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1.
Small ; 18(12): e2106196, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35322558

RESUMO

Cell mechanical forces play fundamental roles in regulating cellular responses to environmental stimulations. The shortcomings of conventional methods, including force resolution and cellular throughput, make them less accessible to mechanical heterogeneity at the single-cell level. Here, a DNA tensioner platform is introduced with high throughput (>10 000 cells per chip) and pN-level resolution. A microfluidic-based cell array is trapped on "hairpin-structured" DNA tensioners that enable transformation of the mechanical information of living cells into fluorescence signals. By using the platform, one can identify enhanced mechanical forces of drug-resistant cells as compared to their drug-sensitive counterparts, and mechanical differences between metastatic tumor cells in pleural effusion and nonmetastatic histiocytes. Further genetic analysis traces two genes, VEGFA and MINK1, that may play deterministic roles in regulating mechanical heterogeneities. In view of the ubiquity of cells' mechanical forces in the extracellular microenvironment (ECM), this platform shows wide potential to establish links of cellular mechanical heterogeneity to genetic heterogeneity.


Assuntos
DNA , Microfluídica
2.
Front Oncol ; 12: 976224, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36185176

RESUMO

Background: Several studies have reported an association between the occurrence of immune-related adverse events (irAEs) and prognosis in patients with melanoma treated with immune checkpoint inhibitors (ICIs), but the results remain controversial. We conducted a systematic review and meta-analysis to investigate the association between irAEs and survival in patients with melanoma treated with ICIs. Methods: We searched the PubMed, Web of Science, and China National Knowledge Infrastructure databases through May 5, 2022 for clinical studies evaluating the association between irAEs and in melanoma patients treated with ICIs. Combined hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were calculated using fixed- or random-effects models based on heterogeneity. Results: A total of 60 articles were included, with 16,520 patients. In patients with melanoma treated with ICIs, the occurrence of irAEs was significantly associated with better OS (HR, 0.58; 95% confidence interval [CI], 0.51-0.66; P<0.00001) and PFS (HR, 0.61; 95%CI, 0.51-0.72; P<0.00001). Endocrine irAEs (OS, HR, 0.81; 95%CI, 0.72-0.92; P=0.001; PFS: HR, 0.84; 95%CI, 0.73-0.96, P=0.009), skin irAEs (OS, HR, 0.59; 95%CI, 0.41-0.85; P=0.004; PFS: HR, 0.43; 95%CI, 0.36-0.52; P<0.00001), vitiligo (OS, HR, 0.22; 95%CI, 0.15-0.31; P<0.00001; PFS, HR, 0.33; 95%CI, 0.25-0.44; P<0.00001), and grade 1-2 irAEs (OS, HR, 0.67; 95%CI, 0.58-0.78; P<0.00001; PFS, HR, 0.62; 95%CI, 0.51-0.76; P<0.00001) showed similar results. However, thyroid, lung, gastrointestinal, liver, and grade 3-4 irAEs were not significantly associated with OS and PFS. The occurrence of non-thyroid endocrine irAEs was significantly associated with better OS (HR, 0.22; 95%CI, 0.15-0.31; P<0.00001). In patients with melanoma treated with anti-programmed cell death protein 1 (OS, HR, 0.61; 95%CI, 0.51-0.72; P<0.00001; PFS, HR, 0.59; 95%CI, 0.47-0.74; P<0.00001), the association between irAEs and clinical benefit was clearer than in patients treated with anti-cytotoxic T-lymphocyte-associated protein 4 (OS, HR, 0.68; 95%CI, 0.52-0.89; P=0.005; PFS, HR, 0.93; 95%CI, 0.49-1.78; P=0.83). Conclusion: Among patients with melanoma treated with ICIs, those who developed non-thyroid endocrine irAEs and cutaneous irAEs have better prognosis. This suggests that non-thyroid endocrine irAEs and cutaneous irAEs may be a prognostic biomarker for patients with melanoma treated with ICIs. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022338308.

