The influence of a modified p53 C-terminal peptide by using a tumor-targeting sequence on cellular apoptosis and tumor treatment.

The restoration of the function of p53 in tumors is a therapeutic strategy for the highly frequent mutation of the TP53 tumor suppressor gene. P460 is a wild-type peptide derived from the p53 C-terminus and has been proven to be capable of restoring the tumor suppressor function of p53. The poor accumulation of drugs in tumors is a serious hindrance to tumor treatment. For enhancing the activity of P460, the tumor-targeting sequence Arg-Gly-Asp-Arg (RGDR, C-end rule peptide) was introduced into the C-terminus of P460 to generate the new peptide P462. P462 presented better activity than P460 in inhibiting the proliferation of cancer cells and increasing the number of tumor cells undergoing apoptosis. Cell adhesion analysis and tumor imaging results revealed that P462 showed more specific and extensive binding with tumor cells and greater accumulation in tumors than the wild-type peptide. Importantly, treatment with P462 was more efficacious than that with P460 in vivo and was associated with considerably improved tumor-homing activity. This study highlights the importance of the roles of the tumor-homing sequence RGDR in the enhancement in cell attachment and tumor accumulation. The results of this work indicate that P462 could be a novel drug candidate for tumor treatment.

Retinol binding protein 1-dependent activation of NF- κB signaling enhances the malignancy of non-glioblastomatous diffuse gliomas.

Nonglioblastomatous diffuse glioma (non-GDG) is a heterogeneous neuroepithelial tumor that exhibits a varied survival range from 4 to 13 years based on the diverse subtypes. Recent studies demonstrated novel molecular markers can predict prognosis for non-GDG patients; however, these findings as well as pathological classification strategies show obvious limitations on malignant transition due to the heterogeneity among non-GDGs. Therefore, developing reliable prognostic biomarkers and therapeutic targets have become an urgent need for precisely distinguishing non-GDG subtypes, illuminating the underlying mechanism. Nuclear factor κß (NF-κB) has been proved to be a significant nuclear transcriptional regulator with specific DNA-binding sequences to participate in multiple pathophysiological processes. However, the underlying mechanism of NF-κB activation still needs to be further investigated. Herein, our results indicated retinol-binding protein 1 (RBP1) was significantly upregulated in the IDHWT and 1p19qNon co-del non-GDG subtypes and enriched RBP1 expression was markedly correlated with more severe outcomes. Additionally, malignant signatures of the non-GDG cells including proliferation, migration, invasion, and self-renewal were significantly suppressed by lentiviral knockdown of RBP1. To further explore the underlying molecular mechanism, bioinformatics analysis was performed using databases, and the results demonstrated RBP1 was strongly correlated with tumor necrosis factor α (TNFα)-NF-κB signaling. Moreover, exogenous silencing of RBP1 reduced phosphorylation of IkB-kinase α (IKKα) and thus decreased NF-κB expression via decreasing the degradation of the IκBα protein. Altogether, these data suggested RBP1-dependent activation of NF-κB signaling promoted malignancy of non-GDG, indicating that RBP1 could be a reliable prognostic biomarker and potential therapeutic target for non-GDG.

Association of ST6GAL1 and CYP19A1 polymorphisms in the 3'-UTR with astrocytoma risk and prognosis in a Chinese Han population.

BACKGROUND: Astrocytoma is a common type of central nervous system tumor. In this study, we investigated the correlation between ST6GAL1 and CYP19A1 polymorphisms and the risk and prognosis of astrocytoma. METHODS: A total of 365 astrocytoma patients and 379 healthy controls were genotyped using the Agena MassARRAY system. The correlation between ST6GAL1 and CYP19A1 variants and astrocytoma risk was calculated using logistic regression. The survival rate of patients with astrocytoma was analyzed to evaluate prognosis. RESULTS: We found that the ST6GAL1-rs2239611 significantly decreased the risk of astrocytoma in the codominant model (p = 0.044) and dominant model (p = 0.049). In stratified analyses, CYP19A1-rs2255192 might be associated with a higher risk of astrocytoma among the low-grade subgroup under recessive (p = 0.034) and additive (p = 0.030) models. However, CYP19A1-rs4646 had a risk-decreasing effect on the high-grade subgroup in the codominant model (p = 0.044). The results of Cox regression analysis showed that the CYP19A1-rs2239611 and -rs1042757 polymorphisms were significantly correlated with the prognosis of astrocytoma. CONCLUSION: Our results suggest that ST6GAL1 and CYP19A1 genes may be a potential biomarker of genetic susceptibility and prognosis to astrocytoma in the Chinese Han population.

