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1.
Spectrochim Acta A Mol Biomol Spectrosc ; 284: 121777, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36058171

RESUMO

A novel multicolor fluorescent nano-probe based on the hybridization of Tb3+ ion with gold nanoclusters (Au NCs) was synthesized to monitor and on-site visual assay of 2,6-pyridinedicarboxylic acid (DPA), a biomarker of bacterial spores. DPA can replace the water molecule in the center of Tb3+ and strongly coordinate with Tb3+ based on the analyte-triggered antenna effect. Simultaneously, the red fluorescence of Au NCs is not influenced after addition of DPA and can be used as steady inside fluorescence reference channel to measure background noise. On this basis, the multicolor fluorescence nano-probe based on Tb3+-doped Au NCs for fast analysis of DPA was fabricated. The linear range of this method is 0 to 12.5 µM and the limit of detection is 3.4 nM, which is well below the quantity of DPA concentration of 60 µM released by the spore transmission dose of anthrax infection. The proposed multicolor fluorescence nano-probe was successfully detecting DPA in actual sample with good sensitivity and specificity. In addition, the visual paper-based nano-probe is designed to detect DPA by using the color scanning application of smart phone. This developed platform possesses abroad application prospects with advantages of effective, convenient carrying, simple operation, good selectivity and repeatability.


Assuntos
Ouro , Térbio , Biomarcadores/análise , Corantes Fluorescentes/análise , Ácidos Picolínicos/análise , Água
2.
J Hazard Mater ; 441: 129863, 2023 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-36088880

RESUMO

Heavy metals (HMs) from smelters pose severe challenges to the environmental soil quality of surrounding farmlands, and threaten human health through the food chain. This study explored the environmental effects of smelting activities on farmland soil, and additionally assessed the enrichment, transfer and health risk of HMs in soil-wheat systems. Multiple characterization results were combined to demonstrate that HMs from smelter waste were transferred to the surrounding soil. It was determined that the enrichment of HMs in soil-wheat systems is mainly controlled by the total HM concentration and pH in soil. Furthermore, the priority pollutant in soil-wheat systems was found to be Cd, and Cd affected the transfer of Cu, Mn and Pb from soil to wheat roots. Interestingly, the -OH stretching, C-H stretching, N-H amide and C-O bending were involved in detoxifying HMs in wheat. The mean values of non-carcinogenic and carcinogenic risks by consuming wheat grain were 9.1, 1.4E-02 (adults) and 11.3, 3.3E-03 (children), respectively, indicating a noteworthy health risk. This study highlighted the critical issues arising from Pb/Zn smelting activities on agricultural soils. Notwithstanding, to ensure food security, the affected regions could opt to follow up on the type of crops grown.


Assuntos
Metais Pesados , Poluentes do Solo , Adulto , Amidas , Cádmio/análise , Criança , China , Monitoramento Ambiental/métodos , Humanos , Chumbo , Metais Pesados/análise , Medição de Risco , Solo/química , Poluentes do Solo/análise , Triticum/química , Zinco
3.
J Environ Sci (China) ; 124: 146-155, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36182125

RESUMO

In this study, the effects of soluble readily biodegradable COD (sCOD) and particulate slowly biodegradable COD (pCOD) on anammox process were investigated. The results of the long-term experiment indicated that a low sCOD/N ratio of 0.5 could accelerate the anammox and denitrification activity, to reach as high as 84.9%±2.8% TN removal efficiency. Partial denitrification-anammox (PDN/anammox) and denitrification were proposed as the major pathways for nitrogen removal, accounting for 91.3% and 8.7% of the TN removal, respectively. Anammox bacteria could remain active with high abundance of anammox genes to maintain its dominance. Candidatus Kuenenia and Thauera were the predominant genera in the presence of organic matter. Compared with sCOD, batch experiments showed that the introduction of pCOD had a negative effect on nitrogen removal. The contribution of denitrification to nitrogen removal decreased from approximately 14% to 3% with increasing percentage of pCOD. In addition, the analysis result of the process data using an optimized ASM1 model indicated that high percentage of pCOD resulted in serious N2O emission (the peak value up to 0.25 mg N/L), which was likely due to limited mass diffusion and insufficient available carbon sources for denitrification. However, a high sCOD/N ratio was beneficial for alleviating N2O accumulation.


