Causal effect of sarcopenia-related traits on the occurrence and prognosis of breast cancer - A bidirectional and multivariable Mendelian randomization study.

Introduction: Background and aims: although sarcopenia is associated with several types of cancer, there is limited research regarding its effect on breast cancer. We aimed to explore the causality between sarcopenia-related traits and the incidence and prognosis of breast cancer. Methods: two-sample bidirectional and multivariate Mendelian randomization (MR) analyses were utilized in this study. Genome-wide association studies were used to genetically identify sarcopenia-related traits, such as appendicular lean mass, grip strength of both hands, and walking pace. Data on the incidence and prognosis of breast cancer were collected from two extensive cohort studies. Multivariate MR analysis was used to adjust for body mass index, waist circumference, and whole-body fat mass. The primary method used for analysis was inverse-variance weighted analysis. Results: a significant association was found between appendicular lean mass and ER- breast cancer (OR = 0.873, 95 % CI: 0.817-0.933, p = 6.570 × 10-5). Increased grip strength of the left hand was associated with a reduced risk of ER- breast cancer (OR = 0.744, 95 % CI: 0.579-0.958, p = 0.022). Stronger grip strength of the right hand was associated with prolonged survival time of ER+ breast cancer patients (OR = 0.463, 95 % CI: 0.242-0.882, p = 0.019). In the multivariable MR analysis, appendicular lean mass, grip strength of both hands, and walking pace were still genetically associated with the development of total breast cancer and ER-/+ breast cancer. Conclusions: several sarcopenia-related traits were genetically associated with the occurrence and prognosis of breast cancer. It is crucial for elderly women to increase their strength and muscle mass to help prevent breast cancer.

Introducción: Antecedentes y objetivos: aunque la sarcopenia se asocia a múltiples tipos de cáncer, los estudios sobre sus efectos sobre el cáncer de mama son limitados. Nuestro objetivo es explorar la relación causal entre las características relacionadas con la sarcopenia y la incidencia y el pronóstico del cáncer de mama. Método: este estudio utilizó un análisis de aleatorización mendeliana (MR) bidireccional y multivariable de doble muestra. Los estudios de asociación genómica completa se utilizan para identificar genéticamente características relacionadas con la sarcopenia, como la masa magra apendicular, la fuerza de agarre de las manos y la velocidad al caminar. Los datos de incidencia y pronóstico del cáncer de mama provienen de dos amplios estudios de cohortes. El análisis de MR multivariable se utilizó para ajustar el índice de masa corporal, la circunferencia de la cintura y la masa grasa corporal total. El principal método de análisis fue el análisis ponderado por ANOVA inverso. Resultados: la masa magra apendicular se asoció significativamente al cáncer de mama ER- (OR = 0,873, IC 95 %: 0,817-0,933, p = 6,570 × 10-5), el aumento de la fuerza de agarre del lado izquierdo se asoció a una disminución del riesgo de cáncer de mama ER- (OR = 0,744, IC 95 %: 0,579-0,958, p = 0,022) y el aumento de la fuerza de agarre del lado derecho se asoció a una mayor supervivencia de los pacientes con cáncer de mama ER+ (OR = 0,463, IC 95 %: 0,24-0,882, P = 0,019). En el análisis MR multivariable, la masa magra apendicular, la fuerza de agarre de ambas manos y la velocidad al caminar mantuvieron su asociación genética con la aparición del cáncer de mama total y del cáncer de mama ER-/+. Conclusión: varios rasgos relacionados con la sarcopenia tienen correlación genética con la aparición y el pronóstico del cáncer. Mejorar la fuerza y la masa muscular de las mujeres mayores es fundamental para ayudar a prevenir el cáncer de mama.

TRPV1+ sensory nerves suppress conjunctival inflammation via SST-SSTR5 signaling in murine allergic conjunctivitis.

