tRF-Leu reverse breast cancer cells chemoresistance by regulation of BIRC5.

OBJECTIVE: Accumulating studies reported the crucial roles of tRFs in tumorigenesis. However, their further mechanisms and clinical values remains unclear. This study aimed at the further investigation of tRF-Leu in breast cancer chemotherapy resistance. METHODS: The high-throughput sequencing was performed and identified the downregulation of tRF-Leu in MCF7/ADR cells. The function of tRF-Leu in breast cancer cells and breast cancer chemotherapy resistance was investigated in vitro and in vivo, including colony formation assay, CCK-8 assay, transwell assay and apoptosis assay. The binding site of tRF-Leu on BIRC5 was verified by dual-luciferase assay. RESULTS: tRF-Leu was downregulated in MCF7/ADR cells. Overexpression of tRF-Leu inhibited the migration of breast cancer cells. Furthermore, tRF-Leu could reverse the resistance of MCF7/ADR cells to Adriamycin both in vitro and in vivo. BIRC5 was a target of tRF-Leu, which might be involved in the chemotherapy resistance regulation. CONCLUSION: We demonstrated that tRF-Leu could inhibit the chemotherapy resistance of breast cancer by targeting BIRC5. These findings might identify new biomarkers of breast cancer therapy and bring new strategies to reverse chemotherapy resistance.

Glutamine supplementation improves the activity and immunosuppressive action of induced regulatory T cells in vitro and in vivo.

BACKGROUND: Glutamine is crucial for the activation and efficacy of T cells, and may play a role in regulating the immune environment. This study aimed to investigate the potential role of glutamine in the activation and proliferation of induced regulatory T cells (iTregs). METHODS: CD4+CD45RA+T cells were sorted from peripheral blood mononuclear cells and cultured to analyze iTreg differentiation. Glutamine was then added to the culture system to evaluate the effects of glutamine on iTregs by determining oxidative phosphorylation (OXPHOS), apoptosis, and cytokine secretion. Additionally, a humanized murine graft-versus-host disease (GVHD) model was constructed to confirm the efficacy of glutamine-treated iTregs in vivo. RESULTS: After being cultured in vitro, glutamine significantly enhanced the levels of Foxp3, CTLA-4, CD39, CD69, IL-10, TGF-ß, and Ki67 (CTLA-4, IL-10, TGF-ß are immunosuppressive markers of iTregs) compared with that of the control iTregs (P < 0.05). Furthermore, the growth curve showed that the proliferative ability of glutamine-treated iTregs was better than that of the control iTregs (P < 0.01). Compared with the control iTregs, glutamine supplementation significantly increased oxygen consumption rates and ATP production (P < 0.05), significantly downregulated Annexin V and Caspase 3, and upregulated BCL2 (P < 0.05). However, GPNA significantly reversed the effects of glutamine (P < 0.05). Finally, a xeno-GVHD mouse model was successfully established to confirm that glutamine-treated iTregs increased the mice survival rate, delayed weight loss, and alleviated colon injury. CONCLUSION: Glutamine supplementation can improve the activity and immunosuppressive action of iTregs, and the possible mechanisms by which this occurs are related to cell proliferation, apoptosis, and OXPHOS.

Nur77 inhibition of ß-catenin expression mediates Hepatoblastoma progression and enhances cisplatin's therapeutic effect.

Hepatoblastoma (HB) is the most common malignant tumor in children under 5 years old, but its pathogenesis remains unclear. Nur77 has been reported to be an important regulator for cancer progression in various cancer types. This study found that Nur77 was downregulated in HB tumors, compared with paracancer tissue. Knockout or overexpression of Nur77 in HB tumor cell line HepG2 and HuH6 could significantly enhance or inhibit the proliferation, migration and invasion of tumor cells both in vitro and in vivo. Further studies illustrated that Nur77 regulated the proliferation of tumor cells by affecting the expression of ß-catenin. Nur77 agonist Csn-B effectively enhanced the therapeutic effect of cisplatin on HB tumors both in vitro and in vivo. This study confirms that Nur77 may act as an oncogene in HB tumors and mediate the progression of HB by inhibiting the expression of ß-catenin, which provides a new targeted therapy for the clinical treatment of HB patients; meanwhile, the combination of Nur77 agonist and cisplatin treatment may improve the chemotherapeutic efficacy of HB patients, which provides a new idea for the improvement of the clinical prognosis of HB patients.