3.
Medicine (Baltimore) ; 101(38): e30562, 2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36197177

RESUMO

Ischemic stroke, one of the prevalent causes of death and disability worldwide, is linked to environmental and genetic factors, including polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene involved in homocysteine metabolism. The present study aimed to explore the relationship between the MTHFR C677T variant, plasma homocysteine, and risk of developing large-artery atherosclerotic ischemic stroke (LAAIS) among Han Chinese. A population-based case-control study, which included 1810 patients with LAAIS and 1765 unrelated control subjects, was conducted. Compared to the controls, LAAIS patients had a significantly higher prevalence of hypertension, diabetes mellitus, smoking, and alcohol consumption (P < .001), as well as significantly higher mean fasting blood glucose, triglyceride, total cholesterol, and plasma homocysteine levels (P < .001). The TT homozygous genotype correlated with increased risk of developing LAAIS, as indicated by a significantly higher odds ratio (OR) compared to the CT and CC genotypes, in both additive (OR = 3.215, P = .01) and recessive models (OR = 3.265, P = .01). The plasma homocysteine level was genotype-dependent according to the following trend: TT > CT > CC. In conclusion, our data demonstrate that, in spite of its low prevalence in both patients and controls (1.5% vs 0.8%), the MTHFR C677T variant could, at least in part, affect homocysteine levels and this, either alone or in combination with other factors, increases the risk of LAAIS.

4.
Genet Med ; 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36112137

RESUMO

PURPOSE: Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is characterized by congenital absence of the uterus, cervix, and the upper part of the vagina in females. Whole-gene deletion and loss-of-function variants in TBX6 have been identified in association with MRKHS. We aimed to expand the spectrum of TBX6 variants in MRKHS and explore the biological effect of the variant alleles. METHODS: Rare variants in TBX6 were called from a combined multiethnic cohort of 622 probands with MRKHS who underwent exome sequencing or genome sequencing. Multiple in vitro functional experiments were performed, including messenger RNA analysis, western blotting, transcriptional activity assay, and immunofluorescence staining. RESULTS: We identified 16 rare variants in TBX6 from the combined cohort, including 1 protein-truncating variant reported in our previous study and 15 variants with unknown effects. By comparing the prevalence of TBX6 variants in the Chinese MRKHS cohort vs 1038 female controls, we observed a significant mutational burden of TBX6 in affected individuals (P = .0004, odds ratio = 5.25), suggesting a causal role of TBX6 variants in MRKHS. Of the 15 variants with uncertain effects, 7 were shown to induce a loss-of-function effect through various mechanisms. The c.423G>A (p.Leu141=) and c.839+5G>A variants impaired the normal splicing of TBX6 messenger RNA, c.422T>C (p.Leu141Pro) and c.745G>A (p.Val249Met) led to decreased protein expression, c.10C>T (p.Pro4Ser) and c.400G>A (p.Glu134Lys) resulted in perturbed transcriptional activity, and c.356G>A (p.Arg119His) caused protein mislocalization. We observed incomplete penetrance and variable expressivity in families carrying deleterious variants, which indicates a more complex genetic mechanism than classical Mendelian inheritance. CONCLUSION: Our study expands the mutational spectrum of TBX6 in MRKHS and delineates the molecular pathogenesis of TBX6 variants, supporting the association between deleterious variants in TBX6 and MRKHS.

5.
Chemosphere ; 308(Pt 1): 136307, 2022 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-36067812

RESUMO

Anaerobic ammonium oxidation (anammox) is carbon friendly biological nitrogen removal process, and recently more focus is given to improving the anammox activity. Because of its high adsorption and modifiability, graphene and its derivative in wastewater treatment have received much attention. However, the specific effects and mechanisms of graphene oxide (GO) and reduced graphene oxide (RGO) on anammox are still controversial. Extensive data analysis was performed to explore the effects of GO and RGO on anammox. Statistical analysis revealed that 100 mg/L GO significantly promoted the anammox process, while 200 mg/L of GO inhibited the anammox process. The promotion of anammox performance under the influence of RGO was dependent on the temperature. The Logistic model was utilized for depicting the variation of nitrogen removal efficiency under promoting dosage of graphene oxides. A neural network model-based analysis was performed to reach anammox's potential mechanisms under the influence of two graphene oxides. Spearman correlation analysis showed that GO and RGO had significant positive correlations with nitrogen removal efficiency and specific anammox activity (p < 0.01), especially for RGO. In addition, the abundance of Planctomycetes and Nitrospirae was positively correlated with the addition of graphene oxides. This work comprehensively unraveled the role of graphene oxide materials on the anammox process and provided practical directions for the enhancement of anammox.