Allergic conjunctivitis (AC), an allergen-induced ocular inflammatory disease, primarily involves mast cells (MCs) and eosinophils. The role of neuroimmune mechanisms in AC, however, remains to be elucidated. We investigated the effects of transient receptor potential vanilloid 1 (TRPV1)-positive sensory nerve ablation (using resiniferatoxin) and TRPV1 blockade (using Acetamide, N-[4-[[6-[4-(trifluoromethyl)phenyl]-4-pyrimidinyl]oxy]-2-benzothiazolyl] (AMG-517)) on ovalbumin-induced conjunctival allergic inflammation in mice. The results showed an exacerbation of allergic inflammation as evidenced by increased inflammatory gene expression, MC degranulation, tumor necrosis factor-α production by MCs, eosinophil infiltration and activation, and C-C motif chemokine 11 (CCL11) (eotaxin-1) expression in fibroblasts. Subsequent findings demonstrated that TRPV1+ sensory nerves secrete somatostatin (SST), which binds to SST receptor 5 (SSTR5) on MCs and conjunctival fibroblasts. SST effectively inhibited tumor necrosis factor-α production in MCs and CCL11 expression in fibroblasts, thereby reducing eosinophil infiltration and alleviating AC symptoms, including eyelid swelling, lacrimation, conjunctival chemosis, and redness. These findings suggest that targeting TRPV1+ sensory nerve-mediated SST-SSTR5 signaling could be a promising therapeutic strategy for AC, offering insights into neuroimmune mechanisms and potential targeted treatments.

Effect and potential mechanisms of sludge-derived chromium, nickel, and lead on soil nitrification: Implications for sustainable land utilization of digested sludge.

Increasing occurrence of heavy metals (HMs) in sewage sludge threatens its widespread land utilization in China due to its potential impact on nutrient cycling in soil, requiring a better understanding of HM-induced impacts on nitrification. Herein, lab-scale experiments were conducted over 185-day, evaluating the effect of sludge-derived chromium (Cr3+), nickel (Ni2+), and lead (Pb2+) on soil nitrification at different concentrations. Quantitative polymerase chain reaction and linear regression results revealed an inhibitory sequence of gene abundance by HMs' labile fraction: ammonia-oxidizing bacteria (AOB)-ammonia monooxygenase (amoA)> nitrite oxidoreductase subunit alpha (nxrA)> nitrite oxidoreductase subunit beta (nxrB). The toxicity of HMs' incremental labile fraction decreased in the order of Ni2+>Cr3+>Pb2+, with respective threshold values of 5.01, 24.03 and 38.42 mg·kg-1. Furthermore, extending incubation time reduced HMs inhibition on ammonia oxidation, mainly related to their fraction bound to carbonate minerals. Random Forest analysis, variation partitioning analysis, and Mantel test indicated that soil physicochemical properties primarily affected nitrification genes, especially in the test of Cr3+ on AOB-amoA, nxrA, nxrB, Ni2+ for complete ammonia-oxidizing bacteria-amoA, and Pb2+ for nxrA and nxrB. These findings underline the importance of labile HMs fractions and soil physicochemical properties to nitrification, guiding the establishment of HM control standards for sludge utilization.

IL13Rα2 as a crucial receptor for Chi3l1 in osteoclast differentiation and bone resorption through the MAPK/AKT pathway.

BACKGROUND: Previous research has revealed that the 18 glycoside hydrolase gene family (GH18) member Chitinase 3-like 1 (Chi3l1) can regulate osteoclast differentiation and bone resorption. However, its downstream receptors and molecular mechanisms during osteoclastogenesis have yet to be elucidated. METHODS: Initially, we conducted a comprehensive investigation to evaluate the effects of recombinant Chi3l1 protein or Chi3l1 siRNA on osteoclast differentiation and the RANKL-induced MAPK/AKT signaling pathways. Moreover, we used immunofluorescence and immunoprecipitation assays to identify IL13Rα2 as the downstream receptor of Chi3l1. Subsequently, we investigated the impact of IL13Rα2 recombinant protein or IL13Rα2-siRNA on osteoclast differentiation and the associated signaling pathways. Finally, we performed in vivo experiments to examine the effect of recombinant IL13Rα2 protein in an LPS-induced mouse model of cranial osteolysis. RESULTS: Our findings highlight that the administration of recombinant Chi3l1 protein increased the formation of osteoclasts and bolstered the expression of several osteoclast-specific genes (TRAP, NFATC1, CTR, CTSK, V-ATPase d2, and Dc-STAMP). Additionally, Chi3l1 significantly promoted the RANKL-induced MAPK (ERK/P38/JNK) and AKT pathway activation, whereas Chi3l1 silencing inhibited this process. Next, using immunofluorescence and co-immunoprecipitation assays, we identified IL13Rα2 as the binding partner of Chi3l1 during osteoclastogenesis. IL13Rα2 recombinant protein or IL13Rα2-siRNA also inhibited osteoclast differentiation, and IL13Rα2-siRNA attenuated the RANKL-induced activation of the MAPK (ERK/P38/JNK) and AKT pathways, similar to the effects observed upon silencing of Chi3l1. Moreover, the promoting effect of recombinant Chi3l1 protein on osteoclastogenesis and the activation of the MAPK and AKT pathways was reversed by IL13Rα2 siRNA. Finally, recombinant LI13Rα2 protein significantly attenuated the LPS-induced cranial osteolysis and the number of osteoclasts in vivo. CONCLUSIONS: Our findings suggested that IL13Rα2 served as a crucial receptor for Chi3l1, enhancing RANKL-induced MAPK and AKT activation to promote osteoclast differentiation. These findings provide valuable insights into the molecular mechanisms of Chi3l1 in osteoclastogenesis, with potential therapeutic implications for osteoclast-related diseases. Video Abstract.

