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Journal For Immunotherapy of Cancer Apr 2024Combining immune checkpoint inhibitors (ICIs) with chemotherapy has become a standard treatment for patients with non-small cell lung cancer (NSCLC) lacking driver gene...
BACKGROUND
Combining immune checkpoint inhibitors (ICIs) with chemotherapy has become a standard treatment for patients with non-small cell lung cancer (NSCLC) lacking driver gene mutations. Reliable biomarkers are essential for predicting treatment outcomes. Emerging evidence from various cancers suggests that early assessment of serum metabolites could serve as valuable biomarkers for predicting outcomes. This study aims to identify metabolites linked to treatment outcomes in patients with advanced NSCLC undergoing first-line or second-line therapy with programmed cell death 1 (PD-1) inhibitors plus chemotherapy.
METHOD
200 patients with advanced NSCLC receiving either first-line or second-line PD-1 inhibitor plus chemotherapy, and 50 patients undergoing first-line chemotherapy were enrolled in this study. The 200 patients receiving combination therapy were divided into a Discovery set (n=50) and a Validation set (n=150). These sets were further categorized into respond and non-respond groups based on progression-free survival PFS criteria (PFS≥12 and PFS<12 months). Serum samples were collected from all patients before treatment initiation for untargeted metabolomics analysis, with the goal of identifying and validating biomarkers that can predict the efficacy of immunotherapy plus chemotherapy. Additionally, the validated metabolites were grouped into high and low categories based on their medians, and their relationship with PFS was analyzed using Cox regression models in patients receiving combination therapy.
RESULTS
After the impact of chemotherapy was accounted for, two significant differential metabolites were identified in both the Discovery and Validation sets: N-(3-Indolylacetyl)-L-alanine and methomyl (VIP>1 and p<0.05). Notably, upregulation of both metabolites was observed in the group with a poorer prognosis. In the univariate analysis of PFS, lower levels of N-(3-Indolylacetyl)-L-alanine were associated with longer PFS (HR=0.59, 95% CI, 0.41 to 0.84, p=0.003), and a prolonged PFS was also indicated by lower levels of methomyl (HR=0.67, 95% CI, 0.47 to 0.96, p=0.029). In multivariate analyses of PFS, lower levels of N-(3-Indolylacetyl)-L-alanine were significantly associated with a longer PFS (HR=0.60, 95% CI, 0.37 to 0.98, p=0.041).
CONCLUSION
Improved outcomes were associated with lower levels of N-(3-Indolylacetyl)-L-alanine in patients with stage IIIB-IV NSCLC lacking driver gene mutations, who underwent first-line or second-line therapy with PD-1 inhibitors combined with chemotherapy. Further exploration of the potential predictive value of pretreatment detection of N-(3-Indolylacetyl)-L-alanine in peripheral blood for the efficacy of combination therapy is warranted.
STATEMENT
The combination of ICIs and chemotherapy has established itself as the new standard of care for first-line or second-line treatment in patients with advanced NSCLC lacking oncogenic driver alterations. Therefore, identifying biomarkers that can predict the efficacy and prognosis of immunotherapy plus chemotherapy is of paramount importance. Currently, the only validated predictive biomarker is programmed cell death ligand-1 (PD-L1), but its predictive value is not absolute. Our study suggests that the detection of N-(3-Indolylacetyl)-L-alanine in patient serum with untargeted metabolomics prior to combined therapy may predict the efficacy of treatment. Compared with detecting PD-L1 expression, the advantage of our biomarker is that it is more convenient, more dynamic, and seems to work synergistically with PD-L1 expression.
Topics: Humans; B7-H1 Antigen; Biomarkers; Carcinoma, Non-Small-Cell Lung; Immune Checkpoint Inhibitors; Lung Neoplasms; Metabolomics; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38641349
DOI: 10.1136/jitc-2023-008190 -
Metabolites Aug 2023Many pesticides have been identified as endocrine and metabolism-disrupting chemicals with hepatotoxic effects. However, data are limited for insecticides in the...
