Associations of weight control related behaviors with current cigarette smoking among Chinese adolescents: Results from an ongoing school-based survey in Zhejiang province.

INTRODUCTION: Previous studies have suggested that adolescents may smoke cigarettes to control weight, but relevant research is scarce in Chinese youth. This study was conducted to examine the associations of weight control related behaviors with cigarette smoking in Chinese students. METHODS: This was a secondary analysis of data for 24835 middle and high school students drawn from the 2022 Zhejiang Youth Risk Behavior Survey of China which collected self-reported information of cigarette smoking, weight control strategies and other health-related behaviors. Multivariable logistic regression models were used to estimate the adjusted odds ratios (AORs) with 95% confidence intervals (CIs) for the study associations. RESULTS: Overall, there were 998 (4.02%) current cigarette smokers in this wave of the Zhejiang YRBS (2022). Neither trying to control weight nor healthy weight control behavior of exercising was associated with current cigarette smoking (AOR=1.15; 95% CI: 0.97-1.37 and AOR=1.01; 95% CI: 0.85-1.20, respectively). Meanwhile, unhealthy weight control behaviors of taking laxatives (AOR=1.52; 95% CI: 1.03-2.26), taking diet pills (AOR=1.82; 95% CI: 1.26-2.62), dieting (AOR=1.24; 95% CI: 1.04-1.49), and fasting (AOR=1.81; 95% CI: 1.40-2.34) were significantly associated with increased odds of current cigarette smoking. CONCLUSIONS: Screening and developing interventions for unhealthy weight control behaviors should be considered as part of smoking prevention programs among adolescents.

Single-cell RNA sequencing reveals that MYBL2 in malignant epithelial cells is involved in the development and progression of ovarian cancer.

Background: Ovarian carcinoma (OC) is a prevalent gynecological malignancy associated with high recurrence rates and mortality, often diagnosed at advanced stages. Despite advances in immunotherapy, immune exhaustion remains a significant challenge in achieving optimal tumor control. However, the exploration of intratumoral heterogeneity of malignant epithelial cells and the ovarian cancer tumor microenvironment is still limited, hindering our comprehensive understanding of the disease. Materials and methods: Utilizing single-cell RNA sequencing (scRNA-seq), we comprehensively investigated the cellular composition across six ovarian cancer patients with omental metastasis. Our focus centered on analysis of the malignant epithelial cells. Employing CytoTRACE and slingshot pseudotime analyses, we identified critical subpopulations and explored associated transcription factors (TFs) influencing ovarian cancer progression. Furthermore, by integrating clinical factors from a large cohort of bulk RNA sequencing data, we have established a novel prognostic model to investigate the impact of the tumor immune microenvironment on ovarian cancer patients. Furthermore, we have investigated the condition of immunological exhaustion. Results: Our study identified a distinct and highly proliferative subgroup of malignant epithelial cells, known as C2 TOP2A+ TCs. This subgroup primarily consisted of patients who hadn't received neoadjuvant chemotherapy. Ovarian cancer patients with elevated TOP2A expression exhibited heightened sensitivity to neoadjuvant chemotherapy (NACT). Moreover, the transcription factor MYBL2 in this subgroup played a critical role in ovarian cancer development. Additionally, we developed an independent prognostic indicator, the TOP2A TCs Risk Score (TTRS), which revealed a correlation between the High TTRS Group and unfavorable outcomes. Furthermore, immune infiltration and drug sensitivity analyses demonstrated increased responsiveness to Paclitaxel, Cisplatin, and Gemcitabine in the Low TTRS Group. Conclusion: This research deepens our understanding of malignant epithelial cells in ovarian cancer and enhances our knowledge of the ovarian cancer immune microenvironment and immune exhaustion. We have revealed the heightened susceptibility of the C2 TOP2A+ TCs subgroup to neoadjuvant chemotherapy and emphasized the role of MYBL2 within the C2 subgroup in promoting the occurrence and progression of ovarian cancer. These insights provide valuable guidance for the management of ovarian cancer treatment.

Targeting Metabolic-Redox Nexus to Regulate Drug Resistance: From Mechanism to Tumor Therapy.

