Revealing molecular and cellular heterogeneity in hypopharyngeal carcinogenesis through single-cell RNA and TCR/BCR sequencing.

Introduction: Hypopharyngeal squamous cell carcinoma (HSCC) is one of the malignant tumors with the worst prognosis in head and neck cancers. The transformation from normal tissue through low-grade and high-grade intraepithelial neoplasia to cancerous tissue in HSCC is typically viewed as a progressive pathological sequence typical of tumorigenesis. Nonetheless, the alterations in diverse cell clusters within the tissue microenvironment (TME) throughout tumorigenesis and their impact on the development of HSCC are yet to be fully understood. Methods: We employed single-cell RNA sequencing and TCR/BCR sequencing to sequence 60,854 cells from nine tissue samples representing different stages during the progression of HSCC. This allowed us to construct dynamic transcriptomic maps of cells in diverse TME across various disease stages, and experimentally validated the key molecules within it. Results: We delineated the heterogeneity among tumor cells, immune cells (including T cells, B cells, and myeloid cells), and stromal cells (such as fibroblasts and endothelial cells) during the tumorigenesis of HSCC. We uncovered the alterations in function and state of distinct cell clusters at different stages of tumor development and identified specific clusters closely associated with the tumorigenesis of HSCC. Consequently, we discovered molecules like MAGEA3 and MMP3, pivotal for the diagnosis and treatment of HSCC. Discussion: Our research sheds light on the dynamic alterations within the TME during the tumorigenesis of HSCC, which will help to understand its mechanism of canceration, identify early diagnostic markers, and discover new therapeutic targets.

Multi-instance learning based artificial intelligence model to assist vocal fold leukoplakia diagnosis: A multicentre diagnostic study.

OBJECTIVE: To develop a multi-instance learning (MIL) based artificial intelligence (AI)-assisted diagnosis models by using laryngoscopic images to differentiate benign and malignant vocal fold leukoplakia (VFL). METHODS: The AI system was developed, trained and validated on 5362 images of 551 patients from three hospitals. Automated regions of interest (ROI) segmentation algorithm was utilized to construct image-level features. MIL was used to fusion image level results to patient level features, then the extracted features were modeled by seven machine learning algorithms. Finally, we evaluated the image level and patient level results. Additionally, 50 videos of VFL were prospectively gathered to assess the system's real-time diagnostic capabilities. A human-machine comparison database was also constructed to compare the diagnostic performance of otolaryngologists with and without AI assistance. RESULTS: In internal and external validation sets, the maximum area under the curve (AUC) for image level segmentation models was 0.775 (95 % CI 0.740-0.811) and 0.720 (95 % CI 0.684-0.756), respectively. Utilizing a MIL-based fusion strategy, the AUC at the patient level increased to 0.869 (95 % CI 0.798-0.940) and 0.851 (95 % CI 0.756-0.945). For real-time video diagnosis, the maximum AUC at the patient level reached 0.850 (95 % CI, 0.743-0.957). With AI assistance, the AUC improved from 0.720 (95 % CI 0.682-0.755) to 0.808 (95 % CI 0.775-0.839) for senior otolaryngologists and from 0.647 (95 % CI 0.608-0.686) to 0.807 (95 % CI 0.773-0.837) for junior otolaryngologists. CONCLUSIONS: The MIL based AI-assisted diagnosis system can significantly improve the diagnostic performance of otolaryngologists for VFL and help to make proper clinical decisions.

Fabrication of a Coculture Organoid Model in the Biomimetic Matrix of Alginate to Investigate Breast Cancer Progression in a TAMs-Leading Immune Microenvironment.

