Enhanced abscopal anti-tumor response via a triple combination of thermal ablation, IL-21, and PD-1 inhibition therapy.

Despite the success of immune checkpoint inhibitors (ICIs) in treating solid tumors, lots of patients remain unresponsive to this therapy. Microwave ablation (MWA) stimulates systemic adaptive immunity against tumor cells by releasing tumor antigens. Additionally, IL-21 has demonstrated importance in stimulating T-cell effector function. The combination of these three therapies-MWA, IL-21, and anti-PD-1 monoclonal antibodies (mAbs)-has yet to be explored in the context of cancer treatment.In this study, we explored the impact of thermal ablation on IL-21R expression in tumor-infiltrating lymphocytes (TILs). Subsequently, we assessed alterations in the tumor microenvironment (TME) and peripheral lymphoid organs. Additionally, we conducted a thorough examination of tumor-infiltrating CD45+ immune cells across various treatment groups using single-cell RNA sequencing (scRNA-seq). Moreover, we determined the potential anti-tumor effects of the triple combination involving MWA, IL-21, and anti-PD-1 mAbs.Our findings revealed that MWA upregulated the expression of IL-21R on various immune cells in the untreated tumors. The combination of MWA with IL-21 exhibited a robust abscopal anti-tumor effect, enhancing the effector function of CD8+ T cells and facilitating dendritic cells' maturation and antigen presentation in the untreated tumor. Notably, the observed abscopal anti-tumor effect resulting from the combination is contingent upon T-cell recirculation, indicating the reliance of systemic adaptive immunity for this treatment regimen. Additionally, the combination of MWA, IL-21, and PD-1 mAbs demonstrated profound abscopal anti-tumor efficacy. Our findings provide support for further clinical investigation into a triple combination therapy involving MWA, IL-21, and ICIs for the treatment of metastatic cancer.

Fine particulate matter contributes to COPD-like pathophysiology: experimental evidence from rats exposed to diesel exhaust particles.

BACKGROUND: Ambient fine particulate matter (PM2.5) is considered a plausible contributor to the onset of chronic obstructive pulmonary disease (COPD). Mechanistic studies are needed to augment the causality of epidemiologic findings. In this study, we aimed to test the hypothesis that repeated exposure to diesel exhaust particles (DEP), a model PM2.5, causes COPD-like pathophysiologic alterations, consequently leading to the development of specific disease phenotypes. Sprague Dawley rats, representing healthy lungs, were randomly assigned to inhale filtered clean air or DEP at a steady-state concentration of 1.03 mg/m3 (mass concentration), 4 h per day, consecutively for 2, 4, and 8 weeks, respectively. Pulmonary inflammation, morphologies and function were examined. RESULTS: Black carbon (a component of DEP) loading in bronchoalveolar lavage macrophages demonstrated a dose-dependent increase in rats following DEP exposures of different durations, indicating that DEP deposited and accumulated in the peripheral lung. Total wall areas (WAt) of small airways, but not of large airways, were significantly increased following DEP exposures, compared to those following filtered air exposures. Consistently, the expression of α-smooth muscle actin (α-SMA) in peripheral lung was elevated following DEP exposures. Fibrosis areas surrounding the small airways and content of hydroxyproline in lung tissue increased significantly following 4-week and 8-week DEP exposure as compared to the filtered air controls. In addition, goblet cell hyperplasia and mucus hypersecretions were evident in small airways following 4-week and 8-week DEP exposures. Lung resistance and total lung capacity were significantly increased following DEP exposures. Serum levels of two oxidative stress biomarkers (MDA and 8-OHdG) were significantly increased. A dramatical recruitment of eosinophils (14.0-fold increase over the control) and macrophages (3.2-fold increase) to the submucosa area of small airways was observed following DEP exposures. CONCLUSIONS: DEP exposures over the courses of 2 to 8 weeks induced COPD-like pathophysiology in rats, with characteristic small airway remodeling, mucus hypersecretion, and eosinophilic inflammation. The results provide insights on the pathophysiologic mechanisms by which PM2.5 exposures cause COPD especially the eosinophilic phenotype.

