Enhancement of protein production in Aspergillus niger by engineering the antioxidant defense metabolism.

BACKGROUND: Research on protein production holds significant importance in the advancement of food technology, agriculture, pharmaceuticals, and bioenergy. Aspergillus niger stands out as an ideal microbial cell factory for the production of food-grade proteins, owing to its robust protein secretion capacity and excellent safety profile. However, the extensive oxidative folding of proteins within the endoplasmic reticulum (ER) triggers ER stress, consequently leading to protein misfolding reactions. This stressful phenomenon results in the accelerated generation of reactive oxygen species (ROS), thereby inducing oxidative stress. The accumulation of ROS can adversely affect intracellular DNA, proteins, and lipids. RESULT: In this study, we enhanced the detoxification of ROS in A. niger (SH-1) by integrating multiple modules, including the NADPH regeneration engineering module, the glutaredoxin system, the GSH synthesis engineering module, and the transcription factor module. We assessed the intracellular ROS levels, growth under stress conditions, protein production levels, and intracellular GSH content. Our findings revealed that the overexpression of Glr1 in the glutaredoxin system exhibited significant efficacy across various parameters. Specifically, it reduced the intracellular ROS levels in A. niger by 50%, boosted glucoamylase enzyme activity by 243%, and increased total protein secretion by 88%. CONCLUSION: The results indicate that moderate modulation of intracellular redox conditions can enhance overall protein output. In conclusion, we present a strategy for augmenting protein production in A. niger and propose a potential approach for optimizing microbial protein production system.

Liraglutide reduces bone marrow adipogenesis by miR-150-5p/ GDF11 axis in diabetic rats.

In recent years, a common-used antidiabetic drug, liraglutide, was identified with extra effects on lipid metabolism. Its effects against excessive lipid deposition in bone marrow were gained much attention but not well established. Our aim in the present study is to explore the interaction of miRNAs-mRNAs altered by liraglutide administration during bone marrow adipogenesis in diabetes. To establish the diabetic animal model, rats were treated with high fat diet (HFD) and STZ injection. We then identified the lowering effect of liraglutide on lipids metabolism in the diabetes. During this process, high-throughput sequencing and bioinformatics analyses on miRNAs extracted from bone marrow mesenchymal stem cells (BMSCs) were conducted after liraglutide administration. We then identified five differentially expressed miRNAs (miRNA-150-5p, miRNA-129-5p, miRNA-201-3p, miRNA-201-5p, and miRNA-214-5p). The expressions of the DE miRNAs were verified as temporal specific expression patterns in Day 3 and in Day 7. Among them, miRNA-150-5p expression was more stable and consistent with the sequencing data. Of interest, miR-150-5p overexpression facilitated adipogenesis of BMSCs. But this promotion was alleviated by liraglutide. The predicted target gene of miR-150-5p, GDF11, was validated to be involved in liraglutide alleviated BMSCs' lipid accumulation in diabetes. In vitro, liraglutide increased the GDF11 expression, rescued its down-expression by siGDF11 and inhibit the adipogenesis of BMSCs cultured in high glucose medium. In vivo, liraglutide reversed the HFD-STZ induced excessive lipid droplets by up-regulation of GDF11 expression, which was discounted by agomiR-150-5p injection. Above all, liraglutide might alleviate bone marrow fat accumulation via inactivating miR-150-5p/GDF11 axis in diabetes.

Possible adverse events of imidazole antifungal drugs during treatment of vulvovaginal candidiasis: analysis of the FDA Adverse Event Reporting System.

Azole antifungal drugs are commonly used to treat vulvovaginal candidiasis (VVC). The nephrotoxicity and developmental toxicity of azole drugs have not been systematically analyzed in the real world. We used the FDA Adverse Event Reporting System (FAERS) to investigate the adverse events (AEs) associated with imidazole therapy for VVC. FAERS data (from quarter 1 2004 to quarter 3 2022) were retrieved using OpenVigil 2.1, and AEs were retrieved and standardized according to the Medical Dictionary for Regulatory Activities (MedDRA). In the top 10 System Organ Class (SOC), all four drugs have been found to have kidney and urinary system diseases and pregnancy. We found significant signals, including clotrimazole [bladder transitional cell carcinoma, (report odds ratio, ROR = 291.66)], [fetal death, (ROR = 10.28)], ketoconazole[nephrogenic anemia (ROR = 22.1)], [premature rupture of membranes (ROR = 22.91 46.45, 11, 3)], Miconazole[hematuria (ROR = 19.03)], [neonatal sepsis (ROR = 123.71)], [spontaneous abortion (ROR = 5.98)], Econazole [acute kidney injury (ROR = 4.41)], [spontaneous abortion (ROR = 19.62)]. We also discovered new adverse reactions that were not reported. Therefore, when using imidazole drugs for treatment, it is necessary to closely monitor the patient's renal function, pay attention to the developmental toxicity of the fetus during pregnancy, and be aware of potential adverse reactions that may occur.

