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1.
Langmuir ; 2020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-32293900

RESUMO

Lactic acid-functionalized chiral fullerene (C60) molecules are used as models to understand chiral selection in macroionic solutions involving chiral macroions, chiral counterions, and/or chiral co-ions. With the addition of Zn2+ cations, the C60 macroions exhibit slow self-assembly behavior into hollow, spherical, blackberry-type structures, as confirmed by laser light scattering (LLS), transmission electron microscopy (TEM), and atomic force microscopy (AFM) techniques. Chiral counterions with high charge density show no selection to the chirality of AC60 macroions (LAC60 and DAC60) during their self-assembly process, while obvious chiral discrimination between the assemblies of LAC60 and DAC60 is observed when chiral counterions with low charge density are present. Compared with chiral counterions, chiral co-ions show weaker effects on chiral selection with larger amounts needed to trigger the chiral discrimination between LAC60 and DAC60. However, they can induce a higher degree of discrimination when abundant chiral co-ions are present in solution. Furthermore, the self-assembly of chiral AC60 macroions is fully suppressed by adding significant amounts of neutral molecules with opposite chirality. Thermodynamic parameters from isothermal titration calorimetry (ITC) reveal that chiral selection is controlled by the ion pairing and the destruction of solvent shells between ions, and meanwhile originates from the delicate balance between electrostatic interaction and molecular chirality.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32161072

RESUMO

Sulforaphane (SFN), a potent antioxidant and antiinflammatory agent, has been shown to protect against cancers especially at early stages. However, how SFN affects UVB-mediated epigenome/DNA methylome and transcriptome changes in skin photodamage has not been fully assessed. Herein, we investigated the transcriptomic and DNA methylomic changes during tumor initiation, promotion, and progression and its impact and reversal by SFN using next-generation sequencing (NGS) technology. The results show that SFN reduced tumor incidence and tumor number. SFN's protective effects were more dramatic in the early stages than with later stages. Bioinformatic analysis of RNA sequencing (RNA-seq) data shows differential expressed genes and identifies the top canonical pathways related to SFN treatment of UVB-induced different stages of epidermal carcinogenesis. These pathways include p53 signaling, cell cycle: G2-M DNA damage checkpoint regulation, Th1, and Th2 activation pathway, and PTEN signaling pathways. The top upstream regulators related to UVB and SFN treatment as time progressed include dextran sulfate, TP53, NFE2L2 (Nrf2), IFNB1, and IL10RA. Bioinformatic analysis of Methyl-seq data shows several differential methylation regions induced by UVB were attenuated by SFN. These include Notch1, Smad6, Gnai3, and Apc2 Integrative analysis of RNA-seq and DNA-seq/CpG methylome yields a subgroup of genes associated with ultraviolet B (UVB) and SFN treatment. The changes in gene expression were inversely correlated with promoter CpG methylation status. These genes include Pik3cd, Matk, and Adm2 In conclusion, our study provides novel insights on the impact of SFN on the transcriptomic and DNA methylomic of UVB-induced different stages of skin cancer in mice.

3.
ACS Appl Mater Interfaces ; 12(13): 14784-14796, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32141282

RESUMO

Ideal wound dressing materials should be active components in the healing process. Bacterial cellulose (BC) has attracted a great deal of attention as novel wound dressing materials; however, it has no intrinsic antimicrobial activity. To explore the practical application values of BC and develop novel wound dressing materials, a series of composite membranes based on BC and polymeric ionic liquids (BC/PILs, composed of BC, and PILs formed by choline and different amino acids) with antimicrobial activity were synthesized by an ex situ method. The physicochemical and antimicrobial properties and biocompatibility of these membranes were systematically investigated. The results indicated that BC/PIL membranes with excellent properties could be obtained by adjusting the concentration and type of PILs. Several kinds of BC/PIL membranes exhibited good biocompatibility and high antimicrobial activity against Gram-positive and Gram-negative bacteria and fungus. The anionic PILs played important roles in the antimicrobial activity of BC/PIL membranes. The obtained membranes provided a novel promising candidate for wound dressing materials.

