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1.
J Comput Biol ; 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32031890

RESUMO

This study aimed to explore the similarity between the physical and chemical properties of different acaricides, determine whether Lipinski's Rule of Five (RO5) used in the design of drug molecules is suitable for screening acaricides, and provide methods for selection of new acaricides. We evaluated and predicted the molecular properties of >180 acaricides using Molinspiration. We calculated physicochemical property parameters, such as log p, molecular weight (MW), and number of hydrogen bond donors (HBDs), hydrogen bond acceptors (HBAs), and rotatable bonds (Rot B). We then conducted qualitative and quantitative analyses of the physicochemical properties of acaricides. The MW of all acaricides ranged from 141 to 663, with an average value of 337.8. The number of HBDs ranged from 0 to 5, with an average value of 0.46. The number of HBAs ranged from 0 to 9, with an average value of 4.07. The log p ranged from -0.79 to 8.74, with an average value of 4.61. The number of Rot B ranged from 0 to 14, with an average value of 5.62. Except for the microbial and plant-derived acaricides, the molecular properties of the remaining acaricides are in accordance with the Lipinski's RO5. Therefore, the Lipinski's RO5 can provide a basis for screening new acaricide drugs.

2.
J Cell Mol Med ; 24(2): 1529-1540, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31894895

RESUMO

Emerging evidence has shown that exosomes derived from drug-resistant tumour cells are able to horizontally transmit drug-resistant phenotype to sensitive cells. However, whether exosomes shed by EGFR T790M-mutant-resistant NSCLC cells could transfer drug resistance to sensitive cells has not been investigated. We isolated exosomes from the conditioned medium (CM) of T790M-mutant NSCLC cell line H1975 and sensitive cell line PC9. The role and mechanism of exosomes in regulating gefitinib resistance was investigated both in vitro and in vivo. Exosome-derived miRNA expression profiles from PC9 and H1975 were analysed by small RNA sequencing and confirmed by qRT-PCR. We found that exosomes shed by H1975 could transfer gefitinib resistance to PC9 both in vitro and in vivo through activating PI3K/AKT signalling pathway. Small RNA sequencing and RT-PCR confirmed that miR-3648 and miR-522-3p were the two most differentially expressed miRNAs and functional study showed that up-regulation of miR-522-3p could induce gefitinib resistance in PC9 cell. The findings of our study reveal an important mechanism of acquired resistance to EGFR-TKIs in NSCLC.

4.
Eur Arch Otorhinolaryngol ; 277(1): 221-226, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31541294

RESUMO

OBJECTIVE: Nasopharyngeal carcinoma (NPC) is a common malignancy in Southern China and Southeast Asia. Genetic susceptibility is a major contributing factor in determining the individual risk of NPC in these areas. To test the association between NPC and variants in regenerating gene 1A (REG1A), we conducted a hospital-based case-control study in a Cantonese-speaking population from Guangdong province. METHODS: We endeavored to determine whether genetic variants of the REG1A gene were associated with the risk of NPC amidst the Cantonese population in a hospital-based case-control study using polymerase chain reaction-restriction and direct sequencing analysis in 211 NPC patients and 150 healthy controls. The association between NPC risk and the 14C/T, 20C/T, 369G/T, 1201A/G, and 2922C/T polymorphisms was examined after adjustment for age and sex. RESULTS: We found an increased risk of developing NPC in individuals with REG1A 2922C/T variant genotype (p = 0.003, OR 0.419, 95% CI 0.235-0.746), and after adjustment for sex and age (p = 0.003, OR 0.406, 95% CI 0.226-0.732). No association between other polymorphisms (14C/T, 20C/T, 369G/T, and 1201A/G) and the risk of NPC was observed, before or after adjustment for age and sex. CONCLUSION: Our findings suggest that the REG1A 2922C/T polymorphism is associated with an increased risk of developing NPC in a Cantonese population from Guangdong province. Larger studies are required to confirm our findings and unravel the underlying mechanisms.

