Optimizing health risk assessment for soil trace metals under low-precision sampling conditions: A case study of agricultural soil.

Cost limitations often lead to the adoption of lower precision grids for soil sampling in large-scale areas, potentially causing deviations in the observed trace metal (TM) concentrations from their true values. Therefore, in this study, an enhanced Health Risk Assessment (HRA) model was developed by combining Monte Carlo simulation (MCS) and Empirical Bayesian kriging (EBK), aiming to improve the accuracy of health risk assessment under low-precision sampling conditions. The results showed that the increased sampling scale led to an overestimation of the non-carcinogenic risk for children, resulting in potential risks (the maximum Hazard index value was 1.08 and 1.64 at the 500 and 1000 m sampling scales, respectively). EBK model was suitable for predicting soil TM concentrations at large sampling scale, and the predicted concentrations were closer to the actual value. Furthermore, we found that the improved HRA model by combining EBK and MCS effectively reduced the possibility of over- or under-estimation of risk levels due to the increasing sampling size, and enhanced the accuracy and robustness of risk assessment. This study provides an important methodology support for health risk assessment of soil TMs under data limitation.

The efficacy and safety of Bazi Bushen Capsule in treating premature aging: A randomized, double blind, multicenter, placebo-controlled clinical trial.

PURPOSE: It is unclear whether traditional Chinese patent medicines can resist premature aging. This prospective study investigated the effects of Bazi Bushen Capsule (BZBS) which is a traditional Chinese patent medicine for tonifying the kidney essence on premature senility symptoms and quality of life, telomerase activity and telomere length. STUDY DESIGN AND METHODS: It was a parallel, multicenter, double-blind, randomized, and placebo-controlled trial. Subjects (n = 530) aged 30-78 years were randomized to receive BZBS or placebo capsules 12 weeks. The primary outcome was the clinical feature of change in kidney deficiency for aging evaluation scale (CFCKD-AES) and tilburg frailty indicator (TFI). The secondary outcomes were SF-36, serum sex hormone level, five times sit-to-stand time (FTSST), 6MWT, motor function test-grip strength, balance test, walking speed, muscle mass measurement, telomerase and telomere length. RESULTS: After 12 weeks of treatment, the CFCKD-AES and TFI scores in the BZBS group decreased by 13.79 and 1.50 respectively (6.42 and 0.58 in the placebo group, respectively); The SF-36 in the BZBS group increased by 98.38 (23.79 in the placebo group). The FTSST, motor function test grip strength, balance test, walking speed, and muscle mass in the elderly subgroup were all improved in the BZBS group. The telomerase content in the BZBS group increased by 150.04 ng/ml compared to the placebo group. The fever led one patient in the placebo group to discontinue the trial. One patient in the placebo group withdrew from the trial due to pregnancy. None of the serious AEs led to treatment discontinuation, and 3 AEs (1.14%) were assessed as related to BZBS by the primary investigator. CONCLUSIONS: BZBS can improve premature aging symptoms, frailty scores, and quality of life, as well as improve FTSST, motor function: grip strength, balance test, walking speed, and muscle mass in elderly subgroups of patients, and enhance telomerase activity, but it is not significantly associated with increasing telomere length which is important for healthy aging. TRIAL REGISTRY: https://www.chictr.org.cn/showproj.html?proj=166181.

Transcutaneous auricular vagal nerve stimulation for consciousness recovery in patients with prolonged disorders of consciousness (TAVREC): study protocol for a multicenter, triple-blind, randomized controlled trial in China.