Sleep and liver function biomarkers in relation to risk of incident liver cancer: a nationwide prospective cohort study.

BACKGROUND: To assess the largely undetermined separate and joint effects of sleep and liver function biomarkers on liver cancer. METHODS: Data of 356,894 participants without cancer at baseline in the UK Biobank were analyzed. Sleep score was evaluated using five sleep traits (sleep duration, chronotype, insomnia, snoring, and excessive daytime sleepiness) and dichotomized into healthy or unhealthy sleep. Circulating liver function biomarkers were measured. Cox proportional hazard model was performed to investigate the independent and joint associations of sleep and liver function biomarkers with liver cancer incidence. RESULTS: After a median follow-up time of 13.1 years, 394 cases of incident liver cancer were documented. The multivariable-adjusted hazard ratio (HR) for liver cancer was 1.46 (95% confidence interval: 1.15-1.85) associated with unhealthy sleep (vs. healthy sleep), and was 1.17 (1.15-1.20), 1.20 (1.18-1.22), 1.69 (1.47-1.93), 1.06 (1.06-1.07), 1.08 (1.07-1.09), 1.81 (1.37-2.39), or 0.29 (0.18-0.46) associated with each 10-unit increase in alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin (TBIL), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), total protein (TP), or albumin (ALB), respectively. Individuals with unhealthy sleep and high (≥ median) ALT, AST, TBIL, GGT, ALP, or TP or low (< median) ALB level had the highest HR of 3.65 (2.43-5.48), 4.03 (2.69-6.03), 1.97 (1.40-2.77), 4.69 (2.98-7.37), 2.51 (1.75-3.59), 2.09 (1.51-2.89), or 2.22 (1.55-3.17) for liver cancer, respectively. Significant additive interaction of unhealthy sleep with high TP level on liver cancer was observed with relative excess risk due to an interaction of 0.80 (0.19-1.41). CONCLUSIONS: Unhealthy sleep was associated with an increased risk of liver cancer, especially in participants with lower ALB levels or higher levels of ALT, AST, TBIL, GGT, ALP, or particularly TP.

High methylation of the same promoter of lncRNA ZNF582-AS1/ZNF582 promotes malignant progression of esophageal cancer.

Aim: This study aimed to investigate the functions of ZNF582-AS1 and ZNF582 in esophageal cancer (EC). Materials & methods: Bioinformatics analysis, qRT-PCR and western blot were used to analyze the expression levels. Biological functions were evaluated using cell-counting kit 8, colony formation, Transwell assays and flow cytometry. FISH was used to detect subcellular localization, and methylation-specific PCR determined gene methylation levels. Animal experiments validated the impact on tumor progression. Results: ZNF582-AS1 and ZNF582 were highly methylated and downregulated in EC. Overexpression of ZNF582-AS1 up-regulated the expression of ZNF582, thereby inhibiting EC cell viability and metastasis, promoting apoptosis and inhibiting tumor growth. Conclusion: Low expression of ZNF582-AS1/ZNF582 mediated by DNA hypermethylation facilitates the malignant progression of EC.

Promoter hypermethylation silences ZNF582-AS1 and ZNF582, driving esophageal cancer progression, which has the potential for novel therapeutic strategies. # Methylation # Esophageal Cancer.

Plasma EBV quantification is associated with the efficacy of immune checkpoint blockade and disease monitoring in patients with primary pulmonary lymphoepithelioma-like carcinoma.