Assuntos
Desnitrificação , Microbiota , Oxidação Anaeróbia da Amônia , Reatores Biológicos/microbiologia , Carbono , Nitrogênio , Oxirredução , Material Particulado , Esgotos/microbiologia , Águas Residuárias
4.
J Colloid Interface Sci ; 630(Pt A): 604-617, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36272215

RESUMO

The preparation of carboxylated cellulose nanocrystals (cCNCs) and their stabilization in oil-in-water (O/W) Pickering emulsions hold great potential for application and research value. In this work, a novel integrated oxidation strategy was proposed to prepare needle-like cCNCs by sodium periodate (NaIO4)/Fenton (SF-cCNCs) with considerable yield (58.58 %), plentiful carboxyl groups (1.28 mmol/g), and high crystallinity (83.3 %). The distinctive features of smaller size and high viscosity accelerated the as-prepared SF-cCNCs to be used in stabilizing Pickering emulsion. Moreover, the effects of oil-water ratio (OWR), SF-cCNCs content, pH, and sodium chloride (NaCl) content on the stability of SF-cCNCs-stabilized Pickering emulsions were also investigated systematically. Interestingly, the stability of the as-obtained emulsions was dependent on pH and salt. Afterwards, the rheological behaviors validated that the emulsion viscosity increased rapidly after adding NaCl, which was dominated by the elastic behavior. Finally, the main stabilization mechanism was confirmed to be interfacial adsorption of SF-cCNCs rather than the formation of spatial network structures between droplets. This study reports a synthetic strategy to efficiently prepare SF-cCNCs, endowing the SF-cCNCs stabilized Pickering emulsion with environmentally friendly, long-term stable and highly anti-agglomeration abilities for cosmetics and food products.


Assuntos
Celulose , Nanopartículas , Celulose/química , Emulsões/química , Cloreto de Sódio , Emulsificantes , Nanopartículas/química , Água/química
5.
Gene ; 851: 147028, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36334618

RESUMO

Smith-Magenis syndrome (SMS, OMIM# 182290) is a rare congenital disorder which characterized by multiple abnormalities involving in craniofacial, skeletal, otorhinolaryngolocial, neurological, behavioral and others. 17p11.2 microdeletion and RAI1 mutations have been proven to be genetic lesions of this disease. However, the relationship between RAI1 variants and different phenotypes is still unclear. The discoveries of more RAI1 mutations in patients with different phenotypes will help to elucidate the pathogenesis of the RAI1 gene. Here, we describe a young patient with schizophrenia and headache as the main clinical presentation, with SMS-like features including depression, sleep disturbance and pain-free status. Whole exome sequencing and Sanger sequencing suggested that a de novo mutation (NM_030665.3: c.4256C > T/p.S1419F) of RAI1 may be the genetic lesion of the patient. The bioinformatic program predicted that the new mutation (p.S1419F), located in an evolutionarily conserved site of RAI1, was deleterious. Further, western blot analysis suggested that the novel mutation may decrease the protein levels of RAI1 in the patient. Hence, we reported a novel mutation of RAI1 in a patient with SMS, schizophrenia and headache. Our study may expand the spectrum of RAI1 mutations which may further contribute to the mechanisms underlying SMS, schizophrenia and headache.


Assuntos
Esquizofrenia , Síndrome de Smith-Magenis , Humanos , Síndrome de Smith-Magenis/genética , Transativadores/genética , Esquizofrenia/genética , Fatores de Transcrição/genética , Fenótipo , Mutação , Cefaleia , Tretinoína
6.
Spectrochim Acta A Mol Biomol Spectrosc ; 286: 121986, 2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36265303