INTRODUCTION: Prolonged disorders of consciousness (pDoC) are a catastrophic condition following brain injury with few therapeutic options. Transcutaneous auricular vagal nerve stimulation (taVNS), a safe, non-invasive intervention modulating thalamo-cortical connectivity and brain function, is a possible treatment option of pDoC. We developed a protocol for a randomised controlled study to evaluate the effectiveness of taVNS on consciousness recovery in patients with pDoC (TAVREC). METHODS AND ANALYSIS: The TAVREC programme is a multicentre, triple-blind, randomised controlled trial with 4 weeks intervention followed by 4 weeks follow-up period. A minimum number of 116 eligible pDoC patients will be recruited and randomly receive either: (1) conventional therapy plus taVNS (30 s monophasic square current of pulse width 300 µs, frequency of 25 Hz and intensity of 1 mA followed by 30 s rest, 60 min, two times per day, for 4 weeks); or (2) conventional therapy plus taVNS placebo. Primary outcome of TAVREC is the rate of improved consciousness level based on the Coma Recovery Scale-Revised (CRS-R) at week 4. Secondary outcomes are CRS-R total and subscale scores, Glasgow Coma Scale score, Full Outline of UnResponsiveness score, ECG parameters, brainstem auditory evoked potential, upper somatosensory evoked potential, neuroimaging parameters from positron emission tomography/functional MRI, serum biomarkers associated with consciousness level and adverse events. ETHICS AND DISSEMINATION: This study was reviewed and approved by the Research Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (Reference number: 2023-SR-392). Findings will be disseminated in a peer-reviewed journal and presented at relevant conferences. TRIAL REGISTRATION NUMBER: ChiCTR2300073950.

MiR-31-5p alleviates septic cardiomyopathy by targeting BAP1 to inhibit SLC7A11 deubiquitination and ferroptosis.

Septic cardiomyopathy is one of the most severe and common complications in patients with sepsis and poses a great threat to their prognosis. However, the potential mechanisms and effective therapeutic drugs need to be explored. The control of cardiac cell death by miRNAs has emerged as a prominent area of scientific interest in the diagnosis and treatment of heart disorders in recent times. In the present investigation, we discovered that overexpression of miR-31-5p prevented LPS-induced damage to H9C2 cells and that miR-31-5p could inhibit BAP1 production by binding to its 3'-UTR. BRCA1-Associated Protein 1 (BAP1) is a ubiquitin carboxy-terminal hydrolase. BAP1 upregulation blocked effect of miR-31-5p on H9C2 cell injury. Moreover, BAP1 inhibited the expression of solute carrier family 7 member 11 (SLC7A11) by deubiquitinating histone 2 A (H2Aub) on the promoter of SLC7A11. Furthermore, overexpression of miR-31-5p and downregulation of BAP1 inhibited SLC7A11 mediated ferroptosis. In addition, the downregulation of SLC7A11 reversed the inhibitory effect of miR-31-5p on the expression of myocardial injury and inflammatory factors, and cell apoptosis was reversed. In conclusion, these results indicate that miR-31-5p alleviates malignant development of LPS-induced H9C2 cell injury by targeting BAP1 and regulating SLC7A11 deubiquitination-mediated ferroptosis, which confirmed the protective effect of miR-31-5p on H9C2 cell injury and revealed potential mechanisms that may provide new targets for treatment of septic cardiomyopathy.

Facile and scalable synthesis of functionalized hierarchical porous polymers for efficient uranium adsorption.

Efficient uranium capture from wastewater holds great importance for the environmental remediation and sustainable development of nuclear energy, but it is a tremendous challenge. Herein, a facile and scalable approach is reported to fabricate functionalized hierarchical porous polymers (PPN-3) decorated with high density of phosphate groups for uranium adsorption. The as-constructed hierarchical porous structure could allow rapid diffusion of uranyl ions, while abundant phosphate groups that serve as adsorption sites could provide the high affinity for uranyl. Consequently, PPN-3 shows a high uranium adsorption uptake of 923.06 mg g-1 and reaches adsorption equilibrium within simply 10 min in uranium-spiked aqueous solution. Moreover, PPN-3 affords selective adsorption of uranyl over multiple metal ions and possesses a rapid and high removal rate of U(VI) in real water systems. Furthermore, this study offers direct polymerization strategy for the cost-effective fabrication of phosphate-functionalized porous organic polymers, which may provide promising application potential for uranium extraction.

