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1.
Artigo em Inglês | MEDLINE | ID: mdl-31974643

RESUMO

PURPOSE: Chronic ankle instability with a long symptom duration is often accompanied by medial compartment ankle osteoarthritis (OA). However, the outcomes of individuals after ligament stabilization have rarely been reported. The radiographic and clinical outcomes after ligament stabilization in individuals with chronic ankle instability and medial compartment OA were investigated. METHODS: The study investigated 27 ankles with chronic ankle instability and medial compartment OA that underwent lateral ankle ligament reconstruction from 2007 to 2015 with a follow-up period of at least 1 year. Ligament stabilization was performed via either the modified Broström procedure (MBP) or lateral ankle reconstruction (LAR) using semitendinosus tendon allografts. RESULTS: The median instability duration was 60 (range 12-480) months, and the median follow-up period was 39 (range 12-108) months. The preoperative Takakura ankle OA stage was predominantly stage I (20 patients (74.1%)), followed by stage II (five patients (18.5%)). Ankle MRI (20 ankles) revealed medial cartilage denudation in three cases (15%), cartilage thinning in nine cases (45%), osteophyte formation in ten cases (50%), and loose body formation in six cases (30%). According to the arthroscopic results, the modified Outerbridge grade was two in nine cases and four in ten cases, so these grades were the most common (37.5% and 41.7%, respectively). The MBP was performed in 14 patients, and LAR was performed in 13 patients (52% and 48%, respectively); the bone marrow stimulation procedure was performed in 15 patients (55%). The visual analogue scale score decreased from 6.0 (SD 1.6) preoperatively to 1.8 (SD 1.6) postoperatively (p = 0.000). The American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot score improved from 61.9 (SD 14.2) to 89.7 (SD 6.2), and the Karlsson-Peterson score improved from 54.7 (SD 13.9) to 88.3 (SD 9.0) (p = 0.000). There were no serious complications, and all patients were satisfied. CONCLUSIONS: Ligament stabilization with arthroscopic procedures for individuals with chronic ankle instability and medial ankle OA yielded significant functional outcomes with high patient satisfaction, even without radiographic improvement. LEVEL OF EVIDENCE: IV.

3.
J Urol ; 203(1): 137-144, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31347951

RESUMO

PURPOSE: We compared early continence recovery after surgical treatment of prostate cancer with Retzius sparing robot-assisted radical prostatectomy and conventional robot-assisted radical prostatectomy. MATERIALS AND METHODS: Robot-assisted radical prostatectomy was done by a single surgeon in 1,863 cases between October 2005 and May 2018 using the conventional and the Retzius sparing technique in 1,150 and 713, respectively. To compare continence outcomes between the groups propensity score matching was performed using 9 preoperative variables, including age, body mass index, prostate specific antigen, biopsy Gleason Grade Group, clinical T stage, prostate volume on transrectal ultrasound, and the I-PSS (International Prostate Symptom Score), I-PSS quality of life score and International Index of Erectile Function-5 scores. Continence was assessed by the pad count every month postoperatively until month 6 and was converted to a binary outcome. RESULTS: After propensity score matching 609 cases per group were matched with no significant difference in all 9 variables. The Kaplan-Meier curve analysis revealed that Retzius sparing robot-assisted radical prostatectomy was associated with a significantly better continence recovery rate than conventional robot-assisted radical prostatectomy during the 6-month study period (p <0.001). CONCLUSIONS: Based on propensity score matching with multiple variables and a large case series, Retzius sparing robot-assisted radical prostatectomy can be a candidate for future robot-assisted radical prostatectomy. It achieves better early continence recovery, a short operative time and early recovery compared to conventional robot-assisted radical prostatectomy.


Assuntos
Complicações Pós-Operatórias/fisiopatologia , Prostatectomia/métodos , Neoplasias da Próstata/cirurgia , Procedimentos Cirúrgicos Robóticos/métodos , Incontinência Urinária/fisiopatologia , Idoso , Disfunção Erétil/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Pontuação de Propensão , Neoplasias da Próstata/patologia , Qualidade de Vida , Recuperação de Função Fisiológica
4.
Exp Mol Med ; 51(12): 153, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31827068

RESUMO

During viral infection, virus-derived cytosolic nucleic acids are recognized by host intracellular specific sensors. The efficacy of this recognition system is crucial for triggering innate host defenses, which then stimulate more specific adaptive immune responses against the virus. Recent studies show that signal transduction pathways activated by sensing proteins are positively or negatively regulated by many modulators to maintain host immune homeostasis. However, viruses have evolved several strategies to counteract/evade host immune reactions. These systems involve viral proteins that interact with host sensor proteins and prevent them from detecting the viral genome or from initiating immune signaling. In this review, we discuss key regulators of cytosolic sensor proteins and viral proteins based on experimental evidence.

