Combined toxicity of abamectin and carbendazim on enzymatic and transcriptional levels in the soil-earthworm microcosm.

To reveal the toxicological mechanisms of pesticide mixtures on soil organisms, this study concentrated on evaluating enzymatic activity and gene expression changes in the earthworm Eisenia fetida (Savigny 1826). Despite being frequently exposed to multiple pesticides, including the common combination of abamectin (ABA) and carbendazim (CAR), environmental organisms have primarily been studied for the effects of individual pesticides. Acute toxicity results exhibited that the combination of ABA and CAR caused a synergistic impact on E. fetida. The levels of MDA, ROS, T-SOD, and caspase3 demonstrated a significant increase across most individual and combined groups, indicating the induction of oxidative stress and cell death. Additionally, the expression of three genes (hsp70, gst, and crt) exhibited a significant decrease following exposure to individual pesticides and their combinations, pointing toward cellular damage and impaired detoxification function. In contrast, a noteworthy increase in ann expression was observed after exposure to both individual pesticides and their mixtures, suggesting the stimulation of reproductive capacity in E. fetida. The present findings contributed to a more comprehensive understanding of the potential toxicity mechanisms of the ABA and CAR mixture, specifically on oxidative stress, cell death, detoxification dysfunction, and reproductive capacity in earthworms. Collectively, these data offered valuable toxicological insights into the combined effects of pesticides on soil organisms, enhancing our understanding of the underlying risks associated with the coexistence of different pesticides in natural soil environments.

Comprehensive multi-omics investigation of sub-chronic toxicity induced by Cadmium and Triazophos Co-exposure in hook snout carps (Opsariichthys bidens).

The coexistence of heavy metals and pesticides poses a critical challenge in agricultural ecosystems. Traditional toxicity assessments often focus only on the individual impacts of either pesticides or heavy metals. Here, the untargeted metabolomics and 16 S rRNA sequencing were used to assess the individual and combined effects of cadmium (Cd) and triazophos (TRI) on hook snout carps (Opsariichthys bidens). Cd caused much more serious impacts on hepatic metabolism and gut microbiota than those in TRI. Combined Cd and TRI exposure synergistically affected hepatic metabolism, causing mitochondrial dysfunction and even oxidative damage. Simultaneously, 16 S rRNA sequencing highlighted significant variations in the composition and abundance of gut microbiota. A noteworthy connection emerged between these distinct microbiota profiles and disruptions in energy metabolism, ultimately leading to disorders in metabolites. These findings enhanced the understanding of risks posed by heavy metals and pesticides, providing insights for better environmental risk assessments of aquatic organisms.

Scar Hypertrophy Causing Nasal Obstruction Reconstruction.

Reconstructive surgery plays a crucial role in addressing congenital defects, posttraumatic deformities, and related conditions, providing transformative solutions for patients. Its primary goal is to restore or enhance damaged tissue structures, improving both functionality and appearance, and empowering individuals to lead fulfilling lives. Take, for example, a female patient who experienced a nasal infection after a cat bite. Despite initial treatment, she developed severe scar contractures and excessive scar tissue within her nostrils, significantly impacting her quality of life. Seeking assistance, she consulted the authors' plastic and reconstructive surgery team. By utilizing various flap techniques, the authors embarked on the intricate journey of reconstructing her nasal framework, ultimately restoring both form and function.

Clinical validation of the Ion Torrent Oncomine Myeloid Assay GX v2 on the Genexus Integrated Sequencer as a stand-alone assay for single-nucleotide variants, insertions/deletions, and fusion genes: Challenges, performance, and perspectives.

