[Methylselenocysteine Promotes Etoposide Cytotoxicity by Enhancing Homotypic Gap Junctions Composed of Connexin 26].

Objective: To investigate the effect of methylselenocysteine (MSC) on the function of homotypic gap junction (GJ) composed of connexin (Cx) 26 and its regulation of chemotherapeutic drug cytotoxicity. Methods: The Tet-on HeLa cells transfected with and stably expressing Cx26 were used as the tool cells. Effects of MSC on cell growth, GJ function, and Cx26 protein expression were examined by MTT method, parachute assay, and Western blot analysis, respectively. The cytotoxicity of chemotherapeutic drugs was determined by standard colony-forming assay, and the relationship between MSC's effect on cytotoxicity of these chemotherapeutic drugs and its regulation of GJ was further analyzed. Results: In Tet-on HeLa cells, doxycycline (Dox) can induce the expression of Cx26, which could then form functional GJs. Within a concentration range of 50 µmol/L, MSC had no significant effect on HeLa cell growth. Non-toxic concentrations of MSC can enhance GJs in a concentration-dependent manner and exert its effect at the nanomolar level. This effect was associated with an induction of Cx26 protein expression by MSC. Among the three common chemotherapeutic agents with different mechanisms of action, etoposide (Eto) presented cytotoxicity differences between HeLa cells cultured at low density (nonconfluent, no GJ formed) and high density (confluent, GJ formed). What's more, the inhibitory effect of Eto combined with MSC on HeLa cell colony formation was stronger than that of Eto alone, and this effect occurred only in HeLa cells with GJ formation. Conclusion: MSC can potentiate the cytotoxicity of Eto by enhancing the GJs composed of Cx26, indicating that combined strategy of selenide and chemotherapy shows potential value in the treatment of malignant tumors.

Hemostasis functions are associated with hemorrhagic transformation in non-atrial fibrillation patients: a case-control study.

BACKGROUND: Hemorrhagic transformation (HT) is a serious neurological complication of acute ischemic stroke (AIS) after revascularization. The majority of AIS patients do not have atrial fibrillation (AF) which could also develop into HT. In this study, we aimed to explore whether hemostasis parameters are risk factors of HT in non-AF patients. METHODS: We consecutively enrolled 285 AIS patients with HT. Meanwhile, age- and sex-matched 285 AIS patients without HT were included. The diagnosis of HT was determined by brain CT or MRI during hospitalization. All patients were divided into two subgroups based on the presence of AF and explore the differences between the two subgroups. Blood samples were obtained within 24 h of admission, and all patients were evenly classified into three tertiles according to platelet counts (PLT) levels. RESULTS: In this study, we found the first PLT tertile (OR = 3.509, 95%CI = 1.268-9.711, P = 0.016) was independently associated with HT in non-AF patients, taking the third tertile as a reference. Meanwhile, we also found mean platelet volume (MPV) (OR = 0.605, 95%CI = 0.455-0.805, P = 0.001) and fibrinogen (FIB) (OR = 1.928, 95%CI = 1.346-2.760, P < 0.001) were significantly associated with HT in non-AF patients. But in AF patients, hemostasis parameters showed no significant difference. Meanwhile, we found the MPV (OR = 1.314, 95%CI = 1.032-1.675, P = 0.027) and FIB (OR = 1.298, 95%CI = 1.047-1.610, P = 0.018) were significantly associated with long-term outcomes in non-AF HT patients. CONCLUSIONS: Low PLT, low MPV, and high FIB levels were independently associated with HT in non-AF patients. Additionally, MPV and FIB levels were significantly associated with unfavorable long-term outcomes in non-AF HT patients. Our study showed that hemostasis functions at admission may be beneficial for clinicians to recognize patients with a high risk of HT at an early stage and improve unfavorable long-term outcomes in non-AF patients.

Maintenance Treatment With Low-Dose Decitabine After Allogeneic Hematopoietic Cell Transplantation in Patients With Adult Acute Lymphoblastic Leukemia.

