Intensity and drivers of subtypes interference between seasonal influenza viruses in mainland China: A modeling study.

Subtype interference has a significant impact on the epidemiological patterns of seasonal influenza viruses (SIVs). We used attributable risk percent [the absolute value of the ratio of the effective reproduction number (Rₑ) of different subtypes minus one] to quantify interference intensity between A/H1N1 and A/H3N2, as well as B/Victoria and B/Yamagata. The interference intensity between A/H1N1 and A/H3N2 was higher in southern China 0.26 (IQR: 0.11-0.46) than in northern China 0.17 (IQR: 0.07-0.24). Similarly, interference intensity between B/Victoria and B/Yamagata was also higher in southern China 0.14 (IQR: 0.07-0.24) than in norther China 0.10 (IQR: 0.04-0.18). High relative humidity significantly increased subtype interference, with the highest relative risk reaching 20.59 (95% CI: 6.12-69.33) in southern China. Southern China exhibited higher levels of subtype interference, particularly between A/H1N1 and A/H3N2. Higher relative humidity has a more pronounced promoting effect on subtype interference.

LINC02454-CCT complex interaction is essential for telomerase activity and cell proliferation in head and neck squamous cell carcinoma.

Telomerase activity is upregulated in head and neck squamous cell carcinoma (HNSCC), yet its regulatory mechanisms remain unclear. Here, we identified a cancer-specific lncRNA (LINC02454) associated with poor prognosis by using LncRNA chip of our HNSCC cohorts and external datasets. Through employing negative-stain transmission electron microscopy (NS-TEM), we discovered an interaction between LINC02454 and CCT complex which would augment telomerase activity for maintaining telomere homeostasis. Supporting this, in the telomerase repeat amplification protocol (TRAP) assay and quantitative fluorescence in situ hybridization (Q-FISH) analysis, LINC02454 depletion significantly reduced telomerase activity and shortened telomere length. Consistently, pathways related to telomerase, mitosis, and apoptosis were significantly impacted upon LINC02454 knockdown in RNAseq analysis. Functionally, LINC02454-deficient cells exhibited a more significant senescence phenotype in ß-galactosidase staining, cell cycle, and apoptosis assays. We further confirmed the role of LINC02454 in HNSCC proliferation through a combination of in vitro and in vivo experiments. The therapeutic potential of targeting LINC02454 was verified by adenovirus-shRNA approach in HNSCC patient-derived xenograft (PDX) models. In summary, our findings provided valuable insights into the molecular mechanisms of HNSCC tumorigenesis and potential targets for future treatment modalities.

Too anthropomorphized to keep distance: The role of social psychological distance on meat inclinations.

Keeping a distance from food animals helps alleviate moral conflicts associated with meat consumption. Prior research on the 'meat paradox' has shown that physical distance from animals reduces negative emotional responses when consuming meat. However, even with physical distance, the presence of animals in meat advertisements and packaging can establish psychological contact. The impact of psychological distance on meat consumption and purchase inclinations has not been well explored. Through four experiments, we discovered that animal anthropomorphism psychologically brings consumers closer to food animals, resulting in reduced intentions to consume and purchase meat. Anthropomorphized animal images notably reduced social psychological distance for consumers with moderate to high (vs. lower) levels of anthropomorphic tendencies. Furthermore, the effect of anthropomorphism was influenced by moral self-efficacy. Specifically, when social psychological distance was reduced, consumers with higher (vs. lower) moral self-efficacy exhibited a significant decrease in their willingness to consume and purchase meat. These findings expand our understanding of the role of anthropomorphism in meat marketing, its limitations, and offer insights for sales strategies. Additionally, the research could inform public health policies on meat consumption, addressing environmental and ethical concerns tied to meat production amid growing worries about animal welfare.

Comparative Proteomic Analysis of Aqueous Humor Reveals Biochemical Disparities in the Eyes of High Myopic Patients.

