The transition of surgical simulation training and its learning curve: a bibliometric analysis from 2000 to 2023.

BACKGROUND: Proficient surgical skills are essential for surgeons, making surgical training an important part of surgical education. The development of technology promotes the diversification of surgical training types. This study analyzes the changes in surgical training patterns from the perspective of bibliometrics, and applies the learning curves as a measure to demonstrate their teaching ability. METHOD: Related papers were searched in the Web of Science database using the following formula: TS=((training OR simulation) AND (learning curve) AND (surgical)). Two researchers browsed the papers to ensure that the topics of articles were focused on the impact of surgical simulation training on the learning curve. CiteSpace, VOSviewer and R packages were applied to analyze the publication trends, countries, authors, keywords and references of selected articles. RESULT: Ultimately, 2461 documents were screened and analyzed. The USA is the most productive and influential country in this field. Surgical endoscopy and other interventional techniques publish the most articles, while surgical endoscopy and other interventional techniques is the most cited journal. Aggarwal Rajesh is the most productive and influential author. Keyword and reference analyses reveal that laparoscopic surgery, robotic surgery, virtue reality (VR) and artificial intelligence (AI) were the hotspots in the field. CONCLUSION: This study provided a global overview of the current state and future trend in the surgical education field. The study surmised the applicability of different surgical simulation types by comparing and analyzing the learning curves, which is helpful for the development of this field.

Enterotoxin-related genes PPFIA4 and SCN3B promote colorectal cancer development and progression.

To identify the role of enterotoxin-related genes in colorectal cancer (CRC) development and progression. Upregulated differentially expressed genes shared by three out of five Gene Expression Omnibus (GEO) data sets were included to screen the key enterotoxin-induced oncogenes (EIOGs) according to criteria oncogene definition, enrichment, and protein-protein interaction (PPI) network analysis, followed by prognosis survival, immune infiltration, and protential drugs analyses was performed via integration of RNA-sequencing data and The Cancer Genome Atlas-derived clinical profiles. We screened nine common key EIOGs from at least three GEO data sets. A Cox proportional hazards regression models verified that more alive cases, decreased overall survival, and highest 4-year survival prediction in CRC patients with high-risk score. Protein tyrosine phosphatase receptor type F polypeptide-interacting protein alpha-4 (PPFIA4), STY11, SCN3B, and SPTBN5 were shared in the same PPI network. Immune infiltration results showed that SCN3B and synaptotagmin 11 expression were obviously associated with B cell, macrophage, myeloid dendritic cell, neutrophils, and T cell CD4+ and CD8+ in both colon adenocarcinoma and rectal adenocarcinoma. CHIR-99021, MLN4924, and YK4-279 were identified as the potential drugs for treatment. Finally, upregulated EIOGs genes PPFIA4 and SCN3B were found in colon adenocarcinoma and PPFIA4 and SCN3B were proved to promote cell proliferation and migration in vitro. We demonstrated here that EIOGs promoting a malignancy phenotype was related with poor survival and prognosis in CRC, which might be served as novel therapeutic targets in CRC management.

Genetically predicted blood metabolites mediate the association between circulating immune cells and pancreatic cancer: A Mendelian randomization study.

