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1.
Viruses ; 12(3)2020 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-32210095

RESUMO

Marek's disease virus (MDV), an alpha herpes virus, causes a lymphoproliferative state in chickens known as Marek's disease (MD), resulting in severe monetary losses to the poultry industry. Because lymphocytes of bursa of Fabricius and spleen are prime targets of MDV replication during the early cytolytic phase of infection, the immune response in bursa and spleen should be the foundation of late immunity induced by MDV. However, the mechanism of the MDV-mediated host immune response in lymphocytes in the early stage is poorly understood. The present study is primarily aimed at identifying the crucial genes and significant pathways involved in the immune response of chickens infected with MDV CVI988 and the very virulent RB1B (vvRB1B) strains. Using the RNA sequencing approach, we analyzed the generated transcriptomes from lymphocytes isolated from chicken bursa and spleen. Our findings validated the expression of previously characterized genes; however, they also revealed the expression of novel genes during the MDV-mediated immune response. The results showed that after challenge with CVI988 or vvRB1B strains, 634 and 313 differentially expressed genes (DEGs) were identified in splenic lymphocytes, respectively. However, 58 and 47 DEGs were observed in bursal lymphocytes infected with CVI988 and vvRB1B strains, respectively. Following MDV CVI988 or vvRB1B challenge, the bursal lymphocytes displayed changes in IL-6 and IL-4 gene expression. Surprisingly, splenic lymphocytes exhibited an overwhelming alteration in the expression of cytokines and cytokine receptors involved in immune response signaling. On the other hand, there was no distinct trend between infection with CVI988 and vvRB1B and the expression of cytokines and chemokines, such as IL-10, IFN-γ, STAT1, IRF1, CCL19, and CCL26. However, the expression profiles of IL-1ß, IL-6, IL8L1, CCL4 (GGCL1), and CCL5 were significantly upregulated in splenic lymphocytes from chickens infected with CVI988 compared with those of chickens infected with vvRB1B. Because these cytokines and chemokines are considered to be associated with B cell activation and antigenic signal transduction to T cells, they may indicate differences of immune responses initiated by vaccinal and virulent strains during the early phase of infection. Collectively, our study provides valuable data on the transcriptional landscape using high-throughput sequencing to understand the different mechanism between vaccine-mediated protection and pathogenesis of virulent MDV in vivo.

2.
Biomed Pharmacother ; 125: 110032, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32187961

RESUMO

This study was devised to investigate if P-glycoprotein (P-gp) mediated the drug-drug interaction (DDI) between genistein and repaglinide. When genistein was added, the plasma concentrations of repaglinide in rats were increased. The maximum plasma concentration (Cmax) of repaglinide increased from 70.80 ± 7.98 ng/mL to 124.71 ± 9.02 ng/mL and the area under the plasma concentration-time curve (AUC) increased from 134.89 ± 13.65 µg·h/L to 245.95 ± 7.24 µg·h/L. Intestinal absorption of repaglinide was markedly enhanced by genistein or P-gp inhibitor verapamil (Ver), both in situ rat jejunal perfusion studies and in vitro transport assays using everted rat intestinal sac preparations. Furthermore, the accumulation of repaglinide in both Caco-2 cells and IEC-6 cells also increased significantly in the presence of genistein and Ver. The transepithelial transport rate of repaglinide from basolateral-to-apical in MDR1-MDCK cells was 3.6-fold higher than the apical-to-basolateral rate with a net efflux ratio of 1.92 compared with mock-MDCK cells, which was significantly decreased following co-administration with genistein or Ver. In an intracellular accumulation experiment using Rhodamine 123 as a P-gp substrate, genistein significantly increased the intracellular fluorescence of Rhodamine 123. These results indicated that genistein had an inhibitory effect on the efflux function of P-gp. Through molecular docking assays we further found that genistein could bind to the nucleotide-binding domains (NBD) in the cytoplasm of P-gp, thus affecting the functions of P-gp. In conclusion, genistein inhibited the efflux of repaglinide mediated by P-gp in rats and in vitro. The findings suggested that the DDI between genistein and repaglinide is mediated by P-gp, and a dosage adjustment may be needed when they are co-administered in a clinical setting.