5.
Exp Mol Med ; 51(10): 128, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31666502

RESUMO

Dysregulated immune responses and impaired function in intestinal epithelial cells contribute to the pathogenesis of inflammatory bowel disease (IBD). Growth arrest and DNA damage-inducible 45 beta (Gadd45ß) has been implicated in the pathogenesis of various inflammatory symptoms. However, the role of Gadd45ß in IBD is completely unknown. This study aimed to evaluate the role of Gadd45ß in IBD. Gadd45ß-KO mice exhibited drastically greater susceptibility to dextran sulfate sodium (DSS)-induced colitis and mortality than C57BL/6J mice. Bone marrow transplantation experiments revealed that Gadd45ß functions predominantly in the intestinal epithelium and is critical during the recovery phase. Gadd45ß regulates the TGF-ß signaling pathway in colon tissue and epithelial cells by inhibiting Smurf-mediated degradation of TGF-ß receptor type 1 via competitive binding to the N-terminal domain of Smad7. Furthermore, these results indicate that the Gadd45ß-regulated TGF-ß signaling pathway is involved in wound healing by enhancing epithelial restitution. These results expand the current understanding of the function of Gadd45ß and its therapeutic potential in ulcerative colitis.

6.
Sci Rep ; 9(1): 15042, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31636298

RESUMO

Fibrosarcoma is a skin tumor that is frequently observed in humans, dogs, and cats. Despite unsightly appearance, studies on fibrosarcoma have not significantly progressed, due to a relatively mild tumor severity and a lower incidence than that of other epithelial tumors. Here, we focused on the role of a recently-found dermis zinc transporter, ZIP13, in fibrosarcoma progression. We generated two transformed cell lines from wild-type and ZIP13-KO mice-derived dermal fibroblasts by stably expressing the Simian Virus (SV) 40-T antigen. The ZIP13-/- cell line exhibited an impairment in autophagy, followed by hypersensitivity to nutrient deficiency. The autophagy impairment in the ZIP13-/- cell line was due to the low expression of LC3 gene and protein, and was restored by the DNA demethylating agent, 5-aza-2'-deoxycytidine (5-aza) treatment. Moreover, the DNA methyltransferase activity was significantly increased in the ZIP13-/- cell line, indicating the disturbance of epigenetic regulations. Autophagy inhibitors effectively inhibited the growth of fibrosarcoma with relatively minor damages to normal cells in xenograft assay. Our data show that proper control over autophagy and zinc homeostasis could allow for the development of a new therapeutic strategy to treat fibrosarcoma.

7.
Mol Cells ; 42(10): 721-728, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31600868

RESUMO

Non-structural protein 1 (NS1) of influenza virus has been shown to inhibit the innate immune response by blocking the induction of interferon (IFN). In this study, we isolated two single-stranded RNA aptamers specific to NS1 with K d values of 1.62 ± 0.30 nM and 1.97 ± 0.27 nM, respectively, using a systematic evolution of ligand by exponential enrichment (SELEX) procedure. The selected aptamers were able to inhibit the interaction of NS1 with tripartite motif-containing protein 25 (TRIM25), and suppression of NS1 enabled retinoic acid inducible gene I (RIG-I) to be ubiquitinated regularly by TRIM25. Additional luciferase reporter assay and quantitative real-time PCR (RT-PCR) experiments demonstrated that suppression of NS1 by the selected aptamers induced IFN production. It is noted that viral replication was also inhibited through IFN induction in the presence of the selected aptamers. These results suggest that the isolated aptamers are strongly expected to be new therapeutic agents against influenza infection.


