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1.
J Cell Mol Med ; 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32227583

RESUMO

Chemokine receptor 5 (CCR5) is a pivotal regulator of macrophage trafficking in the kidneys in response to an inflammatory cascade. We investigated the role of CCR5 in experimental ischaemic-reperfusion injury (IRI) pathogenesis. To establish IRI, we clamped the bilateral renal artery pedicle for 30 min and then reperfused the kidney. We performed adoptive transfer of lipopolysaccharide (LPS)-treated RAW 264.7 macrophages following macrophage depletion in mice. B6.CCR5-/- mice showed less severe IRI based on tubular epithelial cell apoptosis than did wild-type mice. CXCR3 expression in CD11b+ cells and inducible nitric oxide synthase levels were more attenuated in B6.CCR5-/- mice. B6.CCR5-/- mice showed increased arginase-1 and CD206 expression. Macrophage-depleted wild-type mice showed more injury than B6.CCR5-/- mice after M1 macrophage transfer. Adoptive transfer of LPS-treated RAW 264.7 macrophages reversed the protection against IRI in wild-type, but not B6.CCR5-/- mice. Upon knocking out CCR5 in macrophages, migration of bone marrow-derived macrophages from wild-type mice towards primary tubular epithelial cells with recombinant CCR5 increased. Phospho-CCR5 expression in renal tissues of patients with acute tubular necrosis was increased, showing a positive correlation with tubular inflammation. In conclusion, CCR5 deficiency favours M2 macrophage activation, and blocking CCR5 might aid in treating acute kidney injury.

2.
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.
PLoS One ; 15(1): e0227744, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929596

RESUMO

PURPOSE: To evaluate early recovery of urinary continence after robot-assisted radical prostatectomy (RARP) with urethral realignment using bladder neck preservation (BNP) and maximal urethral length preservation (MULP). METHODS: Patients who underwent RARP between 2014 and 2017 owing to prostate cancer with a Gleason score ≤ 7 (3+4), ≤ cT2c stage, and prostate-specific antigen level < 20 ng/ml were investigated. Patients with tumors of the bladder neck or apex on magnetic resonance imaging were excluded. A total of 266 patients underwent the operation using the standard method between 2014 and 2015 (group 1), while 305 patients underwent urethral realignment between 2016 and 2017 (group 2). Continence was defined as wearing no pad or one security pad. RESULTS: The continence rates immediately after Foley catheter removal, at 2 weeks, and at 1, 3, 6, and 12 months after operation in group 2 were 46.9%, 63.0%, 73.4%, 90.1%, 94.8%, and 98.7%, respectively. The continence rate at 1 month in group 2 was significantly higher than that in group 1 (65.4% versus 73.4%, p = 0.037). The multivariate regression analysis showed that age and surgical method were factors affecting early continence recovery. The positive surgical margin rates were 18.0% and 14.8% in groups 1 and 2, respectively (p = 0.288). Biochemical recurrence occurred in 14.7% and 8.2% in groups 1 and 2, respectively (p = 0.015). CONCLUSION: Urethral realignment using BNP and MULP resulted in rapid continence recovery and good oncological results after RARP in young patients with a Gleason score ≤ 7 and organ-confined disease.

