Clinical implications of aberrant PD-1 expression for acute leukemia prognosis.

BACKGROUND: Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are the most common types of leukemia in adults with an overall poor prognosis. PD-1 alone or combined with other immune checkpoint blockade is a promising research direction for the treatment of acute leukemia (AL) patients. However, clinical Implications of aberrant PD-1 expression in peripheral CD4+ and CD8+ T lymphocytes of AML and ALL patients in assessing the prognosis of diseases, remains inconclusive. METHODS: In the present study, we used flow cytometry to evaluate PD-1 expression on the surface of CD4+ and CD8+ T lymphocytes in the peripheral circulation of AML and ALL patients and its clinical significance. A total of 53 AML patients, 44 ALL patients and 28 healthy controls were enrolled in this study and peripheral blood specimens were detected by flow cytometry. RESULTS: Our results indicated that percentages of CD4+ PD1+ and CD8+ PD1+ T lymphocytes in newly diagnosed and non-remission groups were significantly higher than healthy control both in AML and ALL patients. The high level of CD4+ PD1+ and CD8+ PD1+ T lymphocytes were respectively poor prognostic indicators of AML patients and ALL patients but had no significant correlation with most common clinical risks. CONCLUSIONS: Our findings show that aberrant PD-1 expression correlates with the prognosis of AL patient and may thus serve as poor prognostic indicators. Immunotherapy using PD-1 inhibitors may be a promising strategy for AML and ALL patients with peripheral circulating CD4+ PD1+ and CD8+ PD1+ T lymphocytes positively expressed, respectively.

[Analysis of risk factors of acute respiratory distress syndrome secondary to severe multiple trauma].

OBJECTIVE: To explore the risk factors of acute respiratory distress syndrome (ARDS) secondary to severe multiple trauma and the role of clinical guidance. METHODS: The clinical data of 115 patients with severe multiple trauma admitted to the trauma center of Zhenjiang First People's Hospital from December 2017 to September 2020 were retrospectively analyzed. According to whether ARDS occurred within 1 week of the disease course, the patients were divided into ARDS group and non-ARDS group. The basic post-traumatic data, initial treatment measures (within 24 hours), pathophysiology, stress metabolism, and post-traumatic complications of the two groups of patients were selected for univariate analysis, the statistically different indicators of univariate analysis were incorporated into the multivariate Logistic regression analysis to screen out independent high-risk factors that affect the occurrence of ARDS in patients with severe multiple trauma, and a receiver operating characteristic curve (ROC curve) was drawn to analyze the effects of each risk factor on the occurrence of ARDS. RESULTS: Among 115 patients, there were 45 cases in the ARDS group and 70 cases in the non-ARDS group. Compared with the non-ARDS group, the patients in the ARDS group were older (years: 57.45±15.37 vs. 45.68±12.70), and the proportion of patients combined with moderate-severe chest trauma, traumatic brain injury (TBI), shock, and massive blood transfusion were higher (71.11% vs. 31.43%, 44.44% vs. 28.57%, 80.00% vs. 67.14%, 46.67% vs. 27.14%). In the ARDS group, procalcitonin [PCT (µg/L): 29.73±6.08 vs. 12.45±2.12], thrombomodulin [TM (ng/L): 83.43±16.34 vs. 37.66±14.64], blood glucose (mmol/L: 17.2±5.0 vs. 10.3±2.4), triacylglycerol [TG (mmol/L): 3.77±0.57 vs. 2.22±0.63], interleukin-6 [IL-6 (ng/L): 38.97±10.79 vs. 25.98±5.40], tumor necrosis factor-α [TNF-α (ng/L): 48.78±13.99 vs. 35.30±13.03], intra-abdominal pressure [mmHg (1 mmHg = 0.133 kPa): 25.21±3.59 vs. 11.98±4.91], serum creatinine [SCr (µmol/L): 180.45±42.35 vs. 132.17±49.36] and blood urea nitrogen [BUN (mmol/L): 13.83±4.97 vs. 8.80±4.32] were significantly higher than those in the non-ARDS group; the proportion of patients with crystal infusion volume ≥ 3 000 mL (26.67% vs. 34.29%) and platelet count [PLT (×109/L): 72.67±7.96 vs. 127.99±17.65] and the levels of plasma glutathione peroxidase [GSH-Px (kU/L): 87.15±27.81 vs. 161.15±17.94], plasma superoxide dismutase [SOD (kU/L): 92.65±32.67 vs. 125.58±38.96] were significantly lower than those in the non-ARDS group, the differences were statistically significant (all P < 0.05). Multivariate Logistic regression analysis showed that 11 indicators such as age, combined moderate-severe chest trauma, combined TBI, massive blood transfusion, PCT, TM, blood glucose, TNF-α, plasma GSH-Px, intra-abdominal pressure and SCr were independent risk factors that could predict ARDS secondary to severe multiple trauma, the odds ratio (OR) and 95% confidence interval (95%CI) were 1.201 (1.035-1.165), 3.414 (1.217-8.876), 2.889 (1.124-8.109), 3.134 (1.322-9.261), 1.467 (1.096-2.307), 2.428 (0.024-0.973), 5.787 (1.246-9.642), 1.106 (0.949-5.108), 7.450 (1.587-10.261), 3.144 (1.217-8.876), 1.051 (1.002-1.542) respectively, the P values were 0.008, 0.024, 0.044, 0.017, 0.018, 0.045, 0.026, 0.037, 0.005, 0.029, 0.033 respectively. ROC curve analysis showed that plasma GSH-Px had a higher predictive value for ARDS secondary to severe multiple trauma, the area under ROC curve (AUC) = 0.873, 95%CI was 0.798-0.928, P = 0.000, when the best cut-off value at 72.22 kU/L, its sensitivity was 86.7%, specificity was 75.7%, positive predictive value was 69.6%, and negative predictive value was 89.8%. The Logistic regression model established by 11 independent high-risk factors had an accuracy rate of 81.74% in predicting ARDS secondary to severe multiple trauma, which had a good guiding significance for predicting ARDS. CONCLUSIONS: Our study showed that there are many risk factors for ARDS secondary to severe multiple trauma, involving basic post-traumatic data, initial treatment measures, pathophysiology, stress metabolism, post-traumatic complications, etc. Early identification and intervention may be beneficial to improve the success rate of treatment for such patients.