Assuntos
Aptâmeros de Nucleotídeos/metabolismo , Proteína DEAD-box 58/metabolismo , Fatores de Transcrição/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Proteínas não Estruturais Virais/metabolismo , Animais , Células HEK293 , Humanos , Interferons/metabolismo , Camundongos , Ligação Proteica , Células RAW 264.7 , Replicação Viral
8.
Vet Microbiol ; 236: 108374, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31500734

RESUMO

Foot-and-mouth disease (FMD) is a highly contagious disease and causes economic damage at a national level. In particular, the type O FMD virus (FMDV) is a serotype that causes FMD outbreaks most frequently in the world. In recent years, Southeast Asia (SEA), Middle East-South Asia (ME-SA), and Cathay topotype-mediated FMD are prevalent in Asia, among which the SEA and ME-SA topotypes cause a majority of the outbreaks. The SEA topotype virus is more likely to infect both cattle and pigs simultaneously, thereby resulting in more severe damages; thus, it is necessary to study the protection ability of the candidate vaccines of this topotype after immunization. In this study, an experimental vaccine for pigs was produced using a vaccine strain that contains the structural protein of the O Taiwan97 strain, which was derived from the Cathay topotype, and its effect was evaluated. In the immunization test in pigs and cattle, the antibody titers were found to be elevated two weeks after immunization and very high titers of neutralizing antibodies were formed after four weeks. After the second inoculation, very high titers of neutralizing antibodies were produced in both species in the fourth week after immunization, and the antibodies maintained for up to six months and three months in cattle and pigs, respectively. No significant immunological difference in antibody production was observed in cattle and pigs. This study confirmed that complete protection from the challenge of the SEA topotype virus (O/Jincheon/SKR/2014), although the antibody titers against O/Jincheon/SKR/2014 strain were not that high, was achieved through immunization with the newly developed Cathay topotype vaccine in pigs.


Assuntos
Vírus da Febre Aftosa/classificação , Febre Aftosa/prevenção & controle , Doenças dos Suínos/prevenção & controle , Vacinas Virais/imunologia , Animais , Anticorpos Antivirais/sangue , Febre Aftosa/epidemiologia , Febre Aftosa/virologia , Camundongos , Camundongos Endogâmicos ICR , República da Coreia/epidemiologia , Suínos , Doenças dos Suínos/virologia , Eliminação de Partículas Virais
9.
PLoS Pathog ; 15(8): e1008004, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31412082

RESUMO

Fas-associated factor 1 is a death-promoting protein that induces apoptosis by interacting with the Fas receptor. Until now, FAF1 was reported to interact potentially with diverse proteins and to function as a negative and/or positive regulator of several cellular possesses. However, the role of FAF1 in defense against bacterial infection remains unclear. Here, we show that FAF1 plays a pivotal role in activating NADPH oxidase in macrophages during Listeria monocytogenes infection. Upon infection by L. monocytogenes, FAF1 interacts with p67phox (an activator of the NADPH oxidase complex), thereby facilitating its stabilization and increasing the activity of NADPH oxidase. Consequently, knockdown or ectopic expression of FAF1 had a marked effect on production of ROS, proinflammatory cytokines, and antibacterial activity, in macrophages upon stimulation of TLR2 or after infection with L. monocytogenes. Consistent with this, FAF1gt/gt mice, which are knocked down in FAF1, showed weaker inflammatory responses than wild-type mice; these weaker responses led to increased replication of L. monocytogenes. Collectively, these findings suggest that FAF1 positively regulates NADPH oxidase-mediated ROS production and antibacterial defenses.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Proteínas Reguladoras de Apoptose/fisiologia , Imunidade Inata/imunologia , Inflamação/imunologia , Listeriose/imunologia , Macrófagos/imunologia , NADPH Oxidases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Citocinas/metabolismo , Inflamação/metabolismo , Inflamação/microbiologia , Listeria monocytogenes/imunologia , Listeriose/metabolismo , Listeriose/microbiologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidases/genética , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Transdução de Sinais
10.
Mol Cells ; 42(7): 530-545, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31362469

RESUMO

Tumor cells can vary epigenetically during ionizing irradiation (IR) treatment. These epigenetic variegations can influence IR response and shape tumor aggressiveness. However, epigenetic disturbance of histones after IR, implicating in IR responsiveness, has been elusive. Here, we investigate whether altered histone modification after IR can influence radiation responsiveness. The oncogenic CXCL12 mRNA and protein were more highly expressed in residual cancer cells from a hepatoma heterotopic murine tumor microenvironment and coculture of human hepatoma Huh7 and normal IMR90 cells after radiation. H3K4 methylation was also enriched and H3K9 methylation was decreased at its promoter region. Accordingly, invasiveness and the subpopulation of aggressive CD133+/CD24- cells increased after IR. Histone demethylase inhibitor IOX1 attenuated CXCL12 expression and the malignant subpopulation, suggesting that responses to IR can be partially mediated via histone modifications. Taken together, radiation-induced histone alterations at the CXCL12 promoter in hepatoma cells are linked to CXCL12 upregulation and increased aggressiveness in the tumor microenvironment.


