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BACKGROUND: Data regarding the performance of computational fractional flow reserve in patients with diabetes mellitus (DM) remain scarce. This study sought to explore the impact of DM on quantitative flow ratio (QFR) and its association with intravascular ultrasound (IVUS)-derived anatomical references.MethodsâandâResults: IVUS and QFR were retrospectively analyzed in 237 non-diabetic and 93 diabetic patients with 250 and 102 intermediate lesions, respectively. Diabetics were further categorized based on adequate (HbA1c <7.0%: 47 patients with 53 lesions) or poor (HbA1c ≥7.0%: 46 patients with 49 lesions) glycemic control. Lesions with QFR ≤0.8 or minimum lumen area (MLA) ≤4.0 mm2and plaque burden (PB, %) ≥70 were considered functionally or anatomically significant, respectively. PB increased, and MLA decreased stepwise across non-diabetics, diabetics with adequate glycemic control and those with poor glycemic control. In contrast, QFR was similar among the 3 groups. PB correlated significantly with the QFR for lesions in non-diabetics, but not for lesions in diabetics. DM was independently correlated with the functionally non-significant lesions (QFR >0.8) with high-risk IVUS features (MLA ≤4.0 mm2and PB ≥70; OR 2.053, 95% CI: 1.137-3.707, P=0.017). When considering the effect of glycemic control, HbA1c was an independent predictor of anatomical-functional discordance (OR 1.347, 95% CI: 1.089-1.667, P=0.006). CONCLUSIONS: Anatomical-functional discordance of intermediate coronary lesions assessed by IVUS and QFR is exacerbated in patients with diabetes, especially when glycemia is poorly controlled.
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Estenose Coronária , Diabetes Mellitus , Reserva Fracionada de Fluxo Miocárdico , Humanos , Angiografia Coronária/métodos , Estudos Retrospectivos , Hemoglobinas Glicadas , Ultrassonografia de Intervenção/métodos , Diabetes Mellitus/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Valor Preditivo dos Testes , Índice de Gravidade de DoençaRESUMO
To investigate the mechanism of action of inflammatory molecules regulating the tumor microenvironment and anti-tumor through Yifei Qinghua granules and phloroglucinol-containing serum intervening in the changes of tumor microenvironment in vitro in the co-culture of lung cancer cells and bone marrow cells. A549 lung adenocarcinoma cell line and ST2 bone marrow stromal cell line were selected and a transwell chamber was used to establish the co-culture system of the two kinds of cells. They were divided into normal saline, phloroglucinol, Qifei Qinghua granule, and phloroglucinol + Yifei Qinghua granule groups. They were given drug-containing serum interventions respectively. A549 cells and ST2 cells cultured separately were used as control. Flow cytometry was used to detect the proportions of MDSCs and Tregs in bone marrow cells of ST2 cells. ELISA was used to detect the levels of inflammatory factors in the culture supernatant. Western blot was used to detect the expressions of inflammatory pathways in A549 and ST2 cells. ST2 cells and A549 cells were co-cultured. The ratio of MDSCs and Treg in ST2 cells was increased. The levels of some inflammatory factors in the culture supernatant were increased. The expression level of the inflammatory pathway in ST2 cells was increased. However, the expression level of the inflammatory pathway in A549 cells had no obvious change. While Yifei Qinghua granule and phloroglucinol could partially reverse these changes. The combination of the two was more effective than a single drug. The conversion of cells to MDSCs and Treg was accelerated after the co-culture of ST2 cells and A549 cells. The combination of Yifei Qinghua granules with phloroglucinol can reshape the tumor microenvironment, prevent this phenomenon from occurring, reduce inflammatory secretion and inhibit tumor cell growth. This may be related to the inhibition of the expressions of TNF-α/IL-1- and NF-κB/STAT3 inflammatory pathways.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Microambiente Tumoral , Proteína 1 Semelhante a Receptor de Interleucina-1 , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma de Pulmão/tratamento farmacológico , Células A549RESUMO