Comparative analysis of transnasal endoscopic reconstruction techniques for managing cerebrospinal fluid rhinorrhea in skull base defects.

The nasal skull base is located into the deep position of nasal cavity and closely related to important nerves and vessels. The complete removal of tumors in this area poses a complex surgical challenge.In order to investigate the clinical efficacy of utilizing free middle turbinate mucosa (FMT), fascia lata, and pedicled nasal septum flap (known as the Hadad-Bassagasteguy flap, HBF) for the treatment of cerebrospinal fluid (CSF) rhinorrhea, a retrospective analysis was conducted on clinical data from 65 patients who underwent skull base reconstruction following endoscopic resection of nasal-skull base tumors. The selection of the repair material was based on the size and location of the defect. For defects less than 1.5 cm (n = 24), FMT was chosen, while for defects greater than or equal to 1.5 cm (n = 16), HBF was preferred. In cases where HBF was not available or not suitable (specifically, when the defect was located on the posterior wall of the frontal sinus), fascia lata was selected (n = 25). The repair outcomes of all 65 patients were summarized, and subsequently, a comparison was made between the use of fascia lata and HBF. The overall success rate for one-time repairs was 93.8 %. Specifically, the success rates for repairs using FMT, fascia lata, and HBF were 91.7 %, 96.0 %, and 93.8 %, respectively. Throughout the follow-up period, there were 2 cases of postoperative CSF leakage out of 24 patients who underwent FMT reconstruction, 1 case out of 25 patients who underwent fascia lata reconstruction, and 1 case out of 16 patients who underwent HBF reconstruction. The occurrence of postoperative complications, such as intracranial infection, lung infection, and epistaxis, was observed in both the fascia lata group and the HBF group. However, there were no statistically significant differences between the two groups. The transnasal endoscopic reconstruction of skull base defect using HBF, fascia lata, and FMT demonstrated satisfactory repair effects in managing CSF rhinorrhea. Generally, FMT has been found to be a dependable repair material for small defects measuring less than 1.5 cm, while in the case of larger defects equal to or exceeding 1.5 cm, both HBF and fascia lata can be utilized with comparable repair outcomes. The selection of fascia lata becomes a viable option when HBF is unavailable or not suitable.

The oxidant-antioxidant imbalance was involved in the pathogenesis of chronic rhinosinusitis with nasal polyps.

Background: Although oxidative stress is involved in the pathophysiological process of chronic rhinosinusitis with nasal polyps (CRSwNP), the specific underlying mechanism is still unclear. Whether antioxidant therapy can treat CRSwNP needs further investigation. Methods: Immunohistochemistry, immunofluorescence, western blotting and quantitative polymerase chain reaction (qPCR) analyses were performed to detect the distribution and expression of oxidants and antioxidants in nasal polyp tissues. qPCR revealed correlations between oxidase, antioxidant enzymes and inflammatory cytokine levels in CRSwNP patients. Human nasal epithelial cells (HNEpCs) and primary macrophages were cultured to track the cellular origin of oxidative stress in nasal polyps(NPs) and to determine whether crocin can reduce cellular inflammation by increasing the cellular antioxidant capacity. Results: The expression of NOS2, NOX1, HO-1 and SOD2 was increased in nasal epithelial cells and macrophages derived from nasal polyp tissue. Oxidase levels were positively correlated with those of inflammatory cytokines (IL-5 and IL-6). Conversely, the levels of antioxidant enzymes were negatively correlated with those of IL-13 and IFN-γ. Crocin inhibited M1 and M2 macrophage polarization as well as the expression of NOS2 and NOX1 and improved the antioxidant capacity of M2 macrophages. Moreover, crocin enhanced the ability of antioxidants to reduce inflammation via the KEAP1/NRF2/HO-1 pathway in HNEpCs treated with SEB or LPS. Additionally, we observed the antioxidant and anti-inflammatory effects of crocin in nasal explants. Conclusion: Oxidative stress plays an important role in the development of CRSwNP by promoting various types of inflammation. The oxidative stress of nasal polyps comes from epithelial cells and macrophages. Antioxidant therapy may be a promising strategy for treating CRSwNP.