6.
Front Cell Dev Biol ; 10: 927300, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36046337

RESUMO

Pure ground glass nodules (GGNs) and solid nodules (SNs) represent early and relatively late stages of lung adenocarcinoma (LUAD) in radiology, respectively. The cellular and molecular characteristics of pure GGNs and SNs have not been comprehensively elucidated. Additionally, the mechanism driving the progression of lung adenocarcinoma from pure GGN to SN in radiology is also elusive. In this study, by analyzing the single-cell transcriptomic profiles of 76,762 cells from four pure GGNs, four SNs, and four normal tissues, we found that anti-tumor immunity mediated by NK and CD8+T cells gradually weakened with the progression of LUAD and humoral immunity mediated by plasma B cells was more active in SNs. Additionally, the proliferation ability of some special epithelial cell increased during the progression process from pure GGN to SN. Furthermore, stromal cells and M2 macrophages could assist the progression of LUAD. Through comprehensive analyses, we revealed dynamic changes in cellular components and intercellular interactions during the progression of LUAD. These findings could facilitate our understanding of LUAD and discovery of novel therapeutic targets.

7.
Anal Chim Acta ; 1227: 340327, 2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36089300

RESUMO

In this work, electrostatic interactions, hydrogen bonding and other interactions between a variety of pesticides and H-beta zeolite are discussed based on thermodynamics (Gibbs free energy, enthalpy, and entropy). Combined with the physical properties of the target compounds (octanol-water partition coefficient and molar volume), the characteristics of the physical adsorption on the synthetic zeolite were analyzed, the results of H-beta zeolite adsorption showed that the adsorption rate had a nonlinear relationship with the physical properties, and the adsorption reaction was dominated by the adsorption on the surface and in the pores of the H-beta zeolite. Based on the principle of zeolite adsorption, the parameters of absorbent amount, adsorption time, sample pH, ion strength, sample volume and desorption solvent were optimized, a vortex-assisted dispersive solid-phase extraction procedure coupled with liquid chromatography-tandem mass spectrometry was developed for the analysis of multiple pesticides in surface water. The sample was adjusted by phosphate buffer or hydrochloric acid to pH 4, then adsorbed by 50 mg of zeolite within 10 min, adding 2% (g/v) sodium chloride to the solution. The absorbent was eluted with a mixture of acetonitrile-methanol containing 0.5% formic acid after separation, then filtered prior to analysis. The optimized vortex-assisted dispersive solid-phase extraction method simultaneously achieved a low adsorbent dosage, a high enrichment factor of 25, rapid pre-concentration for 30 min, a low solvent usage of 2 mL and multi-target simultaneous analysis. Method performance in terms of accuracy, precision, limit of detection, and limit of quantitation was performed to validate the reliability of the procedure. The proposed protocol achieved acceptable accuracy (recoveries between 62% and 107%), and precision (relative standard deviation < 20%). The limit of detection of the method was below 0.1 µg/L, and the limit of quantitation was 0.08 µg/L or 0.2 µg/L. The results indicated that zeolite is a promising adsorbent with high adsorption capacity. It has the advantages of being a fast, simple, green and economical method for determining residual pesticides in water.


Assuntos
Praguicidas , Zeolitas , Praguicidas/análise , Reprodutibilidade dos Testes , Solventes/química , Água
8.
Int J Mol Sci ; 23(17)2022 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-36077254

RESUMO

Boswellic acids, triterpenoids derived from the genus Boswellia (Burseraceae), are known for their anti-inflammatory and anti-tumor efficacy. Atopic dermatitis is a chronic, non-infectious inflammatory skin disease. However, the effects of α-boswellic acid on atopic dermatitis have not been studied. Therefore, in this study we examined the expression level of pro-inflammatory cytokines, histopathological analysis, and physiological data from BALB/c mice with atopic-like dermatitis induced by 2,4-dinitrochlorobenzene and TNF-α/IFN-γ-stimulated HaCaT cells to better understand the agent's anti-atopic dermatitis efficacy. First, we found that α-boswellic reduced the epidermal thickening, mast cell numbers, and dermal infiltration of 2,4-dinitrochlorobenzene-induced atopic-like dermatitis in BALB/c mice. Furthermore, we also found that α-boswellic acid can restore transepidermal water loss and skin reddening in mice. In human keratinocytes inflamed by TNF-α/IFN-γ, α-boswellic acid inhibited MAP kinase activation and showed a reduction in NF-κB nuclear translocation. Finally, α-boswellic acid can reduce the expression level of cytokines (IL-1ß, IL-6, and IL-8) following the stimulation of TNF-α/IFN-γ in HaCaT cells. Taken together, our study suggests that α-boswellic acids are a potential component for the development of anti-atopic dermatitis drugs.