Hypoxia-based critical gene biomarkers as prognostic reporters for gastric adenocarcinoma.

BACKGROUND: Gastric cancer is the most common malignant tumour of the digestive system, yet there is a lack of reported prognostic biomarkers for STAD patients. METHODS: Transcriptomic expression data of STAD from GEO database, single cell sequencing data from OMIX gastric cancer database. Conservative molecular typing of gastric cancer was constructed using non-negative matrix factorization (NMF). The abundance of 28 immune cells in the tumour samples was assessed using ssGSEA. The R package "oncoPredict" was used to predict chemotherapy response. TIDE website for immunotherapy response prediction. Finally, single cell analysis was performed to clarify the specific type annotation of STAD cells and to analysis their spatial expression. RESULTS: Hypoxia-score demonstrated excellent prognostic discrimination in TCGA gastric cancer samples. Among multiple deconvolution-based algorithms for immune infiltration, Hypoxia-score presented a general immunosuppressive efficacy across multiple datasets, as evidenced by a broad negative correlation with immune cell infiltration. By the likelihood that each group may have specific drug sensitivity to multiple chemotherapeutic and targeted agents. Results showed that high-risk scoring patients were more sensitive to Staurosporine, Sabutoclax, and AZD8055, while low-risk patients were more sensitive to Bortezomib, Dactinomycin, Docetaxel, Daporinad, Sepantronium, and bromide. In the immunotherapy cohort, the Hypoxia-score presented the ability to discriminate for immunotherapy efficacy. The distribution of Hypoxia-score in single-cell descending space was calculated using AddModuleScore and was found to be distributed across the various cell types annotated in the single-cell analysis. It is suggested that various cells in the tumour microenvironment are involved in hypoxia gene set processes to varying degrees. CONCLUSION: The Hypoxia-score proves to be a valuable tool for assessing the prognosis of gastric cancer patients and guiding drug treatments, providing significant guidance for clinical diagnosis and treatment in the context of gastric cancer.

N4-acetylcytidine-dependent GLMP mRNA stabilization by NAT10 promotes head and neck squamous cell carcinoma metastasis and remodels tumor microenvironment through MAPK/ERK signaling pathway.

N4-acetylcytidine (ac4C) is a post-transcriptional RNA modification that regulates in various important biological processes. However, its role in human cancer, especially lymph node metastasis, remains largely unknown. Here, we demonstrated N-Acetyltransferase 10 (NAT10), as the only known "writer" of ac4C mRNA modification, was highly expressed in head and neck squamous cell carcinoma (HNSCC) patients with lymph node metastasis. High NAT10 levels in the lymph nodes of patients with HNSCC patients are a predictor of poor overall survival. Moreover, we found that high expression of NAT10 was positively upregulated by Nuclear Respiratory Factor 1 (NRF1) transcription factor. Gain- and loss-of-function experiments displayed that NAT10 promoted cell metastasis in mice. Mechanistically, NAT10 induced ac4C modification of Glycosylated Lysosomal Membrane Protein (GLMP) and stabilized its mRNA, which triggered the activation of the MAPK/ERK signaling pathway. Finally, the NAT10-specific inhibitor, remodelin, could inhibit HNSCC tumorigenesis in a 4-Nitroquinoline 1-oxide (4NQO)-induced murine tumor model and remodel the tumor microenvironment, including angiogenesis, CD8+ T cells and Treg recruitment. These results demonstrate that NAT10 promotes lymph node metastasis in HNSCC via ac4C-dependent stabilization of the GLMP transcript, providing a potential epitranscriptomic-targeted therapeutic strategy for HNSCC.

Dlk2 interacts with Syap1 to activate Akt signaling pathway during osteoclast formation.