MCC950 Inhibits NLRP3 Inflammasome and Alleviates Axonal Injures in Early Stages of Diffuse Axonal Injury in Rats.

Increasing evidence has revealed that neuroinflammation plays a pivotal role in axonal injures. Nucleotide oligomerization domain (NOD)-like receptor protein (NLRP3) inflammasome is reported to be widely involved with the pathology of central nervous system disorders. But the role of NLRP3 in diffuse axonal injury (DAI) are rarely reported. The purpose of this study was to investigate the expression of NLRP3 after diffuse axonal injury and the role of NLRP3 in axonal injures. The lateral head rotation device was used to establish DAI model of rats. Immunohistochemical staining for ß-amyloid precursor protein and Bielschowsky silver staining were used to assess axonal injures and axonal loss. Terminal Deoxynucleotidyl Transferase-Mediated Digoxigenin-dUTP-Biotin Nick-End Labelling Assay was used to detect cell apoptosis. Brain water content was used to assess cerebral edema and the modified Neurologic Severity Score was used to assess the neurological deficits. Components of NLRP3 inflammasome, such as NLRP3, apoptosis-associated speck-like (ASC) adapter protein and caspase-1, and pro-inflammatory cytokines, for example IL-18 and IL-1ß, were over-expressed in early stages of DAI. MCC950, a selective small-molecule inhibitor of NLRP3 inflammasome, inhibited the over-expression of NLRP3 inflammasome and pro-inflammatory cytokines after DAI. MCC950 alleviated axonal injures and cell apoptosis. MCC950 also decreased brain water content and alleviated neurologic deficits 1 day and 3 days after DAI but not 7 days after DAI. These results suggest that MCC950 treatment in the early stages of DAI has a time limiting effect in preventing from axonal injuries and neurological deficits, and that NLRP3 inflammasome plays an important role in axonal injures and may be a potential candidate for axonal injures following DAI.

Impact of ANXA5 polymorphisms on glioma risk and patient prognosis.

BACKGROUND: Glioma, the most common primary malignant brain tumor, is highly malignant with a poor prognosis. We aimed to clarify the relevance of ANXA5 polymorphisms to glioma risk and prognosis among the Chinese Han population. METHOD: Six single-nucleotide polymorphisms (SNPs) of ANXA5 were genotyped by Agena MassARRAY in 593 glioma patients and 589 healthy controls. Logistic regression model was used to calculate odds ratios (OR) and 95% confidence intervals (CI). The association between polymorphisms and survival were evaluated using the log-rank test, Kaplan-Meier analysis and Cox regression model. RESULTS: We found that rs117677079 polymorphism was strongly associated with an increased risk of glioma (OR 1.64, p = 0.003) and a worse prognosis for glioma, especially in high-grade glioma (HR 1.76, p = 0.005). Whereas, rs145619195 CT genotype might weaken the susceptibility (OR 0.63, p = 0.024) and prognosis (HR 0.20, p = 0.025) of glioma. Haplotype analysis showed that haplotype ″GACCG″ in the block (rs41278075, rs2306420, rs117677079, rs2306415 and rs1131239) significantly decreased the susceptibility of glioma (OR 0.61, p = 0.003). Furthermore, we also found that age, extent of resection and chemotherapy were key prognostic factors in glioma patients. CONCLUSION: This study firstly provided evidence for the impact of ANXA5 polymorphism on the susceptibility and prognosis of glioma, suggesting ANXA5 variants might have potential roles in the etiology of glioma.

[Effect of Telbivudine Tablet Combined Jianpi Bushen Recipe on HBV Specific Cytotoxic T Lymphocyte and HBeAg Seroconversion in Patients with HBeAg Positive Chronic Hepatitis B].

