1.34 [1.24–1.45], P<0.0001). Higher TME risk scores consistently associated with worse survival within every pathologic stage (HR range: 2.18-3.11, P<0.02) and among patients who received surgery only. The TME risk score provided additional prognostic value beyond stage, and combination of the two improved prognostication accuracy (likelihood-ratio test χ2 = 235.4 vs. 187.6, P<0.0001; net reclassification index: 23%). The TME risk score can predict the survival benefit of adjuvant chemotherapy in non-metastatic patients (stage I-III) (interaction test P<0.02). Patients were divided into four TME subtypes that demonstrated distinct genetic and molecular patterns and complemented established genomic and molecular subtypes. Conclusion: We developed and validated a TME-based risk score as an independent prognostic and predictive factor, which has the potential to guide personalized management of gastric cancer.
Bailiang Li, Yuming Jiang, Guoxin Li, George A. Fisher, Ruijiang Li
BACKGROUND. Lower-grade gliomas (LGGs) vary widely in terms of the patient’s overall survival (OS). There is a lack of valid method that could exactly predict the survival. The effects of intratumoral immune infiltration on clinical outcome have been widely reported. Thus, we aim to develop an immune infiltration signature to predict the survival of LGG patients. METHODS. We analyzed 1216 LGGs from 5 public datasets, including 2 RNA-Seq datasets and 3 microarray datasets. Least absolute shrinkage and selection operator (LASSO) Cox regression was used to select an immune infiltration signature and build a risk score. The performance of the risk score was assessed in the training set (329 patients), internal validation set (140 patients), and 4 external validation sets (405, 118, 88, and 136 patients). RESULTS. An immune infiltration signature consisting of 20 immune metagenes was used to generate a risk score. The performance of the risk score was thoroughly verified in the training and validation sets. Additionally, we found that the risk score was positively correlated with the expression levels of TGFβ and PD-L1, which were important targets of combination immunotherapy. Furthermore, a nomogram incorporating the risk score, patient’s age, and tumor grade was developed to predict the OS, and it performed well in all the training and validation sets (C-index: 0.873, 0.881, 0.781, 0.765, 0.721, and 0.753, respectively). CONCLUSIONS. The risk score based on the immune infiltration signature has reliable prognostic and predictive value for patients with LGGs and might be a potential biomarker for the co-targeting immunotherapy. FUNDING. The National Natural Science Foundation of China (Grant No. 81472370 and 81672506), the Natural Science Foundation of Beijing (Grant No. J180005), the National High Technology Research and Development Program of China (863 Program, Grant No. 2014AA020610) and the National Basic Research Program of China (973 Program, Grant No. 2014CB542006).
Lai-Rong Song, Jian-Cong Weng, Cheng-Bei Li, Xu-Lei Huo, Huan Li, Shu-Yu Hao, Zhen Wu, Liang Wang, Da Li, Jun-Ting Zhang
Background: Metabolic disorders such as type 2 diabetes have been associated with a decrease in insulin pulse frequency and amplitude. We hypothesized that the T-allele at rs7903146 in TCF7L2, previously associated with β–cell dysfunction, would be associated with changes in these insulin pulse characteristics. Methods: 29 nondiabetic subjects (age = 46 ± 2, BMI = 28 ± 1 Kg/M2) participated in this study. Of these, 16 were homozygous for the C allele at rs7903146 and 13 were homozygous for the T allele. Deconvolution of peripheral C-peptide concentrations allowed the reconstruction of portal insulin secretion over time. This data was used for subsequent analyses. Pulse orderliness was assessed by Approximate Entropy (ApEn) and the dispersion of insulin pulses was measured by a Frequency Dispersion Index (FDI) applied to a Fourier Transform of individual insulin secretion rates. Results: During fasting conditions, the CC genotype group exhibited decreased pulse disorderliness compared to the TT genotype group (1.10 ± 0.03 vs. 1.19 ± 0.04, p = 0.03). FDI decreased in response to hyperglycemia in the CC genotype group, perhaps reflecting less entrainment of insulin secretion during fasting.Conclusion: Diabetes-associated variation in TCF7L2 is associated with decreased orderliness and pulse dispersion unchanged by hyperglycemia. Quantification of ApEn and FDI could represent novel markers of β-cell health.
