Ultrasound Viscosity Imaging in Breast Lesions: A Multicenter Prospective Study.

RATIONALE AND OBJECTIVES: To explore and validate the clinical value of ultrasound (US) viscosity imaging in differentiating breast lesions by combining with BI-RADS, and then comparing the diagnostic performances with BI-RADS alone. MATERIALS AND METHODS: This multicenter, prospective study enrolled participants with breast lesions from June 2021 to November 2022. A development cohort (DC) and validation cohort (VC) were established. Using histological results as reference standard, the viscosity-related parameter with the highest area under the receiver operating curve (AUC) was selected as the optimal one. Then the original BI-RADS would upgrade or not based on the value of this parameter. Finally, the results were validated in the VC and total cohorts. In the DC, VC and total cohorts, all breast lesions were divided into the large lesion, small lesion and overall groups respectively. RESULTS: A total of 639 participants (mean age, 46 years ± 14) with 639 breast lesions (372 benign and 267 malignant lesions) were finally enrolled in this study including 392 participants in the DC and 247 in the VC. In the DC, the optimal viscosity-related parameter in differentiating breast lesions was calculated to be A'-S2-Vmax, with the AUC of 0.88 (95% CI: 0.84, 0.91). Using > 9.97 Pa.s as the cutoff value, the BI-RADS was then modified. The AUC of modified BI-RADS significantly increased from 0.85 (95% CI: 0.81, 0.88) to 0.91 (95% CI: 0.87, 0.93), 0.85 (95% CI: 0.80, 0.89) to 0.90 (95% CI: 0.85, 0.93) and 0.85 (95% CI: 0.82, 0.87) to 0.90 (95% CI: 0.88, 0.92) in the DC, VC and total cohorts respectively (P < .05 for all). CONCLUSION: The quantitative viscous parameters evaluated by US viscosity imaging contribute to breast cancer diagnosis when combined with BI-RADS.

STEAP3 promotes colon cancer cell proliferation and migration via regulating histone acetylation.

Colorectal cancer (CRC) is the third most prevalent diagnosed cancer in men and second most prevalent cancer in women. H3K27ac alterations are more commonly than gene mutations in colorectal cancer. Most colorectal cancer genes have significant H3K27ac changes, which leads to an over-expression disorder in gene transcription. Over-expression of STEAP3 is involved in a variety of tumors, participating in the regulation of cancer cell proliferation and migration. The purpose of this work is to investigate the role of STEAP3 in the regulation of histone modification (H3K27ac) expression in colon cancer. Bioinformatic ChIP-seq, ChIP-qPCR and ATAC-seq were used to analyze the histone modification properties and gene accessibility of STEAP3. Western blot and qRT-PCR were used to evaluate relative protein and gene expression, respectively. CRISPR/Cas9 technology was used to knockout STEAP3 on colon cancer cells to analyze the effect of ATF3 on STEAP3. STEAP3 was over-expressed in colon cancer and associated with higher metastases and more invasive and worse stage of colon cancer. ChIP-seq and ChIP-qPCR analyses revealed significant enrichment of H3K27ac in the STEAP3 gene. In addition, knocking down STEAP3 significantly inhibits colon cancer cell proliferation and migration and down-regulates H3K27ac expression. ChIP-seq found that ATF3 is enriched in the STEAP3 gene and CRISPR/Cas9 technology used for the deletion of the ATF3 binding site suppresses the expression of STEAP3. Over-expression of STEAP3 promotes colon cancer cell proliferation and migration. Mechanical studies have indicated that H3K27ac and ATF3 are significantly enriched in the STEAP3 gene and regulate the over-expression of STEAP3.

Hypoxia-induced factor-1α promotes radioresistance of esophageal cancer cells by transcriptionally activating LINC01116 and suppressing miR-3612 under hypoxia.

