ABSTRACT
Treatment options for epidermal growth factor receptor (EGFR)-mutant advanced non-small cell lung cancer (NSCLC) following tyrosine kinase inhibitor (TKI) failure are limited, and platinum-based chemotherapy remains the main treatment. The development of effective immunotherapy for this disease has been challenging. In the present study, 37 patients with EGFR-mutant advanced NSCLC who were treated with programmed cell death-1 (PD-1) inhibitor-based combinations after TKI failure were reviewed. The total cohort had a median progression-free survival (mPFS) of 5.2 months (95% CI, 4.077-6.323 months) and a median overall survival (mOS) of 18.3 months (95% CI, 12.932-23.668 months). Patients with Eastern Cooperative Oncology Group performance-status (ECOG-PS) scores of 0 or 1 had longer mPFS than those with ECOG-PS scores of 2 (5.4 vs. 2.4 months; P=0.006). In addition, a PFS benefit was observed in patients with EGFR T790M-negative compared with EGFR T790M-positive tumors (mPFS 6.2 vs. 4.4 months; P=0.041). Patients treated with immunotherapy-based combinations as a front-line therapy had a longer mPFS than those in which the combinations were used as a late-line therapy (6.2 vs. 2.4 months; P<0.001). PD-1 inhibitor combined with chemotherapy and bevacizumab did not show a clear advantage over PD-1 inhibitor combined with chemotherapy alone (mPFS, 6.2 vs. 4.4 months; P=0.681), although it resulted in an improved overall response rate (ORR) and disease control rate. Notably, the 7 patients with a programmed cell death ligand-1 (PD-L1) tumor proportion score of ≥50% had an ORR of 100% and an mPFS of 8.3 months. Therefore, it is suggested that PD-1 inhibitor-based combinations should be a priority treatment option in selective populations, such as those with low ECOG-PS scores, T790M-negative status or high PD-L1 expression in EGFR-mutant NSCLC after TKI failure. The use of immunotherapy and chemotherapy in combination with antiangiogenic agents appears to be a promising combination therapy for such patients.
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BACKGROUND: The objective of this study is to investigate the incidence, potential risk factors, and clinical outcomes of incomplete device endothelialization (IDE) in atrial fibrillation (AF) patients undergoing Watchman left atrial appendage closure (LAAC). METHODS: In this study, 68 AF patients who underwent successful implantation of the Watchman device without peri-device leak (PDL) during follow-up were included. The endothelialization status was assessed using Transesophageal echocardiography (TEE) and LAA computed tomography angiography (CTA) at 6 weeks and 6 months post-implantation. Adverse cerebro-cardiac events were documented at one-year follow-up. Baseline characteristics, including age, device sizes, and clinical indicators, were analyzed as potential predictors for IDE. RESULTS: IDE was observed in 70.6% and 67.6% of patients at 6 weeks and 6 months after implantation, respectively. Higher levels of high-density lipoprotein cholesterol (HDL-C) [odds ratio (OR): 15.109, 95% confidence interval (CI): 1.637-139.478, p = 0.017 and OR: 11.015, 95% CI: 1.365-88.896, p = 0.024] and lower aspartate aminotransferase (AST) (OR 0.924, 95% CI: 0.865-0.986, p = 0.017 and OR: 0.930, 95% CI: 0.874-0.990, p = 0.023) at baseline were found to be significantly associated with IDE at 6 weeks and 6 months, respectively, although no significant difference in adverse cerebro-cardiac events was noted between incomplete and complete DE groups during 1-year follow-up CONCLUSIONS: IDE is found to be a prevalent occurrence in humans following LAAC. Elevated HDL-C and reduced AST levels are shown to be linked to an increased risk of IDE after LAAC.