Marcello C. Laurenti, Chiara Dalla Man, Ron T. Varghese, James C. Andrews, Robert A. Rizza, Aleksey Matveyenko, Giuseppe De Nicolao, Claudio Cobelli, Adrian Vella
BACKGROUND. Seizure-induced inhibition of respiration plays a critical role in sudden unexpected death in epilepsy (SUDEP). However, the mechanisms underlying seizure-induced central apnea in pediatric epilepsy are unknown. METHODS. We studied eight pediatric patients with intractable epilepsy undergoing intracranial electroencephalography (iEEG). We recorded respiration during seizures and during electrical stimulation mapping of 174 forebrain sites. A machine learning algorithm was used to delineate brain regions that inhibit respiration. RESULTS. In two patients, apnea coincided with seizure spread to the amygdala. Supporting a role for the amygdala in breathing inhibition in children, electrically stimulating the amygdala produced apnea in all eight subjects (3- to 17-years-old). These effects did not depend on epilepsy type and were relatively specific to the amygdala as no other site affected breathing. Remarkably, patients were unaware that they had stopped breathing, and none reported dyspnea or arousal, findings critical for SUDEP. Finally, a machine learning algorithm based on 45 stimulation sites and 210 stimulation trials identified a focal subregion in the human amygdala that consistently produced apnea. This site, which we refer to as the Amygdala Inhibition of Respiration (AIR) site includes the medial subregion of the basal nuclei, cortical and medial nuclei, amygdala transition areas, and intercalated neurons. CONCLUSIONS. A focal site in the amygdala inhibits respiration and induces apnea (AIR site) when electrically stimulated and during seizures in children with epilepsy. This site may prove valuable for determining those at greatest risk for SUDEP and as a therapeutic target. TRIAL REGISTRATION. This study was not affiliated with any formal clinical trial. FUNDING. NIH, CNS, Roy J. Carver Charitable Trust.
Ariane E. Rhone, Christopher K. Kovach, Gail I.S. Harmata, Alyssa W. Sullivan, Daniel Tranel, Michael A. Ciliberto, Matthew A. Howard, George B. Richerson, Mitchell Steinschneider, John A. Wemmie, Brian J. Dlouhy
Background Salt-sensitive hypertension is often accompanied by insulin resistance in obese individuals, but the underlying mechanisms are obscure. Microvascular function is known to affect both salt-sensitivity of blood pressure and metabolic insulin sensitivity. We hypothesized that excessive salt intake increases blood pressure and decreases insulin-mediated glucose disposal, at least in part by impairing insulin-mediated muscle microvascular recruitment (IMMR). Methods In 20 lean and 20 abdominally obese individuals, we assessed mean arterial pressure (MAP; 24h ABPM), insulin-mediated whole body glucose disposal (M/I-value; hyperinsulinemic, euglycemic clamp technique), IMMR (contrast enhanced ultrasound), osmolyte and water balance, and excretion of mineralocorticoids, glucocorticoids, and amino and organic acids after a low and high salt diet during seven days in a randomized double-blind cross-over design. Results On a low, as compared to a high salt intake, MAP was lower, M/I-value was lower and IMMR was greater in both lean and abdominally obese individuals. In addition, Ln IMMR was inversely associated with MAP in lean participants on a low salt diet only. On a high salt diet, free water clearance decreased, and excretion of glucocorticoids and of amino acids involved in the urea cycle increased. Conclusion Our findings imply that hemodynamic and metabolic changes resulting from alterations in salt intake are not necessarily associated. Moreover, they are consistent with the concept that a high salt intake increases muscle glucose uptake as a response to high-salt-induced, glucocorticoid-drive muscle catabolism to stimulate urea production and thereby renal water conservation. Clinical Trial Registration Number: NCT02068781
Monica T.J. Schütten, Yvo H.A.M. Kusters, Alfons J.H.M. Houben, Hanneke E. C. Niessen, Jos op 't Roodt, Jean L.J. M. Scheijen, Marjo P. van de Waarenburg, Casper G. Schalkwijk, Peter W. de Leeuw, Coen D.A. Stehouwer
