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1.
Innate immune remodeling by short-term intensive fasting.
Qian, J, Fang, Y, Yuan, N, Gao, X, Lv, Y, Zhao, C, Zhang, S, Li, Q, Li, L, Xu, L, et al
Aging cell. 2021;(11):e13507
Abstract
Previous studies have shown that long-term light or moderate fasting such as intermittent fasting can improve health and prolong lifespan. However, in humans short-term intensive fasting, a complete water-only fasting has little been studied. Here, we used multi-omics tools to evaluate the impact of short-term intensive fasting on immune function by comparison of the CD45+ leukocytes from the fasting subjects before and after 72-h fasting. Transcriptomic and proteomic profiling of CD45+ leukocytes revealed extensive expression changes, marked by higher gene upregulation than downregulation after fasting. Functional enrichment of differentially expressed genes and proteins exposed several pathways critical to metabolic and immune cell functions. Specifically, short-term intensive fasting enhanced autophagy levels through upregulation of key members involved in the upstream signals and within the autophagy machinery, whereas apoptosis was reduced by down-turning of apoptotic gene expression, thereby increasing the leukocyte viability. When focusing on specific leukocyte populations, peripheral neutrophils are noticeably increased by short-term intensive fasting. Finally, proteomic analysis of leukocytes showed that short-term intensive fasting not only increased neutrophil degranulation, but also increased cytokine secretion. Our results suggest that short-term intensive fasting boost immune function, in particular innate immune function, at least in part by remodeling leukocytes expression profile.
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2.
N-Formyl Methionine Peptide-Mediated Neutrophil Activation in Systemic Sclerosis.
Kuley, R, Stultz, RD, Duvvuri, B, Wang, T, Fritzler, MJ, Hesselstrand, R, Nelson, JL, Lood, C
Frontiers in immunology. 2021;:785275
Abstract
Exaggerated neutrophil activation and formation of neutrophil extracellular traps (NETs) are reported in systemic sclerosis (SSc) but its involvement in SSc pathogenesis is not clear. In the present study we assessed markers of neutrophil activation and NET formation in SSc patients in relation to markers of inflammation and disease phenotype. Factors promoting neutrophil activation in SSc remain largely unknown. Among the neutrophil activating factors, mitochondrial-derived N-formyl methionine (fMet) has been reported in several autoinflammatory conditions. The aim of the current study is to assess whether SSc patients have elevated levels of fMet and the role of fMet in neutrophil-mediated inflammation on SSc pathogenesis. Markers of neutrophil activation (calprotectin, NETs) and levels of fMet were analyzed in plasma from two SSc cohorts (n=80 and n=20, respectively) using ELISA. Neutrophil activation assays were performed in presence or absence of formyl peptide receptor 1 (FPR1) inhibitor cyclosporin H. Elevated levels of calprotectin and NETs were observed in SSc patients as compared to healthy controls (p<0.0001) associating with SSc clinical disease characteristics. Further, SSc patients had elevated levels of circulating fMet as compared to healthy controls (p<0.0001). Consistent with a role for fMet-mediated neutrophil activation, fMet levels correlated with levels of calprotectin and NETs (r=0.34, p=0.002; r=0.29, p<0.01 respectively). Additionally, plasma samples from SSc patients with high levels of fMet induced de novo neutrophil activation through FPR1-dependent mechanisms. Our data for the first time implicates an important role for the mitochondrial component fMet in promoting neutrophil-mediated inflammation in SSc.
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3.
Prognostic value of pre-treatment Naples prognostic score (NPS) in patients with osteosarcoma.
Yang, Q, Chen, T, Yao, Z, Zhang, X
World journal of surgical oncology. 2020;(1):24
Abstract
BACKGROUND This study aimed to evaluate the clinical significance of pre-treatment Naples prognostic score (NPS) in patients with osteosarcoma. METHODS The clinical data of 133 osteosarcoma patients between January 2011 and February 2018 in our hospital was retrospectively collected and analyzed. NPS was calculated from four parameters, including serum albumin level, serum total cholesterol (TC), lymphocyte-to-monocyte ratio (LMR), and neutrophil-to-lymphocyte ratio (NLR). Patients were divided into three groups (group 1-3) based on NPS. The relationships between NPS and clinical features, overall survival (OS), and progression-free survival (PFS) were analyzed. Two prediction models based on NPS and clinical parameters were developed: clinical parameters model (model A), and the combined model of NPS and clinical parameters (model B). Their predictive performances were further evaluated and compared. RESULTS The median follow-up time of this cohort was 46.0 (range, 5-75) months, while the median OS and PFS was 40 (range, 5-75) months and 36 (range, 5-71) months, respectively. NPS was significantly correlated with gender, tumor location, Enneking stage, pathological fracture, local recurrence, and metastasis (all P < 0.05). Variables of NPS, Enneking stage, local recurrence, metastasis, and NLR were confirmed as independent prognostic factors for OS and PFS by univariate and multivariate Cox analysis. Prediction model B obtained larger AUCs for OS and PFS and showed better consistency between nomogram-predicted and actual survival than that of model A at the follow-up time of 1-, 3-, and 5-year. CONCLUSIONS NPS was a novel, reliable, and multidimensional prognostic scoring system with favorable predictive performance for patients with osteosarcoma.