OBJECTIVES: Myeloid neoplasms require comprehensive characterization of genetic abnormalities, including single-nucleotide variants, small insertions and deletions, and fusions and translocations for management. The Oncomine Myeloid Assay GX v2 (Thermo Fisher Scientific) analyzes 17 full genes, 28 hotspot genes, 30 fusion driver genes, and 5 expression genes. METHODS: The validation set included 192 DNA samples, 28 RNA samples, and 9 cell lines and contrived controls. The DNA and RNA were extracted from both peripheral blood and bone marrow. Library preparation, templating, and sequencing was performed on the fully automated Genexus Integrated Sequencer (Thermo Fisher Scientific). The sequencing data were analyzed by manual curation, default Oncomine filters and the Oncomine Reporter (Thermo Fisher Scientific). RESULTS: Of the 600 reference pathogenic DNA variants targeted by the assay, concordance was seen in 98.3% of unfiltered variant call format files. Precision and reproducibility were 100%, and the lower limit of detection was 2% variant allele frequency for DNA. Inability to detect variants in long homopolymer regions intrinsic to the Ion Torrent chemistry led to 7 missed variants; 100% concordance was seen with reference RNA samples. CONCLUSIONS: This extensive clinical validation of the Oncomine Myeloid Assay GX v2 on the Genexus Integrated Sequencer with its built-in bioinformatics pipeline and Ion Torrent Oncomine Reporter shows robust performance in terms of variant calling accuracy, precision, and reproducibility, with the advantage of a rapid turnaround time of 2 days. The greatest limitation is the inability to detect variants in long homopolymer regions.

PD-1/PD-L1 Provides Protective Role in Hypoxia-Induced Pulmonary Vascular Remodeling.

BACKGROUND: Hypoxia-induced pulmonary hypertension (HPH) is a T helper 17 cell response-driven disease, and PD-1 (programmed cell death 1)/PD-L1 (programmed cell death-ligand 1) inhibitor-associated pulmonary hypertension has been reported recently. This study is designed to explore whether the PD-1/PD-L1 pathway participates in HPH via regulating endothelial dysfunction and T helper 17 cell response. METHODS: Lung tissue samples were obtained from eligible patients. Western blotting, immunohistochemistry, and immunofluorescence techniques were used to assess protein expression, while immunoprecipitation was utilized to detect ubiquitination. HPH models were established in C57BL/6 WT (wild-type) and PD-1-/- mice, followed by treatment with PD-L1 recombinant protein. Adeno-associated virus vector delivery was used to upregulate PD-L1 in the endothelial cells. Endothelial cell function was assessed through assays for cell angiogenesis and adhesion. RESULTS: Expression of the PD-1/PD-L1 pathway was downregulated in patients with HPH and mouse models, with a notable decrease in PD-L1 expression in endothelial cells compared with the normoxia group. In comparison to WT mice, PD-1-/- mice exhibited a more severe HPH phenotype following exposure to hypoxia, However, administration of PD-L1 recombinant protein and overexpression of PD-L1 in lung endothelial cells mitigated HPH. In vitro, blockade of PD-L1 with a neutralizing antibody promoted endothelial cell angiogenesis, adhesion, and pyroptosis. Mechanistically, hypoxia downregulated PD-L1 protein expression through ubiquitination. Additionally, both in vivo and in vitro, PD-L1 inhibited T helper 17 cell response through the PI3K (phosphoinositide 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target of rapamycin) pathway in HPH. CONCLUSIONS: PD-1/PD-L1 plays a role in ameliorating HPH development by inhibiting T helper 17 cell response through the PI3K/AKT/mTOR pathway and improving endothelial dysfunction, suggesting a novel therapeutic indication for PD-1/PD-L1-based immunomodulatory therapies in the treatment of HPH.

Validation of the China mortality prediction model in trauma based on the ICD-10-CM codes.

The China mortality prediction model in trauma, based on the International Classification of Diseases, Tenth Revision, Clinical Modification lexicon (CMPMIT-ICD-10), is a novel model for predicting outcomes in patients who experienced trauma. This model has not yet been validated using data acquired from patients at other trauma centers in China. This retrospective study used data retrieved from the Peking University People's Hospital discharge database and included all patients admitted for trauma between 2012 and 2022 for model validation. Model performance was categorized into discrimination and calibration. In total, 23,299 patients were included in this study, with an overall mortality rate of 1.2%. CMPMIT-ICD-10 showed good discrimination and calibration, with an area under the curve of 0.84 (95% confidence interval: 0.82-0.87) and a Brier score of 0.02. The performance of the CMPMIT-ICD-10 during validation was satisfactory, and the application of the model will be scaled up in future studies.