OBJECTIVE: To explore the effect of Telbivudine (LDT) Tablet combined with Jianpi Bushen Recipe (JBR) on serum hepatitis B virus (HBV) specific cytotoxic T lymphocyte (CTL) and HBeAg seroconversion in chronic hepatitis B (CHB) patients. METHODS: Totally 90 HBeAg-positive and human leukocyte antigen (HLA)-A2 positive CHB patients were randomly assigned to the treatment group and the control group, 45 cases in each group. Patients in the treatment group took LDT Tablet (600 mg, once per day) combined with JBR granule (twice per day), while those in the control group took LDT Tablet alone. The therapeutic course for all was one year. HBV DNA negative conversion rate, HBeAg seroconversion rate, and level of HBV specific CTL were compared after 1 year treatment; liver function, drug resistance mutations, and adverse reactions were also compared between the two groups. RESULTS: After 1 year treatment, HBV DNA negative conversion rate and HBeAg seroconversion rate were 88.89% (40/45) and 40.00% (18/45) in the treatment group, higher than those of the control group [68.89% (31/45) and 20.00% (9/45)], with statistical difference (P < 0.05). Level of HBV specific CTL in the treatment group was 0.78% +/- 0.09% after treatment, higher than that of the control group after 1 year treatment (0.54% +/- 0.11%) and that before treatment (0.36% +/- 0.07%), with statistical difference (P < 0.01). Level of HBV specific CTL in 27 patients with HBeAg seroconversion was 0.81% 0.10%, higher than that of 63 patients without HBeAg seroconversion (0.60% +/- 0.09%), with statistical difference (P < 0.01). ALT returned to normal in 44 cases of the treatment group (97.78%), while it was 42 cases (93.33%) of the control group, with no statistical difference between the two groups (P > 0.05). Total bilirubin (TBil) in the two groups all turned to normal. rtM204I variation occurred in 1 case (2.22%) of the treatment group and 2 cases (4.44%) in the control group. No obvious adverse reaction occurred in the two groups. CONCLUSION: LDT Tablet combined with JBR could elevate levels of HBV specific CTL and HBeAg seroconversion in CHB patients.

[Treatment of early and mid-term primary biliary cirrhosis by Qingying Huoxue Decoction Combined ursodeoxycholic acid: a clinical observation].

UNLABELLED: OBJECTIVE To observe the clinical efficacy by Qingying Huoxue Decoction (QHD) combined ursodeoxycholic acid (UDCA) in treating patients with early and mid-term primary biliary cirrhosis (PBC). METHODS Totally 78 patients were randomly assigned to the treatment group and the control group, 39 in each group. All patients received basic treatment and took UDCA (at the daily dose of 13-15 mg/kg). Patients in the treatment group took QHD, one dose per day. The treatment course for all was 6 weeks. Clinical efficacy, gamma-glutamyl transferase (γ-GGT), alkaline phospatase (ALP), TBIL, alanine aminotransferase (ALT), and aspartate transaminase (AST) were observed before and after treatment. RESULTS Totally 21 (53. 8%) patients obtained complete response in the treatment group, with statistical difference when compared with that of the control group (11 cases, 30. 8%). Levels of GGT, ALP, ALT, AST, and TBIL decreased in the two groups after treatment (P < 0.01). Levels of ALP, GGT, and TBIL were obviously lower in the treatment group than in the control group (P < 0.05). CONCLUSIONS: QHD combined UDCA in treating early and mid-term PBC patients was superior to the effect of using UDCA alone. It also could improve patients' liver function.

Dynamic expression of the suppressor of cytokine signaling-3 and cytokines in the cerebral basilar artery of rats with subarachnoid hemorrhage, and the effect of acetylcholine.

