Identification of a ferroptosis-related long noncoding RNA signature with a prognostic value in adrenocortical carcinoma.

Background: Adrenocortical carcinoma (ACC) is an uncommon endocrine malignancy associated with poor clinical outcome. As a novel form of cell death, ferroptosis is reliant on the accumulation of iron and reactive oxygen species and is involved in the pathogenesis of various tumors, including ACC. Our study aimed to identify and characterize the prognostic ferroptosis-related lncRNA signature (FerRLSig) in ACC. Methods: A regulatory network of ferroptosis-related lncRNAs (FerRLs) and mRNAs was constructed based on The Cancer Genome Atlas (TCGA). Univariate and multivariate Cox regression assays were performed to construct the FerRLSig. Results: Twenty-four FerRLs were identified in the prognostic model, and the high-risk FerRLSig was related to the worse overall survival (OS) in ACC [hazard ratio (HR): 1.936 (1.484-2.526), p < 0.001]. The area under the curve (AUC) value of the FerRLSig was 0.936 according to the receiver operating characteristic (ROC) analyses, superior to other traditional clinicopathological features, further supported the utility in prognosis prediction of ACC. We further established a prognostic nomogram combining clinical factors with the FerRLSig, which showed favorable efficacy for survival prediction. Next, gene set enrichment analysis (GSEA) revealed that gene sets were involved in many immune regulatory biological processes related to malignancies. T-cell function of type II INF response and the immune checkpoints, including CD40, CD276, IDO2, NRP1, and CD80, were expressed with a significant difference between the low- and high-risk groups. Conclusion: This study offered new insights into the pathogenesis of ACC. The novel FerRLSig could be useful in predicting survival and may provide information of immunological research and treatment for ACC patients.

Nomograms for Individualized Evaluation of Prognosis in Adrenocortical Carcinomas for the Elderly: A Population-Based Analysis.

BACKGROUND: Adrenocortical carcinoma (ACC) is extremely rare in elderly patients. Thus, this study aimed to identify the incidence rate and develop nomogram models for predicting survival in elderly ACC patients. METHODS: Data of ACC patients aged >60 years from 1975 to 2016 were obtained from the Surveillance, Epidemiology, and End Results dataset. The national incidence rate was estimated, and survival was subjected to Kaplan-Meier analysis. A multivariate Cox regression model was used to identify predictors of survival. Nomograms were generated to predict survival, calibrated and internally validated. RESULTS: We identified 583 cases. Univariate analysis showed that patients with younger age (≤67 years), female sex, lower tumor grade, surgical treatment performed, and earlier European Network for the Study of Adrenal Tumors (ENSAT) stage had a better survival (P < 0.05). In the Cox regression analysis, no surgery performed (hazard ratio [HR]: 3.544, 95% CI: 1.142-10.995, P = 0.029 for overall survival [OS]; HR: 3.230, 95% CI: 1.040-10.034, P = 0.043 for disease-specific survival [DSS]) and advanced ENSAT stage (HR: 3.328, 95% CI: 1.628-6.801, P = 0.001 for OS; HR: 3.701, 95% CI: 1.682-8.141, P = 0.001 for DSS) were associated with worse outcomes. Age, sex, histologic grade, surgical resection, radiotherapy, and ENSAT stage were included in the nomograms, with a C-index of 0.692 for OS and 0.694 for DSS, demonstrating a good accuracy in predicting survival. CONCLUSIONS: This study is the largest review of ACC in elderly patients. We present nomograms to predict survival in elderly ACC patients using clinicopathologic data, which could aid in accurate clinical decision-making.

The association of MTHFR C677T variant with increased risk of ischemic stroke in the elderly population: a meta-analysis of observational studies.

