TMEM16A inhibits autophagy and promotes the invasion of hypopharyngeal squamous cell carcinoma through mTOR pathway.

Previous studies have indicated that transmembrane protein 16A (TMEM16A) plays a crucial role in the pathogenesis and progression of various tumors by influencing multiple signaling pathways. However, the role of TMEM16A in regulating autophagy via the mammalian target of rapamycin (mTOR) pathway and its impact on the development of hypopharyngeal squamous cell carcinoma (HSCC) remain unclear. Immunohistochemistry and western blotting were used to assess the expression of TMEM16A in HSCC tissues and metastatic lymph nodes. Manipulation of TMEM16A expression levels was achieved in the FaDu cell line through overexpression or knockdown, followed by assessment of its biological effects using cell colony formation, wound healing, transwell, and invasion assays. Additionally, apoptosis and autophagy-related proteins, as well as autophagosome formation, were evaluated through western blotting, transmission electron microscopy, and immunofluorescence following TMEM16A knockdown or overexpression in FaDu cells. Our study revealed significantly elevated levels of TMEM16A in both HSCC tissues and metastatic lymph nodes compared to normal tissues. In vitro experiments demonstrated that silencing TMEM16A led to a notable suppression of HSCC cell proliferation, invasion, and migration. Furthermore, TMEM16A silencing effectively inhibited tumor growth in xenografted mice. Subsequent investigations indicated that knockdown of TMEM16A in HSCC cells could suppress mTOR activation, thereby triggering autophagic cell death by upregulating sequestosome-1 (SQSTM1/P62) and microtubule-associated protein light chain 3 II (LC3II). This study highlights the crucial role of TMEM16A in modulating autophagy in HSCC, suggesting its potential as a therapeutic target for the treatment of this malignancy.

IL-6 mediates olfactory dysfunction in a mouse model of allergic rhinitis.

BACKGROUND: Immune-inflammatory response is a key element in the occurrence and development of olfactory dysfunction (OD) in patients with allergic rhinitis (AR). As one of the core factors in immune-inflammatory responses, interleukin (IL)-6 is closely related to the pathogenesis of allergic diseases. It may also play an important role in OD induced by diseases, such as Sjögren's syndrome and coronavirus disease 2019. However, there is no study has reported its role in OD in AR. Thus, this study aimed to investigate the role of IL-6 in AR-related OD, in an attempt to discover a new target for the prevention and treatment of OD in patients with AR. METHODS: Differential expression analysis was performed using the public datasets GSE52804 and GSE140454 for AR, and differentially expressed genes (DEGs) were obtained by obtaining the intersection points between these two datasets. IL-6, a common differential factor, was obtained by intersecting the DEGs with the General Olfactory Sensitivity Database (GOSdb) again. A model of AR mice with OD was developed by sensitizing with ovalbumin (OVA) to verify the reliability of IL-6 as a key factor of OD in AR and explore the potential mechanisms. Furthermore, a supernatant and microglia co-culture model of nasal mucosa epithelial cells stimulated by the allergen house dust mite extract Derp1 was established to identify the cellular and molecular mechanisms of IL-6-mediated OD in AR. RESULTS: The level of IL-6 in the nasal mucosa and olfactory bulb of AR mice with OD significantly increased and showed a positive correlation with the expression of olfactory bulb microglia marker Iba-1 and the severity of OD. In-vitro experiments showed that the level of IL-6 significantly increased in the supernatant after the nasal mucosa epithelial cells were stimulated by Derp1, along with significantly decreased barrier function of the nasal mucosa. The expression levels of neuroinflammatory markers IL-1ß and INOS increased after a conditioned culture of microglia with the supernatant including IL-6. Then knockdown (KD) of IL-6R by small interfering RNA (siRNA), the expression of IL-1ß and INOS significantly diminished. CONCLUSION: IL-6 plays a key role in the occurrence and development of OD in AR, which may be related to its effect on olfactory bulb microglia-mediated neuroinflammation.

Establishment of an in situ model to explore the tumor immune microenvironment in head and neck squamous cell carcinoma.