The current research models of breast cancer are usually limited in their capacity to recapitulate the tumor microenvironment in vitro. The lack of an extracellular matrix (ECM) oversimplifies cell-cell or cell-ECM cross-talks. Moreover, the lack of tumor-associated macrophages (TAMs), that can comprise up to 50% of some solid neoplasms, poses a major problem for recognizing various hallmarks of cancer. To address these concerns, a type of direct breast cancer cells (BCCs)-TAMs coculture organoid model was well developed by a sequential culture method in this study. Alginate cryogels were fabricated with appropriate physical and mechanical properties to serve as an alternative ECM. Then, our previous experience was leveraged to polarize TAMs inside of the cryogels for creating an in vitro immune microenvironment. The direct coculture significantly enhanced BCCs organoid growth and cancer aggressive phenotypes, including the stemness, migration, ECM remodeling, and cytokine secretion. Furthermore, transcriptomic analysis and protein-protein interaction networks implied certain pathways (PI3K-Akt pathway, MAPK signaling pathway, etc.) and targets (TNF, PPARG, TLR2, etc.) during breast cancer progression in a TAM-leading immune microenvironment. Future studies to advance treatment strategies for BCC patients may benefit from using this facile model to reveal and target the interactions between cancer signaling and the immune microenvironment.

Comparison of two single-pill dual combination antihypertensive therapies in Chinese patients: a randomized, controlled trial.

BACKGROUND: Current hypertension guidelines recommend combination of an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker with a calcium-channel blocker or thiazide diuretic as initial antihypertensive therapy in patients with monotherapy uncontrolled hypertension. However, to what extent these two different combinations are comparable in blood pressure (BP)-lowering efficacy and safety remains under investigation, especially in the Chinese population. We investigated the BP-lowering efficacy and safety of the amlodipine/benazepril and benazepril/hydrochlorothiazide dual therapies in Chinese patients. METHODS: In a multi-center, randomized, actively controlled, parallel-group trial, we enrolled patients with stage 1 or 2 hypertension from July 2018 to June 2021 in 20 hospitals and community health centers across China. Of the 894 screened patients, 560 eligible patients were randomly assigned to amlodipine/benazepril 5/10 mg (n = 282) or benazepril/hydrochlorothiazide 10/12.5 mg (n = 278), with 213 and 212 patients, respectively, who completed the study and had a valid repeat ambulatory BP recording during follow-up and were included in the efficacy analysis. The primary outcome was the change from baseline to 24 weeks of treatment in 24-h ambulatory systolic BP. Adverse events including symptoms and clinically significant changes in physical examinations and laboratory findings were recorded for safety analysis. RESULTS: In the efficacy analysis (n = 425), the primary outcome, 24-h ambulatory systolic BP reduction, was - 13.8 ± 1.2 mmHg in the amlodipine/benazepril group and - 12.3 ± 1.2 mmHg in the benazepril/hydrochlorothiazide group, with a between-group difference of - 1.51 (p = 0.36) mmHg. The between-group differences for major secondary outcomes were - 1.47 (p = 0.18) in 24-h diastolic BP, - 2.86 (p = 0.13) and - 2.74 (p = 0.03) in daytime systolic and diastolic BP, and - 0.45 (p = 0.82) and - 0.93 (p = 0.44) in nighttime systolic and diastolic BP. In the safety analysis (n = 560), the incidence rate of dry cough was significantly lower in the amlodipine/benazepril group than in the benazepril/hydrochlorothiazide group (5.3% vs 10.1%, p = 0.04). CONCLUSIONS: The amlodipine/benazepril and benazepril/hydrochlorothiazide dual therapies were comparable in ambulatory systolic BP lowering. The former combination, compared with the latter, had a greater BP-lowering effect in the daytime and a lower incidence rate of dry cough. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03682692. Registered on 18 September 2018.

The Detection of Nasopharyngeal Carcinomas Using a Neural Network Based on Nasopharyngoscopic Images.