Many pesticides have been identified as endocrine and metabolism-disrupting chemicals with hepatotoxic effects. However, data are limited for insecticides in the n-methyl carbamate class, including methomyl. Here, we investigate the liver and systemic metabolic effects of methomyl in a mouse model. We hypothesize that methomyl exposure will disrupt xenobiotic and intermediary metabolism and promote hepatic steatosis in mice. Male C57BL/6 mice were exposed daily to 0-5 mg/kg methomyl for 18 days. Mice were fed water and regular chow diet ad libitum. Metabolic phenotyping was performed, and tissue samples were collected. Effects were generally greatest at the highest methomyl dose, which induced . Methomyl decreased whole body weight while the liver:body weight and testes:body weight ratios were increased. Hepatic steatosis increased while plasma LDL decreased. Fasting blood glucose and the glucose tolerance test area under the curve decreased along with hepatic glycogen stores. Methomyl, however, did not increase liver oxidative stress or injury. Collectively, these data demonstrate that methomyl disrupts hepatic xenobiotic and intermediary metabolism while increasing the testes:body weight ratio, suggesting that it may be an endocrine disrupting chemical. Besides methomyl's known action in cholinesterase inhibition, it may be involved in aryl hydrocarbon receptor activation. The potential impact of n-methyl carbamate insecticides on metabolic health and diseases, including toxicant-associated steatotic liver disease (TASLD), warrants further investigation.
PubMed: 37623845
DOI: 10.3390/metabo13080901 -
BMC Chemistry Oct 2023The emergence of pest resistance of Spodoptera littoralis (order; Lepidoptera, family; Noctuidae) towards the large scale of different classes of insecticides...
The emergence of pest resistance of Spodoptera littoralis (order; Lepidoptera, family; Noctuidae) towards the large scale of different classes of insecticides necessitates the development of some new poly-functionalized biphenyl and azabiphenyl with highly anticipated insecticidal bioresponse. Four new biphenyl carboxamidines 4a-d and four aza-analogue picolinamidine derivatives 8a-d were designed and prepared via the treatment of their corresponding carbonitriles with lithium-bis trimethylsilylamide [LiN(TMS)], followed by hydrolysis with hydrogen chloride. Furthermore, these compounds were elucidated by spectral data, and their toxicity and insecticidal activity were screened against Spodoptera littoralis. Whereby, toxicological and biochemical aspects of the inventively synthesized biphenyl and azabiphenyl derivatives against the cotton leafworm, Spodoptera littoralis were inspected. As regards the indomitable LC and LC values, biphenyl and aza-analogues 8d, 8a, 4b, and 8b, revealed the furthermost forceful toxic effects with LC values of 113.860, 146.265, 216.624, and 289.879 ppm, respectively. Whereby, their LC values are 1235.108, 1679.044, 2656.296, and 3381.256 ppm, respectively, and toxicity index being 22.31%, 17.36%, 11.72%, and 8.76%, respectively, comparing with the already recommended, methomyl insecticide, lannate 90% SP (LC, 25.396 and LC, 57.860 and toxicity index, 100%). Additionally, electrochemical parameters via DFT studies were carried out for demonstrating and elucidation of structure-activity relationship (SAR) according to highly motived compounds descriptors, and the in vivo insecticidal activities.
PubMed: 37891573
DOI: 10.1186/s13065-023-01050-w -
Ecotoxicology and Environmental Safety Dec 2023The extensive use of carbamate pesticides has led to a range of environmental and health problems, such as surface and groundwater contamination, and endocrine disorders...
The extensive use of carbamate pesticides has led to a range of environmental and health problems, such as surface and groundwater contamination, and endocrine disorders in organisms. In this study, we focused on examining the effects of toxic exposure to the carbamate pesticide methomyl on the hatching, morphology, immunity and developmental gene expression levels in zebrafish embryos. Four concentrations of methomyl (0, 2, 20, and 200 μg/L) were administered to zebrafish embryos for a period of 96 h. The study found that exposure to methomyl accelerated the hatching process of zebrafish embryos, with the strongest effect recorded at the concentration of 2 μg/L. Methomyl exposure also trigged significantly reductions in heart rate and caused abnormalities in larvae morphology, and it also stimulated the synthesis and release of several inflammatory factors such as IL-1β, IL-6, TNF-α and INF-α, lowered the IgM contents, ultimately enhancing inflammatory response and interfering with immune function. All of these showed the significant effects on exposure time, concentration and their interaction (Time × Concentration). Furthermore, the body length of zebrafish exposed to methomyl for 96 h was significantly shorter, particularly at higher concentrations (200 μg/L). Methomyl also affected the expression levels of genes associated with development (down-regulated igf1, bmp2b, vasa, dazl and piwi genes), demonstrating strong developmental toxicity and disruption of the endocrine system, with the most observed at the concentration of 200 μg/L and 96 h exposure to methomyl. The results of this study provide valuable reference information on the potential damage of methomyl concentrations in the environment on fish embryo development, while also supplementing present research on the immunotoxicity of methomyl.
