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1.
Anal Biochem ; 660: 114970, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36341768

RESUMO

OBJECTIVE: To establish and validate a robust LC-MS/MS method for simultaneously measuring 8-oxoGuo, 8-oxodG, and NMN in serum and urine to evaluate the oxidative stress status. METHODS: A Waters TQ-XS triple quadrupole mass spectrometer system coupled with an Acquity UPLC Primer HSS T3 column was chosen. The clinical performance was verified according to the CLSI C62-A and EP-15 guidelines. Furthermore, matched serum and urine samples from 22 apparently healthy check-ups, 20 patients with atherosclerosis, and 18 individuals with dementia were evaluated. RESULTS: The recovery for serum 8-oxoGuo, urine 8-oxoGuo, serum 8-oxodG, urine 8-oxodG, serum NMN, and urine NMN was 88.8-112.4%, 102.4-114.1%, 88.5-107.7%, 94.9-102.6%, 98.4-108.9%, and 88.5-108.6%, respectively. Based on the inter-assay results, total coefficient of variation, matrix effect, and carryover, the LC-MS/MS method was deemed robust. The limit of quantification was 0.017, 0.018, and 0.150 nmol/L for 8-oxoGuo, 8-oxodG, and NMN, respectively, which are suitable for accurate measurements in human serum and urine samples. Higher 8-oxoGuo and 8-oxodG levels and lower NMN levels, indicative of significantly higher oxidative stress status, were found in patients with dementia compared to healthy subjects. CONCLUSION: We established and validated a robust LC-MS/MS method to simultaneously measure 8-oxoGuo, 8-oxodG, and NMN in serum and urine.


Assuntos
Demência , Espectrometria de Massas em Tandem , Humanos , Cromatografia Líquida , 8-Hidroxi-2'-Desoxiguanosina
2.
Clin Chem Lab Med ; 61(1): 86-92, 2023 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-36103653

RESUMO

OBJECTIVES: Measurement of the serum levels of vitamin B12 (VB12) is key for evaluating VB12 deficiency-dependent anemia. Immunoassay, the major method for determining VB12, tends to give false-normal results because of the presence of anti-intrinsic factor (IF-Ab) or other factors such as heterophilic antibodies et al. This study aimed to develop a liquid chromatography tandem mass spectrometry (LC-MS/MS) method that is helpful for distinguish false normal VB12 results measured by the immunoassay. METHODS: Different forms of VB12 were derivatized into CN-B12, which was collected through solid-phase extraction and analyzed via LC-MS/MS. 236 serum samples were measured both by LC-MS/MS and immunoassay, results were compared, and the IF-Ab effect was evaluated. RESULTS: The LC-MS/MS assay afforded a linear slope from 20 to 4,000 pmol/L for CN-B12. OH-VB12, methyl-VB12, and CoA-VB12 showed recovery within 89.3-109.5%. The intra-assay CV of VB12 was 2.6-4.1%, whereas the total CV was 9.3-9.8%. Passing-Bablok regression between LC-MS/MS and immunoassay results showed that the slope was 1.085 and the intercept was -15.691. The Bland-Altman plot showed that the mean difference and difference% were -34.6 pmol/L and 0.3%, respectively. Inter-rater agreement analysis showed that the linear weighted kappa value was 0.885, implying good agreement between the two methods. However, two samples were falsely elevated and one sample was falsely normal in the immunoassay compared with LC-MS/MS. The LC-MS/MS method helped in the distinction of false-normal VB12 results shown by the immunoassay. CONCLUSIONS: The VB12 LC-MS/MS method can be used as an arbiter of clinically discordant immunoassay results.