OBJECTIVE: To construct and validate a deep convolutional neural network (DCNN)-based artificial intelligence (AI) system for the detection of nasopharyngeal carcinoma (NPC) using archived nasopharyngoscopic images. METHODS: We retrospectively collected 14107 nasopharyngoscopic images (7108 NPCs and 6999 noncancers) to construct a DCNN model and prepared a validation dataset containing 3501 images (1744 NPCs and 1757 noncancers) from a single center between January 2009 and December 2020. The DCNN model was established using the You Only Look Once (YOLOv5) architecture. Four otolaryngologists were asked to review the images of the validation set to benchmark the DCNN model performance. RESULTS: The DCNN model analyzed the 3501 images in 69.35 s. For the validation dataset, the precision, recall, accuracy, and F1 score of the DCNN model in the detection of NPCs on white light imaging (WLI) and narrow band imaging (NBI) were 0.845 ± 0.038, 0.942 ± 0.021, 0.920 ± 0.024, and 0.890 ± 0.045, and 0.895 ± 0.045, 0.941 ± 0.018, and 0.975 ± 0.013, 0.918 ± 0.036, respectively. The diagnostic outcome of the DCNN model on WLI and NBI images was significantly higher than that of two junior otolaryngologists (p < 0.05). CONCLUSION: The DCNN model showed better diagnostic outcomes for NPCs than those of junior otolaryngologists. Therefore, it could assist them in improving their diagnostic level and reducing missed diagnoses. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:127-135, 2024.

Laryngoscopy-based scoring system for the diagnosis of vocal fold leukoplakia.

OBJECTIVE: To propose a scoring system based on laryngoscopic characteristics for the differential diagnosis of benign and malignant vocal fold leukoplakia. METHODS: Laryngoscopic images from 200 vocal fold leukoplakia cases were retrospectively analysed. The laryngoscopic signs of benign and malignant vocal fold leukoplakia were compared, and statistically significant features were assigned and accumulated to establish the leukoplakia finding score. RESULTS: A total of five indicators associated with malignant vocal fold leukoplakia were included to construct the leukoplakia finding score, with a possible range of 0-10 points. A score of 6 points or more was indicative of a diagnosis of malignant vocal fold leukoplakia. The sensitivity, specificity and accuracy values of the leukoplakia finding score were 93.8 per cent, 83.6 per cent and 86.0 per cent, respectively. The consistency in the leukoplakia finding score obtained by different laryngologists was strong (kappa = 0.809). CONCLUSION: This scoring system based on laryngoscopic characteristics has high diagnostic value for distinguishing benign and malignant vocal fold leukoplakia.

Intermittent theta burst stimulation to the left dorsolateral prefrontal cortex improves cognitive function in polydrug use disorder patients: a randomized controlled trial.

Background: Polydrug abuse is common among opioid users. Individuals who use both heroin and methamphetamine (MA) have been shown to experience a wide range of cognitive deficits. Previous research shows that repetitive transcranial magnetic stimulation (rTMS) can change cerebral cortical excitability and regulate neurotransmitter concentration, which could improve cognitive function in drug addiction. However, the stimulation time, location, and possible mechanisms of rTMS are uncertain. Methods: 56 patients with polydrug use disorder were randomized to receive 20 sessions of 10 Hz rTMS (n = 19), iTBS (n = 19), or sham iTBS (n = 18) to the left DLPFC. All patients used MA and heroin concurrently. Cognitive function was assessed and several related proteins including EPI, GABA-Aα5, IL-10, etc. were quantified by ELISA before and after the treatment. Results: Baseline RBANS scores were lower than normal for age (77.25; IQR 71.5-85.5). After 20 treatment sessions, in the iTBS group, the RBANS score increased by 11.95 (95% CI 0.02-13.90, p = 0.05). In particular, there were improvements in memory and attention as well as social cognition. Following treatment, serum EPI and GABA-Aα5 were reduced and IL-10 was elevated. The improvement of immediate memory was negatively correlated with GABA-Aα5 (r = -0.646, p = 0.017), and attention was positively correlated with IL-10 (r = 0.610, p = 0.027). In the 10 Hz rTMS group, the improvement of the RBANS total score (80.21 ± 14.08 before vs.84.32 ± 13.80 after) and immediate memory (74.53 ± 16.65 before vs.77.53 ± 17.78 after) was statistically significant compared with the baseline (p < 0.05). However, compared with the iTBS group, the improvement was small and the difference was statistically significant. There was no statistically significant change in the sham group (78.00 ± 12.91 before vs.79.89 ± 10.92 after; p > 0.05). Conclusion: Intermittent theta burst stimulation to the left DLPFC may improve cognitive function in polydrug use disorder patients. Its efficacy appears to be better than that of 10 Hz rTMS. The improvement of cognitive function may be related to GABA-Aα5 and IL-10. Our findings preliminarily demonstrate the clinical value of iTBS to the DLPFC to augment neurocognitive recovery in polydrug use disorders.