3.
Pancreatology ; 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-32007358

RESUMO

BACKGROUND/OBJECTIVES: Carboxyl ester lipase is a pancreatic enzyme encoded by CEL, an extremely polymorphic human gene. Pathogenic variants of CEL either increases the risk for chronic pancreatitis (CP) or cause MODY8, a syndrome of pancreatic exocrine and endocrine dysfunction. Here, we aimed to characterize a novel duplication allele of CEL (CEL-DUP2) and to investigate whether it associates with CP or pancreatic cancer. METHODS: The structure of CEL-DUP2 was determined by a combination of Sanger sequencing, DNA fragment analysis, multiplex ligation-dependent probe amplification and whole-genome sequencing. We developed assays for screening of CEL-DUP2 and analyzed cohorts of idiopathic CP, alcoholic CP and pancreatic cancer. CEL protein expression was analyzed by immunohistochemistry. RESULTS: CEL-DUP2 consists of an extra copy of the complete CEL gene. The allele has probably arisen from non-allelic, homologous recombination involving the adjacent pseudogene of CEL. We found no association between CEL-DUP2 carrier frequency and CP in cohorts from France (cases/controls: 2.5%/2.4%; P = 1.0), China (10.3%/8.1%; P = 0.08) or Germany (1.6%/2.3%; P = 0.62). Similarly, no association with disease was observed in alcohol-induced pancreatitis (Germany: 3.2%/2.3%; P = 0.51) or pancreatic cancer (Norway; 2.5%/3.2%; P = 0.77). Notably, the carrier frequency of CEL-DUP2 was more than three-fold higher in Chinese compared with Europeans. CEL protein expression was similar in tissues from CEL-DUP2 carriers and controls. CONCLUSIONS: Our results support the contention that the number of CEL alleles does not influence the risk of pancreatic exocrine disease. Rather, the pathogenic CEL variants identified so far involve exon 11 sequence changes that substantially alter the protein's tail region.

4.
Langmuir ; 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32011891

RESUMO

Molecular dynamics simulations were conducted to investigate the generation and evolution of nanobubbles on heated gold-like nanoparticles (GNPs). The effects of surface wettability (ß) and heating intensity (Q) of the GNPs are studied. We found that nanobubbles are generated faster on the superhydrophobic GNP than on the superhydrophilic GNP where nanobubble formation appears after a delay. In the case of the superhydrophilic GNP, the nanobubble is observed to grow explosively because it is initially generated at a distance from the GNP surface instead of on its surface. In the case of the superhydrophobic GNP, the faster generation of the nanobubble is promoted by the larger temperature difference between the GNP and the surrounding fluid and an ultrathin low-density layer that exists before the GNP is heated. For a given ß, faster generation and growth of nanobubbles are observed with increasing Q. Furthermore, the maximum radius of the nanobubble is found to be dependent on ß and not Q. The mechanism is elaborated based on the thermal resistance analysis at the melting point of GNPs. Additionally, it was found that there exists a threshold Q for nanobubble generation and the threshold value for the case of the superhydrophobic GNP is lower than that for the case of the superhydrophilic GNP. The present results have demonstrated that the superhydrophobic GNP is favorable for fast and energy-saving nanobubble generation. Our work provides further understanding in the generation and evolution of nanobubbles and potentially offers a new insight for nanobubble manipulation.

5.
Apoptosis ; 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31938895

RESUMO

Emerging evidence has indicated that microRNAs are involved in multiple processes of cancer development. Previous studies have demonstrated that microRNA-499a (miR-499a) plays both oncogenic and tumor suppressive roles in several types of malignancies, and genetic variants in miR-499a are associated with the risk of cervical cancer. However, the biological roles of miR-499a in cervical cancer have not been investigated. Quantitative real-time PCR was used to assess miR-499a expression in cervical cancer cells. Mimics or inhibitor of miR-499a was transfected into cervical cancer cells to upregulate or downregulate miR-499a expression. The effects of miR-499a expression change on cervical cancer cells proliferation, colony formation, tumorigenesis, chemosensitivity, transwell migration and invasion were assessed. The potential targets of miR-499a were predicted using online database tools and validated using real-time PCR, Western blot and luciferase reporter experiments. miR-499a was significantly upregulated in cervical cancer cells. Moreover, overexpression of miR-499a significantly enhanced the proliferation, cell cycle progression, colony formation, apoptosis resistance, migration and invasion of cervical cancer cells, while inhibiting miR-499a showed the opposite effects. Further exploration demonstrated that Sex-determining region Y box 6 was the direct target of miR-499a. miR-499a-induced SOX6 downregulation mediated the oncogenic effects of miR-499a in cervical cancer. Inhibiting miR-499a could enhance the anticancer effects of cisplatin in the xenograft mouse model of cervical cancer. Our findings for the first time suggest that miRNA-499a may play an important role in the development of cervical cancer and could serve as a potential therapeutic target.

