Case report: The effect of second-line vebreltinib treatment on a patient with advanced NSCLC harboring the MET exon 14 skipping mutation after tepotinib treatment.

Background: Highly selective type Ib mesenchymal-epithelial transition gene (MET) tyrosine kinase inhibitors (TKIs) are the standard-of-care (SOC) therapy for previously untreated non-small cell lung cancer (NSCLC) harboring MET exon 14 (METex14) skipping mutations. However, there are rare reports describing effective regimens for patients who fail SOC without identifying resistant mutations or tissue transformation. Case report: We report the first case of a 74-year-old woman with lung adenocarcinoma (cT1cNxM0) harboring METex14 splice region mutation, which was identified by a next-generation sequencing (NGS)-based assay. The patient was administered two treatments, including first-line tepotinib and second-line vebreltinib. The patient achieved progression-free survival (PFS) of 7.6 months, and then disease progression of tepotinib was observed. A re-biopsy was performed for NGS, which revealed the same mutations as before, with no new gene mutations detected. The woman received subsequent vebreltinib therapy and experienced durable clinical benefits. In the first 6.8 months, chest computed tomography demonstrated stable disease. Then, she achieved partial response (PR). The durable PR lasted for more than 13 months, and the PFS is currently over 20 months, exceeding the prior treatment. Conclusion: This case highlights the importance of considering re-biopsy and reanalysis of genetic profiles in NSCLC patients harboring METex14 skipping mutations after progressive disease in MET TKI treatment. This raises the possibility that vebreltinib may have long-term survival benefits for patients without mutations conferring resistance (funded by Beijing Pearl Biotechnology Co., Ltd; ClinicalTrials.gov number, NCT04258033).

Neurotoxicity of Combined Exposure to the Heavy Metals (Pb and As) in Zebrafish (Danio rerio).

Lead (Pb) and arsenic (As) are commonly occurring heavy metals in the environment and produce detrimental impacts on the central nervous system. Although they have both been indicated to exhibit neurotoxic properties, it is not known if they have joint effects, and their mechanisms of action are likewise unknown. In this study, zebrafish were exposed to different concentrations of Pb (40 µg/L, 4 mg/L), As (32 µg/L, 3.2 mg/L) and their combinations (40 µg/L + 32 µg/L, 4 mg/L + 3.2 mg/L) for 30 days. The histopathological analyses showed significant brain damage characterized by glial scar formation and ventricular enlargement in all exposed groups. In addition, either Pb or As staining inhibited the swimming speed of zebrafish, which was enhanced by their high concentrations in a mixture. To elucidate the underlying mechanisms, we examined changes in acetylcholinesterase (AChE) activity, neurotransmitter (dopamine, 5-hydroxytryptamine) levels, HPI axis-related hormone (cortisol and epinephrine) contents and neurodevelopment-related gene expression in zebrafish brain. The observations suggest that combined exposure to Pb and As can cause abnormalities in swimming behavior and ultimately exacerbate neurotoxicity in zebrafish by interfering with the cholinergic system, dopamine and 5-hydroxytryptamine signaling, HPI axis function as well as neuronal development. This study provides an important theoretical basis for the mixed exposure of heavy metals and their toxicity to aquatic organisms.

Neofunctionalization of an OMT cluster dominates polymethoxyflavone biosynthesis associated with the domestication of citrus.

