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1.
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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Mucin adsorbed by E. coli can affect neutrophil activation in vitro.
Mikhalchik, E, Balabushevich, N, Vakhrusheva, T, Sokolov, A, Baykova, J, Rakitina, D, Scherbakov, P, Gusev, S, Gusev, A, Kharaeva, Z, et al
FEBS open bio. 2020;(2):180-196
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Abstract
Bacteria colonizing human intestine adhere to the gut mucosa and avoid the innate immune system. We previously demonstrated that Escherichia coli isolates can adsorb mucin from a diluted solution in vitro. Here, we evaluated the effect of mucin adsorption by E. coli cells on neutrophil activation in vitro. Activation was evaluated based on the detection of reactive oxygen species production by a chemiluminescent reaction (ChL), observation of morphological alterations in neutrophils and detection of exocytosis of myeloperoxidase and lactoferrin. We report that mucin adsorbed by cells of SharL1 isolate from Crohn's disease patient's inflamed ileum suppressed the potential for the activation of neutrophils in whole blood. Also, the binding of plasma complement proteins and immunoglobulins to the bacteria was reduced. Desialylated mucin, despite having the same adsorption efficiency to bacteria, had no effect on the blood ChL response. The effect of mucin suggests that it shields epitopes that interact with neutrophils and plasma proteins on the bacterial outer membrane. Potential candidates for these epitopes were identified among the proteins within the bacterial outer membrane fraction by 2D-PAGE, fluorescent mucin binding on a blot and HPLC-MS/MS. In vitro, the following proteins demonstrated mucin adsorption: outer membrane porins (OmpA, OmpC, OmpD and OmpF), adhesin OmpX, the membrane assembly factor OmpW, cobalamine transporter, ferrum uptake protein and the elongation factor Ef Tu-1. In addition to their other functions, these proteins are known to be bacterial surface antigens. Therefore, the shielding of epitopes by mucin may affect the dynamics and intensity of an immune response.
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Circulating Neutrophils Do Not Predict Subclinical Coronary Artery Disease in Women with Former Preeclampsia.
Meeuwsen, JAL, de Vries, J, Zoet, GA, Franx, A, Fauser, BCJM, Maas, AHEM, Velthuis, BK, Appelman, YE, Visseren, FL, Pasterkamp, G, et al
Cells. 2020;(2)
Abstract
UNLABELLED : Introduction: Preeclampsia (PE) represents a hypertensive pregnancy disorder that is associated with increased cardiovascular disease (CVD) risk. This increased risk has been attributed to accelerated atherosclerosis, with inflammation being a major contributor. Neutrophils play an important role in the onset and progression of atherosclerosis and have been associated with vascular damage in the placenta as well as the chronic inflammatory state in women with PE. We therefore investigated whether circulating neutrophil numbers or reactivity were associated with the presence and severity of subclinical atherosclerosis in women with a history of PE. METHODS Women aged 45-60 years with a 10 to 20 years earlier history of early onset preeclampsia (delivery <34 weeks of gestation) (n = 90), but without symptomatic CVD burden were screened for the presence of subclinical coronary artery disease (CAD) using both contrast-enhanced and non-contrast coronary CT angiography. Subclinical CAD was defined as a coronary artery calcium (CAC) score ≥100 Agatston Units and/or ≥50% coronary luminal stenosis. We assessed whether the numbers and activity of circulating neutrophils were associated with the presence of subclinical CAD and as secondary outcome measurements, with the presence of any calcium (CAC score > 0 AU) or stenosis, categorized as absent (0%), minimal to mild (>0 and <50%), and moderate to severe (≥50%) narrowing of the coronary artery. Blood was drawn just before CT and neutrophil numbers were assessed by flow cytometry. In addition, the presence of the chemokine receptors CXCR2 and CXCR4, which are known to be instrumental in neutrophil recruitment, and neutrophil activity upon stimulation with the bacterial peptide N-Formylmethionyl-leucyl-phenylalanine (fMLF) was assessed by flow cytometry. RESULTS Of the participating women, with an average age of 49 years, 13% (12 out of 90) presented with subclinical signs of CAD (CAC score ≥100 AU and/or ≥50% luminal stenosis), and 37% (33 out of 90) had a positive CAC score (>0). Total white blood cell count and neutrophil counts were not associated with the presence of subclinical CAD or with a positive CAC score. When assessing the presence of the chemokine receptors CXCR4 and CXCR2, we observed a slight decrease of neutrophil CXCR2 expression in women with CAC (median MFI 22.0 [interquartile range (IQR) 20.2-23.8]) compared to women without CAC (23.8 [IQR 21.6-25.6], p = 0.02). We observed no differences regarding neutrophil CXCR4 expression. In addition, expression of the early activity marker CD35 was slightly lower on neutrophils of women with subclinical CAD (median MFI 1.6 [IQR 1.5-1.9] compared to 1.9 [IQR 1.7-2.1] in women without CAD, p = 0.02). However, for all findings, statistical significance disappeared after adjustment for multiple testing. CONCLUSION Our findings indicate that neutrophil counts and (re)activity are not directly associated with silent CAD disease burden and as such are not suitable as biomarkers to predict the presence of subclinical CAD in a high-risk population of women with a history of preeclampsia.
