RSPO2-associated mitochondrial metabolism defines molecular subtypes with distinct clinical and immune features in esophageal cancer.

BACKGROUND: Esophageal cancer is a highly aggressive malignancy with limited treatment options and poor prognosis. The identification of novel molecular subtypes and therapeutic targets is crucial for improving clinical outcomes. METHOD: In this study, we investigated the role of R-spondin 2 (RSPO2) in esophageal cancer and its association with mitochondrial metabolism. Using bioinformatics analysis of publicly available datasets, we identified a panel of RSPO2-related mitochondrial metabolism genes and their expression patterns in esophageal cancer. Based on these genes, we stratified esophageal cancer patients into distinct molecular subtypes with different survival rates, immune cell infiltration profiles, and drug sensitivities. RESULTS: Our findings suggest that RSPO2-related mitochondrial metabolism genes may serve as potential therapeutic targets and prognostic markers for esophageal cancer. These genes play an important role in the prognosis, immune cell infiltration and drug sensitivity of esophageal cancer. CONCLUSION: The identified molecular subtypes provide valuable insights into the underlying molecular mechanisms of esophageal cancer and could guide personalized treatment strategies in the future.

The m6 A modification of Il17a in CD4+ T cells promotes inflammation in psoriasis.

Psoriasis is a chronic inflammatory skin disorder. The mechanism of psoriasis pathogenesis is not entirely clear. Here, we reported that the level of the N6-methyladenosine (m6 A) modification was increased in psoriatic CD4+ T cells compared with healthy controls. In the psoriasis mouse model, depletion of the RNA demethylase, Alkbh5, from CD4+ T cells promoted the psoriasis-like phenotype and inflammation. Intriguingly, this phenotype and inflammation were alleviated by the ablation of the m6 A methyltransferase Mettl3 in CD4+ T cells. Mechanistically, we found that the m6 A modification of IL17A mRNA increased the expression of IL-17A (an important pro-inflammatory factor in psoriasis) and promoted psoriasis. Thus, our study provided evidence that the m6 A modification of IL17A in CD4+ T cells regulates inflammation in psoriasis.

A novel DNA methylation marker to identify lymph node metastasis of colorectal cancer.

Lymph node metastasis (LNM) of colorectal cancer (CRC) is an important factor for both prognosis and treatment. Given the deficiencies of conventional tests, we aim to discover novel DNA methylation markers to efficiently identify LNM status of CRC. In this study, genome-wide methylation sequencing was performed in a cohort (n=30) using fresh CRC tissue to discover differentially methylated markers. These markers were subsequently validated with fluorescence quantitative PCR in a cohort (n=221), and the optimal marker was compared to conventional diagnostic methods. Meanwhile, immunohistochemistry was used to verify the effectiveness of the antibody corresponding to this marker in a cohort (n=56). LBX2 achieved an AUC of 0.87, specificity of 87.3%, sensitivity of 75.7%, and accuracy of 81.9%, which outperformed conventional methods including imaging (CT, PET-CT) with an AUC of 0.52, CA199 with an AUC of 0.58, CEA with an AUC of 0.56. LBX2 was also superior to clinicopathological indicators including the depth of tumor invasion and lymphatic invasion with an AUC of 0.61and 0.63 respectively. Moreover, the AUC of LBX2 antibody was 0.84, which was also better than these conventional methods. In conclusion, A novel methylation marker LBX2 could be used as a simple, cost-effective, and reliable diagnostic method for LNM of CRC.

A novel DNA methylation signature associated with lymph node metastasis status in early gastric cancer.