6.
J Cell Physiol ; 235(4): 3309-3319, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31587272

RESUMO

The aim of this study was to explore whether rhein could enhance the effects of pemetrexed (PTX) on the therapy of non-small-cell lung cancer (NSCLC) and to clarify the associated molecular mechanism. Our study shows that rhein in combination with PTX could obviously increase the systemic exposure of PTX in rats, which would be mediated by the inhibition of organic anion transporters (OATs). Furthermore, the toxicity of PTX was significantly raised by rhein in A549 cells in a concentration-dependent manner. Concomitant administration of rhein and PTX-induced cell apoptosis compared with PTX alone in flow cytometry assays, which was further validated by the protein expressions of the apoptotic markers B-cell lymphoma-2/Bcl-2-associated x (Bcl-2/Bax) and Cleaved-Caspase3 (Cl-Caspase3). Meanwhile, the results of monodansylcadaverine (MDC) dyeing experiments showed that PTX-induced autophagy could be enhanced by combination therapy with rhein in A549 cells. Western blot analysis indicated that the synergistic effect of rhein on PTX-mediated autophagy may be interrelated to PI3K-AKT-mTOR pathway inhibition and to the enhancement of p-AMPK and light chain 3-II (LC3-II) protein levels. From these findings, it could be surmised that rhein enhanced the antitumor activity of PTX through influencing autophagy and apoptosis by modulating the PI3K-AKT-mTOR pathway and Bcl-2 family of proteins in A549 cells. Our findings demonstrated that the potential application of rhein as a candidate drug in combination with PTX is promising for treatment of the human lung cancer.

7.
J Gastroenterol Hepatol ; 35(2): 343-352, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31318997

RESUMO

BACKGROUND AND AIM: Diabetes mellitus (DM) is a common complication of idiopathic chronic pancreatitis (ICP), which impairs the quality of life for patients. This study aimed to identify risk factors and develop nomogram for DM in ICP to help early diagnosis. METHODS: Idiopathic chronic pancreatitis patients admitted to our center from January 2000 to December 2013 were included. Cumulative rates of DM were calculated by Kaplan-Meier method. Patients were randomly assigned, in a 2:1 ratio, to the training and validation cohort. Based on training cohort, risk factors for DM were identified through Cox proportional hazards regression model, and nomogram was developed. Internal and external validations were performed based on the training and validation cohort, respectively. RESULTS: Totally, 1633 patients with ICP were finally enrolled. The median follow-up duration was 9.8 years. DM was found in 26.3% (430/1633) of patients after the onset of CP. Adult at onset of ICP, biliary stricture at/before diagnosis of CP, steatorrhea at/before diagnosis of CP, and complex pathologic changes in main pancreatic duct were identified risk factors for DM development. The nomogram achieved good concordance indexes in the training and validation cohorts, respectively, with well-fitted calibration curves. CONCLUSIONS: Risk factors were identified, and nomogram was developed to determine the risk of DM in ICP patients. Patients with one or more of the risk factors including adult at onset of ICP, biliary stricture at/before diagnosis of CP, steatorrhea at/before diagnosis of CP, and complex pathologic changes in main pancreatic duct have higher incidence of DM.