4.
Mediators Inflamm ; 2020: 6309238, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32089646

RESUMO

Oral lichen planus (OLP) is a chronic inflammatory oral mucosal disorder mediated by T cells, with a multifactorial etiology. Hashimoto's thyroiditis (HT) is a common autoimmune disease characterized by hypothyroidism. Although many clinical studies conducted over the past several decades have reported the cooccurrence of OLP and HT, the underlying mechanism remains unclear. This review summarizes potential mechanisms that might be involved in the cooccurrence of OLP and HT. We find that OLP and HT share a common or overlapping pathogenesis in terms of immune, heredity, environmental, and hormonal factors, which might cause cooccurrence. Furthermore, considering the latency of HT, a routine screen for thyroid diseases, particularly HT, is suggested for confirmed OLP patients.

5.
Mol Cell Endocrinol ; 504: 110689, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31891771

RESUMO

Cyp19a1a is a key gene responsible for the production of estradiol-17ß (E2), the main functional estrogen and a major downstream regulator of reproduction in teleost fish. It is widely known that CYP19 gene expression, aromatase activity, and E2 production can influence gonadal differentiation and sex reversal in teleost fish, but the feedback mechanisms whereby E2 regulates cyp19a1a remain poorly understood, especially regarding the potential roles of endogenous small RNA molecules (miRNAs). Here, we identified miR-26a-5p as a regulatory factor of its predicted target gene (cyp19a1a). In vitro and in vivo studies showed that miR-26a-5p can decrease cyp19a1a expression. Furthermore, high doses of E2 act as a repressor of miR-26a-5p. This study proposes a regulatory feedback loop whereby E2 regulates cyp19a1a through miR-26a-5p, and suggests that this positive feedback is an important aspect of the control of E2 production.

6.
FASEB J ; 34(1): 1304-1318, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914691

RESUMO

Phosphatase and tensin homolog located on chromosome 10 (PTEN) is a tumor suppressor gene and one of the most frequently mutated/deleted genes in human prostate cancer (PCa). However, how PTEN deletion would impact the epigenome and transcriptome alterations remain unknown. This hypothesis was tested in a prostate-specific PTEN-/- (KO) mouse prostatic adenocarcinoma model through DNA methyl-Seq and RNA-Seq analyses. Examination of cancer genomic datasets revealed that PTEN is expressed at lower levels in PTEN-deleted tumor samples than in normal solid tissue samples. Methylome and transcriptome profiling identified several inflammatory responses and immune response signaling pathways, including NF-kB signaling, IL-6 signaling, LPS/IL-1-mediated inhibition of RXR Function, PI3K in B lymphocytes, iCOS-iCOSL in T helper cells, and the role of NFAT in regulating the immune response, were affected by PTEN deletion. Importantly, a small subset of genes that showed DNA hypermethylation or hypomethylation was correlated with decreased or increased gene expression including CXCL1. quantitative polymerase chain reaction analyses of representative genes validated the RNA-Seq results. Histopathological examinations showed that the severity of prostatic intraepithelial neoplasia and inflammation development gradually increased as PTEN null mice aged. Collectively, these findings suggest that loss of PTEN drives global changes in DNA CpG methylation and transcriptomic gene expression and highly associated with several inflammatory and immune molecular pathways during PCa development. These biomarkers could be valuable molecular targets for cancer drug discovery and development against PCa.