Esophageal cancer (EC) is a challenging tumor to treat with radiotherapy, often exhibiting resistance to this treatment modality. To explore the factors influencing radioresistance, we focused on the role of hypoxia-induced factor-1α (HIF-1α), and its interaction with the long noncoding RNA long intergenic nonprotein coding RNA 1116 (LINC01116). We analyzed the LINC01116 expression in EC and EC cell lines/human normal esophageal epithelial cell line (Het-1A). LINC01116 was silenced/overexpressed in EC109/KYSE30 cells under hypoxia, followed by radioresistance assessment. We measured HIF-1α levels in hypoxic EC cells and further validated the binding of HIF-1α with LINC01116, analyzing their interaction in EC cells. We then performed experiments in EC109 cells by transfection them with sh-HIF-1α/oe-LINC01116 to verify the effects. Additonally, we analyzed the localization of LINC01116 and its binding with miR-3612, followed by a combined experiment performed to validate the results. Our findings indicated that LINC01116 was highly expressed in EC and further elevated in hypoxic EC cells. LINC01116 was expressed at a high level in EC, which was further elevated in EC cells under hypoxic conditions. Knockdown of LINC01116 triggered EC cell apoptosis, thus suppressing radioresistance. Further investigation revealed that HIF-1α transcriptionally activated LINC01116 expression under hypoxia, and silencing HIF-1α lowered EC cell radioresistance by downregulating LINC01116. Under hypoxic conditions, LINC01116 could function as a sponge for miR-3612 and inhibit its expression. This interaction between LINC01116 and miR-3612 played a crucial role in mediating radioresistance in EC cells. Briefly, under hypoxic conditions, HIF-1α facilitates radioresistance of EC cells by transcriptionally activating LINC01116 expression and downregulating miR-3612.

High expression of NOLC1 as an independent prognostic factor for survival in patients with colorectal cancer.

BACKGROUND: As a phosphorylated protein, NOLC1 is mainly located in the nucleus and is highly expressed in a variety of tumors, participating in the regulation of cell proliferation and aging. This study further investigated the role of NOLC1 in colorectal cancer tumors, aiming to provide sufficient scientific evidence for the clinical treatment of colorectal cancer. METHODS: We used TCGA, GEO, TNMplot, GEPIA, and other databases to explore the expression level of NOLC1 in colorectal cancer patients, as well as the correlation between the clinical characteristics of colorectal cancer patients and their expression, and conducted the prognostic analysis. Immunohistofluorescence (IHF) staining verified the analytical results. Subsequently, KEGG and GO enrichment analysis was used to identify the potential molecular mechanism of NOLC1 promoting the occurrence and development of colorectal cancer. The influence of NOLC1 expression on the immune microenvironment of colorectal cancer patients was further investigated using the TIMER database. GDSC database analysis was used to screen out possible anti-colorectal cancer drugs against NOLC1. Finally, we demonstrated the effect of NOLC1 on the activity and migration of colorectal cancer cells by Edu Cell proliferation assay and Wound Healing assay in vitro. RESULTS: Our results suggest that NOLC1 is overexpressed in colorectal cancer, and that overexpression of NOLC1 is associated with relevant clinical features. NOLC1, as an independent risk factor affecting the prognosis of colorectal cancer patients, can lead to a poor prognosis of colorectal cancer. In addition, NOLC1 may be associated with MCM10, HELLS, NOC3L, and other genes through participating in Wnt signaling pathways and jointly regulate the occurrence and development of colorectal cancer under the influence of the tumor microenvironment and many other influencing factors. Related to NOLC1: Selumetinib, Imatinib, and targeted drugs such as Lapatinib have potential value in the clinical application of colorectal cancer. NOLC1 enhances the proliferation and migration of colorectal cancer cells. CONCLUSIONS: High expression of NOLC1 as an independent prognostic factor for survival in patients with colorectal cancer. NOLC1 enhances the proliferation and migration of colorectal cancer cells. Further studies and clinical trials are needed to confirm the role of NOLC1 in the development and progression of colorectal cancer.

Developing a weakly supervised deep learning framework for breast cancer diagnosis with HR status based on mammography images.