5.
Acad Radiol ; 27(2): 233-243, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31031186

RESUMO

OBJECTIVE: To explore the feasibility of reducing radiation dose and improving image quality in CT portal venography (CTPV) using 80 kV and adaptive statistical iterative reconstruction-V(ASIR-V) in slender patients in comparison with conventional protocol using 120 kV and ASIR. METHODS: Sixty slender patients for enhanced abdominal CT scanning were randomly divided into group A and group B. Group A used the conventional 120 kV tube voltage, 600 mgI/kg contrast dose and reconstructed with the recommended 40% ASIR. Group B used 80 kV tube voltage, 350 mgI/kg contrast dose and reconstructed with ASIR-V from 40% to 100% with 10% interval. The CT values and standard deviation (SD) values of the main portal vein, left branch, and right branch of portal vein, liver, and erector spinae at the same level were measured to calculate the signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR). The image quality was subjectively scored by two experienced radiologists blindly using a 5-point criterion. The contrast dose, volumetric CT dose index, and dose length product were recorded in both groups and the effective dose was calculated. RESULTS: There was no significant difference in general data between the two groups (p > 0.05), the effective dose and contrast dose in group B were reduced by 63.3% (p < 0.001) and 39.7% (p < 0.001), respectively compared with group A. With the percentage of ASIR-V increased in group B, the CT values showed no significant difference, while the SD values gradually decreased and SNR values and CNR values increased accordingly. Compared with group A, group B demonstrated similar CT values (p > 0.05), while the SD values with 80% ASIR-V to 100% ASIR-V were significantly lower than those of 40% ASIR (p < 0.001), and the SNR values and CNR values with 70% ASIR-V to 100% ASIR-V were significantly higher than those of 40% ASIR (p < 0.001). The subjective image quality scores by the two radiologists had excellent consistency (kappa value>0.75, p < 0.001), and the final subjective image quality scores and the subjective scores in each of the 5 scoring categories with 60% ASIR-V to 100% ASIR-V were all significantly higher than those of 40% ASIR, and 80% ASIR-V obtained the highest subjective score among different reconstructions. CONCLUSION: In CTPV, the application of 80 kV and ASIR-V reconstruction in slender patients can significantly reduce radiation dose (by 63.3%) and contrast agent dose (by 39.7%). Compared with the recommended 40% ASIR using 120 kV, ASIR-V with 80% to 100% percentages can further improve image quality and with 80% ASIR-V being the best reconstruction algorithm. ADVANCES IN KNOWLEDGE: CTPV with 80 kV and ASIR-V algorithm in slender patients can significantly reduce radiation dose and contrast agent dose as well as improve image quality, compared with the conventional 120 kV protocol using 40% ASIR.

6.
Lung Cancer ; 139: 133-139, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31786475

RESUMO

OBJECTIVES: Advanced non-small cell lung cancer (NSCLC) patients harboring non-resistant uncommon epidermal growth factor receptor (EGFR) mutations have stepped into the era of targeted therapy. This study aimed to investigate the incidence of acquired T790M mutation and their outcome to subsequent osimertinib in patients of advanced NSCLC harboring uncommon EGFR mutations. PATIENTS AND METHODS: Patients with EGFR mutation and performed re-biopsy after progression on prior EGFR-tyrosine kinase inhibitors (TKIs) were reviewed and analyzed. Those with T790M mutation and received subsequent osimertinib treatment were further collected for survival analysis. RESULTS: Finally, 754 patients, including 48 with uncommon mutation, 362 with 19del and 344 with L858R were enrolled. T790M mutation was identified in 341 patients (341/754, 45.2 %). The incidence of T790M mutation was 27.1 % in patients harboring uncommon mutations, significantly lower than 55.2 % and 37.2 % of 19del and L858R (p < 0.001). Logistic regression analysis further found uncommon mutation associated with significantly lower probability of developing T790M (odds ratio [OR] = 0.32, 95 % confidence interval [CI] 0.16-0.64). Among 236 patients received subsequent osimertinib treatment (including 12 uncommon mutation, 145 19del and 79 L858R), patients harboring uncommon mutations showed significantly shorter progression free survival (PFS) (median: 4.6 vs. 11.6 vs. 12.1 months, p < 0.001) and overall survival (OS) (median: 8.1 vs. 35.4 vs. 24.9 months, p = 0.001) compared with 19del and L858R, also associated with numerically lower objective response rate (ORR) (p = 0.085) and lower disease control rate (DCR) (p = 0.074). Multivariate analysis further found that uncommon mutation was the only one significantly associated with both PFS (hazard ratio [HR] = 3.44, 95 %CI 1.79-6.58) and OS (HR = 3.64, 95 %CI 1.66-7.99). CONCLUSIONS: Uncommon EGFR mutation showed a significantly lower incidence of acquired T790M mutation and benefited significantly less from subsequent osimertinib treatment than common EGFR mutations in patients with advanced NSCLC.