Excessive osteoclast formation and bone resorption are related to osteolytic diseases. Delta drosophila homolog-like 2 (Dlk2), a member of the epidermal growth factor (EGF)-like superfamily, reportedly regulates adipocyte differentiation, but its roles in bone homeostasis are unclear. In this study, we demonstrated that Dlk2 deletion in osteoclasts significantly inhibited osteoclast formation in vitro and contributed to a high-bone-mass phenotype in vivo. Importantly, Dlk2 was shown to interact with synapse-associated protein 1 (Syap1), which regulates Akt phosphorylation at Ser473. Dlk2 deletion inhibited Syap1-mediated activation of the AktSer473, ERK1/2 and p38 signaling cascades. Additionally, Dlk2 deficiency exhibits increased bone mass in ovariectomized mice. Our results reveal the important roles of the Dlk2-Syap1 signaling pathway in osteoclast differentiation and osteoclast-related bone disorders.

A Combined Model Integrating Radiomics and Deep Learning Based on Contrast-Enhanced CT for Preoperative Staging of Laryngeal Carcinoma.

RATIONALE AND OBJECTIVES: Accurate staging of laryngeal carcinoma can inform appropriate treatment decision-making. We developed a radiomics model, a deep learning (DL) model, and a combined model (incorporating radiomics features and DL features) based on the venous-phase CT images and explored the performance of these models in stratifying patients with laryngeal carcinoma into stage I-II and stage III-IV, and also compared these models with radiologists. MATERIALS AND METHODS: Three hundreds and nineteen patients with pathologically confirmed laryngeal carcinoma were randomly divided into a training set (n = 223) and a test set (n = 96). In the training set, the radiomics features with inter- and intraclass correlation coefficients (ICCs)> 0.75 were screened by Spearman correlation analysis and recursive feature elimination (RFE); then support vector machine (SVM) classifier was applied to develop the radiomics model. The DL model was built using ResNet 18 by the cropped 2D regions of interest (ROIs) in the maximum tumor ROI slices and the last fully connected layer of this network served as the DL feature extractor. Finally, a combined model was developed by pooling the radiomics features and extracted DL features to predict the staging. RESULTS: The area under the curves (AUCs) for radiomics model, DL model, and combined model in the test set were 0.704 (95% confidence interval [CI]: 0.588-0.820), 0.724 (95% CI: 0.613-0.835), and 0.849 (95% CI: 0.755-0.943), respectively. The combined model outperformed the radiomics model and the DL model in discriminating stage I-II from stage III-IV (p = 0.031 and p = 0.020, respectively). Only the combined model performed significantly better than radiologists (p < 0.050 for both). CONCLUSION: The combined model can help tailor the therapeutic strategy for laryngeal carcinoma patients by enabling more accurate preoperative staging.

[Analysis of efficacy and prognosis of neoadjuvant chemotherapy and （or） surgery plus radiotherapy for hypopharyngeal squamous cell carcinoma].

Objective:To analyze the risk factors that affect the prognosis of patients with hypopharyngeal squamous cell carcinoma（HPSCC） and to compare the efficacy of surgical resection followed by adjuvant radiotherapy（SR） with that of neoadjuvant therapy consisting of platinum-based chemotherapy and fluorouracil combined with either cetuximab or nimotuzumab, followed by SR. The study also aimed to evaluate the overall survival（OS） of patients, their postoperative eating function, tracheostomy decannulation rate, and tumor response to the two neoadjuvant chemotherapies. Methods:A retrospective analysis was performed on the medical records of HPSCC patients who received SR or neoadjuvant therapy followed by SR treatment at the Shanghai General Hospital from 2012 to 2019 and had not undergone any prior treatment. The prognostic factors were analyzed, and the survival analysis of patients who underwent SR treatment with two neoadjuvant chemotherapy regimens was performed. Results:A total of 108 patients were included in the study. The results of the univariate analysis showed that gender（P=0.850） had no significant correlation with the survival rate of HPSCC patients who underwent SR. However, age, smoking history, alcohol consumption history, platelet-to-lymphocyte ratio（PLR）, neutrophil-to-lymphocyte ratio（NLR）, T stage, N stage, neoadjuvant therapy with either cetuximab or nimotuzumab combined with platinum-based chemotherapy and fluorouracil, and histological grade were significantly associated with prognosis（P<0.05）. The multivariate analysis revealed that smoking history, histological grade, and neoadjuvant therapy with either cetuximab or nimotuzumab combined with platinum-based chemotherapy and fluorouracil were independent risk factors affecting the prognosis of HPSCC（P<0.05）. Patients who received neoadjuvant therapy had longer OS than those who underwent SR only（P<0.001）. There was no significant difference in tumor response to the two neoadjuvant therapies and in OS（P>0.05）, and there was no significant difference in the rate of oral feeding and tracheostomy decannulation among the three treatment groups（P>0.05）. Conclusion:Univariate analysis showed that age at tumor onset, smoking history, alcohol consumption history, NLR, PLR, T stage, N stage, whether receiving neoadjuvant chemotherapy, and pathological grade were associated with the prognosis of HPSCC patients receiving SR treatment. Multivariate analysis showed that smoking history, pathological grade, and neoadjuvant chemotherapy were independent risk factors affecting the prognosis. Neoadjuvant chemotherapy with cetuximab or nimotuzumab can prolong the OS of patients, providing a certain basis and reference for the treatment of HPSCC.