Polymethoxyflavones (PMFs) are a class of abundant specialized metabolites with remarkable anticancer properties in citrus. Multiple methoxy groups in PMFs are derived from methylation modification catalyzed by a series of hydroxylases and O-methyltransferases (OMTs). However, the specific OMTs that catalyze the systematic O-methylation of hydroxyflavones remain largely unknown. Here, we report that PMFs are highly accumulated in wild mandarins and mandarin-derived accessions, while undetectable in early-diverging citrus species and related species. Our results demonstrated that three homologous genes, CreOMT3, CreOMT4, and CreOMT5, are crucial for PMF biosynthesis in citrus, and their encoded methyltransferases exhibit multisite O-methylation activities for hydroxyflavones, producing seven PMFs in vitro and in vivo. Comparative genomic and syntenic analyses indicated that the tandem CreOMT3, CreOMT4, and CreOMT5 may be duplicated from CreOMT6 and contributes to the genetic basis of PMF biosynthesis in the mandarin group through neofunctionalization. We also demonstrated that N17 in CreOMT4 is an essential amino acid residue for C3-, C5-, C6-, and C3'-O-methylation activity and provided a rationale for the functional deficiency of OMT6 to produce PMFs in early-diverging citrus and some domesticated citrus species. A 1,041-bp deletion in the CreOMT4 promoter, which is found in most modern cultivated mandarins, has reduced the PMF content relative to that in wild and early-admixture mandarins. This study provides a framework for reconstructing PMF biosynthetic pathways, which may facilitate the breeding of citrus fruits with enhanced health benefits.

The efficacy of furmonertinib in untreated advanced NSCLC patients with sensitive EGFR mutations in a real-world setting: a single institutional experience.

Background: Furmonertinib is the standard treatment option in the first-line setting for advanced non-small cell lung cancer (NSCLC) with sensitive epidermal growth factor receptor (EGFR) mutations in China. However, there are limited real-world data available. Methods: We conducted a retrospective study at a single center, analyzing a cohort of 73 NSCLC patients who tested positive for EGFR mutations and were treated with furmonertinib as their initial therapy between August 2022 and December 2023. The primary endpoint was progression-free survival (PFS), with secondary endpoints including objective response rate (ORR), overall survival (OS), and safety profile. Results: The median observation period was 9 months (95% confidence interval [CI], 8.0-20.0). The median PFS was 19.5 months (95% CI, 14.6-24.4). OS data were not yet mature. Univariate analysis showed no significant correlation between PFS and factors such as Eastern Cooperative Oncology Group performance status (ECOG PS) score, presence of brain or liver metastases, sex, age, EGFR mutation status, or number of metastatic sites. However, multivariate analysis indicated a potential trend toward extended PFS in patients younger than 65 years (p = 0.053, 95% CI, 0.10-1.02), although the p-value was only marginally significant. The most common adverse events were diarrhea (24%), anemia (36%), and liver injury (32%); however, only four cases experienced severe adverse events. Conclusion: In a real-world setting, furmonertinib appears to be a favorable treatment option for EGFR-mutated patients. The manageable nature of adverse events further supports its use in clinical practice.

Efficacy of chemo-immunotherapy in metastatic BRAF-mutated lung cancer: a single-center retrospective data.

Background: The effectiveness of combining immune checkpoint inhibitors (ICIs) with chemotherapy in treating non-small cell lung cancers (NSCLCs) with BRAF mutations has not been sufficiently explored. Methods: We compiled data from 306 NSCLC patients with identified BRAF mutations. We looked at efficacy by assessing the objective response rate (ORR) and disease control rate (DCR), as well as survival through measuring progression-free survival (PFS) and overall survival (OS). Results: Out of the patient pool, 44 were treated with a regimen of immune-chemotherapy. Patients undergoing ICI in combination with chemotherapy had a median PFS of 4 months, and the median OS was recorded at 29 months. There was a notable increase in OS in patients receiving first-line treatment versus subsequent lines (29 vs 9.75 months, p=0.01); however, this was not the case with PFS (9 vs 4 months, p=0.46). The ORR for patients on ICIs was 36.3%. PFS and OS rates did not significantly differ between patients with the BRAF-V600E mutation and those with non-V600E mutations (p=0.75 and p=0.97, respectively). Additionally, we found a significant variation in PD-L1 expression between those who responded to treatment and those who didn't (p=0.04). Conclusion: Our findings indicate that chemo-immunotherapy as an initial treatment may lead to improved OS in patients with BRAF-mutated NSCLC when compared to its use in subsequent lines of therapy. Further studies are needed to validate these results and to delve deeper into how specific types of BRAF mutations and PD-L1 expression levels might predict a patient's response to treatments in NSCLC.