Adaptive Super-Twisting Sliding Mode Control for Robot Manipulators with Input Saturation.

The paper investigates a modified adaptive super-twisting sliding mode control (ASTSMC) for robotic manipulators with input saturation. To avoid singular perturbation while increasing the convergence rate, a modified sliding mode surface (SMS) is developed in this method. Using the proposed SMS, an ASTSMC is developed for robot manipulators, which not only achieves strong robustness but also ensures finite-time convergence. The boundary of lumped uncertainties cannot be easily obtained. A modified adaptive law is developed such that the boundaries of time-varying disturbance and its derivative are not required. Considering input saturation in practical cases, an ASTSMC with saturation compensation is proposed to reduce the effect of input saturation on tracking performances of robot manipulators. The finite-time convergence of the proposed scheme is analyzed. Through comparative simulations against two other sliding mode control schemes, the proposed method has been validated to possess strong adaptability, effectively adjusting control gains; simultaneously, it demonstrates robustness against disturbances and uncertainties.

S100P facilitates LUAD progression via PKA/c-Jun-mediated tumor-associated macrophage recruitment and polarization.

S100P, a member of the S100 calcium-binding protein family, is closely associated with abnormal proliferation, invasion, and metastasis of various cancers. However, its role in the lung adenocarcinoma (LUAD) tumor microenvironment (TME) remains unclear. In this study, we observed specific expression of S100P on tumor cells in LUAD patients through tissue immunofluorescence analysis. Furthermore, this expression was strongly correlated with the recruitment and polarization of tumor-associated macrophages (TAMs). Bioinformatics analysis revealed that high S100P expression is associated with poorer overall survival in LUAD patients. Subsequently, a subcutaneous mouse model demonstrated that S100P promotes recruitment and polarization of TAMs towards the M2 type. Finally, in vitro studies on LUAD cells revealed that S100P enhances the secretion of chemokines and polarizing factors by activating the PKA/c-Jun pathway, which is implicated in TAM recruitment and polarization towards the M2 phenotype. Moreover, inhibition of c-Jun expression impedes the ability of TAMs to infiltrate and polarize towards the M2 phenotype. In conclusion, our study demonstrates that S100P facilitates LUAD cells growth by recruiting M2 TAMs through PKA/c-Jun signaling, resulting in the production of various cytokines. Considering these findings, S100P holds promise as an important diagnostic marker and potential therapeutic target for LUAD.

CDC45 promotes the stemness and metastasis in lung adenocarcinoma by affecting the cell cycle.

OBJECTIVE: This study aimed to assess the functions of cell division cycle protein 45 (CDC45) in Non-small cell lung cancer (NSCLC) cancer and its effects on stemness and metastasis. METHODS: Firstly, differentially expressed genes related to lung cancer metastasis and stemness were screened by differential analysis and lasso regression. Then, in vitro, experiments such as colony formation assay, scratch assay, and transwell assay were conducted to evaluate the impact of CDC45 knockdown on the proliferation and migration abilities of lung cancer cells. Western blotting was used to measure the expression levels of related proteins and investigate the regulation of CDC45 on the cell cycle. Finally, in vivo model with subcutaneous injection of lung cancer cells was performed to verify the effect of CDC45 on tumor growth. RESULTS: This study identified CDC45 as a key gene potentially influencing tumor stemness and lymph node metastasis. Knockdown of CDC45 not only suppressed the proliferation and migration abilities of lung cancer cells but also caused cell cycle arrest at the G2/M phase. Further analysis revealed a negative correlation between CDC45 and cell cycle-related proteins, stemness-related markers, and tumor mutations. Mouse experiments confirmed that CDC45 knockdown inhibited tumor growth. CONCLUSION: As a novel regulator of stemness, CDC45 plays a role in regulating lung cancer cell proliferation, migration, and cell cycle. Therefore, CDC45 may serve as a potential target for lung cancer treatment and provide a reference for further mechanistic research and therapeutic development.

