Mechanisms and applications of ferroptosis-associated regulators in cancer therapy and drug resistance.

Iron is an essential element for almost all living things. Both iron excess and iron deficiency can damage the body's health, but the body has developed complex mechanisms to regulate iron balance. The imbalance of iron homeostasis and lipid peroxidation are important features of ferroptosis. In this review, we summarize the latest regulatory mechanisms of ferroptosis, the roles of relevant regulators that target ferroptosis for cancer therapy, and their relationship to drug resistance. In conclusion, targeting ferroptosis is an important strategy for cancer therapy.

A Chinese boy with familial Duchenne muscular dystrophy owing to a novel hemizygous nonsense mutation (c.6283C>T) in an exon of the DMD gene.

Duchenne muscular dystrophy is a severe, X-linked, progressive neuromuscular disorder clinically characterised by muscle weakening and extremely high serum creatine kinase levels. A 1-year-old Chinese patient was diagnosed with early-onset Duchenne muscular dystrophy. Next-generation gene sequencing was conducted and the Sanger method was used to validate sequencing. We identified a novel nonsense mutation (c.6283C>T) in DMD that caused the replacement of native arginine at codon 2095 with a premature termination codon (p.R2095X), which may have had a pathogenic effect against dystrophin in our patient's muscle cell membranes. We discovered a novel nonsense mutation in DMD that will expand the pathogenic mutation spectrum for Duchenne muscular dystrophy.

Construction of a novel ceRNA network and identification of lncRNA ADAMTS9-AS2 and PVT1 as hub regulators of miRNA and coding gene expression in gastric cancer.

BACKGROUND: Studies on the interactions of single long non-coding RNA, microRNA, and mRNA have many limitations; therefore, it is necessary to study the complex regulatory network of gastric cancer (GC) pathogenesis systematically. METHODS: In this study, gene and miRNA expression data for GC were downloaded from The Cancer Genome Atlas and used for transcriptome profiling, differential gene analysis, and construction of an lncRNA-miRNA-mRNA regulatory network in conjunction with an online database to identify the key genes and subnetworks in GC pathogenesis. Real-time quantitative polymerase chain reaction was used to detect the expression of hub lncRNAs in 54 paired GC and matched normal mucosal tissues. RESULTS: We constructed an lncRNA-miRNA-mRNA competitive endogenous RNA regulatory network containing 1,626 network nodes and 2,704 interactions. LncRNA ADAMTS9-AS2 and PVT1 were identified as key node genes in this competitive endogenous RNA network. Quantitative reverse transcription-polymerase chain reaction revealed ADAMTS9-AS2 downregulation and PVT1 upregulation in 54 pairs of GC and normal tissues adjacent to the cancer tissues. CONCLUSIONS: This study systematically analysed the lncRNA-miRNA-mRNA regulatory network in GC and identified ADAMTS9-AS2 and PVT1 as key regulatory genes in this network, providing new understanding of GC pathogenesis and insights for its early diagnosis and treatment.

Nomograms combined with SERPINE1-related module genes predict overall and recurrence-free survival after curative resection of gastric cancer: a study based on TCGA and GEO data.

BACKGROUND: Serpin peptidase inhibitor, clade E, member 1 (SERPINE1) has been investigated as an oncogene and potential biomarker in several cancers, including gastric cancer (GC). This study aimed to investigate SERPINE1 expression and its diagnostic and prognostic value by analyzing data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. METHODS: A meta-analysis was performed to investigate SERPINE1 expression levels in GC tissues and adjacent normal tissues. Gene set enrichment, multi experiment matrix (MEM), and protein-protein interaction (PPI) network analyses were performed to identify the most enriched signaling pathways and SERPINE1-related module genes. A Cox regression model was used to develop a nomogram that was able to predict the overall survival (OS) and recurrence-free survival (RFS) of individual patients. RESULTS: Meta-analyses revealed an elevated trend in SERPINE1 expression levels in TCGA [standard mean difference (SMD) =0.95; 95% confidence interval (CI), 0.53-1.36; P<0.001]. The diagnostic meta-analysis results indicated that the area under the curve (AUC) of the summary receiver operating characteristic (SROC) was 0.80 (95% CI, 0.77-0.84). The factors identified to predict OS were age ≥60 years [hazard ratio (HR), 2.14; 95% CI, 1.45-3.16; P<0.01], R2 margins (HR, 2.70; 95% CI, 1.41-5.14; P<0.05), lymph node-positive proportion (HR, 3.38; 95% CI, 2.03-5.63; P<0.001), patient tumor status (HR, 3.33; 95% CI, 2.28-4.87; P<0.001), and OS risk score (HR, 2.72; 95% CI, 1.82-4.05; P<0.05). The following variables were associated with RFS: male sex (HR, 2.55; 95% CI, 1.46-4.45; P<0.01), R2 margins (HR, 13.08; 95% CI, 4.26-40.15; P<0.001), lymph node-positive proportion (HR, 2.55; 95% CI, 1.20-5.45; P<0.05), and RFS risk score (HR, 2.70; 95% CI, 1.82-4.06; P<0.001). The discriminative ability of the final model for OS and RFS was assessed using C statistics (0.755 for OS and 0.745 for RFS). CONCLUSIONS: SERPINE1 was upregulated in GC, showed a high diagnostic value, and was associated with poorer OS and RFS. The OS and RFS risk for an individual patient could be estimated using these nomograms, which could lead to individualized therapeutic choices.

