Neoadjuvant immunochemotherapy for pulmonary large-cell neuroendocrine carcinoma: case report.

BACKGROUND: Pulmonary large-cell neuroendocrine carcinoma (pLCNEC) represents a rare malignancy characterized by its aggressive behavior and a notably high recurrence rate. Remarkably, there is currently no established standard treatment protocol for this condition. CASE DESCRIPTION: In this report, we present an intriguing case of pLCNEC diagnosed at clinical-stage IIB. This case involves a 64-year-old man with a smoking history spanning four decades. In our approach, we initiated a course of neoadjuvant chemotherapy in combination with pembrolizumab, administered for two cycles prior to surgical resection. This innovative treatment strategy resulted in a significant pathological response, culminating in a major pathological remission (MPR). As of the time of composing this report, the patient has been diligently monitored for 39 months post-surgery, exhibiting no indications of recurrence, and has demonstrated exceptional tolerance to the entire treatment regimen. CONCLUSIONS: We have first reported a clinically successful case of neoadjuvant combination chemotherapy with pembrolizumab in the treatment of pLCNEC. This case offers promising clinical insights and suggests that this therapeutic approach could be a viable option for managing pLCNEC.

Research on smart city public health detection system and improvement technology based on intelligent multi-objective.

Introduction: With the increase of urban population density, urban sanitation becomes more severe; urban sanitation has important influence on public health. Therefore, in order to realize the detection of public health in smart cities, the research will use cutting-edge scientific and technological methods to improve urban environmental health, so as to promote the realization of public health achievements. This study introduces public health detection and optimizationtechnologies for smart cities. Methods: Firstly, a data detection system for urban public health environment was established using sensors and intelligent multi-objective technology to evaluate the water quality, air quality, and noise level of the city. Then, an intelligent garbage management system based on Tensor-flow was constructed to achieve efficient garbage collection and treatment. Finally, an intelligent traffic management system was developed to monitor and regulate urban traffic flow. Results: The results of the simulation experiment demonstrated that the life data detection system was operationally stable, with a high success rate of 98%. Furthermore, its accuracy in detecting residents' living environment data was above 95%, the maximum relative error was only 0.0465, making it a reliable and efficient tool. The waste recycling system achieved a minimum accuracy of 83.6%, the highest accuracy rate was 95.3%, making it capable of sorting and recycling urban waste effectively. Additionally, the smart traffic management system led to a 20% reduction in traffic congestion rates, 20 tonnes less tailpipe emissions and an improvement in public health and well-being. Discussion: In summary, the plan proposed in this study aims to create a more comfortable, safe, and healthy urban public health environment, while providing theoretical support for environmental health management in smart cities.

Exploiting the potential of a novel "in-situ latent heat recovery" in hollow-fiber vacuum membrane distillation process for simultaneously improved water production and energy efficiency.

Thermal driven membrane distillation (MD) technology is a promising method for purifying & recovering various salty (especially high salty) or contaminated wastewaters with low-grade heat sources. However, the drawbacks of "high energy consumption" and "high cooling water consumption" pose special challenges for the future development of this technology. In this article, we report an innovative strategy called "in-situ heat transfer", which is based on the jacketed structure composed of hollow fiber membranes and capillary heat exchange tubes, to simplify the migration steps of condensation latent heat in MD heat recovery process. The results indicate that the novel heat recovery strategy exhibits higher growth rates both in the flux and gained output ratio (47.4 % and 173.1 %, respectively), and further reduces the system's dependence on cooling water. In sum, under the control of the "in-situ heat transfer" mechanism, the functional coupling of "vapor condensation (exothermic)" and "feed evaporation (endothermic)" in limited-domain space is an attractive alternative solution, because it eliminates the disadvantages of the imbalance between heat supply and demand in traditional heat recovery methods. Our research may facilitate the development of MD heat recovery modules for industrial applications, which will help to further achieve the goal of energy saving and emission reduction.

'Environmental standard limit concentration' arsenic exposure is associated with anxiety, depression, and autism-like changes in early-life stage zebrafish.