Subject(s)
Atrial Appendage , Atrial Fibrillation , Cardiac Catheterization , Echocardiography, Transesophageal , Humans , Atrial Fibrillation/diagnosis , Atrial Fibrillation/epidemiology , Atrial Fibrillation/physiopathology , Atrial Fibrillation/surgery , Atrial Appendage/diagnostic imaging , Atrial Appendage/physiopathology , Male , Female , Aged , Risk Factors , Incidence , Middle Aged , Treatment Outcome , Time Factors , Cardiac Catheterization/adverse effects , Cardiac Catheterization/instrumentation , Computed Tomography Angiography , Risk Assessment , Aged, 80 and over , Left Atrial Appendage ClosureABSTRACT
Due to the pathological production of liver disease in utility particularly complexity, the morbidity and mortality of liver disease including viral hepatitis, liver fibrosis/cirrhosis and hepatocellular carcinoma (HCC) are rapidly increasing worldwide. Considering its insidious onset, rapid progression and drug resistance, finding an effective therapy is particularly worthwhile. Phyllanthus urinaria L. (P. urinaria), an ethnic medicine, can be applied at the stages of viral hepatitis, liver fibrosis/cirrhosis and HCC, which demonstrates great potential in the treatment of liver disease. Currently, there are numerous reports on the application of P. urinaria in treating liver diseases, but a detailed analysis of its metabolites and a complete summary of its pharmacological mechanism are still scarce. In this review, the phytochemical metabolites and ethnopharmacological applications of P. urinaria are summarized. Briefly, P. urinaria mainly contains flavonoids, lignans, tannins, phenolic acids, terpenoids and other metabolites. The mechanisms of P. urinaria are mainly reflected in reducing surface antigen secretion and interfering with DNA polymerase synthesis for anti-viral hepatitis activity, reducing hepatic stellate cells activity, inflammation and oxidative stress for anti-liver fibrosis/cirrhosis activity, as well as preventing tumor proliferation, invasion and angiogenesis for anti-HCC activity via relevant signaling pathways. Accordingly, this review provides insights into the future application of natural products in the trilogy of liver diseases and will provide a scientific basis for further research and rational utilization of P. urinaria.
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Background: Centromere protein U (CENPU) is key for mitosis in the carcinogenesis of cancers. However, the roles of CENPU have not been inspected in nasopharyngeal carcinoma (NPC). Thus, we aimed to explore the functions and mechanisms of CENPU in NPC. Methods: Expression of CENPU was evaluated by real-time quantitative polymerase chain reaction, western blotting and immunohistochemistry. The biological functions of CENPU were evaluated in vitro and in vivo. Gene chip analysis, ingenuity pathway analysis, and coimmunoprecipitation experiments were used to explore the mechanisms of CENPU. Results: CENPU was highly expressed in NPC. High expression of CENPU was associated with advanced tumor, node and metastasis (TNM) stage and poor overall survival. Cox regression analysis demonstrated that CENPU expression was an independent prognostic factor in NPC. Knockdown of CENPU inhibited proliferation and migration in vitro and in vivo. Knockdown of CENPU upregulated dual specificity phosphatase 6 (DUSP6) expression. The expression of CNEPU was inversely correlated with the expression of DUSP6 in NPC tissues. Mechanistic studies confirmed that CENPU increased the activation of the ERK1/2 and p38 signaling pathways by suppressing the expression of DUSP6. Conclusions: CENPU acts as an oncogene in NPC by interacting with DUSP6, and may represent a promising prognostic biomarker for patients with NPC.
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Single-atom catalysts (SACs), combining the advantages of multiphase and homogeneous catalysis, have been increasingly investigated in various catalytic applications. Carbon-based SACs have attracted much attention due to their large specific surface area, high porosity, particular electronic structure, and excellent stability. As a cheap and readily available carbon material, biochar has begun to be used as an alternative to carbon nanotubes, graphene, and other such expensive carbon matrices to prepare SACs. However, a review of biochar-based SACs for environmental pollutant removal and energy conversion and storage is lacking. This review focuses on strategies for synthesizing biochar-based SACs, such as pre-treatment of organisms with metal salts, insertion of metal elements into biochar, or pyrolysis of metal-rich biomass, which are more simplistic ways of synthesizing SACs. Meanwhile, this paper attempts to 1) demonstrate their applications in environmental remediation based on advanced oxidation technology and energy conversion and storage based on electrocatalysis; 2) reveal the catalytic oxidation mechanism in different catalytic systems; 3) discuss the stability of biochar-based SACs; and 4) present the future developments and challenges regarding biochar-based SACs.
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Background: How to ingeniously design multi-effect photosensitizers (PSs), including multimodal imaging and multi-channel therapy, is of great significance for highly spatiotemporal controllable precise phototherapy of malignant tumors. Methods: Herein, a novel multifunctional zinc(II) phthalocyanine-based planar micromolecule amphiphile (ZnPc 1) was successfully designed and synthesized, in which N atom with photoinduced electron transfer effect was introduced to enhance the near-infrared absorbance and nonradiative heat generation. After simple self-assembling into nanoparticles (NPs), ZnPc 1 NPs would exhibit enhanced multimodal imaging properties including fluorescence (FL) imaging (FLI) /photoacoustic (PA) imaging (PAI) /infrared (IR) thermal imaging, which was further used to guide the combined photodynamic therapy (PDT) and photothermal therapy (PTT). Results: It was that under the self-guidance of the multimodal imaging, ZnPc 1 NPs could precisely pinpoint the tumor from the vertical and horizontal boundaries achieving highly efficient and accurate treatment of cancer. Conclusion: Accordingly, the integration of FL/PA/IR multimodal imaging and PDT/PTT synergistic therapy pathway into one ZnPc 1 could provide a blueprint for the next generation of phototherapy, which offered a new paradigm for the integration of diagnosis and treatment in tumor and a promising prospect for precise cancer therapy.