BACKGROUND: Pancreatic cancer is characterized by metabolic dysregulation and unique immunological profiles. Nevertheless, the comprehensive understanding of immune and metabolic dysregulation of pancreatic cancer remains unclear. In the present study, we aimed to investigate the causal relationship of circulating immune cells and pancreatic cancer and identify the blood metabolites as potential mediators. METHODS: The exposure and outcome genome-wide association studies (GWAS) data used in the present study were obtained from the GWAS open-access database (https://gwas.mrcieu.ac.uk). The study used 731 circulating immune cell features, 1400 types of blood metabolites and pancreatic cancer from GWAS. We then performed bidirectional Mendelian randomization (MR) analyses to explore the causal relationships between the circulating immune cells and pancreatic cancer, and two-step MR to discover potential mediating blood metabolites in this process. All statistical analyses were performed in R software. The STROBE-MR (i.e. Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomization) checklist for the reporting of MR studies was also used. RESULTS: MR analysis identified seven types of circulating immune cells causally associated with pancreatic cancer. Furthermore, there was no strong evidence that genetically predicted pancreatic cancer had an effect on these seven types of circulating immune cells. Further two-step MR analysis found 10 types of blood metabolites were causally associated with pancreatic cancer and the associations between circulating CD39+CD8+ T cells and pancreatic cancer were mediated by blood orotates with proportions of 5.18% (p = 0.016). CONCLUSIONS: The present study provides evidence supporting the causal relationships between various circulating immune cells, especially CD39+CD8+ T cells, and pancreatic cancer, with a potential effect mediated by blood orotates. Further research is needed on additional risk factors as potential mediators and establish a comprehensive immunity-metabolism network in pancreatic cancer.

CD3, CD8, IFN-γ, tumor and stroma inflammatory cells as prognostic indicators for surgically resected SCLC: evidences from a 10-year retrospective study and immunohistochemical analysis.

Current clinical guidelines limit surgical intervention to patients with cT1-2N0M0 small cell lung cancer (SCLC). Our objective was to reassess the role of surgery in SCLC management, and explore novel prognostic indicators for surgically resected SCLC. We reviewed all patients diagnosed with SCLC from January 2011 to April 2021 in our institution. Survival analysis was conducted using the Kaplan-Meier method, and independent prognostic factors were assessed through the Cox proportional hazard model. In addition, immunohistochemistry (IHC) staining was performed to evaluate the predictive value of selected indicators in the prognosis of surgically resected SCLC patients. In the study, 177 SCLC patients undergoing surgical resection were ultimately included. Both univariate and multivariate Cox analysis revealed that incomplete postoperative adjuvant therapy emerged as an independent risk factor for adverse prognosis (p < 0.001, HR 2.96). Survival analysis revealed significantly superior survival among pN0-1 patients compared to pN2 patients (p < 0.0001). No significant difference in postoperative survival was observed between pN1 and pN0 patients (p = 0.062). Patients with postoperative stable disease (SD) exhibited lower levels of tumor inflammatory cells (TIC) (p = 0.0047) and IFN-γ expression in both area and intensity (p < 0.0001 and 0.0091, respectively) compared to those with postoperative progressive disease (PD). Conversely, patients with postoperative SD showed elevated levels of stromal inflammatory cells (SIC) (p = 0.0453) and increased counts of CD3+ and CD8+ cells (p = 0.0262 and 0.0330, respectively). Survival analysis indicated that high levels of SIC, along with low levels of IFN-γ+ cell area within tumor tissue, may correlate positively with improved prognosis in surgically resected SCLC (p = 0.017 and 0.012, respectively). In conclusion, the present study revealed that the patients with pT1-2N1M0 staging were a potential subgroup of SCLC patients who may benefit from surgery. Complete postoperative adjuvant therapy remains an independent factor promoting a better prognosis for SCLC patients undergoing surgical resection. Moreover, CD3, CD8, IFN-γ, TIC, and SIC may serve as potential indicators for predicting the prognosis of surgically resected SCLC.

Downregulation of GPX8 in hepatocellular carcinoma: impact on tumor stemness and migration.