Human health risks of heavy metal(loid)s mediated through crop ingestion in a coal mining area in Eastern China.

The heavy metal(loid)s (HMs) in soils can be accumulated by crops grown, which is accompanied by crop ingestion into the human body and then causes harm to human health. Hence, the health risks posed by HMs in three crops for different populations were assessed using Health risk assessment (HRA) model coupled with Monte Carlo simulation. Results revealed that Zn had the highest concentration among three crops; while Ni was the main polluting element in maize and soybean, and As in rice. Non-carcinogenic risk for all populations through rice ingestion was at an "unacceptable" level, and teenagers suffered higher risk than adults and children. All populations through ingestion of three crops might suffer Carcinogenic risk, with the similar order of Total carcinogenic risk (TCR): TCRAdults > TCRTeenagers > TCRChildren. As and Ni were identified as priority control HMs in this study area due to their high contribution rates to health risks. According to the HRA results, the human health risk was associated with crop varieties, HM species, and age groups. Our findings suggest that only limiting the Maximum allowable intake rate is not sufficient to prevent health risks caused by crop HMs, thus more risk precautions are needed.

GPX8+ cancer-associated fibroblast, as a cancer-promoting factor in lung adenocarcinoma, is related to the immunosuppressive microenvironment.

BACKGROUND: Cancer-associated fibroblasts (CAFs) play a crucial role in the tumor microenvironment of lung adenocarcinoma (LUAD) and are often associated with poorer clinical outcomes. This study aimed to screen for CAF-specific genes that could serve as promising therapeutic targets for LUAD. METHODS: We established a single-cell transcriptional profile of LUAD, focusing on genetic changes in fibroblasts. Next, we identified key genes associated with fibroblasts through weighted gene co-expression network analysis (WGCNA) and univariate Cox analysis. Then, we evaluated the relationship between glutathione peroxidase 8 (GPX8) and clinical features in multiple independent LUAD cohorts. Furthermore, we analyzed immune infiltration to shed light on the relationship between GPX8 immune microenvironment remodeling. For clinical treatment, we used the tumor immune dysfunction and exclusion (TIDE) algorithm to assess the immunotherapy prediction efficiency of GPX8. After that, we screened potential therapeutic drugs for LUAD by the connectivity map (cMAP). Finally, we conducted a cell trajectory analysis of GPX8+ CAFs to show their unique function. RESULTS: Fibroblasts were found to be enriched in tumor tissues. Then we identified GPX8 as a key gene associated with CAFs through comprehensive bioinformatics analysis. Further analysis across multiple LUAD cohorts demonstrated the relationship between GPX8 and poor prognosis. Additionally, we found that GPX8 played a role in inducing the formation of an immunosuppressive microenvironment. The TIDE method indicated that patients with low GPX8 expression were more likely to be responsive to immunotherapy. Using the cMAP, we identified beta-CCP as a potential drug-related to GPX8. Finally, cell trajectory analysis provided insights into the dynamic process of GPX8+ CAFs formation. CONCLUSIONS: This study elucidates the association between GPX8+ CAFs and poor prognosis, as well as the induction of immunosuppressive formation in LUAD. These findings suggest that targeting GPX8+ CAFs could potentially serve as a therapeutic strategy for the treatment of LUAD.

Improving prediction of soil heavy metal(loid) concentration by developing a combined Co-kriging and geographically and temporally weighted regression (GTWR) model.