Assuntos
Dermatite Atópica , Triterpenos , Animais , Citocinas/metabolismo , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/metabolismo , Dinitroclorobenzeno/toxicidade , Células HaCaT , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Extratos Vegetais/farmacologia , Pele/metabolismo , Triterpenos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
9.
Hum Genet ; 2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36098810

RESUMO

The craniovertebral junction (CVJ) is an anatomically complex region of the axial skeleton that provides protection of the brainstem and the upper cervical spinal cord. Structural malformation of the CVJ gives rise to life-threatening neurological deficits, such as quadriplegia and dyspnea. Unfortunately, genetic studies on human subjects with CVJ malformation are limited and the pathogenesis remains largely elusive. In this study, we recruited 93 individuals with CVJ malformation and performed exome sequencing. Manual interpretation of the data identified three pathogenic variants in genes associated with Mendelian diseases, including CSNK2A1, MSX2, and DDX3X. In addition, the contribution of copy number variations (CNVs) to CVJ malformation was investigated and three pathogenic CNVs were identified in three affected individuals. To further dissect the complex mutational architecture of CVJ malformation, we performed a gene-based rare variant association analysis utilizing 4371 in-house exomes as control. Rare variants in LGI4 (carrier rate = 3.26%, p = 3.3 × 10-5) and BEST1 (carrier rate = 5.43%, p = 5.77 × 10-6) were identified to be associated with CVJ malformation. Furthermore, gene set analyses revealed that extracellular matrix- and RHO GTPase-associated biological pathways were found to be involved in the etiology of CVJ malformation. Overall, we comprehensively dissected the genetic underpinnings of CVJ malformation and identified several novel disease-associated genes and biological pathways.

10.
J Med Virol ; 2022 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-36089764

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic caused extensive loss of life worldwide. Further, the COVID-19 and influenza mix-infection had caused great distress to the diagnosis of the disease. To control illness progression and limit viral spread within the population, a real-time reverse-transcription PCR (RT-PCR) assay for early diagnosis of COVID-19 was developed, but detection was time-consuming (4-6 h). To improve the diagnosis of COVID-19 and influenza, we herein developed a recombinase polymerase amplification (RPA) method for simple and rapid amplification of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19 and Influenza A (H1N1, H3N2) and B (influenza B). Genes encoding the matrix protein (M) for H1N1, and the hemagglutinin (HA) for H3N2, and the polymerase A (PA) for Influenza B, and the nucleocapsid protein (N), the RNA-dependent-RNA polymerase (RdRP) in the open reading frame 1ab (ORF1ab) region, and the envelope protein (E) for SARS-CoV-2 were selected, and specific primers were designed. We validated our method using SARS-CoV-2, H1N1, H3N2 and influenza B plasmid standards and RNA samples extracted from COVID-19 and Influenza A/B (RT-PCR-verified) positive patients. The method could detect SARS-CoV-2 plasmid standard DNA quantitatively between 102 and 105 copies/ml with a log linearity of 0.99 in 22 min. And this method also be very effective in simultaneous detection of H1N1, H3N2 and influenza B. Clinical validation of 100 cases revealed a sensitivity of 100% for differentiating COVID-19 patients from healthy controls when the specificity was set at 90%. These results demonstrate that this nucleic acid testing method is advantageous compared with traditional PCR and other isothermal nucleic acid amplification methods in terms of time and portability. This method could potentially be used for detection of SARS-CoV-2, H1N1, H3N2 and influenza B, and adapted for point-of-care (POC) detection of a broad range of infectious pathogens in resource-limited settings.