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Neutrophil-to-lymphocyte ratio and histological type might predict clinical responses to eriburin-based treatment in patients with metastatic breast cancer.
Myojin, M, Horimoto, Y, Ito, M, Kitano, S, Ishizuka, Y, Sasaki, R, Uomori, T, Himuro, T, Murakami, F, Nakai, K, et al
Breast cancer (Tokyo, Japan). 2020;(4):732-738
Abstract
BACKGROUND Metastatic breast cancer (MBC) is generally considered to be incurable. Although many options are available for treating MBC, physicians often encounter difficulties in choosing the most appropriate treatment because the MBCs of individual patients respond differently even to the same treatments. Thus, predictive markers for therapeutic efficacy are urgently needed. Neutrophil- and platelet-to-lymphocyte ratios (NLR and PLR, respectively), have been studied and established as prognostic markers for breast cancer patients but whether either or both of these markers are predictive of treatment responses is still unclear. Herein, we investigated predictive markers for eribulin-based treatment responsiveness in patients with MBC, by examining clinicopathological features, including several markers of immunocompetent cells in peripheral blood. METHODS Clinicopathological features of the 104 patients with metastatic/Stage IV breast cancer given eribulin-based regimens were investigated in relation to clinical responses to eribulin-based treatments and progression-free-survival (PFS). RESULTS Special histological types and high NLR at baseline were independently related to poor clinical responses to the treatments (p = 0.023 and 0.039, respectively). The Cox hazard model revealed that patients with oestrogen receptor (ER)-negative tumours and high NLR, monocyte-to-lymphocyte ratio (MLR) and PLR showed significantly shorter PFS (p = 0.021, 0.005, 0.008 and 0.030, respectively). On multivariate analysis, only ER status and NLR remained independent factors related to PFS (p = 0.011 and 0.003, respectively). CONCLUSIONS Our data revealed that special histological types and high NLR might be factors related to low responsiveness to eribulin-based regimens in patients with MBC.
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Neutrophil-lymphocyte ratio and nutritional status are clinically useful in predicting prognosis in colorectal cancer patients.
Silva, TH, Schilithz, AOC, Peres, WAF, Murad, LB
Nutrition and cancer. 2020;(8):1345-1354
Abstract
Background: Neutrophil-lymphocyte ratio (NLR) and nutritional status may provide a prognostic value in colorectal cancer (CRC). Thus, aim of this study was to evaluate the prognostic value of nutritional status and NLR in CRC patients.Methods: A retrospective analysis was conducted in CRC patients. The independent variables were body mass index (BMI), weight loss (WL) and NLR. Logistic regression was used to estimate the odds chance of low NLR. Kaplan-Meier curves and Cox regression were used to evaluate the overall survival at 5 years old.Results: In the 148 patients evaluated, the most prevalent nutritional status was overweight/obesity (43.2%) and 27.0% had severe WL. Sixty-seven subjects (45.3%) had NLR ≥ 3 that was associated with the lower OS (P < 0.001). There was a higher OS for overweight/obese patients (P = 0.002) and a lower among subjects with severe WL (P = 0.009). The NLR ≥3 (HR: 3.639; 95% CI, 1.708-7.771) was an independent poor prognostic factor for OS. Patients without WL (HR: 0.367, 95% CI, 0.141-0.954) and classified as overweight/obesity (HR: 0.260; 95% CI, 0.106-0.639) presented better prognostic.Conclusion: NLR, WL, BMI assessments are promising prognostic indicators in the CRC.