Objectives: Primary pulmonary lymphoepithelioma-like carcinoma (PLELC) is a subtype of lung carcinoma associated with the Epstein-Barr virus (EBV). The clinical predictive biomarkers of immune checkpoint blockade (ICB) in PLELC require further investigation. Methods: We prospectively analysed EBV levels in the blood and immune tumor biomarkers of 31 patients with ICB-treated PLELC. Viral EBNA-1 and BamHI-W DNA fragments in the plasma were quantified in parallel using quantitative polymerase chain reaction. Results: Progression-free survival (PFS) was significantly longer in EBNA-1 high or BamHI-W high groups. A longer PFS was also observed in patients with both high plasma EBNA-1 or BamHI-W and PD-L1 ≥ 1%. Intriguingly, the tumor mutational burden was inversely correlated with EBNA-1 and BamHI-W. Plasma EBV load was negatively associated with intratumoral CD8+ immune cell infiltration. Dynamic changes in plasma EBV DNA level were in accordance with the changes in tumor volume. An increase in EBV DNA levels during treatment indicated molecular progression that preceded the imaging progression by several months. Conclusions: Plasma EBV DNA could be a useful and easy-to-use biomarker for predicting the clinical activity of ICB in PLELC and could serve to monitor disease progression earlier than computed tomography imaging.

The Application of Pneumatic Arm in Neuroendoscopic Transsphenoidal Pituitary Adenoma Resection.

OBJECTIVE: To summarize the application experience of the pneumatic arm in transnasal sphenoidal pituitary adenoma resection under neuroendoscope. METHODS: A retrospective analysis was conducted on the clinical data of 52 patients with pituitary adenoma who underwent endoscopic transsphenoidal surgery with pneumatic arm fixation in the Neurosurgery Department of the First Affiliated Hospital of Anhui Medical University from July 2021 to March 2024. Among them, there were 5 cases of pituitary microadenoma, 35 cases of macroadenoma, and 12 cases of giant adenoma. Head CT and a full set of hormones were re-examined within 24 hours after surgery to evaluate the surgical effect. Follow-up was conducted by the outpatient department after surgery to assess the clinical symptoms, hormone level, and imaging of all patients. RESULTS: Among 52 patients, gross total resection was achieved in 48 cases (92.3%), subtotal resection in 3 cases (5.8%), and partial resection in 1 case (1.9%). Preoperatively, 43 patients had diminished vision, with 40 showing improvement postoperatively, 1 worsening, and 2 having no significant improvement. Thirty-eight patients had headaches preoperatively, and all showed varying degrees of improvement postoperatively. Routine hormone examination within 24 hours after surgery showed that all 20 prolactinoma patients had restored normal hormone levels, 10 of 12 growth hormone-secreting adenoma patients normalized, and 4 of 6 cases of adrenocorticotropic hormone-secreting adenoma immediately relieved after surgery. Postoperative complications included intracranial hematoma in 1 case, cerebrospinal fluid leakage in 2 cases, transient diabetes insipidus in 6 cases, intracranial infection in 1 case, and no death cases. The median follow-up time of 52 patients was 18.6 months (range: 1-32 mo). During the follow-up period, the initial clinical symptoms of all patients improved to varying degrees, and they were able to work and live normally. At the last follow-up, 1 patient had recurrent tumor and 1 patient had progression. CONCLUSION: Transnasal sphenoidal resection of pituitary adenoma using a pneumatic arm-fixed neuroendoscope allows the operator to perform the surgery with both hands, resulting in satisfactory overall tumor resection and fewer surgical complications. This technique has good clinical value for promotion.

Environmental and Sublethal Concentrations of Polystyrene Nanoplastics Induced Antioxidant System, Transcriptomic Responses, and Disturbed Gut Microbiota in Oyster Magallana Hongkongensis.

Nanoplastics (NPs) are emerging contaminants having persistent nature, diverse ecological impacts, and potential food safety risks. Here, we examined the ecotoxicity of 80 nm polystyrene nanoplastics (PS-NPs) at environmentally relevant concentrations (ERCs, 10 and 100 µg/L), and sublethal concentrations (SLCs, 500 and 2500 µg/L) in Magallana hongkongensis. Results showed that SLCs significantly (p < 0.05) increased superoxide dismutase (SOD), catalase (CAT), and alkaline phosphatase (AKP) activities and altered tnfα, cat, gst, sod, and se-gpx genetic expressions. Further, PS-NP exposure at both levels reduced beneficial bacteria and increased potentially pathogenic bacteria in the gut. In transcriptomic analysis, 5118 and 4180 differentially expressed genes (DEGs) were identified at ERCs, while 5665 and 4817 DEGs were found at SLCs, respectively. Upregulated DEGs enriched lysosomes, ABC transporters, and apoptosis pathways, while downregulated DEGs enriched ribosomal pathways. Overall, ERCs significantly altered gut microbiota and transcriptomic responses, while SLCs, in addition, also impacted the antioxidant and immune systems.