8.
Langmuir ; 36(1): 456-464, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31840509

RESUMO

In this work, we use molecular dynamics (MD) simulations to investigate the dependences of formation and transition of surface condensation mode on wettability (ß) and vapor-to-surface temperature difference (ΔT). We build a map of different surface condensation modes against ß and ΔT based on plenty of MD simulation results and reveal five formation mechanisms and two transition mechanisms. At low ß and ΔT, the high free energy barrier (ΔG*) prevents any surface clusters from surviving, therefore no-condensation (NC) is observed. The formation of dropwise condensation (DWC) could evolve from either nucleation or film rupture. Similarly, the formation of filmwise condensation (FWC) could evolve from either nucleation or the adsorption-induced film. The transition between NC and DWC is determined by ΔG* according to classical nucleation theory. The transition between DWC and FWC depends on the stability of condensate film; there emerges the competition between the trend that the uneven condensate film contracts and ruptures to droplets favored by lower ß and the trend that the uneven condensate film continues growing promoted by higher ΔT. We finally present a schematic overview of all of the mechanisms revealed for a better understanding of the physical phenomenon of the surface condensation mode.

9.
World J Clin Cases ; 7(22): 3807-3811, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31799308

RESUMO

BACKGROUND: Congenital scrotal agenesis (CSA) is very rare. There are 11 cases of congenital scrotal agenesis or absence reported in the literature, most of which are bilateral and accompanied by cryptorchidism. Only two cases of which are unilateral scrotal agenesis and not accompanied by cryptorchidism. This is the first reported case of unilateral scrotal agenesis with cryptorchidism and scrotoplasty. CASE SUMMARY: A 2-year-old boy was admitted to our hospital with left cryptorchidism and ipsilateral CSA. An innovative method was used in the patient where a scrotal skin pedicle from the right part of scrotal skin was transplanted to the left side. At the same time, descent orchiopexy was performed. At the 4-mo follow-up, the left testicle was located in the scrotum and the size and shape were normal. CONCLUSION: For unilateral CSA with ipsilateral cryptorchidism, contralateral scrotal pedicle transplantation and descent orchiopexy appear to be a successful surgical option.

10.
Medicine (Baltimore) ; 98(49): e17606, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31804303

RESUMO

BACKGROUND: This aim of this study is to assess the effectiveness and safety of acupuncture for the treatment of patients with postoperative pain (PPP). METHODS: We will carry out a systematic review of the published literature and will comprehensively search Cochrane Library, MEDLINE, EMBASE, CINAHL, PsycINFO, Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure from inception to the present with no language restrictions. Randomized controlled trials comparing acupuncture with other interventions or sham acupuncture will be included. Two reviewers will independently conduct study selection, data collection, and study quality. A third reviewer will resolve any discrepancies. We will apply RevMan 5.3 software for statistical analysis. RESULTS: The protocol of this study will systematically assess the effectiveness and safety of acupuncture for patients with PPP. The primary outcome is postoperative pain intensity. The secondary outcomes comprise of: analgesic consumption, postoperative recovery parameters, vital signs, quality of life, and treatment related adverse events. CONCLUSION: This study will summarize the current evidence base for the effectiveness and safety of acupuncture for patients with PPP.


Assuntos
Terapia por Acupuntura/métodos , Dor Pós-Operatória/terapia , Humanos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa
11.
Medicine (Baltimore) ; 98(48): e17984, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31770208

RESUMO

Pediatric patients suffer from chronic pancreatitis (CP), especially those with diabetes mellitus (DM). This study aimed to identify the incidence of and risk factors for DM in pediatric CP.CP patients admitted to our center from January 2000 to December 2013 were assigned to the pediatric (<18 years old) and adult group according to their age at onset of CP. Cumulative rates of DM and risk factors for both groups were calculated and identified.The median follow-up duration for the whole cohort was 7.6 years. In these 2153 patients, 13.5% of them were pediatrics. The mean age at the onset and the diagnosis of CP in pediatrics were 11.622 and 19.727, respectively. DM was detected in 13.1% patients and 31.0% patients in the pediatric group and adult group, respectively. Age at the onset of CP, smoking history, body mass index (BMI), and etiology of CP were identified risk factors for DM in pediatrics.DM was detected in 13.1% pediatric patients. Age at the onset of CP, smoking history, BMI, and etiology of CP were identified risk factors for the development of DM in pediatric CP patients. The high-risk populations were suggested to be monitored frequently. They could also benefit from a lifestyle modification.