BACKGROUND: There are complex interactions between acetylcholine (ACh), the suppressor of cytokine signaling-3 (SOCS-3), and cytokines, however, little is known about their dynamic expression or their effects on cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH). Therefore, we aimed to describe and clarify the dynamic expression of SOCS-3 and cytokines after SAH, as well as the relationships between the levels of SOCS-3, cytokines, and ACh. METHODS: The rat model of single cisterna magna injection was used to mimic acute SAH. The degree of CVS was indicated by lumen diameter and artery wall thickness under H&E staining. A semi-quantitative immunohistochemical analysis method was used to clarify the role of SOCS-3 in the CVS after SAH. We also measured the content of IL-6 and IL-10 in cerebrospinal fluid. RESULTS: We found that SOCS-3 expression levels increased rapidly within 12 h after SAH, more slowly after 12 h, and did not reach a peak within 48 h. Interleukin 6 (IL-6) levels rapidly increased within 24 h after SAH, reached a peak 24 h after SAH, and decreased slightly at 48 h. IL-10 levels increased during the first 6 h after SAH, after which this increase tapered off. ACh treatment reduced IL-6 levels and resulted in elevated levels of SOCS-3, but had no effect on IL-10 expression. Furthermore, ACh treatment relieved basilar arterial vasospasm, whereas mecamylamine pretreatment counteracted the activity of ACh. CONCLUSIONS: Taken together, these data indicate that SOCS-3 was involved in vasospasm via an IL-6- and IL-10-related mechanism, and that CVS following SAH could be reversed by the intraventricular injection of ACh.

[Effect of compound qizhu granule on cellular immunity of chronic hepatitis B patients].

OBJECTIVE: To explore the effect of compound qizhu granule (CQG) on cellular immunity of chronic hepatitis B (CHB) patients. METHODS: Totally 103 CHB patients treated with lamivudin (LAM) for 6 months, who had partial virological response (HBeAg positive) were randomly assigned to two groups, 50 in the treatment group and 53 in the control group. All patients took LAM 100 mg (once a day) plus ADV 10 mg (once a day). Patients in the treatment group additionally took CQG, one dose per day. After one-year treatment hepatitis B virus (HBV) DNA negative rates, HBeAg seroconversion, levels of HBV specific cytotoxic T lymphocyte (CTL), non-specific CTL and natural killing (NK) cells were compared between the two groups. RESULTS: After 1-year treatment, HBV DNA negative rate of the treatment group was 88: 0% in 44 cases, slightly higher than that of the control group (41 cases, 77.4%), but with no statistical difference (P >0.05). HBeAg seroconversion of the treatment group was 32.0% in 16 cases, higher than that of the control group (8 cases, 15.1%), with statistical difference (P <0.05). Levels of HBV specific CTL (0.79%±0. 07%), non-specific CTL (19.4%±1.8%) and NK cells (14. 1%± 1.5%) of the treatment group were higher than those of the control group (0.58% ± 0.08%, 17.5% ± 1.7%, and 11.1%±1.5%, respectively; allP <0.01). CONCLUSION: Treating CHB patients with partial virological response by ADV plus CQG could improve specific and non-specific cellular immunity, thereby elevating HBeAg seroconversion rate.

Observation on the Effect of Sequentially Combined Multi-modal Artificial Liver Treatment on HBV-related Acute-on-chronic Liver Failure.

OBJECTIVE: To observe the short-term effect of sequentially combined multimodal artificial liver treatment (SCMALT) on HBV-related acute-on-chronic liver failure (HBV-ACLF). METHODS: HBV-ACLF patients 155 cases undergoing artificial liver treatment were analyzed, and they were sorted into the SCMALT group and the conventional-modal artificial liver treatment (CALT) group. The clinical data of all patients were recorded and the serum levels of interleukin-8 (IL-8), chemokine interferon-inducible protein-10 (IP-10), and interleukin-6 (IL-6) were detected. The changes in the 30-day survival rate, cytokine level, model for end-stage liver disease (MELD) score, and complications of artificial liver treatment were analyzed. RESULTS: After being followed up for 30 days, 104 patients survived and 51 died. At the end of the whole-course treatment, the decreases in IL-6, IP-10, and IL-8 levels and MELD scores in the SCMALT group were greater than in the CALT group. Cox regression suggested WBC (OR=1.066 ， 95% CI 1.012-1.123 ， P=0.017), AT-III activity (OR=0.935 ， 95% CI 0.907-0.964 ， P=0.000) at baseline, artificial liver treatment mode (OR=0.362，95% CI 0.164-0.800，P=0.012), number of artificial liver treatments (OR=0.656 ， 95% CI 0.436-0.986 ， P=0.043), spontaneous peritonitis (OR=0.337，95% CI 0.165-0.689，P=0.003), and hepatic encephalopathy (OR=0.104, 95% CI 0.028-0.388 ， P=0.001) were independent influencing factors of 30-day survival rate. SCMALT can significantly prolong the survival period of the patient. No obvious difference was shown in the proportions of bleeding and circulation instability between the two groups (P>0.05). CONCLUSION: Compared with the CALT, SCMALT can more effectively remove inflammatory mediators and reduce the MELD score in HBV-ACLF patients, which can obviously ameliorate the prognosis, with less effect on the platelet count.