Value of frontal QRS axis for risk stratification of individuals with prolonged PR interval.

BACKGROUND: There is ongoing controversy regarding the prognostic value of PR prolongation among individuals free of cardiovascular diseases. It is necessary to risk-stratify this population according to other electrocardiographic parameters. METHODS: This study is based on the Third National Health and Nutrition Examination Survey. Cox proportional hazard models were constructed and Kaplan-Meier method was used. RESULTS: A total of 6188 participants (58.1 ± 13.1 years; 55% women) were included. The median frontal QRS axis of the entire study population was 37° (IQR: 11-60°). PR prolongation was present in 7.6% of the participants, of whom 61.2% had QRS axis ≤37°. In a multivariable-adjusted model, mortality risk was highest in the group with concomitant prolonged PR interval and QRS axis ≤37° (hazard ratio [HR]: 1.20; 95% confidence interval [CI]: 1.04-1.39). In models with similar adjustment where population were reclassified depending on PR prolongation and QRS axis, prolonged PR interval and QRS axis ≤37° was still associated with increased risk of mortality (HR: 1.18; 95% CI: 1.03-1.36) compared with normal PR interval. CONCLUSIONS: QRS axis is an important factor for risk stratification in population with PR prolongation. The extent to which this population with PR prolongation and QRS axis ≤37° is at higher risk of death compared with the population without PR prolongation.

Prognostic values of tissue-resident CD8+T cells in human hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

BACKGROUND: Tissue-resident CD8+T cells (CD103+CD8+T cells) are the essential effector cell population of anti-tumor immune response in tissue regional immunity. And we have reported that IL-33 can promote the proliferation and effector function of tissue-resident CD103+CD8+T cells. As of now, the immunolocalization and the prognostic values of tissue-resident CD8+T cells in human hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) still remain to be illustrated. METHODS: In our present study, we used the tissue microarrays of HCC and ICC, the multicolor immunohistochemistry (mIHC), and imaging analysis to characterize the tissue-resident CD8+T cells in HCC and ICC tissues. The prognostic values and clinical associations were also analyzed. We also studied the biological functions and the cell-cell communication between tumor-infiltrating CD103+CD8+T cells and other cell types in HCC and ICC based on the published single-cell RNA sequencing (scRNA-seq) data. RESULTS: Our work unveiled the expressions of CD8 and CD103 and immunolocalization of tissue-resident CD8+T cells in human HCC and ICC. Elevated CD8+T cells indicated a better overall survival (OS) rate, implying that tumor-infiltrating CD8+T cells in HCC and ICC could serve as an independent prognostic factor. Moreover, the number of CD103+CD8+T cells was increased in HCC and ICC tissues compared with adjacent normal tissues. HCC patients defined as CD8highCD103high had a better OS, and the CD8lowCD103low group tended to have a poorer prognosis in ICC. Evaluation of the CD103+CD8+T-cell ratio in CD8+T cells could also be a prognostic predictor for HCC and ICC patients. A higher ratio of CD103+CD8+T cells over total CD8+T cells in HCC tissues was negatively and significantly associated with the advanced pathological stage. The percentage of higher numbers of CD103+CD8+T cells in ICC tissues was negatively and significantly associated with the advanced pathological stage. In contrast, the higher ratio of CD103+CD8+T cells over total CD8+T cells in ICC tissues was negatively and significantly associated with the advanced pathological stage. In addition, single-cell transcriptomics revealed that CD103+CD8+T cells were enriched in genes associated with T-cell activation, proliferation, cytokine function, and T-cell exhaustion. CONCLUSION: The CD103+ tumor-specific T cells signified an important prognostic marker with improved OS, and the evaluation of the tissue-resident CD103+CD8+T cells might be helpful in assessing the on-treatment response of liver cancer.

Influence of preoperative simulation on the reduction quality and clinical outcomes of open reduction and internal fixation for complex proximal humerus fractures.