Myopia accounts for a significant proportion of visual lesions worldwide and has the potential to progress toward pathological myopia. This study aims to reveal the difference in protein content in aqueous humor between high myopic and nonhigh myopic patients, as well as better understand the dysregulation of proteins in myopic eyes. Aqueous humor was collected for liquid chromatograph mass spectrometer (LC/MS) analysis from 30 individual eyes that underwent phacoemulsification and intraocular lens (IOL) implantation. Results showed that a total of 190 differentially expressed proteins were identified, which revealed their involvement in cell metabolism, immune and inflammatory response, and system and anatomical structure. Further analysis focused on 15 intensively interacted hub proteins, encompassing functions related to complement cascades, lipoprotein metabolism, and fibrin biological function. Subsequent validations demonstrated elevated levels of APOE (apolipoprotein E), C3 (complement 3), and AHSG (α-2-HS-glycoprotein) in the high myopia group (31 eyes of cataracts and 45 eyes of high myopia with cataracts). AHSG had a significant positive correlation with axial length in high myopic patients, with good efficacy in distinguishing between myopic and nonmyopic groups. AHSG may be a potential indicator of the pathological severity and participator in the pathological progress of high myopia. This study depicted differential expression characteristics of aqueous humor in patients with high myopia and provided optional information for further experimental research on exploring the molecular mechanisms and potential therapeutic targets for high myopia. Data are available via ProteomeXchange with the identifier PXD047584.

Spatial transcriptomics reveals that metabolic characteristics define the tumor immunosuppression microenvironment via iCAF transformation in oral squamous cell carcinoma.

Tumor progression is closely related to tumor tissue metabolism and reshaping of the microenvironment. Oral squamous cell carcinoma (OSCC), a representative hypoxic tumor, has a heterogeneous internal metabolic environment. To clarify the relationship between different metabolic regions and the tumor immune microenvironment (TME) in OSCC, Single cell (SC) and spatial transcriptomics (ST) sequencing of OSCC tissues were performed. The proportion of TME in the ST data was obtained through SPOTlight deconvolution using SC and GSE103322 data. The metabolic activity of each spot was calculated using scMetabolism, and k-means clustering was used to classify all spots into hyper-, normal-, or hypometabolic regions. CD4T cell infiltration and TGF-ß expression is higher in the hypermetabolic regions than in the others. Through CellPhoneDB and NicheNet cell-cell communication analysis, it was found that in the hypermetabolic region, fibroblasts can utilize the lactate produced by glycolysis of epithelial cells to transform into inflammatory cancer-associated fibroblasts (iCAFs), and the increased expression of HIF1A in iCAFs promotes the transcriptional expression of CXCL12. The secretion of CXCL12 recruits regulatory T cells (Tregs), leading to Treg infiltration and increased TGF-ß secretion in the microenvironment and promotes the formation of a tumor immunosuppressive microenvironment. This study delineates the coordinate work axis of epithelial cells-iCAFs-Tregs in OSCC using SC, ST and TCGA bulk data, and highlights potential targets for therapy.

Preoperative and postoperative complications as risk factors for delayed gastric emptying following pancreaticoduodenectomy: A single-center retrospective study.

BACKGROUND: Mortality rates after pancreaticoduodenectomy (PD) have significantly decreased in specialized centers. However, postoperative morbidity, particularly delayed gastric emptying (DGE), remains the most frequent complication following PD. AIM: To identify risk factors associated with DGE after the PD procedure. METHODS: In this retrospective, cross-sectional study, clinical data were collected from 114 patients who underwent PD between January 2015 and June 2018. Demographic factors, pre- and perioperative characteristics, and surgical complications were assessed. Univariate and multivariate analyses were performed to identify risk factors for post-PD DGE. RESULTS: The study included 66 males (57.9%) and 48 females (42.1%), aged 33-83 years (mean: 62.5), with a male-to-female ratio of approximately 1.4:1. There were 63 cases (55.3%) of PD and 51 cases (44.7%) of pylorus-preserving pancreatoduodenectomy. Among the 114 patients who underwent PD, 33 (28.9%) developed postoperative DGE. Univariate analysis revealed significant differences in four of the 14 clinical indexes observed: pylorus preservation, retrocolonic anastomosis, postoperative abdominal complications, and early postoperative albumin (ALB). Logistic regression analysis further identified postoperative abdominal complications [odds ratio (OR) = 4.768, P = 0.002], preoperative systemic diseases (OR = 2.516, P = 0.049), and early postoperative ALB (OR = 1.195, P = 0.003) as significant risk factors. CONCLUSION: Postoperative severe abdominal complications, preoperative systemic diseases, and early postoperative ALB are identified as risk factors for post-PD DGE.

Efficacy and Safety of Implantable Collamer Lens V4c Implantation in 1,834 Myopic Eyes for 1 Year of Follow-up.