Subject(s)
Indoles , Isoindoles , Multimodal Imaging , Nanoparticles , Photochemotherapy , Photosensitizing Agents , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacology , Multimodal Imaging/methods , Animals , Humans , Indoles/chemistry , Indoles/pharmacology , Photochemotherapy/methods , Nanoparticles/chemistry , Mice , Zinc Compounds/chemistry , Organometallic Compounds/chemistry , Organometallic Compounds/pharmacology , Cell Line, Tumor , Photoacoustic Techniques/methods , Photothermal Therapy/methods , Neoplasms/diagnostic imaging , Neoplasms/therapy , Neoplasms/drug therapy , Mice, Inbred BALB C , Phototherapy/methods , FemaleABSTRACT
Ehrlichia chaffeensis infects and proliferates inside monocytes or macrophages and causes human monocytic ehrlichiosis (HME), an emerging life-threatening tick-borne zoonosis. After internalization, E. chaffeensis resides in specialized membrane-bound inclusions, E. chaffeensis-containing vesicles (ECVs), to evade from host cell innate immune responses and obtain nutrients. However, mechanisms exploited by host cells to inhibit E. chaffeensis growth in ECVs are still largely unknown. Here we demonstrate that host cells recognize E. chaffeensis Ech_1067, a penicillin-binding protein, and then upregulate the expression of PIT1, which is a phosphate transporter and transports phosphate from ECVs to the cytosol to inhibit bacterial growth. We found that host cells upregulate the PIT1 expression upon E. chaffeensis infection using transcriptome sequencing, qRT-PCR and Western blotting, and PIT1 is localized on the ECV membrane in infected THP-1 cells using confocal microscopy. Silence of PIT1 using shRNA enhances E. chaffeensis intracellular growth. Finally, we found that E. chaffeensis Ech_1067 induces the upregulation of PIT1 expression through the MyD88-NF-κB pathway using recombinant protein for stimulation and siRNA for silence. Our findings deepen the understanding of the innate immune responses of host cells to inhibit bacterial intracellular growth and facilitate the development of new therapeutics for HME.
Subject(s)
Ehrlichia chaffeensis , Humans , Ehrlichia chaffeensis/metabolism , Ehrlichia chaffeensis/genetics , THP-1 Cells , Up-Regulation , Ehrlichiosis/microbiology , Ehrlichiosis/metabolism , Host-Pathogen Interactions , Macrophages/metabolism , Macrophages/microbiology , Macrophages/immunology , Phosphates/metabolism , NF-kappa B/metabolism , Monocytes/metabolism , Monocytes/microbiologyABSTRACT
Atom-dispersed low-coordinated transition metal-Nx catalysts exhibit excellent efficiency in activating peroxydisulfate (PDS) for environmental remediation. However, their catalytic performance is limited due to metal-N coordination number and single-atom loading amount. In this study, low-coordinated nitrogen-doped graphene oxide (GO) confined single-atom Mn catalyst (Mn-SA/NGO) was synthesized by molten salt-assisted pyrolysis and coupled to PDS for degradation of tetracycline (TC) in water. Aberration-corrected high-angle annular dark-field scanning transmission electron microscopy (AC-HAADF-STEM) and X-ray absorption fine structure spectroscopy (XAFS) analysis showed the successful doping of single-atom Mn (weight percentage 1.6%) onto GO and the formation of low-coordinated Mn-N2 sites. The optimized parameters obtained by Box-Behnken Design achieved 100% TC removal in both prediction and experimental results. The Mn-SA/NGO + PDS system had strong anti-interference ability for TC removal in the presence of anions. Besides, Mn-SA/NGO possessed good reusability and stability. O2â¢-, â¢OH, and 1O2 were the main active species for TC degradation, and the TC mineralization reached 85.1%. Density functional theory (DFT) calculations confirmed that the introduction of single atoms Mn could effectively enhance adsorption and activation of PDS. The findings provide a reference for the synthesis of high-performance single-atom catalysts for effective removal of antibiotics.
