Tumor-associated characteristics and immune dysregulation in nasopharyngeal carcinoma under the regulation of m7G-related tumor microenvironment cells.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a type of malignant tumor with high morbidity. Aberrant levels of N7-methylguanosine (m7G) are closely associated with tumor progression. However, the characteristics of the tumor microenvironment (TME) in NPC associated with m7G modification remain unclear. METHODS: A total of 68,795 single cells from single-cell RNA sequencing data derived from 11 NPC tumor samples and 3 nasopharyngeal lymphatic hyperplasia (NLH) samples were clustered using a nonnegative matrix factorization algorithm according to 61 m7G RNA modification regulators. RESULTS: The m7G regulators were found differential expression in the TME cells of NPC, and most m7G-related immune cell clusters in NPC tissues had a higher abundance compared to non-NPC tissues. Specifically, m7G scores in the CD4+ and CD8+ T cell clusters were significantly lower in NPC than in NLH. T cell clusters differentially expressed immune co-stimulators and co-inhibitors. Macrophage clusters differentially expressed EIF4A1, and high EIF4A1 expression was associated with poor survival in patients with head and neck squamous carcinoma. EIF4A1 was upregulated in NPC tissues compared to the non-NPC tissues and mainly expressed in CD86+ macrophages. Moreover, B cell clusters exhibited tumor biological characteristics under the regulation of m7G-related genes in NPC. The fibroblast clusters interacted with the above immune cell clusters and enriched tumor biological pathways, such as FGER2 signaling pathway. Importantly, there were correlations and interactions through various ligand-receptor links among epithelial cells and m7G-related TME cell clusters. CONCLUSION: Our study revealed tumor-associated characteristics and immune dysregulation in the NPC microenvironment under the regulation of m7G-related TME cells. These results demonstrated the underlying regulatory roles of m7G in NPC.

Nomogram to diagnosis of obstructive sleep apnoea-hypopnoea syndrome in high-risk Chinese adult patients.

INTRODUCTION: Many scales are designed to screen for obstructive sleep apnoea-hypopnoea syndrome (OSAHS); however, there is a lack of an efficiently and easily diagnostic tool, especially for Chinese. Therefore, we conduct a cross-sectional study in China to develop and validate an efficient and simple clinical diagnostic model to help screen patients at risk of OSAHS. METHODS: This study based on 782 high-risk patients (aged >18 years) admitted to the Sleep Medicine department of the Sixth Affiliated Hospital, Sun Yat-sen University from 2015 to 2021. Totally 34 potential predictors were evaluated. We divided all patients into training and validation dataset to develop diagnostic model. The univariable and multivariable logistic regression model were used to build model and nomogram was finally built. RESULTS: Among 602 high-risk patients with median age of 46 (37, 56) years, 23.26% were women. After selecting using the univariate logistic model, 15 factors were identified. We further used the stepwise method to build the final model with five factors: age, BMI, total bilirubin levels, high Berlin score, and symptom of morning dry mouth or mouth breathing. The AUC was 0.780 (0.711, 0.848), with sensitivity of 0.848 (0.811, 0.885), specificity of 0.629 (0.509, 0.749), accuracy of 0.816 (0.779, 0.853). The discrimination ability had been verified in the validation dataset. Finally, we established a nomogram model base on the above final model. CONCLUSION: We developed and validated a predictive model with five easily acquire factors to diagnose OSAHS patient in high-risk population with well discriminant ability. Accordingly, we finally build the nomogram model.

Identification of RNA Modification-Associated Alternative Splicing Signature as an Independent Factor in Head and Neck Squamous Cell Carcinoma.