7.
Exp Dermatol ; 29(3): 223-230, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30307062

RESUMO

BACKGROUND: Diffuse alopecia areata (DAA) often leads to a complete hair shedding within a few months. OBJECTIVE: To explore features and mechanisms underlying DAA. MATERIALS AND METHODS: Scalp and hair root dermoscopy were conducted on 23 DAA patients throughout the disease process, 20 patchy Alopecia areata patients, 23 acute telogen effluvium (ATE) patients and 10 normal controls. Histopathology was also evaluated. RESULTS: We found almost all hair roots were anagen in early stage DAA in 18 patients (18/23, 78.3%) within the first 4-8 weeks after hair loss onset. Anagen effluvium (~4 weeks) was followed by catagen (~4 weeks) and then telogen/exogen (~8 weeks) effluvium with overlap. Hair root and proximal hair shaft depigmentation was more prominent in later DAA disease stages. Black dots, exclamation mark hairs and inconsistent thickness of hair shafts were found more often in early than later DAA (Ps < 0.01). Early DAA histopathology revealed more prominent inflammation and hair follicle regression than that observed in the later stages. Patchy alopecia areata patients showed mixed anagen, catagen and telogen hair roots while ATE patients showed increased exogen and mildly decreased hair root pigmentation. CONCLUSION: Sequential cyclic staging of shed hairs in DAA indicates the insult may be hair-cycle specific. We suggest that DAA is initially an anagen effluvium disease involving an intense inflammatory insult, later progressing to a brief catagen effluvium, and then to telogen effluvium with premature exogen, in later stages of DAA.

8.
J Eval Clin Pract ; 26(1): 26-34, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31840330

RESUMO

OBJECTIVE: Venous thromboembolism (VTE) is a fatal complication and the most common preventable cause of death in hospitals. The risk-to-benefit ratio of thromboprophylaxis depends on the performance of the risk assessment model. A linear model, the Padua model, is recommended for medical inpatients in the United States but is not suitable for Chinese inpatients due to differences in race and disease spectrum. Currently, machine learning (ML) methods show advantages in modeling complex data patterns and have been applied to clinical data analysis. This study aimed to build VTE risk assessment ML models among Chinese inpatients and compare the predictive validity of the ML models with that of the Padua model. METHODS: We used 376 patients, including 188 patients with VTE, to build a model and then evaluate the predictive validity of the model in a consecutive clinical dataset from Peking Union Medical College Hospital. Nine widely used ML methods were trained on the model derivation set and then compared with the Padua model. RESULTS: Among the nine ML methods, random forest (RF), boosting-based methods, and logistic regression achieved a higher specificity, Youden index, positive predictive value, and area under the receiver operating characteristic curve than the Padua model on both the test and clinical validation sets. However, their sensitivities were inferior to that of the Padua model. Combined with the receiver operating characteristic curve, RF, as the best performing model, maintained high specificity with relatively better sensitivity and captured VTE patients' patterns more precisely. CONCLUSIONS: Advances in ML technology provide powerful tools for medical data analysis, and choosing models conforming to the disease pattern would achieve good performance. Popular ML models do not surpass the Padua model on all indicators of validity, and the drawback of low sensitivity should be improved upon in the future.

9.
Nature ; 577(7789): 266-270, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31827282

RESUMO

Acute myeloid leukaemia (AML) is a heterogeneous disease characterized by transcriptional dysregulation that results in a block in differentiation and increased malignant self-renewal. Various epigenetic therapies aimed at reversing these hallmarks of AML have progressed into clinical trials, but most show only modest efficacy owing to an inability to effectively eradicate leukaemia stem cells (LSCs)1. Here, to specifically identify novel dependencies in LSCs, we screened a bespoke library of small hairpin RNAs that target chromatin regulators in a unique ex vivo mouse model of LSCs. We identify the MYST acetyltransferase HBO1 (also known as KAT7 or MYST2) and several known members of the HBO1 protein complex as critical regulators of LSC maintenance. Using CRISPR domain screening and quantitative mass spectrometry, we identified the histone acetyltransferase domain of HBO1 as being essential in the acetylation of histone H3 at K14. H3 acetylated at K14 (H3K14ac) facilitates the processivity of RNA polymerase II to maintain the high expression of key genes (including Hoxa9 and Hoxa10) that help to sustain the functional properties of LSCs. To leverage this dependency therapeutically, we developed a highly potent small-molecule inhibitor of HBO1 and demonstrate its mode of activity as a competitive analogue of acetyl-CoA. Inhibition of HBO1 phenocopied our genetic data and showed efficacy in a broad range of human cell lines and primary AML cells from patients. These biological, structural and chemical insights into a therapeutic target in AML will enable the clinical translation of these findings.