PURPOSE: GPX8, which is found in the endoplasmic reticulum lumen, is a member of the Glutathione Peroxidases (GPXs) family. Its role in hepatocellular carcinoma (HCC) is unknown. METHODS: Immunohistochemical staining was used to detect the protein levels of GPX8 in HCC tissue microarrays. A short hairpin RNA lentivirus was used to knock down GPX8, and the main signaling pathways were investigated using transcriptome sequencing and a phosphorylated kinase array. The sphere formation assays, cloning-formation assays and cell migration assays were used to evaluate the stemness and migration ability of HCC cells. Identifying the GPX8-interacting proteins was accomplished through immunoprecipitation and protein mass spectrometry. RESULTS: The GPX8 protein levels were downregulated in HCC patients. Low expression of GPX8 protein was related to early recurrence and poor prognosis in HCC patients. GPX8 knockdown could enhance the stemness and migration ability of HCC cells. Consistently, Based on transcriptome analysis, multiple signaling pathways that include the PI3K-AKT and signaling pathways that regulate the pluripotency of stem cells, were activated after GPX8 knockdown. The downregulation of GPX8 could increase the expression of the tumor stemness markers KLF4, OCT4, and CD133. The in vivo downregulation of GPX8 could also promote the subcutaneous tumor-forming and migration ability of HCC cells. MK-2206, which is a small-molecule inhibitor of AKT, could reverse the tumor-promoting effects both in vivo and in vitro. We discovered that GPX8 and the 71-kDa heat shock cognate protein (Hsc70) have a direct interaction. The phosphorylation of AKT encouraged the translocation of Hsc70 into the nucleus and the expression of the PI3K p110 subunit, thereby increasing the downregulation of GPX8. CONCLUSION: The findings from this study demonstrate the anticancer activity of GPX8 in HCC by inactivating the Hsc70/AKT pathway. The results suggest a possible therapeutic target for HCC.

ITPRIPL1 binds CD3ε to impede T cell activation and enable tumor immune evasion.

Cancer immunotherapy has transformed treatment possibilities, but its effectiveness differs significantly among patients, indicating the presence of alternative pathways for immune evasion. Here, we show that ITPRIPL1 functions as an inhibitory ligand of CD3ε, and its expression inhibits T cells in the tumor microenvironment. The binding of ITPRIPL1 extracellular domain to CD3ε on T cells significantly decreased calcium influx and ZAP70 phosphorylation, impeding initial T cell activation. Treatment with a neutralizing antibody against ITPRIPL1 restrained tumor growth and promoted T cell infiltration in mouse models across various solid tumor types. The antibody targeting canine ITPRIPL1 exhibited notable therapeutic efficacy against naturally occurring tumors in pet clinics. These findings highlight the role of ITPRIPL1 (or CD3L1, CD3ε ligand 1) in impeding T cell activation during the critical "signal one" phase. This discovery positions ITPRIPL1 as a promising therapeutic target against multiple tumor types.

Comprehensive analysis of bulk and single-cell transcriptomic data reveals a novel signature associated with endoplasmic reticulum stress, lipid metabolism, and liver metastasis in pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with high probability of recurrence and distant metastasis. Liver metastasis is the predominant metastatic mode developed in most pancreatic cancer cases, which seriously affects the overall survival rate of patients. Abnormally activated endoplasmic reticulum stress and lipid metabolism reprogramming are closely related to tumor growth and metastasis. This study aims to construct a prognostic model based on endoplasmic reticulum stress and lipid metabolism for pancreatic cancer, and further explore its correlation with tumor immunity and the possibility of immunotherapy. METHODS: Transcriptomic and clinical data are acquired from TCGA, ICGC, and GEO databases. Potential prognostic genes were screened by consistent clustering and WGCNA methods, and the whole cohort was randomly divided into training and testing groups. The prognostic model was constructed by machine learning method in the training cohort and verified in the test, TCGA and ICGC cohorts. The clinical application of this model and its relationship with tumor immunity were analyzed, and the relationship between endoplasmic reticulum stress and intercellular communication was further explored. RESULTS: A total of 92 characteristic genes related to endoplasmic reticulum stress, lipid metabolism and liver metastasis were identified in pancreatic cancer. We established and validated a prognostic model for pancreatic cancer with 7 signatures, including ADH1C, APOE, RAP1GAP, NPC1L1, P4HB, SOD2, and TNFSF10. This model is considered to be an independent prognosticator and is a more accurate predictor of overall survival than age, gender, and stage. TIDE score was increased in high-risk group, while the infiltration levels of CD8+ T cells and M1 macrophages were decreased. The number and intensity of intercellular communication were increased in the high ER stress group. CONCLUSIONS: We constructed and validated a novel prognostic model for pancreatic cancer, which can also be used as an instrumental variable to predict the prognosis and immune microenvironment. In addition, this study revealed the effect of ER stress on cell-cell communication in the tumor microenvironment.