Drug resistance is currently one of the biggest challenges in cancer treatment. With the deepening understanding of drug resistance, various mechanisms have been revealed, including metabolic reprogramming and alterations of redox balance. Notably, metabolic reprogramming mediates the survival of tumor cells in harsh environments, thereby promoting the development of drug resistance. In addition, the changes during metabolic pattern shift trigger reactive oxygen species (ROS) production, which in turn regulates cellular metabolism, DNA repair, cell death, and drug metabolism in direct or indirect ways to influence the sensitivity of tumors to therapies. Therefore, the intersection of metabolism and ROS profoundly affects tumor drug resistance, and clarifying the entangled mechanisms may be beneficial for developing drugs and treatment methods to thwart drug resistance. In this review, we will summarize the regulatory mechanism of redox and metabolism on tumor drug resistance and highlight recent therapeutic strategies targeting metabolic-redox circuits, including dietary interventions, novel chemosynthetic drugs, drug combination regimens, and novel drug delivery systems.

Heterogeneity of Wnt1-Cre-marked and Pax2-Cre-marked first branchial arch cranial neural crest cells in mice.

OBJECTIVES: This study aimed to explore the heterogeneity and gene ontology of Wnt1-Cre-marked and Pax2-Cre-marked first branchial arch cranial neural crest cells (CNCs) in mice. METHODS: The embryos of Wnt1-Cre;R26RmTmG and Pax2-Cre;R26RmTmG at embryonic day (E)8.0-E9.25 were collected for histological observation. We performed immunostaining to compare green fluorescent protein (GFP)-positive CNCs in Pax2-Cre;R26RAi9 and Wnt1-Cre;R26RAi9 mice at E15.5. Single-cell RNA sequencing (scRNA-seq) was used to analyze the first branchial arch GFP-positive CNCs from Wnt1-Cre;R26RmTmG and Pax2-cre;R26RmTmGmice at E10.5. Real time fluorescence quantitative polymerase chain reaction (q-PCR) was performed to validate the differential genes. RESULTS: Wnt1-Cre-marked and Pax2-Cre-marked CNCs migrated from the neural plateto first and second branchial arches and to the first branchial arch, respectively, at E8.0. Although Wnt1-Cre-marked and Pax2-Cre-marked CNCs were found mostly in cranial-facial tissues, the former had higher expression in palate and tongue. The results of scRNA-seq showed that Pax2-Cre-marked CNCs specifically contributed to osteoblast differentiation and ossification, while Wnt1-Cre-marked CNCs participated in limb development, cell migration, and ossification. The q-PCR data also confirmed the results of gene ontology analysis. CONCLUSIONS: Pax2-Cre mice are perfect experimental animal models for research on first branchial arch CNCs and derivatives in osteoblast differentiation and ossification.

Air pollution and cancer daily mortality in Hangzhou, China: an ecological research.

BACKGROUND: Long-term exposure to air pollution has been linked to cancer incidence. However, the evidence is limited regarding the effect of short-term exposure to air pollution on cancer mortality. OBJECTIVES: This study aimed to investigate associations between short-term exposure to air pollutants (sulfur dioxide (SO2), nitrogen dioxide (NO2), particulate matter with an aerodynamic diameter <10 mm (PM10) and PM2.5) and cancer daily mortality. METHODS: This study used air quality, meteorological and daily cancer death data from 2014 to 2019 in Hangzhou, China. Generalised additive models (GAM) with quasi-Poisson regression were used to analyse the associations between air pollutants and cancer mortality with adjustment for confounding factors including time trends, day of week, temperature and humidity. Then, we conducted stratified analyses by sex, age, season and education. In addition, stratified analyses of age, season and education were performed within each sex to determine whether sex difference was modified by such factors. RESULTS: After adjusting for potential confounders, the GAM results indicated a statistically significant relationship between increased cancer mortality and elevated air pollution concentrations, but only in the female population. For every 10 µg/m3 rise in pollutant concentration, the increased risk of cancer death in females was 6.82% (95% CI 3.63% to 10.10%) for SO2 on lag 03, and 2.02% (95% CI 1.12% to 2.93%) for NO2 on lag 01 and 0.89% (95% CI 0.46% to 1.33%) for PM10 on lag 03 and 1.29% (95% CI 0.64% to 1.95%) for PM2.5 on lag 03. However, no statistically significant association was found among males. Moreover, the differences in effect sizes between males and females were more pronounced during the cold season, among the elderly and among subjects with low levels of education. CONCLUSIONS: Increased cancer mortality was only observed in females with rising concentrations of air pollutants. Further research is required to confirm this sex difference. Advocate for the reduction of air pollutant emissions to protect vulnerable groups.

