MYBL2 regulates de novo purine synthesis by transcriptionally activating IMPDH1 in hepatocellular carcinoma cells.

BACKGROUND: Metabolic reprogramming is a hallmark of cancer, alteration of nucleotide metabolism of hepatocellular carcinoma (HCC) is not well-understood. MYBL2 regulates cell cycle progression and hepatocarcinogenesis, its role in metabolic regulation remains elusive. PATIENTS AND METHODS: Copy number, mRNA and protein level of MYBL2 and IMPDH1 were analyzed in HCC, and correlated with patient survival. Chromatin Immunoprecipitation sequencing (Chip-seq) and Chromatin Immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR) were used to explore the relationship between MYBL2 and IMPDH1. Metabolomics were used to analyze how MYBL2 affected purine metabolism. The regulating effect of MYBL2 in HCC was further validated in vivo using xenograft models. RESULTS: The Results showed that copy-number alterations of MYBL2 occur in about 10% of human HCC. Expression of MYBL2, IMPDH1, or combination of both were significantly upregulated and associated with poor prognosis in HCC. Correlation, ChIP-seq and ChIP-qPCR analysis revealed that MYBL2 activates transcription of IMPDH1, while knock-out of MYBL2 retarded IMPDH1 expression and inhibited proliferation of HCC cells. Metabolomic analysis post knocking-out of MYBL2 demonstrated that it was essential in de novo purine synthesis, especially guanine nucleotides. In vivo analysis using xenograft tumors also revealed MYBL2 regulated purine synthesis by regulating IMPDH1, and thus, influencing tumor progression. CONCLUSION: MYBL2 is a key regulator of purine synthesis and promotes HCC progression by transcriptionally activating IMPDH1, it could be a potential candidate for targeted therapy for HCC.

The efficacy and safety of thalidomide in the treatment of refractory Crohn's disease in adults: a double-center, double-blind, randomized-controlled trial.

Background: Thalidomide is applied in therapy for refractory Crohn's disease (CD) in adults, but systematic and rigorous clinical evidence is scant. The aim was to provide theoretical references for the efficacy of thalidomide in the therapy for refractory CD in adults. Methods: A double-center, double-blind, placebo-controlled, randomized clinical trial of refractory CD in adults in two inflammatory bowel disease centers in China. In the double-blind trial, patients were randomly assigned to 100 mg of thalidomide or placebo daily for 8 weeks. The primary outcome was considered as the clinical remission rate calculated based on the Crohn's disease activity index at the eighth week following thalidomide or placebo treatment. In open label, non-response to placebo was additionally treated with 8 weeks of thalidomide; all responders were continuously treated with thalidomide until the 48th week. Results: Twenty-five patients were randomly assigned to each group. At the eighth week, the clinical remission rate in the thalidomide group was significantly higher than that in the placebo group (68.0% [17/25] vs 16.0% [4/25]; relative risk, 4.2; 95% confidence interval, 1.8-10.9, P < 0.001). After a 48-week follow-up, the continuous treatment rate of thalidomide was 46.3% (19/41). Adverse events during the whole process were reported in 58.5% of patients, mainly involving drowsiness, rash, and peripheral neuropathy that were mild and tolerable. Conclusion: Thalidomide can be used in the induction and maintenance therapy of refractory CD in adults. And it could be one of the treatment options for refractory CD.

Ustekinumab trough concentration affects clinical and endoscopic outcomes in patients with refractory Crohn's disease: a Chinese real-world study.

