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1.
Zootaxa ; 5026(1): 59-70, 2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34810941

RESUMO

A newly identified tardigrade species from China, Pilatobius nuominensis sp. nov., belongs to the group of species with cuticle of the dorsal and lateral caudal region with evident irregular polygonal sculpture. Nucleotide sequences of two nuclear (18S rRNA, 28S rRNA) and one mitochondrial (COI) DNA fragments of the new species are provided, which allows an independent verification of the taxonomic status of the new species. This is the first record of the genus Pilatobius in the Great Hinggan Mountains.


Assuntos
Tardígrados , Animais , Sequência de Bases , China , Filogenia , RNA Ribossômico 18S , RNA Ribossômico 28S , Tardígrados/genética
2.
Mol Med ; 27(1): 142, 2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34732131

RESUMO

BACKGROUND: Cardiotoxicity is a common complication following anthracycline chemotherapy and represents one of the serious adverse reactions affecting life, which severely limits the effective use of anthracyclines in cancer therapy. Although some genes have been investigated by individual studies, the comprehensive analysis of key genes and molecular regulatory network in anthracyclines-induced cardiotoxicity (AIC) is lacking but urgently needed. METHODS: The present study integrating several transcription profiling datasets aimed to identify key genes associated with AIC by weighted correlation network analysis (WGCNA) and differentially expressed analysis (DEA) and also constructed miRNA-transcription factor-gene regulatory network. A total of three transcription profiling datasets involving 47 samples comprising 41 rat heart tissues and 6 human induced pluripotent stem cell-derived cardiomyocytes (hiPSCMs) samples were enrolled. RESULTS: The WGCNA and DEA with E-MTAB-1168 identified 14 common genes affected by doxorubicin administrated by 4 weeks or 6 weeks. Functional and signal enrichment analyses revealed that these genes were mainly enriched in the regulation of heart contraction, muscle contraction, heart process, and oxytocin signaling pathway. Ten (Ryr2, Casq1, Fcgr2b, Postn, Tceal5, Ccn2, Tnfrsf12a, Mybpc2, Ankrd23, Scn3b) of the 14 genes were verified by another gene expression profile GSE154603. Importantly, three key genes (Ryr2, Tnfrsf12a, Scn3b) were further validated in a hiPSCMs-based in-vitro model. Additionally, the miRNA-transcription factor-gene regulatory revealed several top-ranked transcription factors including Tcf12, Ctcf, Spdef, Ebf1, Sp1, Rcor1 and miRNAs including miR-124-3p, miR-195-5p, miR-146a-5p, miR-17-5p, miR-15b-5p, miR-424-5p which may be involved in the regulation of genes associated with AIC. CONCLUSIONS: Collectively, the current study suggested the important role of the key genes, oxytocin signaling pathway, and the miRNA-transcription factor-gene regulatory network in elucidating the molecular mechanism of AIC.

3.
Front Genet ; 12: 730519, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34777467

RESUMO

Illumina is the leading sequencing platform in the next-generation sequencing (NGS) market globally. In recent years, MGI Tech has presented a series of new sequencers, including DNBSEQ-T7, MGISEQ-2000 and MGISEQ-200. As a complex application of NGS, cancer-detecting panels pose increasing demands for the high accuracy and sensitivity of sequencing and data analysis. In this study, we used the same capture DNA libraries constructed based on the Illumina protocol to evaluate the performance of the Illumina Nextseq500 and MGISEQ-2000 sequencing platforms. We found that the two platforms had high consistency in the results of hotspot mutation analysis; more importantly, we found that there was a significant loss of fragments in the 101-133 bp size range on the MGISEQ-2000 sequencing platform for Illumina libraries, but not for the capture DNA libraries prepared based on the MGISEQ protocol. This phenomenon may indicate fragment selection or low fragment ligation efficiency during the DNA circularization step, which is a unique step of the MGISEQ-2000 sequence platform. In conclusion, these different sequencing libraries and corresponding sequencing platforms are compatible with each other, but protocol and platform selection need to be carefully evaluated in combination with research purpose.