Co-exposure to cadmium and triazophos induces variations at enzymatic and transcriptional levels in Opsariichthys bidens.

Heavy metals and pesticides are significant pollutants in aquatic environments, often leading to combined pollution and exerting toxic effects on aquatic organisms. With the rapid growth of modern industry and agriculture, heavy metal cadmium (Cd) and pesticide triazophos (TRI) are frequently detected together in various water bodies, particularly in agricultural watersheds. However, the combined toxic mechanisms of these pollutants on fish remain poorly understood. This experiment involved a 21-day co-exposure of Cd and TRI to the hook snout carp Opsariichthys bidens to investigate the toxic effects on liver tissues at both enzymatic and transcriptional levels. Biochemical analysis revealed that both individual and combined exposures significantly increased the content or activity of caspase-3 (CASP-3) and malondialdehyde (MDA). Moreover, the impact on these parameters was greater in the combined exposure groups compared to the corresponding individual exposure groups. These findings suggested that both individual and combined exposures could induce mitochondrial dysfunction and lipid peroxidation damage, with combined exposure exacerbating the toxicological effects of each individual pollutant. Furthermore, at the molecular level, both individual and combined exposures upregulated the expression levels of cu-sod, cat, and erß, while downregulating the expression of il-1. Similar to the patterns observed in the biochemical parameters, the combined exposure group exhibited a greater impact on the expression of these genes compared to the individual exposure groups. These results indicated that exposure to Cd, TRI, and their combination induced oxidative stress, endocrine disruption, and immunosuppression in fish livers, with more severe effects observed in the combined exposure group. Overall, the interaction between Cd and TRI appeared to be synergistic, shedding light on the toxic mechanisms by which fish livers responded to these pollutants. These findings contributed to the understanding of mixture risk assessment of pollutants and were valuable for the conservation of aquatic resources.

Particulate matter, polycyclic aromatic hydrocarbons and metals, platelet parameters and blood pressure alteration: Multi-pollutants study among population.

Epidemiological findings have determined the linkage of fine particulate matter (PM2.5) and the morbidity of hypertension. However, the mode of action and specific contribution of PM2.5 component in the blood pressure elevation remain unclear. Platelets are critical for vascular homeostasis and thrombosis, which may be involved in the increase of blood pressure. Among 240 high-PM2.5 exposed, 318 low-PM2.5 exposed workers in a coking plant and 210 workers in the oxygen plant and cold-rolling mill enrolled in present study, both internal and external exposure characteristics were obtained, and we performed linear regression, adaptive elastic net regression, quantile g-computation and mediation analyses to analyze the relationship between urine metabolites of polycyclic aromatic hydrocarbons (PAHs) and metals fractions with platelets indices and blood pressure indicators. We found that PM2.5 exposure leads to increased systolic blood pressure (SBP) and pulse pressure (PP). Specifically, for every 10 µg/m3 increase in PM2.5, there was a 0.09 mmHg rise in PP. Additionally, one IQR increase in urinary 1-hydroxypyrene (1.06 µmol/mol creatinine) was associated with a 3.43 % elevation in PP. Similarly, an IQR increment of urine cobalt (2.31 µmol/mol creatinine) was associated with a separate 1.77 % and 4.71 % elevation of SBP and PP. Notably, platelet-to-lymphocyte ratio (PLR) played a mediating role in the elevation of SBP and PP induced by cobalt. Our multi-pollutants results showed that PAHs and cobalt were deleterious contributors to the elevated blood pressure. These findings deepen our understanding of the cardiovascular effects associated with PM2.5 constituents, highlighting the importance of increased vigilance in monitoring and controlling the harmful components in PM2.5.

Peripheral Th17/Treg imbalance in Chinese patients with untreated antisynthetase syndrome associated interstitial lung disease.