Objective: Head and neck squamous cell carcinoma (HNSCC) is a highly heterotopic malignant tumor. Alternative splicing (AS) and RNA modification have been reported to be involved in tumorigenesis. Therefore, we constructed RNA modification-associated AS (RMA-AS) signature model to predict the prognosis of HNSCC. Methods: AS events and RNA-modified gene expression information were downloaded from TCGA-HNSCC database. Univariate Cox regression analysis was employed for analyzing prognosis-related AS events. RMA-AS events were obtained by constructing a coexpression network between RNA modification-associated genes and AS events using WGCNA package. The prognostic signatures were analyzed by LASSO, univariate Cox, and multivariate Cox regression. Kaplan-Meier survival analysis, proportional hazard model, and ROC curve were performed to verify the prognostic value. "ESTIMATE" R package, ssGSEA algorithm, and CIBERSORT method were used to detect immune microenvironment in HNSCC. Cytoscape was utilized to build a regulatory network of splicing factor-regulated RMA-AS. Results: There were 16,574 prognostic AS events and 4 differentially expressed RNA modification-associated genes in HNSCC. Based on RMA-AS events, we obtained a risk model consisting of 14 AS events, named RMA-AS_Score. The samples were divided into RMA-AS_Score high- and RMA-AS_Score low-risk groups, according to the risk score. The RMA-AS_Score high group was related to poor prognosis. Moreover, the RMA-AS_Score signature was an independent prognostic predictor and was related to tumor grade. Meanwhile, the AUC value of RMA-AS_Score was 0.652, which is better than other clinical characteristics. Besides, a nomogram prediction model of quantitative prognosis has also been developed, which has robust effectiveness in predicting prognosis. In addition, the prognostic signature was observably related to immune microenvironment and immune checkpoint. Finally, 14 splicing factors were identified and constructed into a network of splicing factor-regulated RMA-AS. Conclusion: We identified the RMA-AS signature of HNSCC. This signature could be treated as an independent prognostic predictor.

Stimuli-Responsive Nanoplatform-Assisted Photodynamic Therapy Against Bacterial Infections.

Bacterial infections are common diseases causing tremendous deaths in clinical settings. It has been a big challenge to human beings because of the antibiotics abuse and the newly emerging microbes. Photodynamic therapy (PDT) is a reactive oxygen species-based therapeutic technique through light-activated photosensitizer (PS). Recent studies have highlighted the potential of PDT as an alternative method of antibacterial treatment for its broad applicability and high efficiency. However, there are some shortcomings due to the low selectivity and specificity of PS. Growing evidence has shown that drug delivery nanoplatforms have unique advantages in enhancing therapeutic efficacy of drugs. Particularly, stimuli-responsive nanoplatforms, as a promising delivery system, provide great opportunities for the effective delivery of PS. In the present mini-review, we briefly introduced the unique microenvironment in bacterial infection tissues and the application of PDT on bacterial infections. Then we review the stimuli-responsive nanoplatforms (including pH-, enzymes-, redox-, magnetic-, and electric-) used in PDT against bacterial infections. Lastly, some perspectives have also been proposed to further promote the future developments of antibacterial PDT.

Tanshinones inhibit NLRP3 inflammasome activation by alleviating mitochondrial damage to protect against septic and gouty inflammation.

Tanshinones, the active ingredients derived from the roots of Salvia miltiorrhiza, have been widely used as traditional medicinal herbs for treating human diseases. Although tanshinones showed anti-inflammatory effects in many studies, large knowledge gaps remain regarding their underlying mechanisms. Here, we identified 15 tanshinones that suppressed the activation of NLRP3 inflammasome and studied their structure-activity relationships. Three tanshinones (tanshinone IIA, isocryptotanshinone, and dihydrotanshinone I) reduced mitochondrial reactive-oxygen species production in lipopolysaccharide (LPS)/nigericin-stimulated macrophages and correlated with altered mitochondrial membrane potentials, mitochondria complexes activities, and adenosine triphosphate and protonated-nicotinamide adenine dinucleotide production. The tanshinones may confer mitochondrial protection by promoting autophagy and the AMP-activated protein kinase pathway. Importantly, our findings demonstrate that dihydrotanshinone I improved the survival of mice with LPS shock and ameliorated inflammatory responses in septic and gouty animals. Our results suggest a potential pharmacological mechanism whereby tanshinones can effectively treat inflammatory diseases, such as septic and gouty inflammation.

Compound AD16 Reduces Amyloid Plaque Deposition and Modifies Microglia in a Transgenic Mouse Model of Alzheimer's Disease.

