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Significance The mitochondrial enzyme glutaminase (GLS) is frequently up-regulated in cancer cells, and a GLS-selective inhibitor is being evaluated in clinical trials. Previous screens identified succinylated lysine residues on GLS, but the functional consequences of these posttranslational modifications have remained unclear. Here, we report that the mitochondrial desuccinylase SIRT5 stabilizes GLS. Both GLS and SIRT5 are upregulated during cellular transformation, and high expression of SIRT5 in human breast tumors correlates with poor patient prognosis. Mechanistically, SIRT5-mediated desuccinylation of residue K164 protects GLS from ubiquitination at K158 and from subsequent degradation. These findings reveal an important role for SIRT5 in mammary tumorigenesis and establish a posttranslational mechanism regulating GLS levels. Collectively, they support further investigation of SIRT5 as a potential therapeutic target.

The effects of post-mastectomy radiotherapy (PMRT) on different subtypes of T1-2N1M0 breast cancer remain controversial. Patients with T1-2N1M0 breast cancer treated by mastectomy or mastectomy and PMRT were identified from the 2010-2013 dataset from the Surveillance, Epidemiology and End Results (SEER) registry. A total of 7,466 patients with the 7th American Joint Committee on Cancer stage (Tumor-Node-Metastasis stages 1-2, 1 and 0, respectively) including 2,760 cases (36.97%) treated by mastectomy and PMRT and 4,706 cases (63.03%) treated by mastectomy alone were analyzed in this study. The follow-up time for patients in the dataset used from the SEER registry was 0-59 months. The breast cancer-specific survival (BCSS) of the patients was derived from the SEER dataset and stratified by treatment approach. A propensity score matching (PSM) analysis (experimental group: Control group ratio, 1:1) was conducted. Using univariate and multivariate analyses Cox proportional hazards analyses, PMRT was identified as an independent prognostic factor for triple-negative breast cancer (TNBC). Before PSM analysis, the BCSS favored PMRT in the hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)+ (P=0.025) and HR-/HER2- groups (P=0.010) but not in the HR+/HER2- (P=0.346) and HR-/HER2+ (P=0.288) groups. Following PSM analysis, BCSS favored PMRT alone in the TNBC (HR-/HER2-) group (P=0.025). Patients with T1-2N1M0 TNBC may benefit from radiotherapy post-mastectomy.

Background Microsatellite instability (MSI) and Epstein-Barr virus (EBV)-positive molecular subtypes exhibit complex immune responses in gastric cancer (GC), and PD-L1 has emerged as a prognostic biomarker associated with the cancer immune microenvironment. This study aimed to determine the prognostic value of molecular subtypes and whether the addition of PD-L1 would accurately predict the prognosis and guide postoperative chemotherapy for GC patients. Methods We performed molecular subtyping of tissue microarray slides from 226 GC patients who were treated with radical gastrectomy. The MSI status and PD-L1 expression were evaluated through immunohistochemistry (IHC) and EBV status through situ hybridization. Multiplex polymerase chain reaction (PCR) was also performed on 50 cases to validate the accuracy of IHC in defining MSI status. Differences in overall survival (OS) were assessed using the Kaplan-Meier method, log-rank test and Cox proportional hazards regression model. Results Among the 226 GC patients, 52 (23.2%) patients were classified as the MSI subtype, 11 (4.9%) were EBV+ subtype, and 161 (71.9%) were MSS (Microsatellite stable) /EBV− subtype according to TCGA analysis. Two patients were both positive for MSI and EBV infection. EBV+ cases showed higher PD-L1 positivity than MSI cases and MSS/EBV− cases (81.8% vs. 50.0% vs. 35.4%, P = 0.003). Compared with the non-MSS/EBV− (MSI or EBV+ cases) subgroup, GC patients with MSS/EBV− were associated with the worst outcomes (HR = 1.610, 95% CI [1.046–2.479], P = 0.031). MSS/EBV− GCs alone could benefit from postoperative chemotherapy (HR = 0.452, 95% CI [0.299–0.682], P P = 0.033) in this subgroup. Considering both chemotherapy efficacy and PD-L1 expression in the MSS/EBV− subgroup, chemotherapy could improve the prognosis for PD-L1-negative MSS/EBV− GCs (HR = 0.357, 95% CI [0.217–0.587], P − GCs. Conclusions Molecular subtyping combined with PD-L1 expression could serve as a potential strategy to better predict prognosis and guide postoperative chemotherapy of GC patients.

