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BACKGROUND: In recent years, immunotherapy has made great progress, and the regulatory role of epigenetics has been verified. However, the role of 5-methylcytosine (m(5)C) in the tumor microenvironment (TME) and immunotherapy response remains unclear. METHODS: Based on 11 m(5)C regulators, we evaluated the m(5)C modification patterns of 572 lung adenocarcinoma (LUAD) patients. The m(5)C score was constructed by principal component analysis (PCA) algorithms in order to quantify the m(5)C modification pattern of individual LUAD patients. RESULTS: Two m(5)C methylation modification patterns were identified according to 11 m(5)C regulators. The two patterns had a remarkably distinct TME immune cell infiltration characterization. Next, 226 differentially expressed genes (DEGs) related to the m(5)C phenotype were screened. Patients were divided into three different gene cluster subtypes based on these genes, which had different TME immune cell infiltration and prognosis characteristics. The m(5)C score was constructed to quantify the m(5)C modification pattern of individual LUAD patients. We found that the high m(5)C score group had a better prognosis. The role of the m(5)C score in predicting prognosis was also verified in the dataset GSE31210. CONCLUSIONS: Our study revealed that m(5)C modification played a significant role in TME regulation of LUAD. Investigation of the m(5)C regulation mode may have some implications for tumor immunotherapy in the future.

Nan Jiang,1,2,* Xiao-Lin Ge,2,* Zhao-Yue Zhang,2 Jia Liu,2 Pei-Pei Wang,2 Xin-Chen Sun,1,2 Min Yang1 1The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, 210000, People’s Republic of China; 2Department of Radiotherapy, Jiangsu Province Hospital, Nanjing, Jiangsu, 210000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Min YangThe First School of Clinical Medicine, Nanjing Medical University, No. 818 of Tianyuan Road, Jiangning District, Nanjing, Jiangsu, 210000, People’s Republic of ChinaTel +86 13701516659Email yangmin@jsinm.orgXin-Chen SunDepartment of Radiotherapy, Jiangsu Province Hospital, No. 300 of Guangzhou Road, Gulou District, Nanjing, Jiangsu, 210000, People’s Republic of ChinaTel +86 13770662828Email sunxinchen2012@163.comPurpose: Intensity-modulated radiotherapy (IMRT) can improve the prognosis of patients with esophageal cancer. This study aimed to evaluate clinical factors relevant to the prognosis of patients with esophageal cancer who received intensity-modulated radiotherapy (IMRT) alone.Patient and Methods: Data of 103 patients with pathologically confirmed esophageal cancer who were admitted to our hospital between October 2011 and November 2017 were retrospectively reviewed. All patients had squamous cell carcinoma. All patients received IMRT. Patients with stage I–IVA tumors were included to represent the real-world clinical practice. We performed univariate and multivariate analyses to identify prognostic factors for overall survival (OS) and progression-free survival (PFS). In univariate analyses, the Kaplan–Meier method was used to estimate OS and PFS for various subgroups. In multivariate analyses, hazard ratios were calculated.Results: Single-factor analysis revealed that T stage (P=0.019), N stage (P =0.047), and lesion length (P =0.000) were associated with the prognosis of esophageal cancer patients who received IMRT. Cox regression analysis revealed that T stage (odds ratio [OR] = 4.68; P < 0.05), N stage (OR = 0.28; P < 0.05), and lesion length (OR = 0.09; P < 0.05) were independent factors relevant to prognosis.Conclusion: T stage, N stage, and lesion length influenced the long-term curative effects of IMRT for esophageal cancer and were prognostic factors for patients with esophageal cancer receiving definitive radiotherapy alone. The higher the stage and the longer the tumor, the lower the survival rate.Keywords: esophageal neoplasms, prognosis, intensity-modulated radiotherapy, retrospective studies