PURPOSE: Proximal humerus fractures (PHFs) are common. With the development of locking plates, open reduction and internal fixation (ORIF) of the proximal humerus can provide excellent clinical outcomes. The quality of fracture reduction is crucial in the locking plate fixation of proximal humeral fractures. The purpose of this study was to determine the impact of 3-dimensional (3D) printing technology and computer virtual technology assisted preoperative simulation on the reduction quality and clinical outcomes of 3-part and 4-part proximal humeral fractures. METHOD: A retrospective comparative analysis of 3-part and 4-part PHFs undergoing open reduction internal fixation was performed. Patients were divided into 2 groups according to whether computer virtual technology and 3D printed technology were used for preoperative simulation: the simulation group and the conventional group. Operative time, intraoperative bleeding, hospital stay, quality of fracture reduction, Constant scores, American Society for Shoulder and Elbow Surgery (ASES) scores, shoulder range of motion, complications, and revision surgeries were assessed. RESULTS: This study included 67 patients (58.3%) in the conventional group and 48 patients (41.7%) in the simulation group. The patient demographics and fracture characteristics were comparable in these groups. Compared with the conventional group, the simulation group had shorter operation time and less intraoperative bleeding (P < 0.001, both). Immediate postoperative assessment of fracture reduction showed a higher incidence of greater tuberosity cranialization of < 5 mm, neck-shaft angle of 120° to 150°, and head shaft displacement of < 5 mm in the simulation group. The incidence of good reduction was 2.6 times higher in the simulation group than in the conventional group (95% CI, 1.2-5.8). At the final follow-up, the chance of forward flexion > 120° (OR 5.8, 95% CI 1.8-18.0) and mean constant score of > 65 (OR 3.4, 95% CI 1.5-7.4) was higher in the simulation group than the conventional group, as well as a lower incidence of complications in the simulation group was obtained (OR 0.2, 95% CI 0.1-0.6). CONCLUSIONS: This study identified that preoperative simulation assisted by computer virtual technology and 3D printed technology can improve reduction quality and clinical outcomes in treatment of 3-part and 4-part PHFs.

Angiotensin-converting enzyme 2 in peripheral lung club cells modulates the susceptibility to SARS-CoV-2 in chronic obstructive pulmonary disease.

Accumulating evidence has confirmed that chronic obstructive pulmonary disease (COPD) is a risk factor for development of severe pathological changes in the peripheral lungs of patients with COVID-19. However, the underlying molecular mechanisms remain unclear. Because bronchiolar club cells are crucial for maintaining small airway homeostasis, we sought to explore whether the altered susceptibility to SARS-CoV-2 infection of the club cells might have contributed to the severe COVID-19 pneumonia in COPD patients. Our investigation on the quantity and distribution patterns of angiotensin-converting enzyme 2 (ACE2) in airway epithelium via immunofluorescence staining revealed that the mean fluorescence intensity of the ACE2-positive epithelial cells was significantly higher in club cells than those in other epithelial cells (including ciliated cells, basal cells, goblet cells, neuroendocrine cells, and alveolar type 2 cells). Compared with nonsmokers, the median percentage of club cells in bronchiolar epithelium and ACE2-positive club cells was significantly higher in COPD patients. In vitro, SARS-CoV-2 infection (at a multiplicity of infection of 1.0) of primary small airway epithelial cells, cultured on air-liquid interface, confirmed a higher percentage of infected ACE2-positive club cells in COPD patients than in nonsmokers. Our findings have indicated the role of club cells in modulating the pathogenesis of SARS-CoV-2-related severe pneumonia and the poor clinical outcomes, which may help physicians to formulate a novel therapeutic strategy for COVID-19 patients with coexisting COPD.

Multiplexed analysis of circulating IgA antibodies for SARS-CoV-2 and common respiratory pathogens in COVID-19 patients.