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Incorporation of dynamic segmented neutrophil-to-monocyte ratio with leukocyte count for sepsis risk stratification.
Fang, WF, Chen, YM, Wang, YH, Huang, CH, Hung, KY, Fang, YT, Chang, YC, Lin, CY, Chang, YT, Chen, HC, et al
Scientific reports. 2019;(1):19756
Abstract
The association between sepsis and segmented neutrophil-to-monocyte (SeMo) ratio is unclear. We postulated that an increase in dynamic SeMo ratio measurement can be applied in risk stratification. This retrospective study included 727 consecutive sepsis patients in medical intensive care units (ICUs), including a subpopulation of 153 patients. According to the leukocyte (white blood cell, WBC) count on day 3 (normal range, between 4,000/µL and 12,000/µL) and delta SeMo (value of SeMo ratio on day 3 minus value of SeMo ratio on day 1; normal delta SeMo, <7), patients were grouped into 3 (delta SeMo & WBC tool). The survival lines separated significantly with hazard ratios of 1.854 (1.342-2.560) for the delta SeMo or WBC abnormal group and 2.860 (1.849-4.439) for the delta SeMo and WBC abnormal group compared to the delta SeMo and WBC normal group. Delta SeMo & WBC tool and delta sequential organ failure assessment (SOFA) tool performed better than the other tools (delta SeMo, delta WBC, day 3 WBC, and day 1 WBC). Severity in delta SeMo & WBC tool and delta SeMo tool reflected the immune dysfunction score, cytokine expression, and human leukocyte antigen D-related monocyte expression on day 1 and day 3. There was correspondence between delta SOFA and delta WBC and between delta SeMo and delta cytokine expression. Incorporation of dynamic SeMo ratio with WBC count provides risk stratification for sepsis patients admitted in the ICU.
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5.
Prognostic and predictive role of neutrophil/lymphocytes ratio in metastatic colorectal cancer: a retrospective analysis of the TRIBE study by GONO.
Dell'Aquila, E, Cremolini, C, Zeppola, T, Lonardi, S, Bergamo, F, Masi, G, Stellato, M, Marmorino, F, Schirripa, M, Urbano, F, et al
Annals of oncology : official journal of the European Society for Medical Oncology. 2018;(4):924-930
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Abstract
BACKGROUND Neutrophil/lymphocyte ratio (NLR), defined as absolute neutrophils count divided by absolute lymphocytes count, has been reported as poor prognostic factor in several neoplastic diseases but only a few data are available about unresectable metastatic colorectal cancer (mCRC) patients (pts). The aim of our study was to evaluate the prognostic and predictive role of NLR in the TRIBE trial. PATIENTS AND METHODS Pts enrolled in TRIBE trial were included. TRIBE is a multicentre phase III trial randomizing unresectable and previously untreated mCRC pts to receive FOLFOXIRI or FOLFIRI plus bevacizumab. A cut-off value of 3 was adopted to discriminate pts with low (NLR < 3) versus high (NLR ≥ 3) NLR, as primary analysis. As secondary analysis, NLR was treated as an ordinal variable with three levels based on terciles distribution. RESULTS NLR at baseline was available for 413 patients. After multiple imputation at univariate analysis, patients with high NLR had significantly shorter progression-free survival (PFS) [hazard ratio (HR) 1.27 (95% CI 1.05-1.55), P = 0.017] and overall survival (OS) [HR 1.56 (95% CI 1.25-1.95), P < 0.001] than patients with low NLR. In the multivariable model, NLR retained a significant association with OS [HR 1.44 (95% CI 1.14-1.82), P = 0.014] but not with PFS [HR 1.18 (95% CI 0.95-1.46), P = 0.375]. No interaction effect between treatment arm and NLR was evident in terms of PFS (P for interaction = 0.536) or OS (P for interaction = 0.831). Patients with low [HR 0.84 (95% CI 0.64-1.08)] and high [HR 0.73 (95% CI 0.54-0.97)] NLR achieved similar PFS benefit from the triplet and consistent results were obtained in terms of OS [HR 0.83 (95% CI 0.62-1.12) for low NLR; HR 0.82 (95% CI 0.59-1.12) for high NLR]. CONCLUSION This study confirmed the prognostic role of NLR in mCRC pts treated with bevacizumab plus chemotherapy in the first line, showing the worse prognosis of pts with high NLR. The advantage of the triplet is independent of NLR at baseline.
