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1.
Front Pediatr ; 10: 951127, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36090563

RESUMO

Background: Rotavirus vaccination has been proven to effectively protect against rotavirus gastroenteritis. However, there are concerns about the relationship between rotavirus vaccination and the risk of autoimmune disorders. Thus, we conducted a systematic review and meta-analysis to comprehensively assess the association between rotavirus vaccination and type 1 diabetes (T1D) or celiac disease (CD) risk. Methods: A systematic review and meta-analysis were conducted to evaluate the type 1 diabetes or celiac disease associated with rotavirus vaccination. The following journal databases were searched to identify potential studies for inclusion: PubMed, Embase, and Cochrane Library databases. Results: Seven articles involving more than 5,793,055 children were included. Our results showed that rotavirus vaccination does not alter the subsequent risk of T1D (RR 0.94, 95% CI: 0.82-1.09) or CD (RR 0.86, 95% CI: 0.64-1.17) after vaccination. Furthermore, the risk of T1D was not increased or decreased for children fully exposed to rotavirus vaccination (RR 0.86, 95% CI, 0.54-1.36) and for children partially exposed to rotavirus vaccination (RR 1.05, 95% CI, 0.87-1.26). However, younger (<5 years) vaccinated children at the end of study (RR 0.84, 95% CI = 0.75-0.95) may be at a lower risk for T1D than older (≥5 years) vaccinated children (RR 0.93, 95% CI, 0.81-1.07). Conclusion: The findings of this study suggest that rotavirus vaccination does not appear to be associated with T1D or CD in children. The protective effect of rotavirus vaccination on T1D may be presented by time dependent.

2.
Front Aging Neurosci ; 14: 977985, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36092799

RESUMO

Background: Identifying individuals with high-risk Parkinson's disease (PD) at earlier stages is an urgent priority to delay disease onset and progression. In the present study, we aimed to develop and validate clinical risk models using non-motor predictors to distinguish between early PD and healthy individuals. In addition, we constructed prognostic models for predicting the progression of non-motor symptoms [cognitive impairment, Rapid-eye-movement sleep Behavior Disorder (RBD), and depression] in de novo PD patients at 5 years of follow-up. Methods: We retrieved the data from the Parkinson's Progression Markers Initiative (PPMI) database. After a backward variable selection approach to identify predictors, logistic regression analyses were applied for diagnosis model construction, and cox proportional-hazards models were used to predict non-motor symptom progression. The predictive models were internally validated by correcting measures of predictive performance for "optimism" or overfitting with the bootstrap resampling approach. Results: For constructing diagnostic models, the final model reached a high accuracy with an area under the curve (AUC) of 0.93 (95% CI: 0.91-0.96), which included eight variables (age, gender, family history, University of Pennsylvania Smell Inventory Test score, Montreal Cognitive Assessment score, RBD Screening Questionnaire score, levels of cerebrospinal fluid α-synuclein, and SNCA rs356181 polymorphism). For the construction of prognostic models, our results showed that the AUC of the three prognostic models improved slightly with increasing follow-up time. The overall AUCs fluctuated around 0.70. The model validation established good discrimination and calibration for predicting PD onset and progression of non-motor symptoms. Conclusion: The findings of our study facilitate predicting the individual risk at an early stage based on the predictors derived from these models. These predictive models provide relatively reliable information to prevent PD onset and progression. However, future validation analysis is still needed to clarify these findings and provide more insight into the predictive models over more extended periods of disease progression in more diverse samples.