Exploring the potential of Paris polyphylla var. yunnanensis pollen manipulation in modifying seed dormancy.

Paris polyphylla var. yunnanensis, a well-known Chinese medicinal herb, shows a unique physiological trait characterized by the cyclic opening and closing of its anthers after pollen maturation. The aim of this study was to explore the implications of this phenomenon on breeding. RNA sequencing coupled with methylation sequencing was used to scrutinize and compare gene expression profiles and methylation alterations in pollen and seeds during anther opening and closing, along with cold exposure. Genes enriched within Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were examined to identify gene clusters susceptible to temperature-related methylation changes in both pollen and seeds. Four pollen treatment models, namely, normal control, "pollen protected from low temperatures," "pollen from just-opened anther," and "pollen from close-blocked anther," were used to produce corresponding seeds via artificial pollination. Subsequently, qRT-PCR was used to validate modifications in the expression patterns of marker genes in pollinated seeds under diverse treatment scenarios. Genes exhibiting significant differences in expression between anthers and normal tissues, along with gene regions linked to methylation variations attributed to low-temperature-treated pollen and seeds, were identified through transcriptomic analysis. Convergence was observed in three signaling pathways: oxidative phosphorylation (ko00190), plant hormone signal transduction (Ko04075), and zeatin biosynthesis (ko00908). Notably, gene clusters prone to temperature-induced methylation changes, such as NADH-ubiquinone oxidoreductase chain 5, plasma membrane ATPase 4, cytochrome c oxidase subunit 2, cis-zeatin O-glucosyltransferase, ABSCISIC ACID-INSENSITIVE 5-like protein 4, and indole-3-acetic acid-amido synthetase (IAAS), were identified. Evaluation using various pollen pollination models revealed altered expression patterns of five dormancy-regulating marker genes: IAAS, sucrose synthase (SUS), gibberellin 2-oxidase (GA2ox), ABA INSENSITIVE 2 (ABI2), and auxin-repressed protein (ARP), in seeds pollinated with pollen from close-blocked anthers, cold-protected pollen, and pollen from freshly opened anthers. The close-blocked anther treatment led to significantly upregulated expression of IAAS, SUS, GA2ox, and ABI2, whereas ARP expression decreased markedly, indicating a propensity toward prolonged seed dormancy. Conversely, in the low-temperature-protected anther model, SUS, ARP, GA2ox, and IAAS exhibited reduced expression levels, whereas the expression of ABI2 was upregulated, overall facilitating seed germination.

Groundwater health risk assessment of North China Plain based on Monte Carlo model sensitivity analysis and morphological analysis: A case study of Shijiazhuang City.

The rapid development of the social economy and the influence of human activities can lead to aggravated groundwater pollution. Groundwater safety is the premise of residents' health. Therefore, studying the sustainable utilization and health risks of groundwater quality is important. The groundwater quality and potential health risks were evaluated in the Shijiazhuang area, which is located in the North China Plain in this paper. Based on 159 groundwater samples collected in the study area, the potential health risks of As, Cr6+, Ni, Pb, F-, and NO3 - to humans were evaluated from oral and skin contact. Results of the human health risk assessment showed that the average carcinogenic risk and non-carcinogenic risk of children are higher than those of adults. According to the spatial distribution of the total risk value, adults and children in the southwest of the study area face higher risks. Because of the uncertainty of USEPA, Monte Carlo simulation was used to calculate the probability of health risk assessment and prioritization of contaminant treatment. The results of the Monte Carlo simulation showed that the acceptable range for children is 6.82%, and the acceptable range for adults is 18.07%. According to the HRWM model, carcinogenic pollutants mainly include As, Cr6+, and Ni. The most important chemical species of As is HAsO4 2-, followed by H2AsO4 -. Similarly, CrO4 2- and Ni2+ are the main forms of Cr6+ and Ni. The results of this study can provide data support for the protection and management of groundwater quality in the North China Plain. PRACTITIONER POINTS: Children are more susceptible to carcinogenic risk than adults. After calculation, the main influencing elements are Ni and Cr. Metal morphology analysis was carried out, and the results showed that HAsO4 2-, CrO4 2-, and Ni2+ were the main types.