4.
Physiol Mol Biol Plants ; 27(9): 1919-1931, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34616114

RESUMO

Fructokinase (FRK) is the main fructose phosphorylase and plays an important role in catalyzing the irreversible reaction of free fructose phosphorylation. In order to study the regulatory effect of different forms and concentrations of nitrogen on PtFRK genes in Populus trichocarpa, seven genes encoding the hypothetical FRK proteins were identified in Populus trichocarpa genome by bioinformatics method. Phylogenetic analysis revealed that PtFRK family genes can be divided into two subgroups: SI (PtFRK 1, 3, 4, 6) and SII (PtFRK 2, 5, 7). The tissue-specific expression data obtained from PopGenIE indicate that PtFRK2, 3, 4 and 5 are expressed highly in the stem. Quantitative real-time RT-PCR illustrate that PtFRK1-7 showed different expression patterns in different tissues under different concentrations and morphological nitrogen application. Under high nitrate treatment, the expression levels of PtFRK1, 2, 3 and 6 in stem increased significantly, while under low nitrate treatment, only the expression of PtFRK1, 4 in the upper stem and the expression of PtFRK3, 5 in the lower stem increased significantly. In contrast, ammonium tends to inhibit the expression of PtFRKs in lower stems, the expression levels of PtFRK2, 3, 4 and 5 are significantly reduced under ammonium treatment. However, high ammonium had significant effects on PtFRK6 in the apical bud and upper leaves, which were 6 and 8 times of the control, respectively. These results laid the foundation for the study of the PtFRK gene family of poplar and provided a theoretical basis for the molecular mechanism of nitrogen regulating cell wall development. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-021-01055-6.

5.
World J Gastroenterol ; 27(35): 5946-5957, 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34629811

RESUMO

BACKGROUND: Crohn's disease (CD) is an incurable intestinal disorder with unclear etiology and pathogenesis. Currently, there is a lack of specific biomarkers and drug targets for CD in clinical practice. It is essential to identify the precise pathophysiological mechanism of CD and investigate new therapeutic targets. AIM: To explore a new biomarker and therapeutic target for CD and verify its role in the CD pathological mechanism. METHODS: Proteomics was performed to quantify the protein profile in the plasma of 20 CD patients and 20 matched healthy controls. Hub genes among the selected differentially expressed proteins (DEPs) were detected via the MCODE plugin in Cytoscape software. The expression level of one hub gene with an immunoregulatory role that interested us was verified in the inflamed intestinal tissues of 20 CD patients by immunohistochemical analysis. After that, the effects of the selected hub gene on the intestinal inflammation of CD were identified in a CD cell model by examining the levels of proinflammatory cytokines by enzyme-linked immunosorbent assays and the expression of the NF-κB signalling pathway by quantitative real-time PCR analysis and Western blot assays. RESULTS: Thirty-five DEPs were selected from 393 credible proteins identified by proteomic analysis. Among the DEPs, fibrinogen-like protein 1 (FGL1), which attracted our attention due to its function in the regulation of the immune response, had 1.722-fold higher expression in the plasma of CD patients and was identified as a hub gene by MCODE. Furthermore, the expression of FGL1 in the intestinal mucosal and epithelial tissues of CD patients was also upregulated (P < 0.05). In vitro, the mRNA levels of FGL1 and NF-κB; the protein expression levels of FGL1, IKKα, IKKß, p-IKKα/ß, p-IκBα, and p-p65; and the concentrations of the proinflammatory cytokines IL-1ß, IL-6, IL-17, and TNF-α were increased (P < 0.05) after stimulation with lipopolysaccharide, which were reversed by knockdown of FGL1 with siRNA transfection (P < 0.05). Conversely, FGL1 overexpression enhanced the abovementioned results (P < 0.05). CONCLUSION: FGL1 can induce intestinal inflammation by activating the canonical NF-κB signalling pathway, and it may be considered a potential biomarker and therapeutic target for CD.


Assuntos
Doença de Crohn , Doença de Crohn/tratamento farmacológico , Doença de Crohn/genética , Fibrinogênio , Humanos , NF-kappa B , Proteômica , Fator de Necrose Tumoral alfa
6.
J Fluoresc ; 2021 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-34687397

RESUMO

Hydrogen sulfide and biothiol molecules such as Cys and GSH acted important roles in many physiological processes. To simultaneously detect and distinguish them was quite necessary by a suitable fluorescent probe. A novel chemosensor 4-(4-(benzo[d]thiazol-2-yl)-2-methoxyphenoxy)-7-nitrobenzo[c][1,2,5]oxadiazole (BMNO) was designed to detect H2S/Cys/GSH using the combination of nitrobenzofurazan (NBD) and benzothiazole fluorophores linked by a facile ether bond. The probe BMNO was developed for simultaneous identification of H2S, Cys and GSH. Noticeably, the color changes (from colorless to light purple, light orange and light yellow) of probe BMNO solutions for sensing H2S, Cys and GSH could be observed by naked eyes, respectively. The probe BMNO exhibited high selectivity and sensitivity for H2S, Cys and GSH showing distinct optical signal with detection limit as low as 0.15 µM, 0.03 µM and 0.14 µM, respectively. The sensing mechanism was clarified by spectrum analysis and some controlled experiments. In addition, these outstanding properties of probe BMNO enabled its practical applications in detection H2S in beer, and in cell imaging for Cys and GSH as well.