3.
J Am Chem Soc ; 2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36384291

RESUMO

Nitrogen-rich compounds have attracted significant fundamental and practical interest owing to their ability to accommodate diverse nitrogen-bonding patterns and their feasibility as high-energy-density materials. Herein, we examine a wide range of chemical compositions in the compressed Ga-N system using first-principles structural search and experimental preparation using a laser-heated diamond anvil cell. Our investigations have theoretically identified three thermodynamically stable stoichiometries─GaN15, GaN10, and GaN5─with surprisingly versatile polymeric nitrogen framework topologies. Strikingly, our results show that the required synthetic pressures for forming polymeric nitrogen phases in GaN10 and GaN5 are much lower than that for pure solid nitrogen. Finally, we evaluated the energy involved in decomposing the compounds and validated that they are promising candidates for high-energy-density materials. These findings have broad implications for designing and synthesizing novel nitrogen-rich compounds through the reaction between p electron elements and nitrogen at modest pressures and for nitrogen chemistry under extreme conditions.

4.
BMC Med Res Methodol ; 22(1): 275, 2022 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-36266618

RESUMO

BACKGROUND: Currently, the direct method is the main approach for establishment of reference interval (RI). However, only a handful of studies have described the effects of sample size on establishment of RI and estimation of sample size. We describe a novel approach for estimation of the sample size when establishing RIs using the transformed parametric and non-parametric methods. METHODS: A total of 3,697 healthy participants were enrolled in this study. We adopted a two-layer nested loop sample size estimation method to determine the effects of sample size on RI, using thyroid-related hormone as an example. The sample size was selected as the calculation result when the width of the confidence interval (CI) of the upper and lower limit of the RI were both stably < 0.2 times the width of RI. Then, we calculated the sample size for establishing RIs via transformed parametric and non-parametric methods for thyroid-related hormones. RESULTS: Sample sizes for thyroid stimulating hormone (TSH), as required by parametric and non-parametric methods to establish RIs were 239 and 850, respectively. Sample sizes required by the transformed parametric method for free triiodothyronine (FT3), free thyroxine (FT4), total triiodothyronine (TT3) and total thyroxine (TT4) were all less than 120, while those required by the non-parametric method were more than 120. CONCLUSION: We describe a novel approach for estimating sample sizes for establishment of RI. A corresponding open-source code has been developed and is available for applications. The established method is suitable for most analytes, with evidence based on thyroid-related hormones indicating that different sample sizes are required to establish RIs using different methods for analytes with different variations.


Assuntos
Tiroxina , Tri-Iodotironina , Humanos , Tamanho da Amostra , Valores de Referência , Tireotropina , Mineração de Dados
6.
Hematol Oncol ; 2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36301018

RESUMO

Myelodysplastic syndrome (MDS) represents a group of neoplasms with extensive heterogeneity. Recurrent mutations in dozens of driver genes have been identified in over 90% of MDS cases, although fusion genes are rarely seen. We first report the competitive evolved sub-clonal breakpoint cluster region (BCR)::ABL1 and novel MSI2::PC fusion gene in MDS with del(5q) in initial diagnosis that underwent dismal progression. However, the BCR::ABL1 clone vanished while the MSI2::PC clone rose to the major one with disease progression. A novel MSI2::PC fusion transcript was identified in initial diagnosis and disease progression of the patient through transcriptome sequencing (RNA-seq) and Quantitative reverse transcription polymerase Chain Reaction (PCR) showed MSI2::PC/ABL1 expression at initial diagnosis and disease progression. In addition, mutation screening of 300 leukemia driver genes identified ARID2 c.5046del/p.F1682Lfs*19 and ZNF292 c.4565A > G/p.Q1522R mutation in bone marrow sample at initial diagnosis and disease progression. In conclusion, the dynamic process of the two fusion and phenotype manifestations may help to understand further the molecular significance of the anomalies of BCR::ABL1, MSI2, and PC in oncogenesis.