7.
Food Funct ; 11(1): 1165-1175, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31872841

RESUMO

Humulus lupulus is a perennial climbing plant of the subfamily Cannabioideae native to the Northern Hemisphere. The primary use of H. lupulus is in the brewing industry, where it is an essential ingredient for imparting a unique flavor (bitterness and aroma) to beer. The female flowers of H. lupulus are also used in traditional Chinese medicine, but the biologically active ingredients underlying its benefits remain unclear. China is the largest producer and consumer of H. lupulus in Asia. Using the waste from the beer-brewing process of H. lupulus as raw materials, the biologically active polysaccharides can be screened. This is useful for the full utilization of H. lupulus, potentially leading to disease prevention and treatment. In this study, we isolated a homogeneous polysaccharide (HLP50-1) with a molecular weight of 49.13 kDa from female flowers of H. lupulus via a DEAE-Cellulose 52 anion exchange column and a Sephadex G-75 gel filtration column. Methylation, GC-MS, and NMR analyses revealed that the HLP50-1 comprised →4)-α-d-Glcp-(1→, →6)-α-d-Manp-(1→, →3)-α-l-Rhap-(1→, ß-d-Glcp-(1→, α-l-Araf-(1→, →4,6)-2-OAc-ß-d-Galp-(1→, ß-d-Galp-(1→, →3,6)-ß-d-Glcp-(1→, →2,3,4)-α-d-Xylp-(1→, →6)-α-d-Glcp-(1→, →3)-α-d-Galp-(1→, →4)-α-d-Galp-(1→. Advanced structural analysis showed that the HLP50-1 contained irregular fragments of different sizes and shapes with a smooth surface. The aggregates appeared be composed of accumulated crystals. Furthermore, the osteogenic activities of the HLP50-1 were evaluated via MC3T3-E1 cells in vitro. The results showed that 0.13 µM HLP50-1 led to outstanding proliferation, differentiation, and mineralization of the MC3T3-E1 cells. Therefore, HLP50-1 has osteogenic effects, and it may be a candidate for the treatment of osteoporosis. It has broad application prospects in functional foods, health-care products, and pharmaceuticals.

8.
Food Chem ; 308: 125596, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-31648097

RESUMO

The protective mechanism of glycerol on ß-lactoglobulin were studied in 0-60% glycerol solutions by experimental and molecular simulation approaches. Results showed that the stability of ß-lactoglobulin increased with glycerol concentration, with little secondary structure changes induced by glycerol. The tertiary structure altered slightly with glycerol concentration, resulting in a stronger near UV circular dichroism signal and intrinsic tryptophan fluorescence quenching, indicating aromatic side chains closer to hydrophobic microenvironment. The Rg of ß-lactoglobulin increased with glycerol concentration without dimer dissociation, due to expansion of the quaternary structures. Moreover, the flexibility (RMSF) of ß-lactoglobulin decreased by glycerol. Distance between areas enclosing Asp33 and Arg40 from separate chains did not increase, suggesting possibly reinforced electrostatic attractions. In conclusion, the stabilization of ß-lactoglobulin in glycerol solution is probably the comprehensive results of the decreased molecular flexibility, the strengthened hydrophobic interaction in individual chain, and the possibly reinforced electrostatic attractions between two chains of ß-lactoglobulin.