Increased incidence risks of cardiovascular disease among cancer patients: Evidence from a population-based cohort study in China.

BACKGROUND: Cardiovascular disease (CVD) is becoming a major concern among cancer patients, leading to the development of a new field named cardio-oncology. However, previous studies were mainly based on the western population and focused on CVD mortality. Evidence from the Chinese population is limited. Furthermore, few studies investigated the incidence risks of CVD among cancer patients. METHODS: 85,787 eligible cancer patients were included from Hangzhou city, China. Age-standardized standard incidence ratio (SIR) was used to reflect the incidence risks of CVD among cancer patients as compared with the standard population, which was defined as all residents in Hangzhou city during the same period. RESULTS: After three years of follow-up, cancer patients showed elevated incidence risks of CVD (SIR = 1.41, 95%CI: 1.35-1.47) as compared with the standard population. The elevated risks of CVD were highest in the first year after cancer diagnosis (SIR = 1.68, 95%CI: 1.58-1.78), then followed by the second (SIR = 1.21, 95%CI: 1.11-1.31) and the third (SIR = 1.18, 95%CI: 1.07-1.29) year. These results were consistent in males and females. Furthermore, different risks of CVD were observed among different cancer sites. Patients with pancreatic cancer showed the highest risks of CVD, then followed by liver cancer, lung cancer, kidney cancer, gastric cancer, bladder cancer, prostate cancer, and colorectal cancer. CONCLUSIONS: Cancer patients have increased incidence risks of CVD, especially in the first year after cancer diagnosis. The increased risks of CVD vary by different cancer sites. Our findings highlight the importance of paying close attention to the CVD risks among cancer patients.

The whole-blood Epstein-Barr virus DNA can serve as a valuable molecular marker for diagnosis and prognosis prediction of nasopharyngeal carcinoma.

The clinical significance and prognostic role of whole-blood EBV-DNA in EBV-associated nasopharyngeal carcinoma (NPC) have not been thoroughly investigated. This study aims to explore the diagnostic and prognostic value of EBV-DNA for NPC in a non-endemic region of China. We enrolled patients with chronic active EBV infection (CAEBV), nasopharyngitis (NA), extranodal NK/T-cell lymphoma, nasal type (ENKTCL-NT), and NPC. Demographic and clinical data were collected and the diagnostic and prognostic values of EBV-DNA were analyzed. Immunohistochemistry was performed to detect EBV-encoded small ribonucleic acids (EBER), as well as the expression of p53, Ki-67, and epidermal growth factor receptor (EGFR). The levels of pretreatment Epstein-Barr virus DNA (preEBV-DNA) in new NPC cases were found to differ from those in other diseases and exhibited varying age distributions. The threshold value of preEBV-DNA for distinguishing NPC from CAEBV and NA was determined. We confirmed that epistaxis, diabetes mellitus, T3N2 or T4N0-2 stage, and IgM positivity were associated with higher levels of preEBV-DNA, and identified risk factors associated with the prognosis of locoregionally advanced NPC (La-NPC). Patients with intermittently or persistently positive EBV-DNA (IPCP), higher preEBV-DNA levels, and positive Epstein-Barr virus-encoded small RNA (EBER) status (EBERpos) had worse survival. New cases of NPC with elevated levels of EBV in the whole-blood and positive EBER status were shown to have a poor prognosis upon progression to La-NPC. EBV-DNA was found to be an indicator for predicting prognosis in La-NPC and could also be used to distinguish new NPC cases.

SMAD7 gene polymorphisms and their influence on patients with colorectal cancer.

Colorectal cancer (CRC) is a prevalent malignant tumor, and its pathogenesis is still not fully understood. Studies have shown that SMAD7 gene polymorphisms can affect CRC susceptibility, but the results have been inconsistent and require additional confirmation. Our study aimed to evaluate the effect of SMAD7 variants on the risk of CRC in the Chinese Han population. A total of five single nucleotide polymorphisms (SNPs) in SMAD7 were genotyped among 696 CRC patients and 696 healthy participants using the MassARRAY iPLEX platform. SNPs were evaluated for their associations with CRC using logistic regression analysis under multiple genetic models. The false-positive report probability (FPRP) analysis was used to validate the positive findings. Our study indicated that rs11874392 showed an increased association with CRC risk (odds ratio, 1.31; 95% confidence interval, 1.04-1.67; p = 0.024). Stratified analysis showed that rs11874392 might increase the risk of CRC in females (OR = 1.70, p = 0.028), individuals with smoking (OR = 1.87, p = 0.026), and drinking (OR = 1.38, p = 0.027). The rs11874392 was found to be related to an elevated risk of rectal cancer (OR = 1.73, p = 0.003), but not with colon cancer. FPRP analysis demonstrated that all of these associations were statistically significant (FPRP <0.2). Additionally, rs11874392 was the strongest predictive model for CRC. This study provides evidence that the SMAD7 rs11874392 is related to an increased susceptibility to CRC.