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Serum Levels of Autoantibodies Against Extracellular Antigens and Neutrophil Granule Proteins Increase in Patients with COPD Compared to Non-COPD Smokers.
Ma, A, Wen, L, Yin, J, Hu, Y, Yue, X, Li, J, Dong, X, Gupta, Y, Ludwig, RJ, Krauss-Etschmann, S, et al
International journal of chronic obstructive pulmonary disease. 2020;:189-200
Abstract
BACKGROUND Chronic obstructive pulmonary disease (COPD) is a highly prevalent disease leading to irreversible airflow limitation and is characterized by chronic pulmonary inflammation, obstructive bronchiolitis and emphysema. Etiologically, COPD is mediated by toxic gases and particles, eg, cigarette smoke, while the pathogenesis of the disease is largely unknown. Several lines of evidence indicate a link between COPD and autoimmunity but comprehensive studies are lacking. METHODS By using a protein microarray assaying more than 19,000 human proteins we determined in this study the autoantibody profiles of COPD and non-COPD smokers. The discovery cohort included 5 COPD patients under acute exacerbation (AECOPD) and 5 age- and gender-matched non-COPD smokers. One putative candidate autoantibody, anti-lactoferrin IgG, was further investigated by using immunoblotting with a large validation cohort containing 124 healthy controls, 92 patients with AECOPD and 52 patients with stable COPD. RESULTS We show that i) autoantigens targeted by autoantibodies with higher titers in COPD patients were enriched in extracellular regions, while those with lower titers in COPD patients were enriched in intracellular compartments. ii) levels of IgG autoantibodies against many neutrophil granule proteins were significantly higher in COPD patients than in non-COPD smokers. Furthermore, increased levels of anti-lactoferrin antibodies in COPD patients were confirmed in a cohort with a large number of samples. CONCLUSION The comprehensive autoantibody profiles from COPD patients established in this study demonstrated for the first time a shift in the cellular localization of antigens targeted by autoantibodies in COPD.
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Neutrophil to lymphocyte ratio and cancer prognosis: an umbrella review of systematic reviews and meta-analyses of observational studies.
Cupp, MA, Cariolou, M, Tzoulaki, I, Aune, D, Evangelou, E, Berlanga-Taylor, AJ
BMC medicine. 2020;(1):360
Abstract
BACKGROUND Although neutrophils have been linked to the progression of cancer, uncertainty exists around their association with cancer outcomes, depending on the site, outcome and treatments considered. We aimed to evaluate the strength and validity of evidence on the association between either the neutrophil to lymphocyte ratio (NLR) or tumour-associated neutrophils (TAN) and cancer prognosis. METHODS We searched MEDLINE, Embase and Cochrane Database of Systematic Reviews from inception to 29 May 2020 for systematic reviews and meta-analyses of observational studies on neutrophil counts (here NLR or TAN) and specific cancer outcomes related to disease progression or survival. The available evidence was graded as strong, highly suggestive, suggestive, weak or uncertain through the application of pre-set GRADE criteria. RESULTS A total of 204 meta-analyses from 86 studies investigating the association between either NLR or TAN and cancer outcomes met the criteria for inclusion. All but one meta-analyses found a hazard ratio (HR) which increased risk (HR > 1). We did not find sufficient meta-analyses to evaluate TAN and cancer outcomes (N = 9). When assessed for magnitude of effect, significance and bias related to heterogeneity and small study effects, 18 (9%) associations between NLR and outcomes in composite cancer endpoints (combined analysis), cancers treated with immunotherapy and some site specific cancers (urinary, nasopharyngeal, gastric, breast, endometrial, soft tissue sarcoma and hepatocellular cancers) were supported by strong evidence. CONCLUSION In total, 60 (29%) meta-analyses presented strong or highly suggestive evidence. Although the NLR and TAN hold clinical promise in their association with poor cancer prognosis, further research is required to provide robust evidence, assess causality and test clinical utility. TRIAL REGISTRATION PROSPERO CRD42017069131 .
