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1.
Antimicrob Agents Chemother ; 68(1): e0133023, 2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-38054726

RESUMO

FL058 is a novel diazabicyclooctane ß-lactamase inhibitor. This first-in-human study evaluated the safety, tolerability, and population pharmacokinetic (PK)/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects. The results showed that the maximum tolerated dose of FL058 was 3,000 mg after single-dose infusion. FL058 in combination with meropenem did not cause any grade 3 or higher adverse event when the dose was escalated up to 1,000 mg/2,000 mg. FL058 exposure PK parameters showed dose proportionality. FL058 was excreted primarily in urine. No significant PK interaction was found between FL058 and meropenem. Population PK model analysis indicated that the PK profiles of FL058 and meropenem were consistent with the two-compartment model. The impact of covariates, creatinine clearance, concomitant use of meropenem, body weight, sex, and FL058 dose, on FL058 exposure was less than 10%. FL058/meropenem combination was safe and well tolerated up to a 1,000-mg/2,000-mg dose in healthy adults. The recommended minimum dose of FL058/meropenem combination was 500 mg/1,000 mg by intravenous infusion over 2 h every 8 h based on target attainment analysis. The good safety, tolerability, and satisfactory PK profiles of FL058 alone and in combination with meropenem in this first-in-human study will support further clinical development of FL058 in combination with meropenem in patients with target infections (ClinicalTrials.gov identifiers: NCT05055687, NCT05058118, and NCT05058105).


Assuntos
Antibacterianos , Inibidores de beta-Lactamases , Adulto , Humanos , Meropeném/farmacologia , Antibacterianos/farmacocinética , Voluntários Saudáveis , Inibidores de beta-Lactamases/efeitos adversos , Infusões Intravenosas
2.
BMC Cancer ; 24(1): 762, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38918690

RESUMO

BACKGROUND: Despite evidence supporting the high correlation of the novel platelet-to-albumin ratio (PAR) with survival in diverse malignancies, its prognostic relevance in nasopharyngeal carcinoma (NPC) remains underexplored. This study aimed to examine the link between PAR and overall survival (OS) in NPC and to establish a predictive model based on this biomarker. METHODS: We retrospectively assembled a cohort consisting of 858 NPC patients who underwent concurrent chemoradiotherapy (CCRT). Utilizing the maximally selected log-rank method, we ascertained the optimal cut-off point for the PAR. Subsequently, univariate and multivariate Cox proportional hazards models were employed to discern factors significantly associated with OS and to construct a predictive nomogram. Further, we subjected the nomogram's predictive accuracy to rigorous independent validation. RESULTS: The discriminative optimal PAR threshold was determined to be 4.47, effectively stratifying NPC patients into two prognostically distinct subgroups (hazard ratio [HR] = 0.53; 95% confidence interval [CI]: 0.28-0.98, P = 0.042). A predictive nomogram was formulated using the results from multivariate analysis, which revealed age greater than 45 years, T stage, N stage, and PAR score as independent predictors of OS. The nomogram demonstrated a commendable predictive capability for OS, with a C-index of 0.69 (95% CI: 0.64-0.75), surpassing the performance of the conventional staging system, which had a C-index of 0.56 (95% CI: 0.65-0.74). CONCLUSIONS: In the context of NPC patients undergoing CCRT, the novel nutritional-inflammatory biomarker PAR emerges as a promising, cost-efficient, easily accessible, non-invasive, and potentially valuable predictor of prognosis. The predictive efficacy of the nomogram incorporating the PAR score exceeded that of the conventional staging approach, thereby indicating its potential as an enhanced prognostic tool in this clinical setting.


Assuntos
Quimiorradioterapia , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Nomogramas , Humanos , Feminino , Masculino , Estudos Retrospectivos , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/sangue , Carcinoma Nasofaríngeo/patologia , Quimiorradioterapia/métodos , Prognóstico , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/sangue , Neoplasias Nasofaríngeas/patologia , Adulto , Plaquetas/patologia , Idoso , Albumina Sérica/análise , Estadiamento de Neoplasias , Adulto Jovem , Modelos de Riscos Proporcionais , Contagem de Plaquetas , Biomarcadores Tumorais/sangue
3.
Biochem Genet ; 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38429603