3.
Diagn Interv Radiol ; 2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36097638

RESUMO

PURPOSE Radiomics can be used to determine the prognosis of gastric cancer (GC). The objective of this study was to predict the disease-free survival (DFS) after GC surgery based on computed tomography-enhanced images combined with clinical features. METHODS Clinical, imaging, and pathological data of patients who underwent gastric adenocarcinoma resection from June 2015 to May 2019 were retrospectively analyzed. The primary outcome was DFS. Radiomics features were selected using Least Absolute Shrinkage and Selection Operator algorithm and converted into the Rad-score. A nomogram was constructed based on the Radscore and other clinical factors. The Rad-score and nomogram were validated in the training and validation groups. RESULTS Totally, 179 patients were randomly divided into the training (n=124) and validation (n=55) groups. In the training group, validation group, and overall population, the Rad-score could be divided into categories indicating low, moderate, and high risk of recurrence, metastasis, or death; all risk categories showed a significant difference between the training, validation, and overall population groups (all P <.001). Positive lymph nodes (hazard ratio (HR)=3.07, 95% CI: 1.52-6.23, P=.002), cancer antigen-125 (HR=3.24, 95% CI: 1.54-6.80, P=.002), and the Radscore (HR=0.73, 95% CI: 0.61-0.87, P < .001) were independently associated with DFS. These 3 variables were used to construct a nomogram. In the training group, the areas under the curve at 3 years were 0.758 and 0.776 for the Rad-score and the nomogram, respectively, while they were both 1.000 in the validation group. The net benefit rate was analyzed using a decision curve in the training and validation groups, and the nomogram was superior to the single Rad-score. CONCLUSION Rad-score is an independent factor for DFS after gastrectomy for GC. The nomogram established in this study could be an effective tool for the clinical prediction of DFS after gastrectomy.

4.
J Environ Manage ; 323: 116155, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36116256

RESUMO

The effect of sequencing batch membrane bioreactor (SMBR) on external carbon addition and enrofloxacin was investigated to treat synthetic mariculture wastewater. Anoxic/anaerobic and low COD/TN can improve the ammonia oxidation of the system, and the NH4+-N removal efficiency above 99%. External carbon was added and an anoxic environment was set to provide a suitable environment for denitrifying bacteria. When the external carbon source was 50-207 mg/L, the TN removal efficiency (31.82%-37.73%) and the COD of the effluent (28.85-36.58 mg/L) had little change. The partition resistance model showed that cake deposition resistance (RC,irr) and irreversible resistance (RPB) were the main components. And with the increase in cleaning times, the fouling rate of membrane components accelerated. Enrofloxacin can promote the TN removal efficiency (45.66%-93.74%) and had a significant effect on TM7a, Cohaesibacter, Vibrio and Phaeobacter.

5.
Thorac Cancer ; 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36126963

RESUMO

BACKGROUND: The switch/sucrose nonfermentable complex mutations (SWI/SNF-mut) are common in non-small cell lung cancer (NSCLC). However, the association of SWI/SNF-mut with the clinical outcomes of immune checkpoint inhibitors (ICIs), particularly of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), has not been established. METHODS: We retrospectively collected data of patients at Cancer Hospital Chinese Academy of Medical Sciences. Patients with advanced NSCLC who received programmed cell death protein-1 or programmed cell death ligand 1 (PD-[L]1) inhibitors were included in cohort 1 and those with EGFR mutations (EGFR-mutant) received EGFR-TKIs monotherapy were included in cohort 2. Two reported Memorial Sloan-Kettering Cancer Center (MSKCC) cohorts received immunotherapy alone used as the validation for cohort 1. We analyzed the relationship between SWI/SNF alterations and clinical outcomes in each cohort. RESULTS: In total, 1162 patients were included, of which 230 patients (19.8%) were identified as SWI/SNF-mut with the most common genetic alterations being ARID1A (33.4%) and SMARCA4 (28.3%). In cohort 1 (n = 146), patients with co-mutations of SWI/SNF and Kirsten rat sarcoma oncogene (KRAS) (SWI/SNFmutKRASmut, n = 18) had significantly prolonged progression-free survival (PFS) (8.6 m vs. 1.9 m; hazard ratio [HR],  0.31; 95% confidence intervals [CI], 0.11-0.83; p = 0.032) to PD-(L)1 inhibitors monotherapy, which was consistent with the MSKCC cohorts (not reach [NR] vs. 6.3 m; HR, 0.36, 95% CI, 0.15-0.82; p = 0.016). In cohort 2 (n = 205), ARID1A-mut (n = 16) was associated with improved PFS after EGFR-TKIs (20.6 m vs. 11.2 m; HR, 0.47, 95% CI, 0.27-0.94; p = 0.023). CONCLUSIONS: In advanced NSCLC, patients with SWI/SNFmutKRASmut seem to benefit more from ICIs. Furthermore, ARID1A-mut may provide a protective effect to EGFR-TKIs in EGFR-mutant patients. However, this is a retrospective single-institution analysis that requires further validation by large prospective studies.