The status of hormone receptors (HR) at the molecular level is crucial for accurate diagnosis and effective treatment of breast cancer. Meanwhile, mammography is an effective screening method for detecting breast cancer, which significantly improve survival. However, diagnosing the molecular status of breast cancer involves a pathological biopsy, which can affect the accuracy of the diagnosis. To non-invasively diagnose the hormone receptor (HR) status of breast cancer and reduced manual annotation, we proposed a weakly supervised deep learning framework BSNet which detected breast cancer with HR status and benign tumors. BSNet was trained on 2321 multi-view mammography cases from female undergoing digital mammography for the general population at Harbin Medical University Cancer Hospital in Heilongjiang Province during the period 2017-2018 and was validated on the external cohort. The average AUCs of BSNet on the test set and the external validation set were 0.89 and 0.92, respectively. BSNet demonstrated excellent performance in non-invasive breast cancer diagnosis with HR status, using multiple mammography views without pixel annotation. Furthermore, we developed a web server (http://bsnet.edbc.org) for easy use. BSNet described high-dimensional mammography of breast cancer subtypes, which helped inform early management options.

Prognostic and immunological role of cancer-associated fibroblasts-derived exosomal protein in esophageal squamous cell carcinoma.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are a crucial component of the tumor microenvironment (TME) and play significant roles in tumor initiation, progression, and immune evasion. Despite this, the specific exosomal proteins derived from CAFs and their functions in esophageal squamous cell carcinoma (ESCC) remain unknown. Therefore, this study aims to investigate the impact and prognostic significance of CAFs-derived exosomal proteins in ESCC. MATERIALS AND METHODS: Exosomes obtained from CAFs and normal fibroblasts (NFs) were isolated using ultracentrifugation, and the protein expression profiles of the exosomes were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Tumor proliferation was assessed using CCK-8 and colony formation assays, while cell invasion and migration were evaluated using transwell assays. Lasso regression analysis was employed to establish a signature based on CAFs-derived exosomal proteins using the TCGA database. The immunological and prognostic roles of this signature were comprehensively investigated through survival analysis, gene set enrichment analysis (GSEA), immune analysis, immunotherapy response analysis, and drug sensitivity analysis. The GSE160269 dataset was utilized for single-cell transcriptome analysis to further elucidate the role of the signature in the TME. Additionally, cDNA microarray analysis was utilized to validate the prognostic value of the signature. RESULTS: Our findings demonstrate that exosomes derived from CAFs significantly enhance the proliferation, invasion, and migration of esophageal cancer cells. We identified 842 differentially expressed exosomal proteins through LC-MS/MS analysis, and two key proteins were utilized to establish a risk signature. Survival analysis revealed a significantly worse prognosis in the high-risk group, with multivariate analysis indicating that the risk score serves as an independent prognostic factor. Moreover, we observed a significant correlation between the risk score and immune cell infiltration, immunotherapy response, and sensitivity to chemotherapeutic treatments in the study population. Lastly, single-cell transcriptome analysis further revealed the expression patterns of TNFRSF10B and ILF3 in different cell subpopulations. CONCLUSION: In conclusion, our study has successfully established a robust prognostic signature based on CAFs-derived exosomal proteins, which can serve as a reliable biomarker for predicting prognosis and evaluating the immune microenvironment in ESCC.

Precise subtyping reveals immune heterogeneity for hormone receptor-positive breast cancer.

A significant proportion of breast cancer cases are characterized by hormone receptor positivity (HR+). Clinically, the heterogeneity of HR+ breast cancer leads to different therapeutic effects on endocrine. Therefore, definition of subgroups in HR+ breast cancer is important for effective treatment. Here, we have developed a CMBR method utilizing computational functional networks based on DNA methylation to identify conserved subgroups in HR+ breast cancer. Calculated by CMBR, HR+ breast cancer was divided into five subgroups, of which HR+/negative epidermal growth factor receptor-2 (Her2-) was divided into two subgroups, and HR+/positive epidermal growth factor receptor-2 (Her2+) was divided into three subgroups. These subgroups had heterogeneity in the immune microenvironment, tumor infiltrating lymphocyte patterns, somatic mutation patterns and drug sensitivity. Specifically, CMBR identified two subgroups with the "Hot" tumor phenotype. In addition, these conserved subgroups were broadly validated on external validation datasets. CMBR identified the molecular signature of HR+ breast cancer subgroups, providing valuable insights into personalized treatment strategies and management options.