Upregulated TC1 and downregulated Chibby were correlated with the aberrant ß-catenin expression in laryngeal squamous cell carcinoma.

As an important member of Wnt/ß-catenin signaling pathway, the aberrant expression of ß-catenin has been implicated in many cancers. Chibby, a ß-catenin binding partner, is an antagonist involved in this pathway. In contrast, thyroid cancer 1 (TC1) as an activator of this pathway can relieve the antagonistic activity of Chibby on the ß-catenin-mediated transcription and is high expressed in human tumors. The objectives of this study were to examine the expression of TC1, Chibby, and ß-catenin and investigate the association among them in laryngeal squamous cell carcinoma (LSCC). The expression of TC1, Chibby, ß-catenin, c-Myc, Cyclin D1, and matrix metalloproteinase-7 (MMP-7) were examined by immunohistochemistry in samples from 53 LSCC patients. Compared with normal laryngeal squamous epithelium (NLSE), there were upregulated expression of TC1, downregulated expression of Chibby, and aberrant cytoplasmic expression of ß-catenin in the LSCC tissues (P < .001). The high expression of TC1 was correlated with the tumor site, advanced TNM and T stage, lymphovascular invasion, and poor differentiation in LSCC tissues (P < .050). There were correlations between the aberrant expression of ß-catenin and the tumor site, advanced TNM and T stage, lymphovascular invasion, perineurial invasion, and poor differentiation in LSCC tissues (P < .050). Upregulated TC1 and downregulated Chibby were correlated with aberrant expression of ß-catenin (P < .001), but no correlation between them (P = .076). The percent of abnormal expression of ß-catenin in LSCC was 96.00% in TC1+/Chibby-, 73.68% in TC1+/Chibby+, 0.00% in TC1-/Chibby-, and 0.00% in TC1-/Chibby + group (P < .001). High expression of c-Myc, Cyclin D1, and MMP-7 was observed in LSCC tissues (P < .001). There was statistically significant about the expression of Cyclin D1 and MMP-7 among the groups of TC1+/Chibby-, TC1+/Chibby+, TC1-/Chibby-, and TC1-/Chibby + (P < .001), but was not significance about the expression of c-Myc among them (P = .339). No association was found between overall survival and the expression of TC1, Chibby, and ß-catenin (P > .05). The upregulated expression of TC1 and downregulated expression of Chibby were correlated with the aberrant expression of ß-catenin and the high expression of Cyclin D1 and MMP-7 in LSCC tissues.

STAT5 promotes PD-L1 expression by facilitating histone lactylation to drive immunosuppression in acute myeloid leukemia.

Immunotherapy is a revolutionized therapeutic strategy for tumor treatment attributing to the rapid development of genomics and immunology, and immune checkpoint inhibitors have successfully achieved responses in numbers of tumor types, including hematopoietic malignancy. However, acute myeloid leukemia (AML) is a heterogeneous disease and there is still a lack of systematic demonstration to apply immunotherapy in AML based on PD-1/PD-L1 blockage. Thus, the identification of molecules that drive tumor immunosuppression and stratify patients according to the benefit from immune checkpoint inhibitors is urgently needed. Here, we reported that STAT5 was highly expressed in the AML cohort and activated the promoter of glycolytic genes to promote glycolysis in AML cells. As a result, the increased-lactate accumulation promoted E3BP nuclear translocation and facilitated histone lactylation, ultimately inducing PD-L1 transcription. Immune checkpoint inhibitor could block the interaction of PD-1/PD-L1 and reactive CD8+ T cells in the microenvironment when co-culture with STAT5 constitutively activated AML cells. Clinically, lactate accumulation in bone marrow was positively correlated with STAT5 as well as PD-L1 expression in newly diagnosed AML patients. Therefore, we have illustrated a STAT5-lactate-PD-L1 network in AML progression, which demonstrates that AML patients with STAT5 induced-exuberant glycolysis and lactate accumulation may be benefited from PD-1/PD-L-1-based immunotherapy.

