Pan-cancer transcriptional atlas of minimal residual disease links DUSP1 to chemotherapy persistence.

Chemotherapy is a commonly effective treatment for most types of cancer. However, many patients experience a relapse due to minimal residual disease (MRD) after chemotherapy. Previous studies have analyzed the changes induced by chemotherapy for specific types of cancer, but our study is the first to comprehensively analyze MRD across various types of cancer. We included both bulk and single-cell RNA sequencing datasets. We compared the expression of the entire genome and calculated scores for canonical pathway signatures and immune infiltrates before and after chemotherapy across different types of cancer. Our findings revealed that DUSP1 was the most significantly and widely enriched gene in pan-cancer MRD. DUSP1 was found to be essential for MRD formation and played a role in T cell-fibroblast communications and the cytotoxic function of CD4 + T cells. Overall, our analysis provides a comprehensive understanding of the changes caused by chemotherapy and identifies potential targets for preventing and eliminating MRD, which could lead to long-term survival benefits for patients.

RUNX transcription factors: biological functions and implications in cancer.

Runt-related transcription factors (RUNX) are a family of transcription factors that are essential for normal and malignant hematopoietic processes. Their most widely recognized role in malignancy is to promote the occurrence and development of acute myeloid leukemia. However, it is worth noting that during the last decade, studies of RUNX proteins in solid tumors have made considerable progress, suggesting that these proteins are directly involved in different stages of tumor development, including tumor initiation, progression, and invasion. RUNX proteins also play a role in tumor angiogenesis, the maintenance of tumor cell stemness, and resistance to antitumor drugs. These findings have led to the consideration of RUNX as a tumor biomarker. All RUNX proteins are involved in the occurrence and development of solid tumors, but the role of each RUNX protein in different tumors and the major signaling pathways involved are complicated by tumor heterogeneity and the interacting tumor microenvironment. Understanding how the dysregulation of RUNX in tumors affects normal biological processes is important to elucidate the molecular mechanisms by which RUNX affects malignant tumors.

Identification of the novel biomarkers involved in the mitochondrial metabolism-related reactive oxygen species and their role in lung cancer T-cell exhaustion and immunotherapy.

Purpose: To study the role of mitochondrial metabolism and obtain novel biomarkers in immunotherapy for non-small cell lung cancer (NSCLC). Methods: We collected the 188 genes involved in mitochondrial metabolism(MMGs) from the MSIGDB project and then quantified the activity of mitochondrial metabolism. All the NSCLC patients were divided into C1 and C2 clusters based on the 26 prognosis-related MMGs. The differences in biology, differential immune microenvironment, chronic hypoxia and prognosis between C1 and C2 patients were also analyzed. In addition, we validated the results of bioinformatics analysis in lung cancer tissues and cell lines. Results: Patients in the C2 cluster had a higher level of mitochondrial metabolism. Patients in the C2 cluster responded better to immunotherapy and had a lower level of T-cell exclusion. The markers of T-cell failure were upregulated in the C1 patients. Hypoxia can lead to a high percentage of C1 patients. ADH1C might be involved in mitochondrial metabolism and immunotherapy response, which can be affected by hypoxia, making it an underlying biomarker. The expression levels of ADH1C in BEAS-2B, H1299, A549 and H460 cells were detected, revealing that ADH1C is upregulated in lung cancer cells. We observed that patients with low ADH1C expression had a longer survival time. The enzyme activities of HK, PK, LDH and SDH were significantly reduced in H1299 and H460 cells with ADH1C knockdown, along with more ROS. Furthermore, the expression levels of PD-L1 and HHLA2 in tumor tissues were analyzed, which found that ADH1C was significantly positively correlated with the expression of PD-L1 and HHLA2. Conclusions: In summary, our study comprehensively explored the molecules involved in mitochondrial metabolism and their role in immunotherapy and T lymphocyte failure.

A real-world observation on thrombopoietic agents for patients with cancer treatment-induced thrombocytopenia in China: A multicenter, cross-sectional study.