Assuntos
Carcinoma Hepatocelular/genética , Quimiocina CXCL12/genética , Histonas/metabolismo , Neoplasias Hepáticas/genética , Regiões Promotoras Genéticas , Processamento de Proteína Pós-Traducional , Microambiente Tumoral/genética , Regulação para Cima/genética , Animais , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Quimiocina CXCL12/metabolismo , Epigênese Genética/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Compostos Heterocíclicos/farmacologia , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Nus , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/efeitos da radiação , Processamento de Proteína Pós-Traducional/efeitos da radiação , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/metabolismo , Proteínas Recombinantes/farmacologia , Transcrição Genética/efeitos da radiação , Microambiente Tumoral/efeitos da radiação , Raios X
11.
Nucleic Acids Res ; 47(17): 9160-9179, 2019 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-31340001

RESUMO

The pleiotropic CCCTC-binding factor (CTCF) plays a role in homologous recombination (HR) repair of DNA double-strand breaks (DSBs). However, the precise mechanistic role of CTCF in HR remains largely unclear. Here, we show that CTCF engages in DNA end resection, which is the initial, crucial step in HR, through its interactions with MRE11 and CtIP. Depletion of CTCF profoundly impairs HR and attenuates CtIP recruitment at DSBs. CTCF physically interacts with MRE11 and CtIP and promotes CtIP recruitment to sites of DNA damage. Subsequently, CTCF facilitates DNA end resection to allow HR, in conjunction with MRE11-CtIP. Notably, the zinc finger domain of CTCF binds to both MRE11 and CtIP and enables proficient CtIP recruitment, DNA end resection and HR. The N-terminus of CTCF is able to bind to only MRE11 and its C-terminus is incapable of binding to MRE11 and CtIP, thereby resulting in compromised CtIP recruitment, DSB resection and HR. Overall, this suggests an important function of CTCF in DNA end resection through the recruitment of CtIP at DSBs. Collectively, our findings identify a critical role of CTCF at the first control point in selecting the HR repair pathway.


Assuntos
Fator de Ligação a CCCTC/genética , Proteínas de Transporte/genética , Recombinação Homóloga/genética , Proteína Homóloga a MRE11/genética , Proteínas Nucleares/genética , Quebras de DNA de Cadeia Dupla , Reparo do DNA/genética , Células HeLa , Humanos , Ligação Proteica/genética , Reparo de DNA por Recombinação/genética , Dedos de Zinco/genética
12.
Mol Cells ; 42(6): 502, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31304690

RESUMO

Tumor cells can vary epigenetically during ionizing irradiation (IR) treatment. These epigenetic variegations can influence IR response and shape tumor aggressiveness. However, epigenetic disturbance of histones after IR, implicating in IR responsiveness, has been elusive. Here, we investigate whether altered histone modification after IR can influence radiation responsiveness. The oncogenic CXCL12 mRNA and protein were more highly expressed in residual cancer cells from a hepatoma heterotopic murine tumor microenvironment and coculture of human hepatoma Huh7 and normal IMR90 cells after radiation. H3K4 methylation was also enriched and H3K9 methylation was decreased at its promoter region. Accordingly, invasiveness and the subpopulation of aggressive CD133+/CD24- cells increased after IR. Histone demethylase inhibitor IOX1 attenuated CXCL12 expression and the malignant subpopulation, suggesting that responses to IR can be partially mediated via histone modifications. Taken together, radiation-induced histone alterations at the CXCL12 promoter in hepatoma cells are linked to CXCL12 upregulation and increased aggressiveness in the tumor microenvironment.