10.
J Transl Med ; 17(1): 422, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31847906

RESUMO

BACKGROUND: The growth differentiation factor 11 (GDF11) was shown to reverse age-related hypertrophy on cardiomyocytes and considered as anti-aging rejuvenation factor. The role of GDF11 in regulating metabolic homeostasis is unclear. In this study, we investigated the functions of GDF11 in regulating metabolic homeostasis and energy balance. METHODS: Using a hydrodynamic injection approach, plasmids carrying a mouse Gdf11 gene were delivered into mice and generated the sustained Gdf11 expression in the liver and its protein level in the blood. High fat diet (HFD)-induced obesity was employed to examine the impacts of Gdf11 gene transfer on HFD-induced adiposity, hyperglycemia, insulin resistance, and hepatic lipid accumulation. The impacts of GDF11 on metabolic homeostasis of obese and diabetic mice were examined using HFD-induced obese and STZ-induced diabetic models. RESULTS: Gdf11 gene transfer alleviates HFD-induced obesity, hyperglycemia, insulin resistance, and fatty liver development. In obese and STZ-induced diabetic mice, Gdf11 gene transfer restores glucose metabolism and improves insulin resistance. Mechanism study reveals that Gdf11 gene transfer increases the energy expenditure of mice, upregulates the expression of genes responsible for thermoregulation in brown adipose tissue, downregulates the expression of inflammatory genes in white adipose tissue and those involved in hepatic lipid and glucose metabolism. Overexpression of GDF11 also activates TGF-ß/Smad2, PI3K/AKT/FoxO1, and AMPK signaling pathways in white adipose tissue. CONCLUSIONS: These results demonstrate that GDF11 plays an important role in regulating metabolic homeostasis and energy balance and could be a target for pharmacological intervention to treat metabolic disease.

11.
Int J Nanomedicine ; 14: 8059-8072, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632018

RESUMO

Background: Compared with random copolymers, block copolymerization is easier to prepare for nanoparticles with core-shell structure, and they will have better glucose sensitivity and higher insulin loading. Purpose: In our study, insulin-loaded poly (3-acrylamidophenylboronic acid-block-N-vinyl caprolactam) p(AAPBA-b-NVCL) nanoparticles were successfully prepared and were glucose-sensitive, which could effectively lower the blood sugar levels within 72 hrs. Methods: The polymer of p(AAPBA-b-NVCL) was produced by reversible addition-fragmentation chain transfer polymerization based on different ratios of 3-acrylamidophenylboronic acid (AAPBA) and N-vinylcaprolactam (NVCL), and its structure was discussed by Fourier transform infrared spectroscopy and 1H-nuclear magnetic resonance . Next, the polymer was manufactured into the nanoparticles, and the characteristics of nanoparticles were detected by dynamic light scattering, lower critical solution temperature, and transmission electron microscopy. After that, the cell and animal toxicity of nanoparticles were also investigated. Results: The results demonstrated that p(AAPBA-b-NVCL) was successfully synthesized, and can be easily self-assembled to form nanoparticles. The new nanoparticles included monodisperse submicron particles, with the size of the nanoparticle ranged between 150 and 300nm and are glucose- and temperature-sensitive. Meanwhile, insulin can be easily loaded by p(AAPBA-b-NVCL) nanoparticles and an effective sustained release of insulin was observed when the nanoparticles were placed in physiological saline. Besides, MTT assay revealed that cell viability was more than 80%, and mice demonstrated no negative impact on blood biochemistry and heart, liver, spleen, lung, and kidney after intraperitoneal injection of 10 mg/kg/d of nanoparticles. This suggested that the nanoparticles were low-toxic to both cells and animals. Moreover, they could lower the blood sugar level within 72h. Conclusion: Our research suggested that these p(AAPBA-b-NVCL) nanoparticles might have the potential to be applied in a delivery system for insulin or other hypoglycemic proteins.