Response to immune checkpoint inhibitor combination therapy in metastatic RET-mutated lung cancer from real-world retrospective data.

BACKGROUND: The impact of immune checkpoint inhibitors (ICIs) based treatments on non-small cell lung cancers (NSCLCs) with RET fusions remains poorly understood. METHODS: We screened patients with RET fusions at the First Affiliated Hospital of Zhengzhou University and included those who were treated with ICIs based regimens for further analysis. We evaluated clinical indicators including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). RESULTS: A total of 232 patients with RET fusions were included in the study. Of these, 129 patients had their programmed death-ligand 1 (PDL1) expression levels tested, with 22 patients (17.8%) having a PDL1 level greater than or equal to 50%. Additionally, tumor mutational burden (TMB) status was evaluated in 35 patients, with the majority (30/35, 85.8%) having a TMB of less than 10 mutations per megabase. Out of the 38 patients treated with ICI based regimens, the median PFS was 5 months (95% confidence interval [CI]: 2.4-7.6 months) and the median OS was 19 months (95% CI: 9.7-28.3 months) at the time of data analysis. Stratification based on treatment lines did not show any significant differences in OS (18 vs. 19 months, p = 0.63) and PFS (6 vs. 5 months, p = 0.86). The ORR for patients treated with ICIs was 26.3%. Furthermore, no significant differences were found for PFS (p = 0.27) and OS (p = 0.75) between patients with positive and negative PDL1 expression. Additionally, there was no significant difference in PD-L1 levels (p = 0.10) between patients who achieved objective response and those who did not. CONCLUSIONS: Patients with RET fusion positive NSCLCs may not benefit from ICI based regimens and therefore should not be treated with ICIs in clinical practice.

Early-life antibiotic exposure promotes house dust mite-induced allergic airway inflammation by impacting gut microbiota and lung lipid metabolism.

Asthma is a chronic inflammatory respiratory disease. Early-life antibiotic exposure is a unique risk factor for the incidence and severity of asthma later in life. Perturbations in microbial-metabolite-immune interaction caused by antibiotics are closely associated with the pathogenesis of allergy and asthma. We investigated the effect of early intervention with common oral antibiotics on later asthma exacerbations and found that different antibiotic exposures can amplify different types of immune responses induced by HDM. Cefixime (CFX) promoted a biased type 2 inflammation, azithromycin (AZM) enhanced Th17 immune response, and cefuroxime axetil (CFA) induced eosinophils recruitment. Moreover, early-life antibiotic exposure can have short- and long-term effects on the abundance, composition, and diversity of the gut microbiota. In the model of CFX-promoted type 2 airway inflammation, fecal metabolomics indicated abnormal lipid metabolism and T cell response. Lipidomic also suggested allergic airway inflammation amplified by CFX is closely associated with abnormal lipid metabolism in lung tissues. Moreover, abnormalities in lipid metabolism-related genes (LMRGs) were found to have cellular heterogeneity be associated with asthma severity by bioinformatics analysis.

Cost-Effectiveness Analysis of Pembrolizumab Plus Chemotherapy in Squamous Non-Small-Cell Lung Cancer in China.