Stress-induced premature senescence activated by the SENEX gene mediates apoptosis resistance of diffuse large B-cell lymphoma via promoting immunosuppressive cells and cytokines.

BACKGROUND: The underlying cause of relapsed and refractory (r/r) diffuse large B-cell lymphoma (DLBCL) is usually related to apoptosis resistance to antitumor drugs. The recent years have provided lots of evidence that tumor cells may undergo stress-induced premature senescence (SIPS) in response to chemotherapy, but how SIPS affects lymphoma cells remains inconclusive. METHODS: Fifty-two DLBCL patients, including 6 newly diagnosed (ND), 17 complete remissions (CR), and 29 (r/r), were enrolled in this study. We used a senescence-associated-ß-galactosidase (SA-ß-Gal) staining kit for senescence staining. Suppressive immune cells including regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC) were detected by flow cytometry (FCM). Secreted cytokines were measured by ELISA Kit and SENEX gene expression was detected by a quantitative real-time polymerase chain reaction. We used 40 nM doxorubicin to induce the SIPS model of DLBCL in vitro. Apoptosis and proliferation activity of senescent LY8 cells were respectively detected by FCM and CCK8. SENEX gene was silenced by RNA interference. RESULTS: The proportion of senescent lymphoma cells was significantly increased in r/r DLBCL patients, concomitant with increased Treg, MDSC, and various secreted cytokines with proinflammatory and immunosuppressive effects. The SENEX gene was significantly elevated in the SIPS model. Senescent DLBCL cells had good antiapoptotic ability and proliferative activity accompanied by increased immunosuppressive cytokines. Interestingly, when we silenced the SENEX gene in the DLBCL cell line, the results were the opposite to the above. CONCLUSION: SIPS activated by the SENEX gene mediates apoptosis resistance of r/r DLBCL via promoting immunosuppressive cells and cytokines.