Microglial dysfunction is involved in the pathological cascade of Alzheimer's disease (AD). The regulation of microglial function may be a novel strategy for AD therapy. We previously reported the discovery of AD16, an antineuroinflammatory molecule that could improve learning and memory in the AD model. Here, we studied its properties of microglial modification in the AD mice model. In this study, AD16 reduced interleukin-1ß (IL-1ß) expression in the lipopolysaccharide-induced IL-1ß-Luc transgenic mice model. Compared with mice receiving placebo, the group treated with AD16 manifested a significant reduction of microglial activation, plaque deposition, and peri-plaques microgliosis, but without alteration of the number of microglia surrounding the plaque. We also found that AD16 decreased senescent microglial cells marked with SA-ß-gal staining. Furthermore, altered lysosomal positioning, enhanced Lysosomal Associated Membrane Protein 1 (LAMP1) expression, and elevated adenosine triphosphate (ATP) concentration were found with AD16 treatment in lipopolysaccharide-stimulated BV2 microglial cells. The underlying mechanisms of AD16 might include regulating the microglial activation/senescence and recovery of its physiological function via the improvement of lysosomal function. Our findings provide new insights into the AD therapeutic approach through the regulation of microglial function and a promising lead compound for further study.

[The value of the pharyngeal airway pressure monitoring test in topodiagnosis of OSA].

Objective:To analyses the value of an improved methods of Muller's test, pharyngeal airway pressure monitoring test（PAPMT）, in topodiagnosis of OSA. Method:One hundred and one cases with OSA（AHI≥5 times per hour） and 30 normal adults were included in the study. Under the pressure monitoring, the electronic laryngoscope were stayed at the palatopharyngeal and glossopharyngeum. First, observe the maximum expiratory pressure and the minimum spiratory pressure. And then measure and record changes of pharynx cross-sectional area at palatopharyngeal and glossopharyngeum under the different pressure. At Last, analyses the correlation between changes of Pharynx cross-sectional area with polysomnography（PSG）. Result:①In 101 cases with OSA, the maximal inspiratory pressure of Müller's manerver distribution is between 1 and 8 kPa. ②The changes of pharynx cross-sectional area of OSA at palatopharyngeal and glossopharyngeum is significantly greater than the control group, and there were obvious differences between OSA and the control group. ③In OSA group, the plug rate at palatopharyngea was 96% and the plug rate at glossopharyngeum is 34% at the minimum pressure. There are no cases have pharynx jams at the control group. ④The main cause of the palatopharyngeal obstruction was strictures in left and right（73%）, and the anatomical factors causing obstruction mainly were, thicken of the pharyngeal wall. The main cause of the hypopharyngeal obstruction was strictures in front and back（71%）, and the redundant lymph tissue at tongue base and posterior displacement of the tongue base, and collapse of pharyngeal wall played an important role at tongue-pharyngeal obstruction. ⑤The changes of pharynx cross-sectional area at palatopharyngeal and glossopharyngeum when the pressure is ±4 kPa is greater than when the pressure is ±2 kPa. ⑥When the pressure is ±2 kPa, The changes of pharynx cross-sectional area at palatopharyngeal is greater than at glossopharyngeum. ⑦Diminished pharyngeal apertures and collapsibility were associated with increased rates of apnea and hypopnea index and the suction pressure（P<0.05）. Conclusion:①PAPMT is able to measure and calculate the changes of pharynx cross-sectional area, determine the site of obstruction, and help the treatment. ②The primary site of obstruction is at velopharyngeal in OSA group. ③The changes of pharynx cross-sectional area at palatopharyngeal and glossopharyngeum of patients can reflects the severity of the OSA.

Diagnosis and management of pediatric cerebrospinal fluid leakage secondary to inner ear malformations: A report of 13 cases.