Subject(s)
Graphite , Sulfates , Tetracycline , Water Pollutants, Chemical , Graphite/chemistry , Tetracycline/chemistry , Sulfates/chemistry , Water Pollutants, Chemical/chemistry , Manganese/chemistry , Nitrogen/chemistry , Anti-Bacterial Agents/chemistry , CatalysisABSTRACT
OBJECTIVE: This retrospective analysis aimed to evaluate the efficacy and adverse reactions of metronomic oral vinorelbine and its combination therapy as second- and later-line regimens for advanced non-small-cell lung cancer (NSCLC). METHODS: NSCLC patients undergoing metronomic oral vinorelbine as second- and later-line regimens in Fujian Cancer Hospital from October 2018 to October 2022 were enrolled, and patients' demographic and clinical characteristics were collected. The efficacy and safety of metronomic oral vinorelbine monotherapy and its combination therapy regimens were compared. RESULTS: Of 57 study subjects, 63.2% received third- and later-line therapy, with median progression-free survival (mPFS) of 4 months, overall response rate (ORR) of 10.5%, and disease control rate (DCR) of 80.7%. The incidence of therapy-related adverse events was 42.1%, and there was only one case presenting grades 3 and 4 adverse events (1.8%). Among driver gene-negative participants, vinorelbine combination therapy regimens achieved longer mPFS (4.6 vs. 1.2 months, hazards ratio = 0.11, P < 0.0001) and comparable toxicity in relative to metronomic oral vinorelbine, and metronomic oral vinorelbine combined with immune checkpoint inhibitors showed the highest response, with mPFS of 5.6 months (95% CI 4.8 to 6.4 months), ORR of 25%, and DCR of 81.3%. Among participants with gradual resistance to osimertinib, continuing osimertinib in combination with metronomic oral vinorelbine achieved mPFS of 6.3 months (95% CI 0.1 to 12.5 months) and DCR of 86.7%. CONCLUSION: Metronomic oral vinorelbine and its combination therapy regimens are favorable options as second- and later-line therapy for advanced NSCLC patients, with acceptable efficacy and tolerable toxicity. Vinorelbine combination therapy regimens show higher efficacy and comparable toxicity in relative to metronomic oral vinorelbine, and metronomic oral vinorelbine may have a synergistic effect with immunotherapy and EGFR-TKI targeted therapy.
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A new lignan phyllanins A (1) and a lignan phyllanins B (2) for which the absolute configuration was determined for the first time, along with four known lignans (3-6) were isolated from the branch and leaf extracts of Phyllanthodendron dunnianum. Their planar structures were mainly determined by a combination of 1D and 2D NMR, HRESIMS spectral analyses, and the absolute configurations of the compounds 1 and 2 were established by DFT GIAO 13C NMR and electronic circular dichroism (ECD) calculations. In addition, all these six lignans were firstly tested for the antibacterial activities against MRSA, Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa and Escherichia coli. Among these compounds, 2 and 5 showed potential antibacterial activities against MRSA and S. aureus with MIC values of 4 and 8 µg/mL, respectively.
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With the escalating demand for Astragalus polysaccharides products developed from Radix Astragali (RA), the necessity for quality control of polysaccharides in RA has become increasingly urgent. In this study, a specific method for the simultaneous determination of seven monosaccharides in polysaccharides extracted from Radix Astragali (RA) has been developed and validated using ultra-performance liquid chromatography equipped with an ultraviolet detector (UHPLC-UV) for the first time. The 1-phenyl-3-methyl-5-pyrazolone (PMP) derivatizations were separated on a C18 column (Waters ACQUITYTM, Milfor, MA, USA, 1.8 µm, 2.1 × 100 mm) using gradient elution with a binary system of 5 mm ammonium formate (0.1% formic acid)-acetonitrile for 24 min. Additionally, seven monosaccharides showed good linear relationships (R2, 0.9971-0.9995), adequate precision (RSD < 4.21%), and high recoveries (RSD < 4.70%). The established method was used to analyze 109 batches of RA. Results showed that the Astragalus polysaccharides (APSs) mainly consist of mannose (Man), rhamnose (Rha), glucose (Glu), galactose (Gal), arabinose (Ara), xylose (Xyl); and fucose (Fuc); however, their composition was different among RA samples from different growth patterns, species, growth years, and origins, and the growth mode of RA and the age of wild-simulated RA can be accurately distinguished by principal component analysis (PCA). In addition, the immunological activity of APSs were also evaluated jointly by measurement of the NO release with RAW264.7, with the results showing that APSs have a promoting effect on the release of NO and exhibit a significant correlation with Man, Glu, Xyl, and Fuc contents. Accordingly, the new established monosaccharides analytical method and APS-immune activity determination in this study can provide a reference for quality evaluation and the establishment of quality standards for RA.