Previous studies have revealed a diagnostic role of pathogen-specific IgA in respiratory infections. However, co-detection of serum specific IgA for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and common respiratory pathogens remains largely unexplored. This study utilizes a protein microarray technology for simultaneous and quantitative measurements of specific IgAs for eight different respiratory pathogens including adenovirus, respiratory syncytial virus, influenza virus type A, influenza virus type B, parainfluenza virus, mycoplasma pneumoniae, chlamydia pneumoniae, and SARS-CoV-2 in serum sample of patients with coronavirus disease 2019 (COVID-19). A total of 42 patients with COVID-19 were included and categorized into severe cases (20 cases) and nonsevere cases (22 cases). The results showed that co-detection rate of specific-IgA for SARS-CoV-2 with at least one pathogen were significantly higher in severe cases than that of nonsevere cases (72.2% vs. 46.2%, p = .014). Our study indicates that co-detection of IgA antibodies for respiratory pathogens might provide diagnostic value for the clinics and also be informative for risk stratification and disease management in patients with COVID-19.

Occurrence, distribution, and prediction of iron and manganese in groundwater of opencast mines: an example from Inner Mongolia, China.

Based on the geological and hydrologic data, the generation, enrichment, and transportation of iron (Fe) and manganese (Mn) ions in Yimin open-pit mining area were investigated using water quality analysis of groundwater samples, Statistical Product and Service Solutions (SPSS) principal component analysis, and geostatistics analysis by Geographic Information System (GIS). The water quality test results showed that the groundwater of this area was mainly the Na-Ca-HCO3 type, and the content of Fe and Mn ions significantly exceeded the national standard. The groundwater in the mining area was strongly affected by human activity, deep groundwater mixing effect, and water-rock interaction associated with mining activities. It was also found that Fe and Mn in the research area had a large variation in spatial distribution. On the whole, Fe and Mn ion concentrations found in the groundwater to the north of the research area were higher than those in the south area, with the mining area as the dividing line. The removing of non-mineral layer and the draining of gushing water in the mining area resulted in the formation of a water funnel and the strengthening of an effect between each aquifer. The change of hydrogeological and redox conditions in the mining area promoted the dissolution of Fe and Mn in soil and stratum and migration in groundwater.

Gephyromycin C, a novel small-molecule inhibitor of heat shock protein Hsp90, induces G2/M cell cycle arrest and apoptosis in PC3 cells in vitro.

Gephyromycin C (GC), a natural compound isolated from a marine-derived actinomycete Streptomyces sp. SS13I, which exerts anti-proliferative effect on PC3 cells. However, its underlying mechanism of the anti-cancer effect remains unknown. The results of SRB assays showed that GC inhibited the proliferation of PC3 cells with an IC50 value of 1.79 ± 0.28 µM. GC also induced G2/M cell cycle arrest which was accompanied by declining levels of cyclin proteins. Possible mechanisms were investigated and it was found that GC bound to Hsp90 and caused the degradation of Hsp90 client proteins (AKT, CHK1, P53, CDK4, Raf-b, and Raf-1). The fluorescent polarization assay with FITC-labeled geldanamycin (FITC-GA) demonstrated that GC was able to compete with FITC-GA in binding to wild type Hsp90 with an IC50 of 2.15 µM. Results of a docking study also suggested that GC interacted with the N-terminal domain of Hsp90. Our results showed that GC could bind to Hsp90, which resulted in down-regulation of Hsp90 client proteins and G2/M arrest in PC3 cells. Since the antitumor effects of this kind of angucycline via targeting Hsp90 has not been reported before, our results indicate that GC is a novel inhibitor of Hsp90 from marine resources and worthy of further study.

Antifungal resistance-modifying multiplexing action of Momordica charantia protein and phosphorylated derivatives on the basis of growth-dependent gene coregulation in Candida albicans.