The study of heavy metal(loid) (HM) contamination in soil using extensive data obtained from published literature is an economical and convenient method. However, the uneven distribution of these data in time and space limits their direct applicability. Therefore, based on the concentration data obtained from the published literature (2000-2020), we investigated the relationship between soil HM accumulation and various anthropogenic activities, developed a hybrid model to predict soil HM concentrations, and then evaluated their ecological risks. The results demonstrated that various anthropogenic activities were the main cause of soil HM accumulation using Geographically and temporally weighted regression (GTWR) model. The hybrid Co-kriging + GTWR model, which incorporates two of the most influential auxiliary variables, can improve the accuracy and reliability of predicting HM concentrations. The predicted concentrations of eight HMs all exceeded the background values for soil environment in China. The results of the ecological risk assessment revealed that five HMs accounted for more than 90% of the area at the "High risk" level (RQ ≥ 1), with the descending order of Ni (100%) = Cu (100%) > As (98.73%) > Zn (95.50%) > Pb (94.90%). This study provides a novel approach to environmental pollution research using the published data.

2,2-Dichloroacetamide exposure induces behavior and memory disorders in mice: Detrimental effects of long-term dietary restriction on neurotoxicity.

2, 2-dichloroacetamide (DCAcAm), a nitrogen-containing disinfection byproduct (DBPs), is commonly found in potable water. This study aimed to compare the neurotoxicity of DCAcAm in C57/BL6 mice at both environmentally relevant and higher doses through oral exposure over a 28-day period. Furthermore, the potential effects of dietary restriction (DR) on the cerebral toxicity induced by 20 ppb DCAcAm were examined. The findings indicated that DCAcAm exposure and DR treatment resulted in reduced memory retention and cognitive adaptability in mice. Additionally, higher doses of DCAcAm exposure induced severe brain inflammation and oxidative stress. Metabolic profiling revealed disruptions in fatty acid, energy, and amino acid metabolism in the brain. Remarkably, the negative impacts of 20 ppb DCAcAm on the mice brain were worsened by DR treatment. Analysis of 16S rRNA sequencing revealed notable changes in the composition and structure of intestinal microorganisms after exposure to DCAcAm. This study discovered that DCAcAm has both direct effects on the brain and indirect effects through the microbial-brain-intestinal axis, which collectively result in neurotoxicity and dietary restriction exacerbates these effects. This study provides emerging views on the assessment of the toxicity of nitrogen containing DBPs.

RNA 5-methylcytosine writer NSUN5 promotes hepatocellular carcinoma cell proliferation via a ZBED3-dependent mechanism.

Hepatocellular carcinoma (HCC) is one of the leading contributors to cancer-related mortality worldwide. Nop2/Sun domain family member 5 (NSUN5), a conserved RNA 5-methylcytosine methyltransferase, is conventionally recognized as oncogenic. However, its role in HCC development remains unknown. In this study, we observed a remarkable upregulation of NSUN5 expression in both tumor tissues from patients with HCC, establishing a correlation with unfavorable clinical outcomes. NSUN5 knockdown and overexpression significantly inhibited and promoted HCC cell proliferation, respectively. Additionally, employing a combination of methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RIP-seq techniques, we identified zinc finger BED domain-containing protein 3 (ZBED3) as a novel downstream target of NSUN5. Additionally, we found that the overexpression of ZBED3 counteracted the tumor-suppressing effect of NSUN5 knockdown and simultaneously reversed the inhibition of the Wnt/ß-catenin signaling pathway. In summary, we elucidated the oncogenic role of NSUN5 in HCC development and identified the ZBED3/Wnt/ß-catenin signaling pathway as its downstream target. This study provides a novel therapeutic target for further development in HCC treatment.

Research progress of N1-methyladenosine RNA modification in cancer.