Subject(s)
Astragalus propinquus , Drugs, Chinese Herbal , Monosaccharides , Polysaccharides , Chromatography, High Pressure Liquid/methods , Monosaccharides/analysis , Polysaccharides/chemistry , Polysaccharides/analysis , Astragalus propinquus/chemistry , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/analysis , Mice , Animals , RAW 264.7 Cells , Astragalus Plant/chemistry , Immunologic Factors/analysis , Immunologic Factors/chemistryABSTRACT
The main protease of SARS-CoV-2 (SARS-CoV-2 Mpro) plays a critical role in the replication and life cycle of the virus. Currently, how to screen SARS-CoV-2 Mpro inhibitors from complex traditional Chinese medicine (TCM) is the bottleneck for exploring the pharmacodynamic substances of TCM against SARS-CoV-2. In this study, a simple, cost-effective, rapid, and selective fluorescent sensor (TPE-S-TLG sensor) was designed with an AIE (aggregation-induced emission) probe (TPE-Ph-In) and the SARS-CoV-2 Mpro substrate (S-TLG). The TPE-S-TLG sensor was characterized using UV-Vis absorption spectroscopy, fluorescence spectroscopy, dynamic light scattering (DLS), transmission electron microscopy (TEM), zeta potential, and Fourier transform infrared (FTIR) spectroscopy techniques. The limit of detection of this method to detect SARS-CoV-2 Mpro was measured to be 5 ng mL-1. Furthermore, the TPE-S-TLG sensor was also successfully applied to screen Mpro inhibitors from Xuebijing injection using the separation and collection of the HPLC-fully automatic partial fraction collector (HPLC-FC). Six active compounds, including protocatechualdehyde, chlorogenic acid, hydroxysafflower yellow A, caffeic acid, isoquercetin, and pentagalloylglucose, were identified using UHPLC-Q-TOF/MS that could achieve 90% of the Mpro inhibition rate for the Xuebijing injection. Accordingly, the strategy can be broadly applied in the detection of disease-related proteases as well as screening active substances from TCM.
Subject(s)
Coronavirus 3C Proteases , Fluorescent Dyes , Medicine, Chinese Traditional , SARS-CoV-2 , Spectrometry, Fluorescence , SARS-CoV-2/isolation & purification , SARS-CoV-2/drug effects , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/metabolism , Humans , Fluorescent Dyes/chemistry , Spectrometry, Fluorescence/methods , Antiviral Agents/pharmacology , Antiviral Agents/analysis , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/analysis , COVID-19/virology , COVID-19/diagnosis , Limit of Detection , COVID-19 Drug TreatmentABSTRACT
Chemical constituents from the ethanol extract of Picrorhiza scrophulariiflora were isolated and purified by column chromatography. Their structures were identified by HR-MS, 1D and 2D-NMR, and their cytotoxicity was assessed by CCK-8 assay. Four compounds were isolated and identified as follows: 2ß-D-glucosyloxy-3ß,16α,20ß-trihydroxy-9-methyl-19-norlanosterol-5,25-diene-22-one(1), 2ß-D-glucosyloxy-3ß,16α,20ß-trihydroxy-9-methyl-19-norlanosta-5,24-diene-22-one(2), 25-acetoxy-2ß-glucosyloxy-3ß,16α,20ß-trihydroxy-9-methyl-19-norlanosta-5-ene-22-one(3) and 25-acetoxy-2ß-glucosyloxy-3ß,16α,20ß-trihydroxy-9-methyl-19-norlanosta-5,23-(E)-diene-22-one(4). Compound 1 represents a new cucurbitane glycoside. The half inhibitory concentrations of the 4 compounds exceeded 100 µmol·L~(-1) against four tumor cell lines, indicating no significant cytotoxicity.