Fungal growth-dependent gene coregulation is strongly implicated in alteration of gene-encoding target proteases ruling with an antifungal resistance niche and biology of resistant mutants. On the basis of multi-alterative processes in this platform, the resistance-modifying strategy is designed in ketoconazole resistant Candida albicans and evaluated with less selective Momordica charantia protein and allosterically phosphorylated derivatives at the Thr102, Thr24 and Thr255 sites, respectively. We demonstrate absolutely chemo-sensitizing efficacy regarding stepwise-modifying resistance in sensitivity, by a load of only 26.23-40.00 µg/l agents in Sabouraud's dextrose broth. Five successive modifying-steps realize the decreasing of ketoconazole E-test MIC50 from 11.10 to a lower level than 0.10 mg/l. With the ketoconazole resistance-modifying, colony undergoes a high-frequency morphological switch between high ploidy (opaque) and small budding haploid (white). A cellular event in the first modifying-step associates with relatively slow exponential growth (ie, a 4-h delay)-dependent action, mediated by agents adsorption. Moreover, multiple molecular roles are coupled with intracellularly and extracellularly binding to ATP-dependent RNA helicase dbp6; the 0.08-2.45 fold upregulation of TATA-box-binding protein, rRNA-processing protein and translation initiation factor 5A; and the 7.52-55.33% decrease of cytochrome P450 lanosterol 14α-demethylase, glucan 1, 3-ß glucosidase, candidapepsin-1 and 1-acylglycerol-3-phosphate O-acyltransferase. Spatial and temporal gene coregulation, in the transcription and translation initiation stages with rRNA-processing, is a new coprocessing platform enabling target protease attenuations for resistance-impairing. An updated resistance-modifying measure of these agents in the low-dose antifungal strategic design may provide opportunities to a virtually safe therapy that is in high dose-dependency. LAY SUMMARY: A new platform to modify resistance is fungal growth-dependent gene coregulation. MAP30 and phosphorylated derivatives are candidate resistance-modifying agents. Low-dose stepwise treatment absolutely modifies azole resistance in model fungus.

A simple approach to assess N load capacity of rice paddy fields in the southern Taihu Lake watershed.

High nitrogen (N) leaching from irrigated agricultural soils is the result of N input exceeding soil N load capacity (NLC). A simple approach was developed in this research to assess the NLC of paddy soils in the southern Taihu Lake watershed. Paddy soils were classified into four types (Submergenic, Illuvium, Gleyed, and Percogenic) and 28 soil samples representing all four types were collected from across the region. The NLC values of the paddy soils were assessed using a split-line model and the spatial variability of the NLC among various rice paddy soils in the region was also evaluated with Kriging analysis. Results showed the NLC of paddy soils were both soil type and background N content related. The critical N sorption values (NLC plus soil N background) of the Gleyed, Illuvium, Submergenic, and Percogenic paddy soil samples varied from 283.1 to 315.6 mg kg(-1), 203.0 to 270.2 mg kg(-1), 240.6 to 254.4 mg kg(-1), and 177.4 to 186.2 mg kg(-1), respectively. However, on average the NLC of paddy soils in the region was 80.3 mg kg(-1), and the corresponding environmental N load threshold was around 110 kg N ha(-1). Geo-statistic results showed that the NLCs were unevenly distributed throughout the rice paddy dominated areas of the southern Taihu Lake watershed. The NLC assessment approach and spatial distribution information provided helpful guidance to set an environmental N threshold for best N management and hence reduce degradation of water for the whole rice ecosystem.

Microbial community structure and pharmaceuticals and personal care products removal in a membrane bioreactor seeded with aerobic granular sludge.

A process involving the use of membrane bioreactor seeded with aerobic granular sludge (GMBR) was applied to the treatment of sewage containing pharmaceuticals and personal care products (PPCPs). The removal effects of five kinds of medicines in the reactor were investigated, and the microbial communities were constructed by polymerase chain reaction and denaturing gradient gel electrophoresis. We also determined the effects of different sludge retention and hydraulic retention times (SRT and HRT, respectively) and influent organic loading on GMBR's efficiency in processing sewage containing PPCPs. The removal effects of the GMBR on five PPCPs varied. Using the GMBR, the removal rates of prednisolone, naproxen and norfloxacin were 98.56, 84.02 and 87.85%, respectively. The removal rates of sulfamethoxazole and ibuprofen were 77.83 and 63.32%, respectively. In the system, PPCP drugs had relatively less effect on microbial diversity. A certain succession was observed in the structural variation of microbial species in the GMBR. Microorganisms that can degrade PPCPs gradually accumulated, and antibiotic-resistant microorganisms, such as Firmicutes sp., Aeromonas sp. and Nitrospira sp., served a key function in the treatment of sewage containing antibiotics. Long SRT and HRT during the GMBR process can facilitate the removal of most PPCPs. The system efficiently removed PPCPs at high influent organic loading.