Background: The optimal therapeutic strategy in locally advanced esophageal squamous cell carcinoma (ESCC) primarily treated by surgery remains unknown. This study was designed to evaluate the impact of postoperative chemoradiotherapy and postoperative sequential chemoradiotherapy on survival in this population. Methods: The study included a total of 228 consecutive patients who underwent radical esophagectomy and were confirmed to have stage pT3–4 or pN+ ESCC from September 2011 to September 2017 at our institution. All patients received postoperative radiotherapy with or without concurrent or sequential chemotherapy after esophagectomy. Univariate and multivariate analyses were used to compare the survival of patients with postoperative radiotherapy, postoperative concurrent chemoradiotherapy, and postoperative sequential chemoradiotherapy. Results: After a median follow-up of 52 months, the 3- and 5-year overall survival (OS) rates were 70.2% [95% confidence interval (CI), 63.7–76.7%] and 62.2% (95% CI, 54.6–69.8%), respectively. The disease-free survival (DFS) rates at 3 and 5 years were 65.2% (95% CI, 58.7–71.7%) and 55.2% (95% CI, 47.6–62.8%), respectively. The 3- and 5-year locoregional recurrence-free survival (LRFS) rates were 65.1% (95% CI, 58.4–71.8%) and 55.5% (95% CI, 47.7–63.3%). Of the 228 patients, 38 (16.7%) had distant metastases. Subgroup analysis showed that being male and having a higher T stage were independent poor prognostic factors for OS and DFS in patients with pN+ or stage III + IVA ESCC. The results also showed that in patients with stage III + IVA ESCC, the DFS of the patients in the concurrent chemotherapy (CCT) group was improved compared with that in the no CCT group [hazard ratio (HR), 0.551; 95% CI, 0.323–0.938; P=0.028]. Multivariate analysis showed that sequential chemoradiotherapy was associated with poor LRFS (HR, 2.312; 95% CI, 1.078–4.959; P=0.031), especially in stage T3–4 patients, and it was also related to the poor DFS (HR, 1.781; 95% CI, 1.086–2.921; P=0.022) in patients with stage T3–4 ESCC. Conclusions: In patients with locally advanced ESCC, those who underwent sequential chemoradiotherapy had a worse LRFS. Postoperative concurrent chemoradiotherapy was the most effective adjuvant therapy for resected stage III–IVA ESCC. In addition, being male, having a higher T stage, and being node-positive were independent poor prognostic factors for OS and DFS.

BackgroundConcurrent chemoradiotherapy (CCRT) is the standard treatment for nonsurgical esophageal cancer (EC). However, esophageal cancer patients receiving CCRT alone are still unsatisfactory in terms of local control and overall survival (OS) benefit. Clinicians generally add consolidation chemotherapy (CCT) after CCRT. It remains controversial whether CCT following CCRT is beneficial for esophageal cancer. We, therefore, undertook a meta-analysis to assess the need for CCT in inoperable esophageal cancer.Materials and MethodsWe combed PubMed, Embase, Cochrane Library, Web of Science, and CNKI for relevant published articles up to July 2020 that compared CCRT plus CCT to CCRT alone for patients with nonsurgical EC. Our primary endpoint was OS and progression-free survival (PFS), and the secondary endpoint was treatment toxicity. We analyzed the hazard ratio (HR) to estimate the time-to-event data and the odds ratio (OR) to compare the treatment-related effect. To assess heterogeneity, we performed the I2 test and examined publication bias using funnel plots analysis.ResultsThe 11 retrospective studies involved 2008 patients. Of these 2008 patients, 1018 received CCRT plus CCT, and 990 received CCRT. Compared to CCRT alone, CCT after CCRT did not improve disease control rate (DCR) (OR 1.66; 95% CI 0.53–5.15, p=0.384) and objective response rate (ORR) (OR 1.44; 95% CI 0.62–3.35, p=0.393). However, OS (HR 0.72; 95% CI 0.59–0.86, p < 0.001) and PFS (HR 0.61; 95% CI 0.44–0.84, p=0.003) did increase. Our results show that CCT plus CCRT had a clear survival advantage over CCRT alone. The risk of treatment toxicity did not increase for EC patients who received CCT.ConclusionCCT after CCRT significantly increases OS and PFS in patients with nonsurgical EC and could provide them remarkable survival benefits. The results provide an evidence-based framework for the use of CCT after CCRT.

Contralateral axillary lymph node metastasis (CAM) in breast cancer is rare, and the reason is unclear. CAM may be found at the time of primary breast cancer diagnosis or following primary tumor treatment. CAM staging and treatment methods are controversial. Hence, we summarized the features of CAM patients and explored the therapeutic options. We report the case of an 82-year-old woman with right breast cancer accompanied by CAM. The records of breast cancer patients with CAM in PubMed (January 2000-May 2020) were also reviewed. After undergoing comprehensive treatments (neoadjuvant chemotherapy, surgery, radiotherapy, endocrine therapy, and targeted therapy), no signs of recurrence and metastasis were noted during the 25-month follow-up. Overall, 17 studies (36 patients) were selected for the review, of which 15 had synchronous CAM and 21 had metachronous CAM. Nineteen of 22 patients had histologic grade 3. Forty percent (12/30) had ≥4 positive lymph nodes. Among these 36 patients, 9 had triple-negative breast cancers, and 9 were human epidermal growth factor receptor 2 positive. Among the 30 patients staged, 6 (20%) were in stage I; 7 (23.33%), stage II; and 17 (56.67%), stage III. Two patients received systemic therapy, while one received an unknown treatment. The remaining 33 patients all received local treatment (surgery or radiotherapy). The survival time of synchronous and metachronous CAM patients was 12-72 months with the death rate of 1/7 and 12-144 months with that of 3/12, respectively. CAM may be a regional manifestation rather than a distant metastasis. Comprehensive treatment, including surgery and radiotherapy, may provide better control.