Assuntos
Glicerol/química , Lactoglobulinas/química , Dicroísmo Circular , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína
9.
Oncogene ; 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31819169

RESUMO

Endocytosis is an essential component of cell motility, which facilitates the malignant behavior of cancer. Sorting nexin (SNX) family members are associated with tumor progression. However, the role and mechanism of SNX5 in hepatocellular carcinoma (HCC) progression remain largely unknown. In this study, we investigated the clinical significance and possible involvement of SNX5 in the progression of HCC. Here, we showed that SNX5 was upregulated in tumors compared with adjacent nontumorous tissues in HCC patients. The upregulation of SNX5 in HCC was associated with vascular invasion, intrahepatic metastasis, and poor prognosis. The overexpression of SNX5 promoted HCC cell proliferation, migration, invasion, and metastasis, whereas silencing SNX5 expression resulted in decreased cell proliferation, migration, and invasion. Knockdown of SNX5 significantly inhibited HCC cell proliferation by inducing G1/S transition arrest. Mechanistically, we demonstrated that SNX5 promoted cell proliferation, migration, and invasion via the activation of the EGFR-ERK1/2 pathway by blocking EGF-mediated EGFR internalization. We found that SNX5 interacted with EGFR in HCC cells. Moreover, SNX5-induced cell proliferation, migration, and invasion were partially reversed by the knockdown of EGFR or by ERK1/2 inhibitors. In addition, we demonstrated that SNX5 knockdown sensitized HCC cells to tyrosine kinase inhibitors, including erlotinib and sorafenib. Taken together, our results indicate that SNX5 promotes HCC cell proliferation and metastasis via inhibiting the endocytosis and degradation of EGFR, thereby activating the ERK1/2 signaling pathway. Our work also suggests that SNX5 is a potential therapeutic target for HCC.

10.
J Thorac Dis ; 11(9): 3794-3807, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31656652

RESUMO

Background: To investigate the impact of different immune checkpoint inhibitors (ICI), programmed-death ligand 1 (PD-L1) expression and clinical characteristics on clinical outcome of ICI plus conventional treatment in advanced lung cancer patients. Methods: Randomized clinical trials that compared combination therapy versus control group were screened in PubMed, EMBASE, Web of Science, Cochrane Library and included. The pooled hazard ratio (HR) with a 95% confidence interval (95% CI) were used to estimate associations. Cochrane Collaboration tool was used for quality assessment. Results: Thirteen clinical trials were included (n=9,241). The pooled results indicated that combination strategy based on ICI significantly improved PFS (HR =0.66, P<0.001) and OS (HR =0.77, P<0.001) in overall population. Greatest PFS improvement was seen in group of PD-1 based combination (HR =0.54, P<0.001), followed by PD-L1 based (HR =0.66, P<0.001) and CTLA-4 based combination (HR =0.86, P=0.002) (interaction: P<0.001).The improvement in PFS did proportionally differ by PD-L1 expression (interaction: P<0.001). OS HRs favored combination in patients with negative or strong positive group of PD-L1 expression not in the group of weak positive group (HR =0.77, P=0.12). Subgroup analysis demonstrated that OS benefit could be observed in male (HR =0.82, P=0.03), current or former smokers (HR =0.74, P=0.04), non-squamous (HR =0.71, P<0.001) and patients without driver mutations (HR =0.73, P<0.001). OS benefit rather than PFS benefit was appeared in patients with liver metastasis treated with ICI-based combination (HR =0.74, P=0.005). Conclusions: ICI plus conventional treatment could significantly improve PFS and OS in overall advanced lung cancer patients. PD-1-based combination leads to the greatest improvement in both PFS and OS. More data are warranted to address the association of PD-L1 staining intensity with OS improvement. Male, current or former smokers, non-squamous and patients without driver mutations do benefit from ICI-based combination.