BACKGROUND: C677T point mutation in methylenetetrahydrofolate reductase (MTHFR) gene have been found to be associated with ischemic stroke in general population, while the results seem inconsistent. We aim to assess the association between variant MTHFR C677T variant and increased risk of ischemic stroke and focus on the elderly population. METHODS: We searched PubMed, Embase, Cochrane Library, and Web of Science for eligible studies. Odds ratios (ORs) were calculated with the two-tailed 95% confidence intervals (CIs) by using a random effects model to evaluate any possible association. Among the Chinese and non-Chinese populations, we conducted a subgroup analysis. RESULTS: The electronic database search yielded 1,358 citations as of December 2017; finally, nine case-control studies involving 3,337 subjects fulfilled our eligibility criteria for inclusion in the study. The pooled results showed that MTHFR C677T variant increased the risk of ischemic stroke (OR = 1.23, 95%CI 1.06-1.43, P = 0.0067 for CT + TT vs. CC; OR = 1.18, 95%CI 1.01-1.38, P = 0.0333 for CT vs. CC; OR = 1.41, 95%CI 1.14-1.75, P = 0.0016 for TT vs. CC; OR = 1.27, 95%CI 1.05-1.54, P = 0.0145 for TT vs. CC + CT; OR = 1.18, 95%CI 1.06-1.31, P = 0.0023 for T-allele vs. C-allele). Further subgroup analyses in the Chinese population indicated that MTHFR C677T variant was associated with a higher risk of ischemic stroke. CONCLUSION: Our findings showed that T-allele increases risk for stroke in the pooled sample. This association was statistically significant in the Chinese cohorts and showed a similar trend in the non-Chinese cohorts. (Word count: 237).

Clinical characteristics of extranodal NK/T-cell lymphoma-associated hemophagocytic lymphohistiocytosis.

BACKGROUND: Extranodal natural killer (NK) / T cell lymphoma is a subtype of non-Hodgkin's lymphoma (NHL) that usually has an aggressive clinical course. It is the predominant trigger of lymphoma-associated hemophagocytic syndrome (LAHS), which is highly lethal and with extremely poor prognosis. This study is aiming to characterize the associated clinical features and prognostic factors of the disease. PATIENTS AND METHODS: Twenty-eight patients with extranodal NK/T cell lymphoma associated hemophagocytic lymphohistiocytosis (HLH) were retrospectively analyzed. The clinical records were collected, and the associations between clinical or laboratory parameters and overall survival (OS) were assessed. RESULTS: The most frequently clinical characteristics were fever (96.4%), and splenomegaly (81.5%). Concerning the laboratory findings, the most common features were hyperferritinemia (91.7%), grade III/IV thrombocytopenia (64.3%), hypertriglyceridemia (48%), severe anemia (46.4%), hypofibrinogenemia (45%), and grade III/IV neutropenia (32.1%). The interval between the diagnosis of NK/T LAHS and death / last contact was between 4 to 701 days with the median interval of 15 days. We found that higher serum lactic dehydrogenase (LDH) at HLH, hypofibrinogenemia, and splenomegaly were significantly associated with worse survival (P=0.002, 0.003, 0.003). Furthermore, Eastern Cooperative Oncology Group (ECOG) score, extra-upper aerodigestive tract NK/T cell lymphoma (EUNKTL) and cutaneous involvement were risk factors of HLH. CONCLUSION: Our data indicated that levels of LDH, fibrinogen, and presence of splenomegaly were prognostic factors of the disease. Higher ECOG scores, EUNKTL and cutaneous involvement were risk factors of NK/T LAHS. Additional independent, prospective clinical trials will be needed to explore optimal treatment.

Effect of Aging and Glucagon-like Peptide 2 on Intestinal Microbiota in SD Rats.