Disruption of mitochondrial oxidative phosphorylation by chidamide eradicates leukemic cells in AML.

PURPOSE: Nowadays, the oxidative phosphorylation (OXPHOS) correlated with leukemogenesis and treatment response is extensive. Thus, exploration of novel approaches in disrupting OXPHOS in AML is urgently needed. MATERIALS AND METHODS: Bioinformatical analysis of TCGA AML dataset was performed to identify the molecular signaling of OXPHOS. The OXPHOS level was measured through a Seahorse XFe96 cell metabolic analyzer. Flow cytometry was applied to measure mitochondrial status. Real-time qPCR and western blot were used to analyze the expression of mitochondrial or inflammatory factors. MLL-AF9-induced leukemic mice were conducted to measure the anti-leukemia effect of chidamide. RESULTS: Here, we reported that AML patients with high OXPHOS level were in a poor prognosis, which was associated with high expression of HDAC1/3 (TCGA). Inhibition of HDAC1/3 by chidamide inhibited cell proliferation and induced apoptotic cell death in AML cells. Intriguingly, chidamide could disrupt mitochondrial OXPHOS as assessed by inducing mitochondrial superoxide and reducing oxygen consumption rate, as well as decreasing mitochondrial ATP production. We also observed that chidamide augmented HK1 expression, while glycolysis inhibitor 2-DG could reduce the elevation of HK1 and improve the sensitivity of AML cells exposed to chidamide. Furthermore, HDAC3 was correlated with hyperinflammatory status, while chidamide could downregulate the inflammatory signaling in AML. Notably, chidamide eradicated leukemic cells in vivo and prolonged the survival time of MLL-AF9-induced AML mice. CONCLUSION: Chidamide disrupted mitochondrial OXPHOS, promoted cell apoptosis and reduced inflammation in AML cells. These findings exhibited a novel mechanism that targeting OXPHOS would be a novel strategy for AML treatment.

Association between lifestyle and dietary preference factors and conventional adenomas and serrated polyps.

Introduction: Both conventional adenoma (AD) and serrated polyp (SP) were known precursor lesions of colorectal cancer (CRC). Modifiable lifestyle factors were significantly associated with CRC risk, but whether these factors were related to the risk of different precursors of CRC needed to be clarified. This study aimed to evaluate the risks of AD and SP caused by lifestyle factors and compare the risk differences between AD and SP. Methods: The study population was from the CRC screening cohort in Hangzhou, China. A total of 458,457 eligible individuals volunteered to undergo initial screening including the fecal immunochemical test (FIT) and the CRC risk assessment. Finally, 13,993 participants who had undergone colonoscopy tests and had been diagnosed at designated hospitals were selected in this study. All participants were required to fill out a questionnaire during the initial screening for collecting their information. The generalized estimate equation (GEE) model was used to assess the association between lifestyle factors/dietary preferences and AD/SP. Results: The body mass index (BMI) and smoking were positively associated with the risks of only SP (BMI: OR = 1.50, 95%CI: 1.23-1.84; smoking: OR = 1.29, 95%CI: 1.07-1.55), only AD (BMI: OR = 1.53, 95%CI: 1.28-1.82; OR = 1.24, 95%CI: 1.11-1.39), and synchronous SP and AD (BMI: OR = 1.97, 95%CI: 1.40-2.75; smoking: OR = 1.53, 95%CI: 1.27-1.85). In the case-group comparison, smoking was more strongly associated with the risk of synchronous SP and AD than only AD. Alcohol drinking was positively associated with the risk of AD (OR = 1.28, 95%CI: 1.14-1.44), but no statistically significant difference was observed in risks in the case-group comparison. Furthermore, whole-grain intake was associated with a decreased risk of only AD (OR = 0.78, 95%CI: 0.65-0.93). However, white meat intake was positively associated with risks of only SP when compared with AD cases (OR = 1.60, 95%CI: 1.15-2.23). Conclusion: The current study identified common risk factors such as BMI and smoking as well as different risks of certain factors (e.g., alcohol drinking and whole-grain intake) for SP and AD. However, there were still some factors, especially diet-related factors, that have not been fully elucidated in their association with the two lesions. Further research is needed in future to confirm and develop prevention strategies for different lesions.

Isolation, identification, and characterization of corn-derived antioxidant peptides from corn fermented milk by Limosilactobacillus fermentum.