6.
Artigo em Inglês | MEDLINE | ID: mdl-36127253

RESUMO

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common and lethal cancer of the adult kidney. ADAP2 is a GTPase-activating protein was upregulated in clear cell renal cell carcinoma. The role of ADAP2 in ccRCC progression is unknown. METHODS: ADAP2 expression in ccRCC cell lines and tissues was examined via real-time PCR, Western blot and IHC. MTS, colony formation and transwell assay to explore the role of ADAP2 in ccRCC. ADAP2 in growth and metastasis of ccRCC were evaluated in vivo through ccRCC xenograft tumor growth, lung metastatic mice model. The prognostic role of ADAP2 was evaluated by survival analysis. RESULTS: ADAP2 mRNA was expressed at significantly higher levels in 23 pairs of ccRCC tissues than in normal kidney tissues (P < 0.01). Immunohistochemical analysis of 298 ccRCC tissues revealed elevated ADAP2 expression as an independent unfavorable prognostic factor for the overall survival (P = 0.0042) and progression-free survival (P = 0.0232) of patients. The KaplanMeier survival curve showed that patients with a higher expression of ADAP2 showed a significantly lower overall survival rate and disease-free survival rate. Moreover, high expression of ADAP2 at the mRNA level was associated with a worse prognosis for overall survival (P = 0.0083) in The Cancer Genome Atlas (TCGA) cohort. In vivo and in vitro functional study showed that overexpression of ADAP2 promotes ccRCC cell proliferation and metastasis ability, whereas knockdown of ADAP2 inhibited cell proliferation, colony formation, migration and invasion. CONCLUSION: ADAP2 is a novel prognostic marker and could promotes tumor progression in ccRCC.

7.
Artigo em Inglês | MEDLINE | ID: mdl-36127483

RESUMO

Antibodies targeting programmed cell death-1 (PD1) and its ligand (PDL1) have transformed current cancer therapy while little is known about the expression of anti-PD1/PDL1 autoantibodies between lung cancer (LC) patients and normal controls (NC). The expression level of anti-PD1/PDL1 IgG and IgM was detected in plasma of 325 LC and 324 NC by indirect enzyme-linked immune sorbent assay (ELISA). Western blot and indirect immunofluorescence (IIF) were used to verify the ELISA results. The association analysis was used to evaluate the odds ratio (OR) of LC. The expression of anti-PD1/PDL1 IgG in LC samples was significantly higher than NC (P < 0.001 and P < 0.05, respectively). The positive rate of anti-PD1/PDL1 IgG in LC was significantly higher than NC and significant difference was also shown in LC samples of different clinical characteristics, such as clinical stage, nodules diameter, lymph node metastasis and distant metastasis (P < 0.001). Moreover, PD1/PDL1 expression in tissues showed no significant relation with that in plasma (P > 0.05). Anti-PD1/PDL1 IgG were the risk factors related to LC (OR (95% CI): 22.433 (5.426-92.745) and 5.051 (1.316-19.386)), while anti-PD1/PDL1 IgM were the risk factors for LC with ≤ 60 years (OR (95% CI): 6.122 (1.365-27.455) and 7.664 (1.715-34.251)) and anti-PD1 IgM was also the risk factor for male LC cases(OR (95% CI): 6.948 (1.076-44.868)). Plasma anti-PD1/PDL1 IgG and IgM might serve as potential biomarkers and risk predictors for LC.

8.
Artigo em Inglês | MEDLINE | ID: mdl-36129393

RESUMO

Rh-catalyzed dynamic kinetic intramolecular [4+2] cycloaddition reaction of 1,3-disubstituted allene-1,3-dienes afforded cis -fused [4.3.0]bicyclic products with an excellent chemo-, diastereo-, and enantio-selectivity. Many synthetically useful functional groups are tolerated. The synthetic utility has been demonstrated. Based on the careful experimental studies, a mechanism involving the rapid racemization of the allene moiety in the starting materials has been proposed.