Clinical characteristics of patients with 2019 coronavirus disease in a non-Wuhan area of Hubei Province, China: a retrospective study.

BACKGROUND: Since December 2019, the 2019 coronavirus disease (COVID-19) has expanded to cause a worldwide outbreak that more than 600,000 people infected and tens of thousands died. To date, the clinical characteristics of COVID-19 patients in the non-Wuhan areas of Hubei Province in China have not been described. METHODS: We retrospectively analyzed the clinical characteristics and treatment progress of 91 patients diagnosed with COVID-19 in Jingzhou Central Hospital. RESULTS: Of the 91 patients diagnosed with COVID-19, 30 cases (33.0%) were severe and two patients (2.2%) died. The severe disease group tended to be older (50.5 vs. 42.0 years; p = 0.049) and have more chronic disease (40% vs. 14.8%; p = 0.009) relative to mild disease group. Only 73.6% of the patients were quantitative polymerase chain reaction (qPCR)-positive on their first tests, while typical chest computed tomography images were obtained for each patient. The most common complaints were cough (n = 75; 82.4%), fever (n = 59; 64.8%), fatigue (n = 35; 38.5%), and diarrhea (n = 14; 15.4%). Non-respiratory injury was identified by elevated levels of aspartate aminotransferase (n = 18; 19.8%), creatinine (n = 5; 5.5%), and creatine kinase (n = 14; 15.4%) in laboratory tests. Twenty-eight cases (30.8%) suffered non-respiratory injury, including 50% of the critically ill patients and 21.3% of the mild patients. CONCLUSIONS: Overall, the mortality rate of patients in Jingzhou was lower than that of Wuhan. Importantly, we found liver, kidney, digestive tract, and heart injuries in COVID-19 cases besides respiratory problems. Combining chest computed tomography images with the qPCR analysis of throat swab samples can improve the accuracy of COVID-19 diagnosis.

The prognostic value of tumour-associated macrophages in Non-Hodgkin's lymphoma: A systematic review and meta-analysis.

Tumour-associated macrophages (TAMs) play an important role in the tumour environment and were reported to be associated with poor prognosis in several tumours. However, the prognostic significance of TAMs in Non-Hodgkin's Lymphoma (NHL) remains controversial. Consequently, we aimed to evaluate the relationship between subpopulations of TAMs and clinical outcomes in NHL patients. We did a comprehensive search of the PubMed, elsevier ScienceDirect, and Cochrane databases and extracted hazard ratio (HR) and their corresponding 95% confidence intervals (95% CIs) from eligible studies. Pooling total effect value by the stata statistical software and analysing correlation of TAMs with overall survival (OS) and progression-free survival (PFS). Furthermore, subgroup analysis and sensitivity analysis were also conducted. We deemed eleven studies, including 1211 NHL patients. Our study demonstrated that high-density CD68+ TAMs are associated with poor OS (HR: 1.17; 95% CI, 0.81-1.54; P = .000) and poor PFS (HR: 1.15; 95% CI, 0.63-1.67; P = .000) compared with low-density CD68+ TAMs in the tumour microenvironment. Similarly, high-density CD163+ TAMs can also predict poor OS (HR: 1.52; 95% CI, 1.11-1.92; P = .000) and shorter PFS (HR: 1.52; 95% CI, 0.73-2.30; P = .000). In addition, the high CD163+ /CD68+ TAMs ratio is significantly correlated with poor OS (HR: 3.59; 95% CI, 0.77-6.40; P = .013). However, in our subgroup analysis, high-density CD68+ TAMs in the tumour microenvironment is associated with better OS (HR: 0.75; 95% CI, 0.41-1.09; P = .000) in NHL patients treated with rituximab chemotherapy. Our results suggest that TAMs are a robust predictor of outcomes in NHL.

Increased CD14+HLA-DR-/low Myeloid-Derived Suppressor Cells Correlate With Disease Severity in Systemic Lupus Erythematosus Patients in an iNOS-Dependent Manner.