7.
Front Nutr ; 8: 746684, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34651009

RESUMO

Intramuscular fat (IMF) and visceral adipose tissue (VAT) are both lipids, but have significantly different deposition processes. Furthermore, the heterogeneity of lipid molecular characteristics and mechanisms is unclear. Accordingly, this study used non-targeted lipidomics and transcriptomics to analyze the lipid profiles and metabolism of longissimus dorsi muscle (LDM) and VAT from donkeys. A total of 1,146 and 1,134 lipids belonging to 18 subclasses were identified in LDM and VAT, respectively, with LDM having higher glycerophospholipid (GP) and lower glycerolipid (GL) contents. Polyunsaturated fatty acids (PUFAs) were distributed preferentially at the sn-1 positions in triglycerides (TGs), and sn-2 positions in phosphatidylcholine (PC) and phosphatidylethanolamine (PE). The percentage PUFA content in TGs was significantly lower in LDM than in VAT, while the opposite trend was observed for PUFAs in PC and PE. A total of 110 different lipid molecules (72 downregulated and 38 upregulated) were identified in LDM compared with VAT, of which 11 were considered potential lipid markers. These different lipids were involved in 17 metabolic pathways, including GL and GP metabolisms. Of the 578 differentially expressed genes screened, 311 were downregulated and 267 were upregulated in LDM compared with VAT. Enriched ontology analysis of the differentially expressed genes mainly involved sphingolipid signaling pathways, and GP, GL, and sphingolipid metabolisms. Overall, lipidomics and transcriptomics indicated differences in lipid profiles and metabolism in LDM and VAT, providing new perspectives for the study of heterogeneity in IMF and VAT.

8.
STAR Protoc ; 2(4): 100794, 2021 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-34632413

RESUMO

This CloneSeq protocol combines clonal expansion inside 3D hydrogel spheres and droplet-based RNA sequencing to resolve the limited sensitivity of single-cell approaches. CloneSeq can reveal rare subpopulations and support cellular stemness. CloneSeq can be adapted to different biological systems to discover rare subpopulations by leveraging clonal enhanced sensitivity. Important considerations include the hydrogel composition, adaptation of 3D cultured clones to the inDrops system, and inherent adhesive properties of the cells. CloneSeq is only validated for cell lines so far. For complete details on the use and execution of this protocol, please refer to (Bavli et al., 2021).

9.
Stem Cell Res ; 56: 102562, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34634758

RESUMO

The FLNC gene encodes the sarcomeric protein filamin C which plays a central role in cardiomyocytes. Truncating FLNC mutations (stop or frameshift etc.) also cause dilated cardiomyopathy (DCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC). To further understand the exact role of FLNC in DCM, we have generated a human FLNC knockout cell line from the original embryonic stem cell line H9 by CRISPR/Cas9 gene editing technology in this study. The establishment cell line WAe009-A-70 have a compound heterozygous 4 bp deletion/13 bp deletion in the exon 1 of FLNC which resulted in a frameshift in the translation of FLNC. No filamin C protein was detected in cardiomyocytes differentiated from this cell line. Moreover, WAe009-A-70 also expressed pluripotency markers, maintained the ability to differentiate into the three germ layers in vitro and had a normal karyotype.