CircRNAs play essential roles in various physiological processes and involves in many diseases, in particular cancer. Global downregulation of circRNA expression has been observed in hepatocellular carcinoma (HCC) in many studies. Previous studies revealed that the pre-mRNA 3' end processing complex participates in circRNA cyclization and plays an important role in HCC tumorigenesis. Therefore, we explored the role of CPSF4, for 3' end formation and cleavage, in circRNA formation. Clinical research has shown that CPSF4 expression is upregulated in HCC and that high expression of CPSF4 is associated with poor prognosis in HCC patients. Mechanistic studies have demonstrated that CPSF4 reduces the levels of circRNAs, which possess a polyadenylation signal sequence and this decrease in circRNAs reduces the accumulation of miRNA and disrupts the miRNA-mediated gene silencing in HCC. Experiments in cell culture and xenograft mouse models showed that CPSF4 promotes the proliferation of HCC cells and enhances tumorigenicity. Moreover, CPSF4 antagonizes the tumor suppressor effect of its downstream circRNA in HCC. In summary, CPSF4 acts as an oncogene in HCC through circRNA inhibition and disruption of miRNA-mediated gene silencing.

The karyotype is highly important for diagnosis and prognosis in myelodysplastic syndrome (MDS). The objective of the present study was to investigate the cytogenetic characteristics of patients with MDS in China. The karyotypes of 665 Chinese patients with MDS were analyzed, and it was identified that 298 cases (298/665, 44.8%) had abnormal karyotypes. Among the 298 patients with abnormal karyotypes, the 75 patients with trisomy 8 (+8) constituted the most common subset (75/298, 25.2%). The incidence of abnormal karyotypes was significantly higher in patients who were ≥51 years old compared with those

Background: The prognostic significance of podoplanin (PDPN) in tumor cells for cancer patients’ survival remains controversial. Therefore, we performed this meta-analysis to clarify the relationship between the podoplanin-positive tumor cells and cancer prognosis. Method: Eligible studies were identified by searching the Pubmed and EBSCO online databases up to August 2019. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to evaluate the correlation between podoplanin expression and overall survival (OS) and/or disease-free survival (DFS) and odds ratios (ORs) with 95% CIs severed as the summarized statistics for clinicopathological characteristic. Results: A total of 2155 patients from 21 eligible studies were included. The results revealed that high expression of podoplanin was associated with a poor survival rate in cancer patients. Further subgroup analysis stratified by tumor type showed that podoplanin-positive tumor cell infiltration had a negative prognostic effect associated with survival in esophageal cancer and oropharyngeal cancer. In addition, high expression of these cells was significantly associated with N stage, T stage, TNM stage and vascular invasion. Conclusion: Our study suggests the over-expression of podoplanin might be a significant prognostic indicator for patients with esophageal and oropharyngeal cancer.