OBJECTIVE: Establish an in situ model for investigating HNSCC, focusing on tumor growth, metastasis, and the immune microenvironment. METHODS: Generated a monoclonal SCCVII-ZsGreen cell line through lentiviral transfection. Selected monoclonal lines with growth rates similar to the original SCCVII for in vivo tumorigenesis. Monitored tumor development and metastasis through fluorescence in vivo imaging. Employed immunohistochemistry to assess immune cell distribution in the tumor microenvironment. RESULTS: SCCVII-ZsGreen exhibited comparable proliferation and in vivo tumorigenicity to SCCVII. In situ tumor formation on day 10, with cervical metastasis in C57BL/6 mice by day 16. No significant fluorescence signals in organs like liver and lungs, while SCCVII-ZsGreen presence confirmed in cervical lymph node metastases. Immunohistochemistry revealed CD4+ T, CD8+ T, B, and dendritic cells distribution, with minimal macrophages. CONCLUSION: Our model is a valuable tool for studying HNSCC occurrence, metastasis, and immune microenvironment. It allows dynamic observation of tumor development, aids preclinical drug experiments, and facilitates exploration of the tumor immune contexture.

Advances in co-pathogenesis of the united airway diseases.

According to the concept of "united airway diseases", the airway is a single organ in which upper and lower airway diseases are commonly comorbid. A range of inflammatory factors have been found to play an important role in the chain reaction of upper and lower airway diseases. However, the amount of research on this concept remains limited. The underlying mechanism of the relationship between typical diseases of the united airway, such as asthma, allergic rhinitis, and chronic sinusitis, also needs to be further explored. This review highlights the interaction between upper and lower respiratory diseases gathered from epidemiological, histoembryology, neural mechanistic, microbiological, and clinical studies, revealing the relationship between the upper and lower respiratory tracts.

Proteomic and metabolomic proof of concept for unified airways in chronic rhinosinusitis and asthma.

BACKGROUND: The pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) with comorbid asthma remains unclear. OBJECTIVE: To assess upper and lower airway unity and identify a possible common pathogenesis in CRSwNP with asthma. METHODS: This study analyzed the expression of proteins and metabolites in nasal lavage fluid cells (NLFCs) and induced sputum cells (ISCs). Differentially expressed proteins and their function-related metabolites in the upper and lower airways of patients having CRSwNP with or without asthma were identified; relevant signaling pathways were analyzed, and key pathway-related proteins were identified. Parallel reaction monitoring was used to verify these target proteins. RESULTS: Protein or metabolite expression between NLFCs and ISCs was highly correlated and conservative on the basis of expression profiles and weighted gene coexpression network analysis. There were 17 differentially coexpressed proteins and their function-related 13 metabolites that were identified in the NLFCs and ISCs of CRSwNP, whereas 11 proteins and 11 metabolites were identified in CRSwNP with asthma. An asthma pathway was involved in the copathogenesis of upper and lower airways in whether CRSwNP or CRSwNP with asthma. The asthma pathway-related proteins proteoglycan 2 and eosinophil peroxidase, as the core of the protein-metabolism interaction networks between the upper and lower airways, were both highly coexpressed in NLFCs and ISCs in patients having either CRSwNP or CRSwNP with asthma by parallel reaction monitoring validation. CONCLUSION: Proteomics and metabolomics reveal upper and lower airway unity. Asthma pathway-related proteins proteoglycan 2 and eosinophil peroxidase from the upper airway could be used to assess the potential risk of lower airway dysfunction in CRSwNP.

Anlotinib suppressed tumor cell proliferation and migration in hypopharyngeal carcinoma.

OBJECTIVE: The purpose of this study is to study the in-vitro effects of multitarget inhibitor anlotinib on hypopharyngeal cancer cell proliferation and cell migration, and the underlying mechanism, which will provide new drug choices for hypopharyngeal cancer treatment. METHODS: The Hypopharyngeal cancer Fadu cells were treated with anlotinib at a concentration of 0, 5, and 10 µmoL/L, respectively. Cell counting kit-8 and the colony-forming assay were used to detect the inhibition of cell proliferation. Wound-healing assay and transwell assay were used to detect the migration and invasion ability of cells. Flow cytometry was used to detect the effects of anlotinib on cell cycle and apoptosis. RT-qPCR and Western blot were used to measure gene expression levels. RESULTS: CCK-8 and colony-forming assay showed that anlotinib could significantly inhibit cell proliferative activity. Wound-healing assay and transwell assay showed that anlotinib could inhibit cell migration and scratch. These results showed that anlotinib has obvious antitumor activity. Flow cell cycle experiment showed that anlotinib could promote Fadu cell apoptosis and block the G2/M phase for inhibiting cell proliferation. In addition, anlotinib decreased the expression of HIF-1α. CONCLUSIONS: Anlotinib has an excellent suppressing effect on the proliferation, migration, and invasion of hypopharyngeal cancer Fadu cells in-vitro. Moreover, it can play an anti-tumor role through blocking cell cycle G2/M and promoting apoptosis, which may be related to the decrease of HIF-1a expression. Our study would provide a potential treatment method for patients with hypopharyngeal cancer. LEVEL OF EVIDENCE: Level 3.