BACKGROUND: Ustekinumab (UST), a newly-used biologic targeting p40 subunit of IL12 and IL23 in China, exerts a confirmed therapeutic effect on the induction and maintenance therapies for refractory Crohn's disease (CD). Therapeutic drug monitoring based on trough and antibody concentration is of core importance when treating patients who lose response to UST. We aimed to analyze the UST exposure-response relationship in CD treatment in the real-world setting. METHODS: We retrospectively enrolled patients with CD who received UST between March 1, 2020 and May 31, 2021, at the inflammatory bowel disease (IBD) center of the Sun Yat-Sun Affiliated Sixth Hospital. Baseline characteristic information, biomarker examination, clinical outcomes determined by the Crohn's disease activity index (CDAI), and endoscopic outcomes evaluated using a simple endoscopic score for Crohn's disease (SES-CD) at week 16/20 were collected. The optimal UST cut-off trough concentration was identified using receiver operating characteristic curve (ROC) analysis. RESULTS: Nineteen eligible patients were included in the study, the mean age was 29.1 ± 9.1 years and the mean disease duration was 5.5 ± 4.7 years. At the initiation of the study, 89.5% of the patients had been exposed to prior biologics, 42.1% had previous CD-related surgeries, and 52.6% had perianal diseases. At week 16/20 after the UST initiation, clinical response, clinical remission, endoscopic response, and endoscopic remission were 89.5%, 84.2%, 42.2%, and 73.7%, respectively. The cut-off optimal trough concentration for UST was 1.12 µg/mL, as determined by the ROC with an area under the curve (AUC) of 0.78, sensitivity of 87.5%, and specificity of 72.7%. Patients with a UST trough concentration > 1.12 µg/mL had a significantly higher rate of endoscopic remission than those without (70.0% vs. 11.1%, P = 0.02). CONCLUSIONS: UST is an effective therapeutic option for refractory CD treatment. A UST trough concentration above 1.12 µg/mL was associated with endoscopic remission at week 16/20 after UST initiation. Trial registration This study was approved and retrospectively registered by the Ethics Committee of Sun Yat-Sen University (2021ZSLYEC-066, March 29, 2021) and the Clinical Trial Registry (NCT04923100, June 10, 2021).

Observations on the Efficacy of Dong's Extra-point Pricking Bloodletting Therapy for Female Chloasma of Liver Depression and Qi Stagnation Type / 上海针灸杂志

Objective To investigate the clinical efficacy of Dong's extra-point pricking bloodletting therapy for female chloasma of liver depression and qi stagnation type. Methods One hundred and twenty female patients with chloasma of liver depression and qi stagnation type were randomized to treatment and control groups, 60 cases each. The control group received Dong's extra-point pricking bloodletting therapy and the treatment group, conventional acupuncture. The symptom and sign score was recorded in the two groups before and after treatment. The clinical therapeutic effects were compared between the two groups. Results The total efficacy rate was 95.5％ in the treatment group and 81.7％ in the control group; there was a statistically significant difference between the two groups (P<0.05). The pre-/post-treatment symptom and sign score difference value was (0.98±0.23) in the treatment group and (0.81±0.18) in the control group; there was a statistically significant difference between the two groups (P<0.05). Conclusion Dong's extra-point pricking bloodletting therapy is an effective way to treat female chloasma of liver depression and qi stagnation type.

The utility of platelet, mean platelet volume, and red cell distribution width in the diagnosis of active Crohn's disease and intestinal tuberculosis.

OBJECTIVE: To evaluate the diagnostic utility of platelet count (PLT), mean platelet volume (MPV), and red cell distribution width (RDW) in patients with active Crohn's disease (CD) and intestinal tuberculosis (ITB). METHODS: This study was conducted in the Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China. Sixty-eight patients with active CD, 35 with ITB, and 22 as control group were recruited. Blood routine test including white blood cell, red blood cell, PLT, MPV, RDW, and so forth was investigated. RESULTS: Patients with active CD and ITB have increased PLT and RDW (both p<0.001), and decreased MPV (p=0.002). The RDW performed preferably in predicting both active CD (odds ratio [OR]=2.390, p=0.007), and ITB (OR=2.338, p=0.017), and had better diagnostic value (area under the receiver operating characteristics curve [AUC] - 0.812; p<0.001) than CRP (AUC - 0.716; p=0.007) and ESR (AUC - 0.804; p<0.001) in ITB diagnosis. CONCLUSION: Among the laboratory markers, RDW not only possessed the favorable capability to predict active CD, but also showed outstanding predicting capability, and good diagnostic value in ITB.