Antithrombin III activity is associated with prognosis, infection, and inflammation in patients with hepatitis B virus-related acute-on-chronic liver failure.

OBJECTIVE: Patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) are characterized by severe liver function impairment, coagulation disorder, and multiple organ function impairment. The aim of this study was to explore the predictive value of antithrombin Ⅲ activity to the prognosis of HBV-ACLF patients. METHODS: A total of 186 HBV-ACLF patients were included in the analysis, and the baseline clinical data of patients were recorded to analyze the risk factors affecting the 30-day survival outcome of patients. Bacterial infection, sepsis, and hepatic encephalopathy were observed in ACLF patients. Antithrombin Ⅲ activity and serum cytokine levels were determined. RESULTS: The antithrombin Ⅲ activity of ACLF patients in the death group was significantly lower than that in the survival group, and antithrombin Ⅲ activity was independent factors affecting the 30-day outcome. The areas under the receiver operation characteristic (ROC) curve of antithrombin Ⅲ activity to predict the 30-day mortality of ACLF was 0.799. Survival analysis showed that the mortality of patients with antithrombin Ⅲ activity less than 13% was significantly increased. Patients with bacterial infection and sepsis had lower antithrombin Ⅲ activity than those without infection. Antithrombin Ⅲ activity was positively correlated with platelet count, fibrinogen, interferon (IFN)-γ, interleukin (IL)-13, IL-1ß, IL-4, IL-6, tumor necrosis factor-α, IL-23, IL-27, and IFN-α, but negatively correlated with C-reactive protein, D dimer, total bilirubin, and creatinine levels. CONCLUSION: As a natural anticoagulant, antithrombin Ⅲ can be regarded as a marker of inflammation and infection in patients with HBV-ACLF, and as a predictor of survival outcome in patients with ACLF.

[Clinical Characteristics and Risk Factors for 30-Day Mortality in Patients with Hematologic Diseases Infected by Carbapenem-Resistant Organisms].

OBJECTIVE: To explore the clinical characteristics of hospitalized patients with hematologic diseases complicated with carbapenem-resistant organisms (CRO) infection and analyze the risk factors of 30-day all-cause mortality. METHODS: The clinical data and laboratory test data of 77 hospitalized patients with hematologic diseases complicated with CRO infection in department of hematology of the Third Hospital of Shanxi Medical University from January 2015 to December 2020 were retrospectively analysed, the risk factors of 30-day all-cause mortality after CRO infection were analyzed by multivariate logistic regression. RESULTS: Among the total of 77 patients with hematologic diseases complicated with CRO infection, 29 died and 48 survived within 30 days of infection, with a case fatality rate of 37.66%. A total of 93 strains of CRO were isolated from these patients, of which Acinetobacter baumannii had the highest detection rate (25.81%, 24/93), followed by Pseudomonas aeruginosa (18.28%, 17/93). The lung was the most common site of CRO infection. The detected pathogens were highly resistant to carbapenems, and 64.52% (60/93) of the pathogens were resistant to imipenem with minimum inhibitory concentration (MIC)≥16 µg/ml. The results of the univariate analysis showed that albumin concentration <25 g/L (P =0.048), serum creatinine concentration≥120 µmol/L (P =0.023), age-adjusted Charlson comorbidity index (ACCI) (P =0.037) and primary treatments (supportive treatment, immunosuppressive therapy, chemotherapy, HSCT) (P =0.048) were significantly associated with 30-day all-cause mortality after infection. The results of multivariate logistic regression analysis showed that when CRO infection confirmed, albumin concentration <25 g/L (P =0.014, OR=6.171), serum creatinine concentration≥120 µmol/L (P =0.009, OR=10.867) were independent risk factors for 30-day mortality of patients with hematologic diseases complicated with CRO infection. CONCLUSION: The mortality rate of CRO-infected patients with hematologic diseases is high. The detected pathogenic bacteria are highly resistant to imipenem. The albumin concentration <25 g/L and the serum creatinine concentration≥ 120 µmol/L at diagnosis of CRO infection were independent risk factors for 30-day mortality of the patients with hematologic diseases.