Interstitial lung disease (ILD) is a common and fatal manifestation of antisynthetase syndrome (ASS). The aim of this study was to provide new insight into investigate peripheral blood lymphocytes, CD4+ T cells, cytokine levels and their relation to the clinical profile of untreated patients with ASS-ILD. The retrospective study population included thirty patients diagnosed with ASS-ILD and 30 healthy controls (HCs). Baseline clinical and laboratory data were collected for all subjects, including peripheral blood lymphocyte, CD4+ T cell subsets measured by flow cytometry, and serum cytokine levels measured by multiple microsphere flow immunofluorescence. Their correlations with clinical and laboratory findings were analyzed by Pearson's or Spearman's correlation analysis. In addition, the Benjamini-Hochberg method was used for multiple correction to adjust the p-values. Patients with ASS-ILD had lower CD8+ T cells, higher proportion of Th17 cells and Th17/Treg ratio than HCs. Serum cytokine levels (IL-1ß, IL-6, IL-12, IL-17, IL-8, IL-2, IL-4, IL-10, TNF-α and IFN-γ) were higher in patients with ASS-ILD than HCs. Moreover, Th17/Treg ratio was negatively correlated with diffusing capacity of carbon monoxide (DLCO)%. Our study demonstrated abnormalities of immune disturbances in patients with ASS-ILD, characterized by decreased CD8+ T cells and an increased Th17/Treg ratio, due to an increase in the Th17 cells. These abnormalities may be the immunological mechanism underlying the development of ILD in ASS.

A Novel Internal Fixation Design for the Treatment of AO/OTA-31A3.3 Intertrochanteric Fractures: Finite Element Analysis.

OBJECTIVE: AO/OTA 31-A3.3 intertrochanteric fracture is the most unstable type of intertrochanteric fracture, with a high rate of postoperative complications and implant failure. We have designed a new intramedullary fixation, proximal femoral totally bionic nail (PFTBN), for the treatment of A3.3 intertrochanteric fracture. To test its biomechanical performance, we adopted the method of finite element analysis and compared PFTBN with proximal femoral nail antirotation (PFNA) and proximal femoral bionic nail (PFBN, another internal fixation we previously designed for stable intertrochanteric fractures). METHODS: Mimics, 3-matic, ANSYS, and other software were used to construct a highly precise and realistic 3D digital model of the human femur. An AO/OTA 31-A3.3 intertrochanteric fracture of the femur was constructed according to the 2018 classification of AO/OTA, and then assembled with PFNA, PFBN and PFTBN models, respectively. The stress distribution and displacement distribution of the three groups of constructs were tested under three times the body weight load and one-foot standing configuration. RESULTS: In terms of maximum stress and maximum displacement, the PFTBN group outperforms the PFBN group, and the PFBN group, in turn, surpasses the PFNA group. The maximum stress of PFTBN group was 408.5 Mpa, that of PFBN group was 525.4 MPa, and that of PFNA group was 764.3 Mpa. Comparatively, the maximum stress in the PFTBN group was reduced by 46.6% when contrasted with the PFNA group. Moreover, the stress dispersion within the PFTBN group was more evenly distributed than PFNA group. Regarding maximum displacement, the PFTBN group displayed the least displacement at 5.15 mm, followed by the PFBN group at 7.32 mm, and the PFNA group at 7.73 mm. Notably, the maximum displacement of the PFTBN group was 33.4% less than that observed in the PFNA group. Additionally, the relative displacement between the fragment and implant at the tip of pressure screw or helical blade was 0.22 mm in the PFTBN group, 0.34 mm in the PFBN group, and substantially higher 0.51 mm in the PFNA group. CONCLUSION: The "lever-reconstruction-balance" theory provides a new perspective for us to understand the mechanical conduction of the proximal femur. Compared with PFNA, in treating A3.3 intertrochanteric fractures PFTBN can better reconstruct the function of lateral wall, restore physiological mechanical conduction, increase postoperative stability, and finally reduce the risk of postoperative cut-out and implant failure. It might be a better alternative for the treatment of A3.3 intertrochanteric fracture.

Lensless shadow microscopy-based shortcut analysis strategy for fast quantification of microplastic fibers released to water.