Background To determine the diagnostic accuracy of preoperative T/N stage with magnetic resonance imaging (MRI) in lower and middle rectal cancer patients and the impacts on clinical decision‐making. Patients and methods A total of 211 patients were recruited from October 2015 to March 2017 in this retrospective study. High‐resolution MRI was performed within 2 weeks before surgery. Histopathologic results were evaluated for the postoperative T/N stage and the diagnostic accuracy of MRI was assessed according to the postoperative histopathologic results. The accuracy, sensitivity, specificity, positive predictive value and negative predictive value were evaluated for T/N staging and κ values were used to evaluate MRI consistent analysis compared with postoperative histopathologic staging. Results The overall MRI diagnostic accuracy was 79.62% for T1‐4 staging and 54.50% for N0‐2 staging. The κ values were 0.619 and 0.255 for T1‐4 and N0‐2 staging, respectively. The diagnostic accuracy of MRI for treatment decision‐making was 80.57%. Conclusion MRI allows a highly accurate preoperative assessment of T stage but only a fairly accurate preoperative assessment of N stage for rectal cancer. The diagnostic accuracy of MRI for treatment decision‐making is promising, but additional studies are needed to validate these findings in a larger sample size from multiple centers.

SUMMARYMammalian organs are nourished by nutrients carried by the blood circulation. These nutrients originate from diet and internal stores, and can undergo various interconversions before their eventual use as tissue fuel. Here we develop isotope tracing, mass spectrometry, and mathematical analysis methods to determine the direct sources of circulating nutrients, their interconversion rates, and eventual tissue-specific contributions to TCA cycle metabolism. Experiments with fifteen nutrient tracers enabled extensive accounting both for circulatory metabolic cycles and tissue TCA inputs, across fed and fasted mice on either high carbohydrate or ketogenic diet. We find that a majority of circulating carbon flux is carried by two major cycles: glucose-lactate and triglyceride-glycerol-fatty acid. Futile cycling through these pathways is prominent when dietary content of the associated nutrients is low, rendering internal metabolic activity robust to food choice. The presented in vivo flux quantification methods are broadly applicable to different physiological and disease states.

NADH provides electrons for aerobic ATP production. In cells deprived of oxygen or with impaired electron transport chain activity, NADH accumulation can be toxic. To minimize such toxicity, elevated NADH inhibits the classical NADH producing pathways: glucose, glutamine, and fat oxidation. Here, through deuterium tracing studies in cultured cells and mice, we show that folate-dependent serine catabolism also produces substantial NADH. Strikingly, when respiration is impaired, serine catabolism through methylene tetrahydrofolate dehydrogenase (MTHFD2) becomes a major NADH source. In cells whose respiration is slowed by hypoxia, metformin, or genetic lesions, mitochondrial serine catabolism inhibition partially normalizes NADH levels and facilitates cell growth. In mice with engineered mitochondrial complex I deficiency (NDUSF4-/-), serine’s contribution to NADH is elevated and progression of spasticity is modestly slowed by pharmacological blockade of serine degradation. Thus, when respiration is impaired, serine catabolism contributes to toxic NADH accumulation.