Purpose: The five-year update data from the KEYNOTE-407 study have unveiled noteworthy improvements in survival outcomes achieved with pembrolizumab plus chemotherapy (Pembro+Chemo) compared to placebo plus chemotherapy (Placebo+Chemo) for patients with previously untreated metastatic squamous non-small cell lung cancer (NSCLC). Building upon this finding, our study sought to evaluate the cost-effectiveness of Pembro+Chemo, utilizing the latest available data, from the perspective of the Chinese health care system. Patients and Methods: A Markov model was employed to compare the quality-adjusted life-year (QALY), life-year (LY), total cost, and incremental cost-effectiveness ratio (ICER) between Pembro+Chemo and Placebo+Chemo. The clinical and safety data were derived from the five-year update date of the KEYNOTE-407 study. Sensitivity analyses were conducted to assess the uncertainty of the model, and additional subgroup analyses were performed to explore specific subpopulations. Results: For patients with previously untreated metastatic squamous NSCLC, the utilization of Pembro+Chemo resulted in a improvement of 0.61 quality-adjusted life years (QALYs) along with a cost reduction of $17,491.52 when compared to Placebo+Chemo. Notably, across various subgroups with different tumor proportion scores (TPS), Pembro+Chemo demonstrated enhanced QALYs and lower total costs. Conclusion: From the perspective of the Chinese health care system, first-line Pembro+Chemo emerges as a dominant treatment option over Placebo+Chemo for the treatment of metastatic squamous NSCLC.

[Progress in the application of novel nano-materials to the safety analysis of agricultural products].

The quality and safety of agricultural products are strongly related to human livelihood. Thus, the government and consumers have recently paid increased attention to the quality and safety of agricultural products. The development of efficient, rapid, and sensitive analytical methods for detecting pesticides, veterinary drugs, heavy metals, mycotoxins, and environmental pollutants in agricultural products is of great significance. Owing to the complexity of many sample matrices and the low concentration of pollutants in a typical sample, appropriate sample pretreatment steps are necessary to enrich pollutants in agricultural products. Solid-phase extraction (SPE) is the most widely used sample pretreatment technology; in this technique, the adsorbent generally determines the selectivity and efficiency of the extraction process. An increasing number of novel materials have been used as SPE adsorbents. The extraction efficiency, extraction selectivity, and analytical throughput of SPE could be greatly improved by combining these novel materials with various extraction modes (e. g., solid-phase microextraction, dispersed SPE, and magnetic SPE (MSPE)) during sample preparation. Because of their large specific surface area and high affinity toward target analytes, nanomaterials are often used as SPE adsorbents, thereby greatly improving the selectivity and sensitivity of the analytical technology. More importantly, these materials have become a priority area of research on preconcentration technologies for trace compounds in agricultural products. This paper summarizes the adsorption characteristics of several new nanomaterials, including magnetic materials, carbon-based materials, metal nanomaterials (MNs), metal oxide nanomaterials (MONs), metal organic frameworks (MOFs), and covalent organic frameworks (COFs). These nanomaterials present numerous advantages, such as large specific surface areas, high adsorption capacities, and tailorable structural designs. MSPE employs magnetic materials as sorbents to afford fast dispersion and efficient recycling when applied to complex sample matrices under an external magnetic field. The use of MSPE can avoid several typical problems associated with SPE such as poor adsorbent packing and high pressure, thereby greatly simplifying the pretreatment process and providing a high flux for sample analysis. Carbon-based materials are powdered or bulk nonmetallic solid materials with carbon as the main component; carbon and nitrogen materials, mesoporous carbon, carbon nanotubes, and graphene are some examples of these materials. These materials provide large specific surface areas, abundant pore structures, good thermal stability, high mechanical strength and adsorption capacity, and controllable morphology. Pure and modified carbon nanomaterials have been successfully used to purify target analytes from agricultural products. Given their unique physical and chemical properties, MNs and MONs have attracted significant interest for use in sample preparation. MNs and MONs with excellent thermal and mechanical stabilities show good resistance to a wide pH range and diverse organic solvents, which is crucial in adsorbent-based extraction methods. The surface of these materials can be easily modified with various ligands to improve their selectivity. MOFs and COFs present many advantages such as large specific surface areas, high porosity, adjustable pore performance, and good thermal stability. Several methods that employ novel adsorbent materials to analyze pollutants in a variety of agricultural products, such as chromatography, spectroscopy, mass spectrometry, and other detection technologies, have been established. This paper also reviews the application of adsorbent materials in the analysis of agricultural product quality and safety, and discusses the future development trends of these sorbents in sample preparation for the safety analysis of agricultural products.