Arsenic is a worldwide environmental pollutant that can impair human health. Previous studies have identified mental disorders induced by arsenic, but the environmental exposure concentrations in the early life stages associated with these disorders are poorly understood. In the present study, early-life stage zebrafish were used to explore the effects on mental disorders under 'environmental standard limit concentrations' arsenic exposures of 5, 10, 50, 150, and 500 µg/L. The results showed that arsenic exposure at these concentrations changed the locomotor behavior in larval zebrafish and was further associated with anxiety, depression, and autism-like behavior in both larval and juvenile zebrafish. Changes were noted at benchmark dose limit (BMDL) concentrations as low as 0.81 µg/L. Transcriptomics showed that immediate early genes (IEGs) fosab, egr1, egr2a, ier2b, egr3, and jund were decreased after arsenic exposure in larval and juvenile zebrafish. Nervous system impairment and anxiety, depression, and autism-like behaviors in early-life stage zebrafish at 'environmental standard limit concentrations' may be attributed to the downregulation of IEGs. These findings in zebrafish provided new experimental support for an arsenic toxicity threshold for mental disorders, and they suggest that low levels of environmental chemicals may be causative developmental factors for mental disorders.

Fe-Mn binary oxides improve the methanogenic performance and reduce the environmental health risks associated with antibiotic resistance genes during anaerobic digestion.

Increasing evidence indicates that metal oxides can improve the methanogenic performance during anaerobic digestion (AD) of piggery wastewater. However, the impacts of composite metal oxides on the methanogenic performance and risk of antibiotic resistance gene (ARG) transmission during AD are not fully understood. In this study, different concentrations of Fe-Mn binary oxides (FMBO at 0, 250, 500, and 1000 mg/L) were added to AD to explore the effects of FMBO on the process. The methane yield was 7825.1 mL under FMBO at 250 mg/L, 35.2% higher than that with FMBO at 0 mg/L. PICRUSt2 functional predictions showed that FMBO promoted the oxidation of acetate and propionate, and the production of methane from the substrate, as well as increasing the abundances of most methanogens and genes encoding related enzymes. Furthermore, under FMBO at 250 mg/L, the relative abundances of 14 ARGs (excluding tetC and sul2) and four mobile gene elements (MGEs) decreased by 24.7% and 55.8%, respectively. Most of the changes in the abundances of ARGs were explained by microorganisms, especially Bacteroidetes (51.20%), followed by MGEs (11.98%). Thus, the methanogenic performance of AD improved and the risk of horizontal ARG transfer decreased with FMBO, especially at 250 mg/L.

Plasma sPD-L1 and VEGF levels are associated with the prognosis of NSCLC patients treated with combination immunotherapy.

The clinical significance of plasma soluble programmed cell death ligand 1 (sPD-L1) and vascular endothelial growth factor (VEGF) for non-small cell lung cancer (NSCLC) treated with the combination of anti-angiogenic therapy and anti-PD-L1 antibody (Ab) remain unknown. This study aimed to explore the association between plasma sPD-L1 and VEGF levels and the prognosis of NSCLC patients treated with the combination of Envafolimab and Endostar. Peripheral blood samples were collected from 24 NSCLC patients at baseline and after 6 weeks of treatment and were detected for sPD-L1 and VEGF levels. Both baseline and posttreatment sPD-L1 were significantly higher in progressive disease (PD) group than in controlled disease (CD) group (median: 77.5 pg/ml vs. 64.6 pg/ml, P  = 0.036, median: 8451 pg/ml vs. 5563 pg/ml, P  = 0.012). In multivariate analysis, lower baseline sPD-L1 levels were significantly associated with longer progression-free survival (PFS) (HR = 6.834, 95% CI: 1.350-34.592, P  = 0.020). There were significantly higher posttreatment VEGF levels in PD group compared with CD group (median: 323.7 pg/ml vs. 178.5 pg/ml, P  = 0.009). Higher posttreatment VEGF levels were significantly associated with shorter PFS in multivariate analysis (HR = 5.911, 95% CI: 1.391-25.122, P  = 0.016). Plasma sPD-L1 and VEGF levels are associated with the clinical response and prognosis of NSCLC patients treated with the combination of PD-L1 inhibitors and anti-angiogenetic therapy.

Identification of novel serum metabolic signatures to predict chronic kidney disease among Chinese elders using UPLC-Orbitrap-MS.