Assuntos
Diabetes Mellitus/epidemiologia , Diabetes Mellitus/etiologia , Pancreatite Crônica/complicações , Adolescente , Criança , Bases de Dados Factuais , Feminino , Humanos , Incidência , Masculino , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
12.
BMC Bioinformatics ; 20(1): 524, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31660850

RESUMO

BACKGROUND: Stable isotope tracing can follow individual atoms through metabolic transformations through the detection of the incorporation of stable isotope within metabolites. This resulting data can be interpreted in terms related to metabolic flux. However, detection of a stable isotope in metabolites by mass spectrometry produces a profile of isotopologue peaks that requires deconvolution to ascertain the localization of isotope incorporation. RESULTS: To aid the interpretation of the mass spectroscopy isotopologue profile, we have developed a moiety modeling framework for deconvoluting metabolite isotopologue profiles involving single and multiple isotope tracers. This moiety modeling framework provides facilities for moiety model representation, moiety model optimization, and moiety model selection. The moiety_modeling package was developed from the idea of metabolite decomposition into moiety units based on metabolic transformations, i.e. a moiety model. The SAGA-optimize package, solving a boundary-value inverse problem through a combined simulated annealing and genetic algorithm, was developed for model optimization. Additional optimization methods from the Python scipy library are utilized as well. Several forms of the Akaike information criterion and Bayesian information criterion are provided for selecting between moiety models. Moiety models and associated isotopologue data are defined in a JSONized format. By testing the moiety modeling framework on the timecourses of 13C isotopologue data for uridine diphosphate N-acetyl-D-glucosamine (UDP-GlcNAc) in human prostate cancer LnCaP-LN3 cells, we were able to confirm its robust performance in isotopologue deconvolution and moiety model selection. CONCLUSIONS: SAGA-optimize is a useful Python package for solving boundary-value inverse problems, and the moiety_modeling package is an easy-to-use tool for mass spectroscopy isotopologue profile deconvolution involving single and multiple isotope tracers. Both packages are freely available on GitHub and via the Python Package Index.


Assuntos
Metabolômica , Teorema de Bayes , Isótopos de Carbono/análise , Linhagem Celular Tumoral , Humanos , Marcação por Isótopo , Masculino , Espectrometria de Massas/métodos , Metabolômica/métodos , Neoplasias da Próstata
13.
J Exp Clin Cancer Res ; 38(1): 402, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519193

RESUMO

BACKGROUND: Dihydroartemisinin (DHA) has been shown to exert anticancer activity through iron-dependent reactive oxygen species (ROS) generation, which is similar to ferroptosis, a novel form of cell death. However, whether DHA causes ferroptosis in glioma cells and the potential regulatory mechanisms remain unclear. METHODS: Effects of DHA on the proliferation, cell death, ROS and lipid ROS generation as well as reduced gluthione consumption were assessed in glioma cells with or without ferroptosis inhibitor. The biological mechanisms by which glioma cells attenuate the pro-ferroptotic effects of DHA were assessed using molecular methods. RESULTS: DHA induced ferroptosis in glioma cells, as characterized by iron-dependent cell death accompanied with ROS generation and lipid peroxidation. However, DHA treatment simultaneously activated a feedback pathway of ferroptosis by increasing the expression of heat shock protein family A (Hsp70) member 5 (HSPA5). Mechanistically, DHA caused endoplasmic reticulum (ER) stress in glioma cells, which resulted in the induction of HSPA5 expression by protein kinase R-like ER kinase (PERK)-upregulated activating transcription factor 4 (ATF4). Subsequent HSPA5 upregulation increased the expression and activity of glutathione peroxidase 4 (GPX4), which neutralized DHA-induced lipid peroxidation and thus protected glioma cells from ferroptosis. Inhibition of the PERK-ATF4-HSPA5-GPX4 pathway using siRNA or small molecules increased DHA sensitivity of glioma cells by increasing ferroptosis both in vitro and in vivo. CONCLUSIONS: Collectively, these data suggested that ferroptosis might be a novel anticancer mechanism of DHA in glioma and HSPA5 may serve as a negative regulator of DHA-induced ferroptosis. Therefore, inhibiting the negative feedback pathway would be a promising therapeutic strategy to strengthen the anti-glioma activity of DHA.