Clinical effect and safety of dendritic cell-cytokine-induced killer cell immunotherapy for pancreatic cancer: a systematic review and meta-analysis.

BACKGROUND: Although promising results have recently been reported using dendritic cells (DCs) and cytokine-induced killer cells (CIKs) to treat pancreatic cancer (PC), its clinical effect and safety are associated with some controversy, and lack sufficient evidence. Here, we conducted a meta-analysis of 21 clinical trials to better evaluate the efficacy of DC-CIK immunotherapy in clinical practice to treat PC. METHODS: PubMed, Cochrane Library, China National Knowledge Infrastructure (CNKI) and Wanfang Data Knowledge Service Platform (WANFANG Data) were searched to identify clinical trials that used DC-CIK immunotherapy for PC. Meta-analysis was performed using RevMan 5.3 and Stata 12.0. RESULTS: A total of 21 clinical trials involving 1549 patients were included. Compared with traditional treatment, DC-CIK immunotherapy improved and increased the clinical indices such as complete remission, partial remission, overall response rate, disease control rate, overall survival (0.5-y OS, 1-y OS, 1.5-y OS, 2-y OS and 3-y OS), interferon γ and CD3+, CD4+, CD4+/CD8+ and CD3+CD56+ lymphocyte. Additionally, DC-CIK immunotherapy reduced stable disease, progression disease, mortality, CD8+, CD4+CD25+CD127 low lymphocyte and interleukin-4. Furthermore, it showed a low incidence of adverse reactions (22%). CONCLUSION: In contrast to traditional therapy, DC-CIK immunotherapy not only shows improved short-term effect, long-term effect and immunologic function, but also reduces mortality and negative immunoregulatory index, and shows mild adverse reactions. This is the first study to evaluate the clinical effect and safety of DC-CIK immunotherapy for PC, and it indicated that DC-CIK immunotherapy may be suitable for patients with advanced PC or intolerance to radiotherapy and chemotherapy.

Identification of two novel mutations in the ATP7B gene that cause Wilson's disease.

BACKGROUND: Wilson's disease is an autosomal recessive disorder characterized by liver disease and/or neurologic deficits due to copper accumulation and is caused by pathogenic mutations in the ATP7B gene. DATA SOURCES: Two unrelated Chinese patients born to nonconsanguineous parents who were diagnosed with earlyonset Wilson's disease. DNA sequencing and bioinformation analysis were conducted. RESULTS: We have identified four mutations in two family trios, of which two were novel, namely, c. 3028A>G (p. K1010E) and c.3992T>G (p.Y1331X), in each patient. CONCLUSIONS: Gene testing is playing an important role in diagnosis of Wilson's disease. The early-onset of Wilson's disease is apparently not associated with P-ATPase domain in the ATP7B protein. Our findings further widen the spectrum of mutations involving the ATP7B gene.

[The 18F-FDG myocardial metabolic imaging in twenty seven pilots with regular aerobic training].

OBJECTIVE: To evaluate the characteristics of myocardial (18)F-FDG imaging in pilots with regular aerobic exercise training. METHODS: Twenty seven healthy male pilots with regular aerobic exercise training were included in this study. The subjects were divided into fasting (n = 17) or non-fasting group (n = 10). Fluorine-18-labeled deoxyglucose and Tc-99m-sestamibi dual-nuclide myocardial imaging were obtained at rest and at target heart rate during bicycle ergometer test. The exercise and rest myocardial perfusion imaging were analyzed for myocardial ischemia presence. The myocardial metabolism imaging was analyzed with the visual semi-quantitative analyses model of seventeen segments. RESULTS: The secondary-extreme heart rate (195-age) was achieved in all subjects. There was no myocardial ischemia in all perfusion imaging. In the visual qualitative analyses, four myocardial metabolism imaging failed in the fasting group while one failed in the non-fasting group (P > 0.05). In the visual semi-quantitative analyses, myocardial metabolism imaging scores at rest or exercise in all segments were similar between two groups (P > 0.05). In the fasting group, the myocardial metabolism imaging scores during exercise were significantly higher than those at rest in 6 segments (P < 0.05). In the non-fasting group, the scores of 3 exercise myocardial metabolism imaging were significantly higher than those at rest (P < 0.05). CONCLUSION: Satisfactory high-quality myocardial metabolism imaging could be obtained at fasting and exercise situations in subjects with regular aerobic exercise.