7.
Clin Chim Acta ; 536: 162-168, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36191613

RESUMO

BACKGROUND: Trimethylamine N-oxide (TMAO) and phenylacetylglutamine (PAGln) are associated with acute myocardial infarction (AMI) and type 2 diabetes mellitus (T2DM). This study developed and validated a simple method firstly for simultaneously quantifying serum TMAO and PAGln using liquid chromatography-tandem mass spectrometry (LC-MS/MS). METHODS: Serum samples from patients with T2DM, AMI, and healthy subjects were analyzed using a new LC-MS/MS method to evaluate TMAO and PAGln levels. Statistical analyses were performed to evaluate TMAO and PAGln distributions among different groups. RESULTS: Retention and separation of the two metabolites were achieved within 5 min. For both analytes, the assay was linear in a 0.02-10 µg/mL range, with >0.99 average linear correlation coefficients, and quantification limit values of approximately 0.010 µg/mL. The average recoveries of TMAO and PAGln were 96.3 % and 96.4 %, respectively. The intra-run and total coefficient variations were 3.5-4.8 % and 3.9-5.7 % respectively for TMAO; and 4.0-5.1 % and 4.6-6.3 % respectively for PAGln. TMAO and PAGln showed a moderate correlation (P < 0.001) and their levels in patients with T2DM were significantly higher than those in healthy individuals (P < 0.001). TMAO levels were higher in patients with T2DM than in patients with AMI (P < 0.01). Patients with AMI had higher PAGln levels than healthy individuals (P < 0.05). After adjusting for sex and age, the top tertile of PAGln was positively correlated with T2DM and AMI while that of TMAO was positively correlated with T2DM. CONCLUSIONS: Overall, a robust isotope dilution LC-MS/MS method was established, which may be beneficial for assessing the association between two metabolites with AMI and T2DM.


Assuntos
Diabetes Mellitus Tipo 2 , Infarto do Miocárdio , Cromatografia Líquida/métodos , Glutamina/análogos & derivados , Humanos , Isótopos , Metilaminas , Infarto do Miocárdio/diagnóstico , Espectrometria de Massas em Tandem/métodos
8.
J Pharmacol Sci ; 150(2): 110-122, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36055749

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases, and there are no effective drugs available so far. Lactucin and Lactucopicrin belong to sesquiterpene lactones and are extracted from Cichorium glandulosum Boiss. et Huet (CG) possesses multiple biopharmacological activities. However, the therapeutic effects of both Lactucin and Lactucopicrin on many diseases and their underlying mechanisms remain largely unknown. Here, we analyzed the both natural compounds hypolipidemic effects on FFA-induced HepG2 cells and their potential mechanisms based on transcriptomics and experimental tests. Our results indicated that Lactucin (10 µM) and Lactucopicrin (20 µM) remarkably reduced TG accumulation. Transcriptomics analysis identified 1960, 1645, and 1791 differentially expressed genes (DEGs) and obtained 611 and 635 specific genes in different comparisons, respectively. The enrichment analysis and experimental validations (RT-qPCR and Western Blot) showed that their hypolipidemic activities were most probably exerted via regulating numerous key DEGs involved in lipid metabolism. Taken together, both Lactucin and Lactucopicrin may represent potent hepatoprotective agents. Both of them exhibited therapeutic effects against liver diseases such as NAFLD by regulating multi-gene and proteins like HADHA, ADAM17, SQSTM1, and GBA and modulating multi-pathways like fatty acid oxidation metabolic signaling.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Sesquiterpenos , Células Hep G2 , Humanos , Lactonas/farmacologia , Lactonas/uso terapêutico , Metabolismo dos Lipídeos/genética , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Forbóis , Sesquiterpenos/farmacologia , Sesquiterpenos/uso terapêutico
9.
Nat Commun ; 13(1): 5234, 2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36068224

RESUMO

The development of organic solid-state luminescent materials, especially those sensitive to aggregation microenvironment, is critical for their applications in devices such as pressure-sensitive elements, sensors, and photoelectric devices. However, it still faces certain challenges and a deep understanding of the corresponding internal mechanisms is required. Here, we put forward an unconventional strategy to explore the pressure-induced evolution of the aggregation microenvironment, involving changes in molecular conformation, stacking mode, and intermolecular interaction, by monitoring the emission under multiple excitation channels based on a luminogen with aggregation-induced emission characteristics of di(p-methoxylphenyl)dibenzofulvene. Under three excitation wavelengths, the distinct emission behaviors have been interestingly observed to reveal the pressure-induced structural evolution, well consistent with the results from ultraviolet-visible absorption, high-pressure angle-dispersive X-ray diffraction, and infrared studies, which have rarely been reported before. This finding provides important insights into the design of organic solid luminescent materials and greatly promotes the development of stimulus-responsive luminescent materials.