Biomarkers-Based Cost-Effectiveness of Toripalimab Plus Chemotherapy for Patients with Treatment-Naive Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: This study examined the cost-effectiveness of first-line toripalimab plus chemotherapy (TC) for patients with advanced non-small cell lung cancer (NSCLC), excluding patients with nonsquamous NSCLC and EGFR/ALK mutations. It further analyzed the cost-effectiveness of this strategy in biomarker-based subgroups, all within the context of the Chinese healthcare system. METHODS: Eighteen Markov models with 21-day Markov cycle lengths and 30-year time horizons were constructed in this study. Clinical effectiveness data were derived from the CHOICE-01 trial. Health state utilities and costs data were obtained from various sources. The primary outputs were the calculation of incremental cost-effectiveness ratios (ICERs), which were then compared to a willingness-to-pay (WTP) threshold of $17,961 per quality-adjusted life-year (QALY). This comparison was used to determine the treatment that offered greater cost-effectiveness. To account for uncertainty in the model, sensitivity analyses were conducted. RESULTS: For the overall patient population, the estimated ICER between first-line TC and placebo plus chemotherapy (PC) was $9445/QALY, significantly lower than the WTP threshold used in the model. In subgroups based on pathologic types, first-line TC had an ICER of $16,757/QALY for patients with nonsquamous NSCLC, slightly below the WTP threshold; first-line TC demonstrated dominance in patients with squamous NSCLC, indicating both better effectiveness and lower costs compared to first-line PC. In biomarkers-based subgroups, first-line TC was dominant over first-line PC in the subgroups with programmed cell death ligand 1 (PD-L1) expression ≥ 50% and SMARCA4 mutations. Moreover, first-line TC had ICERs lower than the WTP threshold in other subgroups, except for the subgroup with RB1 mutations. Sensitivity analysis confirmed the robustness of these findings. CONCLUSION: From the perspective of the Chinese healthcare system, this study's findings suggested that first-line TC represents a cost-effective strategy for patients with advanced NSCLC. However, the cost-effectiveness of first-line TC varied across different subgroups when considering predictive biomarkers.

Corrigendum: Case Report: Durable response to immuno-chemotherapy in a case of ROS1 fusion-positive advanced lung adenocarcinoma: A case report.

[This corrects the article DOI: 10.3389/fphar.2022.898623.].

Epidemiological analysis of death among patients on maintenance hemodialysis: results from the beijing blood purification quality Control and Improvement Center.

BACKGROUND: China has the largest number of patients on maintenance hemodialysis (MHD) worldwide. Despite continuous improvements in hemodialysis techniques, patients on MHD have a higher mortality rate than the general population. Understanding the characteristics of death in this population can better promote clinical practice, thereby improving patients' survival. METHODS: We collected demographic and clinical data for patients on MHD registered in the Beijing Blood Purification Quality Control and Improvement Center database from 2014 to 2020. The annual mortality rate was calculatedand the primary cause of end-stage renal disease (ESRD), dialysis vintage, and cause of death among deceased patients were analyzed. RESULTS: (1) 24,363 patients on MHD were included, of which 6,065 patients died from 2014 to 2020. The annual mortality rate fluctuated between 7.4% and 8.0%. The median age of death was 70.0 (60.8-79.0) years and the male to female ratio was 1.27:1 (2). The top three primary causes of ESRD in deceased patients were chronic glomerulonephritis (CGN), diabetic nephropathy (DN), and hypertensive nephropathy (HN). Comparison of the annual mortality rate showed DN > HN > CGN (3). The median dialysis vintage of deceased patients was 3.7 (1.8-6.9) years, which slowly increased annually. Patients with diabetes had a shorter dialysis vintage than patients without diabetes (3.4 vs. 4.1 years, Z = 8.3, P < 0.001) (4). The major causes of death were cardiovascular disease (20.2%), sudden death (18.1%), infection (17.9%), and cerebrovascular disease (12.6%). Proportions of death from cardiovascular disease, infection, and sudden death were higher in patients with diabetes (22.2%, 20.2%, and 20.0%) than patients without diabetes (18.4%, 15.8%, and 16.3%). Sudden death was the leading cause of death in young (18-44 years; 27.0%) and middle aged (45-64 years; 20.8%) patients, whereas infection was the leading cause of death in patients aged ≥ 75 years (24.5%). CONCLUSION: The annual mortality rate of patients on MHD in Beijing was relatively stable from 2014 to 2020. Sudden death was more likely to occur in young and middle-aged patients, and more patients aged ≥ 75 years died from infections.