PURPOSE: To evaluate visual outcomes of patients with myopia after EVO Implantable Collamer Lens (ICL) (STAAR Surgical) implantation and predict risk factors of postoperative vault abnormalities. METHODS: In this single-center, retrospective analysis, 1,834 eyes of 926 patients with myopia who underwent EVO ICL implantation were recruited between 2020 and 2021. Patients were followed up for 1 year, during which surgery outcomes were evaluated. In addition, 31 eyes with vault abnormalities who underwent secondary surgery were enrolled to form a generalized linear model, which aimed to predict risk factors contributing to vault abnormalities. RESULTS: At the final follow-up visit, safety and efficacy indexes were 1.12 ± 0.17 and 1.10 ± 0.19, respectively, and there was no statistical significance between the low and high myopia groups. Furthermore, 79.18% of eyes achieved a residual spherical equivalent within ±0.50 diopters. Except for the temporary elevation of intraocular pressure at 1 week postoperatively, IOP and endothelial cell density remained stable during follow-up visits. The rate of postoperative adverse events was 21.97% and most adverse events were transient. Vault abnormalities accounted for the majority of complications (9.54%). Results of generalized linear model showed that age was a risk factor for postoperative vault abnormalities, and the anterior chamber depth served as a protective factor (P < .05). CONCLUSIONS: Visual outcomes of EVO ICL implantation were satisfactory in safety and efficacy indexes in both the low and high myopia groups for 1 year of follow-up, with acceptable stability in postoperative spherical equivalent, intraocular pressure, and endothelial cell density. This study emphasized cautious ICL size selection for older patients and those with shallow anterior chamber depth. [J Refract Surg. 2023;39(10):694-704.].

Prevalence of hepatitis E virus in China from 1997 to 2022: a systematic review and meta-analysis.

Introduction: Several studies have reported on hepatitis E virus (HEV) prevalence in various regions of China, but the results vary widely. Herein, we conducted a systematic review and meta-analysis to assess the seroprevalence, RNA-positive rate, genotype distribution of HEV in China, and its risk factors. Methods: We included 208 related studies involving 1,785,569 participants published between 1997 and 2022. Random-effects models were used to pool prevalence, and subgroup analyses were conducted by population, gender, age, study period, regions, and rural-urban distribution. The meta regression models and pooled odds ratios (OR) were performed to identify risk factors for HEV infections. Results: The pooled anti-HEV IgG, IgM, and Ag seroprevalence, and RNA detection rates in China from 1997 to 2022 were 23.17% [95% confidence interval (CI): 20.23-26.25], 0.73% (95% CI: 0.55-0.93), 0.12% (95% CI: 0.01-0.32), and 6.55% (95% CI: 3.46-12.05), respectively. The anti-HEV IgG seropositivity was higher in the occupational population (48.41%; 95% CI: 40.02-56.85) and older adult aged 50-59 years (40.87%; 95% CI: 31.95-50.11). The dominant genotype (GT) of hepatitis E in China was GT4. Notably, drinking non-tap water (OR = 1.82; 95% CI: 1.50-2.20), consumption of raw or undercooked meat (OR = 1.47; 95% CI: 1.17-1.84), and ethnic minorities (OR = 1.50; 95% CI: 1.29-1.73) were risk factors of anti-HEV IgG seroprevalence. Discussions: Overall, the prevalence of hepatitis E was relatively high in China, especially among older adults, ethnic minorities, and humans with occupational exposure to pigs. Thus, there is a need for preventive measures, including HEV infection screening and surveillance, health education, and hepatitis E vaccine intervention in high-risk areas and populations. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023397036.

Global burden and trends of respiratory syncytial virus infection across different age groups from 1990 to 2019: A systematic analysis of the Global Burden of Disease 2019 Study.