Selenium-enriched peptides identified from selenium-enriched soybean protein hydrolysate: protective effects against heat damage in Caco-2 cells.

Our previous study evaluated the antioxidant and anti-inflammatory activities of selenium-enriched soybean peptides (SePPs) in vivo. In this study, we purified SePPs via gel filtration chromatography and obtained five fractions (F1, F2, F3, F4 and F5), among which F3 displayed the highest antioxidant and anti-inflammatory activities. Nineteen selenium-enriched peptides were identified in F3 by mass spectrometry. Two selenium-enriched peptides with sequences ESeCQIQKL (Sep-1) and SELRSPKSeC (Sep-2) were selected for synthesis based on their score and the number of hydrophobic amino acids, acidic and basic amino acids. Both Sep-1 and Sep-2 exhibited preventive effects on the heat stress-induced impairment of intestinal epithelial cell integrity, oxidative stress and inflammatory responses in a Caco-2 cell model. Pretreatment of the cells with Sep-1 or Sep-2 for 24 h reduced intracellular reactive oxygen species (ROS) generation, prevented the disruption of tight junction (TJ) proteins, and decreased paracellular permeability. Western blot results showed that Sep-1 and Sep-2 could improve the abnormal expressions of Nrf2, Keap1, NLRP3, caspase-1 and ASC/TMS1, thereby enhancing the glutathione (GSH) redox system and reducing IL-1ß and IL-18 concentrations. Sep-1 activated the Nrf2-Keap1 signaling pathway significantly more than Sep-2. Molecular docking results indicated that Sep-1 and Sep-2 are both bound to Keap1 and NLRP3 in the form of hydrogen bonds, hydrophobic interactions and salt bridges, which interferes with Nrf2 and NLRP3 signaling. Molecular dynamics simulations suggested that more hydrogen bonds were formed during the resultant process of Sep-1 with Keap1, and the compactness and stability of the complex structure were better than those of Sep-2. These findings confirm the value of both Sep-1 and Sep-2 in the development of dietary supplements as potential alternatives for heat damage and related disease prevention.

Deep learning-assisted diagnosis of benign and malignant parotid tumors based on contrast-enhanced CT: a multicenter study.

OBJECTIVES: To develop deep learning-assisted diagnosis models based on CT images to facilitate radiologists in differentiating benign and malignant parotid tumors. METHODS: Data from 573 patients with histopathologically confirmed parotid tumors from center 1 (training set: n = 269; internal-testing set: n = 116) and center 2 (external-testing set: n = 188) were retrospectively collected. Six deep learning models (MobileNet V3, ShuffleNet V2, Inception V3, DenseNet 121, ResNet 50, and VGG 19) based on arterial-phase CT images, and a baseline support vector machine (SVM) model integrating clinical-radiological features with handcrafted radiomics signatures were constructed. The performance of senior and junior radiologists with and without optimal model assistance was compared. The net reclassification index (NRI) and integrated discrimination improvement (IDI) were calculated to evaluate the clinical benefit of using the optimal model. RESULTS: MobileNet V3 had the best predictive performance, with sensitivity increases of 0.111 and 0.207 (p < 0.05) in the internal- and external-testing sets, respectively, relative to the SVM model. Clinical benefit and overall efficiency of junior radiologist were significantly improved with model assistance; for the internal- and external-testing sets, respectively, the AUCs improved by 0.128 and 0.102 (p < 0.05), the sensitivity improved by 0.194 and 0.120 (p < 0.05), the NRIs were 0.257 and 0.205 (p < 0.001), and the IDIs were 0.316 and 0.252 (p < 0.001). CONCLUSIONS: The developed deep learning models can assist radiologists in achieving higher diagnostic performance and hopefully provide more valuable information for clinical decision-making in patients with parotid tumors. KEY POINTS: • The developed deep learning models outperformed the traditional SVM model in predicting benign and malignant parotid tumors. • Junior radiologist can obtain greater clinical benefits with assistance from the optimal deep learning model. • The clinical decision-making process can be accelerated in patients with parotid tumors using the established deep learning model.