RESUMO

Cervical cancer (CC) is considered to be the most prevalent female malignancies across the globe and a prime cause of mortality among women. RNA-binding motif protein 15 (RBM15) has been elucidated to participate in tumorigenesis in various cancers by regulating RNA N6-methyladenosine (m6A) methylation. However, its significance and detailed molecular mechanisms remain uncertain in CC. Using CGA database and qRT-PCR, the RBM15 expression was found to be elevated in CC tissues. After performing EdU, wound healing, Transwell migration, and xenograft tumor assays, RBM15 knockdown inhibited the malignant properties of CC cells along with the tumor development of CC cells in vivo. Moreover, qRT-PCR, MeRIP, and western blotting experiments were also confirmed that decorin (DCN) downregulated in CC was a direct substrate of RBM15 m6A methylation, and RBM15 knockdown could enhance DCN expression in CC cells. The anti-tumor effects of RBM15 knockdown could be abolished by DCN silencing. Overall, RBM15 knockdown lowered the tumorigenesis of CC both in vitro and in vivo, and it does so via mediating m6A modification of DCN mRNA in CC cells.

4.
J Asian Nat Prod Res ; 26(7): 803-811, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38721701

RESUMO

Two new triterpenes mayteneri A (1), mayteneri B (2), and seven known compounds (3-9) were isolated from stems of Maytenus hookeri Loes. The chemical structures of compounds 1 and 2 were established by 1D, 2D NMR, HRESIMS analysis, and calculating electronic circular dichroism (ECD). The structures of known compounds 3-9 were determined by comparison of their spectral with those reported. Compounds 4-7 showed significant inhibitory activity for NLRP3 inflammasome, with the IC50 values of 2.36-3.44 µM.


Assuntos
Maytenus , Ácido Oleanólico , Estrutura Molecular , Ácido Oleanólico/química , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/isolamento & purificação , Ácido Oleanólico/farmacologia , Maytenus/química , Triterpenos/química , Triterpenos/farmacologia , Triterpenos/isolamento & purificação , Caules de Planta/química , Animais , Camundongos , Inflamassomos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores
5.
Pak J Med Sci ; 40(6): 1158-1162, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38952517

RESUMO

Objective: To determine the impacts to research the impacts of pain's Specialized Pain Management Nursing Care in the perioperative period on pain symptoms and life quality of patients experiencing minimally invasive surgery for spinal injury. Method: Eighty patients with a spinal injury who underwent minimally invasive surgery in the Department of Orthopedics of Baoding No.1 Hospital from January 2018 to December 2021 were retrospectively analyzed. They were split into two groups following different nursing methods (n=40 each group). Specialized Pain Management Nursing Care were given to patients in the observation group. Those in the control group were given treated with routine care. Their pain score and nursing effect were compared, after which their quality of life, daily living ability and complication rate compared and analyzed. Results: The pain degree in the control group was considerably more than that in the observation group in the 1st postoperative period. The pain degree, which decreased in both groups, slumped more significantly in the observation group on the 2nd and 3rd postoperative days. The postoperative hospital stays and pain duration in the observation group were shorter than those in the control group (P<0.05), and the nursing effect was significantly better than that in the control group (P<0.05). After postoperative nursing intervention. Conclusion: Minimally invasive surgery integrated with the Specialized Pain Management Nursing Care can remarkably ameliorate pain after spinal injury surgery, reducing complications' incidence, and improving the life quality for patients.

6.
Proc Natl Acad Sci U S A ; 117(52): 33263-33271, 2020 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-33318201

RESUMO

Gap closure to eliminate physical discontinuities and restore tissue integrity is a fundamental process in normal development and repair of damaged tissues and organs. Here, we demonstrate a nonadhesive gap closure model in which collective cell migration, large-scale actin-network fusion, and purse-string contraction orchestrate to restore the gap. Proliferative pressure drives migrating cells to attach onto the gap front at which a pluricellular actin ring is already assembled. An actin-ring segment switching process then occurs by fusion of actin fibers from the newly attached cells into the actin cable and defusion from the previously lined cells, thereby narrowing the gap. Such actin-cable segment switching occurs favorably at high curvature edges of the gap, yielding size-dependent gap closure. Cellular force microscopies evidence that a persistent rise in the radial component of inward traction force signifies successful actin-cable segment switching. A kinetic model that integrates cell proliferation, actin fiber fusion, and purse-string contraction is formulated to quantitatively account for the gap-closure dynamics. Our data reveal a previously unexplored mechanism in which cells exploit multifaceted strategies in a highly cooperative manner to close nonadhesive gaps.