BACKGROUND: Chronic kidney disease (CKD) is a major public health concern. However, validated and broadly applicable biomarkers for early CKD diagnosis are currently not available. We aimed to identify serum metabolic signatures at an early stage of CKD to provide a reference for future investigations into the early diagnostic biomarkers. METHODS: Serum metabolites were extracted from 65 renal dysfunction (RD) patients and 121 healthy controls (discovery cohort: 12 RD patients and 55 health participants; validation cohort: 53 RD patients and 66 health participants). Metabolite extracts were analyzed by ultraperformance liquid chromatography coupled with quadrupole-electrostatic field orbital trap mass spectrometry (UPLC-QE-Orbitrap MS) for untargeted metabolomics. Orthogonal partial least squares-discriminant analysis (OPLS-DA) was performed to detect different compounds between groups. Receiver operating characteristic (ROC) curve analysis was carried out to determine the diagnostic value of the validated differential metabolites between groups. We referred to the Kyoto Encyclopedia of Gene and Genomes (KEGG) to elucidate the metabolic pathways of the validated differential metabolites. RESULTS: A total of 22 and 23 metabolites had significantly different abundances in the discovery and validation cohort, respectively. Six of them (creatinine, L-proline, citrulline, butyrylcarnitine, 1-methylhistidine, and valerylcarnitine) in the RD group was more abundant than that of the health group in both cohorts. The combination of the six validated differential metabolites were able to accurately detect RD (AUC 0.86). Three of the six metabolites are involved in the metabolism of arginine and proline. CONCLUSIONS: The present study highlights that creatinine, L-proline, citrulline, butyrylcarnitine, 1-methylhistidine, and valerylcarnitine are metabolite indicators with potential predictive value for CKD.

UPP1 promotes lung adenocarcinoma progression through the induction of an immunosuppressive microenvironment.

The complexity of the tumor microenvironment (TME) is a crucial factor in lung adenocarcinoma (LUAD) progression. To gain deeper insights into molecular mechanisms of LUAD, we perform an integrative single-cell RNA sequencing (scRNA-seq) data analysis of 377,574 cells from 117 LUAD patient samples. By linking scRNA-seq data with bulk gene expression data, we identify a cluster of prognostic-related UPP1high tumor cells. These cells, primarily situated at the invasive front of tumors, display a stronger association with the immunosuppressive components in the TME. Our cytokine array analysis reveals that the upregulation of UPP1 in tumor cells leads to the increased release of various immunosuppressive cytokines, with TGF-ß1 being particularly prominent. Furthermore, this UPP1 upregulation also elevates the expression of PD-L1 through the PI3K/AKT/mTOR pathway, which contributes to the suppression of CD8 + T cells. Cytometry by time-of-flight (CyTOF) analysis provides additional evidence of the role of UPP1 in shaping the immunosuppressive nature of the TME. Using patient-derived organoids (PDOs), we discover that UPP1high tumors exhibit relatively increased sensitivity to Bosutinib and Dasatinib. Collectively, our study highlights the immunosuppressive role of UPP1 in LUAD, and these findings may provide insights into the molecular features of LUAD and facilitate the development of personalized treatment strategies.

From ferroptosis to cuproptosis, and calcicoptosis, to find more novel metals-mediated distinct form of regulated cell death.

Regulated cell death (RCD), also known as programmed cell death (PCD), plays a critical role in various biological processes, such as tissue injury/repair, development, and homeostasis. Dysregulation of RCD pathways can lead to the development of many human diseases, such as cancer, neurodegenerative disorders, and cardiovascular diseases. Maintaining proper metal ion homeostasis is critical for human health. However, imbalances in metal levels within cells can result in cytotoxicity and cell death, leading to a variety of diseases and health problems. In recent years, new types of metal overload-induced cell death have been identified, including ferroptosis, cuproptosis, and calcicoptosis. This has prompted us to examine the three defined metal-dependent cell death types, and discuss other metals-induced ferroptosis, cuproptosis, and disrupted Ca2+ homeostasis, as well as the roles of Zn2+ in metals' homeostasis and related RCD. We have reviewed the connection between metals-induced RCD and various diseases, as well as the underlying mechanisms. We believe that further research in this area will lead to the discovery of novel types of metal-dependent RCD, a better understanding of the underlying mechanisms, and the development of new therapeutic strategies for human diseases.

Genomic profiling and associated B cell lineages delineate the efficacy of neoadjuvant anti-PD-1-based therapy in oesophageal squamous cell carcinoma.