Fast quantification is the primary challenge in monitoring microplastic fiber (MPF) pollution in water. The process of quantifying the number of MPFs in water typically involves filtration, imaging on a filter membrane, and manual counting. However, this routine workflow has limitations in terms of speed and accuracy. Here, we present an alternative analysis strategy based on our high-resolution lensless shadow microscope (LSM) for rapid imaging of MPFs on a chip and modified deep learning algorithms for automatic counting. Our LSM system was equipped with wide field-of-view submicron-pixel imaging sensors (>1 cm2; ∼500 nm/pixel) and could simultaneously capture the projection image of >3-µm microplastic spheres within 90 s. The algorithms enabled accurate classification and detection of the number and length of >10-µm linear and branched MPFs derived from melamine cleaning sponges in each image (∼0.4 gigapixels) within 60 s. Importantly, neither MPF morphology (dispersed or aggregated) nor environmental matrix had a notable impact on the automatic recognition of the MPFs by the algorithms. This new strategy had a detection limit of 10 particles/mL and significantly reduced the time of MPF imaging and counting from several hours with membrane-based methods to just a few minutes per sample. The strategy could be employed to monitor water pollution caused by microplastics if an efficient sample separation and a comprehensive sample image database were available.

Mechanistic insights into the parental co-exposure of T-2 toxin and epoxiconazole on the F1 generation of zebrafish (Danio rerio).

Mycotoxins and pesticides frequently coexist in agricultural commodities on a global scale. The potential transgenerational consequences induced by these substances pose a significant threat to human health. However, there is a lack of data concerning the effects of co-contamination by these chemicals in the F1 generation following parental exposure. This investigation delved into the mixture effects of T-2 toxin (T-2) and epoxiconazole (EPO) on the offspring of zebrafish (Danio rerio). The findings revealed that exposure across generations to a combination of T-2 and EPO resulted in toxicity in the larvae of the F1 generation. This was demonstrated by a significant increase in the levels or activities of malondialdehyde (MDA), thyroxine (T4), Caspase3, and cas9, along with a decrease in the levels of cyp19a, ERα, and ERß. These outcomes suggested that cross-generational exposure to T-2 and EPO in D. rerio disrupted oxidative balance, induced cell apoptosis, and affected the endocrine system. Moreover, these effects were magnified when the F1 generation was continuously exposed to these compounds. Notably, these adverse effects could persist in subsequent generations without additional exposure. This study underscored the potential dangers associated with the simultaneous presence of T-2 and EPO on the development of fish offspring and the resulting environmental hazards to aquatic ecosystems. These findings emphasized the significant health risks posed by cross-generational exposure and highlighted the need for additional legislative measures to address these concerns.

Joint toxic mechanism of clothianidin and prochloraz in the earthworm (Eisenia fetida).

Pesticides are typically present as combinations within soil ecosystems and have detrimental effects on untamed surroundings. However, the collective impacts and fundamental mechanisms of pesticides on soil living beings are currently inadequately assessed. In our current work, we evaluated the interactive consequences of clothianidin (CLO) and prochloraz (PRO) on earthworms (Eisenia fetida) using several toxicological tests, such as acute adverse effects, biocatalytic activity, and alterations in transcriptional activity. The findings revealed that CLO (with a 14-day LC50 value of 6.08 mg kg-1) exhibited greater toxicity compared to PRO (with a 14-day LC50 value of 79.41 mg kg-1). Moreover, the combinations of CLO and PRO had synergistic acute effects on E. fetida. Additionally, the activities of POD, CAT, and GST were significantly varied in most instances of single and mixed treatments when compared to the control. Surprisingly, the transcriptional levels of four genes (gst, sod, crt, and ann), related to oxidative load, metabolic detoxification systems, endoplasmic reticulum, and oxytocin neuropeptide, respectively, were also altered in response to single and mixture exposures, as compared to the control. Alterations in enzyme activity and gene transcriptional level could serve as early indicators for detecting co-exposure to pesticides. The findings of this research offered valuable holistic understanding regarding the toxicity of pesticide combinations on earthworms. Further research should be conducted to investigate the persistent effects of pesticide mixtures on terrestrial invertebrates in order to draw definitive conclusions about the associated risks.

Assessment of efficacy and safety of MET tyrosine kinase inhibitors in non-small-cell lung cancer patients with MET alterations.

