Objective To study the effect of Tacrolimus on blood lipid after renal transplantation,and the relationship between C825T polymorphism in G protein beta 3 subunit (GNB3) gene and serum lipid levels.Method Eighty-one cases of recipients patients after renal transplantation were divided into two groups in terms of Tacrolimus concentration:normal blood concentration group (group A) and low blood concentration group (group B).The serum lipid levels at 1st,3rd,6th,and 12th month after renal transplantation were measured.Genotype was determined by the simple sequence-specific primer polymerase chain reaction (SSP-PCR).Result The percentage of patients with hypertriglyceride in group A was significantly higher than in group B during the one-year follow-up period.There was significant difference between the two groups in the serum triglyceride levels but no difference in the serum cholesterol levels.The 825C/T polymorphism in the GNB3 gene was not associated with hypertriglyceride in renal transplantations in Wenzhou.Conclusion The serum triglyceride levels in renal transplantations in Wenzhou was associated with the Tacrolimus concentration,and the incidence of hypertriglyceride is not associated with the 825C/T polymorphism in the GNB3 gene.

ObjectiveTo identify the curative effect of minimally invasive plate osteosynthesis (MIPO) and humeral head replacement in treatment of elderly patients with Neer four-part fractures.MethodsUsing the deltoid pectoral approach,28 patients with fresh Neer four-part fractures were treated by the locking plate combined with MIPO (Group A) and 27 by the humeral head replacement (Group B).Neer score,Constant-Murley score and simple shoulder test (SST) questionnaire were adopted for assessing the treatment outcome.ResultsGroup A was followed up for mean 32.1 months,which showed screws protruding into the joint space in two patients,tuberosity upward and backward displacement in one and femoral head ischemic necrosis in one.The mean visual analog scale (VAS) score,the mean Neer score and the mean Constant-Murley score were 2.2 points,88.6 points and 86.5 points respectively.There were average 9.0 answers for “yes” in the SST questionnaire.Group B were followed up for mean 34.6 months,which showed shoulder dislocation or subluxation in four patients,tuberosity displacement or excessive reduction in eight.The mean VAS score,the mean Neer score and the mean Constant-Murley score were 2.4 points,78.9 points and 77.3 points respectively.The mean number of answer for “yes” in SST questionnaire was 8.0 questions.There showed no statistical difference in VAS score between the two groups.While statistical difference was found in complications,Neer score,Constant-Murley score and SST score between two groups,with Group A superior to Group B.Conclusions For most elderly patients with Neer four-part fractures,MIPO has satisfactory results under strict control of surgical indications and technical tips.The humeral head replacement surgery still has many unresolved problems and needs careful consideration.

Objective To systematically evaluate the clinical effect of surgery combined with adjuvant therapy (postoperative chemoradiotherapy or chemotherapy) and single surgery for resectable pancreatic cancers.Methods Literatures were researched using PubMed,Embase,Science Citation Index Expanded,Cochrane Central Register of Controlled Trials and China Biology Medicine disc with the key words including "pancreatic cancer,adjuvant therapy,chemoradiotherapy,radiochemotherapy,chemotherapy,radiotherapy,胰腺癌,辅助治疗,化学治疗and放射治疗”from the time of database building to October 2016.Two reviewers independently screened literatures,extracted data and assessed the risk of bias.All the patients undergoing surgery combined with adjuvant chemoradiotherapy,surgery combined with adjuvant chemotherapy and single surgery were respectively allocated into the first treatment group,second treatment group and control group.The inverse variance was used for mergering hazard ratio (HR) and related statistic data.HR and 95％ confidence interval (CI) were used for assessing the overall survival time and disease-free survival time.The median survival time and 1-,2-,5-year survival rates were evaluated by the relative risk (RR) and 95％CI.The heterogeneity of the studies was analyzed using the I2 test.Results Eleven randomized controlled trials (RCTs) of 9 literatures were retrieved,and the total sample size was 1 482 patients,including 238 patients in the first treatment group,545 in the second treatment group and 699 in the control group.Results of Meta analysis:① overall survival time:there was no significant difference in overall survival time between the first treatment group and control group (HR =0.87,95％ CI:0.56-1.17,P＞ 0.05).There was a significant difference in overall survival time between the second treatment group and control group (HR =0.68,95 ％ CI:0.55-0.80,P＜ 0.05).② Disease-free survival time:there was no significant difference in disease-free survival time between the first treatment group and control group (HR=0.78,95％CI:0.53-1.03,P＞0.05).There was a significant difference in disease-free survival time between the second treatment group and control group (HR=0.56,95％CI:0.45-0.67,P＜0.05).③ Median survival time:there were significant differences in median survival time between the first treatment group and control group (RR=1.82,95％CI:1.35-2.45,P＜0.05) between the second group and control group (RR=1.32,95％CI:1.07-1.62,P＜0.05).④ One-,2-,5-year survival rates:there was no significant difference in 1-,2-,5-year survival rates between the first treatment group and control group (RR=1.24,2.47,1.15,95％ CI:0.72-2.12,0.82-7.41,0.71-1.84,P＞0.05).One-year survival rate in the second treatment group was compared with that in the control group,with no significant difference (RR=1.15,95％CI:0.99-1.34,P＞0.05).There were significant differences in 2-and 5-year survival rates between the second treatment group and control group (RR=1.24,1.73,95％CI:1.01-1.50,1.32-2.27,P＜0.05).Conclusions Compared with single surgery,surgery combined with postoperative chemoradiotherapy cannot significantly improve the overall survival time and disease-free survival time of patients.However,surgery combined with adjuvant chemotherapy can prolong the overall survival time and disease-free survival time of patients.