RESUMO

The Golgi apparatus (GA) is a vital organelle in biological systems and excess reactive oxygen species (ROS) is produced during stress in the Golgi apparatus. Hypochlorous acid (HOCl) is a significant reactive oxygen species and has strong oxidative and antibacterial activity, but excessive secretion of hypochlorous acid can affect Golgi structure or function abnormally, it will lead to a series of diseases including Alzheimer's disease, neurodegenerative diseases, autoimmune diseases, and Parkinson's disease. In present work, a novel fluorescent probe for Golgi localization utilizing naphthalimide derivatives was constructed to detect hypochlorous acid. The fluorescent probe used a derivatived 1,8-naphthalimide as the emitting fluorescence group, phenylsulfonamide as the localization group and dimethylthiocarbamate as the sensing unit. When HOCl was absent, the intramolecular charge transfer (ICT) process of the developed probe was hindered and the probe exhibited a weak fluorescence. When HOCl was present, the ICT process occurred and the probe showed strong green fluorescence. When the HOCl concentration was altered from 5.0 × 10-7 to 1.0 × 10-5 mol·L-1, the fluorescence intensity of the probe well linearly correlated with the HOCl concentration. The detection limit of 5.7 × 10-8 mol·L-1 was obtained for HOCl. The HOCl fluorescent probe possessed a rapid reaction time, a high selectivity and a broad working pH scope. In addition, the probe possessed good biocompatibility and had been magnificently employed to image Golgi HOCl in Hela cells. These characteristics of the probe demonstrated its ability to be used for sensing endogenous and exogenous hypochlorous acids within the Golgi apparatus of living cells.


Assuntos
Ácido Hipocloroso , Naftalimidas , Humanos , Ácido Hipocloroso/química , Naftalimidas/química , Corantes Fluorescentes/química , Fluorescência , Células HeLa , Complexo de Golgi
7.
J Hazard Mater ; 443(Pt B): 130293, 2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36444049

RESUMO

Mesosulfuron-methyl is a widely used herbicide in wheat fields. We previously reported that mesosulfuron-methyl alters the bacterial/fungal community structure in experimental indoor microcosms, ultimately affecting NO3--N and NH4+-N contents in soil nitrogen (N) cycling. However, how mesosulfuron-methyl application alter soil N cycling by changing microbial community assembly is unknown. Here, we designed an outdoor experiment comprising 2-month periods to investigate changes in soil N-cycle functional genes and structural shifts in the microbial community assembly in response to mesosulfuron-methyl applied at 11.25 and 112.5 g a.i. hm-2. Results showed that high mesosulfuron-methyl input significantly decreased AOA amoA and nirK abundances within the initial 15 days, but increased AOB amoA on day 60. The nifH abundance displayed a stimulation-inhibition trend. Moreover, high mesosulfuron-methyl input decreased the network's complexity, and newly formed multiple network modules exhibited strong negative associations with nifH, AOB amoA, nirK and nirS. Further structural equation model demonstrated that mesosulfuron-methyl did reveal strong direct inhibition of nirK, and it indirectly affected nirK by changing nifH abundance and Planomicrobium. Thus mesosulfuron-methyl perturbs N-cycling processes by reshaping bacterial community assembly. Taken together, our study provides theoretical support for determining the microbiological mechanism by which mesosulfuron-methyl affects soil N cycling.


Assuntos
Herbicidas , Microbiota , Herbicidas/farmacologia , Solo , Nitrogênio
8.
J Proteomics ; 271: 104767, 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36336260

RESUMO

Lysine acetylation is a common posttranslational modification that regulates numerous biochemical functions in both eukaryotic and prokaryotic species. In addition, several new non-acetyl acylations are structurally different from lysine acetylation and participate in diverse physiological functions. Here, a comprehensive analysis of several lysine acylomes was performed by combining the high-affinity antibody enrichment with high-resolution LC-MS/MS. In total, we identified 2536 lysine acetylated sites, 4723 propionylated sites, 2150 succinylated sites and 3001 malonylated sites in Bacillus subtilis, respectively. These acylated proteins account for 35.8% of total protein in this bacterium. The four lysine acylomes showed a motif preference for glutamate surrounding the modified lysine residues, and a functional preference for several metabolic pathways, such as carbon metabolism, fatty acid metabolism, and ribosome. In addition, more protein-protein interaction clusters were identified in the propionylated substrates than other three lysine acylomes. In summary, our study presents a global landscape of acylation in the Gram-positive model organism Bacillus and their potential functions in metabolism and physiology.