10.
World J Clin Cases ; 10(20): 7116-7123, 2022 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-36051154

RESUMO

BACKGROUND: Germ cell tumors (GCTs) account for 2% of human malignancies but are the most common malignant tumors among males aged 15-35. Since 1983, an association between mediastinal GCT (MGCT) and hematologic malignancies has been recognized. CASE SUMMARY: We report a case in which malignant histiocytosis was associated with mediastinal GCTs. The clinical data of a male patient with MGCT admitted to Beijing Children's Hospital were collected retrospectively. The patient was first diagnosed according to imaging and pathological features as having MGCT, and was treated with surgery and chemotherapy. One year after stopping chemotherapy, imaging showed metastases in the right supraclavicular, mediastinum, hilar region and retroperitoneal lymph node, right pleura, right lung, and right para-cardiac margin. Pathological diagnosis of the liver nodular and hilar lymph nodes included systemic juvenile xanthogranuloma and Rosai-Dorfman lesions with malignant transformation (i.e., morphological characteristics and immunophenotype of histiocytic sarcoma). Following diagnosis, the patient accepted chemotherapy with vindesine, cytarabine and dexamethasone. Positron emission tomography-computed tomography showed partial remission. The patient was followed-up for 10 mo after the diagnosis of malignant histiocytosis, and no sign of progression or relapse was observed. CONCLUSION: Physicians should recognize the possibility of hematologic malignancies being associated with MGCT. Suitable sites should be selected for pathological examination.

11.
Medicine (Baltimore) ; 101(36): e30170, 2022 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-36086700

RESUMO

BACKGROUND: To evaluate the role and safety of endostar in cervical cancer by comparing the efficacy and adverse reactions of endostar combined with concurrent chemoradiotherapy in patients with locally advanced cervical carcinoma. METHODS: The quality of the included literature was evaluated by searching the database for the comparison of endostar combined with concurrent radiotherapy and chemotherapy in cervical cancer patients; objective response rate (ORR) and disease control rate (DCR) were used as the main outcome indicators, and statistical analysis was performed using RevMan5.3 and State15.3 software. RESULTS: A total of 13 studies were included in this study, including 1057 patients with locally advanced cervical cancer, suggesting that endostar combined with chemoradiotherapy can significantly improve the objective response rate (ORR: odds ratio 3.88, 95% confidence interval 2.77-5.45, P < .00001) and disease control rate (DCR: odds ratio 4.43, 95% confidence interval 2.78-7.04; P < .00001), and there was no significant increase in treatment-related adverse reactions. CONCLUSIONS: In this meta-analysis, endostar combined with concurrent chemoradiotherapy significantly improved ORR and DCR in patients with locally advanced cervical cancer without increasing toxicity. However, this study only analyzed the short-term efficacy of endostar, and its influence on overall survival and progression-free survival needs to be further verified in large randomized controlled trials with long-term follow-up.


Assuntos
Neoplasias do Colo do Útero , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia , Cisplatino/uso terapêutico , Endostatinas , Feminino , Humanos , Proteínas Recombinantes , Neoplasias do Colo do Útero/tratamento farmacológico
12.
Opt Lett ; 47(18): 4628-4631, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36107049

RESUMO

We propose a system to eliminate the graininess of an integral imaging 3D display by using a transmissive mirror device (TMD). The proposed system consists of a 2D display, a micro-lens array (MLA), and a TMD. The TMD comprises square apertures with mirror-reflective inner wall. The light rays pass through the square aperture to form a diffraction spot, and the diffraction light intensity has a Sinc-function distribution. Therefore, the TMD can be used as an optical low-pass filter. In a certain imaging range, the mainlobe of the Sinc-function distribution is almost unchanged. The TMD has the property of a volumetric optical low-pass filter. It can interpolate the interval between discrete 3D pixels. Therefore, the TMD can be used to eliminate the graininess. The resolution of the 3D image is improved by 2.12 times. The experimental results verify the feasibility of the proposed system.