Dairy-derived peptides and corn-derived peptides have been identified as essential ingredients for health promotion in the food industry. The hydrolysis based on lactic acid bacteria (LAB) protease system is one of the most popular methods to prepare bioactive peptides. The objectives of this paper are to develop antioxidant fermented milk and to obtain natural antioxidant peptides. In our study, LAB with antioxidant capacity were screened in vitro, and the corn fermented milk with antioxidant capacity was achieved by the traditional fermentation method. Fermented milk was purified by ultrafiltration and molecular sieve, and identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Our findings demonstrate that Limosilactobacillus fermentum L15 had a scavenging capacity of more than 80% of DPPH radicals, Trolox equivalent antioxidant capacity (TEAC) of 0.348 ± 0.005 mmol/L. Meanwhile, the peptide content of corn fermented milk prepared with L. fermentum L15 was 0.914 ± 0.009 mg/mL and TAEC of 0.781 ± 0.020 mmol/L. Particularly important, IGGIGTVPVGR and LTTVTPGSR isolated and extracted from fermented milk were found to have antioxidant capacity for the first time. The synthetic peptides IGGIGTVPVGR and LTTVTPGSR demonstrated a scavenging capacity of 70.07 ± 2.71% and 70.07 ± 2.77% for DPPH radicals and an antioxidant capacity of 0.62 ± 0.01 mmol/L and 0.64 ± 0.02 mmol/L Trolox equivalent, respectively. This research provides ideas and basis for the development and utilization of functional dairy products.

Overexpression of Laminin 5γ2 Chain Correlates with Tumor Cell Proliferation, Invasion, and Poor Prognosis in Laryngeal Squamous Cell Carcinoma.

Objective: Laryngeal squamous cell carcinoma (LSCC) is a common malignant tumor. Laminin 5γ2 chain (LAMC2) was reported to be associated with tumorigenesis. This study explored the role of LAMC2 on LSCC progression by regulating the integrinß1/FAK/Src/AKT pathway. Methods: The level of LAMC2 in 46 LSCC patients was detected by qRT-PCR and western blot. Then the relationship between LAMC2 expression and LSCC malignancy as well as prognosis was analyzed, and the effect of LAMC2 expression on LSCC patient survival was also analyzed using the Kaplan-Meier survival curves. Afterwards, the LSCC cells were transfected with LAMC2 overexpression and knockdown vectors, the effect of LAMC2 on LSCC cell viability, proliferation ability, cell cycle, cell migration, and invasion were detected by CCK-8, colony formation, flow cytometry, wound healing, and Transwell assays. The expression of EMT-related biomarkers and integrin ß1/FAK/Src/AKT signaling-related proteins was detected by western blot. Moreover, the effect of LAMC2 on LSCC tumor growth was evaluated by in vivo xenograft experiments and western blot. Results: LAMC2 was expressed at high level in LSCC tissues and associated with poor prognosis. LAMC2 overexpression increased TU177 cell viability, proliferation ability, promoted cell cycle, cell migration, and invasion capacity. The expression of N-cadherin, vimentin, and integrinß1/FAK/Src/AKT related proteins was increased, while the expression of E-cadherin protein was decreased. When the LAMC2 knockdown in AMC-HN-8 cells had opposite effects. Furthermore, shLAMC2 decreased tumor volume and the expression of LAMC2, Ki-67 and integrinß1, but increased the expression of E-cadherin in LSCC tumor-bearing mice. Conclusion: The findings suggested that LAMC2 was overexpressed in LSCC and correlated with poor prognosis. LAMC2 knockdown inhibited LSCC progression by regulating the integrinß1/FAK/Src/AKT signaling pathway. Therefore, LAMC2 could be a target for LSCC therapy.

Mutant C/EBPα p30 alleviates immunosuppression of CD8+ T cells by inhibiting autophagy-associated secretion of IL-1ß in AML.