Assuntos
Bacillus subtilis , Lisina , Lisina/metabolismo , Bacillus subtilis/metabolismo , Cromatografia Líquida , Espectrometria de Massas em Tandem , Acetilação , Processamento de Proteína Pós-Traducional
9.
Front Nutr ; 9: 1032289, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36337663

RESUMO

The fermentation medium of a newly identified Cordyceps cicadae S1 was optimized by response surface methodology, with the optimal medium containing sucrose (80 g/L), yeast powder (60 g/L), KH2PO4 (5 g/L), MgSO4·7H2O (1 g/L) and Na2SeO3 (0. 1 g/L). Under these conditions, the extracellular polysaccharide yield was 8.09 g/L. A novel selenium-enriched polysaccharide (PACI-1) was isolated from Cordyceps cicadae, purified and identified as a homofructose polysaccharide with a low average molecular weight of 9.95 × 103 Da. The fine structure of PACI-1 was analyzed using NMR, CD, and AFM. Additionally, the in vitro antioxidant results showed that the PACI-1 had stronger antioxidant capacity than natural polysaccharides. These results provided a candidate strain for producing selenium polysaccharide and a new polysaccharide from C. cicadae, which showed good antioxidant activity.

10.
Front Oncol ; 12: 994285, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36338735

RESUMO

Purpose: To develop an appropriate machine learning model for predicting anaplastic lymphoma kinase (ALK) rearrangement status in non-small cell lung cancer (NSCLC) patients using computed tomography (CT) images and clinical features. Method and materials: This study included 193 patients with NSCLC (154 in the training cohort, 39 in the validation cohort), 68 of whom tested positive for ALK rearrangements and 125 of whom tested negative. From the nonenhanced CT scans, 157 radiomic characteristics were extracted, and 8 clinical features were collected. Five machine learning (ML) models were assessed to find the best classification model for predicting ALK rearrangement status. A radiomic signature was developed using the least absolute shrinkage and selection operator (LASSO) algorithm. The predictive performance of the models based on radiomic features, clinical features, and their combination was assessed by receiver operating characteristic (ROC) curves. Results: The support vector machine (SVM) model had the highest AUC of 0.914 for classification. The clinical features model had an AUC=0.805 (95% CI 0.731-0.877) and an AUC=0.735 (95% CI 0.566-0.863) in the training and validation cohorts, respectively. The CT image-based ML model had an AUC=0.953 (95% CI 0.913-1.0) in the training cohort and an AUC=0.890 (95% CI 0.778-0.971) in the validation cohort. For predicting ALK rearrangement status, the ML model based on CT images and clinical features performed better than the model based on only clinical information or CT images, with an AUC of 0.965 (95% CI 0.826-0.882) in the primary cohort and an AUC of 0.914 (95% CI 0.804-0.893) in the validation cohort. Conclusion: Our findings revealed that ALK rearrangement status could be accurately predicted using an ML-based classification model based on CT images and clinical data.

11.
Front Plant Sci ; 13: 1015114, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36340397

RESUMO

Reproductive growth and vegetative growth are a pair of main contradictions in the process of plant growth. Flowering, as part of reproductive growth, is a key switch in the life cycle of higher plants, which affects the yield and economic benefits of plants to a certain extent. The Euphorbiaceae species, including castor bean (Ricinus communis), physic nut (Jatropha curcas), tung tree (Vernicia fordii), cassava (Manihot esculenta), and rubber tree (Hevea brasiliensis), have important economic values because they are raw materials for the production of biodiesel, rubber, etc. The flowering mechanisms are still excluded in the Euphorbiaceae species. The flowering-related genes of Arabidopsis thaliana (Arabidopsis) were used as a reference to determine the orthologs of these genes in Euphorbiaceae genomes. The result showed that 146, 144, 114, 114, and 149 of 207 A. thaliana genes were respectively matched to R. communis, V. fordii, J. curcas, H. brasiliensis, and M. esculenta. These identified genes were clustered into seven pathways including gibberellins, floral meristem identity (FMI), vernalization, photoperiod, floral pathway integrators (FPIs), and autonomous pathways. Then, some key numbers of flowering-related genes are widely conserved in the Euphorbiaceae genomes including but not limited to FPI genes LFY, SOC1, FT, and FMI genes AG, CAL, and FUL. However, some genes, including FRI, FLC, and GO, were missing in several or all five Euphorbiaceae species. In this study, we proposed the putative mechanisms of flowering-related genes to control flowering and provided new candidate flowering genes for using marker-assisted breeding to improve variety quality.