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Marathon Race Affects Neutrophil Surface Molecules: Role of Inflammatory Mediators.
Santos, VC, Sierra, AP, Oliveira, R, Caçula, KG, Momesso, CM, Sato, FT, Silva, MB, Oliveira, HH, Passos, ME, de Souza, DR, et al
PloS one. 2016;(12):e0166687
Abstract
The fatigue induced by marathon races was observed in terms of inflammatory and immunological outcomes. Neutrophil survival and activation are essential for inflammation resolution and contributes directly to the pathogenesis of many infectious and inflammatory conditions. The aim of this study was to investigate the effect of marathon races on surface molecules related to neutrophil adhesion and extrinsic apoptosis pathway and its association with inflammatory markers. We evaluated 23 trained male runners at the São Paulo International Marathon 2013. The following components were measured: hematological and inflammatory mediators, muscle damage markers, and neutrophil function. The marathon race induced an increased leukocyte and neutrophil counts; creatine kinase (CK), lactate dehydrogenase (LDH), CK-MB, interleukin (IL)-6, IL-10, and IL-8 levels. C-reactive protein (CRP), IL-12, and tumor necrosis factor (TNF)-α plasma concentrations were significantly higher 24 h and 72 h after the marathon race. Hemoglobin and hematocrit levels decreased 72 h after the marathon race. We also observed an increased intercellular adhesion molecule-1 (ICAM-1) expression and decreasedTNF receptor-1 (TNFR1) expression immediately after and 24 h after the marathon race. We observed an increased DNA fragmentation and L-selectin and Fas receptor expressions in the recovery period, indicating a possible slow rolling phase and delayed neutrophil activation and apoptosis. Marathon racing affects neutrophils adhesion and survival in the course of inflammation, supporting the "open-window" post-exercise hypothesis.
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Adjuvant sorafenib therapy in patients with resected hepatocellular carcinoma: evaluation of predictive factors.
Zhang, W, Zhao, G, Wei, K, Zhang, Q, Ma, W, Wu, Q, Zhang, T, Kong, D, Li, Q, Song, T
Medical oncology (Northwood, London, England). 2015;(4):107
Abstract
Currently there is no predictor for survival after adjuvant sorafenib in patients with hepatocellular carcinoma (HCC) who have undergone curative resection. Thirty-eight patients who underwent curative resection of HCC received adjuvant sorafenib therapy between August 2009 and March 2012. Clinicopathological parameters including patient factors, tumor factors, liver background, and inflammatory factors (before surgery and dynamic changes after sorafenib therapy) were evaluated to identify predictors for overall survival (OS) and recurrence-free survival (RFS). The recurrence rate, mortality rate, and clinicopathological data were also compared. Increased NLR after sorafenib (HR = 3.199, 95 % CI 1.365-7.545, P = 0.008), increased GGT after sorafenib (HR = 3.204, 95 % CI 1.333-7.700, P = 0.009), and the presence of portal vein thrombosis (HR = 2.381, 95 % CI 1.064-5.328, P = 0.035) were risk factors related to RFS. By contrast, increased NLR after sorafenib was the only independent risk factor related to OS (HR = 4.647, 95 % CI 1.266-17.053, P = 0.021). Patients with increased NLR or increased GGT after sorafenib had a higher incidence of recurrence and death. Patients who had increased NLR tended to have higher preoperative levels of NLR and GGT. There were no differences in clinicopathological factors in patients with increased GGT and decreased GGT. In conclusion, increased NLR predicted a worse OS and RFS in patients with HCC who underwent curative resection with adjuvant sorafenib therapy. Increased GGT predicted a worse OS. NLR and GGT can be monitored dynamically before and after sorafenib therapy.
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Scuba diving induces nitric oxide synthesis and the expression of inflammatory and regulatory genes of the immune response in neutrophils.