BACKGROUND: Studies on various thrombopoietic agents for cancer treatment-induced thrombocytopenia (CTIT) in China are lacking. This study aimed to provide detailed clinical profiles to understand the outcomes and safety of different CTIT treatment regimens. METHODS: In this retrospective, cross-sectional study, 1664 questionnaires were collected from 33 hospitals between March 1 and July 1, 2021. Patients aged >18 years were enrolled who were diagnosed with CTIT and treated with recombinant interleukin 11 (rhIL-11), recombinant thrombopoietin (rhTPO), or a thrombopoietin receptor agonist (TPO-RA). The outcomes, compliance, and safety of different treatments were analyzed. RESULTS: Among the 1437 analyzable cases, most patients were treated with either rhTPO alone (49.3%) or rhIL-11 alone (27.0%). The most common combination regimen used was rhTPO and rhIL-11 (10.9%). Platelet transfusions were received by 117 cases (8.1%). In multivariate analysis, rhTPO was associated with a significantly lower proportion of platelet recovery, platelet transfusion, and hospitalization due to chemotherapy-induced thrombocytopenia (CIT) than rhIL-11 alone. No significant difference was observed in the time taken to achieve a platelet count of >100 × 109/L and chemotherapy dose reduction due to CIT among the different thrombopoietic agents. The outcomes of thrombocytopenia in 170 patients who received targeted therapy and/or immunotherapy are also summarized. The results show that the proportion of platelet recovery was similar among the different thrombopoietic agents. No new safety signals related to thrombopoietic agents were observed in this study. A higher proportion of physicians preferred to continue treatment with TPO-RA alone than with rhTPO and rhIL-11. CONCLUSIONS: This survey provides an overview of CTIT and the application of various thrombopoietic agents throughout China. Comparison of monotherapy with rhIL-11, rhTPO, and TPO-RA requires further randomized clinical trials. The appropriate application for thrombopoietic agents should depend on the pretreatment of platelets, treatment variables, and risk of bleeding. PLAIN LANGUAGE SUMMARY: To provide an overview of the outcome of cancer treatment-induced thrombocytopenia in China, our cross-sectional study analyzed 1437 cases treated with different thrombopoietic agents. Most of the patients were treated with recombinant interleukin 11 (rhIL-11) and recombinant thrombopoietin (rhTPO). rhTPO was associated with a significantly lower proportion of platelet recovery and platelet transfusion compared with rhIL-11.

MUC1 and MUC16: critical for immune modulation in cancer therapeutics.

The Mucin (MUC) family, a range of highly glycosylated macromolecules, is ubiquitously expressed in mammalian epithelial cells. Such molecules are pivotal in establishing protective mucosal barriers, serving as defenses against pathogenic assaults. Intriguingly, the aberrant expression of specific MUC proteins, notably Mucin 1 (MUC1) and Mucin 16 (MUC16), within tumor cells, is intimately associated with oncogenesis, proliferation, and metastasis. This association involves various mechanisms, including cellular proliferation, viability, apoptosis resistance, chemotherapeutic resilience, metabolic shifts, and immune surveillance evasion. Due to their distinctive biological roles and structural features in oncology, MUC proteins have attracted considerable attention as prospective targets and biomarkers in cancer therapy. The current review offers an exhaustive exploration of the roles of MUC1 and MUC16 in the context of cancer biomarkers, elucidating their critical contributions to the mechanisms of cellular signal transduction, regulation of immune responses, and the modulation of the tumor microenvironment. Additionally, the article evaluates the latest advances in therapeutic strategies targeting these mucins, focusing on innovations in immunotherapies and targeted drugs, aiming to enhance customization and accuracy in cancer treatments.

The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2023.