11.
Eur J Cancer ; 121: 98-108, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31569068

RESUMO

INTRODUCTION: Previous studies suggested that epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKIs) plus bevacizumab could significantly prolong progression-free survival (PFS) than EGFR-TKI alone as first-line setting for patients with EGFR-mutant non-small-cell lung cancer (NSCLC). However, whether this combination could benefit patients with multiple brain metastases (BrMs) remains undetermined. METHODS: A total of 208 patients with EGFR-mutant NSCLC and multiple BrM (number >3, at least one of lesions was measurable) were retrospectively identified. Kaplan-Meier curves with two-sided log-rank tests and Cox proportional hazards model with calculated hazard ratios and 95% confidence intervals were used to determine the survival difference. RESULTS: Of all patients, 149 patients received EGFR-TKIs monotherapy and 59 received EGFR-TKIs plus bevacizumab as first-line setting. EGFR-TKIs plus bevacizumab was associated with a significantly higher intracranial objective response rate (ORR, 66.1% vs. 41.6%, P = 0.001), systemic ORR (74.6% vs. 57.1%, P = 0.019), longer intracranial PFS (14.0 vs. 8.2 months; P < 0.001) and systemic PFS (14.4 vs. 9.0 months; P < 0.001). Importantly, addition of bevacizumab also had a significantly longer overall survival (OS, 29.6 vs. 21.7 months; P < 0.001). Multivariate analysis consistently revealed that addition of bevacizumab was independently associated with prolonged intracranial and systemic PFS, and OS. No unexpected serious adverse effects were observed. CONCLUSIONS: EGFR-TKIs plus bevacizumab prolonged not only PFS but also OS in patients with EGFR-mutant NSCLC and multiple BrMs when compared with EGFR-TKIs alone, indicating that this combination could be an alternative therapeutic option for those patients.

12.
Theranostics ; 9(20): 5914-5923, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534528

RESUMO

DNA walker is a powerful type of DNA nanomachine that can produce amplified signals during the "burnt-bridge"-like walking process. Despite their successful application in extracellular bioanalysis, the heterogeneity of the existing DNA walkers makes it difficult to guarantee the consistency of the results during the analysis of different cells. Methods: Here, an all-in-one homogeneous DNA walking nanomachine is reported that can be delivered into living cells for intracellular bioanalysis of miRNA without auxiliary materials. Results: This DNA walking nanomachine is constructed of gold nanoparticles on which two types of interrelated DNA tracks are assembled. The target miRNA, cancer-related miR-21, can be captured by one of the tracks (track 1) and then walk to the other track (track 2), releasing the hybrid of track 1 and track 2 from the nanoparticle to produce a signal. The walking process can proceed in a cyclic 1-2-1-2 manner and thereby produce amplified signals. Thus, sensitive imaging of the miRNA in situ can be achieved. Conclusion: Benefiting from the homogeneity of the detection system, the method can be applied for intracellular analysis without interference induced by the fluctuations of stimuli or accessorial contents.