9.
Cell Prolif ; : e13331, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36124714

RESUMO

OBJECTIVES: Mutant C/EBPα p30 (mp30), the product of C/EBPα double mutations (DM), lacks transactivation domain 1 and has C-terminal loss-of-function mutation. Acute myeloid leukaemia (AML) patients harbouring C/EBPα DM could be classified as a distinct subgroup with favourable prognosis. However, the underlying mechanism remains elusive. MATERIALS AND METHODS: Autophagy regulated by mp30 was detected by western blot and immunofluorescence. Immune infiltration analysis and GSEA were performed to investigate autophagic and inflammatory status of AML patients from the GSE14468 cohort. Flow cytometry was applied to analyse T cell activation. RESULTS: Mp30 inhibited autophagy by suppressing nucleus translocation of NF-κB. Autophagy-associated secretion of IL-1ß was decreased in mp30-overexpressed AML cells. Bioinformatic analysis revealed that inflammatory status was attenuated, while CD8+ T cell infiltration was upregulated in C/EBPα DM AML patients. Consistently, the proportion of CD8+ CD69+ T cells in peripheral blood mononuclear cells (PBMCs) was upregulated after co-culture with mp30 AML cell conditional culture medium. Knock-out of IL-1ß in AML cells also enhanced CD8+ T cell activation. Accordingly, IL-1ß expression was significantly reduced in the bone marrow (BM) cells of C/EBPα DM AML patients compared to the wildtype, while the CD8+ CD69+ T cell proportion was specifically elevated. CONCLUSIONS: C/EBPα DM alleviates immunosuppression of CD8+ T cells by inhibiting the autophagy-associated secretion of IL-1ß, which elucidated that repression of autophagy-related inflammatory response in AML patients might achieve a favourable clinical benefit.

10.
Artigo em Inglês | MEDLINE | ID: mdl-36118088

RESUMO

Purpose: Rheumatoid arthritis (RA) shows abnormal proliferation, apoptosis, and invasion in fibroblast-like synoviocytes (FLSs). Baicalein (BAI), extracted from Scutellaria baicalensis, is used as an anticancer drug through inducing cancer cells apoptosis. However, the mechanism of BAI in RA progression still remains unknown. Here, we demonstrated that BAI inhibited FLS proliferation and migration, whereas it enhanced apoptosis via the PI3K/Akt/mTOR pathway in vitro. Methods: Cell viability and colony formation were analyzed by MTT and plate colony formation assays in SW982 cells, respectively. Apoptosis was detected by flow cytometry and western blotting. Epithelial-mesenchymal transition (EMT), MMP family proteins (MMP2/9), and the PI3K/Akt/mTOR pathway were detected by western blot. Cell migration was detected by scratch healing assay under BAI treatment in SW982 cells. Results: BAI dose-dependently inhibited cell viability and colony forming in SW982 cells. BAI upregulated apoptotic proteins and downregulated EMT-related proteins, resulting in enhanced cell apoptosis and inhibited cell migration in SW982 cells. BAI also dose-dependently inhibited the phosphorylation of PI3K, Akt, and mTOR. Conclusions: These results indicated that BAI inhibited FLSs proliferation and EMT, whereas induced cell apoptosis through blocking the PI3K/Akt/mTOR pathway, supporting clinical application for RA progression.

11.
Front Microbiol ; 13: 934459, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36118209

RESUMO

The gut microbiome is a crucial element that facilitates a host's adaptation to a changing environment. Compared to the western honeybee Apis mellifera, the Asian honeybee, Apis cerana populations across its natural range remain mostly semi-feral and are less affected by bee management, which provides a good system to investigate how gut microbiota evolve under environmental heterogeneity on large geographic scales. We compared and analyzed the gut microbiomes of 99 Asian honeybees, from genetically diverged populations covering 13 provinces across China. Bacterial composition varied significantly across populations at phylotype, sequence-discrete population (SDP), and strain levels, but with extensive overlaps, indicating that the diversity of microbial community among A. cerana populations is driven by nestedness. Pollen diets were significantly correlated with both the composition and function of the gut microbiome. Core bacteria, Gilliamella and Lactobacillus Firm-5, showed antagonistic turnovers and contributed to the enrichment in carbohydrate transport and metabolism. By feeding and inoculation bioassays, we confirmed that the variations in pollen polysaccharide composition contributed to the trade-off of these core bacteria. Progressive change, i.e., nestedness, is the foundation of gut microbiome evolution among the Asian honeybee. Such a transition during the co-diversification of gut microbiomes is affected by environmental factors, diets in general, and pollen polysaccharides in particular.