11.
Comput Struct Biotechnol J ; 20: 5040-5044, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36097552

RESUMO

The binding of SARS-CoV-2 nucleocapsid (N) protein to both the 5'- and 3'-ends of genomic RNA has different implications arising from its binding to the central region during virion assembly. However, the mechanism underlying selective binding remains unknown. Herein, we performed the high-throughput RNA-SELEX (HTR-SELEX) to determine the RNA-binding specificity of the N proteins of various SARS-CoV-2 variants as well as other ß-coronaviruses and showed that N proteins could bind two unrelated sequences, both of which were highly conserved across all variants and species. Interestingly, both sequences are virtually absent from the human transcriptome; however, they exhibit a highly enriched, mutually complementary distribution in the coronavirus genome, highlighting their varied functions in genome packaging. Our results provide mechanistic insights into viral genome packaging, thereby increasing the feasibility of developing drugs with broad-spectrum anti-coronavirus activity by targeting RNA binding by N proteins.

12.
Acta Radiol ; : 2841851221128213, 2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36131377

RESUMO

BACKGROUND: Few studies about lung ground-glass nodules (GGNs) have been done using non-enhancement spectral computed tomography (CT) imaging. PURPOSE: To examine the association between spectral CT parameters, Ki-67 expression, and invasiveness in lung adenocarcinoma manifesting as GGNs. MATERIAL AND METHODS: Spectral CT parameters were analyzed in 106 patients with lung GGNs. The Ki-67 labeling index (Ki-67 LI) was measured, and patients were divided into low expression and high expression groups according to the number of positive-stained cells (low expression ≤10%; high expression >10%). Spectral CT parameters were compared between low and high expression groups. The correlation between spectral CT parameters and Ki-67 LI was estimated by Spearman correlation analysis. Cases were divided into a preinvasive and minimally invasive adenocarcinoma (MIA) group (atypical adenomatous hyperplasia, adenocarcinoma in situ, and MIA) and invasive adenocarcinoma (IA) group. Spectral CT parameters were compared between the two groups. The diagnostic performance was evaluated using receiver operating characteristic analysis. RESULTS: There were significant differences in water concentration of lesions (WCL) and monochromatic CT values between the low and high expression groups. CT 40 keV had the highest correlation coefficient with Ki-67 LI. WCL and monochromatic CT values were significantly higher in the IA group than in the pre/MIA group. The value of area under the curve of CT 40 keV was 0.946 (95% confidence interval=0.905-0.988) for differentiating the two groups; the cutoff was -280.66 Hu. CONCLUSION: Spectral CT is an effective non-invasive method for the prediction of proliferation and invasiveness in lung adenocarcinoma manifesting as GGNs.

13.
Am J Med Genet A ; 2022 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-36161696

RESUMO

TBX6 encodes transcription-factor box 6, a transcription factor critical to paraxial mesoderm segmentation and somitogenesis during embryonic development. TBX6 haploinsufficiency is believed to drive the skeletal and kidney phenotypes associated with the 16p11.2 deletion syndrome. Heterozygous and biallelic variants in TBX6 are associated with vertebral and rib malformations (TBX6-associated congenital scoliosis) and spondylocostal dysostosis, and heterozygous TBX6 variants are associated with increased risk of genitourinary tract malformations. Combined skeletal and kidney phenotypes in individuals harboring heterozygous or biallelic TBX6 variants are rare. Here, we present seven individuals with vertebral and rib malformations and structural kidney differences associated with heterozygous TBX6 gene deletion in trans with a hypomorphic TBX6 allele or biallelic TBX6 variants. Our case series highlights the association between TBX6 and both skeletal and kidney disease.

14.
J Colloid Interface Sci ; 629(Pt A): 206-214, 2022 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-36067599

RESUMO

Photocatalytic CO2 reduction is a promising method to resolve the energy shortage problem. Developing photocatalysts with strong redox capabilities is urgently needed to achieve high photocatalytic activity. Herein, we synthesized TiO2/CsPbBr3 S-scheme heterojunctions with modulated internal electric field by facet engineering of TiO2 to control charge transfer for improved photocatalytic activity. Density functional theory (DFT) calculation reveals that there is a wider Fermi level difference between TiO2-(101) and CsPbBr3 than that between TiO2-(001) and CsPbBr3, which will induce more obvious band bending. Subsequently, more efficient spatial separation will occur around the interface. Thus, TiO2-(101)/CsPbBr3 heterostructures effectively reduce CO2 into CO with the selectivity of 90.2 % and reduction rate of 12.5 µmol h-1, 15.6 and 5.6 times improvement than that of 101-TiO2 and TiO2-(001)/CsPbBr3, respectively. This report proposes a feasible idea of employing facet engineering to take the advantage of S-scheme heterojunction.