Developing innovative strategies of tumor­infiltrating lymphocyte therapy for tumor treatment.

Cancer is the main cause of global mortality, and thus far, effective therapeutic strategies for cancer treatment are in high demand. Adoptive transfer of tumor­infiltrating lymphocytes (TILs) represents a promising avenue in immunotherapy for the management of malignancies. The clinical safety and efficacy of TIL­based therapy have been established through numerous rigorous clinical trials. However, the efficacy of TIL infusion in inducing an anti­tumor response is limited to a subset of clinical patients with cancer. Therefore, there is an urgent need to develop innovative strategies aimed at enhancing the effectiveness of TIL­based therapy. In the present review, the developmental history of TIL­based therapy was systematically summarized and analyzed, while also presenting a unique perspective on enhancing the multi­dimensional anti­tumor capabilities of TILs. The insight and conclusions presented in this review may contribute to improving the efficacy of TIL­based therapy and expediting its development.

Is tumor necrosis factor-α monoclonal therapy with proactive therapeutic drug monitoring optimized for inflammatory bowel disease? Network meta-analysis.

BACKGROUND: The efficacy and safety of anti-tumor necrosis factor-α (TNF-α) monoclonal antibody therapy [adalimumab (ADA) and infliximab (IFX)] with therapeutic drug monitoring (TDM), which has been proposed for inflammatory bowel disease (IBD) patients, are still controversial. AIM: To determine the efficacy and safety of anti-TNF-α monoclonal antibody therapy with proactive TDM in patients with IBD and to determine which subtype of IBD patients is most suitable for proactive TDM interventions. METHODS: As of July 2023, we searched for randomized controlled trials (RCTs) and observational studies in PubMed, Embase, and the Cochrane Library to compare anti-TNF-α monoclonal antibody therapy with proactive TDM with therapy with reactive TDM or empiric therapy. Pairwise and network meta-analyses were used to determine the IBD patient subtype that achieved clinical remission and to determine the need for surgery. RESULTS: This systematic review and meta-analysis yielded 13 studies after exclusion, and the baseline indicators were balanced. We found a significant increase in the number of patients who achieved clinical remission in the ADA [odds ratio (OR) = 1.416, 95% confidence interval (CI): 1.196-1.676] and RCT (OR = 1.393, 95%CI: 1.182-1.641) subgroups and a significant decrease in the number of patients who needed surgery in the proactive vs reactive (OR = 0.237, 95%CI: 0.101-0.558) and IFX + ADA (OR = 0.137, 95%CI: 0.032-0.588) subgroups, and the overall risk of adverse events was reduced (OR = 0.579, 95%CI: 0.391-0.858) according to the pairwise meta-analysis. Moreover, the network meta-analysis results suggested that patients with IBD treated with ADA (OR = 1.39, 95%CI: 1.19-1.63) were more likely to undergo TDM, especially in comparison with patients with reactive TDM (OR = 1.38, 95%CI: 1.07-1.77). CONCLUSION: Proactive TDM is more suitable for IBD patients treated with ADA and has obvious advantages over reactive TDM. We recommend proactive TDM in IBD patients who are treated with ADA.

KCTD15 acts as an anti-tumor factor in colorectal cancer cells downstream of the demethylase FTO and the m6A reader YTHDF2.