OBJECTIVE: Understanding the global patterns of respiratory syncytial virus (RSV) is crucial for developing effective prevention and control strategies. METHODS: Data on RSV-related burden were extracted from the Global Burden of Disease 2019. Joinpoint regression models were used to assess the global temporal trends of RSV and further stratified analyses were conducted according to the Socio-demographic Index (SDI), which is a composite measure of income, education, and total fertility. Age-period-cohort model was used to evaluate age, period, and cohort effects. RESULTS: In 2019, the global age-standardized rate of mortality (ASMR) and disability-adjusted life years (ASR-DALYs) of RSV were 4.79/100,000 (95% uncertainty interval [95% UI]: 1.82/100,000-9.32/100,000) and 218.34/100,000 (95% UI: 92.06/100,000-376.80/100,000), respectively. The burden of RSV was higher in men than women. The highest ASMR (10.26/100,000, 3.80/100,000-20.16/100,000) and ASR-DALYs (478.71/100,000, 202.40/100,000-840.85/100,000) were reported in low-SDI region. Although mortality and DALYs rates in all age groups declined globally, the pace of decline was not uniform across age groups. Mortality rate in the elderly over 70 years surpassed that in children under 5 years in 2019. CONCLUSION: This study highlights the need for targeted interventions to reduce the burden of RSV, particularly in low-SDI region, and among the elderly over 70 years.

Yin Yang 1-Induced Long Noncoding RNA DUXAP9 Drives the Progression of Oral Squamous Cell Carcinoma by Blocking CDK1-Mediated EZH2 Degradation.

LncRNAs play a critical role in oral squamous cell carcinoma (OSCC) progression. However, the function and detailed molecular mechanism of most lncRNAs in OSCC are not fully understood. Here, a novel nuclear-localized lncRNA, DUXAP9 (DUXAP9), that is highly expressed in OSCC is identified. A high level of DUXAP9 is positively associated with lymph node metastasis, poor pathological differentiation, advanced clinical stage, worse overall survival, and worse disease-specific survival in OSCC patients. Overexpression of DUXAP9 significantly promotes OSCC cell proliferation, migration, invasion, and xenograft tumor growth and metastasis, and upregulates N-cadherin, Vimentin, Ki67, PCNA, and EZH2 expression and downregulates E-cadherin in vitro and in vivo, whereas knockdown of DUXAP9 remarkably suppresses OSCC cell proliferation, migration, invasion, and xenograft tumor growth in vitro and in vivo in an EZH2-dependent manner. Yin Yang 1 (YY1) is found to activate the transcriptional expression of DUXAP9 in OSCC. Furthermore, DUXAP9 physically interacts with EZH2 and inhibits EZH2 degradation via the suppression of EZH2 phosphorylation, thereby blocking EZH2 translocation from the nucleus to the cytoplasm. Thus, DUXAP9 can serve as a promising target for OSCC therapy.

[Advances in biodegradation of polyolefin plastics].

Polyolefin plastics are a group of polymers with C-C backbone that have been widely used in various areas of daily life. Due to their stable chemical properties and poor biodegradability, polyolefin plastic waste continues to accumulate worldwide, causing serious environmental pollution and ecological crises. In recent years, biological degradation of polyolefin plastics has attracted considerable attention. The abundant microbial resources in the nature offer the possibility of biodegradation of polyolefin plastic waste, and microorganisms capable of degrading polyolefin have been reported. This review summarizes the research progress on the biodegradation microbial resources and the biodegradation mechanisms of polyolefin plastics, presents the current challenges in the biodegradation of polyolefin plastics, and provides an outlook on future research directions.

A Novel Quantitative Electrocardiography Strategy Reveals the Electroinhibitory Effect of Tamoxifen on the Mouse Heart.

Tamoxifen, a selective estrogen receptor modulator, was initially used to treat cancer in women and more recently to induce conditional gene editing in rodent hearts. However, little is known about the baseline biological effects of tamoxifen on the myocardium. In order to clarify the short-term effects of tamoxifen on cardiac electrophysiology of myocardium, we applied a single-chest-lead quantitative method and analyzed the short-term electrocardiographic phenotypes induced by tamoxifen in the heart of adult female mice. We found that tamoxifen prolonged the PP interval and caused a decreased heartbeat, and further induced atrioventricular block by gradually prolonging the PR interval. Further correlation analysis suggested that tamoxifen had a synergistic and dose-independent inhibition on the time course of the PP interval and PR interval. This prolongation of the critical time course may represent a tamoxifen-specific ECG excitatory-inhibitory mechanism, leading to a reduction in the number of supraventricular action potentials and thus bradycardia. Segmental reconstructions showed that tamoxifen induced a decrease in the conduction velocity of action potentials throughout the atria and parts of the ventricles, resulting in a flattening of the P wave and R wave. In addition, we detected the previously reported prolongation of the QT interval, which may be due to a prolonged duration of the ventricular repolarizing T wave rather than the depolarizing QRS complex. Our study highlights that tamoxifen can produce patterning alternations in the cardiac conduction system, including the formation of inhibitory electrical signals with reduced conduction velocity, implying its involvement in the regulation of myocardial ion transport and the mediation of arrhythmias. A Novel Quantitative Electrocardiography Strategy Reveals the Electroinhibitory Effect of Tamoxifen on the Mouse Heart（Figure 9）. A working model of tamoxifen producing acute electrical disturbances in the myocardium. SN, sinus node; AVN, atrioventricular node; RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle.