BACKGROUND: Lymph node metastasis (LNM) is an important factor for both treatment and prognosis of early gastric cancer (EGC). Current methods are insufficient to evaluate LNM in EGC due to suboptimal accuracy. Herein, we aim to identify methylation signatures for LNM of EGC, facilitate precision diagnosis, and guide treatment modalities. METHODS: For marker discovery, genome-wide methylation sequencing was performed in a cohort (marker discovery) using 47 fresh frozen (FF) tissue samples. The identified signatures were subsequently characterized for model development using formalin-fixed paraffin-embedded (FFPE) samples by qPCR assay in a second cohort (model development cohort, n = 302, training set: n = 151, test set: n = 151). The performance of the established model was further validated using FFPE samples in a third cohorts (validation cohort, n = 130) and compared with image-based diagnostics, conventional clinicopathology-based model (conventional model), and current standard workups. RESULTS: Fifty LNM-specific methylation signatures were identified de novo and technically validated. A derived 3-marker methylation model for LNM diagnosis was established that achieved an AUC of 0.87 and 0.88, corresponding to the specificity of 80.9% and 85.7%, sensitivity of 80.6% and 78.1%, and accuracy of 80.8% and 83.8% in the test set of model development cohort and validation cohort, respectively. Notably, this methylation model outperformed computed tomography (CT)-based imaging with a superior AUC (0.88 vs. 0.57, p < 0.0001) and individual clinicopathological features in the validation cohort. The model integrated with clinicopathological features demonstrated further enhanced AUCs of 0.89 in the same cohort. The 3-marker methylation model and integrated model reduced 39.4% and 41.5% overtreatment as compared to standard workups, respectively. CONCLUSIONS: A novel 3-marker methylation model was established and validated that shows diagnostic potential to identify LNM in EGC patients and thus reduce unnecessary gastrectomy in EGC.

A meta-analysis of bone-patellar tendon-bone autograft versus four-strand hamstring tendon autograft for anterior cruciate ligament reconstruction.

BACKGROUND: There is a lack of comprehensive studies comparing the clinical outcome of anterior cruciate ligament (ACL) reconstruction with either a bone-patellar tendon-bone (BPTB) or four-strand hamstring tendon (4SHT) autografts. The optimal choice of graft for anterior cruciate ligament reconstruction remains controversial. PURPOSE: The objective of this study was to evaluate the effectiveness of BPTB autografts versus 4SHT autografts for the reconstruction of ACL. METHODS: A systematical search of literature was performed in Pubmed, Embase, and the Cochrane library to identify published clinical prospective studies relevant to ACL reconstruction comparing BPTB and 4SHT autografts. The results of the eligible studies were analysed in terms of instrumented laxity measurements, Lachman test, pivot shift test, objective International Knee Documentation Committee (IKDC) scores, return to preinjury activity level, and morbidity of graft failure, anterior knee pain, kneeling pain, extension deficit, and flexion deficit. Study quality was assessed by using the Jadad scale for randomized clinical trial (RCT) and the Newcastle-Ottawa Scale (NOS) for prospective cohort study (PCS). Two reviewers independently assessed each study for quality and extracted data. Subgroup analysis of the primary outcomes was conducted according to the type of study design (RCT or PCS). RESULTS: Twenty-two studies, with 931 patients in the BPTB group and 999 patients in the 4SHT group, met the inclusion criteria. Fourteen studies were randomized controlled trials, and eight were prospective cohort studies. The results of the meta-analysis showed that there were no significant differences between BPTB and 4SHT in terms of instrumented laxity measurements (P=0.06), Lachman test (P=0.58), objective IKDC scores (P=0.31), graft failure (P=0.45), extension deficit (P=0.06) and flexion deficit (P=0.63). However, outcomes in favour of BPTB were found in terms of pivot shift test (P=0.01) and return to preinjury activity level (P=0.03); outcome measures that favours 4SHT included anterior knee pain (P<0.01) and kneeling pain (P<0.01). These findings were still robust during the sensitivity analysis. Results from subgroup analysis of the primary outcomes were consistent with the overall analysis. CONCLUSION: Based on the results above, ACL reconstruction with BPTB autografts might be superior in resuming rotation stability of the knee joint and allow patients to return to higher levels of activity in comparison with 4SHT autografts. Whereas, postoperative complications of the knee joint were lower for 4SHT autografts than for BPTB autografts. There was insufficient evidence to identify which of the two types of grafts was significantly better for ACL reconstruction considering the limitations of this study. More high-quality randomized controlled trials with strictly specified inclusion criteria are highly required before drawing a reliable conclusion.