12.
Front Mol Neurosci ; 15: 1020803, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36340687

RESUMO

Adeno-associated virus (AAV)-mediated gene transfer is an efficient method of gene over-expression in the vestibular end organs. However, AAV has limited usefulness for delivering a large gene, or multiple genes, due to its small packaging capacity (< 5 kb). Co-transduction of dual-AAV vectors can be used to increase the packaging capacity for gene delivery to various organs and tissues. However, its usefulness has not been well validated in the vestibular sensory epithelium. In the present study, we characterized the co-transduction of dual-AAV vectors in mouse utricles following inoculation of two AAV-serotype inner ear (AAV-ie) vectors via canalostomy. Firstly, co-transduction efficiencies were compared between dual-AAV-ie vectors using two different promoters: cytomegalovirus (CMV) and CMV early enhancer/chicken ß-actin (CAG). In the group of dual AAV-ie-CAG vectors, the co-transduction rates for striolar hair cells (HCs), extrastriolar HCs, striolar supporting cells (SCs), and extrastriolar SCs were 23.14 ± 2.25%, 27.05 ± 2.10%, 57.65 ± 7.21%, and 60.33 ± 5.69%, respectively. The co-transduction rates in the group of dual AAV-ie-CMV vectors were comparable to those in the dual AAV-ie-CAG group. Next, we examined the co-transduction of dual-AAV-ie-CAG vectors in the utricles of neonatal mice and damaged adult mice. In the neonatal mice, co-transduction rates were 52.88 ± 3.11% and 44.93 ± 2.06% in the striolar and extrastriolar HCs, respectively, which were significantly higher than those in adult mice. In the Pou4f3+/DTR mice, following diphtheria toxin administration, which eliminated most HCs and spared the SCs, the co-transduction rate of SCs was not significantly different to that of normal utricles. Transgene expression persisted for up to 3 months in the adult mice. Furthermore, sequential administration of two AAV-ie-CAG vectors at an interval of 1 week resulted in a higher co-transduction rate in HCs than concurrent delivery. The auditory brainstem responses and swim tests did not reveal any disruption of auditory or vestibular function after co-transduction with dual-AAV-ie vectors. In conclusion, dual-AAV-ie vectors allow efficient co-transduction in the vestibular sensory epithelium and facilitate the delivery of large or multiple genes for vestibular gene therapy.

13.
Inflamm Res ; 2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36352033

RESUMO

BACKGROUND: Chronic kidney disease (CKD) is inherently a complex immune-inflammatory condition, and heightened inflammation and immune dysfunction are closely related to an increased risk of death. However, evidence regarding the relationship between immune-inflammatory levels and all-cause, cardiovascular, and cancer mortality among patients with CKD is scarce. METHODS: Patients with non-dialysis dependent CKD undergoing coronary angiography (CAG) were included from five Chinese tertiary hospitals. Systemic immune inflammation index (SII) was calculated by multiplying peripheral platelet count with neutrophil-to-lymphocyte ratio, and patients were categorized into four groups by SII quartiles. Cox regression models and competing risk Fine and Gray models were used to examining the relationships between SII levels and all-cause, cardiovascular, and cancer mortality. RESULTS: A total of the 19,327 patients (68.8 ± 10.03 years, female 32.0%) were included in this study. During a median follow-up of 4.5 years, 5,174 deaths occurred, including 2,861 cardiovascular deaths and 375 cancer deaths. Controlling for confounders, all-cause mortality (Q2, Q3, Q4: hazard ratio(HR) [95 CI%] = 1.15 [1.06-1.26], 1.30 [1.19-1.42], 1.48 [1.35-1.62], respectively; p for trend < 0.001) and cardiovascular mortality (Q2, Q3, Q4: HR [95 CI%] = 1.16 [1.03-1.31], 1.40 [1.24-1.58], 1.64 [1.44-1.85], respectively; p for trend < 0.001) increased with higher SII levels, and SII levels was related to cancer mortality comparing last quartile to first quartile of SII (Q2, Q3, Q4: HR [95 CI%] = 1.12 [0.83-1.52], 1.22 [0.90-1.67], 1.50 [1.09-2.08], respectively; p for trend < 0.001). CONCLUSION: Elevated immune inflammation level on admission was an independent risk factor for all-cause, cardiovascular, and cancer mortality among CKD patients. Further research is needed to validate the predictive value of SII for mortality risk among CKD patients.