Analytical performance of the Biosino urea reagent kit.

BACKGROUND: Two kinds of analytical system are used to analyze urea concentration, one is the homogeneous ana- lytical system and the other is the heterogeneous analytical system. No matter which analytical systems are used, their performance characteristics must be evaluated. Here, the performance of a heterogeneous analytical system is evaluated. METHODS: The UV urease-glutamate dehydrogenase (GLDH) reference method was reproduced and its accuracy and precision were verified. The performance characteristics of the Biosino urea reagent kit were evaluated ac- cording to the Clinical and Laboratory Standards Institute (CLSI) EP15-A2, EP6-A, and EP9-A2 guidelines. RESULTS: The performance characteristics of the UV urease-GLDH reference method demonstrate that the urea concentrations of the standard reference material (SRM) 909b I and II are within their prescriptive ranges, the within-run CVs are 0.39% and 0.16%, and the within-laboratory CVs are 0.63% and 0.40%, respectively. The performance characteristics of the Biosino urea reagent kit demonstrate that the within-run CVs are 0.84% and 0.78%, the within-laboratory CVs are 2.26% and 0.92%, the ranges of interference are 0-2.84% (0-1 g/L vitamin C), 0 - -2.86% (0-10 g/L intralipid), 0-2.81% (0-10 g/L hemoglobin), 0 - -2.1% (0-0.4 g/L conjugated bilirubin), 0 - -2.1% (0-0.4 g/L unconjugated bilirubin), and the analytical results are linear within the range of 1.8- 35.0 mmol/L. The analytical results of the Biosino urea analytical method and UV urease-GLDH, Olympus and Beckman urea analytical methods are strongly correlated (r > 0.998; p < 0.001), and the predicted biases are con- sidered acceptable at the three medical decision levels for urea. CONCLUSIONS: The Biosino urea reagent kit can provide reliable analytical results and the results are suitable for clinical uses.

Causal relationship between aspirin consumption and heart failure: a Mendelian randomization study.

AIMS: This study aimed to investigate the causal association of aspirin consumption with the risk of heart failure. METHODS: Our study included a total of 218 208 individuals, with 23 397 cases of heart failure. Genetic summary data on the association between single-nucleotide polymorphisms (SNPs) and aspirin consumption were obtained from a large-scale genome-wide association study involving 462 933 individuals, of which 61 702 people were taking aspirin. After the exclusion of critical confounding factors, we assessed the final and independent association between the aspirin consumption and the risk of heart failure using 3 two-sample Mendelian randomization (MR) methods-inverse variance weighted (IVW), weighted-median, and MR-Egger regression. Sensitivity analyses and directionality test were employed to further validate the stability of the results. RESULTS: After excluding the SNPs that exhibited associations with potential confounders and harmonizing the data, a total of 32 SNPs were finally selected for MR analysis from the initially identified 60 SNPs that displayed strong associations with the exposure. The results of the main method (IVW) showed a significant positive association between aspirin use and the occurrence of heart failure (OR [odds ratio]: 1.085; 95% CI [confidence interval]: 1.015-1.161; P = 0.017), although other methods did not showed statistically significant results (MR-Egger, OR: 1.211, 95% CI: 0.842-1.21, P = 0.896; weighted-median, OR: 1.087, 95% CI: 0.983-1.202, P = 0.105). Heterogeneity test, the MR-Egger intercept, and the funnel plot did not reveal any evidence of heterogeneity (Cochran's Q statistic = 29.263; P = 0.556) or horizontal pleiotropy (intercept = 0.007; P = 0.319). The 'leave-one-out' analysis indicated that no individual SNP exerted a dominant influence on the main estimate. Directionality test confirmed the accuracy of the causal relationship between exposure and outcome direction in our data. CONCLUSIONS: Our results support a potential positive causal relationship between aspirin consumption and the occurrence of heart failure.