Background: While targeted therapy has become the standard treatment for certain non-small-cell lung cancer (NSCLC) patients with gene mutation positivity, there remains a lack of enough reports of the efficacy of mesenchymal-epithelial transition (MET) alterations in the real world. Objectives: We aimed to explore the efficacy and toxicity of targeted therapy in NSCLC patients with different types of MET alterations and hope to provide more clinical medication guidance. Design: Designed different subgroups to compare the efficacy and safety of targeted therapy in NSCLC patients with MET alterations. Methods: We conducted analyses on the efficacy and safety of mesenchymal-epithelial transition factor-tyrosine kinase inhibitor (MET-TKI) therapy in NSCLC patients with MET alterations. Tumor response was evaluated based on the Response Evaluation Criteria in Solid Tumors version 1.1 criteria, and both progression-free survival (PFS) and overall survival were determined using the Kaplan-Meier method. Results: Our study encompassed 116 NSCLC patients with MET alterations, including MET ex14 skipping mutation (n = 50), MET primary amplification (amp) (n = 25), and secondary amp (n = 41). Among treated patients, 34 achieved a partial response, while 52 exhibited stable disease. The overall response rate for the entire cohort was 29.31%, with a disease control rate of 74.14%. A significant difference was observed in the median PFS among patients with MET ex14 skipping mutation, MET primary amplification (amp), and secondary amp (10.4 versus 6.6 versus 4.5 months, p = 0.002). In all, 69 patients experienced drug-related adverse effects, with the most common being peripheral edema (35.34%), nausea and vomiting (21.55%), and fatigue (10.34%). In total, 29 patients (25%) encountered drug-related adverse reactions of grade 3 or higher. Conclusion: MET-TKI therapy works better for MET ex14 skipping mutation than other types of MET gene alteration. In the two MET amplified groups, the secondary amp was less effective. This study may provide more research support for the treatment of these patients.

Exploring the dynamic behaviors of five pesticides in lettuce: Implications for consumer health through field and modeling experiments.

Lettuce, a globally consumed nutritious vegetable, is often linked to concerns regarding pesticide residues. To address this issue, we conducted field trials and utilized dynamiCROP modeling to examine the uptake, distribution, translocation, and dissipation of five pesticides (λ-cyhalothrin, difenoconazole, acetamiprid, dimethomorph, and ß-cypermethrin) commonly detected in lettuce. At harvest, pesticides residues were below the maximum residue limits (MRLs) at 0.05, 0.39, 0.047, 0.72, and 0.072 mg kg-1, respectively. Simulation results elucidated distinct behaviors of the pesticides following application to lettuce foliage across various compartments. However, all pesticides exhibited a common dissipation trend, initially stabilizing or increasing before gradually declining. For all five pesticides, the largest contribution of residues on lettuce leaves came from the leaf surface during the early period after application, and from the soil in the long term. Health risk assessments indicated negligible risks associated with consuming lettuce containing these pesticides, both in the short and long term.

Pyrotinib as a salvage treatment for patients with HER-2 positive advanced lung adenocarcinoma after the progression of afatinib treatment.

BACKGROUND: The efficacy of afatinib or pyrotinib has been demonstrated in HER2-positive advanced non-small cell lung cancer (NSCLC) patients; however, the efficacy of pyrotinib after afatinib progression has yet to be determined. METHOD: Patients with HER2 mutated advanced lung adenocarcinoma administered afatinib or pyrotinib monotherapy were enrolled. Those who received pyrotinib after afatinib were further analyzed to determine the efficacy and safety of pyrotinib after progression on afatinib. Survival curves were plotted with the Kaplan-Meier method. A swimming plot was used to describe the specific treatments. Additionally, patient-derived tumor organoids (PDTOs) were established from HER2-amplified NSCLC patient samples to investigate the antitumor activity of pyrotinib in HER2-amplified tumor cells in vitro. RESULTS: A total of 99 patients were enrolled, 13 of whom were administered pyrotinib after progression on afatinib. No statistical difference in PFS of pyrotinib was observed between patients whether be treated after afatinib progression or not (6.7 months vs. 4.4 months, P = 0.817), thus indicating that progression on afatinib did not affect the efficacy of pyrotinib. Further analysis was conducted on the former patients, which comprising eight patients administered interval chemotherapy after progression on afatinib. Two patients achieved PR after pyrotinib treatment. No independent factors were found to influence the PFS of pyrotinib. PDTOs confirmed the anti-tumor activity of pyrotinib in NSCLC tumor cells with HER2 amplification. CONCLUSIONS: Progression after prior afatinib treatment does not influence the efficacy of pyrotinib treatment. Pyrotinib may be a salvage option for patients with HER2 mutation who have experienced progression on afatinib.