Potassium Channel Tetramerization Domain Containing 15 (KCTD15) participates in the carcinogenesis of several solid malignancies; however, its role in colorectal cancer (CRC) remains unclear. Here we find that KCTD15 exhibits lower expression in CRC tissues as compared to para-carcinoma tissues. Tetracycline (tet)-induced overexpression and knockdown of KCTD15 confirms KCTD15 as an anti-proliferative and pro-apoptotic factor in CRC both in vitro and in xenografted tumors. N6-methyladenosine (m6A) is known to affect the expression, stabilization, and degradation of RNAs with this modification. We demonstrate that upregulation of fat mass and obesity-associated protein (FTO), a classical m6A eraser, prevents KCTD15 mRNA degradation in CRC cells. Less KCTD15 RNA is recognized by m6A 'reader' YTH N6-Methyladenosine RNA Binding Protein F2 (YTHDF2) in FTO-overexpressed cells. Moreover, KCTD15 overexpression decreases protein expression of histone deacetylase 1 (HDAC1) but increases acetylation of critical tumor suppressor p53 at Lys373 and Lys382. Degradation of p53 is delayed in CRC cells post-KCTD15 overexpression. We further show that the regulatory effects of KCTD15 on p53 are HDAC1-dependent. Collectively, we conclude that KCTD15 functions as an anti-growth factor in CRC cells, and its expression is orchestrated by the FTO-YTHDF2 axis. Enhanced p53 protein stabilization may contribute to KCTD15's actions in CRC cells.

Role of long non-coding RNA in chemoradiotherapy resistance of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a malignant tumor originating from the nasopharyngeal epithelial cells. Common treatment methods for NPC include radiotherapy, chemotherapy, and surgical intervention. Despite these approaches, the prognosis for NPC remains poor due to treatment resistance and recurrence. Hence, there is a crucial need for more comprehensive research into the mechanisms underlying treatment resistance in NPC. Long non coding RNAs (LncRNAs) are elongated RNA molecules that do not encode proteins. They paly significant roles in various biological processes within tumors, such as chemotherapy resistance, radiation resistance, and tumor recurrence. Recent studies have increasingly unveiled the mechanisms through which LncRNAs contribute to treatment resistance in NPC. Consequently, LncRNAs hold promise as potential biomarkers and therapeutic targets for diagnosing NPC. This review provides an overview of the role of LncRNAs in NPC treatment resistance and explores their potential as therapeutic targets for managing NPC.

Genetic and molecular characterization of metabolic pathway-based clusters in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive types of squamous cell carcinoma and represents a significant proportion of esophageal cancer. Metabolic reprogramming plays a key role in the occurrence and development of ESCC. Unsupervised clustering analysis was employed to stratify ESCC samples into three clusters: MPC1-lipid type, MPC2-amino acid type, and MPC3-energy type, based on the enrichment scores of metabolic pathways extracted from the Reactome database. The MPC3 cluster exhibited characteristics of energy metabolism, with heightened glycolysis, cofactors, and nucleotide metabolism, showing a trend toward increased aggressiveness and poorer survival rates. On the other hand, MPC1 and MPC2 primarily involved lipid and amino acid metabolism, respectively. In addition, liquid chromatography‒mass spectrometry-based metabolite profiles and potential therapeutic agents were explored and compared among ESCC cell lines with different MPCs. MPC3 amplified energy metabolism markers, especially carnitines. In contrast, MPC1 and MPC2 predominantly had elevated levels of lipids (primarily triacylglycerol) and amino acids, respectively. Furthermore, MPC3 demonstrated a suboptimal clinical response to PD-L1 immunotherapy but showed increased sensitivity to the doramapimod chemotherapy regimen, as evident from drug sensitivity evaluations. These insights pave the way for a more personalized therapeutic approach, potentially enhancing treatment precision for ESCC patients.

An activatable fluorescent-photoacoustic dual-modal probe for highly sensitive imaging of nitroxyl in vivo.