12.
BMC Med Imaging ; 22(1): 157, 2022 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-36057576

RESUMO

OBJECTIVES: We aimed to investigate the value of performing gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) enhanced magnetic resonance imaging (MRI) radiomics for preoperative prediction of microvascular invasion (MVI) of hepatocellular carcinoma (HCC) based on multiple sequences. METHODS: We randomly allocated 165 patients with HCC who underwent partial hepatectomy to training and validation sets. Stepwise regression and the least absolute shrinkage and selection operator algorithm were used to select significant variables. A clinicoradiological model, radiomics model, and combined model were constructed using multivariate logistic regression. The performance of the models was evaluated, and a nomogram risk-prediction model was built based on the combined model. A concordance index and calibration curve were used to evaluate the discrimination and calibration of the nomogram model. RESULTS: The tumour margin, peritumoural hypointensity, and seven radiomics features were selected to build the combined model. The combined model outperformed the radiomics model and the clinicoradiological model and had the highest sensitivity (90.89%) in the validation set. The areas under the receiver operating characteristic curve were 0.826, 0.755, and 0.708 for the combined, radiomics, and clinicoradiological models, respectively. The nomogram model based on the combined model exhibited good discrimination (concordance index = 0.79) and calibration. CONCLUSIONS: The combined model based on radiomics features of Gd-EOB-DTPA enhanced MRI, tumour margin, and peritumoural hypointensity was valuable for predicting HCC microvascular invasion. The nomogram based on the combined model can intuitively show the probabilities of MVI.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Meios de Contraste , Gadolínio DTPA , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/cirurgia , Imageamento por Ressonância Magnética/métodos
13.
Biology (Basel) ; 11(7)2022 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-36101420

RESUMO

Insects are generally associated with gut bacterial communities that benefit the hosts with respect to diet digestion, limiting resource supplementation, pathogen defense, and ecological niche expansion. Heteroptera (true bugs) represent one of the largest and most diverse insect lineages and comprise species consuming different diets and inhabiting various ecological niches, even including underwater. However, the bacterial symbiotic associations have been characterized for those basically restricted to herbivorous stink bugs of the infraorder Pentatomomorpha. The gut microbiota associated with the megadiverse heteropteran lineages and the implications of ecological and diet variance remain largely unknown. Here, we conducted a bacterial 16S rRNA amplicon sequencing of the gut microbiota across 30 species of true bugs representative of different ecological niches and diets. It was revealed that Proteobacteria and Firmicute were the predominant bacterial phyla. Environmental habitats and diets synergistically contributed to the diversity of the gut bacterial community of true bugs. True bugs living in aquatic environments harbored multiple bacterial taxa that were not present in their terrestrial counterparts. Carnivorous true bugs possessed distinct gut microbiota compared to phytophagous species. Particularly, assassin bugs of the family Reduviidae possessed a characterized gut microbiota predominantly composed of one Enterococcus with different Proteobacteria, implying a specific association between the gut bacteria and host. Overall, our findings highlight the importance of the comprehensive surveillance of gut microbiota association with true bugs for understanding the molecular mechanisms underpinning insect-bacteria symbiosis.

14.
Mol Immunol ; 151: 95-102, 2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36113365

RESUMO

OBJECTIVE AND DESIGN: Ozone exposure is an important risk factor for Chronic Obstructive Pulmonary Disease (COPD) which is a global public health concern. Until now, there is no effective approach to reverse airflow limitation and accelerated loss of lung function completely. Here, we delineate the efficacy of mouse allogeneic adipose-derived mesenchymal stem cells (mASCs) in the treatment of COPD mice by intratracheal and intravenous administration. METHODS: In this study, we established ozone-exposed COPD model in mice and were administered intratracheally or intravenously with mASCs which were extracted, cultured, and identified in vitro. RESULTS: We observed that exposure to ozone resulted in a marked lung neutrophilia with high levels of inflammatory cell counts, enhanced expression of cytokines IL-1ß and TNF-α, reduced expression of IL-10, lung function and airspace enlargement. mASCs intratracheal administration rescured the lung neutrophilia, lung function and emphysema-like phenotype. Similar results were observed in mice with mASCs intravenous administration. But the altered levels of serum cytokines in mice with mASCs intratracheal administration appears more robust than those in mice with mASCs intravenous administration. CONCLUSIONS: Collectively, these data indicate that intratracheal administration of mASCs appears more effective in treating ozone-induced COPD compared to intravenous administration of mASCs, although the two approaches can be comparable in safety. mASCs are expected to become a new potential intervention strategy for COPD.

