Preclinical efficacy against acute myeloid leukaemia of SH1573, a novel mutant IDH2 inhibitor approved for clinical trials in China

Acute myeloid leukaemia (AML) is the most common form of acute leukaemia in adults, with increasing incidence with age and a generally poor prognosis. Almost 20% of AML patients express mutant isocitrate dehydrogenase 2 (mIDH2), which leads to the accumulation of the carcinogenic metabolite 2-hydroxyglutarate (2-HG), resulting in poor prognosis. Thus, global institutions have been working to develop mIDH2 inhibitors. SH1573 is a novel mIDH2 inhibitor that we independently designed and synthesised. We have conducted a comprehensive study on its pharmacodynamics, pharmacokinetics and safety. First, SH1573 exhibited a strong selective inhibition of mIDH2 R140Q protein, which could effectively reduce the production of 2-HG in cell lines, serum and tumors of an animal model. It could also promote the differentiation of mutant AML cell lines and granulocytes in PDX models. Then, it was confirmed that SH1573 possessed characteristics of high bioavailability, good metabolic stability and wide tissue distribution. Finally, toxicological data showed that SH1573 had no effects on the respiratory system, cardiovascular system and nervous system, and was genetically safe. This research successfully promoted the approval of SH1573 for clinical trials (CTR20200247). All experiments demonstrated that, as a potential drug against mIDH2 R140Q acute myeloid leukaemia, SH1573 was effective and safe.

The mediating role of internalized stigma between insight and self-esteem among patients with schizo-phrenia / 中华行为医学与脑科学杂志

Objective To explore the relationship between internalized stigma and insight,self-es-teem in patients with schizophrenia. Methods A total of 144 schizophrenic patients were investigated by the general information questionnaire,insight and treatment attitude questionnaire (ITAQ),internalized stigma of mental illness scale-Chinese version (ISMI-C) and the self-esteem scale (SES). Pearson correlative analysis and Bootstrap program mediation effect test were used to data analysis. Results There was a significantly positively correlation between insight score(11. 24±4. 08) and internalized stigma score(2. 18±0. 65) of 144 schizophrenic patients(r=0. 236,P<0. 05). The Self-esteem score(27. 57±3. 76) was negatively correlated with insight score(r=-0. 177,P<0. 05) and internalized stigma score(r=-0. 661,P<0. 05). The mediation effect test analysis showed that the internalized stigma played a full mediating role in the relationship between insight and self-esteem,and the effect size was -0. 143. Conclusion Insight can indirectly affect self-es-teem via internalized stigma in patients with schizophrenia. Taking measures to decrease inpatients' internal-ized stigma level and improve their illness awareness should be paid attention in clinical practice.

The mediating role of internalized stigma between insight and self-esteem among patients with schizophrenia / 中华行为医学与脑科学杂志

Objective@#To explore the relationship between internalized stigma and insight, self-esteem in patients with schizophrenia.@*Methods@#A total of 144 schizophrenic patients were investigated by the general information questionnaire, insight and treatment attitude questionnaire (ITAQ), internalized stigma of mental illness scale-Chinese version (ISMI-C) and the self-esteem scale (SES). Pearson correlative analysis and Bootstrap program mediation effect test were used to data analysis.@*Results@#There was a significantly positively correlation between insight score(11.24±4.08) and internalized stigma score(2.18±0.65) of 144 schizophrenic patients(r=0.236, P<0.05). The Self-esteem score(27.57±3.76) was negatively correlated with insight score(r=-0.177, P<0.05) and internalized stigma score(r=-0.661, P<0.05). The mediation effect test analysis showed that the internalized stigma played a full mediating role in the relationship between insight and self-esteem, and the effect size was -0.143.@*Conclusion@#Insight can indirectly affect self-esteem via internalized stigma in patients with schizophrenia.Taking measures to decrease inpatients' internalized stigma level and improve their illness awareness should be paid attention in clinical practice.

MiR-545-3p/MT1M axis regulates cell proliferation, invasion and migration in hepatocellular carcinoma.

Studies have shown that metallothionein 1 M (MT1M) is a tumor suppressor gene which is frequently down-regulated in human hepatocellular carcinoma (HCC). The methylation of MT1M promoter region is one of the important transcriptional regulation mechanisms that contribute to the loss of its expression. In our study, we found that there are still half of the 55 HCC tumor tissues in our cohort do not share the promoter methylation of MT1M. So, we speculated there maybe another mechanism participating in the downregulation of MT1M in HCC. Then, we provided evidences that miR-545-3p, which served as a tumor promoter, post-transcriptionally regulate MT1M in HCC through binding to its untranslated region (3'UTR). Taking together, we investigated the role of miR-545-3p in the process of HCC through regulating MT1M.

Research on peripheral T, B cell subsets and NK cells under different immune status and hepatitis B cirrhosis with chronic HBV infection / 实用医学杂志

Objective To explore the percentage changes of peripheral T , B cell subsets and NK cells in chronic HBV infectors under different immune states and hepatitis B cirrhosis . Methods Seventy-five chronic HBV infectors, including 20 cases with immune clearance, 20 cases with immunodeficiency (inactive) and 35 cases with cirrhosis, and 20 healthy control were enrolled. The percentages of peripheral T and B lymphocyte subsets and NK cells were detected by Flow Cytometry. The differences of the groups were analyzed. Results Comparing with the control group, CD4+T cells were decreased in the other four groups (P<0.05). The sequence of CD4+T cells, from high to low, was the control group, the immunodeficiency group, the immune clearance group, the compensated cirrhosis group and the de-compensated cirrhosis group. CD4+/CD8+T cell and NK cell were lower , but CD8+T cell and B cell were higher in immune clearance group than that of the control group (P < 0.05). Patients in immunodeficiency group had lower ratio of CD4+/CD8+T cell and higher CD8+T cell than those in the control group (P < 0.05). In all the groups, patients with de-compensated cirrhosis showed highest ratio of CD4+ to CD8+ T cells and B cells, but lowest CD3+T, CD8+ T and NK cells (P < 0.05). Conclusions Results suggests immune dysfunction exists in patients with chronic HBV infection. It has potential clinical value in understanding patients′ immune states and progression of disease by detecting peripheral blood lymphocyte subsets and NK cells.

Serum CA19-9, CA242 and CEA in the diagnosis and prognosis of combined hepatobiliary calculus and cholangiocarcinoma / 中华肝胆外科杂志

Objective To study the values of serum CA19-9,CA242,CEA,alone or in combination in the diagnosis and prognosis of combined hepatobiliary calculus and cholangiocarcinoma (HCWC).Method Serum CA19-9,CA242,CEA in 100 patients with HCWC,70 patients with hepatobiliary calculus combined with cholangitis and 30 patients with hepatic hemangioma (normal bile duct group) were preoperatively studied.Results When the serum levels of CA19-9,CA242,CEA were separately used in the diagnosis of HCWC,the sensitivity of CA19 9 was highest,but its specificity was significantly lower than that of CA242 and CEA (P＜0.01).Patients with all the three tumor markers raised had significantly lower survival than those of patients with only one or two raised markers (P＜0.05).Conclusions The diagnostic rate for CA19 9 in HCWC was better than that of CEA and CA242.A joint detection improved the diagnostic specificity.Raised tumor markers were associated with progression of HCWC.Survival was worse in patients with 3 raised markers than those with 2 or 1 raised markers.