The 2023 update of the Chinese Society of Clinical Oncology (CSCO) Clinical Guidelines for Gastric Cancer focuses on standardizing cancer diagnosis and treatment in China, reflecting the latest advancements in evidence-based medicine, healthcare resource availability, and precision medicine. These updates address the differences in epidemiological characteristics, clinicopathological features, tumor biology, treatment patterns, and drug selections between Eastern and Western gastric cancer patients. Key revisions include a structured template for imaging diagnosis reports, updated standards for molecular marker testing in pathological diagnosis, and an elevated recommendation for neoadjuvant chemotherapy in stage III gastric cancer. For advanced metastatic gastric cancer, the guidelines introduce new recommendations for immunotherapy, anti-angiogenic therapy and targeted drugs, along with updated management strategies for human epidermal growth factor receptor 2 (HER2)-positive and deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) patients. Additionally, the guidelines offer detailed screening recommendations for hereditary gastric cancer and an appendix listing drug treatment regimens for various stages of gastric cancer. The 2023 CSCO Clinical Guidelines for Gastric Cancer updates are based on both Chinese and international clinical research and expert consensus to enhance their applicability and relevance in clinical practice, particularly in the heterogeneous healthcare landscape of China, while maintaining a commitment to scientific rigor, impartiality, and timely revisions.

Comprehensive analysis of m6A modification patterns and m6A-related lncRNAs as potential biomarkers in lung adenocarcinoma.

BACKGROUND: N6-methyladenosine (m6A) methylation is considered to induce tumor cell proliferation, migration, and apoptosis. Understanding the mechanism of m6A-related lncRNAs in the development of lung adenocarcinoma (LUAD) may help predict prognosis. METHODS: m6A-related lncRNAs related to lung cancer were identified and combined with the MeRIP-Seq dataset. The consensus clustering method was utilized to divide LUAD patients, and prognostic model was constructed using the Lasso Cox algorithm. The cluster profiler package was used for gene ontology and KEGG enrichment. The proportion of immune infiltration was estimated using the CIBERSORT algorithm. The decision tree was constructed by the rpart package, and nomograms were built by the rms package. The Connectivity Map database was analyzed for the therapeutic effects of small molecule drugs for LUAD. In addition, qPCR, colony formation and transwell assays were performed to validate functions of m6A-associated lncRNAs. RESULTS: Nineteen m6A-modified lncRNAs in LUAD were identified. LUAD patients were divided into two categories based on the expression of 19 m6A-related lncRNAs. Cluster 2 patients had better antigen production and expression, while naive B cells, plasma cells, and activated NK cells were lower in cluster 1. Nine m6A-related lncRNAs were selected to establish a risk model for evaluating the prognosis of LUAD patients. The high-risk group had higher tumor mutational burden and lower TIDE scores with more gamma delta T cells and neutrophils. Nomograms showed that the prognostic model had predominant predictive ability for LUAD patients based on the risk score analyzed by the decision tree model. Benzo(a)pyrene and neurodazine might improve the prognosis of LUAD patients. The qRT-PCR results confirmed the reliability of the analytical results. CONCLUSION: The establishment of a prognostic model of m6A-related lncRNAs can independently predict overall survival in LUAD and may help to develop personalized immunotherapy strategies.

Baseline radiologic features as predictors of efficacy in patients with pancreatic neuroendocrine tumors with liver metastases receiving surufatinib.

Objective: Currently, pre-treatment prediction of patients with pancreatic neuroendocrine tumors with liver metastases (PNELM) receiving surufatinib treatment was unsatisfying. Our objective was to examine the association between radiological characteristics and efficacy/prognosis. Methods: We enrolled patients with liver metastases in the phase III, SANET-p trial (NCT02589821) and obtained contrast-enhanced computed tomography (CECT) images. Qualitative and quantitative parameters including hepatic tumor margins, lesion volumes, enhancement pattern, localization types, and enhancement ratios were evaluated. The progression-free survival (PFS) and hazard ratio (HR) were calculated using Cox's proportional hazard model. Efficacy was analyzed by logistic-regression models. Results: Among 152 patients who had baseline CECT assessments and were included in this analysis, the surufatinib group showed statistically superior efficacy in terms of median PFS compared to placebo across various qualitative and quantitative parameters. In the multivariable analysis of patients receiving surufatinib (N=100), those with higher arterial phase standardized enhancement ratio-peri-lesion (ASER-peri) exhibited longer PFS [HR=0.039; 95% confidence interval (95% CI): 0.003-0.483; P=0.012]. Furthermore, patients with a high enhancement pattern experienced an improvement in the objective response ratio [31.3% vs. 14.7%, odds ratio (OR)=3.488; 95% CI: 1.024-11.875; P=0.046], and well-defined tumor margins were associated with a higher disease control rate (DCR) (89.3% vs. 68.2%, OR=4.535; 95% CI: 1.285-16.011; P=0.019) compared to poorly-defined margins. Conclusions: These pre-treatment radiological features, namely high ASER-peri, high enhancement pattern, and well-defined tumor margins, have the potential to serve as predictive markers of efficacy in patients with PNELM receiving surufatinib.