SPARC-YAP/TAZ inhibition prevents the fibroblasts-myofibroblasts transformation.

BACKGROUND: Fibrotic scar is a severe side effect of trabeculectomy, resulting in unsatisfactory outcomes for glaucoma surgery. Accumulating evidence showed human Tenon's fibroblasts (HTFs) play an important role in fibrosis formation. We previously reported that the aqueous level of secreted protein acidic and rich in cysteine (SPARC) was higher in the patients with primary angle closure glaucoma, which was associated with the failure of trabeculectomy. In this study, the potential effect and mechanism of SPARC in promoting fibrosis were explored by using HTFs. METHODS: HTFs were employed in this study and examined under a phase-contrast microscope. Cell viability was determined by CCK-8. The expressions of SPARC-YAP/TAZ signaling and the fibrosis-related markers were examined with reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), Western blot, and immunofluorescence, subcellular fractionation was conducted to further determined the variation of YAP and phosphorylated YAP. The differential gene expressions were analyzed with RNA sequencing (RNAseq), followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. RESULTS: Exogenous SPARC induced HTFs-myofibroblast transformation, as evidenced by the increased expression of α-SMA, collagen I and fibronectin in both protein and mRNA levels. SPARC knockdown decreased the expressions of the above genes in TGF-ß2-treated HTFs. KEGG analysis showed that the Hippo signaling pathway was mostly enriched. SPARC treatment increased the expressions of YAP, TAZ, CTGF and CYR61 as well as enhanced YAP translocation from cytoplasm to nucleus, and decreased the phosphorylation of YAP and LAST1/2, which was reversed by SPARC knockdown. Knockdown of YAP1 decreased the fibrosis-related markers, such as α-SMA, collagen I and Fibronectin, in SPARC-treated HTFs. CONCLUSIONS: SPARC induced HTFs-myofibroblast transformation via activating YAP/TAZ signaling. Targeting SPARC-YAP/TAZ axis in HTFs might provide a novel strategy for inhibiting fibrosis formation after trabeculectomy.

Associations of the circulating levels of cytokines with risk of amyotrophic lateral sclerosis: a Mendelian randomization study.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that is accompanied by muscle weakness and muscle atrophy, typically resulting in death within 3-5 years from the disease occurrence. Though the cause of ALS remains unclear, increasing evidence has suggested that inflammation is involved in the pathogenesis of ALS. Thus, we performed two-sample Mendelian randomization (MR) analyses to estimate the associations of circulating levels of cytokines and growth factors with the risk of ALS. METHODS: Genetic instrumental variables for circulating cytokines and growth factors were identified from a genome-wide association study (GWAS) of 8293 European participants. Summary statistics of ALS were obtained from a GWAS including 20,806 ALS cases and 59,804 controls of European ancestry. We used the inverse-variance weighted (IVW) method as the primary analysis. To test the robustness of our results, we further performed the simple-median method, weighted-median method, MR-Egger regression, and MR pleiotropy residual sum and outlier test. Finally, a reverse MR analysis was performed to assess the possibility of reverse causation between ALS and the cytokines that we identified. RESULTS: After Bonferroni correction, genetically predicted circulating level of basic fibroblast growth factor (FGF-basic) was suggestively associated with a lower risk of ALS [odds ratio (OR): 0.74, 95% confidence interval (95% CI): 0.60-0.92, P = 0.007]. We also observed suggestive evidence that interferon gamma-induced protein 10 (IP-10) was associated with a 10% higher risk of ALS (OR: 1.10, 95% CI: 1.03-1.17, P = 0.005) in the primary study. The results of sensitivity analyses were consistent. CONCLUSIONS: Our systematic MR analyses provided suggestive evidence to support causal associations of circulating FGF-basic and IP-10 with the risk of ALS. More studies are warranted to explore how these cytokines may affect the development of ALS.