Assuntos
Acrilamidas/química , Ácidos Borônicos/química , Caprolactama/química , Sistemas de Liberação de Medicamentos , Glucose/análise , Insulina/administração & dosagem , Nanopartículas/química , Acrilamidas/síntese química , Animais , Glicemia/metabolismo , Ácidos Borônicos/síntese química , Caprolactama/análogos & derivados , Caprolactama/síntese química , Sobrevivência Celular/efeitos dos fármacos , Feminino , Hidrodinâmica , Concentração de Íons de Hidrogênio , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Células NIH 3T3 , Nanopartículas/ultraestrutura , Espectroscopia de Prótons por Ressonância Magnética , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática , Temperatura
12.
Stem Cells Int ; 2019: 8928934, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31611919

RESUMO

Skeleton has emerged as an endocrine organ which is both capable of regulating energy metabolism and being a target for it. Glutamine is the most bountiful and flexible amino acid in the body which provides adenosine 5'-triphosphate (ATP) demands for cells. Emerging evidences support that glutamine which acts as the second metabolic regulator after glucose exerts crucial roles in bone homeostasis at cellular level, including the lineage allocation and proliferation of bone mesenchymal stem cells (BMSCs), the matrix mineralization of osteoblasts, and the biosynthesis in chondrocytes. The integrated mechanism consisting of WNT, mammalian target of rapamycin (mTOR), and reactive oxygen species (ROS) signaling pathway in a glutamine-dependent pattern is responsible to regulate the complex intrinsic biological process, despite more extensive molecules are deserved to be elucidated in glutamine metabolism further. Indeed, dysfunctional glutamine metabolism enhances the development of degenerative bone diseases, such as osteoporosis and osteoarthritis, and glutamine or glutamine progenitor supplementation can partially restore bone defects which may promote treatment of bone diseases, although the mechanisms are not quite clear. In this review, we will summarize and update the latest research findings and clinical trials on the crucial regulatory roles of glutamine metabolism in BMSCs and BMSC-derived bone cells, also followed with the osteoclasts which are important in bone resorption.

13.
Cancer Manag Res ; 11: 7197-7210, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534369

RESUMO

Objectives: This study was to assess whether human papillomavirus (HPV) resulting in genetic instability is one reason for the high incidence and mortality of cervical cancer in Longnan. Methods: Between 2012 and 2016, a total of 346 samples from Longnan were collected and divided into four groups: cervicitis group (n=57), cervical intraepithelial neoplasia I group (CIN I, n=63), CIN II/III group (n=79) and invasive squamous cell carcinoma group (SCC, n=147). HPV E6/E7 mRNA was detected by Quantivirus® HPV E6/E7 RNA 3.0 assay (bDNA). The markers of DNA damage response (DDR) - ataxia telangiectasia mutated (ATM) pSer1981, H2AX pSer139 (γH2AX), Chk2 pThr68 and P53 - were analyzed by immunohistochemistry. Results: The activation of ATM, γH2AX, Chk2 and P53 was increased with increasing severity of cervical lesion. A significant difference of ATM expression in simple infection was also shown accompanied by the cervical lesion. The expression of γH2AX between HPV16+ and HPV16- specimens, γH2AX and P53 between HPV58+ and HPV58- groups had statistical significance. The expression and copy number of HPV E6/7 mRNA increases with the cervical lesion severity. A significant difference was shown for P53 expression between HPV E6/7 mRNA+ and mRNA- specimens. A close correlation with CHK2 expression for HPV E6/7 mRNA+ and HPV16 E6/7 mRNA+ specimens and γH2AX and CHK2 expression for SCC specimens was shown between low and high viral load groups. Conclusions: DDR, HPV genotypes and HPV E6/E7 oncogene expression correlated with the level of dysplasia of cervical lesions. HPV infection resulted in genetic instability may be one reason for the high incidence and mortality in Longnan.