Risk factors for skin injuries in cancer patients with peripherally inserted central catheter: A prospective multicenter cohort study.

BACKGROUND: The risk factors for skin injuries remain poorly understood in cancer patients with peripherally inserted central catheters (PICC). We herein aimed at exploring the effect of clinical factors on the risk of PICC-related skin injuries. METHODS: We included 1245 cancer patients with PICC from 16 hospitals in Suzhou, China. The study outcome was in-hospital skin injuries, including contact dermatitis, skin (epidermal) stripping, tension injury, allergic dermatitis, skin tear, maceration, folliculitis, and pressure injury. RESULTS: During hospitalization, 274 patients (22.0%) developed skin injuries after prolonged use of an indwelling catheter. Univariable logistic regression analysis identified several risk factors for PICC-related skin injuries; multivariable logistic regression analysis showed that the following factors independently and significantly (p < 0.05) associated with the risk of PICC-related skin injuries: body mass index (BMI, >25 kg/m2 versus <18.5 kg/m2: odds ratio (OR), 1.79; 95% confidence interval (CI), 1.03-3.11), skin condition (humid vs normal: OR, 2.96; 95% CI, 1.62-5.43), skin indentation (OR, 4.67; 95% CI, 3.31-6.58), allergic history (OR, 2.11; 95% CI, 1.21-3.66), history of dermatitis (OR, 3.05; 95% CI, 1.00-9.28), history of eczema (OR, 3.36; 95% CI, 1.20-9.43), catheter insertion site (under elbow vs. upper arm: OR, 3.32; 95% CI, 1.12-9.90), and PICC maintenance interval (4-5 days vs ⩽3 days: OR, 0.06; 95% CI, 0.01-0.50; 5-7 days vs ⩽3 days: OR, 0.07; 95% CI, 0.02-0.31; 7-9 days vs ⩽3 days: OR, 0.10; 95% CI, 0.02-0.57). CONCLUSIONS: BMI, skin condition, skin indentation, allergic history, history of dermatitis, history of eczema, catheter insertion site, and PICC maintenance interval were independent risk factors for PICC-related skin injuries in cancer patients. This knowledge will guide future studies with formulating optimal treatment strategies for improving the skin health of cancer patients with PICC.

Convolutional neural network based anatomical site identification for laryngoscopy quality control: A multicenter study.

OBJECTIVES: Video laryngoscopy is an important diagnostic tool for head and neck cancers. The artificial intelligence (AI) system has been shown to monitor blind spots during esophagogastroduodenoscopy. This study aimed to test the performance of AI-driven intelligent laryngoscopy monitoring assistant (ILMA) for landmark anatomical sites identification on laryngoscopic images and videos based on a convolutional neural network (CNN). MATERIALS AND METHODS: The laryngoscopic images taken from January to December 2018 were retrospectively collected, and ILMA was developed using the CNN model of Inception-ResNet-v2 + Squeeze-and-Excitation Networks (SENet). A total of 16,000 laryngoscopic images were used for training. These were assigned to 20 landmark anatomical sites covering six major head and neck regions. In addition, the performance of ILMA in identifying anatomical sites was validated using 4000 laryngoscopic images and 25 videos provided by five other tertiary hospitals. RESULTS: ILMA identified the 20 anatomical sites on the laryngoscopic images with a total accuracy of 97.60 %, and the average sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 100 %, 99.87 %, 97.65 %, and 99.87 %, respectively. In addition, multicenter clinical verification displayed that the accuracy of ILMA in identifying the 20 targeted anatomical sites in 25 laryngoscopic videos from five hospitals was ≥95 %. CONCLUSION: The proposed CNN-based ILMA model can rapidly and accurately identify the anatomical sites on laryngoscopic images. The model can reflect the coverage of anatomical regions of the head and neck by laryngoscopy, showing application potential in improving the quality of laryngoscopy.