Activity of ceritinib in crizotinib-resistant ROS1-rearranged non-small-cell lung cancer patients.

As a second-generation selective oral anaplastic lymphoma kinase inhibitor, ceritinib is an effective first-line treatment for c-ros oncogene 1 (ROS1)-rearranged non-small-cell lung cancer (NSCLC). Its efficacy and safety for the treatment of crizotinib-resistant ROS1-rearranged NSCLC were explored in the study. A retrospective single-center study was conducted to investigate the efficacy of ceritinib in crizotinib-resistant ROS1-rearranged NSCLC. The objective response rate was the primary objective, while the disease control rate, progression-free survival and adverse events were secondary objectives. From December 2015 to October 2021, a total of 246 patients with ROS1-rearranged NSCLC were screened, 12 (4.9%) of whom were treated with ceritinib after the development of crizotinib resistance. Among the 12 crizotinib-resistant patients included, 3 displayed the efficacy of partial response and 3 had the efficacy of stable condition. The objective response rate, disease control rate and median progression-free survival of all patients were 25% (95% confidence interval [CI]: -3.7% to 53.7%; 3 of 12 patients), 50% (95% CI: 16.8% to 83.2%; 6 of 12 patients), and 10.5 months (95% CI, 5.7 to 15.3 months), respectively. In addition, of the 6 patients with brain metastases, an intracranial disease control rate of 66.7% (95% CI:12.5% to 120.9%) was obtained. The research results reveal that ceritinib can be a treatment option for ROS1-rearranged NSCLC patients after the development of crizotinib resistance.

The genetic basis of the leafy seadragon's unique camouflage morphology and avenues for its efficient conservation derived from habitat modeling.

The leafy seadragon certainly is among evolution's most "beautiful and wonderful" species aptly named for its extraordinary camouflage mimicking its coastal seaweed habitat. However, limited information is known about the genetic basis of its phenotypes and conspicuous camouflage. Here, we revealed genomic signatures of rapid evolution and positive selection in core genes related to its camouflage, which allowed us to predict population dynamics for this species. Comparative genomic analysis revealed that seadragons have the smallest olfactory repertoires among all ray-finned fishes, suggesting adaptations to the highly specialized habitat. Other positively selected and rapidly evolving genes that serve in bone development and coloration are highly expressed in the leaf-like appendages, supporting a recent adaptive shift in camouflage appendage formation. Knock-out of bmp6 results in dysplastic intermuscular bones with a significantly reduced number in zebrafish, implying its important function in bone formation. Global climate change-induced loss of seagrass beds now severely threatens the continued existence of this enigmatic species. The leafy seadragon has a historically small population size likely due to its specific habitat requirements that further exacerbate its vulnerability to climate change. Therefore, taking climate change-induced range shifts into account while developing future protection strategies.

Characterization of molecular subtypes based on chromatin regulators and identification of the role of NPAS2 in lung adenocarcinoma.