13.
Viruses ; 11(7)2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31277257

RESUMO

The herbs Plantago asiatica and Clerodendrum trichotomum have been commonly used for centuries in indigenous and folk medicine in tropical and subtropical regions of the world. In this study, we show that extracts from these herbs have antiviral effects against the respiratory syncytial virus (RSV) in vitro cell cultures and an in vivo mouse model. Treatment of HEp2 cells and A549 cells with a non-cytotoxic concentration of Plantago asiatica or Clerodendrum trichotomum extract significantly reduced RSV replication, RSV-induced cell death, RSV gene transcription, RSV protein synthesis, and also blocked syncytia formation. Interestingly, oral inoculation with each herb extract significantly improved viral clearance in the lungs of BALB/c mice. Based on reported information and a high-performance liquid chromatography (HPLC) analysis, the phenolic glycoside acteoside was identified as an active chemical component of both herb extracts. An effective dose of acteoside exhibited similar antiviral effects as each herb extract against RSV in vitro and in vivo. Collectively, these results suggest that extracts of Plantago asiatica and Clerodendrum trichotomum could provide a potent natural source of an antiviral drug candidate against RSV infection.

14.
ACS Appl Mater Interfaces ; 11(32): 29041-29046, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31322342

RESUMO

Zero-dimensional-two-dimensional (0D-2D) hybrid optoelectronic devices have demonstrated high sensitivity and high performance due to the high absorption coefficient of 0D materials with a tunable detection range and a high carrier transport property of 2D materials. However, the reported 0D-2D hybrid devices employ toxic nanomaterials as sensitizing layers, which can limit the practical applications. In this study, we first fabricated the 0D-2D hybrid photodetector using nontoxic InP quantum dots (QDs) as a light-absorbing layer and black phosphorus (BP) as a transport layer. The surface treatment using 1,2-ethanedithiol and thermal treatment were carried out to remove the surface long ligands of colloidal QDs, which can accelerate the charge injection of the photogenerated carriers through the interfaces between InP QDs and BP. The InP QDs/BP hybrid photodetector demonstrates a high responsivity of 1 × 109 A/W and detectivity of 4.5 × 1016 Jones at 0.05 µW cm-2 under 405 nm illumination. The results show that 0D-2D hybrid photodetectors based on III-V semiconducting QD materials can be optimized for high-performance photodetectors.

15.
Cell Rep ; 27(7): 2105-2118.e5, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31091449

RESUMO

Small heterodimer partner (SHP) is an orphan nuclear receptor that acts as a transcriptional co-repressor by interacting with nuclear receptors and transcription factors. Although SHP plays a negative regulatory function in various signaling pathways, its role in virus infection has not been studied. Here, we report that SHP is a potent negative regulator of the virus-mediated type I IFN signaling that maintains homeostasis within the antiviral innate immune system. Upon virus infection, SHP interacts specifically with CREB-binding protein (CBP) in the nucleus, thereby obstructing CBP/ß-catenin interaction competitively. Consequently, SHP-deficient cells enhance antiviral responses, including transcription of the type I IFN gene, upon virus infection. Furthermore, SHP-deficient mice show higher levels of IFN production and are more resistant to influenza A virus infection. Our results suggest that SHP is a nuclear regulator that blocks transcription of the type I IFN gene to inhibit excessive innate immune responses.

16.
J Clin Med ; 8(4)2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30959851

RESUMO

Postoperative acute kidney injury (AKI) is still a concern in partial nephrectomy (PN), even with the development of minimally invasive technique. We aimed to compare AKI incidence between patients with and without diabetes mellitus (DM) and to determine the predictive factors for postoperative AKI. This case-matched retrospective study included 884 patients with preoperative creatinine levels ≤1.4 mg/dL who underwent laparoscopic or robot-assisted laparoscopic PN between December 2005 and May 2018. Propensity score matching was employed to match patients with and without DM in a 1:3 ratio (101 and 303 patients, respectively). Of 884 patients, 20.4% had postoperative AKI. After propensity score matching, the incidence of postoperative AKI in DM and non-DM patients was 30.7% and 14.9%, respectively (P < 0.001). In multivariate analysis, male sex and warm ischemia time (WIT) >25 min were significantly associated with postoperative AKI in patients with and without DM. In patients with DM, hemoglobin A1c (HbA1c) >7% was a predictive factor for AKI, odds ratio (OR) = 4.59 (95% CI, 1.47⁻14.36). In conclusion, DM increased the risk of AKI after minimally invasive PN; male sex, longer WIT, and elevated HbA1c were independent risk factors for AKI in patients with DM.