Assuntos
Actinas/metabolismo , Cicatrização , Animais , Fenômenos Biomecânicos , Adesão Celular , Proliferação de Células , Forma Celular , Cães , Imageamento Tridimensional , Cinética , Células Madin Darby de Rim Canino , Microscopia de Força Atômica , Modelos Biológicos , Fatores de Tempo
7.
J Asian Nat Prod Res ; 25(7): 658-666, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36272136

RESUMO

Two new compounds verboncin A (1) and verboncin B (4) and 14 known compounds (2-3 and 5-16) were isolated from Verbena bonariensis, and these 14 compounds were first obtained from this plant. Their chemical structures were established by one and two-dimensional NMR and HRESIMS analysis and the results were compared with literature values. The absolute configuration of 1 was determined by calculating electronic circular dichroism (ECD). The cytotoxicity of some of the compounds against MCF-7, HCT-116, MDA-MB-231, and SW620 human cancer cell lines were evaluated, in which compound 4 showed negligible cytotoxic activity with an IC50 value of 68.08 ± 0.35 µM against the MCF-7 cell line.


Assuntos
Verbena , Verbena/química , Humanos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Modelos Moleculares
8.
Int J Clin Pharmacol Ther ; 60(10): 448-458, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35979900

RESUMO

OBJECTIVE: To compare the pharmacokinetic (PK) characteristics, investigate relative bioavailability, and provide data for potential additional bioequivalence trials between generic fidaxomicin (test (T) formulation) and the original brand (reference (R) formulation) in healthy Chinese subjects. MATERIALS AND METHODS: An open, randomized, single-dose, cross-over study was conducted in 18 healthy Chinese subjects. The subjects randomly received T or R formulations and the alternative formulations were received after a 14-day wash-out period. Blood and fecal samples were collected and tested by liquid chromatography-tandem mass spectrometry (LC-MS/MS). PK parameters were calculated using a non-compartmental model. Relative bioavailability considering commonly established bioequivalence criteria was assessed. RESULTS: Cmax were 3.58 ± 2.74 ng/mL and 6.01 ± 3.93 ng/mL, and AUC0-∞ were 35.71 ± 18.68 h×ng/mL and 52.15 ± 31.31 h×ng/mL for the T and R formulations, respectively. The tmax of both formulations was 5.00 hours. The cumulative fecal excretion rate (Fe0-96h/F) of fidaxomicin and its main active metabolite OP-1118 were similar for both formulations. The geometric mean ratios and 90% confidence intervals (CI) of AUC0-t, AUC0-∞, and Cmax were not completely within the range of 80.00 - 125.00%. Significant within-subject and inter-subject coefficients of variation (> 30%) were found. CONCLUSION: Despite the differences in exposure, PK characteristics and fecal recovery of the two formulations were similar, suggesting that an effective concentration of the generic fidaxomicin could be achieved locally in the gastrointestinal tract. Fidaxomicin was a highly viable drug, thus providing reference for future clinical study design.


Assuntos
Medicamentos Genéricos , Espectrometria de Massas em Tandem , Área Sob a Curva , Disponibilidade Biológica , China , Cromatografia Líquida , Estudos Cross-Over , Medicamentos Genéricos/farmacocinética , Fidaxomicina , Humanos , Projetos Piloto , Comprimidos , Espectrometria de Massas em Tandem/métodos , Equivalência Terapêutica
9.
J Asian Nat Prod Res ; 24(12): 1101-1108, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35043747

RESUMO

Autophagy plays an important role in the pathogenesis of cardiovascular diseases. Dysregulation of autophagy may have a huge effect on cardiac hypertrophy induced by overload pressure although reports on autophagy and cardiac hypertrophy have been contradictory. Some studies showed that autophagy activation attenuated cardiac hypertrophy. However, others suggested that inhibition of autophagy would be protective. Different research models or different pathways involved could be responsible for it. Cardiac hypertrophy may be alleviated through regulation of autophagy. This review aims to highlight the pathways and therapeutic targets identified in the prevention and treatment of cardiac hypertrophy by regulating autophagy.