4.
J Cancer Res Clin Oncol ; 146(1): 221-227, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31612318

RESUMO

PURPOSE: To evaluate biochemical recurrence (BCR) risk in men with localized prostate cancer (PC) of pathological Gleason score (pGS) 8-10. Although such patients have low BCR-free survival (BCRFS) following radical prostatectomy (RP), they are not recommended for adjuvant radiation therapy (ART) as per current guidelines. METHODS: Among an adjuvant treatment-naïve cohort between 1995 and 2015, 1272 men were identified and categorized into group 1 [pGS7 (3 + 4) and pT3; n = 654], group 2 [pGS7 (4 + 3) and pT3; n = 408], and group 3 (pGS 8-10 and pT2; n = 210). The BCR risk of group 3 was compared with that of groups 1 and 2 who are the candidates for ART. RESULTS: At a median follow-up of 60 months (interquartile range: 39-86), 432 men experienced BCR. BCRFS was lower in group 3 than in groups 1 and 2 (p < 0.001 and p = 0.021, respectively). In multivariate analysis, this association persisted and surgical margin (SM) was found to be a significant BCR predictor. Although statistically not significant, BCRFS was lower in group 3 with positive SM (PSM) than in group 2 with PSM (p = 0.101). BCRFS was significantly worse in group 3 with negative SM (NSM) than in group 1 with PSM (p = 0.038), while it was better in group 2 with PSM (p = 0.297). CONCLUSION: Localized high-grade PC with PSM showed lower BCRFS and that with NSM showed better BCRFS without statistical significance than locally advanced GS 7 PC with PSM that are eligible for ART.


Assuntos
Recidiva Local de Neoplasia/patologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Idoso , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Gradação de Tumores , Estadiamento de Neoplasias , Prostatectomia , Neoplasias da Próstata/radioterapia , Radioterapia Adjuvante , Estudos Retrospectivos , Fatores de Risco
5.
BioDrugs ; 34(1): 99-110, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31749113

RESUMO

BACKGROUND: Darbepoetin-alfa is an erythropoiesis-stimulating agent (ESA) with a long elimination half-life that achieves better hemoglobin (Hb) stability than short-acting ESAs. OBJECTIVE: We aimed to evaluate the efficacy and safety of intravenous CKD-11101 (a biosimilar of darbepoetin-alfa) compared with those of darbepoetin-alfa in hemodialysis patients. METHODS: The study was performed in 24 centers in Korea between June 2015 and June 2017. The study subjects were randomized in a double-blind manner. The follow-up duration was 24 weeks, which consisted of 20 weeks of maintenance and 4 weeks of evaluation period. All patients underwent a stabilization period to achieve a target baseline Hb of 10-12 g/dL before randomization. Following randomization, patients received darbepoetin-alfa or CKD-11101 weekly or biweekly. RESULTS: A total of 403 patients were randomized into two groups, and a total of 325 patients (80.6%) completed the investigation. The differences between the two groups in terms of change in the average Hb level from baseline to evaluation were not significant. The average administered dose of ESA was similar between the groups. There was no difference in the proportion of patients who maintained the target Hb during the evaluation period [60.4% vs. 66.2% in the CKD-11101 and darbepoetin-alfa groups, respectively (p = 0.3038)]. In addition, the safety analysis, consisting of adverse events and adverse drug reactions, showed comparable results between the two groups. CONCLUSION: The changes in the level of Hb, dose of erythropoietin, and achievement rate of the target Hb during the study period were comparable between the groups. CKD-11101 has an equivalent efficacy and safety compared with darbepoetin-alfa in patients undergoing hemodialysis.

6.
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.

7.
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.

8.
BMC Ophthalmol ; 19(1): 217, 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31703568

RESUMO

BACKGROUND: To investigate the cytotoxicities of the topical ocular dual-action anti-allergic agents (alcaftadine 0.25%, bepotastine besilate 1.5%, and olopatadine HCL 0.1%) on human corneal epithelial cells (HCECs) and their anti-allergic effects on cultured conjunctival epithelial cells. METHODS: A Methylthiazolyltetrazolium(MTT)-based calorimetric assay was used to assess cytotoxicities using HCECs at concentrations of 10, 20 or 30% for exposure durations of 30 min, 1 h, 2 h, 12 h or 24 h. Cellular morphologies were evaluated by inverted phase-contrast and electron microscopy. Wound widths were measured 2 h, 18 h, or 24 h after confluent HCECs monolayers were scratched. Realtime PCR was used to quantify anti-allergic effects on cultured human conjunctival cells, in which allergic reactions were induced by treating them with Aspergillus antigen. RESULTS: Cell viabilities decreased in time- and concentration-dependent manners. Cells were detached from dishes and showed microvilli loss, cytoplasmic vacuoles, and nuclear condensation when exposed to antiallergic agents; alcaftadine was found to be least cytotoxic. Alcaftadine treated HCECs monolayers showed the best wound healing followed by bepotastine and olopatadine (p < 0.0001). All agents significantly reduced the gene expressions of allergic cytokines (IL-5, IL-25, eotaxin, thymus and activation-regulated chemokine, and thymic stromal lymphopoietin) and alcaftadine had the greatest effect (p < 0.0001 in all cases). CONCLUSIONS: Alcaftadine seems to have less side effects and better therapeutic effects than the other two anti-allergic agents tested. It may be more beneficial to use less toxic agents for patients with ocular surface risk factors or presumed symptoms of toxicity.