BACKGROUND: Post-transplant relapse remains a principal leading cause of failure after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with adult acute lymphoblastic leukemia (ALL). The aim of this study was to investigate the efficacy and safety of low-dose decitabine on the prevention of adult ALL relapse after allo-HSCT. METHODS: In this prospective study, we enrolled 34 patients with ALL who underwent allo-HSCT from August 2016 to April 2020 and received low-dose decitabine maintenance treatment after transplantation. The primary objectives were cumulative incidence of relapse rate (CIR), overall survival (OS), and disease-free survival (DFS). The secondary objectives were graft-versus-host disease (GVHD) and safety. RESULTS: Among the enrolled 34 patients, 6 patients relapsed and 6 patients died. The 2-year CIR, OS, and DFS were 20.2, 77.5, and 73.6%, respectively. Subgroup analysis revealed the 2-year CIR, OS, and DFS rates of 12 patients with T-ALL/lymphoblastic lymphoma (LBL) were 8.3, 90, and 81.5%, respectively. None of the seven patients with T-ALL relapsed. During maintenance treatment, only one patient (2.9%) developed grade IV acute GVHD and four (11.8%) patients had severe chronic GVHD. Thirty-two patients (94.1%) developed only grade I to II myelosuppression, and two patients (5.8%) developed grade III to IV granulocytopenia. CONCLUSIONS: Maintenance treatment with low-dose decitabine after allo-HSCT may be used as a therapeutic option to reduce relapse in patients with adult ALL, especially in patients with T-ALL. Our findings require confirmation in larger-scale controlled trials. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trials Registry, identifier ChiCTR1800014888.

RNA-Seq reveals inflammatory mechanisms of Xiao-Ban-Xia-Tang decoction to ameliorate cisplatin-induced emesis in a rat pica model.

OBJECTIVES: Xiao-Ban-Xia-Tang decoction (XBXT), an antiemetic formula in traditional Chinese medicine, has been proved to be a potential treatment for chemotherapy-induced nausea and vomiting (CINV), but the underlying mechanisms are not adequately understood. This study aimed to investigate changes in the ileum transcriptome after cisplatin and XBXT treatment and to reveal whether the antiemetic mechanisms of XBXT are related to its anti-inflammatory effect. METHODS: The pica model was established by a single intraperitoneal injection of 6 mg/kg cisplatin in Wistar rats. Tissues from the gastric antrum and ileum were stained with hematoxylin-eosin to observe gastrointestinal tract pathological changes. Based on the differentially expressed genes (DEGs) which were altered by cisplatin and reversed by XBXT, the transcriptome data of rat ileum were analyzed by GO, KEGG, and PPI analyses. Several inflammatory DEGs were validated by RT-PCR. RESULTS: XBXT could reduce kaolin intake up to 72 h after modeling and alleviate the inflammatory damage of gastric antrum and ileum induced by cisplatin. According to the transcriptome profile, there were 75 DEGs down-regulated by cisplatin and up-regulated by XBXT and 343 DEGs up-regulated by cisplatin and down-regulated by XBXT. XBXT could blunt the overexpression of tryptophan hydroxylase 1 (the rate-limiting enzyme of serotonin synthesis) in ileum. Enrichment analysis showed that inhibiting overexpression of several conventional inflammation pathways and pro-inflammation cytokines were related to the antiemetic effectiveness of XBXT. CONCLUSIONS: This study implies that inhibiting inflammatory signaling pathways and synthesis of serotonin might be potential mechanisms of XBXT's antiemetic effect against CINV.

Liver Fibrosis Is Associated With Hemorrhagic Transformation in Patients With Acute Ischemic Stroke.

Background: Hemorrhagic transformation (HT) is a frequent, often asymptomatic event that occurs after acute ischemic stroke (AIS). Liver fibrosis, usually subclinical, is common and crucial in the development of liver disease. We aimed to investigate the association between liver fibrosis and HT in patients with AIS. Methods: We performed a single-center and retrospective study. A total of 185 consecutive participants with HT and 199 age- and sex-matched stroke patients without HT were enrolled in this study. We calculated one validated fibrosis index-Fibrosis-4 (FIB-4) score-to assess the extent of liver fibrosis. HT was detected by routine CT or MRI and was radiologically classified as hemorrhagic infarction type 1 or 2 or parenchymal hematoma type 1 or 2. HT was also classified into asymptomatic or symptomatic. We used logistic regression models adjusted for previously established risk factors to assess the risks for HT. Results: The median FIB-4 score was significantly higher among patients who developed HT than among those without HT, whereas standard hepatic assays were largely normal. Patients were assigned to groups of high FIB-4 score and low FIB-4 score based on the optimal cutoff value. Compared with the subjects in the low-FIB-4-score group, incidence of HT for the high-FIB-4-score group was significantly higher. After adjustment for potential confounders, the patients with high FIB-4 score had 3.461-fold risk of HT in AIS compared to the patients with low FIB-4 score [odds ratio, 3.461 (95% CI, 1.404-8.531)]. Conclusion: Liver fibrosis, measured by FIB-4 score, was independently associated with the risk of HT in AIS patients.