BACKGROUND: Neoadjuvant chemoimmunotherapy has offered novel therapeutic options for patients with locally advanced oesophageal squamous cell carcinoma (ESCC). Depicting the landscape of genomic and immune profiles is critical in predicting therapeutic responses. METHODS: We integrated whole-exome sequencing, single-cell RNA sequencing, and immunofluorescence data of ESCC samples from 24 patients who received neoadjuvant treatment with PD-1 inhibitors plus paclitaxel and platinum-based chemotherapy to identify correlations with therapeutic responses. FINDINGS: An elevation of small insertions and deletions was observed in responders. DNA mismatch repair (MMR) pathway alternations were highly frequent in patients with optimal responses and correlated with tumour infiltrating lymphocytes (TILs). Among the TILs in ESCC, dichotomous developing trajectories of B cells were identified, with one lineage differentiating towards LMO2+ germinal centre B cells and another lineage differentiating towards CD55+ memory B cells. While LMO2+ germinal centre B cells were enriched in responding tumours, CD55+ memory B cells were found to correlate with inferior responses to combination therapy, exhibiting immune-regulating features and impeding the cytotoxicity of CD8+ T cells. The comprehensive evaluation of transcriptomic B cell lineage features was validated to predict responses to immunotherapy in patients with cancer. INTERPRETATION: This comprehensive evaluation of tumour MMR pathway alternations and intra-tumoural B cell features will help to improve the selection and management of patients with ESCC to receive neoadjuvant chemoimmunotherapy. FUNDING: National Science Foundation of China (82373371, 82330053), Eastern Scholar Program at Shanghai Institutions of Higher Learning, National Science and Technology Major Project of China (2023YFA1800204, 2020YFC2008402), and Science and Technology Commission of Shanghai Municipality (22ZR1410700, 20ZR1410800).

Metabolomic analysis of hydroxycinnamic acid inhibition on Saccharomyces cerevisiae.

Ferulic acid (FA) and p-coumaric acid (p-CA) are hydroxycinnamic acid inhibitors that are mainly produced during the pretreatment of lignocellulose. To date, the inhibitory mechanism of hydroxycinnamic acid compounds on Saccharomyces cerevisiae has not been fully elucidated. In this study, liquid chromatography-mass spectrometry (LC-MS) and scanning electron microscopy (SEM) were used to investigate the changes in S. cerevisiae cells treated with FA and p-CA. In this experiment, the control group was denoted as group CK, the FA-treated group was denoted as group F, and the p-CA-treated group was denoted as group P. One hundred different metabolites in group F and group CK and 92 different metabolites in group P and group CK were selected and introduced to metaboanalyst, respectively. A total of 38 metabolic pathways were enriched in S. cerevisiae under FA stress, and 27 metabolic pathways were enriched in S. cerevisiae under p-CA stress as identified through Kyoto Encyclopaedia of Genes and Genomes (KEGG) analysis. The differential metabolites involved included S-adenosine methionine, L-arginine, and cysteine, which were significantly downregulated, and acetyl-CoA, L-glutamic acid, and L-threonine, which were significantly upregulated. Analysis of differential metabolic pathways showed that the differentially expressed metabolites were mainly related to amino acid metabolism, nucleotide metabolism, fatty acid degradation, and the tricarboxylic acid cycle (TCA). Under the stress of FA and p-CA, the metabolism of some amino acids was blocked, which disturbed the redox balance in the cells and destroyed the synthesis of most proteins, which was the main reason for the inhibition of yeast cell growth. This study provided a strong scientific reference to improve the durability of S. cerevisiae against hydroxycinnamic acid inhibitors. KEY POINTS: • Morphological changes of S. cerevisiae cells under inhibitors stress were observed. • Changes of the metabolites in S. cerevisiae cells were explored by metabolomics. • One of the inhibitory effects on yeast is due to changes in the metabolic network.

Development of a TLR-Based Model That Can Predict Prognosis, Tumor Microenvironment, and Drug Response for Esophageal Squamous Cell Carcinoma.