9.
BMC Med Res Methodol ; 19(1): 216, 2019 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-31775643

RESUMO

BACKGROUND: Antiretroviral therapy (ART) has significantly reduced HIV-related morbidity and mortality. However, therapeutic benefit of ART is often limited by delayed drug-associated toxicity. Nucleoside reverse transcriptase inhibitors (NRTIs) are the backbone of ART regimens. NRTIs compete with endogenous deoxyribonucleotide triphosphates (dNTPs) in incorporation into elongating DNA chain resulting in their cytotoxic or antiviral effect. Thus, the efficacy of NRTIs could be affected by direct competition with endogenous dNTPs and/or feedback inhibition of their metabolic enzymes. In this paper, we assessed whether the levels of ribonucleotides (RN) and dNTP pool sizes can be used as biomarkers in distinguishing between HIV-infected patients with ART-induced mitochondrial toxicity and HIV-infected patients without toxicity. METHODS: We used data collected through a case-control study from 50 subjects. Cases were defined as HIV-infected individuals with clinical and/or laboratory evidence of mitochondrial toxicity. Each case was age, gender, and race matched with an HIV-positive without evidence of toxicity. We used a range of machine learning procedures to distinguish between patients with and without toxicity. Using resampling methods like Monte Carlo k-fold cross validation, we compared the accuracy of several machine learning algorithms applied to our data. We used the algorithm with highest classification accuracy rate in evaluating the diagnostic performance of 12 RN and 14 dNTP pool sizes as biomarkers of mitochondrial toxicity. RESULTS: We used eight classification algorithms to assess the diagnostic performance of RN and dNTP pool sizes distinguishing HIV patients with and without NRTI-associated mitochondrial toxicity. The algorithms resulted in cross-validated classification rates of 0.65-0.76 for dNTP and 0.72-0.83 for RN, following reduction of the dimensionality of the input data. The reduction of input variables improved the classification performance of the algorithms, with the most pronounced improvement for RN. Complex tree-based methods worked the best for both the deoxyribose dataset (Random Forest) and the ribose dataset (Classification Tree and AdaBoost), but it is worth noting that simple methods such as Linear Discriminant Analysis and Logistic Regression were very competitive in terms of classification performance. CONCLUSIONS: Our finding of changes in RN and dNTP pools in participants with mitochondrial toxicity validates the importance of dNTP pools in mitochondrial function. Hence, levels of RN and dNTP pools can be used as biomarkers of ART-induced mitochondrial toxicity.