15.
World J Pediatr ; 2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36100796

RESUMO

BACKGROUND: The aim of this study was to evaluate the performance of the four scoring tools in predicting mortality in pediatric intensive care units (PICUs) in western China. METHODS: This was a multicenter, prospective, cohort study conducted in six PICUs in western China. The performances of the scoring systems were evaluated based on both discrimination and calibration. Discrimination was assessed by calculating the area under the receiver operating characteristic curve (AUC) for each model. Calibration was measured across defined groups based on mortality risk using the Hosmer-Lemeshow goodness-of-fit test. RESULTS: A total of 2034 patients were included in this study, of whom 127 (6.2%) died. For the entire cohort, AUCs for Pediatric Risk of Mortality Score (PRISM) I, Pediatric Index of Mortality 2 (PIM2), Pediatric Logistic Organ Dysfunction Score-2 (PELOD-2) and PRISM IV were 0.88 [95% confidence interval (CI) 0.85-0.92], 0.84 (95% CI 0.80-0.88), 0.80 (95% CI 0.75-0.85), and 0.91 (95% CI 0.88-0.94), respectively. The Hosmer-Lemeshow goodness-of-fit Chi-square value was 12.71 (P = 0.12) for PRISM I, 4.70 (P = 0.79) for PIM2, 205.98 (P < 0.001) for PELOD-2, and 7.50 (P = 0.48) for PRISM IV [degree of freedom (df) = 8]. The standardized mortality ratios obtained with the PRISM I, PIM2, PELOD-2, and PRISM IV models were 0.87 (95% CI, 0.75-1.01), 0.97 (95% CI, 0.85-1.12), 1.74 (95% CI, 1.58-1.92), and 1.05 (95% CI, 0.92-1.21), respectively. CONCLUSIONS: PRISM IV performed best and can be used as a prediction tool in PICUs in Western China. However, PRISM IV needs to be further validated in NICUs.

16.
Synth Syst Biotechnol ; 7(4): 1142-1147, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36101897

RESUMO

The chemical diversity of terpenoids is typically established by terpene synthase-catalyzed cyclization and diversified by post-tailoring modifications. Fungal bifunctional terpene synthase (BFTS) associated P450 enzymes have shown significant catalytic potentials through the development of various new terpenoids with different biological activities. This study discovered the BFTS and its related gene cluster from the plant endophytic fungus Didymosphaeria variabile 17020. Heterologous expression of the BFTS in Saccharomyces cerevisiae resulted in the characterization of a major product diterpene variediene (1), along with two new minor products neovariediene and neoflexibilene. Further heterologous expression of the BFTS and one cytochrome P450 enzyme VndE (CYP6138B1) in Aspergillus oryzae NSAR1 led to the identification of seven norditerpenoids (19 carbons) with a structurally unique 5/5 bicyclic ring system. Interestingly, in vivo experiments suggested that the cyclized terpene variediene (1) was modified by VndE along with the endogenous enzymes from the host cell A. oryzae through serial chemical conversions, followed by multi-site hydroxylation via A. oryzae endogenous enzymes. Our work revealed that the two-enzymes biosynthetic system and host cell machinery could produce structurally unique terpenoids.

17.
Cell Metab ; 2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36103895

RESUMO

The tumor microenvironment (TME) is a unique niche governed by constant crosstalk within and across all intratumoral cellular compartments. In particular, intratumoral high potassium (K+) has shown immune-suppressive potency on T cells. However, as a pan-cancer characteristic associated with local necrosis, the impact of this ionic disturbance on innate immunity is unknown. Here, we reveal that intratumoral high K+ suppresses the anti-tumor capacity of tumor-associated macrophages (TAMs). We identify the inwardly rectifying K+ channel Kir2.1 as a central modulator of TAM functional polarization in high K+ TME, and its conditional depletion repolarizes TAMs toward an anti-tumor state, sequentially boosting local anti-tumor immunity. Kir2.1 deficiency disturbs the electrochemically dependent glutamine uptake, engendering TAM metabolic reprogramming from oxidative phosphorylation toward glycolysis. Kir2.1 blockade attenuates both murine tumor- and patient-derived xenograft growth. Collectively, our findings reveal Kir2.1 as a determinant and potential therapeutic target for regaining the anti-tumor capacity of TAMs within ionic-imbalanced TME.