13.
Front Genet ; 13: 946845, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36105111

RESUMO

N7-Methylguanosine (m7G) is an RNA modification serving as a key part of colon cancer development. Thus, a comprehensive analysis was executed to explore prognostic roles and associations with the immune status of the m7G-related lncRNA (m7G-RNAs) in colon adenocarcinoma (COAD). Identification of m7G-RNAs was achieved via Pearson's correlation analysis of lncRNAs in the TCGA-COAD dataset and m7G regulators. A prognostic signature was developed via LASSO analyses. ESTIMATE, CIBERSORT, and ssGSEA algorithms were utilized to assess immune infiltration between different risk groups. Survival analysis suggested the high-risk group possesses poor outcomes compared with the low-risk group. According to the ROC curves, the m7G-RNAs signature exhibited a reliable capability of prediction (AUCs at 1, 3, and 5 years were 0.770, 0.766, and 0.849, respectively). Multivariate hazard analysis proved that the signature was an independent predictive indicator for OS. Moreover, the risk score was related to infiltration levels of naïve B cells, CD4+ memory T cells, and resting NK cells. The result revealed the prognostic value of m7G modification in COAD and provided a novel perspective on personalized immunotherapy strategies.

14.
Lancet ; 400(10357): 1020-1032, 2022 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-36154677

RESUMO

BACKGROUND: Despite the substantial burden caused by childhood cancer globally, childhood cancer incidence obtained in a nationwide childhood cancer registry and the accessibility of relevant health services are still unknown in China. We comprehensively assessed the most up-to-date cancer incidence in Chinese children and adolescents, nationally, regionally, and in specific population subgroups, and also examined the association between cancer incidence and socioeconomic inequality in access to health services. METHODS: In this national cross-sectional study, we used data from the National Center for Pediatric Cancer Surveillance, the nationwide Hospital Quality Monitoring System, and public databases to cover 31 provinces, autonomous regions, and municipalities in mainland China. We estimated the incidence of cancer among children (aged 0-14 years) and adolescents (aged 15-19 years) in China through stratified proportional estimation. We classified regions by socioeconomic status using the human development index (HDI). Incidence rates of 12 main groups, 47 subgroups, and 81 subtypes of cancer were reported and compared by sex, age, and socioeconomic status, according to the third edition of the International Classification of Childhood Cancer. We also quantified the geographical and population density of paediatric oncologists, pathology workforce, diagnoses and treatment institutions of paediatric cancer, and paediatric beds. We used the Gini coefficient to assess equality in access to these four health service indicators. We also calculated the proportions of cross-regional patients among new cases in our surveillance system. FINDINGS: We estimated the incidence of cancer among children (aged 0-14 years) and adolescents (aged 15-19 years) in China from Jan 1, 2018, to Dec 31, 2020. An estimated 121 145 cancer cases were diagnosed among children and adolescents in China between 2018 and 2020, with world standard age-standardised incidence rates of 122·86 (95% CI 121·70-124·02) per million for children and 137·64 (136·08-139·20) per million for adolescents. Boys had a higher incidence rate of childhood cancer (133·18 for boys vs 111·21 for girls per million) but a lower incidence of adolescent cancer (133·92 for boys vs 141·79 for girls per million) than girls. Leukaemias (42·33 per million) were the most common cancer group in children, whereas malignant epithelial tumours and melanomas (30·39 per million) surpassed leukaemias (30·08 per million) in adolescents as the cancer with the highest incidence. The overall incidence rates ranged from 101·60 (100·67-102·51) per million in very low HDI regions to 138·21 (137·14-139·29) per million in high HDI regions, indicating a significant positive association between the incidence of childhood and adolescent cancer and regional socioeconomic status (p<0·0001). The incidence in girls showed larger variation (48·45% from the lowest to the highest) than boys (36·71% from lowest to highest) in different socioeconomic regions. The population and geographical densities of most health services also showed a significant positive correlation with HDI levels. In particular, the geographical density distribution (Gini coefficients of 0·32-0·47) had higher inequalities than population density distribution (Gini coefficients of 0·05-0·19). The overall proportion of cross-regional patients of childhood and adolescent cancer was 22·16%, and the highest proportion occurred in retinoblastoma (56·54%) and in low HDI regions (35·14%). INTERPRETATION: Our study showed that the burden of cancer in children and adolescents in China is much higher than previously nationally reported from 2000 to 2015. The distribution of the accessibility of health services, as a social determinant of health, might have a notable role in the socioeconomic inequalities in cancer incidence among Chinese children and adolescents. With regards to achieving the Sustainable Development Goals, policy approaches should prioritise increasing the accessibility of health services for early diagnosis to improve outcomes and subsequently reduce disease burdens, as well as narrowing the socioeconomic inequalities of childhood and adolescent cancer. FUNDING: National Major Science and Technology Projects of China, National Natural Science Foundation of China, Chinese Academy of Engineering Consulting Research Project, Wu Jieping Medical Foundation, Beijing Municipal Administration of Hospitals Incubating Program.