Assuntos
Fator 4 Ativador da Transcrição/metabolismo , Artemisininas/farmacologia , Glioma/metabolismo , Proteínas de Choque Térmico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Resposta a Proteínas não Dobradas/efeitos dos fármacos , eIF-2 Quinase/metabolismo , Animais , Biomarcadores , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Expressão Gênica , Humanos , Camundongos , Espécies Reativas de Oxigênio/metabolismo
14.
World J Gastroenterol ; 25(34): 5185-5196, 2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31558866

RESUMO

BACKGROUND: Compared with traditional open surgery, laparoscopic surgery is preferred due to the advantages of less trauma, less pain, and faster recovery. Nevertheless, many patients still suffer from postoperative pain resulting from the surgical incision and associated tissue injury. Many researchers have reported methods to improve postoperative pain control, but there is not a simple and effective method that can be clinically adopted in a widespread manner. We designed this study to prove the hypothesis that application of ropivacaine in the port site and operative site in patients is an effective and convenient method which can decrease postoperative pain and accelerate recovery. AIM: To evaluate the effects of ropivacaine on pain control after laparoscopic hepatectomy and its contribution to patient recovery. METHODS: From May 2017 to November 2018, 146 patients undergoing laparoscopic hepatectomy were randomized to receive infiltration of either 7.5 mg/mL ropivacaine around the trocar insertions, incision, and cutting surface of the liver (with a gelatin sponge soaked with ropivacaine) at the end of surgery (ropivacaine group), or normal saline (5 mL) at the same sites at the end of surgery (control group). The degree of pain, nausea, vomiting, heart rate (HR), and blood pressure were collected. The length of postoperative hospitalization, complications, and the levels of stress hormones were also compared between the two groups. RESULTS: Compared with the control group, the ropivacaine group showed reduced postoperative pain at rest within 12 h (P < 0.05), and pain on movement was reduced within 48 h. The levels of epinephrine, norepinephrine, and cortisol at 24 and 48 h, HR, blood pressure, and cumulative sufentanil consumption in the ropivacaine group were significantly lower than those in the control group (P < 0.05). In the ropivacaine group, hospitalization after operation was shorter, but the difference was not statistically significant. There were no significant differences in postoperative nausea, vomiting, or other complications, including hydrothorax, ascites, peritonitis, flatulence, and venous thrombus (P > 0.05), although fewer patients in the ropivacaine group experienced these situations. CONCLUSION: Infiltration with ropivacaine in the abdominal wound and covering the cutting surface of the liver with a gelatin sponge soaked with ropivacaine significantly reduce postoperative pain and the consumption of sufentanil.


Assuntos
Analgesia/métodos , Anestésicos Locais/administração & dosagem , Hepatectomia/efeitos adversos , Laparoscopia/efeitos adversos , Dor Pós-Operatória/prevenção & controle , Ferida Cirúrgica/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Hepatectomia/métodos , Humanos , Injeções Intralesionais , Cuidados Intraoperatórios/métodos , Laparoscopia/métodos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/etiologia , Ropivacaina/administração & dosagem , Tampões de Gaze Cirúrgicos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
15.
EBioMedicine ; 47: 195-207, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31409574

RESUMO

BACKGROUND: Accumulating evidence has revealed the critical roles of N6-methyladenosine (m6A) modification of mRNA in various cancers. However, the biological function and regulation of m6A in bladder cancer (BC) are not yet fully understood. METHODS: We performed cell phenotype analysis and established in vivo mouse xenograft models to assess the effects of m6A-modified ITGA6 on BC growth and progression. Methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation and luciferase reporter and mutagenesis assays were used to define the mechanism of m6A-modified ITGA6. Immunohistochemical analysis was performed to assess the correlation between METTL3 and ITGA6 expression in bladder cancer patients. FINDINGS: We show that the m6A writer METTL3 and eraser ALKBH5 altered cell adhesion by regulating ITGA6 expression in bladder cancer cells. Moreover, upregulation of ITGA6 is correlated with the increase in METTL3 expression in human BC tissues, and higher expression of ITGA6 in patients indicates a lower survival rate. Mechanistically, m6A is highly enriched within the ITGA6 transcripts, and increased m6A methylations of the ITGA6 mRNA 3'UTR promotes the translation of ITGA6 mRNA via binding of the m6A readers YTHDF1 and YTHDF3. Inhibition of ITGA6 results in decreased growth and progression of bladder cancer cells in vitro and in vivo. Furthermore, overexpression of ITGA6 in METTL3-depleted cells partially restores the BC adhesion, migration and invasion phenotypes. INTERPRETATION: Our results demonstrate an oncogenic role of m6A-modified ITGA6 and show its regulatory mechanisms in BC development and progression, thus identifying a potential therapeutic target for BC. FUND: This work was supported by National Natural Science Foundation of China (81772699, 81472999).