Subject(s)
Glycosides , Picrorhiza , Glycosides/chemistry , Glycosides/isolation & purification , Humans , Cell Line, Tumor , Picrorhiza/chemistry , Molecular Structure , Magnetic Resonance Spectroscopy , Drugs, Chinese Herbal/chemistry , TriterpenesABSTRACT
Glutathione metabolism (GM) is a crucial part of various metabolic and pathophysiological processes. However, its role in lung adenocarcinoma (LUAD) has not been comprehensively studied. This study aimed to explore the potential relationship between GM genes, the prognosis, and the immune microenvironment of patients with LUAD. We constructed a risk signature model containing seven GM genes using Lasso combined Cox regression and validated it using six GEO datasets. Our analysis showed that it is an independent prognostic factor. Functional enrichment analysis revealed that the GM genes were significantly enriched in cell proliferation, cell cycle regulation, and metabolic pathways. Clinical and gene expression data of patients with LUAD were obtained from the TCGA database and patients were divided into high- and low-risk groups. The high-risk patient group had a poor prognosis, reduced immune cell infiltration, poor response to immunotherapy, high sensitivity to chemotherapy, and low sensitivity to targeted therapy. Subsequently, single-cell transcriptome analysis using the GSE143423 and GSE127465 datasets revealed that the core SMS gene was highly enriched in M2 Macrophages. Finally, nine GEO datasets and multiple fluorescence staining revealed a correlation between the SMS expression and M2 macrophage polarization. Our prognostic model in which the core SMS gene is closely related to M2 macrophage polarization is expected to become a novel target and strategy for tumor therapy.
Subject(s)
Adenocarcinoma of Lung , Gene Expression Regulation, Neoplastic , Glutathione , Lung Neoplasms , Macrophages , Tumor Microenvironment , Humans , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/immunology , Adenocarcinoma of Lung/mortality , Lung Neoplasms/genetics , Lung Neoplasms/immunology , Lung Neoplasms/mortality , Prognosis , Glutathione/metabolism , Macrophages/immunology , Macrophages/metabolism , Tumor Microenvironment/immunology , Tumor Microenvironment/genetics , Databases, Genetic , Macrophage Activation/genetics , Gene Expression Profiling , Biomarkers, Tumor/genetics , FemaleABSTRACT
Using street view data, in replace of remotely sensed (RS) data, to study the health impact of greenspace has become popular. However, direct comparisons of these two methods of measuring greenspace are still limited, and their findings are inconsistent. On the other hand, almost all studies of greenspace focus on urban areas. The effectiveness of greenspace in rural areas remains to be investigated. In this study, we compared measures of greenspace based on the Google Street View data with those based on RS data by calculating the correlation between the two and evaluating their associations with birth outcomes. Besides the direct measures of greenness, we also compared the measures of environmental diversity, calculated with the two types of data. Our study area consists of the States of New Hampshire and Vermont, USA, which are largely rural. Our results show that the correlations between the two types of greenness measures were weak to moderate, and the greenness at an eye-level view largely reflects the immediate surroundings. Neither the street view data- nor the RS data-based measures identify the influence of greenspace on birth outcomes in our rural study area. Interestingly, the environmental diversity was largely negatively associated with birth outcomes, particularly gestational age. Our study revealed that in rural areas, the effectiveness of greenspace and environmental diversity may be considerably different from that in urban areas.
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Campylobacter spp., such as Campylobacter jejuni and Campylobacter coli, are important zoonotic Gram-negative pathogens that cause acute intestinal diseases in humans. In this study, a retrospective analysis was conducted on previously collected Campylobacter isolates from antimicrobial resistance surveillance. A total of 29 optrA-positive C. coli strains were identified and subjected to second-generation sequencing. Multilocus sequence typing and single nucleotide polymorphism analyses demonstrated that the 29 optrA-positive isolates were genetically homogeneous. Notably, among the 29 isolated strains, the ΔoptrA variants exhibit a nonsense mutation at position 979 where the base C is substituted by T, leading to the formation of a premature termination codon. The alignment of sequences and genetic environmental characteristics suggested that ΔoptrA located on a chromosomally carried multidrug-resistant genomic island. There are other resistant genes on the multidrug resistance genomic island, such as aph(2'')-If, aph(3')-III, aadE, tet(O), tet(L), cat, erm(A), optrA and blaOXA-61. As a result, the 29 ΔoptrA-positive strains displayed susceptibility to both florfenicol and linezolid. The ΔoptrA gene is linked to the erm(A) gene, resulting in the formation of translocatable unit (TU) that are encompassed by two copies of IS1216 mobile elements. Multiple occurrences of similar TUs have been documented in numerous C. coli and provided evidence for the significance of TUs in facilitating the transfer of drug resistance genes in C. coli.