[Autologous mononuclear bone marrow cell transplantation by intracoronary route for patients with ischemic heart disease: observation of 2-years follow-up].

OBJECTIVE: To investigate the long-term effect and safety of intracoronary autologous bone marrow mononuclear cell (BMMC) transplantation in patients with ischemic heart disease (IHD). METHODS: Seventy-six patients with IHD, 26 patients with acute myocardial infarction (AMI) and 26 patients with chronic ischemic heart failure (CIHF), underwent routine treatment plus intracoronary autologous BMMC transplantation, and 24 patients, including 10 patients with AMI and 14 patients with CIHF underwent routine treatment as controls. Autologous BMMC transplantation was performed via a balloon catheter placed into the infarct-related artery during balloon dilatation by high pressure infusion to occlude the artery, which was performed 6 - 8 times for 2 minutes each with 2-minute interval or via a balloon catheter without occluding the infarct-related artery. Follow-up was conducted for 2 years. RESULTS: The surgery was safety without major periprocedural complications. There were no other new arrhythmias found by Holter recorder during the 2-years follow-up. In the AMI patients receiving BNNC transplantation, the left ventricular ejection fraction (LVEF) 1 and 2 years later increased by 5.79% (P < 0.05), 3.79% (P > 0.05) respectively; but there was no change in left ventricular end diastolic volume (LVEDV) and left ventricular end systolic volume (LVESV). The LVEF 1 and 2 years later of the control group increased by 8.8% and 9.2% respectively (both P < 0.01) and the LVESV 1 and 2 years later decreased by 20.4% and 27.8% respectively (both P < 0.05), the myocardium defect area 2 years later was not significantly different from that 3 months later. The heart function of the control group became markedly worse. CONCLUSION: Autologous BMMC intracoronary transplantation is safe and effective, especially in patients with CIHF.

[The autologous bone marrow mononuclear cell transplantation by intracoronary route treat patients with severe heart failure after myocardial infarction].

OBJECTIVE: To investigate the chronic effects of intracoronary autologous bone marrow mononuclear cell (BM-MNCs) transplantation in patients with refractory heart failure (RIHF) after myocardial infarction. METHODS: Thirty patients with RIHF (LVEF < 40%) were enrolled in this nonrandomized study, autologous BM-MNCs (5.0 +/- 0.7) x 10(7) were transplanted with via infarct-related coronary artery in 16 patients and 14 patients received standard medical therapy served as control. Baseline and follow up evaluations included complete clinical evaluations, plasma BNP, ANP, ET-1 measurements, echocardiography, PET, and Holter monitoring. RESULTS: Baseline characteristics were similar between the 2 groups. There were no major periprocedural complications. One patient developed ventricular premature contractions during cell infusion for several seconds and recovered spontaneously. Compared to pre-transplantation, plasma BNP and ET-1 significantly decreased and plasma ANP significantly increased at 7 days post transplantation; 6 minutes walking distance increased from (72.1 +/- 31.5) to (201.6 +/- 23.3) m (P < 0.01), LVEF increased 9.9% (P < 0.001) and FDG-PET revealed vital myocardium area increased (10.3 +/- 3.4)% (P < 0.01) at 3 months after BM-MNCs transplantation. At 6 months follow up, the NYHA class improved from (3.4 +/- 0.1 to 2.4 +/- 0.2, P < 0.001) and no patient died and 1 patient rehospitalized due to lower extremities edema. In control group, LVEF decreased 7.2% compared to baseline (P < 0.001) and was significantly lower than transplantation group at 3 months (P < 0.001). At 6 months follow up, the NYHA class increased from (3.5 +/- 0.1 to 3.9 +/- 0.1, P < 0.05), 2 patients died and 10 patients rehospitalized due to aggravated heart failure. CONCLUSION: Present study demonstrates that intracoronary transplantation of autologous BM-MNCs is safe and effective for treating patients with RIHF after myocardial infarction.