Nitroxyl (HNO) plays a vital role in various biological functions and pharmacological activities, so the development of an excellent near-infrared fluorescent (NIRF) and photoacoustic (PA) dual-modality probe is crucial for understanding HNO-related physiological and pathological progression. Herein, we proposed and synthesized a novel NIRF/PA dual probe (QL-HNO) by substituting an indole with quinolinium in hemicyanine for the sensitive detection of exogenous and endogenous HNO in vivo. The designed probe showed the highest sensitivity in NIRF mode and a desirable PA signal-to-noise ratio for HNO detection in vitro and was further applied for NIRF/PA dual-modal imaging of HNO with high contrast in living cells and tumor-bearing animals. Based on the excellent performance of QL-HNO, we believe that this study provides a promising molecular tool for further understanding of HNO-related physiological and pathological progression.

Active targeting tumor therapy using host-guest drug delivery system based on biotin functionalized azocalix[4]arene.

Host-guest drug delivery systems (HGDDSs) provided a facile method for incorporating biomedical functions, including efficient drug-loading, passive targeting, and controlled drug release. However, developing HGDDSs with active targeting is hindered by the difficult functionalization of popular macrocycles. Herein, we report an active targeting HGDDS based on biotin-modified sulfonated azocalix[4]arene (Biotin-SAC4A) to efficiently deliver drug into cancer cells for improving anti-tumor effect. Biotin-SAC4A was synthesized by amide condensation and azo coupling. Biotin-SAC4A demonstrated hypoxia responsive targeting and active targeting through azo and biotin groups, respectively. DOX@Biotin-SAC4A, which was prepared by loading doxorubicin (DOX) in Biotin-SAC4A, was evaluated for tumor targeting and therapy in vitro and in vivo. DOX@Biotin-SAC4A formulation effectively killed cancer cells in vitro and more efficiently delivered DOX to the lesion than the similar formulation without active targeting. Therefore, DOX@Biotin-SAC4A significantly improved the in vivo anti-tumor effect of free DOX. The facilely prepared Biotin-SAC4A offers strong DOX complexation, active targeting, and hypoxia-triggered release, providing a favorable host for effective breast cancer chemotherapy in HGDDSs. Moreover, Biotin-SAC4A also has potential to deliver agents for other therapeutic modalities and diseases.

Exploring a multiparameter MRI-based radiomics approach to predict tumor proliferation status of serous ovarian carcinoma.

OBJECTIVES: To develop a multiparameter magnetic resonance imaging (MRI)-based radiomics approach that can accurately predict the tumor cell proliferation status of serous ovarian carcinoma (SOC). MATERIALS AND METHODS: A total of 134 patients with SOC who met the inclusion and exclusion criteria were retrospectively screened from institution A, spanning from January 2016 to March 2022. Additionally, an external validation set comprising 42 SOC patients from institution B was also included. The region of interest was determined by drawing each ovarian mass boundaries manually slice-by-slice on T2-weighted imaging fat-suppressed fast spin-echo (T2FSE) and T1 with contrast enhancement (T1CE) images using ITK-SNAP software. The handcrafted radiomic features were extracted, and then were selected using variance threshold algorithm, SelectKBest algorithm, and least absolute shrinkage and selection operator. The optimal radiomic scores and the clinical/radiological independent predictors were integrated as a combined model. RESULTS: Compared with the area under the curve (AUC) values of each radiomic signature of T2FSE and T1CE, respectively, the AUC value of the radiomic signature (T1CE-T2FSE) was the highest in the training set (0.999 vs. 0.965 and 0.860). The homogeneous solid component of the ovarian mass was considered the only independent predictor of tumor cell proliferation status among the clinical/radiological variables. The AUC of the radiomic-radiological model was 0.999. CONCLUSIONS: The radiomic-radiological model combining radiomic scores and the homogeneous solid component of the ovarian mass can accurately predict tumor cell proliferation status of SOC which has high repeatability and may enable more targeted and effective treatment strategies. CRITICAL RELEVANCE STATEMENT: The proposed radiomic-radiological model combining radiomic scores and the homogeneous solid component of the ovarian mass can predict tumor cell proliferation status of SOC which has high repeatability and may guide individualized treatment programs. KEY POINTS: • The radiomic-radiological nomogram may guide individualized treatment programs of SOC. • This radiomic-radiological nomogram showed a favorable prediction ability. • Homogeneous slightly higher signal intensity on T2FSE is vital for Ki-67.