Subject(s)
Anti-Bacterial Agents , Campylobacter Infections , Campylobacter coli , Chickens , Drug Resistance, Multiple, Bacterial , Genomic Islands , Campylobacter coli/genetics , Campylobacter coli/drug effects , Genomic Islands/genetics , Chickens/microbiology , Animals , Drug Resistance, Multiple, Bacterial/genetics , Anti-Bacterial Agents/pharmacology , Campylobacter Infections/microbiology , Campylobacter Infections/veterinary , Retrospective Studies , Bacterial Proteins/genetics , Microbial Sensitivity Tests , Multilocus Sequence Typing , Poultry Diseases/microbiology , Polymorphism, Single NucleotideABSTRACT
Background: Grade 4 diffuse gliomas are highly malignant tumours with poor prognosis. Cuproptosis is a novel form of cell death. Cuproptosis genes are associated with various tumours and affect the prognosis of patients with these tumours. However, the relationship between cuproptosis and grade 4 diffuse gliomas remains unclear. Methods: Differentially expressed genes associated with cuproptosis in grade 4 diffuse gliomas were identified. Second, the prognostic model was established by univariate and multivariate COX regression analyses, and the genes (p < 0.05) were selected for subsequent analysis. The endpoint of the study was death. Single-gene analysis was performed in accordance with the expression levels of SLC31A1. Third, based on the expression levels of SLC31A1, gene function enrichment, drug sensitivity, and immune cell infiltration analyses were performed. Finally, the expression and biological functions of SLC31A1 in grade 4 diffuse gliomas were identified using immunohistochemical staining, qRT-PCR, and related biological experiments. Results: We identified six coproptosis genes in the grade 4 diffuse gliomas dataset (SLC31A1, PDHA1, GLS, FDX1, LIPT1, and ATP7B). The six key cuproptosis genes of grade 4 diffuse gliomas were analysed using univariate COX analysis. Basic patient data, including age, race, year of diagnosis, sex, and treatment, were included in the univariate COX analysis. Then, multivariate COX analysis was performed for the factors with p < 0.2 in the univariate COX analysis. Age, year of diagnosis, and SLC31A1, PDHA1, and FDX1 levels were found to be independent prognostic factors. A nomogram was constructed using these 5 factors. Through experiments, we found that SLC31A1 had a higher expression level in cancer tissue than that near cancer among the three genes, SLC31A1, PDHA1, and FDX1; therefore, we focused on SLC31A1. According on the expression level of SLC31A1, we performed gene function enrichment, drug sensitivity, and immune cell infiltration analyses. Navitoclax was the most sensitive drug. Differential gene function enrichment was observed for metalloendopeptidase activity. SLC31A1 is expressed in dendritic cells, macrophages, neutrophils, and CD8+T cells. SLC31A1 is highly expressed in grade 4 diffuse gliomas, whereas SLC31A1 knockdown significantly reduces cell proliferation and mobility. Conclusions: Age, year of diagnosis, and SLC31A1, PDHA1, and FDX1 expression were independent prognostic factors. A nomogram was constructed based on age, year of diagnosis, and SLC31A1, PDHA1, and FDX1 levels. Through analysis and experimental verification, SLC31A1 was found to affect the prognosis and progression of patients with grade 4 diffuse gliomas and was associated with immune cell infiltration.
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Epstein-Barr virus (EBV) encoded microRNA BART8-3p (miR-BART8-3p) was significantly associated with the metastasis in nasopharyngeal carcinoma (NPC). To explore the clinical values of plasma miR-BART8-3p in patients with early NPC. We retrospectively analyzed 126 patients with stage I and II NPC. A receiver operating characteristic curve was used to examine the diagnostic performance. KaplanâMeier analysis was applied to determine survival differences. Cox regression was used for univariate and multivariate analyses. Compared to healthy subjects, plasma EBV miR-BART8-3p was highly expressed in early NPC patients. The sensitivity, specificity, and area under the curve value of plasma miR-BART8-3p combined with plasma EBV DNA was up to 88.9%, 94.4%, and 0.931. Compared to patients with low expression of miR-BART8-3p, patients with high expression of miR-BART8-3p had poorer 5-year overall survival (OS) (98.9% vs. 91.1%, P = 0.025), locoregional recurrence-free survival (LRRFS) (100% vs. 83.9%, P < 0.001) and distant metastasis-free survival (DMFS) (98.9% vs. 88.0%, P = 0.006). Risk stratification analysis revealed that high-risk patients (with high levels of EBV DNA and miR-BART8-3p) had inferior OS, LRRFS, and DMFS than low-risk patients (without high levels of EBV DNA and miR-BART8-3p). Multivariate analysis verified that the high-risk group was an unfavorable factor for OS, LRRFS, and DMFS. A combination of plasma EBV miR-BART8-3p and EBV DNA could be a potential biomarker for the diagnosis and prognosis in early NPC.