The combination of chemotherapy and immunotherapy motivates a potent immune system by triggering immunogenic cell death (ICD), showing great potential in inhibiting tumor growth and improving the immunosuppressive tumor microenvironment (ITM). However, the therapeutic effectiveness has been restricted by inferior drug bioavailability. Herein, we reported a universal bioresponsive doxorubicin (DOX)-based nanogel to achieve tumor-specific co-delivery of drugs. DOX-based mannose nanogels (DM NGs) was designed and choosed as an example to elucidate the mechanism of combined chemo-immunotherapy. As expected, the DM NGs exhibited prominent micellar stability, selective drug release and prolonged survival time, benefited from the enhanced tumor permeability and prolonged blood circulation. We discovered that the DOX delivered by DM NGs could induce powerful anti-tumor immune response facilitated by promoting ICD. Meanwhile, the released mannose from DM NGs was proved as a powerful and synergetic treatment for breast cancer in vitro and in vivo, via damaging the glucose metabolism in glycolysis and the tricarboxylic acid cycle. Overall, the regulation of tumor microenvironment with DOX-based nanogel is expected to be an effectual candidate strategy to overcome the current limitations of ICD-based immunotherapy, offering a paradigm for the exploitation of immunomodulatory nanomedicines.

Aberrant activation of oncogenic signaling pathways in tumors can promote resistance to the antitumor immune response. However, single blockade of these pathways is usually ineffective because of the complex crosstalk and feedback among oncogenic signaling pathways. The enhanced toxicity of free small molecule inhibitor combinations is considered an insurmountable barrier to their clinical applications. To circumvent this issue, we rationally designed an effective tumor microenvironment-activatable prodrug nanomicelle (PNM) for cancer therapy. PNM was engineered by integrating the PI3K/mTOR inhibitor PF-04691502 (PF) and the broad spectrum CDK inhibitor flavopiridol (Flav) into a single nanoplatform, which showed tumor-specific accumulation, activation and deep penetration in response to the high glutathione (GSH) tumoral microenvironment. The codelivery of PF and Flav could trigger gasdermin E (GSDME)-based immunogenic pyroptosis of tumor cells to elicit a robust antitumor immune response. Furthermore, the combination of PNM-induced immunogenic pyroptosis with anti-programmed cell death-1 (αPD-1) immunotherapy further boosted the antitumor effect and prolonged the survival time of mice. Collectively, these results indicated that the pyroptosis-induced nanoplatform codelivery of PI3K/mTOR and CDK inhibitors can reprogram the immunosuppressive tumor microenvironment and efficiently improve checkpoint blockade cancer immunotherapy.

METTL3 and METTL14 are two components that form the core heterodimer of the main RNA m6A methyltransferase complex (MTC) that installs m6A. Surprisingly, depletion of METTL3 or METTL14 displayed distinct effects on stemness maintenance of mouse embryonic stem cell (mESC). While comparable global hypo-methylation in RNA m6A was observed in Mettl3 or Mettl14 knockout mESCs, respectively. Mettl14 knockout led to a globally decreased nascent RNA synthesis, whereas Mettl3 depletion resulted in transcription upregulation, suggesting that METTL14 might possess an m6A-independent role in gene regulation. We found that METTL14 colocalizes with the repressive H3K27me3 modification. Mechanistically, METTL14, but not METTL3, binds H3K27me3 and recruits KDM6B to induce H3K27me3 demethylation independent of METTL3. Depletion of METTL14 thus led to a global increase in H3K27me3 level along with a global gene suppression. The effects of METTL14 on regulation of H3K27me3 is essential for the transition from self-renewal to differentiation of mESCs. This work reveals a regulatory mechanism on heterochromatin by METTL14 in a manner distinct from METTL3 and independently of m6A, and critically impacts transcriptional regulation, stemness maintenance, and differentiation of mESCs.
Animals ; Mice ; Methylation ; Chromatin ; Histones/metabolism* ; RNA, Messenger/genetics* ; Methyltransferases/metabolism* ; RNA/metabolism*