Assuntos
Displasia Arritmogênica Ventricular Direita , Cardiomiopatia Dilatada , Células-Tronco Embrionárias Humanas , Sistemas CRISPR-Cas/genética , Cardiomiopatia Dilatada/genética , Filaminas/genética , Humanos , Mutação
10.
Poult Sci ; 100(12): 101454, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34649058

RESUMO

The large tumor suppressor homolog 2 (LATS2), one of the central regulators of the Hippo/MST signaling pathway, plays an inhibitory role in ovarian function and different organ development and growth in mammals. However, the exact roles and molecular regulatory mechanisms of LATS2 in chicken granulosa cell (GC) proliferation, differentiation, and steroidogenesis required for ovarian follicle growth, development, and follicular selection remain poorly understood. This study demonstrated that the LATS2 protein was predominantly localized in the oocytes and undifferentiated GCs of various-sized prehierarchical follicles of the hen ovary. Expression levels of LATS2 mRNA were significantly higher in the smaller follicles (from 1 mm to 5.9 mm in diameter) and the GCs than in the larger follicles (6-6.9 mm in diameter up to F1). Moreover, we found that high levels of LATS2 suppressed the GC proliferation and the mRNA and protein expression of the genes serving as the biomarkers of follicle selection, GC differentiation, and steroidogenesis in the GCs, including FSHR, STAR, CYP11A1, ESR1, and ESR2. Interestingly, the LATS2 significantly downregulated SAV1 and YAP1 transcripts but upregulated the expression of STK3, STK4, TEAD1, and TEAD3 mRNA. Our study provided evidences that STK3/4-LATS2-YAP1 not only acts as a suppressor of cell proliferation and follicle selection but also LATS2 may serve as an enhancer in cell proliferation and follicle selection through the YAP1-LATS2 and the LATS2-STK3/4 feedback loops by promoting the expression of TEAD1/3 but inhibiting the expression of SAV1 transcripts in the prehierarchical follicle development of hen ovary. Taken together, the present study initially revealed the pivotal role and molecular mechanism of LATS2 in the regulation of hen prehierarchical follicle development by controlling GC proliferation, differentiation, steroidogenesis, and follicle selection via the Hippo/MST signaling pathway.

11.
Transpl Immunol ; 69: 101486, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34678462

RESUMO

INTRODUCTION: Anti-thymocyte globulin (ATG) is used prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) for graft-versus-host disease (GVHD) prophylaxis. Two different ATG doses (7.5 or 10 mg/kg) were evaluated in comparison with a group without ATG therapy. METHODS: We retrospectively analyzed 132 patients who were transplanted with HSCT without ATG (non-ATG), or who received 7.5 mg/kg ATG (ATG-7.5) or 10 mg/kg ATG (ATG-10) prior to transplantation. The immune cells (CD3+CD4+ T cells, CD3+CD8+ T cells, CD19+ B cells and CD16+CD56+ NK cells) were examined in peripheral blood every three months post-HSCT for 12 months. RESULTS: Compared with non-ATG group, combined ATG-7.5/ATG-10 groups had significantly lower CD3+CD4+ T cells and higher CD3+CD8+ T cells at 3, 6, 9, 12 months post-HSCT; thus, displaying a lower CD4/CD8 ratio in the ATG groups compared to non-ATG group. The ratio of CD19+ B cells was statistically lower (at 3rd month, p = .014; at 6th month, p = .025) in combined ATG-7.5/ATG-10 groups at 3 and 6 months post-HSCT, but not at 9 and 12 months after HSCT. The ratios of CD3+CD4+ T cells, CD3+CD8+ T cells, CD19+ B cells and CD16+CD56+ NK cells were similar between the ATG-7.5 and ATG-10 groups at all examined time points. The overall survival (OS), progression-free survival (PFS), relapse and acute GVHD (aGVHD) were comparable among recipients without ATG therapy and with ATG-7.5 or/and ATG-10 therapies. Multivariate analysis revealed that immune cells ratios were not independent factors affecting prognosis. CONCLUSION: The ATG therapy at higher and lower doses led to a delayed reconstitution of T cells and the inversion of CD4/CD8 ratio for at least one year after HSCT.

12.
Ann Transl Med ; 9(16): 1354, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34532491

RESUMO

Osimertinib has efficacy superior to that of standard epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) for the first-line treatment of patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC). However, patients treated with osimertinib eventually acquire drug resistance. MET missense mutations have been demonstrated to mediate resistance to MET-TKIs, such as crizotinib. But the role of MET missense mutations in mediating EGFR TKI resistance is undefined. With the increasing use of next-generation sequencing (NGS) at diagnosis, many mechanisms of acquired resistance have been discovered in patients with activated tyrosine kinase receptors. Herein, we report the first case of MET D1228N mutation mediating acquired resistance to osimertinib in a MET TKI-naïve NSCLC. The patient with advanced lung adenocarcinoma harboring EGFR exon 19 deletion initially responded to osimertinib with progression-free survival (PFS) lasting 11 months and then developed resistance with an acquired mutation of MET D1228N. Subsequently, combination therapy of cabozantinib and osimertinib was administrated to the patient, and her clinical symptoms were rapidly relieved within one week with good tolerance. She remained on the combined treatment for 10 months. Finally, she achieved an overall survival (OS) of 25 months. Based on our findings, patient with MET D1228N mutant lung adenocarcinoma clinically benefited from combinatorial therapy of cabozantinib and osimertinib after osimertinib resistance.