Assuntos
Leucemia , Neoplasias , Adolescente , Criança , China/epidemiologia , Estudos Transversais , Feminino , Serviços de Saúde , Acesso aos Serviços de Saúde , Humanos , Incidência , Masculino , Neoplasias/diagnóstico , Neoplasias/epidemiologia , Fatores Socioeconômicos
15.
Cell Signal ; 100: 110474, 2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36126794

RESUMO

Multiple myeloma (MM) is one of the most common tumors of the hematological system and remains incurable. Recent studies have shown that long noncoding RNA NORAD is a potential oncogene in a variety of tumors. However, the general biological role and clinical value of NORAD in MM remains unknown. In this study, we measured NORAD expression in bone marrow of 60 newly diagnosed MM, 30 post treatment MM and 17 healthy donors by real-time quantitative polymerase chain reaction (qPCR). The NORAD gene was knockdown by lentiviral transfection in MM cell lines, and the effects of NORAD on apoptosis, cell cycle and cell proliferation in MM cells were examined by flow cytometry, CCK8 assay, EDU assay and Western blot, and the differential genes after knockdown of NORAD were screened by mRNA sequencing, followed by in vivo experiments and immunohistochemical assays. We found that knockdown of NORAD promoted MM cell apoptosis, induced cell cycle G1 phase arrest, and inhibited MM cell apoptosis in in vivo and in vitro experiments. Mechanistically, NORAD plays these roles through the BMP6/P-ERK1/2 axis. We discuss a novel mechanism by which NORAD acts pro-tumorigenically in MM via the BMP6/P-ERK1/2 axis.

16.
Plant Biotechnol J ; 2022 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-36161753

RESUMO

Selaginella moellendorffii miltiradiene synthase (SmMDS) is a unique bifunctional diterpene synthase (diTPS) that catalyses the successive cyclization of (E,E,E)-geranylgeranyl diphosphate (GGPP) via (+)-copalyl diphosphate (CPP) to miltiradiene, which is a crucial precursor of important medicinal compounds, such as triptolide, ecabet sodium and carnosol. Miltiradiene synthetic processes have been studied in monofunctional diTPSs, while the precise mechanism by which active site amino acids determine product simplicity and the experimental evidence for reaction intermediates remain elusive. In addition, how bifunctional diTPSs work compared to monofunctional enzymes is attractive for detailed research. Here, by mutagenesis studies of SmMDS, we confirmed that pimar-15-en-8-yl+ is an intermediate in miltiradiene synthesis. Moreover, we determined the apo-state and the GGPP-bound state crystal structures of SmMDS. By structure analysis and mutagenesis experiments, possible contributions of key residues both in class I and II active sites were suggested. Based on the structural and functional analyses, we confirmed the copal-15-yl+ intermediate and unveiled more details of the catalysis process in the SmMDS class I active site. Moreover, the structural and experimental results suggest an internal channel for (+)-CPP produced in the class II active site moving towards the class I active site. Our research is a good example for intermediate identification of diTPSs and provides new insights into the product specificity determinants and intermediate transport, which should greatly facilitate the precise controlled synthesis of various diterpenes.