Targeting cellular metabolism in head and neck cancer precision medicine era: A promising strategy to overcome therapy resistance.

Head and neck squamous cell carcinoma (HNSCC) is among the most prevalent cancer worldwide, with the most severe impact on quality of life of patients. Despite the development of multimodal therapeutic approaches, the clinical outcomes of HNSCC are still unsatisfactory, mainly caused by relatively low responsiveness to treatment and severe drug resistance. Metabolic reprogramming is currently considered to play a pivotal role in anticancer therapeutic resistance. This review aimed to define the specific metabolic programs and adaptations in HNSCC therapy resistance. An extensive literature review of HNSCC was conducted via the PubMed including metabolic reprogramming, chemo- or immune-therapy resistance. Glucose metabolism, fatty acid metabolism, and amino acid metabolism are closely related to the malignant biological characteristics of cancer, anti-tumor drug resistance, and adverse clinical results. For HNSCC, pyruvate, lactate and almost all lipid categories are related to the occurrence and maintenance of drug resistance, and targeting amino acid metabolism can prevent tumor development and enhance the response of drug-resistant tumors to anticancer therapy. This review will provide a better understanding of the altered metabolism in therapy resistance of HNSCC and promote the development of new therapeutic strategies against HNSCC, thereby contribute to a more efficacious precision medicine.

Degradation of HDAC10 by autophagy promotes IRF3-mediated antiviral innate immune responses.

Histone deacetylases (HDACs) play important roles in immunity and inflammation. Through functional screening, we identified HDAC10 as an inhibitor of the type I interferon (IFN) response mediated by interferon regulatory factor 3 (IRF3). HDAC10 abundance was decreased in mouse macrophages in response to innate immune stimuli and was reduced in peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE) compared with that in PBMCs from healthy donors. Deficiency in HDAC10 in mouse embryonic fibroblasts and in mice promoted the expression of genes encoding type I IFNs and of IFN-stimulated genes (ISGs), leading to enhanced antiviral responses in vitro and in vivo. HDAC10 bound in a deacetylase-independent manner to IRF3 in uninfected cells to inhibit the phosphorylation of IRF3 at Ser396 by TANK-binding kinase 1 (TBK1). Upon viral infection, HDAC10 was targeted for autophagy-mediated degradation through its interaction with LC3-II. Consequently, IRF3 phosphorylation was increased, which resulted in enhanced type I IFN production and antiviral responses. Our findings identify a potential target for improving host defense responses against pathogen infection and for treating autoimmune disease.

Alcohol consumption and colorectal cancer risk: A mendelian randomization study.

Background: Previous observational studies have provided inconsistent evidence for the association between alcohol consumption and the risk of colorectal cancer (CRC). To assess this potential causal effect, we performed bidirectional Mendelian randomization (MR) analysis. Methods: We selected six single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) associated with alcohol consumption (ever versus never drinker) and two SNPs representing the number of drinks per week from a genome-wide association study (GWAS) of the Japanese population. Summary data for CRC were obtained from a GWAS meta-analysis in the Japanese population of 6,692 CRC cases and 27,178 controls. MR analysis was performed by the inverse-variance weighted (IVW) method primarily, supplemented with several sensitivity methods including the weighted median method, maximum likelihood method, MR pleiotropy residual sum and outlier (MR-PRESSO) test, MR-Egger regression, Causal Analysis Using Summary Effect estimates (CAUSE) method, as well as constrained maximum likelihood and model averaging and Bayesian information criterion (cML-MA-BIC) method. Multivariable Mendelian randomization (MMR) analyses were used to adjust for potential confounders. Reverse MR analyses were also performed to assess the potential causal effect of CRC on alcohol consumption. Results: Genetically predicted alcohol consumption (ever versus never drinker) was positively associated with the risk of CRC (odds ratio (OR) = 1.08, 95% confidence interval (CI): 1.05-1.12, p = 1.51 × 10-5 by IVW). The number of alcoholic drinks per week was also associated with an increased risk of CRC (OR = 1.39, 95%CI: 1.27-1.52, p = 5.29 × 10-13 by IVW). Sensitivity analysis yielded similar results. Reverse MR analyses found no evidence that CRC contributes to either ever drinkers (OR = 1.00, 95%CI: 0.99-1.00, p = 0.339 by IVW) or added number of drinks per week (OR = 1.01, 95%CI: 0.98-1.05, p = 0.545 by IVW). Conclusion: Our study suggested a potential causal association between alcohol consumption and the risk of CRC among Asians. Reducing drinking may be beneficial to the prevention and management of CRC.