Ultrasmall PtAu2 nanoclusters activate endogenous anti-inflammatory and anti-oxidative systems to prevent inflammatory osteolysis.

Rationale: Inflammatory osteolysis, characterized by abundant immune cell infiltration and osteoclast (OC) formation, is a common complication induced by bacterial products and/or wear particles at the bone-prosthesis interface that severely reduces long-term stability after implantation. Molecular nanoclusters are ultrasmall particles with unique physicochemical and biological properties that have great potential as theranostic agents for treating inflammatory diseases. Methods: In this study, heterometallic PtAu2 nanoclusters with sensitive nitric oxide-responsive phosphorescence turn-on characteristics and strong binding interactions with cysteine were designed, making them desirable candidates for the treatment of inflammatory osteolysis. Results: PtAu2 clusters exhibited satisfactory biocompatibility and cellular uptake behavior, with potent anti-inflammatory and anti-OC activities in vitro. In addition, PtAu2 clusters alleviated lipopolysaccharide-induced calvarial osteolysis in vivo and activated nuclear factor erythroid 2-related factor 2 (Nrf2) expression by disrupting its association with Kelch-like ECH-associated protein 1 (Keap1), thereby upregulating the expression of endogenous anti-inflammatory and anti-oxidative products. Conclusion: Through the rational design of novel heterometallic nanoclusters that activate the endogenous anti-inflammatory system, this study provides new insights into the development of multifunctional molecular therapeutic agents for inflammatory osteolysis and other inflammatory diseases.

Novel Muscle-Homing Peptide FGF1 Conjugate Based on AlphaFold for Type 2 Diabetes Mellitus.

Drugs for metabolic diseases usually require systemic administration and act on multiple tissues, which may produce some unpredictable side effects. There have been many successful studies on targeted drugs, especially antitumor drugs. However, there is still little research on metabolic disease drugs targeting specific tissues. Fibroblast growth factor 1 (FGF1) is a potential therapy for type 2 diabetes (T2D) without the risk of hypoglycemia. However, the major impediment to the clinical application of FGF1 is its mitogenic potential. We previously engineered an FGF1 variant (named FGF1ΔHBS) to tune down its mitogenic activity via reducing the heparin-binding ability. However, other notable side effects still remained, including severe appetite inhibition, pathogenic loss of body weight, and increase in fatality rate. In this study, we used AlphaFold2 and PyMOL visualization tools to construct a novel FGF1ΔHBS conjugate fused with skeletal muscle-targeted (MT) peptide through a flexible peptide linker termed MT-FGF1ΔHBS. We found that MT-FGF1ΔHBS specifically homed to skeletal muscle tissue after systemic administration and induced a potent glucose-lowering effect in T2D mice without hypoglycemia. Mechanistically, MT-FGF1ΔHBS elicits the glucose-lowering effect via AMPK activation to promote the GLUT4 expression and translocation in skeletal muscle cells. Notably, compared with native FGF1ΔHBS, MT-FGF1ΔHBS had minimal effects on food intake and body weight and did not induce any hyperplasia in major tissues of both T2D and normal mice, indicating that this muscle-homing protein may be a promising candidate for T2D treatment. Our targeted peptide strategy based on computer-aided structure prediction in this study could be effectively applied for delivering agents to functional tissues to treat metabolic or other diseases, offering enhanced efficacy and reducing systemic off-target side effects.

Fully Flexible MXene-based Gas Sensor on Paper for Highly Sensitive Room-Temperature Nitrogen Dioxide Detection.