Disturbed meningeal lymphatic function associated with malignancy and progression in patients with intracranial malignant tumors.

BACKGROUND: Meningeal lymphatic vessels (mLVs) have proven to bear a relationship with tumor immunity and therapeutic efficacy of intracranial malignant tumors in pre-clinical animal studies. We aimed to explore the association between mLV function and intracranial malignant tumors in clinical participants. METHODS: The participants were allocated to a control group or a group of patients with intracranial tumors. Dynamic enhanced magnetic resonance was used to evaluate the wash-in and wash-out functions of mLVs around the superior sagittal sinus and the sigmoid sinus. FINDINGS: A total of 246 individuals were recruited for our study. The area under curve and wash-in rate of mLVs in the intracranial tumor group were higher than in the control group (2,749 vs. 2,110, p < 0.001 and 3.72 vs. 2.87, p < 0.001, respectively). The wash-out ratio of mLVs was lower in the intracranial tumor group than in the control group (0.65 vs. 0.73, p < 0.001). Decreased wash-out of mLVs was associated with tumor progression (ß = -0.118; p < 0.001). High-grade glioma and isocitrate dehydrogenase wild type were associated with a lower mLV wash-out function (ß = -0.057, p = 0.044 and ß = -0.069, p = 0.047, respectively). CONCLUSIONS: Intracranial malignant tumors were associated with elevated wash-in function and decreased wash-out function of mLVs. High-grade glioma and isocitrate dehydrogenase wild type were associated with low mLV wash-out function, and long-term decreased mLV wash-out function was a risk factor for tumor progression. FUNDING: There was no funding.

Toripalimab Plus Chemotherapy for Recurrent or Metastatic Nasopharyngeal Carcinoma: The JUPITER-02 Randomized Clinical Trial.

Importance: There are currently no therapies approved by the US Food and Drug Administration for nasopharyngeal carcinoma (NPC). Gemcitabine-cisplatin is the current standard of care for the first-line treatment of recurrent or metastatic NPC (RM-NPC). Objective: To determine whether toripalimab in combination with gemcitabine-cisplatin will significantly improve progression-free survival and overall survival as first-line treatment for RM-NPC, compared with gemcitabine-cisplatin alone. Design, Setting, and Participants: JUPITER-02 is an international, multicenter, randomized, double-blind phase 3 study conducted in NPC-endemic regions, including mainland China, Taiwan, and Singapore. From November 10, 2018, to October 20, 2019, 289 patients with RM-NPC with no prior systemic chemotherapy in the RM setting were enrolled from 35 participating centers. Interventions: Patients were randomized (1:1) to receive toripalimab (240 mg [n = 146]) or placebo (n = 143) in combination with gemcitabine-cisplatin for up to 6 cycles, followed by maintenance with toripalimab or placebo until disease progression, intolerable toxicity, or completion of 2 years of treatment. Main Outcome: Progression-free survival as assessed by a blinded independent central review. Secondary end points included objective response rate, overall survival, progression-free survival assessed by investigator, duration of response, and safety. Results: Among the 289 patients enrolled (median age, 46 [IQR, 38-53 years; 17% female), at the final progression-free survival analysis, toripalimab treatment had a significantly longer progression-free survival than placebo (median, 21.4 vs 8.2 months; HR, 0.52 [95% CI, 0.37-0.73]). With a median survival follow-up of 36.0 months, a significant improvement in overall survival was identified with toripalimab over placebo (hazard ratio [HR], 0.63 [95% CI, 0.45-0.89]; 2-sided P = .008). The median overall survival was not reached in the toripalimab group, while it was 33.7 months in the placebo group. A consistent effect on overall survival, favoring toripalimab, was found in subgroups with high and low PD-L1 (programmed death-ligand 1) expression. The incidence of all adverse events, grade 3 or greater adverse events, and fatal adverse events were similar between the 2 groups. However, adverse events leading to discontinuation of toripalimab or placebo (11.6% vs 4.9%), immune-related adverse events (54.1% vs 21.7%), and grade 3 or greater immune-related adverse events (9.6% vs 1.4%) were more frequent in the toripalimab group. Conclusions and Relevance: The addition of toripalimab to chemotherapy as first-line treatment for RM-NPC provided statistically significant and clinically meaningful progression-free survival and overall survival benefits compared with chemotherapy alone, with a manageable safety profile. These findings support the use of toripalimab plus gemcitabine-cisplatin as the new standard of care for this patient population. Trial Registration: ClinicalTrials.gov Identifier: NCT03581786.