14.
Sci Adv ; 8(44): eadd5503, 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36332019

RESUMO

We report a general route to decipher the apportionment of metal ions in bulk metal-organic frameworks (MOFs) by solid-state nuclear magnetic resonance spectroscopy. We demonstrate this route in Mg1-xNix-MOF-74, where we uncover all eight possible atomic-scale Mg/Ni arrangements through identification and quantification of the distinct chemical environments of 13C-labeled carboxylates as a function of the Ni content. Here, we use magnetic susceptibility, bond pathway, and density functional theory calculations to identify local metal bonding configurations. The results refute the notion of random apportionment from solution synthesis; rather, we reveal that only two of eight Mg/Ni arrangements are preferred in the Ni-incorporated MOFs. These preferred structural arrangements manifest themselves in macroscopic adsorption phenomena as illustrated by CO/CO2 breakthrough curves. We envision that this nondestructive methodology can be further applied to analyze bulk assembly of other mixed-metal MOFs, greatly extending the knowledge on structure-property relationships of MOFs and their derived materials.

15.
Acta Biomater ; 2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36371005

RESUMO

The low permeability of antifungal agents to fungal biofilms, which allows the continued survival of the fungus inside, is a key issue that makes fungal infections difficult to cure. Inspired by the unique dynamic molecule motion properties of the polyrotaxane (PR) nanomedicine, herein, a dynamic delivery system Clo@mPRP/NONOate was fabricated by co-loading nitric oxide (NO) and the antifungal drug clotrimazole (Clo) onto the α-cyclodextrin (α-CD) PR modified mesoporous polydopamine (mPDA) nanoparticles, in which pentaethylenehexamine (PEHA) was grafted to α-CDs. The cationic α-CDs endowed this dynamic NO/Clo codelivery system with the ability to effectively attach to fungal biofilms through electrostatic interaction, while the introduction of PRs with flexible molecule motion (slide and rotation of CDs) enhanced the permeability of nanoparticles to biofilms. Meanwhile, NO could effectively inhibit the formation of fungal hyphae, showing an dissipating effect on mature biofilms, and could be further combined with Clo to completely eradicate fungi inside the biofilms. In addition, the dynamic system Clo@mPRP/NONOate could efficiently and synergistically eliminate planktonic Candida albicans (C. albicans) in a safe and no toxic side effect manner, and effectively cured C. albicans-induced vaginal infection in mice. Therefore, this dynamic NO/Clo codelivery system provided an effective solution to the clinical treatment of C. albicans-induced vaginal infection, and the application prospect could even be extended to other microbial infectious diseases. STATEMENT OF SIGNIFICANCE: A dynamic codelivery system based on cationized cyclodextrin polyrotaxane combining nitric oxide and antifungal drugs clotrimazole was prepared to deal with the issue of clinical fungal biofilm infection. This dynamic codelivery system could be attached to the Candida albicans biofilms and penetrate into biofilm via flexible molecular mobility to effectively eradicate the fungi. This dynamic codelivery system could synergistically and efficiently eliminate planktonic-state Candida albicans, but did not show significant cytotoxicity to normal somatic cells.