Coexistence of multiple anti-neuronal antibodies in autoimmune encephalitis in China: A multi-center study.

Background: Given that the combination of multiple antibodies in autoimmune encephalitis (AE) is rare and its clinical significance is unclear, this study aimed to investigate the clinical characteristics and significance of overlapping multiple anti-neuronal antibodies in patients with AE. Methods: We conducted a retrospective analysis of the clinical characteristics, treatment, and prognostic details of 22 patients with multiple coexisting antibodies from multiple clinical centers in China. Results: Among the 276 patients who were AE antibody-positive, 22 (7.97%) had two or more antibodies. Among the 22 patients with coexisting AE-related antibodies, 14 patients (63.63%) were combined of cell surface and intracellular antibody, and the remaining 8 patients (36.36%) were detected to be cell surface antibody positive only. The main symptoms of the 22 patients in this cohort included fever, seizures, memory impairment, cognitive decline, and sleep disorders. Five (22.73%) patients had tumors, among whom four had small-cell lung cancers, and one had mediastinal tumors. A total of 20 patients were treated with steroids and intravenous immunoglobulin, and 18 showed varying degrees of symptomatic improvement after first-line immunotherapy. Three patients died of tumor progression or chemotherapy complications. Conclusion: The coexistence of multiple anti-neuronal antibodies in patients with AE may cause a superimposition and diversification of clinical manifestations. Combined paraneoplastic antibody positivity may be suggestive of an underlying malignancy.

Preoperative dipstick albuminuria is associated with acute kidney injury in high-risk patients following non-cardiac surgery: a single-center prospective cohort study.

PURPOSE: This study aimed to investigate the association between preoperative dipstick albuminuria (DA) and acute kidney injury (AKI) in high-risk patients following non-cardiac surgery. METHODS: This was a single-center prospective cohort study. Adult patients with high risk of AKI undergoing non-cardiac surgery were enrolled. The primary outcome was AKI, defined according to KDIGO criteria within 7 days following non-cardiac surgery. DA status was determined by urinalysis performed within 24 h of hospital admission. Multivariate logistic regression model was used to analyze the association between preoperative DA and postoperative AKI. RESULTS: During the study period, 552 patients were enrolled and 8.5% of them developed postoperative AKI. The overall rate of preoperative positive DA was 26.4% with 30 and ≥ 100 mg/dL DA accounting for 19.2% and 7.2%, respectively. Patients with more severe preoperative DA had much higher rate of postoperative AKI (5.2% in patients with negative or trace DA, 13.2% in patients with 30 mg/dL DA and 30.0% in patients with ≥ 100 mg/dL DA, P < 0.001). After adjusting for several perioperative variables, preoperative 30 mg/dL DA (OR 2.575; 95% CI 1.049-6.322; P = 0.039) and ≥ 100 mg/dL DA (OR 3.868; 95% CI 1.246-12.010; P = 0.019) showed an independent association with postoperative AKI. In addition, patients with higher DA status demonstrated significantly increased level of postoperative urine biomarkers and their ratio to urine creatinine. CONCLUSIONS: Preoperative DA was independently associated with AKI in high-risk patients following non-cardiac surgery. Preoperative routine urinalysis for determination of DA status was suggested in early risk stratification.

A 3D-printed scaffold-based osteosarcoma model allows to investigate tumor phenotypes and pathogenesis in an in vitro bone-mimicking niche.

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Clinical Experience in the Diagnosis and Treatment of Adult Acute Necrotizing Encephalopathy.