The CC ligand chemokine family members CCL17/CCL22 predict the survival and response to immune checkpoint blockade therapy of patients with head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is considered an immunosuppressive malignancy. Cross-talk between cancer cells and immune cells is modulated in part by CC ligand (CCL) chemokines, having a major effect on tumor progression. However, the predictive value and function of CCL family members in HNSCC have not been elucidated. Here, the predictive value of CCL members in cancer prognosis and Immune checkpoint blockade therapy response was investigated. CCL17 and CCL22 were screened as the key CCL chemokines in HNSCC through co-expression analysis. Further, the correlation between CCL17/CCL22 expression and cancer immune infiltration were evaluated based on TIMER and were validated by a set of scRNA-seq data. Moreover, the expression level of CCL17/CCL22 we evaluated to predict the response to Immune checkpoint blockade therapy in a panel of cancer types by using the TIDE database. Results indicated that CCL17/CCL22 had a high co-expression correlation and had a marginally statistical significance with the overall survival in HNSCC patients (P value = 0.057 and 0.055, respectively). Our findings showed high expression of CCL17/CCL22 was positively correlated with CD4+ T cell infiltration levels in HNSCCs and activate mTORC1 signaling pathway in CD4+ T cells. Further analysis from TIDE showed the high expression of CCL17/CCL22 might predict favorable responses to immune checkpoint blockade therapy in HNSCC patients. These findings provide an insight into the predictive roles of CCL17/CCL22 in HNSCC.

Nuclear translocation of RIG-I promotes cellular apoptosis.

Cell death is important in the elimination of damaged cells such as virus-infected cells and also is closely involved in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). The retinoic acid-inducible gene-I (RIG-I), one cytosolic RNA innate sensor, can trigger antiviral innate response by inducing production of type I interferons (IFN-I). However, the function of RIG-I, once translocated from cytoplasm to nucleus at the late stage of viral infection when IFN-I production is almost terminated, remains poorly understood. Here, we reported that RIG-I is accumulated in the nucleus of macrophages and fibroblasts after virus infection, and nuclear RIG-I is present in peripheral blood mononuclear cells (PBMCs) from SLE patients. We found that nuclear RIG-I interacts with the first 20 amino acids of apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1) and attenuates the anti-apoptotic properties of APEX1, therefore promoting apoptosis of virus-infected cells to suppress viral infection through an IFN-I-independent way at the late stage of viral infection. Together, our findings reveal a non-canonical role of nuclear RIG-I in the induction of cellular apoptosis, besides its activation of IFN-I expression as the cytosolic innate sensor. This study provides new insight to the regulation of infection, IFN-I and autoimmune diseases by nuclear RIG-I-APEX1 interaction.

CBX3 is a Prognostic Biomarker Correlated with ATR Activation and Immune Infiltration in Head and Neck Squamous Cell Carcinoma.

BACKGROUND: Chromobox protein homolog (CBX) family members play important roles in the progression and prognosis of many cancers. However, their functional role in head and neck squamous cell carcinoma (HNSCC) remains largely unknown. METHODS: In this study, we analyzed the expression and functions of CBX family members using The Cancer Genome Atlas data. Most CBX family members were found to be differentially expressed in various tumors, including HNSCC, compared to normal tissues. Multivariate Cox regression analysis showed that CBX3 expression is an independent prognostic factor for HNSCC patients. A nomogram based on CBX3 expression was constructed for use as a diagnostic indicator for HNSCC patients. We also used qPCR to validate the expression of CBX3. RESULTS: Gene set enrichment analysis suggested that CBX3 participates in ataxia-telangiectasia mutated and Rad3-related protein kinase (ATR) activation and tumor progression. Analysis of immune infiltration indicated that CBX3 expression is negatively correlated with mast cells, DCs, immature DCs, and neutrophils. CONCLUSION: Our findings show that high CBX3 expression predicts poor prognosis in HNSCC and that CBX3 may act as an oncoprotein by activating ATR and affecting immune infiltration.