The prediction of drug sensitivity by multi-omics fusion reveals the heterogeneity of drug response in pan-cancer.

Cancer drug response prediction based on genomic information plays a crucial role in modern pharmacogenomics, enabling individualized therapy. Given the expensive and complexity of biological experiments, computational methods serve as effective tools in predicting cancer drug sensitivity. In this study, we proposed a novel method called Multi-Omics Integrated Collective Variational Autoencoders (MOICVAE), which leverages integrated omics knowledge, including genomic and transcriptomic data, to fill in missing cancer-drug associations and enhance drug sensitivity prediction. Our method employs an encoder-decoder network to learn latent feature representations from cell lines. These learned feature vectors are then fed into a collective variational autoencoder network to train an association matrix. We evaluated MOICVAE on the GDSC and CCLE benchmark datasets using 10-fold cross-validation and achieved impressive AUCs of 0.856 and 0.808, respectively, outperforming state-of-the-art methods. Furthermore, on the TCGA dataset, consisting of 25 drugs across 7 cancer types, MOICVAE exhibited an average AUC of 0.91 in predicting drug sensitivity. Additionally, significant differences were observed in survival, tumor inflammatory assessment, and tumor microenvironment between the predicted drug-sensitive and drug-resistant groups. These results are consistent with predictions made on the METABRIC dataset. Moreover, we discovered that fusing omics data based on mRNA and CNV (copy number variations) yielded superior results in drug sensitivity prediction. MOICVAE not only achieved higher accuracy in drug sensitivity prediction but also provided additional value for combining immunotherapy with chemotherapy, offering patients with more precise treatment options. The code and dataset for MOICVAE are freely available at https://github.com/wanggnoc/MOICVAE.

Advanced Glycation End Products' Receptor DNA Methylation Associated with Immune Infiltration and Prognosis of Lung Adenocarcinoma and Lung Squamous Cell Carcinoma.

Background: Advanced glycation end products' receptor (AGER) is a multiligand receptor that interacts with a wide range of ligands. Previous studies have shown that abnormal AGER expression is closely related to immune infiltration and tumorigenesis. However, the AGER DNA methylation relationship between prognosis and infiltrating immune cells in LUAD and LUSC is still unclear. Methods: AGER expression in pan-cancer was obtained by using the UALCAN databases. Kaplan-Meier plotter showed the correlation of AGER mRNA expression levels and clinicopathological parameters. The protein expression levels for AGER were derived from Human Protein Atlas Database Analysis. The copy number, somatic mutation, and DNA methylation of AGER were presented with UCSC Xena database. TIMER platform and TISIDB website were used to show the correlation between AGER expression and tumor immune cell infiltration level. Results: The expression level of AGER was significantly reduced in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Low expression of AGER was significantly correlated with histology, stage, lymph node metastasis, and tumor protein 53 (TP53) mutation and could be used as a potential indicator of poor prognosis of LUAD and LUSC. Moreover, AGER expression was positively correlated with the infiltrating immune cells. Further analysis showed that copy number variation (CNV), mutation, and DNA methylation were involved in AGER downregulation. In addition, we also found that hypermethylated AGER was significantly correlated with tumor-infiltrating lymphocytes. Conclusion: AGER may be a candidate for the prognostic biomarker of LUAD and LUSC related to tumor immune microenvironment.

Are high-risk heavy metal(loid)s contaminated vegetables detrimental to human health? A study of incorporating bioaccessibility and toxicity into accurate health risk assessment.