Flexible chemiresistive gas sensors have attracted growing interest due to their capability in real-time and rapid detection of gas. However, the performance of gas sensors has long been hindered by the poor charge transfer ability between the conventional metal electrode and gas sensing semiconductors. Herein, for the first time, a fully flexible paper-based gas sensor integrated with the Ti3C2Tx-MXene nonmetallic electrode and the Ti3C2Tx/WS2 gas sensing film was designed to form Ohmic contact and Schottky heterojunction in a single gas sensing channel. Ti3C2Tx/WS2 has outstanding physical and chemical properties for both Ti3C2Tx and WS2 nanoflakes, showing high conductivity, effective charge transfer, and abundant active sites for gas sensing. The response of the gas sensor to NO2 (1 ppm) at room temperature is 15.2%, which is about 3.2 and 76.0 times as high as that of the Au interdigital electrode integrated with the Ti3C2Tx/WS2 sensor (4.8%) and the MXene electrode integrated with the Ti3C2Tx sensor (0.2%), respectively. Besides, this design performed at a limit of detection with 11.0 ppb NO2 gas and displayed excellent stability under high humidities. Based on first-principles density functional theory calculation results, the improvement of the gas sensing performance can be mainly attributed to the heterojunction regulation effect, work function matching, and suppressing metal-induced gap states. This work provides a new approach for the design of flexible gas sensors on paper with MXene-based conductive electrodes and gas sensing materials.

The Effect of Magnetic Resonance Imaging Based Radiomics Models in Discriminating stage I-II and III-IVa Nasopharyngeal Carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a common tumor in China. Accurate stages of NPC are crucial for treatment. We therefore aim to develop radiomics models for discriminating early-stage (I-II) and advanced-stage (III-IVa) NPC based on MR images. METHODS: 329 NPC patients were enrolled and randomly divided into a training cohort (n = 229) and a validation cohort (n = 100). Features were extracted based on axial contrast-enhanced T1-weighted images (CE-T1WI), T1WI, and T2-weighted images (T2WI). Least absolute shrinkage and selection operator (LASSO) was used to build radiomics signatures. Seven radiomics models were constructed with logistic regression. The AUC value was used to assess classification performance. The DeLong test was used to compare the AUCs of different radiomics models and visual assessment. RESULTS: Models A, B, C, D, E, F, and G were constructed with 13, 9, 7, 9, 10, 7, and 6 features, respectively. All radiomics models showed better classification performance than that of visual assessment. Model A (CE-T1WI + T1WI + T2WI) showed the best classification performance (AUC: 0.847) in the training cohort. CE-T1WI showed the greatest significance for staging NPC. CONCLUSION: Radiomics models can effectively distinguish early-stage from advanced-stage NPC patients, and Model A (CE-T1WI + T1WI + T2WI) showed the best classification performance.

Berbamine Exerts an Anti-oncogenic Effect on Pancreatic Cancer by Regulating Wnt and DNA Damage-related Pathways.

OBJECTIVE: This study aimed to determine the effects of berbamine on pancreatic cancer as well as the underlying mechanisms. METHODS: The pancreatic cancer cells were treated with different concentrations of berbamine and then subjected to cell viability assay, colony formation assay, cell cycle analysis, and apoptosis detection. Western blotting and immunofluorescence analyses were performed to investigate the mechanisms underlying the biological effects of berbamine on the pancreatic cancer cells. Furthermore, the in vivo anti-pancreatic cancer effect of berbamine was examined using a mouse xenograft model. RESULTS: Berbamine significantly inhibited the proliferation and colony-forming ability of BxPC3 and PANC-1 pancreatic cancer cells while inducing a cell cycle arrest and apoptosis. Moreover, berbamine decreased the expression of ß- catenin and phosphorylation of GSK3ß but increased the expression of γ-H2AX and 53BP1. Meanwhile, in vivo studies revealed that berbamine attenuated the growth of xenograft tumors derived from PANC-1 cells. Notably, berbamine treatment led to an increase in the expression of Cleaved Caspase 3 and γ-H2AX, as well as a decrease in the expression of Ki-67 and ß-catenin in the tumor xenografts. CONCLUSION: Berbamine exerts an anti-pancreatic cancer effect, possibly by regulating Wnt and DNA damage-related pathways, suggestive of its therapeutic potential for pancreatic cancer.

Exosomes Derived from Adipose Mesenchymal Stem Cells Carrying miRNA-22-3p Promote Schwann Cells Proliferation and Migration through Downregulation of PTEN.