17.
J Pediatr Surg ; 57(12): 926-933, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35961818

RESUMO

BACKGROUND: Cervical neuroblastic tumors (NTs) are rare but less aggressive cancer with an above-average survival rate. Little has been published regarding the management and surgical outcomes of patients with cervical NTs based on pathology category. This study compared and identified the preoperative characteristics of cervical NTs in different pathology categories and evaluated the outcomes of patients undergoing surgical resection. MATERIALS AND METHODS: Upon the institutional review board's approval, a retrospective chart review was performed at Beijing Children's Hospital from April 2013 to August 2020. Demographics of patients, imaging data, lab test results, operation details and outcomes were recorded and analyzed. RESULTS: Of 32 cervical NTs, 24(80%) were classified as neuroblastoma (NB) /ganglioneuroblastoma-nodular (GNBn) and 8(20%) as ganglioneuroblastoma-intermixed (GNBi)/ ganglioneuroma (GN). Patients with GNBi/GN were older than those with NB/GNBn (44.5 months (IQR 16-81) vs 9 months (IQR 1-47); P = 0.001). GNBi/GN patients presented more frequently with stage 1 disease compared with NB/GNBn patients (100% vs. 29.2%, P = 0.001), less frequently with tumor-related symptoms (0% vs. 70.8%, P = 0.001), artery encased tumor (0% vs. 41.7%, P = 0.035), and surgical complications (25% vs. 70.8%, P = 0.038). GNBi/GN patients were also less likely to show elevated neuron specific enolase (NSE) (12.5% vs. 79.2%, P = 0.002). CONCLUSIONS: Cervical NB/GNBn and GNBi/GN patients had distinct characteristic clinical presentations and surgical outcomes. For children with features suggestive of benign disease (older age, asymptomatic, normal serum tumor markers) and no artery image-defined risk factors (IDRFs), upfront resection can be considered.


Assuntos
Ganglioneuroblastoma , Ganglioneuroma , Neuroblastoma , Humanos , Criança , Ganglioneuroblastoma/diagnóstico por imagem , Ganglioneuroblastoma/cirurgia , Estudos Retrospectivos , Ganglioneuroma/diagnóstico por imagem , Ganglioneuroma/cirurgia , Neuroblastoma/cirurgia , Resultado do Tratamento
18.
Front Neurosci ; 16: 936760, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35968378

RESUMO

Alzheimer's disease (AD) is the sixth leading cause of death worldwide and cannot be effectively cured or prevented; thus, early diagnosis, and intervention are important. The importance of exosomes, membrane-bound extracellular vesicles produced in the endosome of eukaryotic cells, in the development, diagnosis, and treatment of AD has been recognized; however, their specific functions remain controversial and even unclear. With the development of exosome extraction, isolation, and characterization, many studies have focused on exosomes derived from different cells and body fluids. In this study, we summarized the roles of exosomes derived from different body fluids and cells, such as neuron, glial, stem, and endothelial cells, in the development, diagnosis, monitoring, and treatment of AD. We also emphasize the necessity to focus on exosomes from biological fluids and specific cells that are less invasive to target. Moreover, aside from the concentrations of classic and novel biomarkers in exosomes, the size and number of exosomes may also influence early and differential diagnosis of AD.