Assuntos
Adenosina/análogos & derivados , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Integrina alfa6/genética , RNA Mensageiro/genética , Neoplasias da Bexiga Urinária/genética , Adenosina/farmacologia , Adulto , Idoso , Homólogo AlkB 5 da RNA Desmetilase/genética , Animais , Adesão Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Integrina alfa6/metabolismo , Masculino , Metiltransferases/genética , Camundongos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
16.
Int J Biol Macromol ; 140: 1226-1238, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31445153

RESUMO

Bovine herpesvirus 1 (BoHV-1) is a major pathogen of infectious bovine rhinotracheitis in bovine. Previously, we generated the aptamer IBRV A4 using systemic evolution of ligands by exponential enrichment. This aptamer inhibited infectivity of BoHV-1 by blocking viral particle absorption onto cell membranes. In this study, we found that the major tegument protein VP8 of BoHV-1 was involved in inhibition of infectious virus production by IBRV A4. We improved the affinity of IBRV A4 for VP8 by optimizing aptamer's structure and repeat conformation. An optimized aptamer, IBRV A4.7, was constructed with quadruple binding sites and a new stem-loop structure, which had a stronger binding affinity for VP8 or BoHV-1 than raw aptamer IBRV A4. IBRV A4.7 bound to VP8 with a dissociation constant (Kd) value of 0.2054 ±â€¯0.03948 nM and bound to BoHV-1 with a Kd value of 0.3637 ±â€¯0.05452 nM. Crucially, IBRV A4.7 had improved antiviral activity compared to IBRV A4, with a half-maximal inhibitory concentration of 1.16 ±â€¯0.042 µM. Our results also revealed IBRV A4.7 inhibited BoHV-1 production in MDBK cells through blocking nucleocytoplasmic shuttling of viral VP8 in BoHV-1-infected MDBK cells. In conclusion, the aptamer IBRV A4.7 may have potency in preventing outbreaks in herds due to reactivation of latency.

17.
Digestion ; : 1-11, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31238312

RESUMO

BACKGROUND: Pancreatic stones are pathognomonic of chronic pancreatitis (CP). This study aimed to determine the incidence, identify risk factors, and develop a nomogram for pancreatic stones in CP patients. METHODS: Patients with CP admitted to our center from January 2000 to December 2013 were enrolled. Cumulative rates of pancreatic stones after the onset of CP and after the diagnosis of CP were calculated. Patients were randomly assigned, in a 2:1 ratio, to the training and validation cohort. Based on the training cohort, risk factors were identified through Cox proportional hazards regression model, and nomogram was developed. Internal and external validations were performed based on the training and validation cohort, respectively. RESULTS: With a total of 2,153 CP patients, pancreatic stones were detected in 1,626 (75.5%) patients, with a median follow-up of 7.8 years. Age at the onset of CP, body mass index, smoking, diabetes mellitus, pancreatic pseudocyst, biliary stricture, severe acute pancreatitis, and type of pain were identified risk factors for pancreatic stones development. The nomogram with these 8 factors achieved good accuracy. CONCLUSIONS: The nomogram achieved an individualized prediction of pancreatic stones development in CP. It may help the management of pancreatic stones.