14.
BMC Med Inform Decis Mak ; 19(Suppl 4): 151, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31391095

RESUMO

BACKGROUND: Padua linear model is widely used for the risk assessment of venous thromboembolism (VTE), a common but preventable complication for inpatients. However, genetic and environmental differences between Western and Chinese population limit the validity of Padua model in Chinese patients. Medical records which contain rich information about disease progression, are useful in mining new risk factors related to Chinese VTE patients. Furthermore, machine learning (ML) methods provide new opportunities to build precise risk prediction model by automatic selection of risk factors based on original medical records. METHODS: Medical records of 3,106 inpatients including 224 VTE patients were collected and various types of ontologies were integrated to parse unstructured text. A workflow of ontology-based VTE risk prediction model, that combines natural language processing (NLP) and machine learning (ML) technologies, was proposed. Firstly ontology terms were extracted from medical records, then sorted according to their calculated weights. Next importance of each term in the unit of section was evaluated and finally a ML model was built based on a subset of terms. Four ML methods were tested, and the best model was decided by comparing area under the receiver operating characteristic curve (AUROC). RESULTS: Medical records were first split into different sections and subsequently, terms from each section were sorted by their weights calculated by multiple types of information. Greedy selection algorithm was used to obtain significant sections and terms. Top terms in each section were selected to construct patients' distributed representations by word embedding technique. Using top 300 terms of two important sections, namely the 'Progress Note' section and 'Admitting Diagnosis' section, the model showed relatively better predictive performance. Then ML model which utilizes a subset of terms from two sections, about 110 terms, achieved the best AUC score, of 0.973 ± 0.006, which was significantly better compared to the Padua's performance of 0.791 ± 0.022. Terms found by the model showed their potential to help clinicians explore new risk factors. CONCLUSIONS: In this study, a new VTE risk assessment model based on ontologies extraction from raw medical records is developed and its performance is verified on real clinical dataset. Results of selected terms can help clinicians to discover meaningful risk factors.

15.
Sheng Wu Gong Cheng Xue Bao ; 35(8): 1453-1462, 2019 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-31441616

RESUMO

To evaluate immune efficacy of the recombinant Lactobacillus casei, we constructed pLA-Newcastle disease virus (NDV)-F/L. casei and obtained the expression products. PCR amplified the NDV F gene carrying part of the major epitopes. The target gene was inserted to the shuttle plasmid pLA, and then transformed into Escherichia coli BL21 (DE3) in order to screen positive recombinant plasmid. The positive recombinant plasmid was transformed into L. casei by electroporation to construct pLA-NDV-F/L. casei. The positive strains were identified by PCR. The reactivity of the recombinant bacteria was identified by Western blotting and the protein expression was detected by indirect immunofluorescence, flow cytometry and laser confocal microscopy. The 14-day-old chickens in each group were vaccinated by oral plus nose drops. The pLA-NDV-F/L. casei twice immunization group and three times immunization group, the commercial vaccine group, the pLA/L. casei group, the unchallenge PBS and the challenge PBS group were established. IgG in serum and sIgA in the lavage fluid of intestinal, nasal and lung were detected by ELISA. The protection rate of chickens was evaluated. The results showed that 94.10% of the recombinant bacteria expressed the F protein. The recombinant protein was highly expressed on the surface of L. casei with a protein size of 62 kDa, which specifically bound to anti-NDV serum. The levels of anti-F IgG and sIgA antibodies in each test group were significantly higher than those in the control groups. The duration of antibody in the pLA-NDV-F/L. casei three-time immunization group lasted 28 days longer than that in the twice immunized group, and there was no significant difference between antibody peak values. The attack protection rates in each group of immunized pLA-NDV-F/L. casei three times, twice, attenuated vaccine, pLA/L. casei and PBS were 80%, 80%, 90%, 0% and 0%, respectively. Therefore, the antigenic protein of NDV F was successfully expressed by L. casei expression system, which has of reactogenicity and immunogenicity, and could induce protective immune responses in chickens.