Sureda, A, Batle, JM, Capó, X, Martorell, M, Córdova, A, Tur, JA, Pons, A
Physiological genomics. 2014;(17):647-54
Abstract
OBJECTIVE Scuba diving, characterized by hyperoxia and hyperbaria, could increase reactive oxygen species production which acts as signaling molecules to induce adaptation against oxidative stress. The aim was to study the effects of scuba diving immersion on neutrophil inflammatory response, the induction of oxidative damage, and the NO synthesis. DESIGN Nine male divers performed a dive at 50 m depth for a total time of 35 min. Blood samples were obtained at rest before the dive, after the dive, and 3 h after the diving session. MEASUREMENTS Markers of oxidative and nitrosative damage, nitrite, and the gene expression of genes related with the synthesis of nitric oxide and lipid mediators, cytokine synthesis, and inflammation were determined in neutrophils. RESULTS The mRNA levels of genes related with the inflammatory and immune response of neutrophils, except TNF-α, myeloperoxidase, and toll-like receptor (TLR) 2, significantly increased after the recovery period respect to predive and postdive levels. NF-κB, IL-6, and TLR4 gene expression reported significant differences immediately after diving respect to the predive values. Protein nitrotyrosine levels significantly rose after diving and remained high during recovery, whereas no significant differences were reported in malondialdehyde. Neutrophil nitrite levels as indicative of inducible nitric oxide synthase (iNOS) activity progressively increased after diving and recovery. The iNOS protein levels maintained the basal values in all situations. CONCLUSION Scuba diving which combines hyperoxia, hyperbaria, and acute exercise induces nitrosative damage with increased nitrotyrosine levels and an inflammatory response in neutrophils.
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Regulation of 5-oxo-ETE synthesis by nitric oxide in human polymorphonuclear leucocytes upon their interaction with zymosan and Salmonella typhimurium.
Viryasova, GM, Galkina, SI, Gaponova, TV, Romanova, JM, Sud'ina, GF
Bioscience reports. 2014;(3)
Abstract
In the present study we have presented data on the regulation of LT (leukotriene) and 5-oxo-ETE (5-oxo-6,8,11,14-eicosatetraenoic acid) syntheses in human neutrophils upon interaction with OZ (opsonized zymosan) or Salmonella typhimurium. Priming of neutrophils with PMA (phorbol 12-myristate 13-acetate) and LPS (lipopolysaccharide) elicits 5-oxo-ETE formation in neutrophils exposed to OZ, and the addition of AA (arachidonic acid) significantly increases 5-oxo-ETE synthesis. We found that NO (nitric oxide)-releasing compounds induce 5-oxo-ETE synthesis in neutrophils treated with OZ or S. typhimurium. Exposure of neutrophils to zymosan or bacteria in the presence of the NO donor DEA NONOate (1,1-diethyl-2-hydroxy-2-nitroso-hydrazine sodium) considerably increased the conversion of endogenously formed 5-HETE (5S-hydroxy-6,8,11,14-eicosatetraenoic acid) to 5-oxo-ETE. To our knowledge, this study is the first to demonstrate that NO is a potent regulator of 5-oxo-ETE synthesis in human polymorphonuclear leucocytes exposed to Salmonella typhimurium and zymosan.
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Neutrophil-lymphocyte ratio as a predictor of outcomes for patients with hepatocellular carcinoma undergoing TAE combined with Sorafenib.
Wei, K, Wang, M, Zhang, W, Mu, H, Song, TQ
Medical oncology (Northwood, London, England). 2014;(6):969
Abstract
The aim of this study was to investigate the prognostic significance of blood NLR in patients with intermediate-advanced hepatocellular carcinoma (HCC) who received transcatheter arterial embolization (TAE) combined with Sorafenib. A total of 40 patients with intermediate-advanced HCC from January 1, 2010, through May 31, 2013, treated with concurrent TAE in combination with Sorafenib were admitted to this study in our hospital. Potential prognostic factors, including serum NLR, were analyzed. The pretreatment mean NLR was 3.0; 21 (52.5 %) patients with elevated high NLR (>3.0). The median survival of patients with a high NLR was 14 months (95 % CI 10.1-17.9 months) compared with 26 months (95 % CI 17.4-34.6 months) for patients with a low NLR; a significant difference was found in overall survival (P = 0 0.001). Barcelona Clinical Liver Cancer staging classification and NLR >3.0 were all predictors of poorer over survival. Multivariate analysis showed that high NLR was independent factors associated with worse survival. A high periprocedural NLR independently predicts poor survival in patients with unresectable HCC undergoing TAE combined with Sorafenib.