Background Endometrial cancer (UCEC) is a complex malignant tumor characterized by both genetic level and clinical trial. Patients with UCEC exhibit the similar clinical features, however, they have distinct outcomes due to molecular heterogeneity. The aim of this study was to access the prognostic value of long non-coding RNAs (lncRNAs) in UCEC patients and to identify potential lncRNA signature for predicting patients’ survival and improving patient-tailored treatment. Methods We performed a comprehensive genome-wide analysis of lncRNA expression profiles and clinical data in a large cohort of 301 UCEC patients. UCEC patients were randomly divided into the discovery cohort (n = 150) and validation cohort (n = 151). A novel lncRNA-focus expression signature was identified in the discovery cohort, and independently accessed in the validation cohort. Additionally, the lncRNA signature was evaluated by multivariable Cox regression and stratification analysis as well as functional enrichment analysis. Results We detected a novel lncRNA-focus expression signature (LFES) consisting of 11 lncRNAs that were associated with survival based on risk scoring strategy in UCEC. The risk score based on the LFES was able to separate patients of discovery cohort into high-risk and low-risk groups with significantly different overall survival and progression-free survival, and has been successfully confirmed in the validation cohort. Furthermore, the LFES is an independent prognostic predictor of survival and demonstrates superior prognostic performance compared with the clinical covariates for predicting 5-year survival (AUC = 0.887). Functional analysis has linked the expression of prognostic lncRNAs to well-known tumor suppressor or ontogenetic pathways in endometrial carcinogenesis. Conclusions Our study revealed a novel 11-lncRNA signature to predict survival of UCEC patient. This lncRNA signature may be a valuable and alternative marker for risk evaluation to aid patient-tailored treatment and improve the outcome of patients with UCEC. Electronic supplementary material The online version of this article (10.1186/s12885-017-3983-0) contains supplementary material, which is available to authorized users.

Background To determine the diagnostic accuracy of preoperative T/N stage using MRI in lower and middle rectal cancer patients and the impacts on clinical decision-making. Patients and methods There were 354 patients recruited from May 2017 to February 2019. MRI was performed within 2 weeks before surgery. Histopathologic results were evaluated for the postoperative T/N stage and MRI diagnostic accuracy was assessed based on the postoperative histopathologic results. Accuracy, sensitivity, specificity, positive predictive value, negative predictive value, and Kappa values were used to evaluate MRI diagnostic accuracy and analysis consistency compared with postoperative histopathologic staging. Results Overall MRI diagnostic accuracy was 78.2% and 56.8% for T1–4 and N0–2 staging. The Kappa values were 0.625 and 0.323 for T1–4 and N0–2 staging, respectively. After combination, MRI diagnostic accuracy was 85% and 69.5% for T and N staging. The Kappa values were 0.693 and 0.4 for T and N staging. The diagnostic accuracy of MRI for treatment decision-making was 79.1%. Conclusion MRI enables a highly accurate preoperative assessment of T stage but only a fairly accurate preoperative assessment of the N stage for rectal cancer with surgery. The diagnostic accuracy of MRI for treatment decision-making is promising.

Much understanding of metabolism is based on monitoring chemical reactions in cells with isotope tracers. For this purpose, 13C is well suited due to its stable incorporation into bio-molecules and minimal kinetic isotope effect. For redox reactions, however, deuterium tracing can provide valuable additional information. To date, studies examining NADPH production with deuterated carbon sources have failed to account for roughly half of NADPH’s redox active hydrogen. Here we show that the missing hydrogen is the result of enzyme-catalyzed H-D exchange between water and NADPH. While isolated NADPH does not undergo H-D exchange with water, such exchange is catalyzed by Flavin enzymes and occurs rapidly in cells. Correction for H-D exchange is required for accurate assessment of the biological sources of NADPH’s high energy electrons. Deuterated water (D2O) is frequently used to monitor fat synthesis in vivo, but the chemical pathway of the deuteron into fat remains unclear. We show that D2O labels fatty acids primarily via NADPH. Knowledge of this labeling route enables calculation, without any fitting parameters, of the mass isotope distributions of fatty acids from cells grown in D2O. Thus, knowledge of enzyme-catalyzed H-D exchange between water and NADPH enables chemically accurate interpretation of deuterium tracing studies of redox cofactor and fatty acid metabolism.

Recent studies have demonstrated the utility and superiority of long non-coding RNAs (lncRNAs) as novel biomarkers for cancer diagnosis, prognosis, and therapy. In the present study, the prognostic value of lncRNAs in glioblastoma multiforme was systematically investigated by performing a genome-wide analysis of lncRNA expression profiles in 419 glioblastoma patients from The Cancer Genome Atlas (TCGA) project. Using survival analysis and Cox regression model, we identified a set of six lncRNAs (AC005013.5, UBE2R2-AS1, ENTPD1-AS1, RP11-89C21.2, AC073115.6, and XLOC_004803) demonstrating an ability to stratify patients into high- and low-risk groups with significantly different survival (median 0.899 vs. 1.611 years, p = 3.87e−09, log-rank test) in the training cohort. The six-lncRNA signature was successfully validated on independent test cohort of 219 patients with glioblastoma, and it revealed superior performance for risk stratification with respect to existing lncRNA-related signatures. Multivariate Cox and stratification analysis indicated that the six-lncRNA signature was an independent prognostic factor after adjusting for other clinical covariates. Further in silico functional analysis suggested that the six-lncRNA signature may be involved in the immune-related biological processes and pathways which are very well known in the context of glioblastoma tumorigenesis. The identified lncRNA signature had important clinical implication for improving outcome prediction and guiding the tailored therapy for glioblastoma patients with further prospective validation.