OBJECTIVES: Inner ear malformations (IEM) with cerebrospinal fluid (CSF) leakage in children is a rare condition, nevertheless, it may lead to meningitis. Early diagnosis and treatment are crucial. The aims of the study were to summarize the clinical characteristic of pediatric CSF leakage secondary to IEM, and to recommend transcanal endoscopic ear surgery (TEES) as an effective surgical technique for the treatment of CSF leakage with IEM in children. METHODS: This was a retrospective study. Thirteen children and fourteen ear surgery were included. Demographics, detail history, laboratory data, Audio test, and imageological examination results were recorded. All the pediatric patients underwent TEES. RESULTS: Most (92.31%) of the children presented with a history of rhinorrhea. 69.23% (9/13) of the children had suffered from meningitis, and the other had presented with respiratory tract infections. The follow-up duration ranged from 0.75 years to 5.29 years. Transcanal endoscopic repair of CSF leakage secondary to IEM was the first surgery with a success rate of 92.86% (13 out of 14 cases). A fistula could be found in the stapes footplate in all pediatric patients. CONCLUSION: Even if there has been no history of meningitis, the diagnosis of CSF leakage in children suffering from unilateral rhinorrhea and recurrent respiratory tract infection is considered. Auditory brainstem response (ABR) and Temporal bone computed tomography (CT) examinations are suggested to identify IEM. The TEES procedure is recommended in our study as the first choice that repairs CSF leakage secondary to IEM.

Disulfiram suppresses NLRP3 inflammasome activation to treat peritoneal and gouty inflammation.

The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome plays a vital role in mediating the innate immune system. Its aberrant activation contributes to the progression of several devastating diseases such as acute peritonitis, acute liver injury, sepsis, gout, and others. However, the medications targeting NLRP3 inflammasome are not available in the clinic. Reusing marketed drugs, which have been already proved to possess good pharmacokinetic profiles and safety, is a strategy to develop new NLRP3 inflammasome inhibitors for clinical trials. In this study, we identified disulfiram (DSF), an old marketed drug as a treatment for alcoholism, could effectively inhibit NLRP3 inflammasome activation and suppress pyroptotic cell death. DSF prevented lysosomal cathepsin B releasing into the cytoplasm, which in turn inactivated the NLRP3 inflammasome. DSF also reduced mitochondrial-independent ROS production. More importantly, treatment with DSF showed remarkable therapeutic effects on the LPS-induced peritoneal inflammation and MSU-induced gouty inflammation. This study provides a potential pharmacological approach to treating NLRP3-driven diseases and a tool to study NLRP3 biology.

Clinical and serologic correlations and autoantibody clusters in systemic lupus erythematosus: a retrospective review of 917 patients in South China.

Ethnicity and environmental factors could be involved in the heterogeneity of systemic lupus erythematosus (SLE). We conducted this study to define clinical and serologic correlations and autoantibody clusters in SLE patients in South China. We retrospectively reviewed the records of 917 patients with SLE admitted to our hospital between January 2005 and June 2008. We found the following associations between autoantibodies and clinical manifestations to be statistically significant: anti-double-stranded DNA (anti-dsDNA) with higher prevalence of renal disorder, leukopenia, and anemia; anti-Sm with higher prevalence of malar rash/discoid rash, pericarditis, and leukopenia; anti-ribonucleoprotein (anti-RNP) with higher prevalence of Raynaud phenomenon and photosensitivity; anti-deoxyribonucleoprotein (anti-DNP) with higher prevalence of arthritis and lower prevalence of renal disorder; anti-Scl-70 with higher prevalence of anemia and Raynaud phenomenon; anti-Jo-1 with higher prevalence of pericarditis; and anti-centromere with higher prevalence of Raynaud phenomenon. Three autoantibody clusters were identified: Cluster 1 (anti-Ro, anti-Sm, and anti-RNP [Ro/Sm/RNP], with a significantly lower percentage of elderly SLE and higher prevalence of photosensitivity, malar rash/discoid rash, Raynaud phenomenon, and leukopenia); Cluster 2 (anti-Ro [Ro], with a lower percentage of pediatric SLE); and Cluster 3 (the absence of anti-extractable nuclear antigen antibodies [ENA ve], with a lower percentage of adult SLE and lower prevalence of alopecia). In summary, this study not only confirms both anti-dsDNA and anti-Sm as specific markers for classifying SLE, but also demonstrates that photosensitivity is not associated with anti-Ro but with anti-RNP, and a negative association is found between renal disorder and anti-DNP in patients in South China. These results are different from results found in other populations. The higher prevalence of anti-dsDNA and renal disorder results in less difference in the prevalence of anti-dsDNA and renal disorder among the 3 autoantibody clusters in SLE patients in South China, which could be related to ethnicity and widespread industrial pollution in South China.