Revalidation of the ATTRACTION-4 study in a real-world setting: a multicenter, retrospective propensity score matching study in China.

Background: Immune-checkpoint inhibitors (ICIs) combined with chemotherapy have been successfully used in clinical trials to treat advanced gastric cancer. However, the efficacy and safety of first-line immunotherapy combined with chemotherapy in Chinese patients are unknown. Methods: This multicenter retrospective study included patients with human epidermal growth factor receptor-2 (HER-2) negative advanced gastric cancer treated with first-line chemotherapy or chemotherapy with an ICI between January 2019 and December 2022. Propensity score matching was used to compare progression-free survival (PFS), overall survival, objective response rates, and adverse reactions between cohorts. Results: After propensity score matching, 138 patients, who had balanced baseline characteristics, were included in the chemotherapy and combination treatment groups. The median follow-up duration was 16.90 months, and the median PFS was 8.53 months (95% confidence interval [CI] 7.77-9.28) in the combination treatment group and 5.97 months (95% CI 4.56-7.37) in the chemotherapy group. The median survival duration was 17.05 months (95% CI 14.18-19.92) in the combination treatment group and 16.46 months (95% CI 12.99-19.93) in the chemotherapy group. The PFS subgroup analysis revealed that age ≥65 years, women, Eastern Cooperative Oncology Group performance status of 1, non-signet ring cell carcinoma, esophagogastric junction, liver metastasis, peritoneal metastasis, no massive ascites, only one metastatic organ, and combined platinum-based chemotherapy correlated with treatment benefit. The incidences of adverse events above grade 3 were comparable between groups. Conclusions: Our study confirmed the ATTRACTION-4 trial results. Compared with chemotherapy, first-line ICIs combined with chemotherapy prolonged PFS but did not improve overall survival in patients with HER-2-negative advanced gastric cancer.

Integrated bioinformatics and validation reveal SOX12 as potential biomarker in colon adenocarcinoma based on an immune infiltration-related ceRNA network.

PURPOSE: The primary objective of this study was to construct competing endogenous RNA (ceRNA) networks and evaluate the prognostic significance of tumor-infiltrating immune cells (TIICs) and key biomarkers within the ceRNA networks in colon adenocarcinoma (COAD) patients. METHODS: Comprehensive bioinformatics tools were used to screen differentially expressed genes (DEGs), miRNAs (DEMs), and lncRNAs (DELs) related to COAD, leading to the creation of ceRNA networks. The CIBERSORT technique was employed to assess the significance of TIICs in COAD, and an immune-related prognosis prediction model was subsequently developed. Co-expression analyses were conducted to determine the relationship between key genes in ceRNA networks and immunologically significant TIICs. The study also utilized 5 GEO datasets and web-based databases to externally validate the findings. RESULTS: The study revealed a statistically significant relationship between key hub genes and immune cells, as determined through co-expression analysis. Two hub regulators (SOX12 and H19) demonstrated significant prognostic value in the ceRNA-related prognostic model, and their elevated expression levels were verified across multiple CRC cell lines. Additionally, the knockdown of SOX12 led to a suppression of proliferation, migration, and invasion in colon cancer cells. CONCLUSION: Through the construction of ceRNA networks and evaluation of TIICs, the study successfully established two risk score models and nomograms. These models serve as valuable tools for understanding the molecular processes and predicting the prognosis of COAD patients. Further validation of hub regulators SOX12 and H19 substantiates their potential role as key biomarkers in COAD.