Assuntos
Lactobacillus casei , Vírus da Doença de Newcastle , Vacinas Virais , Animais , Anticorpos Antivirais , Galinhas , Imunização , Vacinas Atenuadas
16.
J Extracell Vesicles ; 8(1): 1643670, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31448068

RESUMO

Early diagnosis of colon cancer (CC) is clinically important, as it can significantly improve patients' survival rate and quality of life. Although the potential role for small extracellular vesicles (sEVs) in early detection of many diseases has been repeatedly mentioned, systematic screening of plasma sEVs derived early CC specific biomarkers has not yet been reported. In this work, plasma sEVs enriched fractions were derived from 15 early-stage (TisN0M0) CC patients and 10 normal controls (NC). RNA sequencing identified a total number of 95 sEVs enriched fraction derived miRNAs with differential expression between CC and NC, most of which (60/95) was in well accordance with tissue results in the Cancer Genome Atlas (TCGA) dataset. Among those miRNAs, we selected let-7b-3p, miR-139-3p, miR-145-3p, and miR-150-3p for further validation in an independent cohort consisting of 134 participants (58 CC and 76 NC). In the validation cohort, the AUC of 4 individual miRNAs ranged from 0.680 to 0.792. A logistic model combining two miRNAs (i.e. let-7b-3p and miR-145-3p) achieved an AUC of 0.901. Adding the 3rd miRNA into this model can further increase the AUC to 0.927. Side by side comparison revealed that sEVs miRNA profile outperformed cell-free plasma miRNA in the diagnosis of early CC. In conclusion, we suggested that circulating sEVs enriched fractions have a distinct miRNA profile in CC patients, and sEVs derived miRNA could be used as a promising biomarker to detect CC at an early stage.

17.
Mol Carcinog ; 58(10): 1738-1753, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31237383

RESUMO

Nonmelanoma skin cancers (NMSCs) are the most common type of skin cancers. Major risk factors for NMSCs include exposure to ultraviolet (UV) irradiation. Ursolic acid (UA) is a natural triterpenoid enriched in blueberries and herbal medicinal products, and possess anticancer activities. This study focuses on the impact of UA on epigenomic, genomic mechanisms and prevention of UVB-mediated NMSC. CpG methylome and RNA transcriptome alterations of early, promotion and late stages of UA treated on UVB-induced NMSC in SKH-1 hairless mice were conducted using CpG methyl-seq and RNA-seq. Samples were collected at weeks 2, 15, and 25, and integrated bioinformatic analyses were performed to identify key pathways and genes modified by UA against UVB-induced NMSC. Morphologically, UA significantly reduced NMSC tumor volume and tumor number. DNA methylome showed inflammatory pathways IL-8, NF-κB, and Nrf2 pathways were highly involved. Antioxidative stress master regulator Nrf2, cyclin D1, DNA damage, and anti-inflammatory pathways were induced by UA. Nrf2, cyclin D1, TNFrsf1b, and Mybl1 at early (2 weeks) and late (25 weeks) stages were identified and validated by quantitative polymerase chain reaction. In summary, integration of CpG methylome and RNA transcriptome studies show UA alters antioxidative, anti-inflammatory, and anticancer pathways in UVB-induced NMSC carcinogenesis. Particularly, UA appears to drive Nrf2 and its upstream/downstream genes, anti-inflammatory (at early stages) and cell cycle regulatory (both early and late stages) genes, of which might contribute to the overall chemopreventive effects of UVB-induced MNSC. This study may provide potential biomarkers/targets for chemoprevention of early stage of UVB-induced NMSC in human.


Assuntos
Metilação de DNA/genética , Neoplasias Induzidas por Radiação/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Transcriptoma/genética , Animais , Anticarcinógenos/farmacologia , Antioxidantes/farmacologia , Dano ao DNA/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Camundongos , Proteínas de Neoplasias , Neoplasias Induzidas por Radiação/genética , Neoplasias Induzidas por Radiação/patologia , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Pele/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Transcriptoma/efeitos da radiação , Triterpenos/farmacologia , Raios Ultravioleta/efeitos adversos
18.
J Int Med Res ; 47(6): 2615-2625, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31099288