13.
Can J Infect Dis Med Microbiol ; 2019: 1547405, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31316681

RESUMO

This study aimed to evaluate the factors that affect 30-day mortality of patients with HAP. The data used in this study were collected from all HAP occurred in our hospital between January 2014 and December 2017. A total of 1158 cases were included. 150 (13.0%) of whom died within 30 days. This reported mortality identified by the univariate Cox regression analysis is found to have been affected by the following factors: age greater than 70 years, presence of diabetes mellitus and chronic obstructive pulmonary disease, gastric tube intubation, administration of proton-pump inhibitor, blood albumin level less than 30 g/l, elevated neutrophil-to-lymphocyte ratio, antibiotics therapy in the preceding 90 days, intensive care unit (ICU) admission, blood lymphocyte count less than 0.8 × 109/L, elevated blood urea nitrogen/albumin (BUN/ALB) level, and presence of multidrug-resistant (MDR) pathogens. In the second multivariate analysis, administration of proton-pump inhibitor, administration of antibiotics in the preceding 90 days, ICU admission, blood lymphocyte count less than 0.8 × 109/L, elevated BUN/ALB level, and presence of MDR pathogens were still associated with 30-day mortality. The area under the receiver operating characteristic curves in the BUN/ALB predicting 30-day mortality due to HAP was 0.685. A high BUN/ALB was significantly associated with a worse survival than a low BUN/ALB (P < 0.001). Therefore, an elevated BUN/ALB level is a risk factor for mortality on patients with HAP.

14.
J Hematol Oncol ; 12(1): 75, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31299995

RESUMO

INTRODUCTION: To depict the genomic landscape of Chinese early-stage lung squamous cell carcinoma (LUSC) and investigate its correlation with tumor mutation burden (TMB), PD-L1 expression, and immune infiltrates. METHODS: Whole-exome sequencing was performed on 189 surgically resected LUSC. TMB was defined as the sum of nonsynonymous single nucleotide and indel variants. CD8+ tumor-infiltrating lymphocyte (TIL) density and PD-L1 expression were evaluated by immunohistochemistry. Six immune infiltrates were estimated using an online database. RESULTS: The median TMB was 9.43 mutations per megabase. Positive PD-L1 expression and CD8+ TILs density were identified in 24.3% and 78.8%. PIK3CA amplification was associated with significantly higher TMB (P = 0.036). Frequent genetic alterations had no impact on PD-L1 expression but PIK3CA amplification and KEAP1 mutation were independently associated with significantly lower CD8+ TIL density (P < 0.001, P = 0.005, respectively). Low TMB and high CD8+ TIL density were independently associated with longer disease-free survival (DFS) while none of them could individually predict the overall survival (OS). Combination of TMB and PD-L1 expression or TMB and CD8+ TIL density could stratify total populations into two groups with distinct prognosis. Classifying tumor-immune microenvironment based on PD-L1 expression and CD8+ TIL density showed discrepant genomic alterations but similar TMB, clinical features, and OS. Notably, patients with different smoking status had distinct prognostic factors. CONCLUSION: The combination of TMB, PD-L1 expression, immune infiltrates, and smoking status showed the feasibility to subgroup stratification in Chinese patients with early-stage LUSC, which might be helpful for future design of personalized immunotherapy trials in LUSC.

15.
Front Microbiol ; 10: 1458, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31293562

RESUMO

Gut microbiota dysbiosis is closely associated with primary hepatocellular carcinoma (HCC). Recent studies have evaluated the early diagnosis of primary HCC through analysis of gut microbiota dysbiosis. However, the relationship between the degree of dysbiosis and the prognosis of primary HCC remains unclear. Because primary HCC is accompanied by dysbiosis and dysbiosis usually increases the circulatory concentrations of endotoxin and other harmful bacterial substances, which further increases liver damage, we hypothesized that level of dysbiosis associated with primary HCC increases with the stage of cancer progression. To test this hypothesis, we introduced a more integrated index referred to as the degree of dysbiosis (Ddys ); and we investigated Ddys of the gut microbiota with the development of primary HCC through high-throughput sequencing of 16S rRNA gene amplicons. Our results showed that compared with healthy individuals, patients with primary HCC showed increased pro-inflammatory bacteria in their fecal microbiota. The Ddys increased significantly in patients with primary HCC compared with that in healthy controls. Moreover, there was a tendency for the Ddys to increase with the development of primary HCC, although no significant difference was detected between different stages of primary HCC. Our findings provide important insights into the use of gut microbiota analysis during the treatment of primary HCC.