13.
Ann Med ; 53(1): 1621-1631, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34498502

RESUMO

PURPOSES: There is increasing concern regarding cardiovascular risk in non-alcoholic fatty liver disease (NAFLD) patients with liver fibrosis. This study aims: (1) to assess the association between NAFLD and liver fibrosis status and the development of carotid plaque (CP), and (2) to identify CP risk factors among general population with different baseline NAFLD and liver fibrosis status. METHODS: This retrospective cohort study included 14,288 adult participants who went for regular health check-ups between 2014 and 2019, in one hospital in Zhejiang, China. NAFLD was diagnosed by abdominal ultrasound and the NAFLD fibrosis score (NFS) was calculated to reflect the extent of liver fibrosis. Cox proportional hazards analyses were applied to assess the risk of CP development across groups with different baseline NAFLD and NFS status. RESULTS: NAFLD participants with high NFS had higher risk of CP compared to non-NAFLD participants (adjusted hazard ratio 1.68, 95% confidence interval [CI] 1.43-1.96, p < .001). Progression from NAFLD free and NAFLD with low NFS to NAFLD with high NFS are associated with 1.56-fold (95% CI 1.21-2.01, p = .001) and 1.43-fold (95% CI 1.11-1.84, p = .006) increased risk of CP, respectively. Risk factors associated with CP vary based on baseline NAFLD and NFS status. Among NAFLD participants with high NFS, hypertension is the only significant risk factor after adjustment for other potential influencing factors. CONCLUSIONS: NAFLD and liver fibrosis status can be an independent predictor for CP development regardless of metabolic abnormalities. Hypertension is a major risk factor for CP development among NAFLD patients with high NFS.KEY MESSAGESNon-alcoholic fatty liver disease (NAFLD) and liver fibrosis status can be an independent predictor for development of carotid plaque.Progression from NAFLD free and NAFLD with low NAFLD fibrosis score (NFS) to NAFLD with high NFS are associated with increased risk of carotid plaque.Risk factors associated with carotid plaque vary based on baseline NAFLD and NFS status, and hypertension plays the most important role among patients with NAFLD and high NFS.

14.
Front Pharmacol ; 12: 627935, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34512316

RESUMO

Background: Despite the development of such multiple therapeutic approaches, approximately 20% patients experience recurrence. Identification of molecular markers for stratifying the different risks of tumour recurrence and progression is considered imperative. Methods: We used a RayBio Human Cytokine Antibody Array that simultaneously detected the levels of 297 proteins and profiled the conditioned medium of HONE1 cells and the radioresistant NPC cells HONE1-IR. We found Angiogenin(ANG) expression to be significantly increased in HONE1-IR and HONE1-IR cells exposed to 4-Gy X-ray radiation. Results: We investigated the expression of ANG in NPC tissues and explored its prognostic significance in patients with NPC. We found that ANG expression was increased in recurrent NPC tissues. Elevated expression of ANG induced radio-resistance in NPC cells, in addition to being significantly associated with shorter PFS, OS, and LRFS in patients with NPC. Multivariate analysis results revealed that ANG was an independent prognostic factor that predicted PFS, OS, and LRFS. Furthermore, a nomogram model was generated to predict OS in terms of ANG expression. Conclusion: Our results found the radioresistant function of ANG and proved the clinical prognostic significance of ANG, and the results could help predict radio-sensitivity and stratify high-risk patients or tumour recurrence.