Prediction of Tumor-Associated Macrophages and Immunotherapy Benefits Using Weakly Supervised Contrastive Learning in Breast Cancer Pathology Images.

The efficacy of immune checkpoint inhibitors is significantly influenced by the tumor immune microenvironment (TIME). RNA sequencing of tumor tissue can offer valuable insights into TIME, but its high cost and long turnaround time seriously restrict its utility in routine clinical examinations. Several recent studies have suggested that ultrahigh-resolution pathology images can infer cellular and molecular characteristics. However, few study pay attention to the quantitative estimation of various tumor infiltration immune cells from pathology images. In this paper, we integrated contrastive learning and weakly supervised learning to infer tumor-associated macrophages and potential immunotherapy benefit from whole slide images (WSIs) of H &E stained pathological sections. We split the high-resolution WSIs into tiles and then apply contrastive learning to extract features of each tile. After aggregating the features at the tile level, we employ weak supervisory signals to fine-tune the encoder for various downstream tasks. Comprehensive experiments on two independent breast cancer cohorts and spatial transcriptomics data demonstrate that the computational pathological features accurately predict the proportion of tumor-infiltrating immune cells, particularly the infiltration level of macrophages, as well as the immune subtypes and potential immunotherapy benefit. These findings demonstrate that our model effectively captures pathological features beyond human vision, establishing a mapping relationship between cellular compositions and histological morphology, thus expanding the clinical applications of digital pathology images.

Distribution characteristics and prognosis of tumor-infiltrating lymphocytes in the brain metastases of small cell lung cancer: a retrospective cohort study.

Background: The efficacy of immunotherapy for brain metastases from small cell lung cancer (SCLC) is relatively low, and the tumor microenvironment of SCLC brain metastases is still unknown. Therefore, we investigated the distribution of tumor-infiltrating lymphocytes (TILs) and the expression of programmed cell death-ligand 1 (PD-L1) in patients with brain metastases from SCLC to explore the tumor microenvironment of SCLC brain metastases. Methods: A retrospective analysis was performed on 12 surgical specimens of brain metastases from patients with SCLC treated in the Department of Neurosurgery of The First Affiliated Hospital of Anhui Medical University from June 2017 to June 2022. The inclusion criteria for this study were the following: (I) a pathologically confirmed diagnosis of SCLC brain metastases; (II) surgical resection of brain metastases; (III) age >18 years; (IV) and complete clinical data. Patient-related data were retrieved from the inpatient medical record system, telephone follow-up of patients date of death, and overall survival (OS). The immunofluorescence-based tissue microenvironment analysis panel (MAP) was utilized for the detection of TILs, including CD3, CD8, programmed cell death 1 (PD-1), and PD-L1, in formalin-fixed and paraffin-embedded archival specimens of brain metastases. The expression levels of PD-L1 in tumor cells were detected by immunohistochemistry. The correlation between the OS and the above-mentioned markers was analyzed in the 12 patients. Results: Twelve patients were included in the study. The patients' ages ranged from 51-78 years with a median of 68 years, with 1 female and 11 males. Among 12 patients with SCLC brain metastases: positive rates of CD3+ TILs in the tumor parenchyma vs. tumor stroma were 0.60%±0.94% vs. 1.76%±2.72% (P=0.01), respectively; positive rates of CD8+ TILs in the tumor parenchyma vs. tumor stroma were 0.80%±0.78% vs. 2.46%±3.72% (P=0.02), respectively. There was no co-expression of CD8+ and PD-1+ TILs in the tumor parenchyma of 11 cases, and the infiltration density of coexpressed CD3+ and PD-1+ TILs was more than 10/mm2 in only 1 case. There was no coexpression of CD3+ and PD-1+ TIL in the stroma of 10 cases, and the infiltration density of CD8+ and PD-1+ TILs was more than 10/mm2 in 2 cases. Immunohistochemistry was used to detect the expression of PD-L1 in 12 cases of SCLC metastatic lesions, and 3 cases (25%) were positive. Survival analysis showed that patients with positive intraepithelial CD3+ TILs had significantly longer OS [hazard ratio 3.383, 95% confidence interval (CI): 0.959-11.940; P=0.04]. Conclusions: Our study further demonstrated the immune microenvironment of SCLC brain metastases. The distribution of TILs in SCLC brain metastases is low and mainly distributed in the stroma, with the expression of PD-L1 in these tumor tissues being low. Further exploration of the immune microenvironment of SCLC brain metastases is of great significance for potential treatment.