Heavy metal(loid)s in the environment threaten food safety and human health. Health risk assessment of vegetables based on total or bioaccessible heavy metal(loid)s was widely used but can overestimate their risks, so exploring accurate methods is urgent for food safety evaluation and management. In this study, a total of 224 frequently consumed vegetables and their corresponding grown soils were collected from Yunnan, Southwest China. The total contents and bioaccessibilities of heavy metal(loid)s in vegetables were measured, their health risks were evaluated using the non-carcinogenic and carcinogenic risk models provided by USEPA. Besides, the gastrotoxicity of high-risk vegetables was also evaluated using a human cell model. Results showed that 6.25-43.8 % of Cr, Cd, and Pb contents in Zea mays L., Coriandrum sativum L., or Allium sativum L. exceeded the maximum permissible level of China, which were not consistent with those in corresponding soils. The bioaccessibility of Cr, Cd, As, Pb, Cu, Zn, Ni, and Mn in vegetables in the gastric phase was 0.41-93.8 %. Health risks based on bioaccessibility were remarkably decreased compared with total heavy metal(loid)s, but the unacceptable carcinogenic risk (CR > 10-4) was found even considering the bioaccessibility. Interestingly, gastric digesta of high-risk vegetables did not trigger adverse effects on human gastric mucosa epithelial cells, indicating existing health risk assessment model should be adjusted by toxic data to accurately reflect its hazards. Taken together, both bioaccessibility and toxicity of heavy metal(loid)s in vegetables should be considered in accurate health risk assessment and food safety-related policy-making and management.

Developing CuS for Predicting Aggressiveness and Prognosis in Lung Adenocarcinoma.

Cuproptosis is a newfound cell death form that depends on copper (Cu) ionophores to transport Cu into cancer cells. Studies on the relationship have covered most common cancer types and analyzed the links between cuproptosis-related genes (CRGs) and various aspects of tumor characteristics. In this study, we evaluated the role of cuproptosis in lung adenocarcinoma (LUAD) and constructed the cuproptosis-related score (CuS) to predict aggressiveness and prognosis in LUAD, so as to achieve precise treatment for patients. CuS had a better predictive performance than cuproptosis genes, possibly due to the synergy of SLC family genes, and patients with a high CuS had a poor prognosis. Functional enrichment analysis revealed the correlation between CuS and immune and mitochondrial pathways in multiple datasets. Furthermore, we predicted six potential drugs targeting high-CuS patients, including AZD3759, which is a targeted drug for LUAD. In conclusion, cuproptosis is involved in LUAD aggressiveness, and CuS can accurately predict the prognosis of patients. These findings provide a basis for precise treatment of patients with high CuS in LUAD.

Systemic Immune-Inflammatory Index, Tumor-Infiltrating Lymphocytes, and Clinical Outcomes in Esophageal Squamous Cell Carcinoma Receiving Concurrent Chemoradiotherapy.

Background: Systemic inflammation may be involved in the entire cancer process as a promoter and is associated with antitumor immunity. The systemic immune-inflammation index (SII) has been shown to be a promising prognostic factor. However, the relationship between SII and tumor-infiltrating lymphocytes (TIL) have not been established in esophageal cancer (EC) patients receiving concurrent chemoradiotherapy (CCRT). Methods: Retrospective analysis of 160 patients with EC was performed, peripheral blood cell counts were collected, and TIL concentration was assessed in H&E-stained sections. Correlations of SII and clinical outcomes with TIL were analyzed. Cox proportional hazard model and Kaplan-Meier method were used to perform survival outcomes. Results: Compared with high SII, low SII had longer overall survival (OS) (P = 0.036, hazard ratio (HR) = 0.59) and progression-free survival (PFS) (P = 0.041, HR = 0.60). Low TIL showed worse OS (P < 0.001, HR = 2.42) and PFS (P < 0.001, HR = 3.05). In addition, research have shown that the distribution of SII, platelet-to-lymphocyte ratio, and neutrophil-to-lymphocyte ratio were negatively associated with the TIL state, while lymphocyte-to-monocyte ratio presented a positive correlation. Combination analysis observed that SIIlow + TILhigh had the best prognosis of all combinations, with a median OS and PFS of 36 and 22 months, respectively. The worst prognosis was identified as SIIhigh + TILlow, with a median OS and PFS of only 8 and 4 months. Conclusion: SII and TIL as independent predictors of clinical outcomes in EC receiving CCRT. Furthermore, the predictive power of the two combinations is much higher than a single variable.