Assuntos
Autofagia , Cardiomegalia , Animais , Camundongos , Estrutura Molecular , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Camundongos Endogâmicos C57BL
10.
J Vasc Interv Radiol ; 32(11): 1519-1528.e2, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34364991

RESUMO

PURPOSE: To investigate the safety and efficacy of catheter-based endovascular denervation (EDN) at the celiac artery and abdominal aorta around the celiac artery on glycemic control in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: With a novel catheter system, EDN was conducted at the celiac artery along with the abdominal aorta around the celiac artery in patients with T2DM whose glycosylated hemoglobin (HbA1c) level was >7.5%. The primary outcome was HbA1c level at 6 months. Other outcomes included safety, oral glucose tolerance test, homeostasis model assessment of insulin resistance (HOMA-IR), fasting plasma glucose (FPG) level, 2-hour postprandial plasma glucose (2hPG) level, and C-peptide test. RESULTS: A total of 11 subjects were included for analysis. The technical success was 100%, and no severe treatment-related adverse events or major complications were observed. Both HbA1c level and HOMA-IR were significantly reduced at 6 months (9.9% vs 8.0%, P = .005; 13.3 vs 6.0, P = .016). Decreases in FPG and 2hPG levels were observed (227.2 vs 181.8 mg/dL, P < .001; 322.2 vs 205.2 mg/dL, P = .001). The C-peptide test indicated improved ß-cell function (area under the curve, 0.23 vs 0.28 pmol/mL, P = .046). A reduction of daily insulin injection (P = .02) and improvement of liver function (alanine aminotransferase, P = .014; γ-glutamyl transpeptidase, P = .021) were also observed. CONCLUSIONS: EDN in the celiac artery and abdominal aorta around the celiac artery elicited a clinically significant improvement in glycemic control and insulin resistance in patients with T2DM, with good tolerability as demonstrated by 6-month follow-up.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Glicemia , Denervação , Hemoglobinas Glicadas , Controle Glicêmico , Humanos , Insulina
11.
Inflammopharmacology ; 29(4): 1187-1200, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34244900

RESUMO

Lagotis brachystachya Maxim is a herb widely used in traditional Tibetan medicine. Our previous study indicated that total extracts from Lagotis brachystachya could lower uric acid levels. This study aimed to further elucidate the active components (luteolin, luteoloside and apigenin) isolated from Lagotis brachystachya and the underlying mechanism in vitro and in vivo. The results showed that treatment with luteolin and luteoloside reversed the reduction of organic anion transporter 1 (OAT1) levels, while apigenin attenuated the elevation of urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) levels in uric acid-treated HK-2 cells, which was consistent with the finding in the kidneys of potassium oxonate (PO)-induced mice. On the other hand, hepatic xanthine oxidase activity was inhibited by the components. In addition, all of these active components improved the morphology of the kidney in hyperuricemic mice. Moreover, molecular docking showed that luteolin, luteoloside and apigenin could bind Toll-like receptor 4 (TLR4) and NLR family pyrin domain containing 3 (NLRP3). Congruently, western blot analysis showed that the components inhibited TLR4/myeloid differentiation primary response 88 (MyD88)/NLRP3 signaling. In conclusion, these results indicated that luteolin, luteoloside and apigenin could attenuate hyperuricemia by decreasing the production and increasing the excretion of uric acid, which were mediated by inhibiting inflammatory signaling pathways.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Hiperuricemia/metabolismo , Rim/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptor 4 Toll-Like/metabolismo , Ácido Úrico/metabolismo , Animais , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/uso terapêutico , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Hiperuricemia/tratamento farmacológico , Rim/efeitos dos fármacos , Masculino , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Plantas Medicinais , Estrutura Secundária de Proteína , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Receptor 4 Toll-Like/antagonistas & inibidores , Ácido Úrico/toxicidade
12.
Angew Chem Int Ed Engl ; 60(51): 26829-26836, 2021 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-34658135