Recent research suggests that intestinal microbiota affect the aging process. Glucagon-like peptide 2 (GLP-2), a growth factor found in the intestinal mucosal epithelium, reduces intestinal permeability and affects intestinal microbiota. The relationship between aging, GLP-2, and intestinal microbiota are still not well understood. The current study examined the influence of aging and GLP-2 on the intestinal microbiota of rats. Twelve 3-month old male SD rats were randomly divided into two groups: a young control group (group C) and a young GLP-2 treatment group (group G). Twelve 26-month old male SD rats were randomly divided into two groups: an aged control group (group L) and an aged GLP-2 treatment group (group T). GLP-2 was intraperitoneally injected into rats from group G and group T for 14 days. Plasma GLP-2 concentration was evaluated by ELISA tests. Fresh intestinal stool samples were collected from each group and total fecal bacterial genomic DNA was extracted from the associated rats. The bacterial composition of fecal samples was analyzed by Miseq high-throughput sequencing and comparison with SRA databases. Overall, the diversity of intestinal microbiota significantly decreases with age in SD rats, while GLP-2 has no significant effect on the diversity of intestinal microbiota. Upon aging, there is a reduction in probiotic bacteria and a concomitant increase in pathogenic bacteria in rats. Treatment with GLP-2 results in a significant reduction in the prevalence of pathogenic bacterial genera and an increase in some potential benefit bacteria in aged rats. In addition, treatment with GLP-2 results in an increase in several probiotics and a reduction in the prevalence of pathogenic bacterial genera in young rats.

Transgelin-2 is a novel target of KRAS-ERK signaling involved in the development of pancreatic cancer.

BACKGROUND: The KRAS mutation is the driving force of pancreatic ductal adenocarcinoma (PDAC). Downstream effectors of KRAS signal pathways are crucial to the development of PDAC. The purpose of this study was to investigate the relationship between KRAS mutation and transgelin-2. Transgelin-2 is highly expressed in PDAC tissues compared with adjacent normal tissues. The underlying mechanism for upregulating transgelin-2 is largely unknown. METHODS: Expression of transgelin-2 was analyzed by microarray data and qRT-PCR. The effect of KRAS signaling on transgelin-2 expression was examined in PDAC cells in the presence or absence of the ERK inhibitor. The interaction of transgelin-2 with ERK was confirmed by immunoprecipitation. ERK-mediated Phosphorylation of transglein-2 was detected by in vivo and in vitro kinase assays. The gain-of-function and loss-of-function approaches were used to examine the role of phosphorylation of transgelin-2 on cell proliferation. Phosphorylation of transgelin-2 was detected by immunohistochemistry in PDAC tissues. RESULTS: Here we found transgelin-2 expression was induced by KRAS mutation. In the case of KRAS mutation, ERK2 interacted with 29-31 amino acids of transgelin-2 and subsequently phosphorylated the S145 residue of transgelin-2. S145 phosphorylation of transgelin-2 played important roles in cell proliferation and tumorigenesis of PDAC. In addition, S145 phosphorylation of transgelin-2 was associated with a poor prognosis in patients with PDAC. CONCLUSIONS: This study indicated that KRAS-ERK-mediated transeglin-2 phosphorylation played an important role in the development of PDAC. Inhibition of transgelin-2 phosphorylation may be a potential therapeutic strategy for targeting PDAC with KRAS mutation.

Role of transgelin-2 in diabetes-associated pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis. Diabetes is a significant risk factor for PDAC and >50% of PDAC patients have concomitant diabetes. How diabetes influences the initiation and progression of PDAC remains elusive. Here, we show that transgelin-2 is dominantly expressed in PDAC tissues compared with adjacent normal tissues. The high level of transgelin-2 indicates poor survival of patients with PDAC. Remarkably, transgelin-2 expression is correlated with diabetic status. Hyperinsulinemia is frequently observed in type 2 diabetes. Our results indicate that upregulation of transgelin-2 is induced by insulin via sterol regulatory element-binding protein (SREBP)-1-mediated transcription in PDAC cells. Transgelin-2 is a novel target of SREBP-1. Our data support a novel mechanism in diabetes-associated PDAC by which transgelin-2 mediates proliferation of PDAC cells upon insulin stimulation. The insulin/SREBP-1/transgelin-2 network should be further explored as a diagnostic marker or a novel therapeutic target for diabetes-associated PDAC.

Phosphorylation of Ser6 in hnRNPA1 by S6K2 regulates glucose metabolism and cell growth in colorectal cancer.