Clinical outcomes and toxicities of locally advanced esophageal squamous cell carcinoma patients treated with early thoracic radiation therapy after induction chemotherapy.

OBJECTIVE: The purpose of this study was to compare the clinical outcomes and toxicities between induction chemotherapy (IC) + chemo-radiotherapy (CRT) and CRT alone in patients with locally advanced esophageal squamous cell carcinoma (ESCC), to explore the appropriate thoracic radiotherapy (TRT) timing after IC and to identify prognostic factors. METHODS: 450 ESCC patients were included from September 2011 to December 2020, 238 of whom received IC/CRT. Propensity score matching was performed to balance potential confounders between the two groups. Multivariate Cox regression analysis was used to identify the independent prognostic factors. RESULTS: Patients who received IC/CRT experienced improved overall survival (OS) (38.5 vs. 28.8 months) and progression-free survival (PFS) (41.0 vs. 22.0 months) before matching, with similar results after matching. In the IC/CRT group, early TRT had more favorable survival than late TRT both matching before and after. In subgroup analysis, early TRT combination concurrent chemotherapy had better OS and PFS than late TRT combination concurrent chemotherapy. In addition, early TRT had better survival benefits regardless of the N stage. Notably, the IC/CRT group and early TRT group had manageable toxicities reaction compared with CRT alone group and the late TRT group. The nomogram was developed to predict the OS and PFS based on multivariate analysis results. The C-index was 0.743 and 0.722, respectively. CONCLUSION: IC/CRT and early TRT could yield satisfactory clinical outcomes and controllable toxicities in locally advanced ESCC. The IC plus early concurrent CRT might be a promising treatment strategy for improving further survival in ESCC.

Heavy metal(loid)s in agricultural soil from main grain production regions of China: Bioaccessibility and health risks to humans.

Unintentional ingestion of metal-contaminated soils may pose a great threat to human health. To accurately evaluate the health risks of heavy metal(loid)s in soils, their bioaccessibility has been widely determined by in vitro assays and increasingly employed to optimize the assessment parameters. Given that, using meta-analysis, we analyzed the literature on farmland heavy metal(loid)s (As, Cd, Cr, Cu, Hg, Pb, Ni, and Zn) in Chinese main grain production regions, and collected their total and bioaccessibility data to accurately assess their human health risks. Monte Carlo simulation was used to reduce the uncertainty in metal concentration, intake rate, toxicity coefficient, and body weight. We found that the mean concentration (0.47 mg/kg) and geological accumulation index (Igeo, 0-5.24) of Cd were the priority position of controlling metals. Moreover, children are more vulnerable to carcinogenic risks than adults. Soil mineralogy, physicochemical properties, Fe, and the types of in vitro assays are the influencing factors of bioaccessibility discrepancy. Furthermore, appropriate bioaccessibility determination methods can be adapted according to the differences in ecological receptors for the risk assessment, like developing a "personalized assessment" scheme for polluted farmland soil management. Collectively, bioaccessibility-based models may provide an accurate and effective approach to human health risk assessment.

Excavation of Molecular Subtypes of Endometrial Cancer Based on DNA Methylation.