RESUMO

Defects have been found to enhance the electrocatalytic performance of NiFe-LDH for oxygen evolution reaction (OER). Nevertheless, their specific configuration and the role played in regulating the surface reconstruction of electrocatalysts remain ambiguous. Herein, cationic vacancy defects are generated via aprotic-solvent-solvation-induced leaking of metal cations from NiFe-LDH nanosheets. DFT calculation and in situ Raman spectroscopic observation both reveal that the as-generated cationic vacancy defects tend to exist as VM (M=Ni/Fe); under increasing applied voltage, they tend to assume the configuration VMOH , and eventually transform into VMOH-H which is the most active yet most difficult to form thermodynamically. Meanwhile, with increasing voltage the surface crystalline Ni(OH)x in the NiFe-LDH is gradually converted into disordered status; under sufficiently high voltage when oxygen bubbles start to evolve, local NiOOH species become appearing, which is the residual product from the formation of vacancy VMOH-H . Thus, we demonstrate that the cationic defects evolve along with increasing applied voltage (VM → VMOH → VMOH-H ), and reveal the essential motif for the surface restructuration process of NiFe-LDH (crystalline Ni(OH)x → disordered Ni(OH)x → NiOOH). Our work provides insight into defect-induced surface restructuration behaviors of NiFe-LDH as a typical precatalyst for efficient OER electrocatalysis.

13.
Bioorg Med Chem Lett ; 30(20): 127479, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32784091

RESUMO

Two classes of piperazinone-containing thieno[3,2-d]pyrimidines were designed and synthesized as new PI3Kδ inhibitors in this study. Detailed SAR study with respect to the piperazinone substituents at the 6-position of thieno[3,2-d]pyrimidine core demonstrated that piperazinone-containing thieno[3,2-d]pyrimidines would be more potent and selective for PI3Kδ than their piperazine counterparts, which led to the discovery of several potent PI3Kδ inhibitors with comparable or better antiproliferative activity against a panel of non-Hodgkin lymphoma (NHL) cell lines as compared with idelalisib. Our study will promote the development of new PI3Kδ inhibitors based on piperazinone-containing thieno[3,2-d]pyrimidine scaffold.


Assuntos
Antineoplásicos/farmacologia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Desenho de Fármacos , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Piperazinas/farmacologia , Pirimidinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Inibidores de Fosfoinositídeo-3 Quinase/química , Piperazinas/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
14.
Bioorg Chem ; 105: 104344, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33091667

RESUMO

PI3Kδ has proved to be an effective target for anti-lymphoma drugs. However, the application of current approved PI3Kδ inhibitors has been greatly limited due to their specific immune-mediated toxicity and increased risk of infection, it is necessary to develop more PI3Kδ inhibitors with new scaffold. In this study, SAR study with respect to piperazinone-containing purine derivatives led to the discovery of a potent and selective PI3Kδ inhibitor, 4-(cyclobutanecarbonyl)-1-((2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperazin-2-one (WNY1613). WNY1613 exhibits good antiproliferative activity against a panel of non-Hodgkin's lymphoma (NHL) cell lines by inducing cancer cell apoptosis and inhibiting the phosphorylation of PI3K and MAPK downstream components. In addition, it can also prevent the tumor growth in both SU-DHL-6 and JEKO-1 xenograft models without observable toxicity. WNY1613 thus could be developed as a promising candidate for the treatment of NHL after subsequent extensive pharmacodynamics and pharmacokinetics investigation.


Assuntos
Antineoplásicos/síntese química , Inibidores Enzimáticos/síntese química , Linfoma não Hodgkin/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Piperazinas/química , Purinas/síntese química , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Xenoenxertos , Humanos , Camundongos SCID , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Simulação de Acoplamento Molecular , Morfolinas/química , Neoplasias Experimentais , Fosforilação , Purinas/farmacologia
15.
Breast Cancer Res Treat ; 175(1): 59-75, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30715658