PURPOSE: We report two cases diagnosed as acute necrotizing encephalopathy (ANE) with acute onset and various clinical manifestations. METHODS: The patients' data were obtained from the medical records of the Binzhou Medical University Hospital in Binzhou, China. The clinical symptoms, laboratory examination, neuroimaging, treatment, and prognosis of the 2 patients were collected and analyzed. RESULTS: We report 2 adult ANE patients with acute onset. The first symptom was fever, followed by symptoms and signs of damage to the central nervous system. The patients were infected with herpes simplex virus and influenza virus, respectively. The main manifestation on brain magnetic resonance imaging was a mixed-signal of a "three-layer structure" in the bilateral thalamus. The first patient died. Based on the experience of the diagnosis and treatment of the first patient, combined with a review of the literature, the second patient was immediately treated with glucocorticoid pulse therapy combined with gamma globulin injection. This patient's condition was controlled, and the prognosis was good. CONCLUSIONS: This study describes the clinical symptoms, laboratory examination, neuroimaging evidence, and treatment experience of ANE in adults. We believe that the progress of the disease may be controlled, and the prognosis may be improved if glucocorticoid pulse therapy combined with gamma globulin injection is used as soon as possible.

Physical confinement in alginate cryogels determines macrophage polarization to a M2 phenotype by regulating a STAT-related mRNA transcription pathway.

The immunologic response is considered to play a pivotal role in the application of biomaterial implants, and intrinsic properties of biomaterials can significantly modulate the anti-inflammatory effects. However, how physical confinement influences M2 polarization of macrophages and the relevant mechanisms have not been clearly elucidated. In this study, pore size and porosity in cryogels can be mediated by utilizing alginates with different viscosities. Cryogels of small pore size and low porosity can restrict M2 polarization of macrophages in vitro, judging from cell morphology, secretion of cytokines and expression of key M2-related genes. In comparison, cryogels of large pore size or high porosity can induce M2 polarization in vivo, resulting in the anti-inflammation effects. High-throughput RNA-seq analysis demonstrates that the mRNA surveillance pathway is key in the polarization process, and four primary transcription factors (PPAR-γ, STAT6, NF-κB, and STAT1) participate probably by competition in DNA binding to regulate M2-related gene expression. This study confirms that enough physical space inside is necessary to promote M2 polarization for the anti-inflammatory performance, which can be applied widely in the fields of tissue engineering and regenerative medicine.

Antidepressant-Like Effect and Mechanism of Ginsenoside Rd on Rodent Models of Depression.

Background: There is growing evidence to suggest that ginsenoside Rd (GRd) has a therapeutic effect on depression, but the specific mechanisms behind its activity require further study. Objective: This study is designed to investigate the antidepressant-like effect and underlying mechanisms of GRd. Methods: In this study, the behavioral despair mouse model of depression and chronic unpredictable mild stress (CUMS) rat model of depression were established to explore the effects of GRd on depression-like behavior and its underlying mechanisms. Behavioral tests were used to evaluate the replication of animal models and depression-like behaviors. The hypoxia-inducible factor-1α (HIF-1α) blocker 2-methoxyestradiol (2-ME) was injected to determine the role of HIF-1α in the antidepressant-like effect of GRd. In addition, molecular biology techniques were used to determine the mRNA and protein expression of HIF-1ɑ signaling pathway and synaptic plasticity-related regulators, that is synapsin 1 (SYN 1) and postsynaptic density protein 95 (PSD 95). In silico binding interaction studies of GRd with focused target proteins were performed using molecular docking to predict the affinity and optimal binding mode between ligands and receptors. Results: Our data show that GRd significantly reversed depression-like behavior and promoted mRNA and protein expression of HIF-1ɑ signaling pathway and synaptic plasticity-related regulators. However, the antidepressant-like effect of GRd disappeared upon inhibition of HIF-1α expression following administration of 2-ME. Furthermore, molecular docking results showed that GRd possessed significant binding affinity for HIF-1α, VEGF, and VEGFR-2. Conclusion: Our results show that GRd exhibits significant antidepressant-like effect and that HIF-1α signaling pathway is a promising target for the treatment of depression.

Capsaicin ameliorates intermittent high glucose-mediated endothelial senescence via the TRPV1/SIRT1 pathway.