15.
BMC Med Inform Decis Mak ; 22(1): 245, 2022 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-36123745

RESUMO

BACKGROUND: Lung cancer is the leading cause of cancer death worldwide. Prognostic prediction plays a vital role in the decision-making process for postoperative non-small cell lung cancer (NSCLC) patients. However, the high imbalance ratio of prognostic data limits the development of effective prognostic prediction models. METHODS: In this study, we present a novel approach, namely ensemble learning with active sampling (ELAS), to tackle the imbalanced data problem in NSCLC prognostic prediction. ELAS first applies an active sampling mechanism to query the most informative samples to update the base classifier to give it a new perspective. This training process is repeated until no enough samples are queried. Next, an internal validation set is employed to evaluate the base classifiers, and the ones with the best performances are integrated as the ensemble model. Besides, we set up multiple initial training data seeds and internal validation sets to ensure the stability and generalization of the model. RESULTS: We verified the effectiveness of the ELAS on a real clinical dataset containing 1848 postoperative NSCLC patients. Experimental results showed that the ELAS achieved the best averaged 0.736 AUROC value and 0.453 AUPRC value for 6 prognostic tasks and obtained significant improvements in comparison with the SVM, AdaBoost, Bagging, SMOTE and TomekLinks. CONCLUSIONS: We conclude that the ELAS can effectively alleviate the imbalanced data problem in NSCLC prognostic prediction and demonstrates good potential for future postoperative NSCLC prognostic prediction.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Algoritmos , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Humanos , Neoplasias Pulmonares/cirurgia , Aprendizado de Máquina , Prognóstico
16.
Aging (Albany NY) ; 14(17): 7156-7169, 2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36107024

RESUMO

Although there are a lot of chemical drugs to treat breast cancer, increasing drug resistance of cancer cells has strongly hindered the effectiveness of chemotherapy. ATP-binding cassette transporters represented by P-glycoprotein (P-gp), multidrug resistance associated protein 1 (MRP1) and breast cancer resistance protein (BCRP) play an important role in drug resistance. This study aims to investigate the effect of 7-O-geranylquercetin (GQ) combining microRNA-451(miR-451) on reversing drug resistance of breast cancer and reveal the mechanism related to P-gp. Real-time RT-PCR and western blot assays showed that miR-326, miR-328, miR-451 and miR-155 inhibitor down-regulated the expression of genes MRP1, BCRP, MDR1 and the corresponding proteins MRP1, BCRP, P-gp, respectively. Cell counting kit-8 (CCK-8) assay indicated that these miRNAs reversed the resistance of MCF-7/ADR cells to Adriamycin (ADR), and miR-451 showed the greatest reversal effect. Combination of GQ and miR-451 enhanced the inhibitory effects of ADR on the proliferation and migration of MCF-7/ADR cells, and attenuated the expression of MDR1 and P-gp in MCF-7/ADR cells. A xenograft tumor model was used to show that GQ and miR-451 amplified the antitumor effect of ADR in nude mice, while western blot and immunohistochemical assays revealed the decreased expression of P-gp in tumor tissues. These results suggest that GQ and miR-451 have synergistic effect on reversing drug resistance through reducing the expression of MDR1 and P-gp in breast cancer MCF-7/ADR cells.


Assuntos
Neoplasias da Mama , MicroRNAs , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/farmacologia , Proteínas de Neoplasias/metabolismo , Quercetina/análogos & derivados , Sincalida/metabolismo
17.
J Pers Med ; 12(9)2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36143288

RESUMO

Clinical exome sequencing (CES) has shown great utility in the diagnosis of Mendelian disorders. CES can unravel secondary findings (SFs) unrelated to the primary diagnosis but with potential health implications. The American College of Medical Genetics and Genomics (ACMG) has published a guideline for reporting secondary findings and recently updated an ACMG SF v3.0 list comprising 73 genes. Several studies have been performed to explore the prevalence of SFs. However, the data were limited in the Chinese population. In this study, we evaluated the genetic data of 2987 individuals from the Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study group in accordance with the ACMG SF v3.0 list. The detected variants were evaluated using the ACMG classification guidelines, HGMD, and ClinVar database. Totally, 157 (157/2987, 5.3%) individuals had reportable variants within genes associated with cancer, cardiovascular, metabolic, and miscellaneous phenotypes. We identified 63 known pathogenic (KP) variants in 72 individuals (72/2987, 2.4%) and 96 expected pathogenic (EP) variants in 105 individuals (3.5%). Forty-five individuals carried SFs in v3.0 newly added genes, which accounted for 1.5% of our cohort. Our findings could contribute to existing knowledge of secondary findings in different ethnicities and indicate the necessity for clinicians to update the SFs gene list.