Myeloid-derived suppressor cells (MDSCs) comprise of a population of cells, which suppress the innate and adaptive immune system via different mechanisms. MDSCs are accumulated under pathological conditions. The present study aimed to clarify the pathological role of MDSCs in systemic lupus erythematosus (SLE) patients. Consequently, the level of circulating M-MDSCs was significantly increased in newly diagnosed SLE patients as compared to healthy controls. An elevated level of M-MDSCs was positively correlated with the disease severity in SLE patients and an immunosuppressive role was exerted in an iNOS-dependent manner. The decrease in the number of M-MDSCs after therapy rendered them as an indicator for the efficacy of treatment. These results demonstrated that M-MDSCs participated in the pathological progress in SLE patients. Thus, MDSCs are attractive biomarkers and therapeutic targets for SLE patients.

Immune dysregulation in primary immune thrombocytopenia patients.

OBJECTIVES: To explore the immunological abnormalities in patients with primary immune thrombocytopenia (ITP), and analyze its relationship with treatment. METHODS: Proportion of different immune cell subsets were detected in the peripheral blood of 124 ITP patients at different time points and 45 normal controls by flow cytometry. The treatments included glucocorticoids, intravenous IgG as first-line treatment and second-line drugs. RESULTS: Elevated CD4/CD8 ratio and decreased the proportion of NK and CD4 + CD25 + CD127low regulatory T cells (Tregs) were found in pre-treated ITP patients than healthy controls. The newly diagnosed group had a significantly higher CD4/CD8 ratio than the relapsed group, but no differences in the proportion of B cells, NK cells and Tregs. No relationships were found between the curative effect and the pre-treated cell subsets within both the effective and ineffective groups. Furthermore, compared with the ineffective group, the effective group had higher Tregs and lower CD4/CD8 ratio post-treatment, but no significant differences in NK and B cells. CONCLUSION: ITP patients presented with a high CD4/CD8 ratio and low levels of Tregs and NK cells, suggesting that immune deregulation was involved in the pathogenesis of ITP. The pre-treated immune status of ITP patients may not be related to the curative effect. Tregs significantly increased in the effective group post-treatment, highlighting that the mechanism of restoring Tregs may be involved in the treatment of ITP. However, whether or not the targeted regulation of Tregs is an effective treatment for ITP still requires further studies.

Therapeutic potential of low-dose IL-2 in immune thrombocytopenia: An analysis of 3 cases.

Immune thrombocytopenia (ITP) is an acquired immune-mediated disorder with regulatory T cells (Tregs) reduction. Recent studies have shown that low-dose interleukin-2 can preferentially induce Treg expansion in vivo, and therefore offers a therapeutic strategy against immune thrombocytopenia. We have demonstrated in a previous study that Tregs and platelet counts significantly improve in an adult with ITP following low-dose IL-2 treatment. Here we report the efficacy of low-dose IL-2 in another three adults with immune thrombocytopenia who failed the first-line treatment. All patients received a dose of 1.0 million IU IL-2/day for 5 consecutive days per week as a cycle for 2 or 4 weeks. In addition to IL-2, vincristine (2 mg IV weekly × 3 weeks) was added to one patient as a combination therapy. No specific treatment was added in the other two patients. Two cases exhibited significantly increased platelet counts with improved levels of Tregs, while no changes were observed for the remaining patient. In summary, administration of daily subcutaneous low-dose IL-2 was safe, and it may be a new therapeutic option for treatment of ITP, especially refractory ITP. © 2017 International Clinical Cytometry Society.

Prognostic Value of NME1 (NM23-H1) in Patients with Digestive System Neoplasms: A Systematic Review and Meta-Analysis.