15.
J Pharm Pharmacol ; 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34559879

RESUMO

OBJECTIVES: Nowadays, one of the most common gastrointestinal cancers is colorectal cancer (CRC). Chemotherapy is still one of the main methods to treat cancer. However, the currently available synthetic chemotherapy drugs often cause serious adverse reactions. Apoptosis is generally considered as an ideal way for induction the death of tumour cells without the body's inflammatory response, and it is reported that lots of natural agents could trigger various cancer cells to apoptosis. The overarching aim of this project was to elucidate the specific mechanisms by which natural substances induce apoptosis in CRC cells and to be used as an alternative therapeutic option in the future. KEY FINDINGS: The mechanisms for the pro-apoptotic effects of natural substances derived from herbs or plants include death receptor pathway, mitochondrial pathway, endoplasmic reticulum stress pathway, related signal transduction pathways (PI3K/Akt, MAPK, p53 signalling), and so on. SUMMARY: This paper updated this information regarding the anti-tumour effects of natural agents via induction of apoptosis against CRC, which would be beneficial for future new drug research regarding natural products from herbs or plants.

16.
Acta Trop ; 224: 106073, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34487719

RESUMO

In western societies, the prevalence of type 2 diabetes (T2D) is related to the hygiene hypothesis, which implies that reduced exposure to infectious factors results in a loss of the immune stimulation necessary to form the immune system during development. In fact, it has been reported that parasites, such as Schistosoma, can improve or prevent the development of T2D, which may be related to the activity of immune cells, including regulatory T cells (Tregs). Hence, Schistosoma, Tregs, and T2D share a close relationship. Schistosoma infection and the molecules released can lead to an increase in Tregs, which play an important role in the suppression of T2D. In this review, we provide an overview of the role of Tregs in the response to Schistosoma infection and the protective mechanism of Schistosoma-related molecular products against T2D.


Assuntos
Diabetes Mellitus Tipo 2 , Linfócitos T Reguladores , Animais , Diabetes Mellitus Tipo 2/prevenção & controle , Schistosoma
17.
Dis Markers ; 2021: 3776854, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34484468

RESUMO

Recent clinical trials of lung adenocarcinoma with immune checkpoint inhibitors revealed that lung adenocarcinoma patients with EGFR mutations have a poor response to immunotherapy. However, the mechanisms have not been addressed. We performed immunohistochemistry analyses of resected lung adenocarcinoma tissues with and without EGFR mutations to investigate and compare the characteristics of the tumor microenvironment (TME). We retrospectively enrolled a total of 323 lung adenocarcinoma patients (164 had EGFR mutations), and their corresponding tissue samples were analyzed by the EGFR mutation test and immunohistochemistry. We selected the markers of the immune checkpoint molecule (PD1, PD-L1, and LAG-3) and immune cell (CD3, CD4, CD8, and Foxp3) as markers of the tumor microenvironment. Our results revealed that patients had a distinct tumor microenvironment between EGFR-mutant and wild-type lung adenocarcinomas; the expression of CD3, CD4, PD-L1, and Foxp3 in EGFR-mutant tumors was significantly higher than that in wild-type tumors, while the expression of LAG3 and PD-1 showed a positive correlation with EGFR-wild-type tumors. In survival analysis, EGFR-wild-type patients had longer disease-free survival (DFS) than EGFR-mutant patients (P = 0.0065). Our research demonstrates significant differences in tumor microenvironment composition between EGFR-mutant and wild-type patients. Our findings provide novel evidence that contributes to understanding the mechanism underlying the poor efficacy of immune checkpoint inhibitors.

18.
Oral Oncol ; 122: 105539, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34547555

RESUMO

BACKGROUND: The goal of this study was to explore the benefits of S-1/capecitabine as maintenance therapy in locoregionally advanced nasopharyngeal carcinoma (NPC) patients with different risks of treatment failure. METHODS: A total of 2205 eligible, locoregionally advanced NPC patients were recruited for this retrospective study. Multivariate Cox regression analysis was performed to identify optimal predictors of overall survival (OS) and distant metastasis-free survival (DMFS) for constructing the nomograms. Patients were stratified into high-risk or low-risk groups based on the total score of the nomograms. Propensity score matching (PSM) was performed to match the maintenance and non-maintenance cohorts in different risk groups. A log-rank test was performed to evaluate correlations between maintenance therapy and survival. RESULTS: A nomogram for OS was established (C-index, 0.664; 95% confidence interval, 0.635-0.693). The 5-year OS rate was significantly higher in the low-risk group than in the high-risk group (83.5% vs. 67.2%, P < 0.001). Patients in the high-risk group who received S-1/capecitabine maintenance therapy achieved significant improvement in the 5-year OS rate (82.8% vs. 67.1%, p = 0.034), whereas patients in the low-risk group did not (86.7% vs. 80.9%, P = 0.081). There was no significant difference in OS, DMFS, progression-free survival (PFS), or toxicities between the S-1 and capecitabine groups (all P > 0.05), and overall treatment-related adverse events (AEs) were not severe (grade 1-2). CONCLUSION: S-1/capecitabine maintenance therapy could prolong OS for locoregionally advanced NPC patients in the high-risk group. The toxicities of S-1/capecitabine maintenance therapy were mild and tolerable. Our findings can help guide maintenance therapy in locoregionally advanced NPC.