OBJECTIVES: Mutant C/EBPα p30 (mp30), the product of C/EBPα double mutations (DM), lacks transactivation domain 1 and has C-terminal loss-of-function mutation. Acute myeloid leukaemia (AML) patients harbouring C/EBPα DM could be classified as a distinct subgroup with favourable prognosis. However, the underlying mechanism remains elusive. MATERIALS AND METHODS: Autophagy regulated by mp30 was detected by western blot and immunofluorescence. Immune infiltration analysis and GSEA were performed to investigate autophagic and inflammatory status of AML patients from the GSE14468 cohort. Flow cytometry was applied to analyse T cell activation. RESULTS: Mp30 inhibited autophagy by suppressing nucleus translocation of NF-κB. Autophagy-associated secretion of IL-1ß was decreased in mp30-overexpressed AML cells. Bioinformatic analysis revealed that inflammatory status was attenuated, while CD8+ T cell infiltration was upregulated in C/EBPα DM AML patients. Consistently, the proportion of CD8+ CD69+ T cells in peripheral blood mononuclear cells (PBMCs) was upregulated after co-culture with mp30 AML cell conditional culture medium. Knock-out of IL-1ß in AML cells also enhanced CD8+ T cell activation. Accordingly, IL-1ß expression was significantly reduced in the bone marrow (BM) cells of C/EBPα DM AML patients compared to the wildtype, while the CD8+ CD69+ T cell proportion was specifically elevated. CONCLUSIONS: C/EBPα DM alleviates immunosuppression of CD8+ T cells by inhibiting the autophagy-associated secretion of IL-1ß, which elucidated that repression of autophagy-related inflammatory response in AML patients might achieve a favourable clinical benefit.

cGAS/STING cross-talks with cell cycle and potentiates cancer immunotherapy.

The correct duplication and transfer of genetic material to daughter cells is the major event of cell division. Dysfunction of DNA replication or chromosome segregation presents challenges in cancer initiation and development as well as opportunities for cancer treatment. Cyclic GMP-AMP synthase (cGAS) of the innate immune system detects cytoplasmic DNA and mediates downstream immune responses through the molecule stimulator of interferon genes (STING). However, how cytosolic DNA sensor cGAS participates in guaranteeing accurate cell division and preventing tumorigenesis is still unclear. Recent evidence indicates malfunction of cGAS/STING pathway in cancer progression. Cell cycle-targeted therapy synergizes with immunotherapy via cGAS/STING activation, leading to promising therapeutic benefit. Here, we review the interactions between cell cycle regulation and cGAS/STING signaling, thus enabling us to understand the role of cGAS/STING in cancer initiation, development, and treatment.

Engineered red blood cell membrane for sensitive and precise electrochemical detection of salivary exosomes.

As a kind of promising non-invasive biomarker, exosomes naturally occurring in saliva have recently attracted considerable attention in view of their potential use in the diagnosis of oral diseases. Herein, we propose a new electrochemical method for the sensitive and precise detection of salivary exosomes. A red blood cell membrane (RBCM) engineered with CD63 aptamer is the core element of the method and is used to camouflage a gold electrode, thus giving the electrode superior antifouling and targeting ability. Target exosomes presented in saliva are recognized and captured by the highly specific interaction between the exosomal CD63 and the aptamers engineered in RBCM. Then, silver nanoparticles modified with CD63 aptamers are recruited onto the electrode surface to generate significant electrochemical signals, which enables the sensitive detection of target exosomes. By using human oral squamous cell carcinoma CAL27 cell-derived exosomes as a model, the method allows target salivary exosome detection in a wide linear range from 5 × 102 to 1 × 106 particles per mL and a low detection limit of 2.07 × 102 particles per mL. Moreover, the method displays good reproducibility and is feasible for detecting target exosomes with high precision in saliva samples. Overall, the method may provide a useful tool for salivary exosome detection and may have great potential for practical use in the clinical diagnosis of oral diseases.

The effects of altered BMP4 signaling in first branchial-arch-derived murine embryonic orofacial tissues.

The first branchial arch (BA1), which is derived from cranial neural crest (CNC) cells, gives rise to various orofacial tissues. Cre mice are widely used for the determination of CNC and exploration of gene functions in orofacial development. However, there is a lack of Cre mice specifically marked BA1's cells. Pax2-Cre allele was previously generated and has been widely used in the field of inner ear development. Here, by compounding Pax2-Cre and R26R-mTmG mice, we found a specific expression pattern of Pax2+ cells that marked BA1's mesenchymal cells and the BA1-derivatives. Compared to Pax2-Cre; R26R-mTmG allele, GFP+ cells were abundantly found both in BA1 and second branchial arch in Wnt1-Cre;R26R-mTmG mice. As BMP4 signaling is required for orofacial development, we over-activated Bmp4 by using Pax2-Cre; pMes-BMP4 strain. Interestingly, our results showed bilateral hyperplasia between the upper and lower teeth. We also compare the phenotypes of Wnt1-Cre; pMes-BMP4 and Pax2-Cre; pMes-BMP4 strains and found severe deformation of molar buds, palate, and maxilla-mandibular bony structures in Wnt1-Cre; pMes-BMP4 mice; however, the morphology of these orofacial organs were comparable between controls and Pax2-Cre; pMes-BMP4 mice except for bilateral hyperplastic tissues. We further explore the properties of the hyperplastic tissue and found it is not derived from Runx2+ cells but expresses Msx1, and probably caused by abnormal cell proliferation and altered expression pattern of p-Smad1/5/8. In sum, our findings suggest altering BMP4 signaling in BA1-specific cell lineage may lead to unique phenotypes in orofacial regions, further hinting that Pax2-Cre mice could be a new model for genetic manipulation of BA1-derived organogenesis in the orofacial region.