16.
Recenti Prog Med ; 113(12): 722-732, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36420848

RESUMO

OBJECTIVE: The results of PD-1/PD-L1 inhibitor combined with chemotherapy for TNBC are controversial. Therefore, a meta-analysis was conducted to evaluate the efficacy and safety after PD-1/PD-L1 inhibitors plus chemotherapy in TNBC patients. METHODS: We systematically searched seven databases and several mainly oncology conferences for prospective clinical trials of chemotherapy combined with immunotherapy to treat TNBC, and we included pathologic complete response (PCR), progression-free survival (PFS), overall survival (OS) and adverse effects as outcome indicators of the study. RESULTS: We analyzed data from six studies involving 4,187 patients. The efficacy analysis indicated that PD1/PD-L1 inhibitor combined with chemotherapy significantly increased PCR rates in neoadjuvant patients (OR: 1.60; 95% CI: 1.18-2.17; p=0.003). There was no correlation between increases in PCR rates and the expression of PD-L1, but the PCR rate was higher in PD-L1+ patients. Subgroup analysis suggested that the lymph node-positive (OR: 2.52; 95% CI: 1.69-3.77; p<0.001) and ECOG PS 0 (OR: 1.9; 95% CI: 1.42-2.53; p<0.001) subgroups benefited from the combination of PD-1/PD-L1 inhibitor plus chemotherapy. In TNBC receiving advanced rescue treatment, PFS was higher in the group receiving PD-1/PD-L1 inhibitor plus chemotherapy than in the group receiving chemotherapy alone (HR: 0.78; 95% CI: 0.70-0.86; p<0.001). Compared with chemotherapy alone, PD-1/PD-L1 inhibitors combined with chemotherapy did not increase the OS of patients (HR=0.88, 95% CI: 0.76~1.03, p=0.12). In addition, the toxicity analysis showed that more grade 3-4 adverse effects and severe adverse effects occurred in the PD-1/PD-L1 inhibitor combined with chemotherapy group. CONCLUSIONS: PD-1/PD-L1 inhibitors combined with chemotherapy can improve the PCR and PFS rate of TNBC patients, but did not improve the OS, and had a higher risk of AEs.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Neoplasias Pulmonares , Neoplasias de Mama Triplo Negativas , Humanos , Antígeno B7-H1 , Inibidores de Checkpoint Imunológico/efeitos adversos , Receptor de Morte Celular Programada 1 , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Estudos Prospectivos
17.
Sci Transl Med ; 14(670): eabn7336, 2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36350986

RESUMO

Chimeric antigen receptor (CAR) T cells have not induced meaningful clinical responses in solid tumors. Loss of T cell stemness, poor expansion capacity, and exhaustion during prolonged tumor antigen exposure are major causes of CAR T cell therapeutic resistance. Single-cell RNA-sequencing analysis of CAR T cells from a first-in-human trial in metastatic prostate cancer identified two independently validated cell states associated with antitumor potency or lack of efficacy. Low expression of PRDM1, encoding the BLIMP1 transcription factor, defined highly potent TCF7 [encoding T cell factor 1 (TCF1)]-expressing CD8+ CAR T cells, whereas enrichment of HAVCR2 [encoding T cell immunoglobulin and mucin-domain containing-3 (TIM-3)]-expressing CD8+ T cells with elevated PRDM1 was associated with poor outcomes. PRDM1 knockout promoted TCF7-dependent CAR T cell stemness and proliferation, resulting in marginally enhanced leukemia control in mice. However, in the setting of PRDM1 deficiency, a negative epigenetic feedback program of nuclear factor of activated T cells (NFAT)-driven T cell dysfunction was identified. This program was characterized by compensatory up-regulation of NR4A3 and other genes encoding exhaustion-related transcription factors that hampered T cell effector function in solid tumors. Dual knockout of PRDM1 and NR4A3 skewed CAR T cell phenotypes away from TIM-3+CD8+ and toward TCF1+CD8+ to counter exhaustion of tumor-infiltrating CAR T cells and improve antitumor responses, effects that were not achieved with PRDM1 and NR4A3 single knockout alone. These data underscore dual targeting of PRDM1 and NR4A3 as a promising approach to advance adoptive cell immuno-oncotherapy.