Exploring mother-daughter communication and social media influence on HPV vaccine refusal for daughters aged 9-17 years in a cross-sectional survey of 11,728 mothers in China.

This study investigated the influences of mother-daughter communication and social media on mothers' HPV vaccine refusal for their daughters aged 9-17. A cross-sectional online survey among 11,728 mothers of girls aged 9-17 in Shenzhen, China was implemented between July and October 2023. Multi-level logistic regression models were fitted. Among 11,728 participants, 43.2% refused to have their daughters receive an HPV vaccination. In multivariate analysis, more openness in the mother-daughter communication (AOR: 0.99, 95%CI: 0.98, 0.99), perceived more positive outcomes of mother-daughter communication (AOR: 0.77, 95%CI: 0.75, 0.79), higher frequency of exposure to testimonials about daughters' HPV vaccination (AOR: 0.81, 95%CI: 0.78, 0.85) and information encouraging parents to vaccinate their daughters against HPV on social media (AOR: 0.76, 95%CI: 0.73, 0.79), and thoughtful consideration of the veracity of the information specific to HPV vaccines (AOR: 0.80, 95%CI: 0.77, 0.83) were associated with lower vaccine refusal. Mothers who were not the main decision-makers of daughters' HPV vaccination (AOR: 1.28 to 1.46), negative outcome expectancies of mother-daughter communication (AOR: 1.06, 95%CI: 1.04, 1.08), and mothers' HPV vaccine refusal (AOR: 2.81, 95%CI: 2.58, 3.06) were associated with higher vaccine refusal for their daughters. The level of mothers' HPV vaccine refusal for their daughters was high in China. Openness and outcome expectancies of mother-daughter communication and information exposure on social media were considered key determinants of HPV vaccine refusal for daughters. Future HPV vaccination programs should consider these interpersonal factors.

AIRE relies on Z-DNA to flag gene targets for thymic T cell tolerization.

AIRE is an unconventional transcription factor that enhances the expression of thousands of genes in medullary thymic epithelial cells and promotes clonal deletion or phenotypic diversion of self-reactive T cells1-4. The biological logic of AIRE's target specificity remains largely unclear as, in contrast to many transcription factors, it does not bind to a particular DNA sequence motif. Here we implemented two orthogonal approaches to investigate AIRE's cis-regulatory mechanisms: construction of a convolutional neural network and leveraging natural genetic variation through analysis of F1 hybrid mice5. Both approaches nominated Z-DNA and NFE2-MAF as putative positive influences on AIRE's target choices. Genome-wide mapping studies revealed that Z-DNA-forming and NFE2L2-binding motifs were positively associated with the inherent ability of a gene's promoter to generate DNA double-stranded breaks, and promoters showing strong double-stranded break generation were more likely to enter a poised state with accessible chromatin and already-assembled transcriptional machinery. Consequently, AIRE preferentially targets genes with poised promoters. We propose a model in which Z-DNA anchors the AIRE-mediated transcriptional program by enhancing double-stranded break generation and promoter poising. Beyond resolving a long-standing mechanistic conundrum, these findings suggest routes for manipulating T cell tolerance.

Fat mass and obesity-associated protein (FTO) mediated m6A modification of circFAM192A promoted gastric cancer proliferation by suppressing SLC7A5 decay.