16.
Biol Reprod ; 101(5): 986-1000, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31350846

RESUMO

SALL1 and SALL3 are transcription factors that play an essential role in regulating developmental processes and organogenesis in many species. However, the functional role of SALL1 and SALL3 in chicken prehierarchical follicle development is unknown. This study aimed to explore the potential role and mechanism of csal1 and csal3 in granulosa cell proliferation, differentiation, and follicle selection within the prehierarchical follicles of hen ovary. Our data demonstrated that the csal1 and csal3 transcriptions were highly expressed in granulosa cells of prehierarchical follicles, and their proteins were mainly localized in the cytoplasm of granulosa cells and oocytes as well as in the ovarian stroma and epithelium. It initially revealed that both csal1 and csal3 may be involved in chicken prehierarchical follicle development via a translocation mechanism. Furthermore, our results showed an abundance of CCND1, Bcat, StAR, CYP11A1, and FSHR mRNA in granulosa cells, and the proliferation levels of granulosa cells from the prehierarchical follicles were significantly increased by siRNA-mediated knockdown of csal1 or/and csal3. Conversely, the overexpression of csal1 or/and csal3 in the granulosa cells led to a remarkably decreased of them. Moreover, csal1 and csal3 together exert a much stronger effect on the regulation than any of csal1 or csal3. These results indicated that csal1 and csal3 play synergistic inhibitory roles on granulosa cell proliferation, differentiation, and steroidogenesis during prehierarchical follicle development in vitro. The current data provide a basis of molecular mechanisms of csal1 and csal3 in controlling the prehierarchical follicle development and growth of hen ovary in vivo.

17.
ACS Nano ; 13(6): 7333-7344, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31180197

RESUMO

A DNA-based stimulus-responsive drug delivery system for synergetic cancer therapy has been developed. The system is built on a triplex-DNA nanoswitch capable of precisely responding to pH variations in the range of ∼5.0-7.0. In extracellular neutral pH space, the DNA nanoswitch keeps a linear conformation, immobilizing multiple therapeutics such as small molecules and antisense compounds simultaneously. Following targeted cancer cell uptake via endocytosis, the nanoswitch inside acidic intracellular compartments goes through a conformational change from linear to triplex, leading to smart release of the therapeutic combination. This stimuli-responsive drug delivery system does not rely on artificial responsive materials, making it biocompatible. Furthermore, it enables simultaneous delivery of multiple therapeutics for enhanced efficacy. Using tumor-bearing mouse models, we show efficient gene silencing and significant inhibition of tumor growth upon intravenous administration of the smart nanoswitch, providing opportunities for combinatorial cancer therapy.

18.
Electrophoresis ; 40(14): 1771-1778, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31090073

RESUMO

A sensitive method of CZE-ultraviolet (UV) detection based on the on-line preconcentration strategy of field-amplified sample injection (FASI) was developed for the simultaneous determination of five kinds of chlorophenols (CPs) namely 4-chlorophenol (4-CP), 2-chlorophenol (2-CP), 2,4-dichlorophenol (2,4-DCP), 2,4,6-trichlorophenol (2,4,6-TCP), and 2,6-dichlorophenol (2,6-DCP) in water samples. Several parameters affecting CZE and FASI conditions were systematically investigated. Under the optimal conditions, sensitivity enhancement factors for 4-CP, 2-CP, 2,4-DCP, 2,4,6-TCP, and 2,6-DCP were 9, 27, 35, 43, and 43 folds, respectively, compared with the direct CZE, and the baseline separation was achieved within 5 min. Then, the developed FASI-CZE-UV method was applied to tap and lake water samples for the five CPs determination. The LODs (S/N = 3) were 0.0018-0.019 µg/mL and 0.0089-0.029 µg/mL in tap water and lake water, respectively. The values of LOQs in tap water (0.006-0.0074 µg/mL) were much lower than the maximum permissible concentrations of 2,4,6-TCP, 2,4-DCP, and 2-CP in drinking water stipulated by World Health Organization (WHO) namely 0.3, 0.04, and 0.01 µg/mL, respectively, and thereby the method was suitable to detect the CPs according to WHO guidelines. Furthermore, the method attained high recoveries in the range of 83.0-119.0% at three spiking levels of five CPs in the two types of water samples, with relative standard deviations of 0.37-8.58%. The developed method was proved to be a simple, sensitive, highly automated, and efficient alternative to CPs determination in real water samples.