Revolutionizing tumor immunotherapy: unleashing the power of progenitor exhausted T cells.

In exploring persistent infections and malignancies, a distinctive subgroup of CD8+ T cells, progenitor exhausted CD8+ T (Tpex) cells, has been identified. These Tpex cells are notable for their remarkable self-renewal and rapid proliferation abilities. Recent strides in immunotherapy have demonstrated that Tpex cells expand and differentiate into responsive exhausted CD8+ T cells, thus underscoring their critical role in the immunotherapeutic retort. Clinical examinations have further clarified a robust positive correlation between the proportional abundance of Tpex cells and enhanced clinical prognosis. Tpex cells have found noteworthy applications in the formulation of inventive immunotherapeutic approaches against tumors. This review describes the functions of Tpex cells in the tumor milieu, particularly their potential utility in tumor immunotherapy. Precisely directing Tpex cells may be essential to achieving successful outcomes in immunotherapy against tumors.

Maimendong decoction regulates M2 macrophage polarization to suppress pulmonary fibrosis via PI3K/Akt/FOXO3a signalling pathway-mediated fibroblast activation.

ETHNOPHARMACOLOGICAL RELEVANCE: Mai Men Dong decoction (MMDD), a traditional Chinese medicine formula, is relevant to ethnopharmacology due to its constituents and therapeutic properties. The formula contains herbs like Ophiopogon japonicus (Thunb.) Ker Gawl., Pinellia ternata (Thunb.) Makino, Panax ginseng C.A.Mey, Glycyrrhiza uralensis Fisch, and Ziziphus jujuba Mill, Oryza sativa L., which have been used for centuries in Chinese medicine. These herbs provide a comprehensive approach to treating respiratory conditions by addressing dryness, cough, and phlegm. Ethnopharmacological studies have explored the scientific basis of these herbs and identified active compounds that contribute to their medicinal effects. The traditional usage of MMDD by different ethnic groups reflects their knowledge and experiences. Examining this formula contributes to the understanding and development of ethnopharmacology. AIM OF THE STUDY: In the case of pulmonary fibrosis (PF), treating it can be challenging due to the limited treatment options available. This study aimed to assess the potential of MMDD as a treatment for PF by targeting macrophages and the PI3K/Akt/FOXO3a signaling pathway. MATERIALS AND METHODS: In a mouse model of PF, we investigated the effects of MMDD on inflammation, fibrosis, and M2 macrophage infiltration in lung tissue. Additionally, we examined the modulation of pro-fibrotic factors and key proteins in the PI3K/Akt/FOXO3a pathway. In vitro experiments involved inducing M2-type macrophages and assessing the impact of MMDD on fibroblast activation and the PI3K/Akt/FOXO3a pathway. RESULTS: Results demonstrated that MMDD improved weight, reduced inflammation, and inhibited M2 macrophage infiltration in mouse lung tissue. It downregulated pro-fibrotic factors, such as TGF-ß1 and PDGF-RB, as well as markers of fibroblast activation. MMDD also exhibited regulatory effects on key proteins in the PI3K/Akt/FOXO3a signaling pathway. CONCLUSIONS: MMDD inhibited M2 macrophage polarization and released profibrotic factors that inhibited pulmonary fibrosis. As a result, the PI3K/Akt/FOXO3a signaling pathway is suppressed. MMDD is proving to be a successful treatment for PF. However, further research is needed to validate its effectiveness in clinical practice.

Design optimization of groundwater circulation well based on numerical simulation and machine learning.