17.
Ann Surg Oncol ; 26(4): 1158-1165, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30719635

RESUMO

PURPOSE: This study was designed to assess the diagnostic accuracy and therapeutic efficacy of probe-based confocal laser endomicroscopy (pCLE), which provides real-time, in vivo histological information during transurethral resection of bladder tumors. METHODS: We performed a prospective study between August 2013 and August 2014. pCLE was performed on a total of 119 lesions in 75 patients. We analyzed the diagnostic accuracy of pCLE by comparing the confocal image reports with the pathology reports of surgical specimen. Confocal images were interpreted by a single urologist blinded to the pathology reports. The therapeutic efficacy was analyzed by comparing the outcomes in pCLE and non-pCLE groups. RESULTS: In a total of 119 lesions, 23 were benign and 96 were malignant. The detection accuracy for malignant lesions with pCLE was determined with a sensitivity and a positive predictive value (PPV) of 91.7% and 93.6%, respectively. For high-grade versus low-grade bladder cancer, sensitivity and PPV of pCLE were 94.5% and 89.7%, respectively. Distinguishing carcinoma in situ from inflammatory lesions also was accurate with sensitivity, specificity, and PPV of 71.4%, 81.3%, and 83.3%, respectively. The Kaplan-Meier curves revealed that the recurrence-free survival rate was significantly higher in the pCLE group than in the non-pCLE group (p = 0.031). CONCLUSIONS: Probe-based confocal laser endomicroscopy is a promising method to provide the surgeon during the transurethral resection of a bladder tumor with real-time tumor histology, regardless of the tumor's gross appearance. Furthermore, it also may improve the therapeutic efficacy with longer recurrence-free periods.


Assuntos
Endoscopia/métodos , Microscopia Confocal/métodos , Neoplasias da Bexiga Urinária/diagnóstico por imagem , Neoplasias da Bexiga Urinária/patologia , Procedimentos Cirúrgicos Urológicos/métodos , Adulto , Idoso , Feminino , Seguimentos , Humanos , Masculino , Microscopia Confocal/instrumentação , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Neoplasias da Bexiga Urinária/cirurgia
18.
Nat Microbiol ; 4(3): 429-437, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30617349

RESUMO

Severe fever with thrombocytopenia syndrome phlebovirus (SFTSV), listed in the World Health Organization Prioritized Pathogens, is an emerging phlebovirus with a high fatality1-4. Owing to the lack of therapies and vaccines5,6, there is a pressing need to understand SFTSV pathogenesis. SFSTV non-structural protein (NSs) has been shown to block type I interferon induction7-11 and facilitate disease progression12,13. Here, we report that SFTSV-NSs targets the tumour progression locus 2 (TPL2)-A20-binding inhibitor of NF-κB activation 2 (ABIN2)-p105 complex to induce the expression of interleukin-10 (IL-10) for viral pathogenesis. Using a combination of reverse genetics, a TPL2 kinase inhibitor and Tpl2-/- mice showed that NSs interacted with ABIN2 and promoted TPL2 complex formation and signalling activity, resulting in the marked upregulation of Il10 expression. Whereas SFTSV infection of wild-type mice led to rapid weight loss and death, Tpl2-/- mice or Il10-/- mice survived an infection. Furthermore, SFTSV-NSs P102A and SFTSV-NSs K211R that lost the ability to induce TPL2 signalling and IL-10 production showed drastically reduced pathogenesis. Remarkably, the exogenous administration of recombinant IL-10 effectively rescued the attenuated pathogenic activity of SFTSV-NSs P102A, resulting in a lethal infection. Our study demonstrates that SFTSV-NSs targets the TPL2 signalling pathway to induce immune-suppressive IL-10 cytokine production as a means to dampen the host defence and promote viral pathogenesis.