Tumor heterogeneity makes the diagnosis and treatment of endometrial cancer difficult. As an important modulator of gene expression, DNA methylation can affect tumor heterogeneity and, therefore, provide effective information for clinical treatment. In this study, we explored specific prognostic clusters based on 482 examples of endometrial cancer methylation data in the TCGA database. By analyzing 4870 CpG clusters, we distinguished three clusters with different prognostics. Differences in DNA methylation levels are associated with differences in age, grade, clinical pathological staging, and prognosis. Subsequently, we screened out 264 specific hypermethylation and hypomethylation sites and constructed a prognostic model for Bayesian network classification, which corresponded to the classification of the test set to the classification results of the train set. Since the tumor microenvironment plays a key role in determining immunotherapy responses, we conducted relevant analyses based on clusters separated from DNA methylation data to determine the immune function of each cluster. We also predicted their sensitivity to chemotherapy drugs. Specific classifications of DNA methylation may help to address the heterogeneity of previously existing molecular clusters of endometrial cancer, as well as to develop more effective, individualized treatments.

ARID1A downregulation promotes cell proliferation and migration of colon cancer via VIM activation and CDH1 suppression.

According to our prior findings, ARID1A expression is decreased in colon cancer, which has a poor prognosis. In this study, we investigated the ARID1A-VIM/CDH1 signalling axis's role in colon cancer proliferation and migration. The differentially expressed genes in cells that might be controlled by ARID1A were discovered by a database screening for ARID1A knockout. qPCR was used to analyse ARID1A and EMT markers expression levels in colon cancer. We utilized siRNA RID1A to explore the influence of ARID1A silencing on EMT in CRC cells. The function of ARID1A in the colon was investigated utilizing the wound healing, transwell and CCK-8 WST- assays. The molecular mechanism by which ARID1A regulates VIM and CDH1 was elucidated using chip-qPCR. Numerous genes involved in EMT were dysregulated in the absence of ARID1A. VIM expression increased in cells lacking ARID1A expression and vice versa. Many COAD samples with high ARID1A mRNA expression had low VIM mRNA expression, despite the relevance. CDH1 gene was positively correlated with ARID1A. Moreover, siRNA-ARID1A-transfected cells accelerated cell migration and invasion and increased cell proliferation rate in vitro. Chip-qPCR analysis showed that ARID1A binds to the promoters of both genes and changes their expression in colon cancer. ARID1A inactivation is associated with VIM activation and CDH1 suppression, which might serve as crucial molecules influencing COAD prognosis, accelerate tumour progression, and shorten patients' survival time, and promote metastases of COAD. Thus, depletion of ARID1A can be therapeutically exploited by targeting downstream effects to improve cancer treatment-related outcomes.

Classification of Subgroups with Immune Characteristics Based on DNA Methylation in Luminal Breast Cancer.

Luminal breast cancer (BC) accounts for a large proportion of patients in BC, with high heterogeneity. Determining the precise subtype and optimal selection of treatment options for luminal BC is a challenge. In this study, we proposed an MSBR framework that integrate DNA methylation profiles and transcriptomes to identify immune subgroups of luminal BC. MSBR was implemented both on a key module scoring algorithm and "Boruta" feature selection method by DNA methylation. Luminal A was divided into two subgroups and luminal B was divided into three subgroups using the MSBR. Furthermore, these subgroups were defined as different immune subgroups in luminal A and B respectively. The subgroups showed significant differences in DNA methylation levels, immune microenvironment (immune cell infiltration, immune checkpoint PD1/PD-L1 expression, immune cell cracking activity (CYT)) and pathology features (texture, eccentricity, intensity and tumor-infiltrating lymphocytes (TILs)). The results also showed that there is a subgroup in both luminal A and B that has the benefit from immunotherapy. This study proposed a classification of luminal BC from the perspective of epigenetics and immune characteristics, which provided individualized treatment decisions.

DNA Methylation-Specific Analysis of G Protein-Coupled Receptor-Related Genes in Pan-Cancer.