The optimal design of groundwater circulation wells (GCWs) is challenging. The key to purifying groundwater using this technique is its proficiency and productivity. However, traditional numerical simulation methods are limited by long modeling times, random optimization schemes, and optimization results that are not comprehensive. To address these issues, this study introduced an innovative approach for the optimal design of a GCW using machine learning methods. The FloPy package was used to create and implement the MODFLOW and MODPATH models. Subsequently, the formulated models were employed to calculate the characteristic indicators of the effectiveness of the GCW operation, including the radius of influence (R) and the ratio of particle recovery (Pr). A detailed collection of 3000 datasets, including measures of operational efficiency and key elements in machine learning, was meticulously compiled into documents through model execution. The optimization models were trained and evaluated using multiple linear regression (MLR), artificial neural networks (ANN), and support vector machines (SVM). The models produced by the three approaches exhibited notable correlations between anticipated outcomes and datasets. For the optimal design of circulating well parameters, machine learning methods not only improve the optimization speed, but also expand the scope of parameter optimization. Consequently, these models were applied to optimize the configuration of the GCW at a site in Xi'an. The optimal scheme for R (Q = 293.17 m3/d, a = 6.09 m, L = 7.28 m) and optimal scheme for Pr (Q = 300 m3/d, a = 3.64 m, L = 1 m) were obtained. The combination of numerical simulations and machine learning is an effective tool for optimizing and predicting the GCW remediation effect.

Epigallocatechin-3-gallate protects sepsis-induced myocardial dysfunction by inhibiting the nuclear factor-κB signaling pathway.

Sepsis-induced myocardial dysfunction (SIMD) has become one of the most lethal complications of sepsis, while the treatment was limited by a shortage of pertinent drugs. Epigallocatechin-3-gallate (EGCG) is the highest content of active substances in green tea, and its application in cardiovascular diseases has broad prospects. This study was conducted to test the hypothesis that EGCG was able to inhibit lipopolysaccharide (LPS) induced myocardial dysfunction and investigate the underlying molecular mechanisms. The cardiac systolic function was assessed by echocardiography. The cardiomyocyte apoptosis was determined by TUNEL staining. The expression of inflammatory factors and apoptosis-related protein, cardiac markers were examined by Western Blot and qRT-PCR. EGCG effectively improve LPS-induced cardiac function damage, enhance left ventricular systolic function, and restore myocardial cell vitality. It can effectively inhibit the upregulation of TLR4 expression induced by LPS and inhibit IκB α/NF- κB/p65 signaling pathway, thereby inhibiting cardiomyocyte apoptosis and improving myocarditis. In conclusion, EGCG protects against SIMD through anti-inflammatory and anti-apoptosis effects; it was mediated by the inhibition of the TLR4/NF-κB signal pathway. Our results demonstrated that EGCG might be a possible medicine for SIMD prevention and treatment.

Precursor exhausted CD8+T cells in colorectal cancer tissues associated with patient's survival and immunotherapy responsiveness.

Exhausted CD8+T cells represent a distinct cellular lineage that emerges during both chronic infections and cancers. Recent studies have shown that persistent antigen exposure can drive the differentiation of precursor exhausted CD8+T cells, termed Tpex cells, which are characterized as TCF-1+PD-1+CD8+T cells. Elevated Tpex cell frequencies in the tumor microenvironment (TME) are associated with improved overall survival (OS) in cancer patients and heightened responsiveness to anti-PD-1 therapy. In our present study, we utilized multi-color immunohistochemistry (mIHC) to determine the localization and clinical implications of tumor-infiltrating Tpex cells within the TME of human colorectal cancer (CRC) tissues. We also conducted a multi-omics integrative analysis using single-cell RNA sequencing (scRNA-seq) data derived from both the murine MC38 tumor model and human CRC tissues. This analysis helped delineate the transcriptional and functional attributes of Tpex cells within the CRC TME. Furthermore, we employed spatial transcriptome sequencing data from CRC patients to investigate the interactions between Tpex cells and other immune cell subsets within the TME. In conclusion, our study not only established a method for Tpex cell detection using mIHC technology but also confirmed that assessing Tpex cells within the CRC TME could be indicative of patients' survival. We further uncovered the transcriptional and functional characteristics of Tpex cells in the TME and ascertained their pivotal role in the efficacy of immunotherapy against CRC.