18.
Front Genet ; 13: 943264, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36159989

RESUMO

Netherton syndrome (NS, OMIM #256500) is a rare autosomal recessive disease characterized by a triad of congenital ichthyosiform erythroderma (CIE) or ichthyosis linearis circumflexa (ILC), trichorrhexis invaginata (TI), and atopic predisposition. The disease is caused by a mutation in the SPINK5 gene (serine protease inhibitor of Kazal type 5) encoding LEKTI (lymphoepithelial Kazal type-related inhibitor). We performed whole-exome sequencing on one Chinese NS family and made genotype-phenotype correlation analysis on the patients clinically diagnosed with NS or congenital ichthyosis erythroderma. We identified a novel frameshift mutation c.2474_2475del (p.Glu825Glyfs*2) in the SPINK5 gene. The N-terminal mutations of LEKTI cause a severer phenotype, while the C-terminal mutations of LEKT1 are related to a milder phenotype. Our findings suggest that Netherton syndrome may be underestimated clinically, and our findings further expand the reservoir of SPINK5 mutations in Netherton syndrome.

19.
J Environ Qual ; 2022 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-36174971

RESUMO

Antibiotics have attracted considerable attention as pollutants; however, they have not been controlled since they cannot be effectively treated via conventional water treatment. In this study, N-doped reduced graphene oxide (N-rGO) was prepared and its adsorption performance on multiple trace antibiotics in water was investigated by considering sulfamethoxazole, levofloxacin, clindamycin, tetracycline, penicillin, and chloramphenicol as target pollutants. The results demonstrated that the adsorption process was completed within 60 min at a removal rate exceeding 80%. The adsorption process was in line with the first-order kinetic equation and the Langmiur isothermal adsorption model, with a theoretical maximum adsorption capacity of 1265.82 mg/g. Meanwhile, the effect of pH value was related to the structure of antibiotics. Simulation studies showed that anions and cations in natural water matrix did not inhibit the adsorption process, while humic acid adversely affected the adsorption effect. Characterizations revealed that the N-rGO surface was wrinkled with abundant and diverse oxygen-containing functional groups, which provided suitable conditions for efficient adsorption. The results indicated that N-rGO rapidly and effectively adsorbed trace antibiotics in water, thus providing a basis for constructing an adsorption-catalytic oxidation system. Overall, the proposed method is excellent for treating trace antibiotics in a water environment. This article is protected by copyright. All rights reserved.

20.
Front Endocrinol (Lausanne) ; 13: 933921, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36105407

RESUMO

Background: The association between glioma risk and body mass index (BMI) remains obscure. Methods: This study aimed to assess the association between glioma risk and BMI in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Cox proportional hazards regression was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). Results: The onset of a total of 269 gliomas was observed during a median follow-up period of 12.04 years. Compared with the normal weight, overweight (HR: 1.05; 95% CI: 0.80, 1.39) and obesity (HR: 0.91; 95% CI: 0.56, 1.39) were not significantly associated with glioma risk. Further analysis showed a nonlinear relationship between glioma risk and BMI in men but not women. The multivariable-adjusted HRs per unit increase in BMI were 0.94 (95% CI: 0.89, 1.00; P = 0.037) in men with BMI >25 kg/m2 and 1.16 (95% CI: 0.98, 1.38; P = 0.075) in men with BMI <25 kg/m2. Conclusion: The present data provide evidence that there may be a nonlinear association between BMI and glioma risk in men. The risk of glioma decreased with increasing BMI among men with BMI >25 kg/m2. Future studies are needed to validate our observation.


Assuntos
Glioma , Neoplasias Ovarianas , Índice de Massa Corporal , Feminino , Glioma/epidemiologia , Glioma/etiologia , Humanos , Masculino , Obesidade/complicações , Obesidade/epidemiologia , Sobrepeso/complicações , Sobrepeso/epidemiologia , Estudos Prospectivos
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