BACKGROUND. The reshaping of the immune landscape by nivolumab (NIVO) and ipilimumab (IPI) and its relation to patient outcomes is not well-described. METHODS. We used high-parameter flow cytometry and a novel computational platform, CytoBrute, to define immunophenotypes of up to 15 markers to assess peripheral blood samples from metastatic melanoma patients receiving sequential NIVO>IPI or IPI>NIVO (CheckMate-064). RESULTS. The two treatments were associated with distinct immunophenotypic changes and had differing profiles associated with response. Only two immunophenotypes were shared but had opposing relationships to response/survival. To understand the impact of sequential treatment on response/survival, phenotypes that changed after the initial treatment and differentiated response in the other cohort were identified. Immunophenotypic changes occurring post-NIVO were predominately associated with response to IPI>NIVO, but changes occurring post-IPI were predominately associated with progression after NIVO>IPI. Among these changes, CD4+CD38+CD39+CD127–GARP– T-cell subsets were increased after IPI treatment and were negatively associated with response/survival for the NIVO>IPI cohort. CONCLUSION. Collectively, these data suggest that the impact of IPI and NIVO on the immunophenotypic landscape of patients is distinct and that the impact of IPI may be associated with resistance to subsequent NIVO therapy, consistent with poor outcomes in the IPI>NIVO cohort of Checkmate-064.
David M. Woods, Andressa S. Laino, Aidan F. Winters, Jason M. Alexandre, Daniel Freeman, Vinay Rao, Santi S. Adavani, Jeffrey S. Weber, Pratip K. Chattopadhyay
BACKGROUND. Epidemiologic studies suggest that metformin has antitumor effects. Laboratory studies indicate metformin impacts cancer stem-like cells (CSCs). As part of a phase II trial, we evaluated the impact of metformin on CSC number, and carcinoma associated mesenchymal stem cells (CA-MSC), and clinical outcomes in non-diabetic patients with advanced stage epithelial ovarian cancer (EOC). METHODS. Thirty-eight patients with confirmed stage IIC(n = 1)/III(n = 25)/IV(n = 12) EOC were treated with either (i) neoadjuvant metformin, debulking surgery and adjuvant chemotherapy + metformin, or (ii) neoadjuvant chemotherapy and metformin, interval debulking surgery, and adjuvant chemotherapy + metformin. Metformin treated tumors, compared to historical controls, were evaluated for CSC number and chemotherapy response. Primary endpoints were (i) a greater than 2-fold reduction in ALDH+CD133+ CSC and (ii) a relapse free survival at 18 months of greater than 50%. RESULTS. Metformin was well-tolerated. Median progression-free survival was 18.0 months (95% CI 14.0–21.6) with relapse-free survival at 18 months of 59.3% (95% CI 38.6–70.5). Median overall survival was 57.9 months (95% CI 28.0 – Not Estimable). Tumors treated with metformin had a 2.4-fold decrease in ALDH+/CD133+ CSC and increased sensitivity to cisplatin ex vivo. Furthermore, metformin altered the methylation signature in CA-MSC which prevented CA-MSC driven chemoresistance in vitro. CONCLUSIONS. Translational studies confirm an impact of metformin on EOC CSC and suggest epigenetic change in the tumor stroma may drive the platinum sensitivity ex vivo. Consistent with this, metformin therapy was associated with better than expected overall survival, supporting the use of metformin in phase-III studies.
Jason R Brown, Daniel K. Chan, Jessica J Shank, Kent A. Griffith, Huihui Fan, Robert Szulawski, Kun Yang, R. Kevin Reynolds, Carolyn Johnston, Karen McLean, Shitanshu Uppal, J. Rebecca Liu, Lourdes Cabrera, Sarah E Taylor, Brian C. Orr, Francesmary Modugno, Pooja Mehta, Michael Bregenzer, Geeta Mehta, Hui Shen, Lan Coffman, Ronald J. Buckanovich
BACKGROUND. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a novel viral pneumonia (COVID-19), which is rapidly spreading in the world. The positive result of nucleic acid test is a golden criterion to confirm SARS-CoV-2 infection, but the detection features remain unclear. METHODS. We performed a retrospective analysis in 5,630 high-risk individuals receiving SARS-CoV-2 nucleic acid tests in Wuhan, China, and investigated their characteristics and diagnosis rates. RESULTS. The overall diagnosis rate was 34.7% (1,952/5,630). Male (P = 0.025) and older age (P = 2.525 × 10–39) were two significant risk factors of SARS-CoV-2 infection. People were generally susceptible, and most cases concentrated in people of 30- to 69-years-old. Besides, we investigated the association between diagnosis rate and the number of testing in 501 subjects. Results revealed a 1.27-fold improvement (35.5%/27.9%) of diagnosis rate from testing once to twice (P = 5.847 × 10–9), and a 1.43-fold improvement (39.9%/27.9%) from testing once to three times (P = 7.797 × 10–14). More than three testing times was not helpful for further improvement. However, this improvement was not observed in subjects with pneumonia (P = 0.097). CONCLUSION. All populations are susceptible to SARS-Cov-2 infection, and male and older age are two significant risk factors. Increasing the number of testing could significantly improve diagnosis rates, except for subjects with pneumonia. It is recommended to test twice in those high-risk individuals whose results are negative for the first time, and to perform three testing times is better if available.
Na Shen, Yaowu Zhu, Xiong Wang, Jing Peng, Weiyong Liu, Feng Wang, Yanjun Lu, Liming Cheng, Ziyong Sun
Background: The Coronavirus Disease-2019 (COVID-19), infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a severe outbreak in China. The host immunity of COVID-19 patients is unknown. Methods: The routine laboratory tests and host immunity in COVID-19 patients with different severity of illness were compared after patient admission. Results: A total of 65 SARS-CoV-2-positive patients were classified as mild (n=30), severe (n=20), and extremely severe (n=15) illness. Many routine laboratory tests such as ferritin, lactate dehydrogenase and D-dimer were increased in severe and extremely severe patients. The absolute numbers of CD4+ T cells, CD8+ T cells and B cells were all gradually decreased with increased severity of illness. The activation markers such as HLA-DR and CD45RO expressed on CD4+ and CD8+ T cells were increased in severe and extremely severe patients compared with mild patients. The co-stimulatory molecule CD28 had opposite results. The percentage of natural regulatory T cells was decreased in extremely severe patients. The percentage of IFN-γ producing CD8+ T cells was increased in both severe and extremely severe patients compared with mild patients. The percentage of IFN-γ producing CD4+ T cells was increased in extremely severe patients. The IL-2R, IL-6, and IL-10 were all increased in extremely severe patients. The activation of DC and B cells was decreased in extremely severe patients. Conclusions: The number and function of T cells are inconsistent in COVID-19 patients. The hyperfunction of CD4+ and CD8+ T cells is associated with the pathogenesis of extremely severe SARS-CoV-2 infection.
Feng Wang, Hongyan Hou, Ying Luo, Guoxing Tang, Shiji Wu, Min Huang, Weiyong Liu, Yaowu Zhu, Qun Lin, Liyan Mao, Minghao Fang, Huilan Zhang, Ziyong Sun
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
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