10.
Artigo em Inglês | MEDLINE | ID: mdl-31758719

RESUMO

BACKGROUND AND AIM: The clinical significance of incidental pancreatic cystic lesions (PCLs) remains unclear in those that are not accompanied by worrisome features or high-risk stigmata. We aimed to investigate the natural course of PCLs without any risk features and examine the clinical factors associated with their progression. METHODS: We conducted a retrospective cohort study of 427 patients with PCLs, which were incidentally detected by computed tomography between January 2003 and December 2012. Progression of PCLs without any risk features and the clinical factors associated with their progression were investigated. The length of time to significant growth was also evaluated. RESULTS: Ninety-four (22.0%) of the 427 patients had asymptomatic PCLs that showed significant growth after a median surveillance period of 5.3 years; approximately 27.7% of the patients showed significant size changes in the first 5 years, while the remaining 72.3% showed significant changes after 5 years. The cumulative rate of patients with significant growth was associated with initial cyst size and high body mass index. In the growth group, additional treatments were required for 12 patients, one of whom developed malignancy. Four patients in the stable group underwent additional treatment and showed no malignant change. CONCLUSIONS: One-fifth of the asymptomatic PCLs significantly increased in size after a long-term follow-up period, which was associated with initial cyst size and obesity. The size of PCLs mostly increased after 5 years; although the malignancy risk of PCLs was low, it was still a concern.

11.
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.

12.
Medicine (Baltimore) ; 98(42): e17627, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626145

RESUMO

Adjuvant radiation therapy (ART) is recommended without consideration of radical prostatectomy Gleason score (RP GS) for cases with adverse features. We compared the outcomes of pathologically localized high-grade (GS 8-10) prostate cancer (PC) with those of pT3 GS 7 PC.A total of 1585 men who underwent RP between 1995 and 2015 comprised the cohort, which was divided into group 1 (RP GS 7(3 + 4) and pT3; n = 760), group 2 (RP GS 7(4 + 3) and pT3; n = 565), and group 3 (RP GS 8-10 and pT2; n = 260). Biochemical recurrence (BCR), all-cause mortality (ACM), and PC-specific mortality (PCSM) risk were compared among groups using Cox regression and competing risk analysis.At a median follow-up of 58 months (interquartile range: 37-85), 721 men experienced BCR and 84 died (22 due to PC). BCR-free survival rates were lower in group 3 than in group 1 (P < .001); nevertheless, no difference was observed between groups 2 and 3 (P = .638). Furthermore, no difference in ACM was noted among groups. PCSM rates were higher in group 3 than in groups 1 and 2 (P = .001 and P = .005, respectively). This association persisted in multivariate models after adjustment for clinicopathological variables.Patients with RP GS 8-10 and pT2 PC had higher BCR and PCSM rates than those with RP GS 7 and pT3 PC. Localized high-grade PC should be considered in decision-making for ART.


Assuntos
Gradação de Tumores/métodos , Próstata/patologia , Prostatectomia/métodos , Neoplasias da Próstata/diagnóstico , Idoso , Causas de Morte/tendências , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Próstata/cirurgia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/cirurgia , República da Coreia/epidemiologia , Estudos Retrospectivos , Taxa de Sobrevida/tendências
13.
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
14.
Transplant Proc ; 51(8): 2575-2581, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31474451

RESUMO

BACKGROUND: This study aimed to investigate the outcomes of kidney transplantation (KT) from deceased acute kidney injury (AKI) donors and analyzed the factors affecting these outcomes. METHODS: All patients who underwent KT from deceased donors at our institution from 1998 to 2016 were retrospectively reviewed. Recipients were divided into the AKI and non-AKI donor groups. We analyzed delayed graft function (DGF), serum creatinine levels at 1 month and 1 year after KT, cold ischemia time, donors' initial and terminal serum creatinine levels, Kidney Donor Profile Index, and patient and graft survival in each group. RESULTS: Of 181 recipients, 30 received kidneys from 21 AKI donors, whereas the remaining 151 received kidneys from donors without AKI. DGF more frequently developed in the AKI donor group than in the non-AKI donor group (40% vs 7.28%; P = .001). Allograft functions at 1 month and 1 year after KT did not differ between the AKI and non-AKI donor groups (1 month: P = .469; 1 year: P = .691). Factors affecting DGF were recipient weight and donor AKI. Recipient factors affecting graft function at 1 year were recipient height, length of hospital stay, serum creatinine levels at 1 month and 6 months, and biopsy-proven acute rejection. Older donor age was the only donor factor that affected graft function at 1 year. CONCLUSION: KT from deceased AKI donors showed a higher DGF rate but favorable patient and graft survival and graft functions. Donor AKI and recipient weight affected DGF, and only older donor age affected graft function at 1 year.