BACKGROUND: Patients with diabetes have accelerated vascular aging when compared with healthy individuals. Hyperglycemia, especially intermittent high glucose (IHG), is the main cause of vascular endothelial senescence. Capsaicin, a major component of chili pepper is thought to contribute to cardiovascular protection by spicy food. OBJECTIVE: To investigate the pathway related with the effects of capsaicin on endothelial cell senescence induced by IHG. METHODS: HUVECs were exposed to IHG (5 mM or 33 mM glucose, alternating every 12 hours for 3 days) and treated with capsaicin at 0.3, 1 and 3 µM. To determine endothelial cell senescence, we examined the senescence-related ß-galactosidase staining, cell cycle arrest, cell viability, as well as production of reactive oxygen species (ROS). To evaluate the involvement of TRPV1/[Ca2+]i/CaMKII/AMPK/SIRT1 pathway in anti- senescence effects of capsaicin, HUVECs were treated with CAPZ (a TRPV1 antagonist), BAPTA-AM (an intracellular calcium chelator), KN62 (a CaMKII antagonist), compound C (an AMPK inhibitor), or EX527 (a SIRT1 inhibitor). To knockdown TRPV1, HUVECs were transfected with shRNA lentivirus targeting TRPV1. The levels of SIRT1, p21, TRPV1, AMPK and phospho-AMPK were evaluated by western blotting. RESULTS: IHG suppressed the levels of SIRT1 and enhanced endothelial senescence. Capsaicin upregulated SIRT1 expression and downregulated the senescence marker, p21, thereby protecting endothelial cells from IHG-induced senescence as indicated by relieved G0/G1 phase arrest, improved cell viabilities, and reduced counts of senescent cells and ROS production. Pre-treatment with CAPZ, BAPTA-AM, KN62 or compound C abrogated the anti-senescence effects of capsaicin. Capsaicin restored AMPK phosphorylation and IHG-inhibited TRPV1 expression. Moreover, TRPV1 silencing suppressed SIRT1 expression and abolished the anti-senescence effects of capsaicin. CONCLUSION: Capsaicin elevates SIRT1 levels through TRPV1/[Ca2+]i/CaMKII/AMPK pathway and suppresses IHG-mediated endothelial cell senescence. This study provides initial evidence that capsaicin is a potential candidate for the prevention of vascular aging in diabetes.

Discovery of Pyridone-Substituted Triazolopyrimidine Dual A2A/A1 AR Antagonists for the Treatment of Ischemic Stroke.

Ischemic stroke is a complex systemic disease characterized by high morbidity, disability, and mortality. The activation of the presynaptic adenosine A2A and A1 receptors modifies a variety of brain insults from excitotoxicity to stroke. Therefore, the discovery of dual A2A/A1 adenosine receptor (AR)-targeting therapeutic compounds could be a strategy for the treatment of ischemic stroke. Inspired by two clinical phase III drugs, ASP-5854 (dual A2A/A1 AR antagonist) and preladenant (selective A2A AR antagonist), and using the hybrid medicinal strategy, we characterized novel pyridone-substituted triazolopyrimidine scaffolds as dual A2A/A1 AR antagonists. Among them, compound 1a exerted excellent A2A/A1 AR binding affinity (K i = 5.58/24.2 nM), an antagonistic effect (IC50 = 5.72/25.9 nM), and good metabolic stability in human liver microsomes, rat liver microsomes, and dog liver microsomes. Importantly, compound 1a demonstrated a dose-effect relationship in the oxygen-glucose deprivation/reperfusion (OGD/R)-treated HT22 cell model. These findings support the development of dual A2A/A1 AR antagonists as a potential treatment for ischemic stroke.

Effects of climate variables on the transmission of COVID-19: a systematic review of 62 ecological studies.

The new severe acute respiratory syndrome coronavirus 2 was initially discovered at the end of 2019 in Wuhan City in China and has caused one of the most serious global public health crises. A collection and analysis of studies related to the association between COVID-19 (coronavirus disease 2019) transmission and meteorological factors, such as humidity, is vital and indispensable for disease prevention and control. A comprehensive literature search using various databases, including Web of Science, PubMed, and Chinese National Knowledge Infrastructure, was systematically performed to identify eligible studies from Dec 2019 to Feb 1, 2021. We also established six criteria to screen the literature to obtain high-quality literature with consistent research purposes. This systematic review included a total of 62 publications. The study period ranged from 1 to 8 months, with 6 papers considering incubation, and the lag effect of climate factors on COVID-19 activity being taken into account in 22 studies. After quality assessment, no study was found to have a high risk of bias, 30 studies were scored as having moderate risks of bias, and 32 studies were classified as having low risks of bias. The certainty of evidence was also graded as being low. When considering the existing scientific evidence, higher temperatures may slow the progression of the COVID-19 epidemic. However, during the course of the epidemic, these climate variables alone could not account for most of the variability. Therefore, countries should focus more on health policies while also taking into account the influence of weather.