N1-methyladenosine (m1A) is a post-transcriptionally modified RNA molecule that plays a pivotal role in the regulation of various biological functions and activities. Especially in cancer cell invasion, proliferation and cell cycle regulation. Over recent years, there has been a burgeoning interest in investigating the m1A modification of RNA. Most studies have focused on the regulation of m1A in cancer enrichment areas and different regions. This review provides a comprehensive overview of the methodologies employed for the detection of m1A modification. Furthermore, this review delves into the key players in m1A modification, known as the "writers," "erasers," and "readers." m1A modification is modified by the m1A methyltransferases, or writers, such as TRMT6, TRMT61A, TRMT61B, TRMT10C, NML, and, removed by the demethylases, or erasers, including FTO and ALKBH1, ALKBH3. It is recognized by m1A-binding proteins YTHDF1, TYHDF2, TYHDF3, and TYHDC1, also known as "readers". Additionally, we explore the intricate relationship between m1A modification and its regulators and their implications for the development and progression of specific types of cancer, we discuss how m1A modification can potentially facilitate the discovery of novel approaches for cancer diagnosis, treatment, and prognosis. Our summary of m1A methylated adenosine modification detection methods and regulatory mechanisms in various cancers provides useful insights for cancer diagnosis, treatment, and prognosis. Video Abstract.

Development of an invasion score based on metastasis-related pathway activity profiles for identifying invasive molecular subtypes of lung adenocarcinoma.

The invasive capacity of lung adenocarcinoma (LUAD) is an important factor influencing patients' metastatic status and survival outcomes. However, there is still a lack of suitable biomarkers to evaluate tumor invasiveness. LUAD molecular subtypes were identified by unsupervised consistent clustering of LUAD. The differences in prognosis, tumor microenvironment (TME), and mutation were assessed among different subtypes. After that, the invasion-related gene score (IRGS) was constructed by genetic differential analysis, WGCNA analysis, and LASSO analysis, then we evaluated the relationship between IRGS and invasive characteristics, TME, and prognosis. The predictive ability of the IRGS was verified by in vitro experiments. Next, the "oncoPredict" R package and CMap were used to assess the potential value of IRGS in drug therapy. The results showed that LUAD was clustered into two molecular subtypes. And the C1 subtype exhibited a worse prognosis, higher stemness enrichment activity, less immune infiltration, and higher mutation frequency. Subsequently, IRGS developed based on molecular subtypes demonstrated a strong association with malignant characteristics such as invasive features, higher stemness scores, less immune infiltration, and worse survival. In vitro experiments showed that the higher IRGS LUAD cell had a stronger invasive capacity than the lower IRGS LUAD cell. Predictive analysis based on the "oncoPredict" R package showed that the high IRGS group was more sensitive to docetaxel, erlotinib, paclitaxel, and gefitinib. Among them, in vitro experiments verified the greater killing effect of paclitaxel on high IRGS cell lines. In addition, CMap showed that purvalanol-a, angiogenesis-inhibitor, and masitinib have potential therapeutic effects in the high IRGS group. In summary we identified and analyzed the molecular subtypes associated with the invasiveness of LUAD and developed IRGS that can efficiently predict the prognosis and invasive ability of the tumor. IRGS may be able to facilitate the precision treatment of LUAD to some extent.

Celastrol Pyrazine Derivative Alleviates Silicosis Progression via Inducing ROS-Mediated Apoptosis in Activated Fibroblasts.

Silicosis is a complex occupational disease without recognized effective treatment. Celastrol, a natural product, has shown antioxidant, anti-inflammatory, and anti-fibrotic activities, but the narrow therapeutic window and high toxicity severely limit its clinical application. Through structural optimization, we have identified a highly efficient and low-toxicity celastrol derivative, CEL-07. In this study, we systematically investigated the therapeutic potential and underlying mechanisms of CEL-07 in silicosis fibrosis. By constructing a silicosis mouse model and analyzing with HE, Masson, Sirius Red, and immunohistochemical staining, CEL-07 significantly prevented the progress of inflammation and fibrosis, and it effectively improved the lung respiratory function of silicosis mice. Additionally, CEL-07 markedly suppressed the expression of inflammatory factors (IL-6, IL-1α, TNF-α, and TNF-ß) and fibrotic factors (α-SMA, collagen I, and collagen III), and promoted apoptosis of fibroblasts by increasing ROS accumulation. Moreover, bioinformatics analysis combined with experimental validation revealed that CEL-07 inhibited the pathways associated with inflammation (PI3K-AKT and JAK2-STAT3) and the expression of apoptosis-related proteins. Overall, these results suggest that CEL-07 may serve as a potential candidate for the treatment of silicosis.