Assuntos
Clorofenóis/análise , Eletroforese Capilar , Água Potável/química , Eletroforese Capilar/métodos , Limite de Detecção , Poluentes Químicos da Água/análise
19.
Cancer Med ; 8(6): 2858-2866, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31016879

RESUMO

BACKGROUND: Although oncogenic driver mutations were thought to be mutually exclusive in non-small cell lung cancer (NSCLC), certain tumors harbor co-occurring mutations and represent a rare molecular subtype. The evaluation of the clinical features and therapeutic response associated with this NSCLC subtype will be vital for understanding the heterogeneity of treatment response and improving the management of these patients. METHODS: This retrospective study included 3774 samples from patients diagnosed with NSCLC. All samples were screened for EGFR, ALK, ROS1, KRAS, and BRAF mutation using the amplification-refractory mutation system. The relationship between concomitant driver mutations and clinicopathologic characteristics, and patient clinical outcomes were evaluated. RESULTS: Sixty-three (1.7%) samples had more than one driver gene mutation. Among these, 43 were coalterations with an EGFR mutation, 20 with an ALK rearrangement, and eight with an ROS1 rearrangement. Except for ROS1 concomitant mutations that were more frequent in male patients (87.5%, P = 0.020), the clinicopathological features of the concomitant mutation patients were not significantly different from those harboring a single EGFR, ALK, or ROS1 mutation. Furthermore, first-line EGFR-TKI treatment did not significantly improve the progression-free survival (PFS) of patients harboring EGFR concomitant mutation, compared to patients harboring a single EGFR mutation. However, for EGFR concomitant mutation patients, TKI therapy was more effective than chemotherapy (median PFS of 10.8 vs 5.2 months, P = 0.023). Lastly, KRAS mutations did not influence the EGFR-TKI therapy treatment effect. CONCLUSION: In this study, concomitant mutations were found in 1.7% of the NSCLC. EGFR-TKI therapy was more effective than chemotherapy for patients harboring EGFR concomitant mutation, and ROS1 concomitant mutations were more frequent in male patients. For patients harboring coalterations with an ALK or ROS1 rearrangement, we should be cautious when considering the therapeutic options.

20.
J Int Med Res ; 47(5): 2135-2144, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30961409

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening syndrome of excessive immune activation. Mesenchymal stem cells (MSCs) generate an immunosuppressive microenvironment by secreting cytokines and have been used to treat autoimmune diseases. We report the first case of refractory secondary HLH treated with umbilical cord MSCs. A 52-year-old Chinese female patient with a history of type 2 diabetes was diagnosed with refractory secondary HLH based upon the HLH-2004 protocol and was treated by infusion of third-party umbilical cord MSCs (1.4 × 106 cells/kg of body weight, 70 × 106 cells in total) from the stem cell bank of Hainan Province. Body temperature recovered to normal on the sixth day after infusion with umbilical cord MSCs, and the levels of inflammatory factors macrophage inflammatory protein (MIP)-1α, interleukin (IL)-12p70, stromal cell-derived factor (SDF)-1α, and IL-7 decreased significantly. Blood glucose levels were significantly lower than before treatment, and the amount of insulin needed was significantly reduced. Umbilical cord MSCs can relieve the symptoms of refractory secondary HLH and have a therapeutic effect on insulin resistance in type 2 diabetes mellitus.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Linfo-Histiocitose Hemofagocítica/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Cordão Umbilical/citologia , Resistência a Medicamentos , Feminino , Humanos , Resistência à Insulina , Linfo-Histiocitose Hemofagocítica/etiologia , Linfo-Histiocitose Hemofagocítica/patologia , Pessoa de Meia-Idade , Resultado do Tratamento
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