Identification of miRNA expression profile in middle ear cholesteatoma using small RNA-sequencing.

BACKGROUND: The present study aims to identify the differential miRNA expression profile in middle ear cholesteatoma and explore their potential roles in its pathogenesis. METHODS: Cholesteatoma and matched normal retroauricular skin tissue samples were collected from patients diagnosed with acquired middle ear cholesteatoma. The miRNA expression profiling was performed using small RNA sequencing, which further validated by quantitative real-time PCR (qRT-PCR). Target genes of differentially expressed miRNAs in cholesteatoma were predicted. The interaction network of 5 most significantly differentially expressed miRNAs was visualized using Cytoscape. Further Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analyses were processed to investigate the biological functions of miRNAs in cholesteatoma. RESULTS: The miRNA expression profile revealed 121 significantly differentially expressed miRNAs in cholesteatoma compared to normal skin tissues, with 56 upregulated and 65 downregulated. GO and KEGG pathway enrichment analyses suggested their significant roles in the pathogenesis of cholesteatoma. The interaction network of the the 2 most upregulated (hsa-miR-21-5p and hsa-miR-142-5p) and 3 most downregulated (hsa-miR-508-3p, hsa-miR-509-3p and hsa-miR-211-5p) miRNAs identified TGFBR2, MBNL1, and NFAT5 as potential key target genes in middle ear cholesteatoma. CONCLUSIONS: This study provides a comprehensive miRNA expression profile in middle ear cholesteatoma, which may aid in identifying therapeutic targets for its management.

Recent progress in aqueous aluminum-ion batteries.

Aqueous aluminum-ion batteries have many advantages such as their safety, environmental friendliness, low cost, high reserves and the high theoretical specific capacity of aluminum. So aqueous aluminum-ion batteries are potential substitute for lithium-ion batteries. In this paper, the current research status and development trends of cathode and anode materials and electrolytes for aqueous aluminum-ion batteries are described. Aiming at the problem of passivation, corrosion and hydrogen evolution reaction of aluminum anode and dissolution and irreversible change of cathode after cycling in aqueous aluminum-ion batteries. Solutions of different research routes such as ASEI (artificial solid electrolyte interphase), alloying, amorphization, elemental doping, electrolyte regulation, etc and different transformation mechanisms of anode and cathode materials during cycling have been summarized. Moreover, it looks forward to the possible research directions of aqueous aluminum-ion batteries in the future. We hope that this review can provide some insights and support for the design of more suitable electrode materials and electrolytes for aqueous aluminum-ion batteries.

Spiderweb-Shaped Iron-Coordinated Polymeric Network as the Novel Coating on Microneedles for Transdermal Drug Delivery Against Infectious Wounds.

Coated microneedles (CMNs) are a minimally invasive platform for immediate-release transdermal drug delivery. However, the practical applications of CMNs have been significantly hindered by the challenges associated with complex formulations, single function, and limited drug loading capacity. In this study, we have developed a spiderweb-shaped iron-coordinated polymeric nanowire network (Fe-IDA NWs). The resulting Fe-IDA NWs are endowed with a certain viscosity due to the synergy of multiple supramolecular interactions. This allows them to replace traditional polymeric thickeners as microneedle coatings. The Fe-IDA NWs-coated microneedles (Fe-IDA MNs) display rapid disintegration in the skin model, which also enables the swift diffusion of Fe-IDA NWs and their payloads into the deeper skin layers. Additionally, Fe-IDA MNs exhibit desirable enzymatic activity and potential antibacterial ability. Thus, Fe-IDA MNs can enhance the therapeutic efficacy against wound infection through synergistic effects, and avoid the overly complicated formulation and the release of non-therapeutic molecules of conventional CMNs. As a proof-of-concept, Fe-IDA MNs loaded with chlorin e6 showed a synergistic chemodynamic-photodynamic antibacterial effect in a methicillin-resistant Staphylococcus aureus-infected wound model in mice. Collectively, this work has significant implications for the future of CMNs-based transdermal drug delivery systems and expands the application fields of metal coordination polymer materials. This article is protected by copyright. All rights reserved.