Tumor heterogeneity presents challenges for personalized diagnosis and treatment of cancer. The identification method of cancer-specific biomarkers has important applications for the diagnosis and treatment of cancer types. In this study, we analyzed the pan-cancer DNA methylation data from TCGA and GEO, and proposed a computational method to quantify the degree of specificity based on the level of DNA methylation of G protein-coupled receptor-related genes (GPCRs-related genes) and to identify specific GPCRs DNA methylation biomarkers (GRSDMs) in pan-cancer. Then, a ridge regression-based method was used to discover potential drugs through predicting the drug sensitivities of cancer samples. Finally, we predicted and verified 8 GRSDMs in adrenocortical carcinoma (ACC), rectum adenocarcinoma (READ), uveal Melanoma (UVM), thyroid carcinoma (THCA), and predicted 4 GRSDMs (F2RL3, DGKB, GRK5, PIK3R6) which were sensitive to 12 potential drugs. Our research provided a novel approach for the personalized diagnosis of cancer and informed individualized treatment decisions.

Blocking exosomal secretion aggravates 1,4-benzoquinone-induced mitochondrial fission activated by the AMPK/MFF/Drp1 pathway in HL-60 cells.

There is in vivo and in vitro evidence that exposure to benzene or its metabolites could affect the mitochondrial function. However, the underlying molecular mechanism of mitochondrial damage remains to be elucidated. In this study, exposure of human promyelocytic leukemia cells (HL-60) to 1,4-benzoquinone (1,4-BQ; an active metabolite of benzene) increased the intracellular reactive oxygen species levels, decreased the mitochondrial membrane potential, adenosine triphosphate production and mitochondrial DNA (mtDNA) copy number, up-regulated the expression of mitochondrial fission proteins Drp1 and Fis1, and down-regulated the expression of mitochondrial fusion proteins Mfn2 and Opa1. Further study showed that 1,4-BQ mediated mitochondrial fission through activation of the AMP-activated protein kinase/mitochondrial fission factor/dynamin-related protein 1 pathway. Additionally, we also examined the role of exosomal secretion in mitochondrial damage under 1,4-BQ treatment. Results showed that 1,4-BQ increased the total protein level and mtDNA content in exosomes. Upon pre-treatment with the mitochondria-targeted antioxidant SS-31, there was attenuation of the mitochondrial damage induced by 1,4-BQ, accompanied by a change in the exosome release characteristics, while inhibition of exosomal secretion using GW4869 aggravated the 1,4-BQ-mediated mitochondrial fission. We concluded that exosomal secretion may serve as a self-protective mechanism of cells against 1,4-BQ-induced mitochondria damage and mitochondrial dynamics interference.

Prognostic significance of platelet-to-albumin ratio in patients with esophageal squamous cell carcinoma receiving definitive radiotherapy.

Accumulating evidence indicates that inflammation and nutrition status are associated with clinical outcomes in patients with various malignancies. This study aimed to evaluate the prognostic significance of the pretreatment platelet to albumin ratio (PAR) in esophageal squamous cell carcinoma (ESCC) patients undergoing definitive radiotherapy. A total of 470 patients who underwent definitive radiotherapy with or without chemotherapy were enrolled. The optimal cut-off values of PAR and other indicators were determined by the X-tile. The Kaplan-Meier method, multivariate analyses Cox regression were conducted to identify the association between those indicators and the survival outcomes. The median follow-up time was 23.5 months. The optimal cut-off value of PAR was 5.7 × 109 and patients were stratified as the low PAR group and the high PAR group. In the univariate analysis, a low overall survival rate was significantly associated with T stage (P = 0.005), TNM stage (P < 0.001), Adjuvant chemotherapy (P = 0.007), neutrophil to lymphocyte ratio (NLR) (P = 0.006), platelet to lymphocyte ratio (P < 0.001), systemic immune-inflammation index (P < 0.001), prognostic nutritional index (P < 0.001) and platelet to albumin ratio (PAR) (P < 0.001). Patients with high PAR were associated with poorer OS and PFS than patients with low PAR. On multivariate analysis, TNM stage (P = 0.001), adjuvant chemotherapy (P < 0.001), and PAR (P = 0.033) were independent prognostic factors in ESCC treated with definitive radiotherapy. PAR is a novel, convenient, and inexpensive prognostic indicator for patients with ESCC undergoing definitive radiotherapy. Future validation from prospective larger-scale studies is warranted.