Inhibition of the ILK-AKT pathway by upregulation of PARVB contributes to the cochlear cell death in Fascin2 gene knockout mice.

The Fscn2 (Fascin2) gene encodes an actin cross-linking protein that is involved in the formation of hair cell stereocilia and retina structure. Mutations in Fscn2 gene have been linked to hearing impairment and retinal degeneration in humans and mice. To understand the function of the Fscn2 gene, we generated the Fscn2 knockout mice, which showed progressive loss of hearing and hair cells. Our goal of the present study was to investigate the mechanism underlying cochlear cell death in the Fscn2 knockout mice. Microarray analysis revealed upregulation of expression of PARVB, a local adhesion protein, in the inner ears of Fscn2 knockout mice at 8 weeks of age. Further studies showed increased levels of PARVB together with cleaved-Caspase9 and decreased levels of ILK, p-ILK, p-AKT, and Bcl-2 in the inner ears of Fscn2 knockout mice of the same age. Knockdown of Fscn2 in HEI-OCI cells led to decreased cell proliferation ability and migration rate, along with increased levels of PARVB and decreased levels of ILK, p-ILK, p-AKT, Bcl-2 and activated Rac1 and Cdc42. Overexpression of Fscn2 or inhibition of Parvb expression in HEI-OC1 cells promoted cell proliferation and migration, with increased levels of ILK, p-ILK, p-AKT, and Bcl-2. Finally, FSCN2 binds with PPAR-γ to reduce its nuclear translocation in HEI-OC1 cells, and inhibition of PPAR-γ by GW9662 decreased the level of PARVB and increased the levels of p-AKT, p-ILK, and Bcl-2. Our results suggest that FSCN2 negatively regulates PARVB expression by inhibiting the entry of PPAR-γ into the cell nucleus, resulting in inhibition of ILK-AKT related pathways and of cochlear cell survival in Fscn2 knockout mice. Our findings provide new insights and ideas for the prevention and treatment of genetic hearing loss.

P2X7 receptor of olfactory bulb microglia plays a pathogenic role in stress-related depression in mice with allergic rhinitis.

The aim of this study was to explore the role and mechanism of the olfactory bulb (OB) microglial P2X7 receptor (P2X7R) in allergic rhinitis (AR)-related depression, with the objective of identifying a potential clinical target. An AR mouse model was induced using ovalbumin (OVA), while chronic stress was employed to induce depression. The study used P2X7R-specific antagonists and OB microglia-specific P2X7R knockdown mice as crucial tools. The results showed that mice in the OVA + stress group exhibited more pronounced depressive-like phenotypes. Furthermore, there was an observed increase in microglial activation in the OB, followed by a rise in the level of inflammation. The pharmacological inhibition of P2X7R significantly mitigated the depression-like phenotype and the OB inflammatory response in OVA + stress mice. Notably, the specific knockdown of microglial P2X7R in the OB resulted in a similar effect, possibly linked to the regulation of IL-1ß via the "ATP-P2X7R-Caspase 1" axis. These findings collectively demonstrate that microglial P2X7R in the OB acts as a direct effector molecule in AR-related depression, and its inhibition may offer a novel strategy for clinical prevention and treatment.

Efficacy and safety of stapokibart (CM310) in uncontrolled seasonal allergic rhinitis (MERAK): an investigator-initiated, placebo-controlled, randomised, double-blind, phase 2 trial.