SLC43A2 and NFκB signaling pathway regulate methionine/cystine restriction-induced ferroptosis in esophageal squamous cell carcinoma via a feedback loop.

Studies have indicated dietary restriction of methionine/cystine provided a therapeutic benefit in diseases such as cancer. However, the molecular and cellular mechanisms that underlie the interaction between methionine/cystine restriction (MCR) and effects on esophageal squamous cell carcinoma (ESCC) have remained elusive. Here, we discovered the dietary restriction of methionine/cystine has a large effect on cellular methionine metabolism as assayed in a ECA109 derived xenograft model. RNA-seq and enrichment analysis suggested the blocked tumor progression was affected by ferroptosis, together with the NFκB signaling pathway activation in ESCC. Consistently, GSH content and GPX4 expression were downregulated by MCR both in vivo and in vitro. The contents of Fe2+ and MDA were negatively correlated with supplementary methionine in a dose-dependent way. Mechanistically, MCR and silent of SLC43A2, a methionine transporter, diminished phosphorylation of IKKα/ß and p65. Blocked NFκB signaling pathway further decreased the expression of SLC43A2 and GPX4 in both mRNA and protein level, which in turn downregulated the methionine intake and stimulated ferroptosis, respectively. ESCC progression was inhibited by enhanced ferroptosis and apoptosis and impaired cell proliferation. In this study, we proposed a novel feedback regulation mechanism underlie the correlation between dietary restriction of methionine/cystine and ESCC progression. MCR blocked cancer progression via stimulating ferroptosis through the positive feedback loop between SLC43A2 and NFκB signaling pathways. Our results provided the theoretical basis and new targets for ferroptosis-based clinical antitumor treatments for ESCC patients.

The application and research progress of anti-angiogenesis therapy in tumor immunotherapy.

Tumor immunotherapy, as the focus of scientific research and clinical tumor treatment in recent years, has received extensive attention. Due to its remarkable curative effect and fewer side effects than traditional treatments, it has significant clinical benefits for the treatment of various advanced cancers and can improve cancer patient survival in the long term. Currently, most patients cannot benefit from immunotherapy, and some patients may experience tumor recurrence and drug resistance even if they achieve remission overcome. Numerous studies have shown that the abnormal angiogenesis state of tumors can lead to immunosuppressive tumor microenvironment, which affects the efficacy of immunotherapy. Actually, to improve the efficacy of immunotherapy, the application of anti-angiogenesis drugs to normalize abnormal tumor vessel has been widely confirmed in basic and clinical research. This review not only discusses the risk factors, mechanisms, and effects of abnormal and normalized tumor angiogenesis state on the immune environment, but summarizes the latest progress of immunotherapy combined with anti-angiogenic therapy. We hope this review provides an applied reference for anti-angiogenesis drugs and synergistic immunotherapy therapy.

Autophagy gene Atg7 regulates the development of radiation-induced skin injury and fibrosis of skin.