Type II Abernethy malformation with cystic fibrosis in a 12-year-old girl: A case report.

BACKGROUND: Abernethy malformation, also known as congenital extrahepatic portosystemic shunt, is an uncommon malformation resulting from aberrant development of the portal venous system. Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by mutations in the CFTR gene. It mainly affects the exocrine glands of the respiratory, digestive and reproductive systems. It is considered extremely rare in the Asian population. We present a clinical case involving a pediatric patient of Asian descent who was diagnosed with Abernethy malformation and CF. CASE SUMMARY: A 12-year-old girl presented with a medical history of recurring respiratory infections and hemoptysis, and chest computed tomography (CT) showed bronchiectasis. Whole exome sequencing was performed for the patient, yielding findings that revealed a compound heterozygous variant of the CFTR gene: c.233_c.234insT/p.Trp79fsTer3 (maternal origin); c.2909G>A/p.Gly970Asp (paternal origin). CF was diagnosed. The physician's attention was drawn to the presence of splenomegaly during disease progression. Abdominal enhanced CT revealed splenomegaly, compression of the left kidney, and multiple tortuous dilated vascular shadows were seen at the splenic hilum, which flowed back into the left renal vein and portal vein, suggesting Abernethy malformation type II. Intraoperatively, the abnormal blood flow was seen to merge into the inferior vena cava through the left renal vein without hepatic processing, and the pathology of liver biopsy showed hypoplastic, dilated or absent portal vein branches, both of which supported the diagnosis of Abernethy malformation type II. This represents the initial documented instance of Abernethy malformation accompanied by a CFTR gene mutation in the existing body of literature. CONCLUSION: Coexisting Abernethy malformation and CF are rare. Detailed medical history information, abdominal enhanced CT, venography and genetic testing contribute to diagnosis as well as differential diagnosis.

Discovery of Inhibitors of the Lipopolysaccharide Transporter MsbA: From a Screening Hit to Potent Wild-Type Gram-Negative Activity.

The dramatic increase in the prevalence of multi-drug resistant Gram-negative bacterial infections and the simultaneous lack of new classes of antibiotics is projected to result in approximately 10 million deaths per year by 2050. We report on efforts to target the Gram-negative ATP-binding cassette (ABC) transporter MsbA, an essential inner membrane protein that transports lipopolysaccharide from the inner leaflet to the periplasmic face of the inner membrane. We demonstrate the improvement of a high throughput screening hit into compounds with on-target single digit micromolar (µM) minimum inhibitory concentrations against wild-type uropathogenic Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae. A 2.98 Å resolution X-ray crystal structure of MsbA complexed with an inhibitor revealed a novel mechanism for inhibition of an ABC transporter. The identification of a fully encapsulated membrane binding site in Gram-negative bacteria led to unique physicochemical property requirements for wild-type activity.

Psychometric properties of the Clinically Useful Depression Outcome Scale supplemented with DSM-5 Mixed subtype questionnaire in Chinese patients with mood disorders.