Abnormal glucose metabolism is critical in colorectal cancer (CRC) development. Expression of the pyruvate kinase (PK) M2 isoform, rather than the PKM1 isoform, serves important functions in reprogramming the glucose metabolism of cancer cells. Preferential expression of PKM2 is primarily driven by alternative splicing, which is coordinated by a group of splicing factors including heterogeneous nuclear ribonucleoprotein (hnRNP)A1, hnRNPA2 and RNA binding motif containing. However, the underlying molecular mechanisms associated with cancer cell expression of PKM2, instead of PKM1, remain unknown. The mRNA levels of PKM isoform and glucose metabolism were analyzed in CRC cells. The results of the present study indicated that S6 kinase 2 (S6K2) promotes glycolysis and growth of CRC cells by regulating alternative splicing of the PKM gene. In addition, chromatin immunoprecipitation assay indicated that S6K2 phosphorylation of Ser6 of hnRNPA1 facilitated hnRNPA1 binding to the splicing site of the PKM gene. As a result, cancer cells preferentially expressed the PKM2 isoform, instead of the PKM1 isoform. Furthermore, Cox regression analysis demonstrated that the phosphorylation of Ser6 of hnRNPA1 was a predictor of poor prognosis for patients with CRC. Therefore, the results of the present study revealed that the phosphorylation of Ser6 in hnRNPA1 by S6K2 was a novel mechanism underlying glucose metabolic reprogramming, and suggested that S6K2 is a potential therapeutic target for CRC treatment.

The association between sex hormone-binding globulin gene polymorphism with bone mineral density.

To investigate the impact of single nucleotide polymorphisms (SNPs) of SHBG gene the neighboring genes on SHBG levels, bone mineral density (BMD) and osteoporosis in Chinese males. A group of Chinese men, aged ⩾ 45 years were included in the analysis. BMD was measured with dual-energy X-ray absorptiometry (DXA), SHBG and total testosterone (TT) was measured using chemiluminescent immunoassay, and free testosterone (FT) was calculated. SNPs of SHBG gene and the neighboring genes were studied by means of improved multiple ligase detection reaction (iMLDR). A total of 404 men were included in our study. In the single locus analysis, significant associations were found between SHBG levels and four polymorphisms (rs11078701, rs9901675, rs9898876 and rs2541012) in age- and BMI-adjusted models. In addition, statistically significant difference was found between osteoporosis patients and control subjects in genotype distributions of rs9898876, rs2541012, rs6259 and rs3853894. In the models with or without adjustment for confounders (age, BMI, SHBG and free testosterone (FT) levels), carriers of variant genotype of rs9898876, rs2541012 and rs6259 had lower BMD and were more likely to suffer from osteoporosis, as compare to carriers of common genotype. Subjects with variant genotype of rs3853894 had higher BMD and were less likely to suffer from osteoporosis, as compared to subjects with common genotype. In the haplotypes analysis, CCGGT (constituted by rs11078701C, rs1017163C, rs9898876G, rs62059836G and rs2541012T) and haplotype CGGT (constituted by rs858521C, rs858518G, rs6259G and rs727428T) was associated with a significant risk effect for osteoporosis. Polymorphisms of SHBG or the neighboring genes were associated with SHBG levels or BMD and osteoporosis, suggesting the involvement of genetic variation of SHBG in bone health.

SREBP1 regulates tumorigenesis and prognosis of pancreatic cancer through targeting lipid metabolism.

Sterol regulatory element-binding protein 1 (SREBP1) is a known transcription factor of lipogenic genes, which plays important roles in regulating de novo lipogenesis. Accumulating evidences indicate SREBP1 is involved in tumorigenesis, yet its role in pancreatic cancer remains unclear. Here, we explored the expression characteristic and function of SREBP1 in pancreatic cancer. Analysis of 60 patients with pancreatic ducat cancer showed that SREBP1 level was significantly higher in pancreatic cancer than that in adjacent normal tissues. High expression of SREBP1 predicted poor prognosis in patients with pancreatic cancer. Multivariate analysis revealed that SREBP1 was an independent factor affecting overall survival. SREBP1 silencing resulted in proliferation inhibition and induction of apoptosis in pancreatic cancer cells. Mechanistically, lipogenic genes (acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), and stearoyl-CoA desaturase-1 (SCD1)) and de novo lipogenesis were promoted by SREBP1. Inhibition of lipogenic genes through specific inhibitors ablated SREBP1-mediated growth regulation. Furthermore, depletion of SREBP1 could suppress lipid metabolism and tumor growth in vivo. Our results indicate that SREBP1 had important role in tumor progression and appears to be a novel prognostic marker for pancreatic cancer.