Laryngoscopic characteristics related to the risk of cancerization of vocal cord leukoplakia.

BACKGROUND: The diagnosis of vocal cord leukoplakia mainly relies on laryngoscopy. The morphology of vocal cord leukoplakia under laryngoscope is closely related to the pathological nature of leukoplakia. The specific manifestations associated with high-risk vocal cord leukoplakia remain to be explored. OBJECTIVE: To investigate the characteristics of low-risk and high-risk vocal cord leukoplakia under conventional white light imaging (WLI) laryngoscopy and its correlations with narrow band imaging (NBI) laryngoscopy. METHODS: One hundred and seventy-five cases of vocal cord leukoplakia were divided into low-risk and high-risk groups. The characteristics of low-risk and high-risk vocal cord leukoplakia under WLI laryngoscopy and its correlations with NBI laryngoscopy were analyzed. RESULTS: Logistic regression analysis showed that thickness and hyperemia were independent factors (p < .05). Hyperemia had a strong consistency with the visualization of spots under NBI laryngoscopy (kappa = 0.758). The sign of hyperemia and the NBI classification had equivalent diagnostic efficacy for predicting the risk of cancerization of vocal cord leukoplakia. CONCLUSION: The sign of hyperemia under WLI laryngoscopy is significantly correlated with the visualized spots under NBI laryngoscopy. Hyperemia is an important feature for predicting malignant potential of vocal cord leukoplakia.

Characteristics and Prognosis of Autoimmune Encephalitis in the East of China: A Multi-Center Study.

Objective: This study aimed to investigate epidemiological characteristics, clinical manifestations, and long-term outcomes of patients with autoimmune encephalitis (AE) in the east of China. Methods: From January 2015 to December 2019, 226 potential AE patients were recruited from five clinical centers, and a total of 185 patients who met the diagnostic criteria were included in the study. We retrospectively reviewed clinical features, auxiliary examinations, details of treatments, and outcomes of AE, and identified risk factors of poor prognosis. Modified Rankin Scale scores were used to evaluate neurological function, and scores of 3-6 indicated a poor-prognosis. Results: Patients with five main subtypes of AE were enrolled in the study, as follows: anti-NMDAR (79), anti-LGI1 (55), anti-CASPR2 (30), anti-GABABR (16), and anti-AMPAR (5). Among 185 patients, 58.38% (108/185) were male and 41.62% (77/185) were female. The median age at disease onset was 41 years (interquartile range, 17-62). The most common clinical manifestations of AE were seizures (146, 78.92%) and memory deficit (123, 66.49%). A total of 95 (51.35%) patients had abnormal brain magnetic resonance imaging results. Electroencephalographic findings were abnormal in 131 (70.81%) patients, and 168 (90.81%) and 26 (14.05%) patients were treated with first- and second-line immunotherapies, respectively. All surviving patients were followed-up for at least 1 year (range 12-36 months). Good clinical outcomes were achieved in 117 (63.24%), while 68 (36.76%) patients had a poor prognosis. Further, 33 (17.84%) patients relapsed and 10 (5.41%) died within 1 year post-discharge. Older patients tended to have a poorer prognosis, and the occurrence of mental behavioral disorders, movement disorders, disturbance of consciousness, central hypoventilation, and tumors were overrepresented in the poor-prognosis group. Conclusions: AE is a treatable disease, and most patients have a good prognosis. There are differences in the clinical manifestations of patients with different AE subtypes. Some with AE will relapse, and long-term follow-up is of great significance for further research.