OBJECTIVE: There is a heated debate on whether the prognostic value of NME1 is favorable or unfavorable. Thus, we carried out a meta-analysis to evaluate the relationship between NME1 expression and the prognosis of patients with digestive system neoplasms. METHODS: We searched PubMed, EMBASE and Web of Science for relevant articles. The pooled odd ratios (ORs) and corresponding 95%CI were calculated to evaluate the prognostic value of NME1 expression in patients with digestive system neoplasms, and the association between NME1 expression and clinicopathological factors. We also performed subgroup analyses to find out the source of heterogeneity. RESULTS: 2904 patients were pooled from 28 available studies in total. Neither the incorporative OR combined by 17 studies with overall survival (OR = 0.65, 95%CI:0.41-1.03, P = 0.07) nor the pooled OR with disease-free survival (OR = 0.75, 95%CI:0.17-3.36, P = 0.71) in statistics showed any significance. Although we couldn't find any significance in TNM stage (OR = 0.78, 95%CI:0.44-1.36, P = 0.38), elevated NME1 expression was related to well tumor differentiation (OR = 0.59, 95%CI:0.47-0.73, P<0.00001), negative N status (OR = 0.54, 95%CI:0.36-0.82, P = 0.003) and Dukes' stage (OR = 0.43, 95%CI:0.24-0.77, P = 0.004). And in the subgroup analyses, we only find the "years" which might be the source of heterogeneity of overall survival in gastric cancer. CONCLUSIONS: The results showed that statistically significant association was found between NME1 expression and the tumor differentiation, N status and Dukes' stage of patients with digestive system cancers, while no significance was found in overall survival, disease-free survival and TNM stage. More and further researches should be conducted to reveal the prognostic value of NME1.

Efficacy and safety of Yinchenwuling powder for hyperlipidemia: a systematic review and Meta-analysis.

OBJECTIVE: To assess the clinical effectiveness and adverse effects of Yinchenwuling powder (YCWLP) in the treatment of hyperlipidemia using Meta-analysis. METHODS: Seven electronic databases were searched for randomized controlled trials designed to evaluate the clinical effectiveness of YCWLP for hyperlipidemia published in any language prior to February 2015. Two reviewers independently identified articles, extracted data, assessed quality, and cross-checked the results. Revman 5.3 was used to analyze the data. RESULTS: Only five randomized controlled trials with poor methodology were included in the analysis. The five trials compared YCWLP with conventional lipid-lowering drugs. Meta-analysis indicated that YCWLP was more effective at the levels of total cholesterol and triglycerides, while increasing the level of high-density lipoprotein cholesterol without serious adverse effects. However, it was not more effective than lipid-lowering drugs in reducing low-density lipoprotein cholesterol and improving hemorheology. CONCLUSION: YCWLP appeared to improve lipid levels. However, given the high risk of bias among the trials, we could not conclude that YCWLP was beneficial to patients with hyperlipidemia. More rigorous trials are required to provide stronger evidence for the conclusion.

Piromelatine decreases triglyceride accumulation in insulin resistant 3T3-L1 adipocytes: role of ATGL and HSL.

Piromelatine, a novel investigational multimodal sleep medicine, is developed for the treatment of patients with primary and co-morbid insomnia. Piromelatine has been shown to inhibit weight gain and improve insulin sensitivity in high-fat/high-sucrose-fed (HFHS) rats. Considering that piromelatine has also been implicated in lowering of triglyceride levels in HFHS rats, this work elucidated whether this effect involves in the regulation of adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) in triglyceride (TG) metabolism. In this study, we investigated the effects of piromelatine and MT2 receptors inhibition on TG content, insulin-stimulated glucose uptake, and the expressions of ATGL and HSL in 3T3-L1 adipocytes preincubated in high glucose and high insulin (HGI) conditions. Our results showed that culturing 3T3-L1 adipocytes under HGI conditions increased triglyceride accumulation with concomitant decrease of ATGL and HSL expression, inducing insulin resistance in 3T3-L1 adipocytes. We also found that triglyceride accumulation was significantly inhibited and the levels of ATGL/HSL increased after melatonin or piromelatine treatment. The effects of melatonin/piromelatine (10 nM) were counteracted by pretreatment with the relatively selective MT2 receptor antagonist luzindole (100 nM). In this study, our data demonstrate that piromelatine reverses high glucose and high insulin-induced triglyceride accumulation in 3T3-L1 adipocytes, possibly through up-regulating of ATGL and HSL expression via a melatonin-dependent manner.