Diagnostic value of osteoporosis self-assessment tool for Asians (OSTA) and quantitative bone ultrasound (QUS) in detecting high-risk populations for osteoporosis among elderly Chinese men.

This study aims to evaluate an osteoporosis self-assessment tool for Asians (OSTA) and quantitative bone ultrasound (QUS) and their combination in detecting populations at high risk for osteoporosis, and to determine the best cutoff value for the diagnosis of osteoporosis among elderly Chinese men. A group of Chinese men, aged ≥ 60 years, recruited from the health checkup population of Zhongshan Hospital, Fudan University, were included. The OSTA index was calculated from age and weight. Bone mineral density (BMD) at left hip (femoral neck, internal, and total hip) and lumbar spine (L1-L4, L-Total) was measured with dual-energy X-ray absorptiometry (DXA), and calcaneal BMD was measured with QUS. Receiver operating characteristic analysis was used to determine the best cutoff values, sensitivity, and specificity. The area under the curve (AUC) between the different screening tools was compared. Our study included 472 men with mean age of 78.0 years. The prevalence of osteoporosis was 27.7%.The best cutoff for OSTA was -3.5 for predicting men with osteoporosis at any site; this yielded a sensitivity and specificity of 47.3% and 76.8%, respectively. The AUC for OSTA was 0.676. The optimal cutoff for QUS-T score was -1.25, with a sensitivity of 80.4% and specificity of 59.7%. The AUC for QUS-T score was 0.762. Combining QUS with OSTA improved the specificity to 92.9% but reduced sensitivity to 36.1%. A new variable derived from a combination of OSTA and the QUS-T score gave a better performance, with sensitivity of 70.1% and specificity of 72.1%; the AUC for this variable was 0.771, which was greater than OSTA but not different from QUS alone. In conclusion, OSTA and QUS, respectively, and their combination may help find populations at high risk for osteoporosis, which could be an alternative method for diagnosing osteoporosis, especially in areas where DXA measurement is not accessible.

Sex hormone-binding globulin (SHBG) as an independent determinant of bone mineral density (BMD) among Chinese middle-aged and elderly men.

The aim of the study was to assess the impact of sex hormone-binding globulin (SHBG) on bone mineral density (BMD) and bone turnover among Chinese middle-aged and elderly men. This cross-sectional study was carried out among 404 Chinese men aged over 45 years. BMD was measured with dual-energy X-ray absorptiometry, and participants' blood was collected for bone-specific alkaline phosphates (BSAP), SHBG and testosterone assay. Osteoporotic men had lower free testosterone (FT) and higher levels of SHBG, and BSAP than the osteopenia and normal groups. When SHBG levels were divided into quartiles, FT levels decreased and prevalence of osteoporosis increased with higher SHBG levels. Compared with subjects in the lowest quartile of SHBG levels (<36.55 nmol/l), subjects in the third quartile [OR (95 % CI) 2.998 (1.460-6.157), p = 0.002] and the highest quartile [OR (95 % CI) 4.439 (2.192-8.991), p < 0.001] were more likely to suffer with osteoporosis. FT was significantly positive related to total hip BMD and total lumbar BMD, whereas there was no association between TT and BMD after adjusting for age, BMI and FT. SHBG levels were also inversely related to BMD. SHBG could explain 1.4-2.1 % of the BMD variance after adjustment for age, BMI and FT. No association was found between BSAP and SHBG, TT and FT. Logistic regression analysis showed that BMI, smoking and FT or SHBG was independently associated with the presence of osteoporosis. Serum FT levels were positively correlated with BMD, while SHBG levels were inversely related to BMD. Increasing SHBG level was an independent risk factor for osteoporosis among Chinese men.