Peripheral nerve injury (PNI) is often resulting from trauma, which leads to severe and permanently disability. Schwann cells are critical for facilitating the regeneration process after PNI. Adipose-derived mesenchymal stem cells (ADSCs) exosomes have been used as a novel treatment for peripheral nerve injury. However, the underlying mechanism remains unclear. In this study, we isolated ADSCs and extracted exosomes, which were verified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blot (WB). Cocultured with Dorsal Root Ganglion (DRG) and Schwann cells (SCs) to evaluate the effect of exosomes on the growth of DRG axons by immunofluorescence, and the proliferation and migration of SCs by CCK8 and Transwell assays, respectively. Through exosomal miRNA sequencing and bioinformatic analysis, the related miRNAs and target gene were predicted and identified by dual luciferase assay. Related miRNAs were overexpressed and inhibited, respectively, to clarify their effects; the downstream pathway through the target gene was determined by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and WB. Results found that ADSC-exosomes could promote the proliferation and migration of SCs and the growth of DRG axons, respectively. Exosomal miRNA-22-3p from ADSCs directly inhibited the expression of Phosphatase and Tensin Homolog deleted on Chromosome 10 (PTEN), activated phosphorylation of the AKT/mTOR axis, and enhanced SCs proliferation and migration. In conclusion, our findings suggest that ADSC-exosomes could promote SCs function through exosomal miRNA-22-3p, which could be used as a therapeutic target for peripheral nerve injury.

Selenium-enriched soybean peptides pretreatment attenuates lung injury in mice induced by fine particulate matters (PM2.5) through inhibition of TLR4/NF-κB/IκBα signaling pathway and inflammasome generation.

This study aimed to identify and prepare peptides from selenium (Se)-enriched soybeans and determine whether dietary Se-enriched soybean peptides (Se-SPep) could inhibit lung injury in mice induced by fine particulate matter 2.5 (PM2.5). BALB/c mice were randomly divided into six groups. The mice in the prevention groups were pretreated with 378 mg kg-1 of Se-SPep, soybean peptides (SPep), and Se-enriched soybean protein (Se-SPro), respectively, for four weeks. The mice in the PM2.5 exposure group received concentrated PM2.5 (15 µg per day mice) for 1 h daily from the third week for two weeks. The results showed that the leukocyte and cytokine (IL-1ß, IL-6, TNF-α) levels in the bronchoalveolar lavage fluid (BALF) of the PM2.5 exposure group were higher than those in the control group. Se-SPep pretreatment decreased the IL-1ß, IL-6, and TNF-α levels compared with the PM2.5 exposure group. Additionally, Se-SPep pretreatment inhibited TLR4/NF-κB/IκBα and NLRP3/ASC/caspase-1 protein expression in the lungs. In conclusion, Se-SPep pretreatment may protect the lungs of the mice against PM2.5-induced inflammation, suggesting that Se-SPep represents a potential preventative agent to inhibit PM2.5-induced lung injury.

Anti-Inflammatory Function of Plant-Derived Bioactive Peptides: A Review.

Inflammation is considered to be a crucial factor in the development of chronic diseases, eight of which were listed among the top ten causes of death worldwide in the World Health Organization's World Health Statistics 2019. Moreover, traditional drugs for inflammation are often linked to undesirable side effects. As gentler alternatives to traditional anti-inflammatory drugs, plant-derived bioactive peptides have been shown to be effective interventions against various chronic diseases, including Alzheimer's disease, cardiovascular disease and cancer. However, an adequate and systematic review of the structures and anti-inflammatory activities of plant-derived bioactive peptides has been lacking. This paper reviews the latest research on plant-derived anti-inflammatory peptides (PAPs), mainly including the specific regulatory mechanisms of PAPs; the structure-activity relationships of PAPs; and their enzymatic processing based on the structure-activity relationships. Moreover, current research problems for PAPs are discussed, such as the shallow exploration of mechanisms, enzymatic solution determination difficulty, low yield and unknown in vivo absorption and metabolism and proposed future research directions. This work aims to provide a reference for functional activity research, nutritional food development and the clinical applications of PAPs.

[Applying a rigid curved video laryngoscope in laryngeal microsurgery of patients with difficult laryngeal exposure].

Objective:To test the feasibility of a rigid curved video laryngoscope in laryngeal microsurgery of patients with difficult laryngeal exposure. Methods:Thirteen patients with difficult laryngeal exposure underwent microlayngeal surgery using a new-design rigid curved video laryngoscope. The clinical data were collected and analyzed. Results:In all of the 13 patients with difficult laryngeal exposure,the fully exposure rate of glottis was 100% using a new-design rigid curved laryngoscope.But only 7 precise surgeries using our rigid curved instruments were completed successfully. Conclusion:Rigid curved laryngoscope is a useful tool to in treating patients with difficult laryngeal exposure in microlaryngeal surgery. Satisfactory glottis exposure, magnified surgical field and precise maneuver of the lesions could be achieved. But manipulation of this tool is challenging, which warrants further investigation．.