BACKGROUND: Radiation-induced skin injury, which may progress to fibrosis, is a severe side effect of radiotherapy in patients with cancer. However, currently, there is a lack of preventive or curative treatments for this injury. Meanwhile, the mechanisms underlying this injury remain poorly understood. Here, we elucidated whether autophagy is essential for the development of radiation-induced skin injury and the potential molecular pathways and mechanisms involved. METHODS AND RESULTS: We used the myofibroblast-specific Atg7 knockout (namely, conditional Atg7 knockout) mice irradiated with a single electron beam irradiation dose of 30 Gy. Vaseline-based 0.2% rapamycin ointment was topically applied once daily from the day of irradiation for 30 days. On day 30 post irradiation, skin tissues were harvested for further analysis. In vitro, human foreskin fibroblast cells were treated with rapamycin (100 nM) for 24 h and pretreated with 3-MA (5 mM) for 12 h. Macroscopic skin manifestations, histological changes, and fibrosis markers at the mRNA and protein expression levels were measured. Post irradiation, the myofibroblast-specific autophagy-deficient (Atg7Flox/Flox Cre+ ) mice had increased fibrosis marker (COL1A1, CTGF, TGF-ß1, and α-SMA) levels in the irradiated area and had more severe macroscopic skin manifestations than the control group (Atg7Flox/Flox Cre- ) mice. Treatment with an autophagy agonist rapamycin attenuated macroscopic skin injury scores and skin fibrosis marker levels with decreased epidermal thickness and dermal collagen deposition in Atg7Flox/Flox Cre+ mice compared with the vehicle control. Moreover, in vitro experiment results were consistent with the in vivo results. Together with studies at the molecular level, we found that these changes involved the Akt/mTOR pathway. In addition, this phenomenon might also relate to Nrf2-autophagy signaling pathway under oxidative stress conditions. CONCLUSION: In conclusion, Atg7 and autophagy-related mechanisms confer radioprotection, and reactivation of the autophagy process can be a novel therapeutic strategy to reduce and prevent the occurrence of radiodermatitis, particularly skin fibrosis, in patients with cancer.

MBD2 facilitates tumor metastasis by mitigating DDB2 expression.

Despite past extensive studies, the pathoetiologies underlying tumor metastasis remain poorly understood, which renders its treatment largely unsuccessful. The methyl-CpG-binding domain 2 (MBD2), a "reader" to interpret DNA methylome-encoded information, has been noted to be involved in the development of certain types of tumors, while its exact impact on tumor metastasis remains elusive. Herein we demonstrated that patients with LUAD metastasis were highly correlated with enhanced MBD2 expression. Therefore, knockdown of MBD2 significantly attenuated the migration and invasion of LUAD cells (A549 and H1975 cell lines) coupled with attenuated epithelial-mesenchymal transition (EMT). Moreover, similar results were observed in other types of tumor cells (B16F10). Mechanistically, MBD2 selectively bound to the methylated CpG DNA within the DDB2 promoter, by which MBD2 repressed DDB2 expression to promote tumor metastasis. As a result, administration of MBD2 siRNA-loaded liposomes remarkably suppressed EMT along with attenuated tumor metastasis in the B16F10 tumor-bearing mice. Collectively, our study indicates that MBD2 could be a promising prognostic marker for tumor metastasis, while administration of MBD2 siRNA-loaded liposomes could be a viable therapeutic approach against tumor metastasis in clinical settings.

Identification and in vitro and in vivo validation of the key role of GSDME in pyroptosis-related genes signature in hepatocellular carcinoma.

We used pyroptosis-related genes to establish a risk-score model for prognostic prediction of liver hepatocellular carcinoma (LIHC) patients. A total of 52 pyroptosis-associated genes were identified. Then, data for 374 LIHC patients and 50 normal individuals were acquired from the TCGA database. Through gene expression analyses, differentially expressed genes (DEGs) were determined. The 13 pyroptosis-related genes (PRGs) confirmed as potential prognostic factors through univariate Cox regression analysis were entered into Lasso and multivariate Cox regression to build a PRGs prognostic signature, containing four PRGs (BAK1, GSDME, NLRP6, and NOD2) determined as independent prognostic factors. mRNA levels were evaluated by qRT-PCR, while overall survival (OS) rates were assessed by the Kaplan-Meier method. Enrichment analyses were done to establish the mechanisms associated with differential survival status of LIHC patients from a tumor immunology perspective. Additionally, a risk score determined by the prognostic model could divide LIHC patients into low- and high-risk groups using median risk score as cut-off. A prognostic nomogram, derived from the prognostic model and integrating clinical characteristics of patients, was constructed. The prognostic function of the model was also validated using GEO, ICGC cohorts, and online databases Kaplan-Meier Plotter. Small interfering RNA-mediated knockdown of GSDME, as well as lentivirus-mediated GSDME knockdown, were performed to validate that knockdown of GSDME markedly suppressed growth of HCC cells both in vivo and in vitro. Collectively, our study demonstrated a PRGs prognostic signature that had great clinical value in prognosis assessment.