Assuntos
Neoplasias , Receptores de Esteroides , Masculino , Humanos , Camundongos , Animais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Linfócitos T CD8-Positivos , Imunoterapia Adotiva/métodos , Receptor Celular 2 do Vírus da Hepatite A/genética , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Neoplasias/patologia , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Receptores de Esteroides/metabolismo , Receptores dos Hormônios Tireóideos/metabolismo , Proteínas do Tecido Nervoso/metabolismo
18.
Toxicology ; 482: 153370, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36334778

RESUMO

Cyanobacterial blooms, usually dominated by Microcystis aeruginosa, pose a serious threat to global freshwater ecosystems owing to their production and release of various harmful secondary metabolites. Detection of the chemicals in M. aeruginosa exudates using metabolomics technology revealed that phytosphingosine (PHS) was one of the most abundant compounds. However, its specific toxicological mechanism remained unclear. CNE-2 cells were selected to illustrate the cytotoxic mechanism of PHS, and it was determined to cause excessive production of reactive oxygen species and subsequently damage the mitochondrial structure. Mitochondrial membrane rupture led to matrix mitochondrial membrane potential disintegration, which induced Ca2+ overload and interrupted ATP synthesis. Furthermore, rupture of the mitochondrial membrane induced the opening of the permeability transition pore, which caused the release of proapoptotic factors into the cytoplasm and the expression of apoptosis-related proteins Bax, Bcl-2, cytochrome-c and cleaved caspase-3 in CNE-2 cells. These events, in turn, activated the mitochondrially mediated intrinsic apoptotic pathway. A mitochondrial repair mechanism, namely, PINK1/Parkin-mediated mitophagy, was then blocked, which further promoted apoptosis. Our findings suggest that more attention should be paid to the ecotoxicity of PHS, which is already listed as a contaminant of emerging concern.


Assuntos
Ecossistema , Esfingosina , Apoptose , Citocromos c
19.
Sci Total Environ ; 859(Pt 1): 160135, 2022 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-36375547

RESUMO

Rapid global industrialization has resulted in widespread cadmium contamination in agricultural soils and products. A considerable proportion of rice consumers are exposed to Cd levels above the provisional safe intake limit, raising widespread environmental concerns on risk management. Therefore, a generalized approach is urgently needed to enable correct evaluation and early warning of cadmium contaminants in rice products. Combining big data and computer science together, this study developed a system named "SMART Cd Early Warning", which integrated 4 modules including genotype-to-phenotype (G2P) modelling, high-throughput sequencing, G2P prediction and rice Cd contamination risk assessment, for rice cadmium accumulation early warning. This system can rapidly assess the risk of rice cadmium accumulation by genotyping leaves at seeding stage. The parameters including statistical methods, population size, training population-testing population ratio, SNP density were assessed to ensure G2P model exhibited superior performance in terms of prediction precision (up to 0.76 ± 0.003) and computing efficiency (within 2 h). In field trials of cadmium-contaminated farmlands in Wenling and Fuyang city, Zhejiang Province, "SMART Cd Early Warning" exhibited superior capability for identification risk rice varieties, suggesting a potential of "SMART Cd Early-Warning system" in OsGCd risk assessment and early warning in the age of smart.

20.
Sci Total Environ ; 859(Pt 1): 160171, 2022 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-36379339

RESUMO

It is not known what the buffering capacity of soils and arsenic (As) enrichment by crops is for calcareous agricultural soils after the end of long-term effluent irrigation. In this study, changes in soil physicochemical properties and factors of influencing As uptake by wheat were investigated in agricultural soils where sewage irrigation had been ceased for nearly 20 years. The results showed that the content of CaCO3 and pH in soil increased compared to the period before the cessation of sewage irrigation, but remained below the soil background value. Furthermore, CaCO3 is by far the main buffering substance in agricultural soils and indirectly contributes to the increase in pH. The As concentration in the soil was 36.4 ± 34.8 mg/kg, which was 0.56-10.28 times and 0.28-5.18 times higher than the soil background and risk screening values, respectively, but showed a decreasing trend. pH and Fe dissolution were the main reasons for the lower As concentration in the soil. Total As in soil was a better predictor of As in wheat, and soil electrical conductivity (EC) and soil organic matter (SOM) promoted As uptake by wheat. The competitive uptake of As by dissolved Si was an important reason for the mismatch between As concentrations in soil and wheat. This study highlighted the key issues of As transport transformation in soil-wheat systems after cessation of effluent irrigation, using agricultural soils, and provided a reference for soil risk management in agricultural soils in mining areas.

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