RESUMO

PURPOSE: To identify a lncRNA signature to predict survival of breast cancer (BRCA) patients. METHODS: A total of 1222 BRCA case and control datasets were downloaded from the TCGA database. The weighted gene co-expression network analysis of differentially expressed mRNAs was performed to generate the modules associated with BRCA overall survival status and further construct a hub on competing endogenous RNA (ceRNA) network. LncRNA signatures for predicting survival of BRCA patients were generated using univariate survival analyses and a multivariate Cox hazard model analysis and validated and characterized for prognostic performance measured using receiver operating characteristic (ROC) curves. RESULTS: A prognostic score model of eight lncRNAs signature was identified as Prognostic score = (0.121 × EXPAC007731.1) + (0.108 × EXPAL513123.1) + (0.105 × EXPC10orf126) + (0.065 × EXPWT1-AS) + (- 0.126 × EXPADAMTS9-AS1) + (- 0.130 × EXPSRGAP3-AS2) + (0.116 × EXPTLR8-AS1) + (0.060 × EXPHOTAIR) with median score 1.088. Higher scores predicted higher risk. The lncRNAs signature was an independent prognostic factor associated with overall survival. The area under the ROC curves (AUC) of the signature was 0.979, 0.844, 0.99 and 0.997 by logistic regression, support vector machine, decision tree and random forest models, respectively, and the AUCs in predicting 1- to 10-year survival were between 0.656 and 0.748 in the test dataset from TCGA database. CONCLUSIONS: The eight-lncRNA signature could serve as an independent biomarker for prediction of overall survival of BRCA. The lncRNA-miRNA-mRNA ceRNA network is a good tool to identify lncRNAs that is correlated with overall survival of BRCA.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , RNA Longo não Codificante/genética , Idoso , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Estimativa de Kaplan-Meier , MicroRNAs/genética , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas , Interferência de RNA , RNA Mensageiro/genética , Curva ROC , Reprodutibilidade dos Testes
16.
Soft Matter ; 15(36): 7203-7210, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31475279

RESUMO

Cancer metastasis has been believed as a genetically programmed process that is commonly marked by biochemical signals. Here using extracellular matrix control of cellular mechanics, we establish that cellular force threshold can also mark in vitro metastatic phenotypic change and malignant transformation in HCT-8 cell colonies. We observe that for prolonged culture time the HCT-8 cell colonies disperse into individual malignant cells, and the metastatic-like dispersion depends on both cell-seeding gel stiffness and colony size. Cellular force microscopies show that gel stiffness and colony size are also two key parameters that modulate cellular forces, suggesting the correlations between the cellular forces and the metastatic phenotypic change. Using our recently developed biophysical model, we construct an extracellular traction phase diagram in the stiffness-size space, filled with experimental data on the colony behavior. From the phase diagram we identify a phase boundary as a traction force threshold above which the metastatic phenotypic transition occurs and below which the cell colonies remain cohesive. Our finding suggests that the traction threshold can be regarded as an effective mechano-marker for the onset of the metastatic-like dispersion and malignant transformation.


Assuntos
Transformação Celular Neoplásica/metabolismo , Células Epiteliais/metabolismo , Adesão Celular , Linhagem Celular Tumoral , Colo/citologia , Matriz Extracelular/metabolismo , Humanos , Mecanotransdução Celular , Modelos Biológicos , Fenótipo , Estresse Mecânico
17.
Metab Brain Dis ; 34(1): 93-101, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30280285

RESUMO

Gallic acid (3,4,5-trihydroxybenzoic acid) is a naturally occurring polyphenolic compound. Previous study has shown that gallic acid possessed significant antidepressant-like activity in mice, which was partly mediated by increasing serotonin and catecholamine levels. The main aim of the present study is to investigate the possible effects of gallic acid on brain-derived neurotrophic factor (BDNF) signaling activation. Mice were exposed to chronic mild stress (CMS) and orally administrated with gallic acid for four weeks. The behavioral results showed that gallic acid not only reversed the decreased sucrose preference, but also attenuated the increased immobility time. In addition, gallic acid promoted both the BDNF and p-TrkB levels in the hippocampus induced by CMS. Moreover, the results also demonstrated that the inactivated Akt-mTOR signaling pathway, as well as its downstream effectors induced by CMS was activated again by gallic acid. Last, immunofluorescence detection indicated that gallic acid reversed the newborn neurons inhibition in the dentate gyrus by CMS. In conclusion, these results show that the activation of the hippocampal BDNF-Akt-mTOR signaling is involved in the antidepressant-like effects of gallic acid.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ácido Gálico/farmacologia , Hipocampo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/metabolismo , Animais , Modelos Animais de Doenças , Hipocampo/metabolismo , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Serina-Treonina Quinases TOR
18.
Sensors (Basel) ; 19(18)2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31527482

RESUMO

Dissolved oxygen is an important index to evaluate water quality, and its concentration is of great significance in industrial production, environmental monitoring, aquaculture, food production, and other fields. As its change is a continuous dynamic process, the dissolved oxygen concentration needs to be accurately measured in real time. In this paper, the principles, main applications, advantages, and disadvantages of iodometric titration, electrochemical detection, and optical detection, which are commonly used dissolved oxygen detection methods, are systematically analyzed and summarized. The detection mechanisms and materials of electrochemical and optical detection methods are examined and reviewed. Because external environmental factors readily cause interferences in dissolved oxygen detection, the traditional detection methods cannot adequately meet the accuracy, real-time, stability, and other measurement requirements; thus, it is urgent to use intelligent methods to make up for these deficiencies. This paper studies the application of intelligent technology in intelligent signal transfer processing, digital signal processing, and the real-time dynamic adaptive compensation and correction of dissolved oxygen sensors. The combined application of optical detection technology, new fluorescence-sensitive materials, and intelligent technology is the focus of future research on dissolved oxygen sensors.