The toll-like receptor (TLR) family is an important class of proteins involved in the immune response. However, little is known about the association between TLRs and Esophageal squamous cell cancer (ESCC). We explored differentially expressed genes (DEGs) between ESCC and esophagus tissues in TCGA and GTEx database. By taking the intersection with TLR gene set and using univariate Cox analysis and multivariate Cox regression analysis to discriminate the hub genes, we created a TLR-prognostic model. Our model separated patients with ESCC into high- and low-risk score (RS) groups. Prognostic analysis was performed with Kaplan-Meier curves. The two groups were also compared regarding tumor immune microenvironment and drug sensitivity. Six hub genes (including CD36, LGR4, MAP2K3, NINJ1, PIK3R1, and TRAF3) were screened to construct a TLR-prognostic model. High-RS group had a worse survival (p < 0.01), lower immune checkpoint expression (p < 0.05), immune cell abundance (p < 0.05) and decreased sensitivity to Epirubicin (p < 0.001), 5-fluorouracil (p < 0.0001), Sorafenib (p < 0.01) and Oxaliplatin (p < 0.05). We constructed a TLR-based model, which could be used to assess the prognosis of patients with ESCC, provide new insights into drug treatment for ESCC patients and investigate the TME and drug response.

Detection and quantification of etomidate and metomidate in human hairs by ultraperformance liquid chromatography with triple quadrupole mass spectrometry (UPLC-MS/MS).

PURPOSE: Intravenous narcotic agents, such as etomidate and metomidate, has been widely spread and abused in the world, including in Korea and China; thus, it is important to establish validated and sensitive analytical method for these compounds. Human hair as a biological sample has various advantages, including a wide detection window of drugs, compared to other typical samples, such as urine and blood in investigation. The purpose of this communication is to develop a reliable and useful method for the simultaneous detection and quantification of etomidate and metomidate in human hair samples by ultraperformance liquid chromatography combined with triple quadrupole mass spectrometry (UPLC-MS/MS), and to apply it for authentic samples in abuse cases. METHODS: The hair samples were washed with a detergent solution, followed by with water and acetone. After drying, they were cut into approximately 2 mm sections and then ground to powder by a low-temperature grinder. The 20 mg of hair powder plus internal standard in 1 mL of methanol was vortexed and then centrifuged to obtain the supernatant layer, followed by subjecting to analysis. RESULTS: The coefficient of determination (r2) values of the calibration curves of etomidate and metomidate in the hair samples were both more than 0.99 in the range of 1-500 ng/mg and 1-500 pg/mg, respectively. The limits of detection and lower limits of quantification were 0.5 and 1 pg/mg, respectively, for the both target compounds. Other tested validation data were all satisfactory. Etomidate and metomidate could be detected in the all hair samples and cigarette oil, which were seized by the police. The concentrations of etomidate and metomidate obtained from 10 samples from suspects were 5.48-45.7 ng/mg and 3.60-377 pg/mg, respectively. The concentrations of etomidate and metomidate in the cigarette oil were 95.8 µg/mg and 2.8 µg/mg, respectively. CONCLUSIONS: In this study, a simple and reliable analytical method for etomidate and metomidate in the human hair has been established. To the best of our knowledge, this is the first report to establish a method for the simultaneous detection and quantification of etomidate and metomidate in the human hair, and to apply it to authentic samples seized in authentic cases.

The Underlying Structure of Preventive Behaviors and Related Factors During the COVID-19 Pandemic: A Comprehensive Network Analysis.

BACKGROUND: Various strategies against COVID-19 have been adopted in different countries, with vaccination and mask-wearing being widely used as self-preventive interventions. However, the underlying structure of these behaviors and related factors remain unclear. PURPOSE: In this study, we aimed to explore the network structure of preventive behaviors during the COVID-19 pandemic and their underlying factors, incorporating age and sex in the network. METHODS: We used a multi-center sample of 20,863 adults who were vaccinated against COVID-19 in China between April 1, 2021, and June 1, 2021. Networks were estimated using unregularized partial correlation models. We also estimated the accuracy and stability of the network. RESULTS: The preventive behaviors related to network factors revealed that self-initiated vaccination was more connected with cognition factors, and mask-wearing was more connected with personal profiles. The two clusters were linked through information-seeking and political beliefs. Moreover, self-initiated vaccination was negatively connected with vaccine hesitancy and concerns about COVID-19 vaccines and positively connected with trust in the vaccines, pandemic-related altruism, political beliefs, and being married. Mask-wearing was negatively connected with being a professional/white collar worker and higher education level and positively connected with regular physical examination, self-rated health, migration, being married, and better family relationships. Incorporation of age and sex into the network revealed relevant associations between age and mask-wearing and age and self-initiated vaccination. The network was highly accurately estimated. The subset bootstrap showed that the order of node strength centrality, betweenness, and closeness were all stable. The correlation stability coefficient (CS-coefficient) also showed the stability of this estimate, with 0.75 for node strength, 0.75 for betweenness, and 0.67 for closeness. CONCLUSIONS: The internal structures of vaccination and mask-wearing behaviors were quite different, the latter of which were mainly affected by socioeconomic status and health-related behaviors and the former by knowledge about vaccines and political beliefs. Information-seeking and family relationships were the bridge factors connecting these two self-preventive behavior clusters, suggesting the direction of future efforts.