Non-Gaussian diffusion metrics with whole-tumor histogram analysis for bladder cancer diagnosis: muscle invasion and histological grade.

PURPOSE: To investigate the performance of histogram features of non-Gaussian diffusion metrics for diagnosing muscle invasion and histological grade in bladder cancer (BCa). METHODS: Patients were prospectively allocated to MR scanner1 (training cohort) or MR2 (testing cohort) for conventional diffusion-weighted imaging (DWIconv) and multi-b-value DWI. Metrics of continuous time random walk (CTRW), diffusion kurtosis imaging (DKI), fractional-order calculus (FROC), intravoxel incoherent motion (IVIM), and stretched exponential model (SEM) were simultaneously calculated using multi-b-value DWI. Whole-tumor histogram features were extracted from DWIconv and non-Gaussian diffusion metrics for logistic regression analysis to develop diffusion models diagnosing muscle invasion and histological grade. The models' performances were quantified by area under the receiver operating characteristic curve (AUC). RESULTS: MR1 included 267 pathologically-confirmed BCa patients (median age, 67 years [IQR, 46-82], 222 men) and MR2 included 83 (median age, 65 years [IQR, 31-82], 73 men). For discriminating muscle invasion, CTRW achieved the highest testing AUC of 0.915, higher than DWIconv's 0.805 (p = 0.014), and similar to the combined diffusion model's AUC of 0.885 (p = 0.076). For differentiating histological grade of non-muscle-invasion bladder cancer, IVIM outperformed a testing AUC of 0.897, higher than DWIconv's 0.694 (p = 0.020), and similar to the combined diffusion model's AUC of 0.917 (p = 0.650). In both tasks, DKI, FROC, and SEM failed to show diagnostic superiority over DWIconv (p > 0.05). CONCLUSION: CTRW and IVIM are two potential non-Gaussian diffusion models to improve the MRI application in assessing muscle invasion and histological grade of BCa, respectively. CRITICAL RELEVANCE STATEMENT: Our study validates non-Gaussian diffusion imaging as a reliable, non-invasive technique for early assessment of muscle invasion and histological grade in BCa, enhancing accuracy in diagnosis and improving MRI application in BCa diagnostic procedures. KEY POINTS: Muscular invasion largely determines bladder salvageability in bladder cancer patients. Evaluated non-Gaussian diffusion metrics surpassed DWIconv in BCa muscle invasion and histological grade diagnosis. Non-Gaussian diffusion imaging improved MRI application in preoperative diagnosis of BCa.

Application value of multi-gene mutation detection in the clinical management of pediatric papillary thyroid carcinoma: a preliminary exploration.

Objectives: Thyroid cancer rarely occurs in children and adolescents. Molecular markers such as BRAF, RAS, and RET/PTC have been widely used in adult PTC. It is currently unclear whether these molecular markers have equivalent potential for application in pediatric patients. This study aims to explore the potential utility of a multi-gene conjoint analysis based on next-generation targeted sequencing for pediatric papillary thyroid carcinoma (PTC). Materials and methods: The patients diagnosed with PTC (aged 18 years or younger) in the pediatrics department of Lishui District Hospital of Traditional Chinese Medicine were retrospectively screened. A targeted enrichment and sequencing analysis of 116 genes associated with thyroid cancer was performed on paraffin-embedded tumor tissues and paired paracancerous tissue of fifteen children (average age 14.60) and nine adults (average age 49.33) PTC patients. Demographic information, clinical indicators, ultrasonic imaging information and pathological data were collected. The Kendall correlation test was used to establish a correlation between molecular variations and clinical characteristics in pediatric patients. Results: A sample of 15 pediatric PTCs revealed a detection rate of 73.33% (11/15) for driver gene mutations BRAF V600E and RET fusion. Compared to adult PTCs, the genetic mutation landscape of pediatric PTCs was more complex. Six mutant genes overlap between the two groups, and an additional seventeen unique mutant genes were identified only in pediatric PTCs. There was only one unique mutant gene in adult PTCs. The tumor diameter of pediatric PTCs tended to be less than 4cm (p<0.001), and the number of lymph node metastases was more than five (p<0.001). Mutations in specific genes unique to pediatric PTCs may contribute to the onset and progression of the disease by adversely affecting hormone synthesis, secretion, and action mechanisms, as well as the functioning of thyroid hormone signaling pathways. But, additional experiments are required to validate this hypothesis. Conclusion: BRAF V600E mutation and RET fusion are involved in the occurrence and development of adolescent PTC. For pediatric thyroid nodules that cannot be determined as benign or malignant by fine needle aspiration biopsy, multiple gene combination testing can provide a reference for personalized diagnosis and treatment by clinical physicians.