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Differential effects of testosterone on circulating neutrophils, monocytes, and platelets in men: Findings from two trials.
Gagliano-Jucá, T, Pencina, KM, Guo, W, Li, Z, Huang, G, Basaria, S, Bhasin, S
Andrology. 2020;(5):1324-1331
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Abstract
BACKGROUND Testosterone treatment increases erythrocytes in men, but its effects on leukocyte and platelet counts are unknown and could affect its safety. OBJECTIVE To determine whether testosterone affects circulating leukocytes and platelets in men. METHODS Secondary analyses of two randomized testosterone trials were performed: the 5α-reductase (5aR) and OPTIMEN trials. In 5aR trial, 102 healthy men, 21-50 years (mean age 38), received a long-acting GnRH agonist, and 50, 125, 300, or 600 mg/week testosterone enanthate (TE) plus placebo or 2.5 mg/ day dutasteride for 20 weeks. In OPTIMEN, 78 functionally limited men, ≥65 years (mean age 72) with protein intake ≤ 0.83 g kg-1 day-1 , were randomized to controlled diets with 0.8 g kg-1 day-1 protein or 1.3 g kg-1 day-1 protein plus placebo or TE (100 mg/week) for 6 months. Changes from baseline in total and differential leukocyte count, and platelet count were evaluated. RESULTS In 5aR, testosterone administration was associated with increases in total leukocyte (estimated change from baseline 40, 490, 1230, and 1280 cells/µL, P < .001), neutrophil (65.1, 436.1, 1177.2, and 1192.2 cells/µL, P < .001), monocyte (-20.2, 24.5, 90.6, and 143.9 cells/µL, P < .001), platelet (-7.3, 8.4, 8.7, and 8.9 × 103 cells/µL, P = .033), and erythrocyte counts. Testosterone did not affect absolute lymphocyte count. Similar increase in total leukocyte count was observed with testosterone treatment in OPTIMEN (change 0.77 × 103 cells/µL, P vs placebo = 0.004). CONCLUSIONS Testosterone administration in men differentially increases neutrophil and monocyte counts. These findings, together with its erythropoietic effects, suggest that testosterone promotes the differentiation of hematopoietic progenitors into the myeloid lineage. These findings have potential mechanistic, therapeutic, and safety implications.
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Effects of recombinant human lactoferrin on calcium signaling and functional responses of human neutrophils.
Grigorieva, DV, Gorudko, IV, Shamova, EV, Terekhova, MS, Maliushkova, EV, Semak, IV, Cherenkevich, SN, Sokolov, AV, Timoshenko, AV
Archives of biochemistry and biophysics. 2019;:108122
Abstract
Lactoferrin is a non-heme iron-binding glycoprotein with multiple health-beneficial functions including antimicrobial, antioxidant, anticarcinogenic, and immunomodulatory effects. There is emerging evidence that neutrophils may serve as targets of lactoferrin in vivo, and here we show how recombinant human lactoferrin (rhLf) can contribute to this regulation. Indeed, our results demonstrate that rhLf binds efficiently to human neutrophils and induces a variety of early cellular responses such as mobilization of intracellular Ca2+, remodeling of actin cytoskeleton, and degranulation (release of lysozyme and myeloperoxidase). In addition, rhLf facilitates lectin-induced H2O2 production and stabilization of lectin-induced cellular aggregates. The role of calcium signaling seems to be essential for rhLf-induced activation of neutrophils, as Ca2+-chelators inhibit degranulation response while lectin-induced H2O2 production correlates significantly with cytoplasmic Ca2+ elevation. Taken together, our findings justify that rhLf can activate neutrophil functions in a calcium-dependent manner and hence, can potentiate innate immune responses.
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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.