Background: There is no trial to assess the benefits of periodically using biologics during the pollen season in patients with uncontrolled seasonal allergic rhinitis (SAR), who have moderate-to-severe symptoms even after standard-of-care. This trial aimed to evaluate the efficacy and safety of the add-on administration of stapokibart, a humanised monoclonal antibody that targets interleukin-4 receptor alpha, in patients with uncontrolled SAR. Methods: In this investigator-initiated, randomised, double-blind, placebo-controlled trial, eligible patients received either stapokibart 600-300 mg weekly (QW), every 2 weeks (Q2W), or placebo QW for 4 weeks. All patients were given mometasone furoate nasal spray and loratadine throughout the trial. The primary endpoint was the mean change from baseline in daily reflective total nasal symptom score (rTNSS) during 2-week treatment. Secondary efficacy outcomes included: the mean change from baseline in daily rTNSS during 4-week treatment; the mean changes and the mean percentage changes from baseline during 2-week and 4-week treatment in 1) daily rTNSS and reflective total ocular symptom score (rTOSS), 2) morning (AM)/evening (PM) rTNSS and rTOSS, 3) AM instantaneous total nasal symptom score (iTNSS) and instantaneous total ocular symptom score (iTOSS), 4) individual nasal and ocular symptoms; the change from baseline in Rhinoconjunctivitis Quality of-Life Questionnaire score during 4-week treatment. Exploratory endpoints included the change of prespecified markers related to type 2 inflammation pre- and post-treatment. Safety, immunogenicity, and pharmacokinetics were also evaluated. This study is registered with www.clinicaltrials.gov (NCT05470647). Findings: Between August 17, 2022, and December 28, 2022, 92 patients with uncontrolled SAR were enrolled from 4 centres in China and randomly assigned to receive stapokibart 600-300 mg QW (n = 31), stapokibart 600-300 mg Q2W (n = 30), or placebo QW (n = 31), of whom 86 (93%) completed the study. Both stapokibart Q2W and QW did not significantly improve mean change from baseline in daily rTNSS compared with placebo in 2 weeks. The least-squares (LS) mean differences (97.5% confidence interval [CI]) compared with placebo were -1.0 (-2.3, 0.2) in stapokibart Q2W group (p = 0.065) and -0.2 (-1.5, 1.0) in stapokibart QW group (p = 0.67). For the secondary outcomes, compared with placebo, stapokibart Q2W presented significant improvements in the mean percentage change from baseline in daily rTNSS in 2 weeks (LS mean difference -12.9%, 95% CI -25.3%, -0.4%, p = 0.043), as well as AM iTNSS over 2 weeks (LS mean difference -17.4%, 95% CI -31.0%, -3.8%, p = 0.013) and 4 weeks (LS mean difference -15.4%, 95% CI -29.0%, -1.9%, p = 0.026). Additionally, the nasal congestion score was significantly lower in stapokibart Q2W than placebo during 2-week (LS mean difference -0.4, 95% CI -0.7, -0.1, p = 0.014) and 4-week (LS mean difference -0.4, 95% CI -0.7, -0.04, p = 0.028) treatment. Treatment-emergent adverse events (TEAEs) occurred in 48% (15/31), 33% (10/30), and 61% (19/31) of patients receiving stapokibart QW, Q2W, and placebo, respectively. Most reported TEAEs were sinus bradycardia, hyperlipidaemia, and blood uric acid increased. Interpretation: In this phase 2 trial, both stapokibart regimens had an acceptable safety and tolerability profile but did not significantly improve daily rTNSS in patients with uncontrolled SAR. The efficacy of stapokibart in patients with uncontrolled SAR is being further investigated in ongoing phase 3 trials (clinicaltrials.gov, NCT05908032). Funding: Ministry of Science and Technology of the People's Republic of China; Ministry of Education of the People's Republic of China; National Natural Science Foundation of China; Chinese Academy of Medical Sciences.

Characteristics of mucin hypersecretion in different inflammatory patterns based on endotypes of chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is usually accompanied by mucin hypersecretion that can lead to mucus accumulation and impair nasal mucociliary clearance, thus exacerbating airway inflammation. Abnormal mucin hypersecretion is regulated by different T helper (Th) cytokines, which are associated with different endotype-driven inflammatory responses. Therefore, it is of great significance to understand how these factors regulate mucin hypersecretion to provide precise treatment strategies for different endotypes of CRS. BODY: Thus far, the most common endotypes of CRS are classified as type 1, type 2, or type 3 immune responses based on innate and adaptive cell-mediated effector immunity, and the representative Th cytokines in these immune responses, such as IFN-γ, TNF-α, IL-4, IL-5, IL-13, IL-10, IL-17, and IL-22, play an important regulatory role in mucin secretion. We reviewed all the related literature in the PubMed database to determine the expression of these Th cytokines in CRS and the role they play in the regulation of mucin secretion. CONCLUSION: We believe that the main Th cytokines involved in specific endotypes of CRS play a key role in regulating abnormal mucin secretion, which contributes to better understanding of the pathogenesis of CRS and provides therapeutic targets for airway inflammatory diseases associated with mucin hypersecretion.