BACKGROUND: Chromatin regulators (CRs) are critical epigenetic modifiers and have been reported to play critical roles during the progression of various tumors, but their role in lung adenocarcinoma (LUAD) has not been comprehensively studied. METHODS: Differential expression and univariate Cox regression analyses were conducted to identify the prognostic CRs. Consensus clustering was applied to classify the subtypes of LUAD based on prognostic CRs. LASSO-multivariate Cox regression method was used for construction of a prognostic signature and development of chromatin regulator-related gene index (CRGI). The capacity of CRGI to distinguish survival was evaluated via Kaplan-Meier method in multiple datasets. Relationship between CRGI and tumor microenvironment (TME) was evaluated. Additionally, clinical variables and CRGI were incorporated to create a nomogram. The role of the prognostic gene NPAS2 in LUAD was elucidated via clinical samples validation and a series of in vitro and in vivo experiments. RESULTS: Two subtypes of LUAD were classified based on 46 prognostic CRs via consensus clustering which had significantly different survival and TME. A prognostic signature consisting of six CRs (MOCS, PBK, CBX3, A1CF, NPAS2, and CTCFL) was developed and proved to be an effective survival predictor in multiple independent datasets. The prognostic signature was also demonstrated to be an indicator of TME and sensitivity to immunotherapy and chemotherapy. The nomogram was suggested to be a simple tool that can predict survival accurately. Clinical samples show that NPAS2 is highly expressed in LUAD tissues, and in vitro and in vivo experiments demonstrated that inhibition of NPAS2 impeded malignant progression of LUAD cells. CONCLUSIONS: Our study comprehensively unveiled the functions of CRs in LUAD, developed a classifier to predict survival and response to treatments, and suggested that NPAS2 promoted LUAD progression for the first time.

Facile synthesis of non-modified yellow emission silicon quantum dots and their visualization of hydrogen sulfide in living cells and onion tissues.

Yellow fluorescent silicon quantum dots (y-SiQDs) with 22.2% fluorescence quantum yield were synthesized by a simple hydrothermal method using 3-glycidoxypropyl triethoxysilane (GOTS) and m-aminophenol. The excitation wavelength is 550 nm with an emission wavelength of 574 nm, which effectively avoids the interference of biological autofluorescence. Notably, the synthesis approach does not require any post-modification and the y-SiQDs can be directly used for hydrogen sulfide (H2S) quantification due to static quenching. It exhibits high sensitivity and excellent selectivity for H2S with a 0.2-10 µM (R2 = 0.9953) linear range and detection limit of 54 nM. y-SiQDs have excellent stability and biocompatibility and can be used for H2S imaging in living cells and onion tissues.

Genome-Wide Splicing Quantitative Expression Locus Analysis Identifies Causal Risk Variants for Non-Small Cell Lung Cancer.

Alternative RNA splicing is an essential mechanism linking genetic variation to human diseases. While the signals from genome-wide association studies (GWAS) have been linked to expression quantitative trait loci (eQTL) in previous studies, further work is needed to better elucidate the relationship to other genetic regulatory mechanisms, such as splicing QTLs (sQTL). Here, we performed a genome-wide sQTL analysis to identify variants that might affect RNA splicing in 1,010 non-small cell lung cancer (NSCLC) samples from The Cancer Genome Atlas. The identified sQTLs were largely independent of eQTLs and were predominantly enriched in exonic regions, genetic regulatory elements, RNA-binding protein (RBP) binding sites, and known NSCLC risk loci. In addition, target genes affected by sQTLs (sGenes) were involved in multiple processes in cancer, including cell growth, apoptosis, metabolism, immune infiltration, and drug responses, and sGenes were frequently altered genetically in NSCLC. Systematic screening of sQTLs associated with NSCLC risk using GWAS data from 15,474 cases and 12,375 controls identified an sQTL variant rs156697-G allele that was significantly associated with an increased risk of NSCLC. The association between the rs156697-G variant and NSCLC risk was further validated in two additional large population cohorts. The risk variant promoted inclusion of GSTO2 alternative exon 5 and led to higher expression of the GSTO2 full-length isoform (GSTO2-V1) and lower expression of the truncated GSTO2 isoform (GSTO2-V2), which was induced by RBP quaking (QKI). Mechanistically, compared with GSTO2-V1, GSTO2-V2 inhibited NSCLC cells proliferation by increasing S-glutathionylation of AKT1 and thereby functionally blocking AKT1 phosphorylation and activation. Overall, this study provides a comprehensive view of splicing variants linked to NSCLC risk and provides a set of genetic targets with therapeutic potential. SIGNIFICANCE: Analysis of sQTL reveals the role of genetically driven mRNA splicing alterations in NSCLC risk and elucidates that rs156697 variant impacts risk by altering GSTO2 splicing.