BACKGROUND: With the modification of DSM-5 mixed features specifier, a brief scale to screen mixed features in patients with mood disorders is needed in clinical practice. This study aimed to explore the psychometric properties of the Chinese version of the Clinically Useful Depression Outcome Scale supplemented with DSM-5 Mixed subtype (CUDOS-M-C) for the Chinese patients with mood disorders. METHODS: Overall, 300 patients with major depressive episode were recruited. All participants were assessed using CUDOS-M-C, Young Mania Rating Scale, Hamilton Anxiety Scale and Montgomery-Asberg Depression Rating Scale. The receiver operating characteristic (ROC) curve analysis was used to calculate the optimal cut-off values of CUDOS-M-C score. The reliability and validity of CUDOS-M-C were examined using Cronbach's alpha, intraclass correlation coefficient (ICC) and principal component analysis (PCA). RESULTS: The results of PCA indicated two-factor structure as the best solution for CUDOS-M-C, which explained 54.82% of cumulative variance. The Cronbach's alpha was 0.892 and the ICC was 0.853. The area under the ROC curve of the CUDOS-M-C for participants with mixed depression was 0.927 (p<0.001) and the suitable cut-off value was 8, with a sensitivity of 91.6% and specificity of 79.9%. LIMITATIONS: Most of the patients were recruited from eastern China and further research with larger sample is warranted. And this study did not perform confirmatory factor analysis to identify the generalization of factor structure of CUDOS-M-C. Besides, the study performed the test-retest reliability of CUDOS-M-C and further analysis is needed to ascertain the patient's post-treatment changes. CONCLUSION: The CUDOS-M-C demonstrated to have satisfactory psychometric properties as a self-report scale, and could be applied to screen patients with mixed depression in clinical practice.

Discovery of a Potent and Selective in Vivo Probe (GNE-272) for the Bromodomains of CBP/EP300.

The single bromodomain of the closely related transcriptional regulators CBP/EP300 is a target of much recent interest in cancer and immune system regulation. A co-crystal structure of a ligand-efficient screening hit and the CBP bromodomain guided initial design targeting the LPF shelf, ZA loop, and acetylated lysine binding regions. Structure-activity relationship studies allowed us to identify a more potent analogue. Optimization of permeability and microsomal stability and subsequent improvement of mouse hepatocyte stability afforded 59 (GNE-272, TR-FRET IC50 = 0.02 µM, BRET IC50 = 0.41 µM, BRD4(1) IC50 = 13 µM) that retained the best balance of cell potency, selectivity, and in vivo PK. Compound 59 showed a marked antiproliferative effect in hematologic cancer cell lines and modulates MYC expression in vivo that corresponds with antitumor activity in an AML tumor model.

Trends in overweight and obesity among children and adolescents in China from 1981 to 2010: a meta-analysis.

BACKGROUND: Overweight/obesity is a serious public health problem that affects a large part of the world population across all age and racial/ethnic groups. However, there has not been a meta-analysis of the prevalence of childhood and adolescent overweight/obesity in China during the past 30 years. METHODS: The China National Knowledge Infrastructure and Wanfang DATA, MEDLINE, EMBASE and Cumulative Index to Nursing and Allied Health Literature were searched for relevant studies published between January 1970 and June 2012. The prevalence of overweight/obesity over time was pooled using Stata/SE, version 9. Summary statistics (odds ratios, ORs) were used to compare sex-specific and urban-rural preponderance of overweight/obesity using Review Manager. RESULTS: After screening 1326 papers, we included 35 papers (41 studies), most of medium quality. The prevalence of overweight/obesity increased from 1.8% (95% confidence interval [CI], 0.4%-3.1%) and 0.4% (95% CI, -0.1% to -0.8%) respectively in 1981-1985 to 13.1% (95% CI, 11.2%-15.0%) and 7.5% (95% CI, 6.6%-8.4%) respectively in 2006-2010. The average annual increase was 8.3% and 12.4% respectively. Boys were more likely to be overweight/obese than girls (OR, 1.36; 95% CI, 1.24-1.49 and OR, 1.68; 95% CI, 1.52-1.86 respectively). The prevalence of overweight/obesity was higher in urban areas than in rural areas (OR, 1.66; 95% CI, 1.54-1.79 and OR, 1.97; 95% CI, 1.68-2.30 respectively). For age-specific subgroup analyses, both overweight and obesity increased more rapidly in the toddler stage than in other developmental stages. Sensitivity analyses showed that sample-size differences, study quality, overweight/obesity criteria and geographical distribution affected overweight/obesity prevalence. CONCLUSIONS: Toddlers and urban boys were at particularly high risk; the prevalence in these groups increased more rapidly than in their counterparts. Public health prevention strategies are urgently needed to modify health behaviors of children and adolescents and control overweight/obesity in China.