Predicting perioperative myocardial injury/infarction after noncardiac surgery in patients under surgical and medical co-management: a prospective cohort study.

BACKGROUND: Perioperative myocardial injury/infarction (PMI) following noncardiac surgery is a frequent cardiac complication. This study aims to evaluate PMI risk and explore preoperative assessment tools of PMI in patients at increased cardiovascular (CV) risk who underwent noncardiac surgery under the surgical and medical co-management (SMC) model. METHODS: A prospective cohort study that included consecutive patients at increased CV risk who underwent intermediate- or high-risk noncardiac surgery at the Second Medical Center, Chinese PLA General Hospital, between January 2017 and December 2022. All patients were treated with perioperative management by the SMC team. The SMC model was initiated when surgical intervention was indicated and throughout the entire perioperative period. The incidence, risk factors, and impact of PMI on 30-day mortality were analyzed. The ability of the Revised Cardiac Risk Index (RCRI), frailty, and their combination to predict PMI was evaluated. RESULTS: 613 eligible patients (mean [standard deviation, SD] age 73.3[10.9] years, 94.6% male) were recruited consecutively. Under SMC, PMI occurred in 24/613 patients (3.9%). Patients with PMI had a higher rate of 30-day mortality than patients without PMI (29.2% vs. 0.7%, p = 0.00). The FRAIL Scale for frailty was independently associated with an increased risk for PMI (odds ratio = 5.91; 95% confidence interval [CI], 2.34-14.93; p = 0.00). The RCRI demonstrated adequate discriminatory capacity for predicting PMI (area under the curve [AUC], 0.78; 95% CI, 0.67-0.88). Combining frailty with the RCRI further increased the accuracy of predicting PMI (AUC, 0.87; 95% CI, 0.81-0.93). CONCLUSIONS: The incidence of PMI was relatively low in high CV risk patients undergoing intermediate- or high-risk noncardiac surgery under SMC. The RCRI adequately predicted PMI. Combining frailty with the RCRI further increased the accuracy of PMI predictions, achieving excellent discriminatory capacity. These findings may aid personalized evaluation and management of high-risk patients who undergo intermediate- or high-risk noncardiac surgery.

Delivery of mRNA Encoding Interleukin-12 and a Stimulator of Interferon Genes Agonist Potentiates Antitumor Efficacy through Reversing T Cell Exhaustion.

T cell exhaustion has emerged as a major hurdle that impedes the clinical translation of stimulator of interferon genes (STING) agonists. It is crucial to explore innovative strategies to rejuvenate exhausted T cells and potentiate the antitumor efficacy. Here, we propose an approach utilizing MSA-2 as a STING agonist, along with nanoparticle-mediated delivery of mRNA encoding interleukin-12 (IL-12) to restore the function of T cells. We developed a lipid nanoparticle (DMT7-IL12 LNP) that encapsulated IL12 mRNA. Our findings convincingly demonstrated that the combination of MSA-2 and DMT7-IL12 LNP can effectively reverse the exhausted T cell phenotype, as evidenced by the enhanced secretion of cytokines, such as tumor necrosis factor alpha, interferon gamma, and Granzyme B, coupled with reduced levels of inhibitory molecules such as T cell immunoglobulin and mucin domain-3 and programmed cell death protein-1 on CD8+ T cells. Furthermore, this approach led to improved survival and tumor regression without causing any systemic toxicity in melanoma and lung metastasis models. These findings suggest that mRNA encoding IL-12 in conjunction with STING agonists has the potential to confer superior clinical outcomes, representing a promising advancement in cancer immunotherapy.