Assuntos
Lesão Renal Aguda , Função Retardada do Enxerto/epidemiologia , Função Retardada do Enxerto/etiologia , Transplante de Rim/métodos , Doadores de Tecidos , Adulto , Fatores Etários , Feminino , Sobrevivência de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Homólogo , Transplantes/fisiopatologia
15.
Prostate ; 79(16): 1805-1810, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31483062

RESUMO

BACKGROUND: Recently, a new prostate cancer (PC) grading system was introduced, where Gleason score (GS) 7 was divided into 3 + 4 = 7 and 4 + 3 = 7 due to the different prognoses associated with each tumor type. However, whether downgrading or upgrading from needle biopsy (NB) to radical prostatectomy (RP) affects oncologic outcomes is currently unknown. Herein, we investigated the prognostic impact of downgrading and upgrading from NB to RP among men with GS 7 PC. METHODS: We retrospectively reviewed the medical records of 3003 patients with localized PC who underwent RP between 2005 and 2014. We included 692 patients with GS 7 PC on both NB and RP specimens. We analyzed the data using Kaplan-Meier methods and Cox proportional hazard models. RESULTS: Of the 692 patients enrolled in this study, 389 (56.2%) and 303 (43.8%) patients had RP GS 3 + 4 = 7 and RP GS 4 + 3 = 7 PC, respectively. On the basis of NB and RP GS, 264 (38.1%), 125 (18.1%), 142 (20.5%), and 161 (23.3%) patients were classified as 3 + 4/3 + 4, 4 + 3/3 + 4, 3 + 4/4 + 3, and 4 + 3/4 + 3, respectively. Kaplan-Meier curves showed significant differences in biochemical recurrence (BCR)-free survival across the groups (P < .001). In the multivariate analyses, these groups were significantly associated with BCR (4 + 3/3 + 4: hazard ratio [HR], 1.675; 3 + 4/4 + 3: HR, 1.908; and 4 + 3/4 + 3: HR, 2.699). CONCLUSIONS: Downgrading and upgrading from NB to RP was an independent predictor of BCR in men with GS 7 PC, which could be due to the amount of Gleason pattern 4.


Assuntos
Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Idoso , Biópsia por Agulha , Intervalo Livre de Doença , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Prostatectomia , Estudos Retrospectivos
16.
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
17.
Sci Rep ; 9(1): 11899, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31417160

RESUMO

Prostate-specific antigen (PSA) kinetics predicts survival in castration-resistant prostate cancer (CRPC); however, the influence of prior treatment on this relationship is unclear. Patients with CRPC were stratified according to time to PSA nadir and time to CRPC progression to investigate their prognostic significance on prostate cancer-specific survival (PCSS) and whether PSA kinetics may serve as prognosticators regardless of prior local treatment. This multicenter retrospective study included 295 patients diagnosed with CRPC between September 2009 and November 2017. PSA kinetics during androgen-deprivation therapy (ADT) including %PSA decline, PSA nadir level, time to PSA nadir, and time to CRPC progression was investigated. Subgroup analysis was performed according to the prior history of local curative treatment. Patients who did not receive prior local treatment with ≥6 months to PSA nadir and <12 months to CRPC, showed lower PCSS rates than those with <6 months to PSA nadir (23.3% vs. 45.3%; p = 0.031) and ≥12 months to CRPC (20.0% vs. 47.8%; p = 0.001). In patients who had received local treatment, PSA kinetic parameters did not influence PCSS. Our results indicate that time to PSA nadir and time to CRPC progression are prognosticators of PCSS in patients with CRPC who did not previously receive curative local treatment.

18.
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
19.
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
20.
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.

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