Pharmacokinetic features of dolutegravir with rifampicin and rifabutin among patients coinfected with human immunodeficiency virus and tuberculosis/mycobacterium avium complex.

BACKGROUND: Rifamycins are the cornerstone of anti-tuberculosis therapy while they are potent inducers of drug metabolizing enzymes. For the first time, we evaluated the effect of rifampicin (RIF) and rifabutin (RBT) on the pharmacokinetics (PK) of dolutegravir (DTG) in patients with HIV and tuberculosis (TB)/ mycobacterium avium complex (MAC) co-infection. METHODS: Both HIV/TB (or MAC) co-infected patients and HIV infected patients without TB/MAC were enrolled. Patients in the RIF group received DTG 50 mg twice daily together with 600mg of RIF, while patients in the RBT group received DTG 50 mg once daily together with 300 mg of RBT. The DTG pharmacokinetic profiles in different groups were assessed. RESULTS: A total of 13 subjects in the RIF group, 12 subjects in the RBT group, and 10 subjects in non-TB/MAC group were enrolled. The geometric mean ratio (GMR) of the trough concentration (Ctr) of DTG in the RIF group to non-TB/MAC group was 1.33 [90% confidence interval (CI):0.97 to 1.81], while the GMR of the maximum concentration (Cmax) of DTG was 1.29 (90% CI: 1.23 to 1.36). The GMR of the Ctr of DTG in the RBT group to non-TB/MAC group was 0.41 (90% CI: 0.30 to 0.57), while the GMR of the Cmax of DTG was 0.55 (90% CI: 0.52 to 0.57). CONCLUSIONS: Due to the relatively low trough concentrations of DTG with RBT, DTG 50mg once daily together with RBT could only serve as an alternative option for HIV/TB (or MAC) co-infected patients.

Downregulation of Sepina3n Aggravated Blood-Brain Barrier Disruption after Traumatic Brain Injury by Activating Neutrophil Elastase in Mice.

Traumatic brain injury (TBI) is the leading cause of death in young adults and the main cause of mortality and disability across all ages worldwide. We previously analyzed the expression profile data of TBI models obtained from the Gene Expression Omnibus (GEO) database and found that the seripina3n mRNA was markedly upregulated in the acute phase of TBI in four mRNA expression profile data sets, indicating that serpina3n may be involved in the pathophysiological process of TBI. Therefore, we further investigated the biological role and molecular mechanism of serpina3n in traumatic brain injury in this study. As a result, the endogenous level of sepina3n was markedly elevated in the cortex around the contusion sit in mice at day 1 and day 3 after TBI. Inhibiting the expression of serpina3n caused aggravation of neutrophil elastase (NE) expression, BBB disruption, and neurological deficit. With the inactivation of NE, even if serpina3n was silenced, the disruption of the BBB was not further aggravated. In vitro experiments further proved that recombinant serpina3n dose-dependently inhibited the activity of recombinant NE. Based on the above, this study demonstrated that the endogenous level of sepina3n was significantly elevated in the cortex around the contusion sit after TBI in mice, which reduced the secondary blood-brain barrier disruption by inhibiting the activity of neutrophil elastase.

The safety of clinically indicated replacement or routine replacement of peripheral intravenous catheters: A randomized controlled study.