LncRNA MNX1-AS1 Contributes to Laryngeal Squamous Cell Carcinoma Growth and Migration by Regulating mir-744-5p/bcl9/ß-Catenin Axis.

Increasing evidence has indicated that long noncoding RNAs (lncRNAs) are involved in the progression of laryngeal squamous cell carcinoma (LSCC). Here, we aimed to disclose the role of MNX1-AS1 in LSCC progression, and explore whether MNX1-AS1 participates in LSCC progression via targeting miR-744-5p to active BCL9/ß-catenin signaling. Sixty-five human LSCC tissues and the paracancerous normal tissues were recruited to determine the levels of MNX1-AS1, miR-744-5p and BCL9 using qRT-PCR. The interaction of miR-744-5p and MNX1-AS1/BCL9 was determined by using the RNA immunoprecipitation (RIP) assay and/or luciferase gene reporter assay. Cell viability, in vivo tumor formation, invasion and migration abilities were detected by MTT, Xenograft models and Transwell assays. MNX1-AS1 level was increased significantly in human LSCC tissues as compared with the normal tissues, which showed a positive correlation with BCL9 level while a negative correlation with miR-744-5p level. High level of MNX1-AS1 predicted a poor prognosis and an advanced clinical process in LSCC patients. miR-744-5p targeted upregulation weakened the luciferase activity of MNX1-AS1 and /BCL9, and downregulated their expression levels-wt, while showed no effect when the binding sites were mutated. Knockdown of MNX1-AS1 markedly weakened cell viability, migration, and invasion abilities, while BCL9 overexpression abolished these tendencies. In addition, MNX1-AS1 downregulation induced decreases in tumor volumes and weights in vivo, accompanied by reductions in BCL9, Ki-67 and ß-catenin expression and an increase in miR-744-5p expression. Collectively, this study reveals that MNX1-AS1 contributes to cell growth and migration by regulating miR-744-5p/BCL9/ß-catenin axis in LSCC.

Facile incorporation of DNA-templated quantum dots for sensitive electrochemical detection of the oral cancer biomarker interleukin-8.

Recent studies reveal a great value of interleukin-8 (IL-8), a pro-inflammatory cytokine, as a potent biomarker for early diagnosis of oral cancer. Herein, a new electrochemical method is proposed to detect IL-8 by facilely incorporating DNA-templated quantum dots (QDs). In principle, target IL-8 is first treated with the reducing agent tris(2-carboxyethyl)phosphine (TCEP) to yield active thiols and then captured by antibody-functionalized magnetic beads (MBs). Thereafter, via the Michael addition reaction between the active thiol and maleimide group, a maleimide-modified DNA probe is linked to the surface of MBs, which can initiate a process of rolling circle amplification. In this way, long-range DNA strands are generated on the MB surface, subsequently recruiting DNA-templated CdTe/CdS QDs (DNA-QDs) to act as electrochemical reporters. By tracing the responses of DNA-QDs, the method allows IL-8 detection in a linear range from 5 to 5000 fg/mL with a detection limit of 3.36 fg/mL. The selectivity, reproducibility, and applicability in complex serum samples are also demonstrated to be favorable, indicating that the method may have a great potential in the future. More importantly, the use of TCEP treatment in the method not only provides a facile way to incorporate DNA-QDs, avoiding the complicated and time-consuming preparation process of antibody-DNA conjugates or functional nanomaterials; but also makes the method capable of being extended to detect other protein biomarkers in view of widespread presence of disulfides, which may hold a broad potential to facilitate efficient biosensing designs.