Macrophage-derived exosomes regulate gastric cancer cell oxaliplatin resistance by wrapping circ 0008253.

Oxaliplatin (OXA) is a first-line chemotherapy drug for gastric cancer. We aimed to investigate the effect of circ 0008253, contained in M2 polarized macrophage-derived exosomes, on OXA resistance of gastric carcinoma cells. Flow cytometry was performed to detect the differentiation of macrophages and cell apoptosis. Cell Counting Kit-8 assay was conducted to examine the cell viability. Transmission electron microscopy, Nanoparticle Tracking Analysis, Western bolt, and Immunofluorescence were carried out. Cell proliferation was detected with a colony formation experiment. Levels of CD206, Arg1, IL-10, and TGF-ß were increased in M2 polarized macrophages. Cell viability was decreased gradually with the increase of time and OXA concentration. Apoptosis of gastric carcinoma cells was decreased after co-culture with M2-polarized macrophages. Exosomes isolated from M2-polarized macrophages (M2-Exos) could be co-located with gastric carcinoma cells. M2-Exos enhanced drug resistance, reduced apoptosis and OXA resistance. Bioinformatics analysis showed that circ 0008253 could be transferred from M2-Exos to gastric carcinoma cells. Overexpressing circ 0008253 increased cell viability, tumor size, and ABCG2 levels, decreased OXA sensitivity. Circ 0008253, contained in M2-Exos, was directly transferred from tumor-associated macrophage to gastric carcinoma cells, finally enhancing OXA resistance.

Characterization of the Complete Mitochondrial Genome of Agelas nakamurai from the South China Sea.

The Agelas genus sponges are widely distributed and provide shelter for organisms that inhabit reefs. However, there is a lack of research on the genetic diversity of the Agelas sponges. Additionally, only one Agelas mitochondrial genome has been documented, leaving the characteristics of the Agelas genus's mitogenome in need of further clarification. To address this research gap, we utilized Illumina HiSeq4000 sequencing and de novo assembly to ascertain the complete mitochondrial genome of Agelas sp. specimens, sourced from the South China Sea. Our analysis of the cox1 barcoding similarity and phylogenetic relationship reveals that taxonomically, the Agelas sp. corresponds to Agelas nakamurai. The mitogenome of Agelas nakamurai is 20,885 bp in length, encoding 14 protein-coding genes, 24 transfer RNA genes, and 2 ribosomal RNA genes. Through a comparison of the mitochondrial genes, we discovered that both Agelas nakamurai and Agelas schmidti have an identical gene arrangement. Furthermore, we observed a deletion in the trnD gene and duplication and remodeling of the trnL gene in the Agelas nakamurai's mitogenome. Our evolutionary analysis also identified lineage-specific positive selection sites in the nad3 and nad5 genes of the Agelas sponges' mitogenome. These findings shed light on the gene rearrangement events and positive selection sites in the mitogenome of Agelas nakamurai, providing valuable molecular insights into the evolutionary processes of this genus.