Gastric cancer (GC) is a common malignant tumor worldwide, especially in East Asia, with high incidence and mortality rate. Epigenetic modifications have been reported to participate in the progression of gastric cancer, among which m6A is the most abundant and important chemical modification in RNAs. Fat mass and obesity-associated protein (FTO) is the first identified RNA demethylase but little is known about its role in gastric cancer. In our study, data from TCGA and clinical samples showed that FTO was highly expressed in gastric cancer tissues. Kaplan-Meier plotter suggested that patients with the high level of FTO had a poor prognosis. In vitro and in vivo experiments confirmed the role of FTO in promoting gastric cancer cell proliferation. Mechanistically, we found that FTO bound to circFAM192A at the specific site and removed the m6A modification in circFAM192A, protecting it from degradation. CircFAM192A subsequently interacted with the leucine transporter solute carrier family 7 member 5 (SLC7A5) and enhancing its stability. As a result, an increased amount of SLC7A5 was on the membrane, which facilitated leucine uptake and activated the mTOR signaling pathway. Therefore, our study demonstrated that FTO promoted gastric cancer proliferation through the circFAM192A/SLC7A5 axis in the m6A-dependent manner. Our study shed new light on the role of FTO in gastric cancer progression.

RBBP7, regulated by SP1, enhances the Warburg effect to facilitate the proliferation of hepatocellular carcinoma cells via PI3K/AKT signaling.

BACKGROUND: Hepatocellular carcinoma (HCC) is characterized by aggressive progression and elevated mortality rates. This study aimed to investigate the regulatory effects of RBBP7 on HCC pathogenesis and the underlying mechanisms. METHODS: The expression and clinical feature of RBBP7 were evaluated using bioinformatics analysis and the assessment of clinical HCC samples. CCK8 and colony formation were employed to estimate cell proliferation function of RBBP7. Aerobic glycolysis levels of RBBP7 were evaluated by measuring ATP levels, lactic acid production, glucose uptake capacity, and the expression of relevant enzymes (PFKM, PKM2, and LDHA). The phosphorylation levels in PI3K/AKT signaling were measured by western blotting. The regulatory effect of transcription factors of specificity protein 1 (SP1) on RBBP7 mRNA expression was confirmed in dual-luciferase reporter assays and chromatin immunoprecipitation experiments. The proliferation- and glycolysis-associated proteins were assessed using immunofluorescence staining in vivo. RESULTS: We found that RBBP7 is expressed at high levels in HCC and predicts poor survival. Functional assays showed that RBBP7 promoted HCC proliferation and glycolysis. Mechanistically, it was demonstrated that RBBP7 activates the PI3K/AKT pathway, a crucial pathway in glycolysis, contributing to the progression of HCC. The outcomes of the dual-luciferase assay further confirmed that SP1 is capable of activating the promoter of RBBP7. CONCLUSIONS: RBBP7, which is up-regulated by SP1, promotes HCC cell proliferation and glycolysis through the PI3K/AKT pathway. The findings of this study suggest that RBBP7 is a potential biomarker for HCC.

Epigenetic regulation in cancer.

Epigenetic modifications are defined as heritable changes in gene activity that do not involve changes in the underlying DNA sequence. The oncogenic process is driven by the accumulation of alterations that impact genome's structure and function. Genetic mutations, which directly disrupt the DNA sequence, are complemented by epigenetic modifications that modulate gene expression, thereby facilitating the acquisition of malignant characteristics. Principals among these epigenetic changes are shifts in DNA methylation and histone mark patterns, which promote tumor development and metastasis. Notably, the reversible nature of epigenetic alterations, as opposed to the permanence of genetic changes, positions the epigenetic machinery as a prime target in the discovery of novel therapeutics. Our review delves into the complexities of epigenetic regulation, exploring its profound effects on tumor initiation, metastatic behavior, metabolic pathways, and the tumor microenvironment. We place a particular emphasis on the dysregulation at each level of epigenetic modulation, including but not limited to, the aberrations in enzymes responsible for DNA methylation and histone modification, subunit loss or fusions in chromatin remodeling complexes, and the disturbances in higher-order chromatin structure. Finally, we also evaluate therapeutic approaches that leverage the growing understanding of chromatin dysregulation, offering new avenues for cancer treatment.