BACKGROUND RNA sequencing (RNA-Seq) is a molecular tool to analyze global transcriptional changes, deduce pathogenic mechanisms, and discover biomarkers. We performed RNA-Seq to investigate gene expression and biological pathways in urinary cells and kidney allograft biopsies during an acute rejection episode and to determine whether urinary cell gene expression patterns are enriched for biopsy transcriptional profiles.METHODS We performed RNA-Seq of 57 urine samples collected from 53 kidney allograft recipients (patients) with biopsies classified as acute T cell–mediated rejection (TCMR; n = 22), antibody-mediated rejection (AMR; n = 8), or normal/nonspecific changes (No Rejection; n = 27). We also performed RNA-Seq of 49 kidney allograft biopsies from 49 recipients with biopsies classified as TCMR (n = 12), AMR (n = 17), or No Rejection (n = 20). We analyzed RNA-Seq data for differential gene expression, biological pathways, and gene set enrichment across diagnoses and across biospecimens.RESULTS We identified unique and shared gene signatures associated with biological pathways during an episode of TCMR or AMR compared with No Rejection. Gene Set Enrichment Analysis demonstrated enrichment for TCMR biopsy signature and AMR biopsy signature in TCMR urine and AMR urine, irrespective of whether the biopsy and urine were from the same or different patients. Cell type enrichment analysis revealed a diverse cellular landscape with an enrichment of immune cell types in urinary cells compared with biopsies.CONCLUSIONS RNA-Seq of urinary cells and biopsies, in addition to identifying enriched gene signatures and pathways associated with TCMR or AMR, revealed genomic changes between TCMR and AMR, as well as between allograft biopsies and urinary cells.
Akanksha Verma, Thangamani Muthukumar, Hua Yang, Michelle Lubetzky, Michael F. Cassidy, John R. Lee, Darshana M. Dadhania, Catherine Snopkowski, Divya Shankaranarayanan, Steven P. Salvatore, Vijay K. Sharma, Jenny Z. Xiang, Iwijn De Vlaminck, Surya V. Seshan, Franco B. Mueller, Karsten Suhre, Olivier Elemento, Manikkam Suthanthiran
BACKGROUND. The relative stabilities of the intact and defective HIV genomes over time during effective antiretroviral therapy (ART) have not been fully characterized. METHODS. We used the intact proviral DNA assay (IPDA) to estimate the rate of change of intact and defective proviruses in HIV-infected adults on ART over several years. We used linear spline models with a knot at seven years; these included a random intercept and slope up to the knot. We also estimated the influence of covariates on starting levels and rates of change. RESULTS. We studied 81 individuals for a median of 7.3 (IQR 5.9–9.6) years. In a model allowing for a change in the rate of decline, we found evidence for a more rapid rate of decline in intact genomes from initial suppression through seven years (15.7% per year decline; CI –22.8%, –8.0%) followed by a slower rate of decline after seven years (3.6% per year; CI –8.1%, +1.1%). The estimated half-life of the reservoir was 4.0 years (CI 2.7–8.3) until year seven and 18.7 years (CI 8.2–infinite) thereafter. There was substantial variability between individuals in the rate of decline until year seven. Intact provirus declined at a faster rate than defective provirus (P < 0.001). Individuals with higher CD4+ T cell nadir values had a faster rate of decline in intact provirus. CONCLUSIONS. These findings provide evidence that the biology of the replication-competent (intact) reservoir differs from that of the replication-incompetent (non-intact) pool of proviruses. The IPDA will likely be informative when investigating the impact of interventions targeting the reservoir. FUNDING. This work was supported the Delaney AIDS Research Enterprise (DARE; AI096109, A127966). The SCOPE cohort receives additional support from the UCSF/Gladstone Institute of Virology & Immunology CFAR (P30 AI027763), the CFAR Network of Integrated Systems (R24 AI067039) and the amfAR Institute for HIV Cure Research (amfAR 109301). Additional support was provided by the I4C and Beat-HIV Collaboratories, the Howard Hughes Medical Institute, Gilead, and the Bill and Melinda Gates Foundation.