A bibliometric analysis of research on R-loop: Landscapes, highlights and trending topics.

R-loop is a necessary intermediate in specific cellular processes. To profile the landscapes, highlights, and trending topics of R-loop, publications related to R-loop from 1976 to 2022 were downloaded and bibliometric analyses were performed by Bibliometrix in R and VOSviewer. 1428 documents (including 1092 articles and 336 reviews) were included. USA, United Kingdom, and China contributed more than one-third of the publications. The annual publication increased rapidly since 2010. The research trend of R-loop has evolved from the discovery of phenomena to the exploration of molecular mechanisms, from the elucidation of biological functions to the analysis of disease correlations. Ongoing roles of R-loop in DNA repair process was highlighted and further analyzed. This study may accelerate R-loop research by highlighting important researches, understanding the trending topic, and integrating with other areas.

The role of calcium channels in prostate cancer progression and potential as a druggable target for prostate cancer treatment.

Prostate cancer (PCa) is the most diagnosed cancer among men. Discovering novel prognostic biomarkers and potential therapeutic targets are critical. Calcium signaling has been implicated in PCa progression and development of treatment resistance. Altered modification of Ca2+ flows leads to serious pathophysiological processes, such as malignant transformation, tumor proliferation, epithelial to mesenchymal transition, evasion of apoptosis, and treatment resistance. Calcium channels control and contribute to these processes. PCa has shown defective Ca2+ channels, which subsequently promotes tumor metastasis and growth. Store-operated Ca2+ entry channels such as Orai and STIM channels and transient receptor potential channels play a significant role in PCa pathogenesis. Pharmacological modulation of these calcium channels or pumps has been suggested as a practical approach. In this review, we discuss the role of calcium channels in PCa development and progression, and we identify current novel discoveries of drugs that target specific calcium channels for the treatment of PCa.

Characterization of molecular subtypes based on chromatin regulators and identification of the role of NPAS2 in lung adenocarcinoma.

BACKGROUND: Chromatin regulators (CRs) are critical epigenetic modifiers and have been reported to play critical roles during the progression of various tumors, but their role in lung adenocarcinoma (LUAD) has not been comprehensively studied. METHODS: Differential expression and univariate Cox regression analyses were conducted to identify the prognostic CRs. Consensus clustering was applied to classify the subtypes of LUAD based on prognostic CRs. LASSO-multivariate Cox regression method was used for construction of a prognostic signature and development of chromatin regulator-related gene index (CRGI). The capacity of CRGI to distinguish survival was evaluated via Kaplan-Meier method in multiple datasets. Relationship between CRGI and tumor microenvironment (TME) was evaluated. Additionally, clinical variables and CRGI were incorporated to create a nomogram. The role of the prognostic gene NPAS2 in LUAD was elucidated via clinical samples validation and a series of in vitro and in vivo experiments. RESULTS: Two subtypes of LUAD were classified based on 46 prognostic CRs via consensus clustering which had significantly different survival and TME. A prognostic signature consisting of six CRs (MOCS, PBK, CBX3, A1CF, NPAS2, and CTCFL) was developed and proved to be an effective survival predictor in multiple independent datasets. The prognostic signature was also demonstrated to be an indicator of TME and sensitivity to immunotherapy and chemotherapy. The nomogram was suggested to be a simple tool that can predict survival accurately. Clinical samples show that NPAS2 is highly expressed in LUAD tissues, and in vitro and in vivo experiments demonstrated that inhibition of NPAS2 impeded malignant progression of LUAD cells. CONCLUSIONS: Our study comprehensively unveiled the functions of CRs in LUAD, developed a classifier to predict survival and response to treatments, and suggested that NPAS2 promoted LUAD progression for the first time.