18.
Front Mol Biosci ; 9: 925404, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36052166

RESUMO

Morphine, the most widely used analgesic, relieves severe pain by activating the µ-opioid receptor (MOR), whereas naloxone, with only slight structural changes compared to morphine, exhibits inhibitory effect, and is used to treat opioid abuse. The mechanism by which the MOR distinguishes between the two is unclear. Molecular dynamics (MD) simulations on a 1-µs time scale and metadynamics-enhanced conformational sampling are used here to determine the different interactions of these two ligands with MOR: morphine adjusted its pose by continuously flipping deeper into the pocket, whereas naloxone failed to penetrate deeper because its allyl group conflicts with several residues of MOR. The endogenous peptide ligand endomorphin-1 (EM-1) underwent almost no significant conformational changes during the MD simulations. To validate these processes, we employed GIRK4S143T, a MOR-activated Gßγ-protein effector, in combination with mutagenesis and electrophysiological recordings. We verified the role of some key residues in the dynamic recognition of naloxone and morphine and identified the key residue I322, which leads to differential recognition of morphine and naloxone while assisting EM-1 in activating MOR. Reducing the side chain size of I322 (MORI322A) transformed naloxone from an inhibitor directly into an agonist of MOR, and I322A also significantly attenuated the potency of MOR on EM-1, confirming that binding deep in the pocket is critical for the agonistic effect of MOR. This finding reveals a dynamic mechanism for the response of MOR to different ligands and provides a basis for the discovery of new ligands for MOR at the atomic level.

19.
Cancer Sci ; 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36056603

RESUMO

Computed tomography (CT), an efficient radiological technology, is used to detect lung cancer in clinic. Carcinoembryonic antigen (CEA), a common tumor biomarker, is applied in the detection of various tumors. To highlight the advantages of the two-dimensional techniques and assist the clinicians in optimizing lung cancer diagnostic scheme, we established a favourable model combined CT and CEA. In the study, univariate analysis was performed to screen independent predictors in training cohort of 271 patients with malignant pulmonary nodules (MPNs) and 92 with benign pulmonary nodules (BPNs). Six machine learning-based models involved 5 CT predictors (mediastinal lymph node enlargement, lobulation, vascular notch sign, spiculation, nodule number) and lnCEA were constructed and validated in an independent cohort of 129 participants (92 MPNs and 37 BPNs) by SPSS Modeler. Nomogram production and Delong test were generated by R software. Finally, the model established by logistic regression owned highest diagnostic efficiency (AUC=0.912). Moreover, the diagnostic ability of logistic model in the validation cohort (AUC=0.882, 80.4% sensitivity, 75.7% specificity) was higher than Peking University model (AUC=0.712, 68.5% sensitivity, 70.3% specificity) and Mayo model (AUC=0.745, 62.0% sensitivity, 75.7% specificity). Interestingly, for the participants with indeterminate nodule (10-30 mm) and CEA-negative, the model reached an AUC of 0.835 (72.3% sensitivity, 83.3% specificity). The AUC for the early lung cancer was as high as 0.822 with 67.3% sensitivity and 78.9% specificity. As a conclusion, the promising model presents a new diagnostic strategy for the clinic to distinguish MPNs from BPNs.

20.
Mol Genet Genomic Med ; : e2039, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36052765

RESUMO

BACKGROUND: The EVEN-plus syndrome (epiphyseal-vertebral-ear-nose dysplasia plus associated findings) is an extremely rare autosomal recessive inherited disease characterised by specific facial features and skeletal dysplasia. It has a prenatal onset due to defects in the HSPA9 gene. The syndrome has not been reported previously in China. METHODS: This study reported the characteristics, examination results, diagnosis and treatment of a female case aged 3 years and 3 months. RESULTS: The patient had global developmental delay and specific facial features, including a prominent forehead, a bilateral auricle deformity, a collapsed nose, a high palatine arch, a short neck and other appearance abnormalities. Her hip joint magnetic resonance imaging (MRI) results showed bilateral femoral head epiphyseal dysplasia with a fork-shaped malformation at the distal end, and her brain MRI showed white matter myelin dysplasia. HSPA9 compound heterozygous variants c.882_c.883delAG and c.613A>G were identified by exome sequencing. CONCLUSIONS: This finding expands the spectra of EVEN-plus syndrome phenotype and pathogenic variants and suggests that c.882_c.883delAG may have a higher distribution frequency in East Asian populations.

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