OBJECTIVE: The primary purpose of this study was to explore the safety of peripheral intravenous catheter (PIVC) replacement every 96 h compared to that of clinically indicated catheter removal. METHODS: A prospective, single-blind, randomized controlled trial was conducted. A random number table method was used. Six hundred patients treated with PIVC intravenous infusion in 10 nursing units of a hospital from September to October 2019 were selected. Sixty were collected from each nursing unit, including 30 in the clinically indicated replacement group and 30 in the routine replacement group. The incidence of phlebitis, catheter-related infection (CRI), occlusion, infiltration, and any form of infusion therapy failure were compared between the two groups. SPSS 23.0 software was used. RESULTS: The dwelling times of PIVC in the clinically indicated replacement group and routine replacement group were significantly different (hours) (83.62 ± 50.08, 69.75 ± 25.54, t = 3.021, p = 0.003). The incidence of any form of infusion therapy failure (RR = 4.448, 95% CI: 3.158-6.265, p < 0.001), phlebitis (RR = 2.416, 95% CI: 1.595-3.660, p < 0.001), occlusion (RR = 6.610, 95% CI: 3.062-14.268, p < 0.001), infiltration (RR = 2.607, 95% CI: 1.130-6.016, p = 0.020), accidental dislodgement (RR = 2.027, 95% CI: 1.868-2.200, p = 0.013), and pain at the insertion site (RR = 2.521, 95% CI: 1.742-3.649, p < 0.001) was higher in the clinically indicated replacement group than that in the routine replacement group. The overall survival curve of PIVC was drawn with Kaplan-Meier survival analysis. The median survival time of intravenous infusion was 59.58 h; the cumulative survival rates of 48 h, 72 h, and 96 h were 77.00%, 51.33%, and 20.33%, respectively. CONCLUSION: Replacement of PIVC every 96 h is safer than clinically indicated.

TGFß1 alleviates axonal injury by regulating microglia/macrophages alternative activation in traumatic brain injury.

Traumatic brain injury (TBI) causes substantial mortality and long-term disability worldwide. TGFß1 is a unique molecular and functional signature in microglia, but the role of TGFß1 in TBI is not clear. The purpose of this study was to investigate the role of TGFß1 in TBI. The weight dropping device was used to establish TBI model of rats. Hematoxylin eosin staining and Bielschowsky silver staining were used to assess tissue loss. Beam walking and muscle strength tests were used to assess neurological deficits. Immunohistochemical staining was used to assess axonal injures. Western blotting was used to detect expression of related proteins. RT-PCR was used to detect expression of cytokines. Immunofluorescence staining was used to assess the microglia/macrophages activation. We observed obvious axonal injury and microglia/macrophages activation in the peri-lesion cortex. The expression of inflammatory cytokines was markedly high after TBI. The expression of TGFß1 and TGFßRI were significantly reduced after TBI. TGFß1 promoted the functional recovery and alleviated axonal injury 1 day after TBI. TGFß1 promoted microglia/macrophages polarizing to alternative activation and alleviated neuroinflammation. These effects of TGFß1 could be inhibited by LY2109761, the inhibitor of TGFRI/II. These results suggested that TGFß1 played a protective role in axonal injury and could be a potential therapeutic target in early stages following TBI.

PDZ-Binding Kinase-Dependent Transcriptional Regulation of CCNB2 Promotes Tumorigenesis and Radio-Resistance in Glioblastoma.

Increasing evidence has indicated that PDZ binding kinase (PBK) promotes proliferation, invasion, and therapeutic resistance in a variety of cancer types. However, the physiological function and therapy-resistant role of PBK in GBM remain underexplored. In this study, PBK was identified as one of the most therapy-resistant genes with significantly elevated expression level in GBM. Moreover, the high expression level of PBK was essential for GBM tumorigenesis and radio-resistance both in vitro and in vivo. Clinically, aberrant activation of PBK was correlated with poor clinical prognosis. In addition, inhibition of PBK dramatically enhanced the efficacy of radiation therapy in GBM cells. Mechanically, PBK-dependent transcriptional regulation of CCNB2 was critical for tumorigenesis and radio-resistance in GBM cells. Collectively, PBK promotes tumorigenesis and radio-resistance in GBM and may serve as a novel therapeutic target for GBM treatment.

Evaluation of Genetic Variants in MIR3142HG in Susceptibility to and Prognosis of Glioma.