Occurrence characteristics and potential risk of microplastics under different land conditions.

Microplastics (MPs) pollution has caused widespread concern, more researchers have focused on MPs in farmland soil. However, the distribution of MPs in different land use types, land restoration years and crop types remained largely unexplored. Therefore, the study investigated the distribution characteristics and evaluated ecological risk of MPs in soil of northern Shaanxi Province, China. The abundance, particle size, morphology and polymer types of MPs in soil were analyzed by sample collection, Raman spectroscopy and laser direct infrared spectroscopy (LDIR). The ecological risk index (H) and pollution load index (PLI) were employed to assess the risks posed by MPs in the soil. It was shown that the concentration of MPs in farmland soil was the highest (4483 items·kg-1) among the different land use types. The average abundance of microplastics in farmland soil was 1.98 times than that in industrial park soil. An increase in restoration years corresponded with a decrease in MPs abundance and an increase in smaller-sized MPs. In addition, the content of MPs in the soil of perennial crops was more stable, with fluctuations less than 25%, and the size of MPs was smaller than that of the annual crops. The main types of MPs in the soil of the study area were PP (28.5%) and PET (24.1%), MPs with size between 20 and 40 µm were dominated. Based on the pollution load index (PLI), 51.9% of the sampling sites were categorized as moderately polluted, and the MPs pollution risk of farmland soil was the highest. Mild and moderate pollution caused fewer adverse impact, while extremely strong pollution was detrimental to ecosystems and human health. In general, the study would provide a foundational understanding of MPs pollution levels and environment risk associated with different land use types, land restoration years and crop types.

Exploration of efficacy of different therapy regimens for advanced NSCLC patients with KRAS mutation in the first-line treatment.

PURPOSE: The treatment of the advanced non-small cell lung cancer (NSCLC) with KRAS mutation has been closely paid more attention. The aim of this study is to investigate the efficacy of different first-line regimens in advanced KRAS-mutated non-small cell lung cancer. METHODS: In our retrospective study, we collected patients with advanced NSCLC with KRAS mutation in Zhejiang Cancer Hospital between January 2015 and May 2023. We analyzed the benefit of different first-line therapy according to theraputic methods and the differential effect of the same treatment method among KRAS-mutated subtypes. We divided the patients into group A (A1, chemotherapy alone; A2, immunotherapy alone) and group B (B1, chemotherapy plus immunotherapy; B2, chemotherapy combined with antiangiogenic therapy; B3, chemotherapy combined with immunotherapy plus antiangiogenic therapy). The Kaplan-Meier survival curve was used to reflect the PFS and OS of different methods. The objective response rate (ORR) and the disease control rate (DCR) were used to evaluated the response. RESULTS: We enrolled 227 patients including eighty-two with KRAS G12C mutation. The ORR and DCR of first-line treatment in the overall population were 32.2% and 80.6% respectively. The median PFS was 6.7 months and the median OS was 17.4 months for the overall population. The PFS of the Group B was significantly better than that of the Group A (7.7 months vs 5.4 months, P = 0.003), while no significant difference in OS was observed (19.4 months vs 15.0 months, P = 0.077). In the Group B, chemotherapy combined immunotherapy with antiangiogenic therapy showed better PFS than chemotherapy plus immunotherapy (14.1 months vs 7.7 months, P = 0.049), and OS also showed that tendency of difference (31.9 months vs 19.3 months, P = 0.158). There was no statistically significant difference between KRAS G12C and non-G12C mutation according to first-line treatment methods, whereas patients with TP53 co-mutation showed a better survival benefit (OS, 23.7 vs 12.5 months, P = 0.023). CONCLUSION: In the first-line treatment, combination regimen has advantages over single regimen. Among them, chemotherapy combined with immunotherapy plus antiangiogenic therapy can achieve significant efficacy benefits.