Michael J. Peluso, Peter Bacchetti, Kristen D. Ritter, Subul A. Beg, Jun Lai, Jeffrey N. Martin, Peter W. Hunt, Timothy J. Henrich, Janet D. Siliciano, Robert F. Siliciano, Gregory M. Laird, Steven G. Deeks
Background: Liver disease in urea cycle disorders (UCDs) ranges from hepatomegaly and chronic hepatocellular injury to cirrhosis and end-stage liver disease. However, the prevalence and underlying mechanisms are unclear. Methods: We estimated the prevalence of chronic hepatocellular injury in UCDs using data from a multicenter, longitudinal, natural history study. We also used ultrasound with shear wave elastography and FibroTestTM to evaluate liver stiffness and markers of fibrosis in individuals with argininosuccinate lyase deficiency (ASLD), a disorder with high prevalence of elevated serum alanine aminotransferase (ALT). To understand the human observations, we evaluated the hepatic phenotype of the AslNeo/Neo mouse model of ASLD. Results: We demonstrate a high prevalence of elevated ALT in ASLD (37%). Hyperammonemia and use of nitrogen-scavenging agents, two markers of disease severity, were significantly (p<0.001; p=0.001) associated with elevated ALT in ASLD. In addition, ultrasound with shear wave elastography and FibroTestTM revealed increased echogenicity and liver stiffness even in individuals with ASLD and normal aminotransferases. The AslNeo/Neo mice mimic the human disorder with hepatomegaly, elevated aminotransferases, and excessive hepatic glycogen noted prior to death (3-5 weeks of age). This excessive hepatic glycogen is associated with impaired hepatic glycogenolysis and decreased glycogen phosphorylase and is rescued with helper-dependent adenovirus expressing Asl using a liver specific (ApoE) promoter. Conclusions: Our results link urea cycle dysfunction and impaired hepatic glucose metabolism and identify a mouse model of liver disease in the setting of urea cycle dysfunction. Trial Registration: NCT03721367, NCT00237315 Funding: NIH, Burroughs Wellcome Fund, NUCDF, Genzyme/ACMG Foundation, CPRIT
Lindsay C. Burrage, Simran Madan, Xiaohui Li, Saima Ali, Mahmoud A. Mohammad, Bridget M. Stroup, Ming-Ming Jiang, Racel Cela, Terry Bertin, Jian Dai, Danielle Guffey, Milton Finegold, Sandesh Nagamani, Charles G. Minard, Juan Marini, Prakash Masand, Deborah Schady, Benjamin L. Shneider, Daniel H. Leung, Deeksha Bali, Brendan Lee
BACKGROUND. Siponimod (BAF312) is a selective sphingosine 1-phosphate receptor 1 and 5 (S1PR1, S1PR5) modulator recently approved for active secondary progressive multiple sclerosis (SPMS). The immunomodulatory effects of siponimod in SPMS have not been previously described. METHODS. We conducted a multi-centered randomized, double-blind, placebo-controlled AMS04 mechanistic study with 36 SPMS participants enrolled in the EXPAND trial. Gene expression profiles were analyzed using RNA derived from whole blood with Affymetrix Human Gene ST 2.1 microarray technology. We performed flow cytometry based assays to analyze the immune cell composition and microarray gene expression analysis on peripheral blood from siponimod-treated participants with SPMS relative to baseline and placebo during the first year randomization phase. RESULTS. Microarray analysis showed that immune-associated genes involved in T and B cell activation and receptor signaling were largely decreased by siponimod, which is consistent with the reduction of CD4+ T cells, CD8+ T cells, and B cells. Analysis done by flow cytometry showed that within the remaining lymphocyte subsets, there was a reduction in the frequencies of CD4 and CD8 naïve T cells and central memory cells, while T effector memory cells, anti-inflammatory Th2, and T regulatory (Treg) cells were enriched. Transitional Bregs (CD24hiCD38hi) and B1 cell subsets (CD43+CD27+) were enriched, shifting the balance in favor of regulatory B cells over memory B cells. The pro-regulatory shift driven by siponimod treatment included a higher proliferative potential of Tregs compared with non-Tregs, and upregulated expression of PD-1 on Tregs. Additionally, a positive correlation was found between regulatory T cells and regulatory B cells in siponimod treated participants. CONCLUSION. The shift toward an anti-inflammatory and suppressive homeostatic immune system may contribute to the clinical efficacy of siponimod in SPMS. TRIAL REGISTRATION. NCT02330965.
Qi Wu, Elizabeth A. Mills, Qin Wang, Catherine A. Dowling, Caitlyn Fisher, Britany Kirch, Steven K. Lundy, David A. Fox, Yang Mao-Draayer
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