Remote imprinting of moiré lattices.

Two-dimensional moiré materials are formed by overlaying two layered crystals with small differences in orientation or/and lattice constant, where their direct coupling generates moiré potentials. Moiré materials have emerged as a platform for the discovery of new physics and device concepts, but while moiré materials are highly tunable, once formed, moiré lattices cannot be easily altered. Here we demonstrate the electrostatic imprinting of moiré lattices onto a target monolayer semiconductor. The moiré potential-created by a lattice of electrons that is supported by a Mott insulator state in a remote MoSe2/WS2 moiré bilayer-imprints a moiré potential that generates flat bands and correlated insulating states in the target monolayer and can be turned on/off by gate tuning the doping density of the moiré bilayer. Additionally, we studied the interplay between the electrostatic and structural relaxation contributions to moiré imprinting. Our results demonstrate a pathway towards gate control of moiré lattices.

Metagenomic binning analyses of swine manure composting reveal mechanism of nitrogen cycle amendment using kaolin.

The efficient control of nitrogen loss in composting and the enhancement of product quality have become prominent concerns in current research. The positive role of varying concentrations kaolin in reducing nitrogen loss during composting was revealed using metagenomic binning combined with reverse transcription quantitative polymerase chain reaction. The results indicated that the addition of 0.5 % kaolin significantly (P < 0.05) up-regulated the expression of nosZ and nifH on day 35, while concurrently reducing norB abundance, resulting in a reduction of NH3 and N2O emissions by 61.4 % and 17.5 %, respectively. Notably, this study represents the first investigation into the co-occurrence of nitrogen functional genes and heavy metal resistance genes within metagenomic assembly genomes during composting. Emerging evidence indicates that kaolin effectively impedes the binding of Cu/Zn to nirK and nosZ gene reductases through passivation. This study offers a novel approach to enhance compost quality and waste material utilization.

FGL1 in plasma extracellular vesicles is correlated with clinical stage of lung adenocarcinoma and anti-PD-L1 response.

Fibrinogen-like protein-1 (FGL1) is confirmed a major ligand of lymphocyte activation gene-3 which could inhibit antigen-mediated T-cell response and evade immune supervision. Although hepatocytes secrete large amounts of FGL1, its high expression also be detected in solid tumors such as lung cancer, leading to a poor efficacy of immune checkpoint inhibitors therapy. Here we reported that FGL1 was overexpressed in lung adenocarcinoma (LUAD) but not in lung squamous cell carcinoma. However, FGL1 in tissue and plasma can only distinguish LUAD patients from healthy donors and cannot correlate with clinical Tumor Node Metastasis (TNM) stage. Using lung cancer cell lines, we confirmed that FGL1 can be detected on extracellular vesicles (EVs) and we established a method using flow cytometry to detect FGL1 on the surface of EVs, which revealed that FGL1 could be secreted via EVs. Both animal model and clinical samples proved that plasma FGL1 in EVs would increase when the tumor was loaded. The level of FGL1 in plasma EVs was correlated with clinical TNM stage and tumor size, and a higher level indicated non-responsiveness to anti-programmed cell death ligand 1 (anti-PD-L1) immunotherapy. Its effect on tumor progression and immune evasion may be achieved by impairing the killing and proliferating capacities of CD8+ T cells. Our result demonstrates that FGL1 levels in plasma EVs, but not total plasma FGL1, could be a promising biomarker that plays an important role in predicting anti-PD-L1 immune therapy in LUAD and suggests a new strategy in LUAD immunotherapy.