18.
Cancer Biomark ; 25(2): 193-201, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31104012

RESUMO

Circular RNAs (circRNAs) have gained attention for their involvement in carcinogenesis, but its functional effects in breast cancer (BC) remains largely unclear. In this study, we aimed to explore the expressing pattern, clinical significance and potential function of a newly identified circRNA, hsa_circ_001569, in BC. RT-PCR was performed to detect the expression of hsa_circ_001569 in both BC tissues and cell lines. The associations between hsa_circ_001569 expression and clinicopathological features and prognosis in BC patients were statistically analyzed. Next, we investigated the effects of hsa_circ_001569 on the proliferation, apoptosis, migration and invasion in BC cells lines. The effects of abnormal hsa_circ_001569 expression on EMT pathway and PI3K/AKT pathway were determined using Western blot. We found that hsa_circ_001569 expression was significantly up-regulated in both BC tissues and cell lines. Overexpression of hsa_circ_001569 was associated with Lymph node metastasis, advanced clinical stage and shorter overall survival. Multivariate assay confirmed that hsa_circ_001569 expression was an independent prognostic factor for 5-year overall survival. Furthermore, functional investigations revealed that knockdown of hsa_circ_001569 significantly suppressed the growth and metastatic potentials of BC cells. Besides, molecular mechanistic study revealed that depression of hsa_circ_001569 impeded the activation of PI3K-AKT signaling in BC cells. Our results indicated that hsa_circ_001569 upregulation was associated with BC lymph-node metastasis, clinical stage, and poor prognosis. Hsa_circ_001569 might contribute to progression of BC by modulating PI3K-AKT pathway.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , MicroRNAs/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Adulto , Idoso , Apoptose/genética , Biomarcadores Tumorais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico
19.
Hum Mutat ; 40(10): 1856-1873, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31131953

RESUMO

It has long been known that canonical 5' splice site (5'SS) GT>GC variants may be compatible with normal splicing. However, to date, the actual scale of canonical 5'SSs capable of generating wild-type transcripts in the case of GT>GC substitutions remains unknown. Herein, combining data derived from a meta-analysis of 45 human disease-causing 5'SS GT>GC variants and a cell culture-based full-length gene splicing assay of 103 5'SS GT>GC substitutions, we estimate that ~15-18% of canonical GT 5'SSs retain their capacity to generate between 1% and 84% normal transcripts when GT is substituted by GC. We further demonstrate that the canonical 5'SSs in which substitution of GT by GC-generated normal transcripts exhibit stronger complementarity to the 5' end of U1 snRNA than those sites whose substitutions of GT by GC did not lead to the generation of normal transcripts. We also observed a correlation between the generation of wild-type transcripts and a milder than expected clinical phenotype but found that none of the available splicing prediction tools were capable of reliably distinguishing 5'SS GT>GC variants that generated wild-type transcripts from those that did not. Our findings imply that 5'SS GT>GC variants in human disease genes may not invariably be pathogenic.

20.
Future Oncol ; 15(17): 2009-2018, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30931608

RESUMO

Aim: To study the expression of EIF5A2 in urinary tract urothelial carcinoma and its clinicopathological features and prognosis. Methods: EIF5A2 expression was detected via immunohistochemistry in 101 patients. Results: Kaplan-Meier analysis showed that the EIF5A2 low expression group had significantly longer overall survival (OS; p < 0.001) and progression-free survival (PFS; p < 0.001) than the EIF5A2 high expression group. The high expression of EIF5A2 significantly predict poor OS and PFS in the subset patients (p < 0.05). EIF5A2 was an independent prognostic factor for OS and PFS (p = 0.003 and p = 0.001). The established nomogram model and its calibration curve predicted the probability of survival accurately. Conclusion: EIF5A2 is a potential molecular marker of poor prognosis in urinary tract urothelial carcinoma.


Assuntos
Carcinoma de Células de Transição/patologia , Neoplasias Renais/patologia , Fatores de Iniciação de Peptídeos/metabolismo , Proteínas de Ligação a RNA/metabolismo , Neoplasias Ureterais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/cirurgia , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Neoplasias Renais/cirurgia , Pelve Renal/patologia , Pelve Renal/cirurgia , Masculino , Pessoa de Meia-Idade , Nefroureterectomia , Prognóstico , Intervalo Livre de Progressão , Ureter/patologia , Ureter/cirurgia , Neoplasias Ureterais/mortalidade , Neoplasias Ureterais/cirurgia
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