Advances in Thyroid Organoids Research and Applications.

INTRODUCTION: Organoids are three-dimensional cellular aggregates derived from stem cells or primary tissues that can self-organize into organotypic structures and showcase the physiological functions of that organ. Organoids typically comprise multiple organ-specific cell types that are responsible for organ function in vivo. They may also incorporate various cellular and molecular stromal components to recapitulate the in vivo microenvironment of the target organ. METHODS: All articles related to thyroid-like organs were synthesized. Articles published between 1959 and 2023 were assessed, categorized, and analyzed using relevant keywords. RESULTS: As such, organoids provide a model of greater physiological relevance than 2D cell culture for basic and translational research. Murine and human organoids of the thyroid have been established from embryonic stem cells (ESCs), pluripotent stem cells (PSCs) and from various healthy or diseased thyroid tissues. These thyroid organoids have been used in basic and translation research on thyroid-related diseases including hyperthyroidism, Graves' disease, and Hashimoto's thyroiditis. In addition, organoids derived from patients with thyroid cancer retain histopathological features and mutational profile of the original tumor. These patient-derived organoids have been successfully used in in vitro evaluation of drug response of individual patients, demonstrating their potential application in personalized treatment of thyroid cancer. CONCLUSION: In this review article, we have discussed various techniques for establishing thyroid organoids and their applications in thyroid-related diseases as disease models, regenerative medicines, or a tool for drug testing.

Cell type-specific molecular mechanisms and implications of necroptosis in inflammatory respiratory diseases.

Necroptosis is generally considered as an inflammatory cell death form. The core regulators of necroptotic signaling are receptor-interacting serine-threonine protein kinases 1 (RIPK1) and RIPK3, and the executioner, mixed lineage kinase domain-like pseudokinase (MLKL). Evidence demonstrates that necroptosis contributes profoundly to inflammatory respiratory diseases that are common public health problem. Necroptosis occurs in nearly all pulmonary cell types in the settings of inflammatory respiratory diseases. The influence of necroptosis on cells varies depending upon the type of cells, tissues, organs, etc., which is an important factor to consider. Thus, in this review, we briefly summarize the current state of knowledge regarding the biology of necroptosis, and focus on the key molecular mechanisms that define the necroptosis status of specific cell types in inflammatory respiratory diseases. We also discuss the clinical potential of small molecular inhibitors of necroptosis in treating inflammatory respiratory diseases, and describe the pathological processes that engage cross talk between necroptosis and other cell death pathways in the context of respiratory inflammation. The rapid advancement of single-cell technologies will help understand the key mechanisms underlying cell type-specific necroptosis that are critical to effectively treat pathogenic lung infections and inflammatory respiratory diseases.

Cortisol Sensitizes Cochlear Hair Cells to Gentamicin Ototoxicity Via Endogenous Apoptotic Pathway.

BACKGROUND: The widespread use of aminoglycosides is a prevalent cause of sensorineural hearing loss. Patients receiving aminoglycosides usually have elevated levels of circulating stress hormones due to disease or physiological stress; however, whether the stress hormone cortisol impacts aminoglycoside-mediated injury of cochlear hair cells has not been fully investigated. METHODS: House Ear Institute-Organ of Corti 1 (HEI-OC1) cells with or without cortisol pretreatment were exposed to gentamicin, we investigated the effect of cortisol pretreatment on gentamicin ototoxicity by assessing cell viability. Molecular pathogenesis was explored by detecting apoptosis and oxidative stress. Meanwhile, by inhibiting glucocorticoid receptors (GR) and mineralocorticoid receptors (MR), the potential roles of receptor types in cortisol-mediated sensitization were evaluated. RESULTS: Cortisol concentrations below 75 µmol/l did not affect cell viability. However, pretreatment with 50 µmol/l cortisol for 24 hours sensitized hair cells to gentamicin-induced apoptosis. Further mechanistic studies revealed that cortisol significantly increased hair cell apoptosis and oxidative stress, and altered apoptosis-related protein expressions induced by gentamicin. In addition, blockade of either GR or MR attenuated cortisol-induced hair cell sensitization to gentamicin toxicity. CONCLUSION: Cortisol pretreatment increased mammalian hair cell susceptibility to gentamicin toxicity. Sensitization was related to the activation of the intrinsic apoptotic pathway and excessive generation of reactive oxygen species. Cortisol may exacerbate aminoglycoside ototoxicity.