19.
mBio ; 12(5): e0222021, 2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34579576

RESUMO

Coronavirus disease 2019 (COVID-19) has caused huge deaths and economic losses worldwide in the current pandemic. The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is thought to be an ideal drug target for treating COVID-19. Leupeptin, a broad-spectrum covalent inhibitor of serine, cysteine, and threonine proteases, showed inhibitory activity against Mpro, with a 50% inhibitory concentration (IC50) value of 127.2 µM in vitro in our study here. In addition, leupeptin can also inhibit SARS-CoV-2 in Vero cells, with 50% effective concentration (EC50) values of 42.34 µM. More importantly, various strains of streptomyces that have a broad symbiotic relationship with medicinal plants can produce leupeptin and leupeptin analogs to regulate autogenous proteases. Fingerprinting and structure elucidation using high-performance liquid chromatography (HPLC) and high-resolution mass spectrometry (HRMS), respectively, further proved that the Qing-Fei-Pai-Du (QFPD) decoction, a traditional Chinese medicine (TCM) formula for the effective treatment of COVID-19 during the period of the Wuhan outbreak, contains leupeptin. All these results indicate that leupeptin at least contributes to the antiviral activity of the QFPD decoction against SARS-CoV-2. This also reminds us to pay attention to the microbiomes in TCM herbs as streptomyces in the soil might produce leupeptin that will later infiltrate the medicinal plant. We propose that plants, microbiome, and microbial metabolites form an ecosystem for the effective components of TCM herbs. IMPORTANCE A TCM formula has played an important role in the treatment of COVID-19 in China. However, the mechanism of TCM action is still unclear. In this study, we identified leupeptin, a metabolite produced by plant-symbiotic actinomyces (PSA), which showed antiviral activity in both cell culture and enzyme assays. Moreover, leupeptin found in the QFPD decoction was confirmed by both HPLC fingerprinting and HRMS. These results suggest that leupeptin likely contributes to the antiviral activity of the QFPD decoction against SARS-CoV-2. This result gives us important insight into further studies of the PSA metabolite and medicinal plant ecosystem for future TCM modernization research.

20.
Elife ; 102021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34491895

RESUMO

Inducible regulatory T (iTreg) cells play a central role in immune suppression. As iTreg cells are differentiated from activated T (Th0) cells, cell metabolism undergoes dramatic changes, including a shift from fatty acid synthesis (FAS) to fatty acid oxidation (FAO). Although the reprogramming in fatty acid metabolism is critical, the mechanism regulating this process during iTreg differentiation is still unclear. Here we have revealed that the enzymatic activity of ATP-citrate lyase (ACLY) declined significantly during iTreg differentiation upon transforming growth factor ß1 (TGFß1) stimulation. This reduction was due to CUL3-KLHL25-mediated ACLY ubiquitination and degradation. As a consequence, malonyl-CoA, a metabolic intermediate in FAS that is capable of inhibiting the rate-limiting enzyme in FAO, carnitine palmitoyltransferase 1 (CPT1), was decreased. Therefore, ACLY ubiquitination and degradation facilitate FAO and thereby iTreg differentiation. Together, we suggest TGFß1-CUL3-KLHL25-ACLY axis as an important means regulating iTreg differentiation and bring insights into the maintenance of immune homeostasis for the prevention of immune diseases.


Assuntos
ATP Citrato (pro-S)-Liase/metabolismo , Aciltransferases/metabolismo , Antineoplásicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Proteínas Culina/metabolismo , Ácidos Graxos/metabolismo , Ubiquitinação , ATP Citrato (pro-S)-Liase/genética , Aciltransferases/genética , Sequência de Aminoácidos , Animais , Linhagem Celular Tumoral , Técnicas de Reprogramação Celular , Colite/patologia , Proteínas Culina/genética , Ácidos Graxos/genética , Feminino , Camundongos , Camundongos Endogâmicos C57BL
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