Topics: Animals; Zebrafish; Methomyl; Embryo, Nonmammalian; Endocrine System; Pesticides; Carbamates; Larva; Water Pollutants, Chemical
PubMed: 37976935
DOI: 10.1016/j.ecoenv.2023.115684 -
Chemosphere Jun 2024This prospective work focuses on the use of two different gaseous oxidants (chlorine dioxide and ozone) to remediate soil polluted with methomyl in two different...
This prospective work focuses on the use of two different gaseous oxidants (chlorine dioxide and ozone) to remediate soil polluted with methomyl in two different applications: ex-situ and in-situ. In the first, the soil washing is integrated with the bubbling of the oxidant, while in the second, the gas was introduced by a perforated pipe located sub-superficially. Regarding the soil washing treatment, results demonstrate that direct use of ozone is not very efficient, although an important improvement is obtained following activation with hydrogen peroxide or UV light. In contrast, chlorine dioxide exhibited complete methomyl depletion from the soil, although with higher energy consumption and technical complexity compared to ozone. The direct dosing of the gaseous oxidants in perforated pipes is effective, achieving methomyl removals of 7.8 % and 9.2 % using ozone and chlorine dioxide, respectively. In these cases, soil conditions are not significantly modified, which becomes an important advantage of the technology as compared with other electrochemically assisted soil remediation process, in which large regions of the treated soil are affected by important changes in the pH or by depletion of ions. This lower impact makes these novel technologies more promising for further evaluations.
PubMed: 38906193
DOI: 10.1016/j.chemosphere.2024.142653 -
ACS Omega Jul 2023Non-fibrous materials (NFMs) are typically discarded during pineapple leaf fiber processing. The underutilized NFM waste was proposed for use in this work as a raw...
Non-fibrous materials (NFMs) are typically discarded during pineapple leaf fiber processing. The underutilized NFM waste was proposed for use in this work as a raw material for the production of biochar . The removal of pesticides (acetamiprid, imidacloprid, or methomyl) from water was then investigated using the NFM derived biochar (NFMBC). The pseudo-second-order kinetic data suggested chemisorption of pesticide on NFMBC. While acetamiprid or imidacloprid adsorption on NFMBC occurred primarily multi-layered adsorption (best fitted with the Freundlich isotherms), the Sips adsorption isotherms matched with the experimental data, implying heterogeneous adsorption of methomyl on the biochar surface. The adsorption capacities for acetamiprid, methomyl, and imidacloprid are 82.18, 36.16, and 28.98 mg g, respectively, which are in agreement with the order of the polarity (low to high) of pesticides. Adsorption capacities indicated that the NFMBC preferably removed low-polarity pesticides from water sources. Since pineapple leaves provide fibers and NFMs for materials development, this study should promote an extended agro-waste utilization approach and full-cycle resource management in pineapple fields.
PubMed: 37521671
DOI: 10.1021/acsomega.3c02328 -
Plants (Basel, Switzerland) Oct 2023Several soil fungi significantly contribute to the enhancement of plant development by improving nutrient uptake and producing growth-promoting metabolites. In the...
Several soil fungi significantly contribute to the enhancement of plant development by improving nutrient uptake and producing growth-promoting metabolites. In the present study, three strains of phosphate-solubilizing fungi, namely, SDBR-CMUI4, SDBR-CMUI1, and SDBR-CMUO2, were examined for their plant-growth-promoting capabilities. The findings demonstrated that all fungi showed positive siderophore production, but only can produce indole-3-acetic acid. All fungi were able to solubilize insoluble phosphate minerals [Ca(PO) and FePO] by producing phosphatase enzymes and organic acids (oxalic, tartaric, and succinic acids). These three fungal species were grown at a water activity ranging from 0.837 to 0.998, pH values ranging from 4 to 9, temperatures between 4 and 40 °C, and 16-17% NaCl in order to evaluate their drought, pH, temperature, and salt tolerances, respectively. Moreover, the results indicated that and were able to tolerate commercial insecticides (methomyl and propargite) at the recommended dosages for field application. The viability of each fungal strain in the inoculum was higher than 50% at 4 and 20 °C after 3 months of storage. Subsequently, all fungi were characterized as plant-growth-promoting strains by improving the root inductions of cassava ( Crantz) and sugarcane ( L.) stem cuttings in greenhouse experiments. No symptoms of plant disease were observed with any of the treatments involving fungal inoculation and control. The cassava and sugarcane stem cuttings inoculated with fungal strains and supplemented with Ca(PO) exhibited significantly increased root lengths, shoot and root dry biomasses, chlorophyll concentrations, and cellular inorganic phosphate contents. Therefore, the application of these phosphate-solubilizing fungi is regarded as a new frontier in the induction of roots and the promotion of growth in plants.