Neurobehavioral toxic effects and mechanisms of 2-aminobenzothiazole exposure on zebrafish.

2-Aminobenzothiazole (NTH), a benzothiazole derivative, exhibits potent biochemical activities and plays a significant role in modern industry. Widespread and intensive utilization of NTH has led to its detection in aquatic environments, encompassing both groundwater and surface water. Despite its wide usage, the effect of NTH on developmental neurotoxicity in aquatic organisms remains uncharted. Therefore, the aim of this investigation was to create exposure models for short- and long-term studies in order to analyze the neurobehavioral toxic impact of NTH (0, 50, 500, and 5000 µg/L) on zebrafish, which includes motor function, anxiety, and memory performance, as well as to examine the mechanism of neurotoxicity. The results revealed a significant suppression of initial embryonic mobility by NTH. However, during short-term exposure experiments, it did not significantly impact the developmental neurobehavioral functions of zebrafish. In addition, significant effects on zebrafish were observed after long-term exposure to 50 and 500 µg/L NTH, mainly impacting locomotion, social behavior, anxiety, and cognitive functions. Moreover, NTH caused oxidative damage in adult zebrafish brain tissue, which was accompanied by abnormal expression of oxidative damage-related genes. Furthermore, the Real-Time PCR results indicated a significant suppression of genes related to exposure to NTH, specifically those in the GABA synthesis pathway (gabrg2, gad2, gad1b, and abat) and the 5-HT synthesis pathway (tph2, tph1b, pet1, and htr1aa). Taken together, this study demonstrates for the first time that chronic exposure to NTH decreases the expression of genes associated with the zebrafish GABA synthesis pathway and the 5-HT synthesis pathway. This suppression is accompanied by oxidative damage, ultimately resulting in neurobehavioral changes related to motor ability, anxiety, and memory performance.

Identification and molecular binding mechanism of novel pancreatic lipase and cholesterol esterase inhibitory peptides from heat-treated adzuki bean protein hydrolysates.

Heat-treated adzuki bean protein hydrolysates exhibit lipid-reducing properties; however, few studies have reported pancreatic lipase (PL) and cholesterol esterase (CE) inhibitory effects and elucidated the underlying mechanisms. In this study, we accomplished the identification of antiobesity peptides through peptide sequencing, virtual screening, and in vitro experiments. Furthermore, the mechanisms were investigated via molecular docking. The findings reveal that the action of pepsin and pancreatin resulted in the transformation of intact adzuki bean protein into smaller peptide fragments. The < 3 kDa fraction exhibited a high proportion of hydrophobic amino acids and displayed superior inhibitory properties for both PL and CE. Five novel antiobesity peptides (LLGGLDSSLLPH, FDTGSSFYNKPAG, IWVGGSGMDM, YLQGFGKNIL, and IFNNDPNNHP) were identified as PL and CE inhibitors. Particularly, IFNNDPNNHP exhibited the most robust biological activity. These peptides exerted their inhibitory action on PL and CE by occupying catalytic or substrate-binding sites through hydrogen bonds, hydrophobic interactions, salt bridges, and π-π stacking.

Integrated multi-omics profiling to dissect the spatiotemporal evolution of metastatic hepatocellular carcinoma.

Comprehensive molecular analyses of metastatic hepatocellular carcinoma (HCC) are lacking. Here, we generate multi-omic profiling of 257 primary and 176 metastatic regions from 182 HCC patients. Primary tumors rich in hypoxia signatures facilitated polyclonal dissemination. Genomic divergence between primary and metastatic HCC is high, and early dissemination is prevalent. The remarkable neoantigen intratumor heterogeneity observed in metastases is associated with decreased T cell reactivity, resulting from disruptions to neoantigen presentation. We identify somatic copy number alterations as highly selected events driving metastasis. Subclones without Wnt mutations show a stronger selective advantage for metastasis than those with Wnt mutations and are characterized by a microenvironment rich in activated fibroblasts favoring a pro-metastatic phenotype. Finally, metastases without Wnt mutations exhibit higher enrichment of immunosuppressive B cells that mediate terminal exhaustion of CD8+ T cells via HLA-E:CD94-NKG2A checkpoint axis. Collectively, our results provide a multi-dimensional dissection of the complex evolutionary process of metastasis.