19.
Pharmazie ; 74(6): 321-325, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31138367

RESUMO

The non-structural protein 4B (NS4B) of hepatitis C virus (HCV) has emerged as a promising target for chronic hepatitis C treatment. The thieno[2,3-b]pyridine HCV inhibitor 2 has demonstrated properties as a NS4B inhibitor. Subsequent hybridization of 2 with our recently published imidazo[2,1-b]thiazole NS4B inhibitor 3 resulted in the discovery of several more potent compounds with sub-micromolar EC50 against HCV genotype 1b replicon. More importantly, the resistant profile study of the new synthesized HCV inhibitors illustrated that the bicyclic scaffold would mediate the resistance of H3R and Q26R mutations, while the piperazinone motif would mediate the resistance of H94R, F98C and V105M mutations, and the C3- amino group would disrupt the interaction between piperazinone motif and NS4B. This structure-resistance relationship detail could help us to develop new NS4B inhibitors with higher resistant barrier in the future.


Assuntos
Antivirais/química , Piridinas/química , Piridinas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Hepacivirus , Humanos , Replicação Viral/efeitos dos fármacos
20.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(1): 80-85, 2019 Feb 28.
Artigo em Zh | MEDLINE | ID: mdl-30837047

RESUMO

Objective To evaluate the value of serum aminoterminal pro-brain natriuretic peptide (NT-proBNP) and interleukin(IL)-6 levels in diagnosis and severity assessment of the preterm infants with respiratory distress syndrome(RDS).Methods Totally 150 preterm infants with RDS who were hospitalized in our center from August 2016 to March 2018 were enrolled in this study as the RDS group. These infants were further divided into grades 1,2,3,and 4 according to chest radiography. In addition,158 preterm infants without RDS hospitalized in our center during the same period were included as the controls (control group). Serum NT-proBNP and IL-6 levels were measured by ELISA on days 1,3,and 7 after birth,and their pulmonary arterial pressure (PAP) was monitored as well.Results Serum NT-proBNP and IL-6 levels in RDS group were significantly higher than those in control group on day 1 (t=-91.04,P=0.000;t=-11.03,P=0.000),day 3 (t=-89.10,P=0.000;t=-9.909,P=0.000),and day 7 (t=-87.91,P=0.000;t=-8.548,P=0.000). There were significant differences in NT-proBNP levels among grades 1,2,3,and 4 on day 1 (F=50.89,P=0.000),day 3 (F=49.16,P=0.000),and day 7 (F=45.45,P=0.000),showing an increasing trend. Serum IL-6 levels showed no significant difference among grades 1,2,3,and 4 on day 1 (F=0.89,P=0.448),day 3 (F=0.76,P=0.518),and day 7 (F=0.85,P=0.469). The PAP of the RDS group on days 1,3,and 7 was (49.3±3.7),(40.1±5.4),and (39.0±2.6)mmHg (1 mmHg=0.133 kPa),which were significantly higher than those of the control group (35.0±2.7)mmHg (t=-90.01,P=0.000),(30.0±3.1)mmHg (t=-81.90,P=0.000),(26.0±3.0)mmHg (t=-88.89,P=0.000). Thus,there was a positive correlation between NT-proBNP and IL-6 levels (r=0.876,P=0.000) and a positive correlation between NT-proBNP and PAP (r=0.916,P=0.000) in preterm infants with RDS.Conclusion Monitoring serum NT-proBN contributes to early diagnosis and disease severity assessment in preterm infants with RDS.


Assuntos
Síndrome do Desconforto Respiratório , Biomarcadores , Diagnóstico Precoce , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Interleucina-6 , Peptídeo Natriurético Encefálico , Fragmentos de Peptídeos
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