PubMed: 37896093
DOI: 10.3390/plants12203630 -
Se Pu = Chinese Journal of... Sep 2023Carbamates are used in broad-spectrum insecticides and herbicides, and have highly efficient, low-residue, and long-lasting characteristics. However, this type of...
[Determination of 10 carbamate pesticide residues in liquid milk by ultra performance liquid chromatography-tandem mass spectrometry with pass-through solid-phase extraction purification].
Carbamates are used in broad-spectrum insecticides and herbicides, and have highly efficient, low-residue, and long-lasting characteristics. However, this type of pesticide exerts mutagenic, teratogenic, carcinogenic, and other adverse effects, and its frequent use can exceed the recommended scope and limits. Research on the determination of carbamate pesticides mainly focuses on foods of plant origin and pays less attention to foods of animal origin. The methods for carbamate determination described in the current national standards have complicated operating procedures and low efficiency. Therefore, highly efficient and accurate methods for carbamate detection in milk must be established. In this work, a rapid method based on pass-through solid-phase extraction (SPE) purification coupled with ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed for the simultaneous determination of 10 carbamate pesticides in liquid milk. The pretreatment and instrument methods were systematically optimized. The milk sample was extracted with acetonitrile, and then purified using a Captiva EMR-Lipid filtration kit. The purified extract was separated on an ACQUITY UPLC BEH C column with mobile phase of methanol and 0.1% formic acid aqueous solution in gradient elution. The flow rate was 0.3 mL/min. Column temperature was 35 ℃. Quantitative analysis was performed using the external standard method with matrix matching curves. The 10 carbamate pesticides showed good linear relationships in the mass concentration range of 2-200 μg/L, with correlation coefficients greater than 0.999. The limits of detection (LODs) and quantification (LOQs) for the 10 carbamate pesticides were 0.045-0.23 and 0.15-0.77 μg/kg, respectively. Recovery tests were conducted using the blank-matrix method at three spiked levels of 15, 50, and 100 μg/kg, and good recoveries for the 10 carbamate pesticides were obtained. In particular, the recoveries for the three spiked levels of 15, 50, and 100 μg/kg were 68.7%-93.3% with relative standard deviations (RSDs) of 1.8%-8.0%. The proposed method is efficient, convenient, accurate, and suitable for the rapid detection of the 10 carbamate pesticides in liquid milk. Compared with the conventional NH and ENVI-18 SPE columns used in the national standard determination method, the proposed method demonstrated better purification effects. The recoveries for aldicarb sulfoxide, aldicarb sulfone, methomyl, and carbaryl after purification using the Captiva EMR-Lipid kit increased from 60% to 80%. Thus, the proposed method is suitable for targets with strong polarity and gives measurement results with good repeatability and accuracy.
Topics: Animals; Pesticide Residues; Carbamates; Milk; Chromatography, Liquid; Tandem Mass Spectrometry; Pesticides; Lipids
PubMed: 37712545
DOI: 10.3724/SP.J.1123.2023.03017 -
Water Research Aug 2023Micropollutants are regularly detected at the outlets of wastewater treatment plants (WWTPs). Across urban and industrial WWTPs, monitoring directives only require...
Micropollutants are regularly detected at the outlets of wastewater treatment plants (WWTPs). Across urban and industrial WWTPs, monitoring directives only require assessment for a handful of chemicals via sampling methods that fail to capture the temporal variability in micropollutant discharge. In this study, we develop a biotest for real-time on-line monitoring of micropollutant discharge dynamics in WWTPs effluents. The selected biomonitoring device ToxMate uses videotracking of invertebrate movement, which was used to deduce avoidance behaviour of the amphipod Gammarus fossarum. Organism conditioning was set up to induce a state of minimal locomotor activity in basal conditions to maximise avoidance signal sensitivity to micropollutant spikes. We showed that with a standardised protocol, it was possible to minimise both overall movement and sensitivity to physio-chemical variations typical to WWTP effluents, as well as capture the spikes of two micropollutants upon exposure (copper and methomyl). Spikes in avoidance behaviour were consistently seen for the two chemicals, as well as a strong correlation between avoidance intensity and spiked concentration. A two-year effluent monitoring case study also illustrates how this biomonitoring method is suitable for real-time on-site monitoring, and shows a promising non-targeted approach for characterising complex micropollutant discharge variability at WWTP effluents, which today remains poorly understood.
Topics: Animals; Wastewater; Avoidance Learning; Water Pollutants, Chemical; Amphipoda; Water Purification; Environmental Monitoring; Waste Disposal, Fluid
PubMed: 37348420
DOI: 10.1016/j.watres.2023.120228