Deregulation of long non-coding RNAs (lncRNAs) expression has been proven to be involved in the development and progression of cancer. However, expression pattern and prognostic value of lncRNAs in breast cancer recurrence remain unclear. Here, we analyzed lncRNA expression profiles of breast cancer patients who did or did not develop recurrence by repurposing existing microarray datasets from the Gene Expression Omnibus database, and identified 12 differentially expressed lncRNAs that were closely associated with tumor recurrence of breast cancer patients. We constructed a lncRNA-focus molecular signature by the risk scoring method based on the expression levels of 12 relapse-related lncRNAs from the discovery cohort, which classified patients into high-risk and low-risk groups with significantly different recurrence-free survival (HR = 2.72, 95% confidence interval 2.07–3.57; p = 4.8e-13). The 12-lncRNA signature also represented similar prognostic value in two out of three independent validation cohorts. Furthermore, the prognostic power of the 12-lncRNA signature was independent of known clinical prognostic factors in at least two cohorts. Functional analysis suggested that the predicted relapse-related lncRNAs may be involved in known breast cancer-related biological processes and pathways. Our results highlighted the potential of lncRNAs as novel candidate biomarkers to identify breast cancer patients at high risk of tumor recurrence.

Long non-coding RNAs (lncRNAs) represent an emerging layer of cancer biology and have been implicated in the development and progression of cancers. However, the prognostic significance of lncRNAs in diffuse large-B-cell lymphoma (DLBCL) remains unclear and needs to be systematically investigated. In this study, we obtained and analyzed lncRNA expression profiles in three cohorts of 1043 DLBCL patients by repurposing the publicly available microarray datasets from the Gene Expression Omnibus (GEO) database. In the discovery series of 207 patients, we identified a set of six lncRNAs that was significantly associated with patients’ overall survival (OS) using univariate Cox regression analysis. The six prognostic lncRNAs were combined to form an expression-based six-lncRNA signature which classified patients of the discovery series into the high-risk group and low-risk group with significantly different survival outcome (HR = 2.31, 95% CI = 1.8 to 2.965, p

Aim This meta-analysis was designed to fully assess the curative effects of radiotherapy-based therapies for human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC). Methods English articles were retrieved through searching Cochrane library, PubMed, and Embase databases updated to February 2017. Studies were selected based on the inclusion and exclusion criteria. The curative effects of radiotherapy-based therapies forHER2+ BC patients were assessed using hazard rates (HRs) or odds ratios (ORs), as well as their 95% confidence intervals (CIs). In addition, Egger test was used to assess publication bias, followed by sensitivity analysis. All statistic methods were conducted using R 3.12 software. Results A total of 9 eligible studies were included into this meta-analysis, which involved 2236 HER2+ BC patients. Egger test showed that the eligible studies had no publication bias (t = 2.198, P = .05918). Sensitivity analysis demonstrated that the results were stable. HER2+ BC patients in radiotherapy group had lower locoregional recurrences than those in other groups. Moreover, meta-analysis showed that no significant difference was found between HER2+ BC patients in radiotherapy group and other groups on the 1-year overall survival (P = 0.5263, I = 65.4%), 3-year overall survival (P = 0.4591, I = 0), and 5-year overall survival (P = 0.06277, I = 0). Conclusion Radiotherapy-based therapies might have certain advantages in treating HER2+ BC patients.

Glucose is catabolized by two fundamental pathways, glycolysis to make ATP and the oxidative pentose phosphate pathway to make reduced nicotinamide adenine dinucleotide phosphate (NADPH). The first step of the oxidative pentose phosphate pathway is catalyzed by the enzyme glucose-6-phosphate dehydrogenase (G6PD). Here we develop metabolite reporter and deuterium tracer assays to monitor cellular G6PD activity. Using these, we show that the most widely cited G6PD antagonist, dehydroepiandosterone, does not robustly inhibit G6PD in cells. We then identify a small molecule (G6PDi-1) that more effectively inhibits G6PD. Across a range of cultured cells, G6PDi-1 depletes NADPH most strongly in lymphocytes. In T cells but not macrophages, G6PDi-1 markedly decreases inflammatory cytokine production. In neutrophils, it suppresses respiratory burst. Thus, we provide a cell-active small molecule tool for oxidative pentose phosphate pathway inhibition, and use it to identify G6PD as a pharmacological target for modulating immune response.