// Xin Zhang 1, * , Deyong Jia 1, * , Junping Ao 2, * , Huijuan Liu 1 , Yi Zang 3 , Mohammad Azam 4 , Samy L. Habib 5 , Jia Li 3 , Xinsen Ruan 1 , Hao Jia 1 , Xueying Wang 6 , Baojie Li 1, 7 1 Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China 2 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China 3 National Center for Drug Screening, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China 4 Divisions of Pathology, Hematology and Cancer Biology, Cancer and Blood Disease Institute, Cincinnati Children’s Hospital and Medical Center, Cincinnati, OH, USA 5 South Texas Veterans Health Care System and Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA 6 Department of Biochemistry, National University of Singapore, Singapore 7 Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China * These authors have contributed equally to this work Correspondence to: Baojie Li, email: libj@sjtu.edu.cn Keywords: Bisindolylmaleimide IX, BCR-ABL, chronic myeloid leukemia (CML) Received: June 08, 2015 Accepted: August 08, 2016 Published: August 24, 2016 ABSTRACT Chronic myeloid leukemia (CML) treatment with BCR-ABL inhibitors is often hampered by development of drug resistance. In a screen for novel chemotherapeutic drug candidates with genotoxic activity, we identified a bisindolylmaleimide derivative, IX, as a small molecule compound with therapeutic potential against CML including drug-resistant CML. We show that Bisindolylmaleimide IX inhibits DNA topoisomerase, generates DNA breaks, activates the Atm-p53 and Atm-Chk2 pathways, and induces cell cycle arrest and cell death. Interestingly, Bisindolylmaleimide IX is highly effective in targeting cells positive for BCR-ABL. BCR-ABL positive cells display enhanced DNA damage and increased cell cycle arrest in response to Bisindolylmaleimide IX due to decreased expression of topoisomerases. Cells positive for BCR-ABL or drug-resistant T315I BCR-ABL also display increased cytotoxicity since Bisindolylmaleimide IX inhibits B-Raf and the downstream oncogene addiction pathway. Mouse cancer model experiments showed that Bisindolylmaleimide IX, at doses that show little side effect, was effective in treating leukemia-like disorders induced by BCR-ABL or T315I BCR-ABL, and prolonged the lifespan of these model mice. Thus, Bisindolylmaleimide IX presents a novel drug candidate to treat drug-resistant CML via activating BCR-ABL-dependent genotoxic stress response and inhibiting the oncogene addiction pathway activated by BCR-ABL.

In this paper we develop a new mathematical model of immunotherapy and cancer vaccination, focusing on the role of antigen presentation and co-stimulatory signaling pathways in cancer immunology. We investigate the effect of different cancer vaccination protocols on the well-documented phenomena of cancer dormancy and recurrence, and we provide a possible explanation of why adoptive (i.e. passive) immunotherapy protocols can sometimes actually promote tumour growth instead of inhibiting it (a phenomenon called immunostimulation), as opposed to active vaccination protocols based on tumour-antigen pulsed dendritic cells. Significantly, the results of our computational simulations suggest that elevated numbers of professional antigen presenting cells correlate well with prolonged time periods of cancer dormancy.

The 2009 Nobel Prize in Physiology or Medicine was awarded to Drs Blackburn, Szostak and Greider for their discovery of how chromosomes are protected by telomeres and the enzyme telomerase. This minireview series consisting of three independent reviews discusses different aspects of this research, an area fuelling clinical applications in various human diseases including ageing and cancer.

Background Telomeres cap chromosome ends and protect the genome. We studied individual telomeres in live human cancer cells. In capturing telomere motions using quantitative imaging to acquire complete high-resolution three-dimensional datasets every second for 200 seconds, telomere dynamics were systematically analyzed. Results The motility of individual telomeres within the same cancer cell nucleus was widely heterogeneous. One class of internal heterochromatic regions of chromosomes analyzed moved more uniformly and showed less motion and heterogeneity than telomeres. The single telomere analyses in cancer cells revealed that shorter telomeres showed more motion, and the more rapid telomere motions were energy dependent. Experimentally increasing bulk telomere length dampened telomere motion. In contrast, telomere uncapping, but not a DNA damaging agent, methyl methanesulfonate, significantly increased telomere motion. Conclusion New methods for seconds-scale, four-dimensional, live cell microscopic imaging and data analysis, allowing systematic tracking of individual telomeres in live cells, have defined a previously undescribed form of telomere behavior in human cells, in which the degree of telomere motion was dependent upon telomere length and functionality.