Gasless Single-Incision Endoscopic Surgery via Subclavicular Approach for Lateral Neck Dissection in Patients with Papillary Thyroid Cancer.

BACKGROUND: The technical difficulties and trauma of remote access methods in endoscopic surgery (ES) for lateral neck dissection (LND) can be daunting for most patients with papillary thyroid cancer (PTC) and surgeons. The purpose of study was to introduce gasless single-incision ES via a subclavicular approach (ESSA) and to explore its safety and efficacy for LND. METHODS: Between January 2022 and February 2023, we retrospectively reviewed 17 patients with PTC who underwent ESSA for LND. In addition, 22 patients who received video-assisted ES (VAES) and 48 patients who underwent open surgery (OP) for LND during the same period were included. Clinicopathological characteristics, complications, and efficacy of the lymph node yield (LNY) were compared between the ESSA and the other two groups (VAES and OP). RESULTS: The LNY from central and lateral neck dissection by ESSA was comparable to that by VAES (9.2 ± 8.1 vs. 9.5 ± 4.2, P = 0.986, and 33.5 ± 11.6 vs. 30.6 ± 9.2, P = 0.382, respectively) and OP (9.2 ± 8.1 vs. 11.0 ± 5.4, P = 0.420, and 33.5 ± 11.6 vs. 31.5 ± 7.9, P = 0.383, respectively). Swallowing impairment scores at 1 and 3 months were significantly lower after ESSA than those after VAES (1.8 ± 1.0 vs. 3.0 ± 1.2, P = 0.003, and 0.9 ± 0.8 vs. 1.7 ± 0.8, P = 0.006, respectively). The cosmetic satisfaction rate 1 month after surgery was significantly higher in the ESSA group than that in the VAES group (100 vs. 31.8%, P < 0.001). CONCLUSIONS: ESSA is a safe and minimally invasive procedure that provides a scarless cervical appearance and has good efficacy for LND. Therefore, ESSA may be a feasible choice for selected patients with N1b PTC with cervical cosmetic needs.

Development and Validation of a Computed Tomography-Based Radiomics Nomogram for the Preoperative Prediction of Central Lymph Node Metastasis in Papillary Thyroid Microcarcinoma.

RATIONALE AND OBJECTIVES: This study aims to develop and validate a computed tomography (CT)-based radiomics nomogram for pre-operatively predicting central lymph node metastasis (CLNM) in patients with papillary thyroid microcarcinoma (PTMC) and explore the underlying biological basis by using RNA sequencing data. METHODS: This study trained 452 PTMC patients across two hospitals from January 2012 to December 2020. The sets were randomly divided into the training (n = 339), internal test (n = 86), external test (n = 27) sets. Radiomics features were extracted from primary lesion's pre-operative CT images for each patient. After screening for features, five algorithms such as K-nearest neighbor, logistics regression, linear-support vector machine (SVM), Gaussian SVM, and polynomial SVM were used to establish the radiomics models. The performance of these five algorithms was evaluated and compared directly to radiologist's interpretation (CT-reported lymph node status). The radiomics signature score (Rad-score) was generated using a linear combination of the selected features. By combining the clinical risk factors and Rad score, a radiomics nomogram was established and compared with Rad-score and clinical model. The performance of the nomogram was evaluated based on the receiver operating characteristic (ROC) curve, calibration curve, and the decision curve analysis (DCA). The potential biological basis of nomogram was revealed by performing genetic analysis based on the RNA sequencing data. RESULTS: A total of 25 radiomic features were ultimately selected to train the machine learning models, and the five machine learning models outperformed the radiologists' interpretation by achieving area under the ROC curves (AUCs) ranging from 0.606 to 0.730 in the internal test set. By incorporating the Rad score and clinical risk factors (sex, age, tumor-diameter, and CT-reported lymph node status), this nomogram achieved AUCs of 0.800 and 0.803 in the internal and external test set, which were higher than that of the Rad-score and clinical model, respectively. Calibration curves and DCA also showed that the nomogram had good performance. As for the biological basis exploration, in patients predicted by nomogram to be PTC patients with CLMN, 109 genes were dysregulated, and some of them were associated with pathways and biological processes such as tumor angiogenesis. CONCLUSION: This radiomics nomogram successfully identified CLNM on pretreatment imaging across multiple institutions, exceeding the diagnostic ability of radiologists and had the potential to be integrated into clinical decision making as a non-invasive pre-operative tool.