Subject(s)
Epstein-Barr Virus Infections , MicroRNAs , Nasopharyngeal Neoplasms , Humans , Nasopharyngeal Carcinoma/diagnosis , Nasopharyngeal Carcinoma/genetics , Nasopharyngeal Carcinoma/pathology , Herpesvirus 4, Human/genetics , Herpesvirus 4, Human/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Prognosis , Epstein-Barr Virus Infections/pathology , Nasopharyngeal Neoplasms/diagnosis , Nasopharyngeal Neoplasms/genetics , Nasopharyngeal Neoplasms/pathology , Retrospective Studies , Biomarkers/metabolism , DNA, Viral/metabolismABSTRACT
BACKGROUND: Nasopharyngeal carcinoma (NPC) is prevalent in southern China. EBV DNA is the most useful biomarker in NPC. However, the value of EBV DNA in posttreatment NPC patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unclear. METHODS: Sixty-four eligible NPC patients were enrolled between December 2022 and February 2023. Patients who met the following criteria were included: had non-metastatic NPC, completed radical treatment, were first firstly infected with SARS-CoV-2 and their EBV DNA changed from undetectable to detectable. RESULTS: At the end of follow-up, 81.25% (52/64) of patients were confirmed not to relapse with undetectable EBV DNA (no-relapse). In addition, 18.75% (12/64) of patients experienced relapse with consistent detection of EBV DNA (yes-relapse). For all 64 patients, the average time from diagnosis of coronavirus disease 2019 (COVID-19) to detection of detectable EBV DNA was 35.41 days (2 to 139 days). For 52 no-relapse patients, the average time from EBV DNA changing from detectable to undetectable was 63.12 days (6 to 147 days). The levels of EBV DNA were greater in yes-relapse patients than that in no-relapse patients, and the average of EBV DNA levels were 1216 copies/ml and 53.18 copies/ml, respectively. Using 62.3 copies/mL as the threshold, the area under the curve for EBV DNA was 0.88 for distinguishing yes-relapse patients from no-relapse patients. The sensitivity and specificity were 81.97% (95% CI 0.71-0.95) and 86.67% (95% CI 0.70-0.95), respectively. CONCLUSION: For NPC patients infected with SARS-CoV-2, EBV DNA alone is insufficient for monitoring relapse after radical therapy. Long-term follow-up and underlying mechanistic investigations of EBV DNA changes are urgently needed.
ABSTRACT
Background: Computed tomography (CT) chest scans have become commonly used in clinical diagnosis. Image quality assessment (IQA) for CT images plays an important role in CT examination. It is worth noting that IQA is still a manual and subjective process, and even experienced radiologists make mistakes due to human limitations (fatigue, perceptual biases, and cognitive biases). There are also kinds of biases because of poor consensus among radiologists. Excellent IQA methods can reliably give an objective evaluation result and also reduce the workload of radiologists. This study proposes a deep learning (DL)-based automatic IQA method, to assess whether the image quality of respiratory phase on CT chest images are optimal or not, so that the CT chest images can be used in the patient's physical condition assessment. Methods: This retrospective study analysed 212 patients' chest CT images, with 188 patients allocated to a training set (150 patients), validation set (18 patients), and a test set (20 patients). The remaining 24 patients were used for the observer study. Data augmentation methods were applied to address the problem of insufficient data. The DL-based IQA method combines image selection, tracheal carina segmentation, and bronchial beam detection. To automatically select the CT image containing the tracheal carina, an image selection model was employed. Afterward, the area-based approach and score-based approach were proposed and used to further optimize the tracheal carina segmentation and bronchial beam detection results, respectively. Finally, the score about the image quality of the patient's respiratory phase images given by the DL-based automatic IQA method was compared with the mean opinion score (MOS) given in the observer study, in which four blinded experienced radiologists took part. Results: The DL-based automatic IQA method achieved good performance in assessing the image quality of the respiratory phase images. For the CT sequence of the same patient, the DL-based IQA method had an accuracy of 92% in the assessment score, while the radiologists had an accuracy of 88%. The Kappa value of the assessment score between the DL-based IQA method and radiologists was 0.75, with a sensitivity of 85%, specificity of 91%, positive predictive value (PPV) of 92%, negative predictive value (NPV) of 93%, and accuracy of 88%. Conclusions: This study develops and validates a DL-based automatic IQA method for the respiratory phase on CT chest images. The performance of this method surpassed that of the experienced radiologists on the independent test set used in this study. In clinical practice, it is possible to reduce the workload of radiologists and minimize errors caused by human limitations.