OBJECTIVES: Studies have demonstrated that genetic variants in the miRNA-coding genes might be associated with cancer susceptibility and survival. Here, we aimed to investigate the influence of MIR3142HG single-nucleotide polymorphisms on the individual's susceptibility to and patients' prognosis of glioma. MATERIALS AND METHODS: Six variants were genotyped by Agena MassARRAY iPLEX Gold assay among 529 glioma patients and 502 healthy controls. Association of MIR3142HG polymorphisms with the risk for and prognosis of glioma was analyzed by logistic regression analysis and Cox proportional hazards model, respectively. RESULTS: In the risk analysis, rs17057846 (odds ratio [OR]=1.93, P=0.047), rs2961920 (OR=1.53, P=0.019), and rs58747524 (OR=1.23, P=0.046) polymorphisms were associated with increased glioma risk, while rs7727115 (OR=0.76, P=0.030) and rs1582417 (female individuals, OR=0.49, P=0.017) variants were associated with decreased risk. In the survival analysis, rs1582417 polymorphism (hazard ratio=1.26, P=0.017) contributed to poorer prognosis overall. Rs17057846, rs1582417, and rs2431689 polymorphisms were associated with prognosis of astrocytoma, and rs1582417, rs17057846, and rs58747524 variants were associated with the survival rate in patients with low-grade glioma (I to II). CONCLUSION: Our study provided the first evidence for the impact of rs1582417, rs17057846, rs2431689, rs2961920, rs58747524, and rs7727115 polymorphisms in MIR3142HG on the susceptibility to and/or prognosis of glioma in the Chinese Han population.

Glial response in early stages of traumatic brain injury.

Traumatic brain in jury affects a number of individuals per year and is a major cause of worldwide death and disability. Yet, its pathophysiological mechanism remains unclear. It is well-known that glial cells, including microglia and astrocytes, are activated and involved in tissue damage and repair in the peri-lesion regions after traumatic brain injury; however, global glial responses are rarely reported. The purpose of this study was to investigate the global activation of microglia and astrocytes 1 day after traumatic brain injury. To test this, we used a weight drop device to inflict traumatic brain injury on left side of the brain and performed hematoxylin-eosin staining to detect tissue damage. We used immunohistochemical staining and western blotting to detect the activation of microglia and astrocytes 1 day after TBI. We found that microglia were significantly activated in ipsilateral regions. Interestingly, we found that astrocytes were also significantly activated in the ipsilateral regions, contralateral cortex, and contralateral corpus callosum. These results suggest that a focal damage can cause a global glial reaction.

Effects of the MAML2 genetic variants in glioma susceptibility and prognosis.

BACKGROUND: Abnormal expression of the mastermind-like transcriptional co-activator 2 (MAML2) gene is oncogenic in several human cancers, including glioma. However, the relevance of MAML2 variants with glioma remains unknown. We aimed to investigate the role of MAML2 polymorphisms in glioma risk and prognosis among the Chinese Han population. METHODS: Seven MAML2 single-nucleotide polymorphisms (SNPs) were genotyped using Agena MassARRAY system among 575 patients with glioma and 500 age- and gender-matched healthy controls. Logistic regression was used to estimate the association between MAML2 polymorphisms and glioma risk by calculating odds ratios (ORs) and 95% confidence intervals (CI). Kaplan-Meier survival analysis and univariate, multivariate Cox proportional hazard regression analyses for hazard ratios (HRs) and 95% CIs were performed to evaluate the contribution of MAML2 polymorphisms to glioma prognosis. RESULTS: MAML2 rs7938889 and rs485842 polymorphisms were associated with the reduced risk of glioma (OR = 0.69, P=0.023; and OR = 0.81, P=0.032, respectively). Rs7115578 polymorphism had a lower susceptibility to glioma in males (OR = 0.68, P=0.034), while rs4598633 variant with a higher risk in females (OR = 1.66, P=0.016). Additionally, rs7115578 AG genotype represented a poorer prognosis of glioma (HR = 1.24, P=0.033) and astrocytoma (log-rank P=0.037, HR = 1.31, P=0.036). Furthermore, rs11021499 polymorphism had lower overall survival (OS) and progression-free survival (PFS) in patients with low-grade glioma. CONCLUSION: We provided some novel data suggesting MAML2 polymorphisms might contribute to glioma risk and prognosis. Future studies are warranted to validate these findings and characterize mechanisms underlying these associations.