Exploring the Connectivity of Neurodegenerative Diseases: Microglia as the Center.

Degenerative diseases affect people's life and health and cause a severe social burden. Relevant mechanisms of microglia have been studied, aiming to control and reduce degenerative disease occurrence effectively. This review discussed the specific mechanisms underlying microglia in neurodegenerative diseases, age-related hearing loss, Alzheimer's disease, Parkinson's disease, and peripheral nervous system (PNS) degenerative diseases. It also reviewed the studies of microglia inhibitors (PLX3397/PLX5622) and activators (lipopolysaccharide), and suggested that reducing microglia can effectively curb the genesis and progression of degenerative diseases. Finally, microglial cells' anti-inflammatory and pro-inflammatory dual role was considered the critical communication point in central and peripheral degenerative diseases. Although it is difficult to describe the complex morphological structure of microglia in a unified manner, this does not prevent them from being a target for future treatment of neurodegenerative diseases.

Meta-analysis of the relationship between montelukast use and neuropsychiatric events in patients with allergic airway disease.

Use of montelukast, as a cause of neuropsychiatric events, in patients with asthma or allergic rhinitis is controversial, and comprehensive statistical analyses verifying this relationship remain lacking. To better understand the relationship between montelukast and neuropsychiatric events, it is vital to guide patients in the effective use of the drug, especially in children whose mothers are concerned about its side effects. In this study, randomized controlled trials (RCTs) investigating montelukast and neuropsychiatric events were retrieved from a literature search of the Medline (1966 to February 2023), Embase (1974 to February 2023), Web of Science, and other related databases. After screening, 18 RCTs were ultimately included in a meta-analysis to merge statistics, which demonstrated no significant increase in neuropsychiatric events compared with placebo. A similar pattern of adverse neuropsychiatric events was observed in patients grouped according to age, with headache being the most common adverse neuropsychiatric event. Overall, montelukast did not significantly increase neuropsychiatric events in patients with allergic rhinitis and/or asthma compared with placebo. Large-sample RCTs are needed to verify the association between neuropsychiatric events and montelukast use in children, and attention is also devoted to FDA warnings.

Construction and validation of a prognostic nine-gene signature associated with radiosensitivity in head and neck squamous cell carcinoma.

Background: Radiotherapy is an effective treatment for head and neck squamous cell carcinoma (HNSCC), however how to predict the prognosis is not clear. Methods: Here we collected 262 radiosensitivity-associated genes, screened and constructed a prognostic nine-gene risk model through univariate COX, lasso regression, stepwise regression and multivariate COX analysis for transcriptome and clinical information of HNSCC patients obtained from the cancer genome atlas (TCGA) and gene expression omnibus (GEO) databases. Results: The reliability and robustness of the risk model were verified by receiver operating characteristic (ROC) curves, risk maps, and Kaplan-Meier (KM) curves analysis. Differences in immune cell infiltration and immune-related pathway enrichment between high-risk and low-risk subgroups were determined by multiple immune infiltration analyses. Meanwhile, the mutation map and the responses to immunotherapy were also differentiated by the prognostic nine-gene signature associated with radiosensitivity. These nine genes expression in HNSCC was verified in the Human Protein Atlas (HPA) database. After that, these nine genes expression was verified to be related to radiation resistance through in-vitro cell experiments. Conclusions: All results showed that the nine-gene signature associated with radiosensitivity is a potential prognostic indicator for HNSCC patients after radiotherapy and provides potential gene targets for enhancing the efficacy of radiotherapy.