Particulate polycyclic aromatic hydrocarbons and metals, DNA methylation and DNA methyltransferase among middle-school students in China.

The main components of particulate matter (PM) had been reported to change DNA methylation levels. However, the mixed effect of PM and its constituents on DNA methylation and the underlying mechanism in children has not been well characterized. To investigate the association between single or mixture exposures and global DNA methylation or DNA methyltransferases (DNMTs), 273 children were recruited (110 in low-exposed area and 163 in high-exposed area) in China. Serum benzo[a]pyridin-7,8-dihydroglycol-9, 10-epoxide (BPDE)-albumin adduct and urinary metals were determined as exposure markers. The global DNA methylation (% 5mC) and the mRNA expression of DNMT1, and DNMT3A were measured. The linear regression, quantile-based g-computation (QGC), and mediation analyses were performed to investigate the effects of individual and mixture exposure. We found that significantly lower levels of % 5mC (P < 0.001) and the mRNA expression of DNMT3A in high-PM exposed group (P = 0.031). After adjustment for age, gender, BMI z-score, detecting status of urinary cotinine, serum folate, and white blood cells, urinary arsenic (As) was negatively correlated with the % 5mC. One IQR increase in urinary As (19.97 µmol/mol creatinine) was associated with a 11.06 % decrease in % 5mC (P = 0.026). Serum BPDE-albumin adduct and urinary cadmium (Cd) were negatively correlated with the levels of DNMT1 and DNMT3A (P < 0.05). Mixture exposure was negatively associated with expression of DNMT3A in QGC analysis (ß: -0.19, P < 0.001). Mixture exposure was significantly associated with decreased % 5mC in the children with non-detected cotinine or normal serum folate (P < 0.05), which the most contributors were PAHs and As. The mediated effect of hypomethylation through DNMT1 or DNMT3A pathway was not observed. Our findings indicated that individual and mixture exposure PAHs and metal components had negative associations with global DNA methylation and decreased DNMT3A expression significantly in school-age individuals.

Efficacy and safety analysis of immunotherapy in non-small cell lung cancer patients with MET alterations.

BACKGROUND: Mesenchymal epithelial transition factor (MET) is a rare oncologic driver gene, and information on immunotherapy for non-small cell lung cancer (NSCLC) patients with this driver gene is limited. Here we evaluate the efficacy and safety of immune checkpoint inhibitors (ICI) under different therapeutic regimen for NSCLC patients with MET alterations. METHODS: From June 2019 to December 2023, we assessed the efficacy and toxicity of ICIs in 42 NSCLC patients with MET alterations. Survival curves were plotted using the Kaplan-Meier method and the Cox proportional hazards model applied for univariate and multivariate analyses. We assessed the size of target lesion according to RECIST v1.1, and objective response rate (ORR) was defined as the sum of complete response (CR) and partial response (PR), disease control rate (DCR) as the sum of CR, PR, and disease stable. RESULTS: A total of 42 NSCLC patients with MET alterations were included in this retrospective study, 10 was MET 14 skipping mutation and 32 was MET amplification. The ORR for ICI treatment was 30.95% and the DCR was 71.43%. Median progression-free survival (mPFS) and median overall survival (OS) were 4.40 and 13.97 months, respectively. There exists statistical differences between the mPFS of ICI monotherapy and combine ICI therapy (2.8 vs 7.8 months, p = 0.022). The incidence of drug-related adverse reactions was 47.62%, mainly bone marrow suppression (14.28%), immune-related pneumonia (7.14%), and liver function impairment (7.14%), and six patients (14.28%) experiencing grade 3 or above adverse events. CONCLUSION: NSCLC patients with MET alterations can benefit from immunotherapy, especially the patients treated by combined ICI therapy. However, special attention should be paid to the occurrence of grade 3/4 adverse reactions while using the combined ICI therapy.