Individualized Prediction Of Stroke-Associated Pneumonia For Patients With Acute Ischemic Stroke.

BACKGROUND: Stroke-associated pneumonia (SAP) is a serious and common complication in stroke patients. PURPOSE: We aimed to develop and validate an easy-to-use model for predicting the risk of SAP in acute ischemic stroke (AIS) patients. PATIENTS AND METHODS: The nomogram was established by univariate and multivariate binary logistic analyses in a training cohort of 643 AIS patients. The prediction performance was determined based on the receiver operating characteristic curve (ROC) and calibration plots in a validation cohort (N=340). Individualized clinical decision-making was conducted by weighing the net benefit in each AIS patient by decision curve analysis (DCA). RESULTS: Seven predictors, including age, NIHSS score on admission, atrial fibrillation, nasogastric tube intervention, mechanical ventilation, fibrinogen, and leukocyte count were incorporated to construct the nomogram model. The nomogram showed good predictive performance in ROC analysis [AUROC of 0.845 (95% CI: 0.814-0.872) in training cohort, and 0.897 (95% CI: 0.860-0.927) in validation cohort], and was superior to the A2DS2, ISAN, and PANTHERIS scores. Furthermore, the calibration plots showed good agreement between actual and nomogram-predicted SAP probabilities, in both training and validation cohorts. The DCA confirmed that the SAP nomogram was clinically useful. CONCLUSION: Our nomogram may provide clinicians with a simple and reliable tool for predicting SAP based on routinely available data. It may also assist clinicians with respect to individualized treatment decision-making for patients differing in risk level.

Reduced Vitamin D Levels are Associated with Stroke-Associated Pneumonia in Patients with Acute Ischemic Stroke.

BACKGROUND AND AIM: Stroke-associated pneumonia (SAP) is a common complication in patients with acute ischemic stroke (AIS). This study explored the potential relationship between serum vitamin D levels and SAP. METHODS: This study recruited 863 consecutive AIS patients. In-hospital SAP was defined as a complication that occurred after stroke, during hospitalization, that was confirmed radiographically. Serum vitamin D levels were measured within 24 hrs of admission and the patients were divided into vitamin D sufficient (>50 nmol/L), insufficient (25-50 nmol/L), and deficient (<25 nmol/L) groups. RESULTS: In this study, 102 (11.8%) patients were diagnosed with SAP. Compared to the patients without SAP, patients with SAP had significantly lower vitamin D levels (P = 0.023). The incidence of SAP was significantly higher in patients with vitamin D deficiency than in those with vitamin D insufficiency or sufficiency (21.2% vs 16.2% & 9.5%, P = 0.006). After adjusting for confounders, vitamin D deficiency and insufficiency were independently associated with SAP (OR = 3.034, 95% CI = 1.207-7.625, P = 0.018; OR = 1.921, 95% CI = 1.204-3.066, P = 0.006, respectively). In multiple-adjusted spline regression, vitamin D levels showed a linear association with the risk of SAP (P < 0.001 for linearity). CONCLUSION: Reduced vitamin D is a potential risk factor of in-hospital SAP, which can help clinicians identify high-risk SAP patients.

Low triiodothyronine syndrome is associated with hemorrhagic transformation in patients with acute ischaemic stroke.

Hemorrhagic transformation (HT) is a severe complication occurring in acute ischemic stroke (AIS) patients. We explored the association between low triiodothyronine (T3) syndrome and HT in AIS patients. A total of 208 consecutive participants with HT and 208 age- and sex-matched stroke patients without HT were enrolled in this study. HT was diagnosed by follow-up imaging assessment, and was radiologically classified as hemorrhagic infarction (HI) type 1 or 2 or parenchymal hematoma (PH) type 1 or 2. HT was also classified into asymptomatic or symptomatic. The incidence of low T3 syndrome was significantly higher among patients who developed HT than among those without HT. Moreover, the more severe the HT, the lower the detected T3 levels. Multivariate-adjusted binary logistic regression showed that low T3 syndrome was an independent risk factor for HT and symptomatic HT in AIS patients. Low T3 syndrome was also significantly associated with a higher risk of PH, but not with the risk of HI. Thus, low T3 syndrome was independently associated with the risk of HT, symptomatic HT, and severe HT (PH) in AIS patients, which suggests monitoring T3 could be a useful means of preventing HT in patients with ischemic stroke.