Assuntos
Interações Hospedeiro-Patógeno , MAP Quinase Quinase Quinases/metabolismo , Phlebovirus/patogenicidade , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais , Proteínas não Estruturais Virais/genética , Proteínas Adaptadoras de Transdução de Sinal , Animais , Infecções por Bunyaviridae/imunologia , Infecções por Bunyaviridae/patologia , Feminino , Células HEK293 , Células HeLa , Humanos , Interleucina-10/administração & dosagem , Interleucina-10/genética , MAP Quinase Quinase Quinases/imunologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Phlebovirus/efeitos dos fármacos , Proteínas Proto-Oncogênicas/imunologia , Células RAW 264.7 , Genética Reversa
19.
Clin Gastroenterol Hepatol ; 17(8): 1551-1560.e1, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30476586

RESUMO

BACKGROUND & AIMS: We investigated the prevalence of sessile serrated polyps (SSPs) and the association between SSP risk and modifiable lifestyle factors in asymptomatic young adults. METHODS: We performed a cross-sectional study using a screening colonoscopy database of 13,618 asymptomatic subjects age 30 to 49 years, and 17,999 subjects age 50 to 75 years. We investigated risk factors of SSP by multivariable analyses of clinical data that included cigarette smoking and alcohol consumption. RESULTS: In subjects age 30 to 49 years, the prevalence of SSP was 2.0% (275 of 13,618 individuals). Of all SSPs, 40.7% (112 of 275 SSPs) were large (≥10 mm). Smoking for 20 or more pack-years was associated with overall SSPs (odds ratio [OR], 1.87; 95% CI, 1.17-2.99) and large SSPs (OR, 3.03; 95% CI, 1.62-5.66). The association between anatomic location and 20 or more pack-years of smoking was stronger for distal SSPs than for proximal SSPs (OR, 2.71; 95% CI, 1.27-5.77 vs OR, 1.60; 95% CI, 1.00-2.54). Cessation of smoking for 5 years or more decreased the risk of SSPs (OR, 0.49; 95% CI, 0.28-0.86) and of large SSPs (OR, 0.23; 95% CI, 0.10-0.54). Alcohol consumption was associated with large SSPs. These findings were similar for subjects age 50 to 75 years. CONCLUSIONS: In an analysis of a screening colonoscopy database, we found that in asymptomatic young adults, smoking and alcohol consumption were associated with any SSPs and large SSPs. Cessation of smoking decreased the risk of SSPs. Therefore, early lifestyle modification may be recommended for primary prevention of SSPs in young adults.

20.
J Virol ; 93(2)2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30355684

RESUMO

Tryptophanyl-tRNA synthetase (WRS) is one of the aminoacyl-tRNA synthetases (ARSs) that possesses noncanonical functions. Full-length WRS is released during bacterial infection and primes the Toll-like receptor 4 (TLR4)-myeloid differentiation factor 2 (MD2) complex to elicit innate immune responses. However, the role of WRS in viral infection remains unknown. Here, we show that full-length WRS is secreted by immune cells in the early phase of viral infection and functions as an antiviral cytokine. Treatment of cells with recombinant WRS protein promotes the production of inflammatory cytokines and type I interferons (IFNs) and curtails virus replication in THP-1 and Raw264.7 cells but not in TLR4-/- or MD2-/- bone marrow-derived macrophages (BMDMs). Intravenous and intranasal administration of recombinant WRS protein induces an innate immune response and blocks viral replication in vivo These findings suggest that secreted full-length WRS has a noncanonical role in inducing innate immune responses to viral infection as well as to bacterial infection.IMPORTANCE ARSs are essential enzymes in translation that link specific amino acids to their cognate tRNAs. In higher eukaryotes, some ARSs possess additional, noncanonical functions in the regulation of cell metabolism. Here, we report a novel noncanonical function of WRS in antiviral defense. WRS is rapidly secreted in response to viral infection and primes the innate immune response by inducing the secretion of proinflammatory cytokines and type I IFNs, resulting in the inhibition of virus replication both in vitro and in vivo Thus, we consider WRS to be a member of the antiviral innate immune response. The results of this study enhance our understanding of host defense systems and provide additional information on the noncanonical functions of ARSs.


Assuntos
Infecções por Rhabdoviridae/imunologia , Triptofano-tRNA Ligase/genética , Triptofano-tRNA Ligase/metabolismo , Vesiculovirus/patogenicidade , Administração Intranasal , Administração Intravenosa , Animais , Linhagem Celular , Citocinas/metabolismo , Células HEK293 , Células HeLa , Humanos , Imunidade Inata , Interferon Tipo I/metabolismo , Camundongos , Células RAW 264.7 , Infecções por Rhabdoviridae/genética , Células THP-1 , Triptofano-tRNA Ligase/administração & dosagem , Vesiculovirus/imunologia
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