19.
Front Genet ; 13: 929049, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36035153

RESUMO

Diabetic retinopathy (DR) is a common complication and the leading cause of blindness in patients with type 2 diabetes. DR has been shown to be closely correlated with blood glucose levels and the duration of diabetes. However, the onset and progression of DR also display clinical heterogeneity. We applied whole-exome sequencing and RNA-seq approaches to study the gene mutation and transcription profiles in three groups of diabetic patients with extreme clinical phenotypes in DR onset, timing, and disease progression, aiming to identify genetic variants that may play roles in the pathogenesis of DR. We identified 23 putatively pathogenic genes, and ingenuity pathway analysis of these mutated genes reveals their functional association with glucose metabolism, diabetic complications, neural system activity, and dysregulated immune responses. In addition, ten potentially protective genes were also proposed. These findings shed light on the mechanisms underlying the pathogenesis of DR and may provide potential targets for developing new strategies to combat DR.

20.
Cell Commun Signal ; 20(1): 121, 2022 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-35971127

RESUMO

BACKGROUND: Immunotherapy has proven to be an emerging treatment for non-small-cell lung cancer in recent years. Notably, smokers show higher programmed cell death ligand-1 (PD-L1) expression and better responses to PD-1/PD-L1 inhibitors than nonsmokers. Genome-wide association studies show that the CHRNΑ5 encoding α5-nicotinic acetylcholine receptor (α5-nAChR) is especially relevant to lung cancer and nicotine dependence. Jab1 is a key regulatory factor and promotes the stabilization of PD-L1. Our previous study reported that α5-nAChR mediates lung adenocarcinoma (LUAD) epithelial-mesenchymal transition (EMT) and metastasis via STAT3/Jab1. However, the link between α5-nAChR and PD-L1 is unclear in LUAD. METHODS: We used various bioinformatics databases to analyze the expression of related genes and their correlations. Expression and clinicopathologic significance of α5-nAChR and PD-L1 were detected by immunohistochemistry in a tissue microarray. α5-nAChR regulated LUAD cell immune escape by targeting the STAT3/Jab1-PD-L1 signalling by Western-blotting and ChIP in vitro. We used T cell coculture, flow cytometry, ELISA, CCK8 assay and crystal violet staining to detect the expression of regulatory T cell (Tregs), IFN-γ, IL-2 and the ability of T cell-mediated tumour cell killing respectively. IF assays were performed in both cancer cells and tumour xenograft paraffin sections to analyze the protein expression. The in vivo experiments in mouse model were performed to show the α5-nAChR-mediated immune escape via PD-L1 pathway. RESULTS: The expression of α5-nAChR was correlated with PD-L1 expression, smoking status and lower survival of LUAD in vivo. In vitro, the expression of α5-nAChR mediated phosphorylated STAT3 (pSTAT3), Jab1 and PD-L1 expression. STAT3 bound to the Jab1 or PD-L1 promoter and mediated PD-L1 expression. Jab1 stabilized PD-L1 expression in LUAD cells. Furthermore, in primary T cell cocultured system, downregulation of α5-nAChR suppressed the function of CD4+CD25+FOXP3+ Tregs, enhanced IFN-γ secretion, and increased T cell-mediated killing of LUAD cells. In the Jurkat T cells and LUAD cells coculture assay, inhibition of α5-nAChR increased IL-2 secretion. In tumour xenograft tissues, α5-nAChR expression was related to PD-L1, Jab1, pSTAT3, CD4 and granzyme B expression (GB). CONCLUSIONS: Our results suggest that the novel α5-nAChR/STAT3-Jab1-PD-L1 axis is involved in LUAD immune escape, which could lead to potential therapeutic strategies for cancer immunotherapy. Video abstract.


Assuntos
Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Receptores Nicotínicos , Adenocarcinoma de Pulmão/patologia , Animais , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Estudo de Associação Genômica Ampla , Humanos , Interleucina-2/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Fator de Transcrição STAT3/metabolismo
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