RACGAP1 promotes the progression and poor prognosis of lung adenocarcinoma through its effects on the cell cycle and tumor stemness.

OBJECTION: Investigating the key genes and mechanisms that influence stemness in lung adenocarcinoma. METHODS: First, consistent clustering analysis was performed on lung adenocarcinoma patients using stemness scoring to classify them. Subsequently, WGCNA was utilized to identify key modules and hub genes. Then, machine learning methods were employed to screen and identify the key genes within these modules. Lastly, functional analysis of the key genes was conducted through cell scratch assays, colony formation assays, transwell migration assays, flow cytometry cell cycle analysis, and xenograft tumor models. RESULTS: First, two groups of patients with different stemness scores were obtained, where the high stemness score group exhibited poor prognosis and immunotherapy efficacy. Next, LASSO regression analysis and random forest regression were employed to identify genes (PBK, RACGAP1) associated with high stemness scores. RACGAP1 was significantly upregulated in the high stemness score group of lung adenocarcinoma and closely correlated with clinical pathological features, poor overall survival (OS), recurrence-free survival (RFS), and unfavorable prognosis in lung adenocarcinoma patients. Knockdown of RACGAP1 suppressed the migration, proliferation, and tumor growth of cancer cells. CONCLUSION: RACGAP1 not only indicates poor prognosis and limited immunotherapy benefits but also serves as a potential targeted biomarker influencing tumor stemness.

Identification of high-risk population of pneumoconiosis using deep learning segmentation of lung 3D images and radiomics texture analysis.

OBJECTION: The aim of this study is to develop an early-warning model for identifying high-risk populations of pneumoconiosis by combining lung 3D images and radiomics lung texture features. METHODS: A retrospective study was conducted, including 600 dust-exposed workers and 300 confirmed pneumoconiosis patients. Chest computed tomography (CT) images were divided into a training set and a test set in a 2:1 ratio. Whole-lung segmentation was performed using deep learning models for feature extraction of radiomics. Two feature selection algorithms and five classification models were used. The optimal model was selected using a 10-fold cross-validation strategy, and the calibration curve and decision curve were evaluated. To verify the applicability of the model, the diagnostic efficiency and accuracy between the model and human interpretation were compared. Additionally, the risk probabilities for different risk groups defined by the model were compared at different time intervals. RESULTS: Four radiomics features were ultimately used to construct the predictive model. The logistic regression model was the most stable in both the training set and testing set, with an area under curve (AUC) of 0.964 (95 % confidence interval [CI], 0.950-0.976) and 0.947 (95 %CI, 0.925-0.964). In the training and testing sets, the Brier scores were 0.092 and 0.14, respectively, with threshold probability ranges of 2 %-99 % and 2 %-85 %. These results indicate that the model exhibits good calibration and clinical benefit. The comparison between the model and human interpretation showed that the model was not inferior in terms of diagnostic efficiency and accuracy. Additionally, the high-risk population identified by the model was diagnosed as pneumoconiosis two years later. CONCLUSION: This study provides a meticulous and quantifiable method for detecting and assessing the risk of pneumoconiosis, building upon accurate diagnosis. Employing risk scoring and probability estimation, not only enhances the efficiency of diagnostic physicians but also provides a valuable reference for controlling the occurrence of pneumoconiosis.