RESUMO

OBJECTIVE: To study the epidemiological characteristics of hand, foot and mouth disease (HFMD) in Tongzhou District, Beijing between 2013 and 2017. METHODS: Data on HFMD infections from 1 January 2013 to 31 December 2017 were collected from the Notifiable Infectious Diseases Reporting Information System and analysed. Serotyping of enteroviruses from samples from patients with HFMD was undertaken using reverse transcription-polymerase chain reaction. RESULTS: A total of 15 341 patients with HFMD were reported and 32 patients (0.2%) were classified as having severe HFMD. The annual mean incidence rate of HFMD was 219.3/100 000 of the general population. The incidence and case-severity rates of HFMD generally decreased between 2013 and 2017. In the floating migrant population, the incidence and cases-severity rates of HFMD were significantly higher than in the local population. The peak incidence and severity-case rates were at 2 years of age and > 90% of patients were ≤5 years. Enterovirus A71 and Coxsackievirus A16 were the predominant pathogens in 2013-2017. CONCLUSIONS: During the 5-year period 2013-2017, the incidence rate and case-severity rate of HFMD generally decreased in Tongzhou District, Beijing. The floating migrant population and children ≤5 years of age were at the highest risk of HFMD.


Assuntos
Emigrantes e Imigrantes/estatística & dados numéricos , Doença de Mão, Pé e Boca/epidemiologia , Adolescente , Fatores Etários , Pequim/epidemiologia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Fatores de Tempo
19.
Nanoscale ; 11(20): 10106-10113, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31089660

RESUMO

Tumor-derived exosomes have emerged as promising cancer biomarkers and attracted increasing interest in non-invasive cancer diagnosis and treatment monitoring. However, the identification and quantification of exosomes in clinical samples such as blood remains challenging due to the difficulty in trade-off between recognition specificity and isolation efficiency. Here we have developed an aptamer-based fluorescence polarization assay for exosome quantification, which is a separation-free, amplification-free and sensitive approach enabling direct quantification of exosomes in human plasma. While the key specificity of this assay is based on the aptamer's inherent affinity to membrane proteins on exosomes, exosomes' inherent huge mass/volume acts as mass-based fluorescence polarization amplifier. Our assay allows quantitative analysis of exosomes in the range of 5 × 102 to 5 × 105 particles per µL with a detect limitation of 500 particles per µL for the cell line deprived exosomes. The total assay time is about 30 min with just one mix-and-read step to achieve high sensitivity. We have also demonstrated quantification of exosomes from lung cancer patients and healthy donors in clinical samples. This work describes a new and simple liquid biopsy assay to directly detect exosomes in the biological matrix, which facilitates cancer diagnosis and therapy monitoring.


Assuntos
Aptâmeros de Nucleotídeos/química , Exossomos/química , Polarização de Fluorescência/métodos , Células A549 , Técnicas Biossensoriais , Exossomos/metabolismo , Humanos , Neoplasias Pulmonares/patologia , Tetraspanina 30/metabolismo
20.
Radiother Oncol ; 133: 93-99, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30935588

RESUMO

BACKGROUND: Synchrotron microbeam radiation therapy (MRT) is a new, evolving form of radiotherapy that has potential for clinical application. Several studies have shown in preclinical models that synchrotron MRT achieves equivalent tumor control to conventional radiotherapy (CRT) but with significantly reduced normal tissue damage. METHODS: To explore differences between these two modalities, we assessed the immune cell infiltrate into EMT6.5 mammary tumors after CRT and MRT. RESULTS: CRT induced marked increases in tumor-associated macrophages and neutrophils while there were no increases in these populations following MRT. In contrast, there were higher numbers of T cells in the MRT treated tumors. There were also increased levels of CCL2 by immunohistochemistry in tumors subjected to CRT, but not to MRT. Conversely, we found that MRT induced higher levels of pro-inflammatory genes in tumors than CRT. CONCLUSION: Our data are the first to demonstrate substantial differences in macrophage, neutrophil and T cell numbers in tumors following MRT versus CRT, providing support for the concept that MRT evokes a different immunomodulatory response in tumors compared to CRT.


Assuntos
Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/radioterapia , Animais , Linhagem Celular Tumoral , Quimiocina CCL2/imunologia , Quimiocina CCL2/metabolismo , Feminino , Macrófagos/imunologia , Macrófagos/efeitos da radiação , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/imunologia , Neutrófilos/efeitos da radiação , Radioterapia/instrumentação , Radioterapia/métodos , Síncrotrons , Linfócitos T/imunologia , Linfócitos T/efeitos da radiação
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