Seven in absentia homolog 1 (Siah1) has been shown plays important roles in the pathogenesis and development of multiple cancers. However, the functions and mechanisms of Siah1 in non-small cell lung cancer (NSCLC) remain unclear. In our study, we found that knock down of Siah1 could inhibit the proliferation of NSCLC cells, while over-expression of Siah1 had the opposite effects. Molecularly, the bioinformatics analysis determined that notch receptor 1 (Notch1) might be the potential target of Siah1. Subsequently, we identified that Siah1 acted as an E3 ligase to promote the ubiquitination and stabilization of Notch1 through the proteasome pathway. Furthermore, the results showed that the Siah1 expression was directly correlated with CTR9 in human NSCLC tissues. Finally, Siah1 could promote Akt phosphorylation through regulating Notch1, thus promoting the proliferation of NSCLC cells. In conclusion, our study demonstrated that Siah1 acts as an oncogene, can ubiquitinate and stabilize Notch1 by proteasome pathway, which promotes Akt phosphorylation and ultimately leads to NSCLC cell proliferation.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Proteínas Nucleares/metabolismo , Receptor Notch1/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Complexo de Endopeptidases do Proteassoma , Proteínas Proto-Oncogênicas c-aktRESUMO
This study sought to investigate the dynamic functional changes of coronary intermediate lesions using quantitative flow ratio (QFR) and its implication on long-term clinical outcomes. Physiology-guided percutaneous coronary intervention in patients with angiographic intermediate lesions has been associated with favorable outcomes. This study consecutively enrolled 1130 patients with deferred intermediate lesions at baseline angiography and subsequently received second-time angiography between 9 months and 2 years later from two centers in China. The functional changes of intermediate lesions at angiographic follow-up (ΔQFR) were defined as (baseline QFR-follow-up QFR)/years. The primary outcome was vessel-oriented composite endpoint (VOCE), defined as the composite of vessel-related cardiac death, vessel-related myocardial infarction (MI), and ischemia-driven target vessel revascularization (ID-TVR) at angiographic follow-up for up to 5 years. Retrospective QFR assessment was available in 820 patients (996 intermediate lesions). QFR ≤ 0.80 at second-time angiography was associated with significantly higher 5-year VOCE (41.9% vs. 13.4%, p < 0.0001). In 777 intermediate lesions with baseline QFR > 0.80, mean ΔQFR was 0.03 ± 0.07 (median: 0.006; Q1: 0; and Q3: 0.04). The optimal cutoff of ΔQFR for predicting the primary outcome was 0.03 (area under the curve [AUC]: 0.68). The cumulative event rate of VOCE in patients with ΔQFR ≥ 0.03 was significantly higher than in those with ΔQFR < 0.03 (33.8% vs. 12.2%, p < 0.0001), driven by higher vessel-related MI and ID-TVR. The ΔQFR was a useful tool for evaluating the dynamic functional change of deferred intermediate lesions, as it demonstrates good prognostic value for long-term target vessel-related adverse events.
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Doença da Artéria Coronariana , Estenose Coronária , Reserva Fracionada de Fluxo Miocárdico , Intervenção Coronária Percutânea , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/terapia , Vasos Coronários , Humanos , Intervenção Coronária Percutânea/efeitos adversos , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Treatment of coronary intermediate lesions remains a controversy, and the role of arterial remodeling patterns determined by intravascular ultrasound in intermediate lesion is still not well known. The aim of this study was to investigate the impact of arterial remodeling of intermediate coronary lesions on long-term clinical outcomes. METHODS: Arterial remodeling patterns were assessed in 212 deferred intermediate lesions from 162 patients after IVUS examination. Negative, intermediate, and positive remodeling was defined as a remodeling index of <0.88, 0.88â¼1.0, and >1.0, respectively. The primary endpoint was the composite vessel-oriented clinical events, defined as the composition of target vessel-related cardiac death, target vessel-related myocardial infarction, and target vessel revascularization. Quantitative flow ratio was assessed for evaluating the functional significance of intermediate lesions. RESULTS: 72 intermediate remodeling lesions were present in 66 patients, whereas 77 negative remodeling lesions were present in 71 patients, and 63 positive remodeling lesions were present in 55 patients. Negative remodeling lesions had the smallest minimum lumen area (4.16 ± 1.03 mm2 vs. 5.05 ± 1.39 mm2 vs. 4.85 ± 1.76 mm2; P < 0.01), smallest plaque burden (63.45 ± 6.13% vs. 66.12 ± 6.82% vs. 71.17 ± 6.45%; P < 0.01), and highest area stenosis rate (59.32% ± 10.15% vs. 54.61% ± 9.09% vs. 51.67% ± 12.96%; P < 0.01). No significant difference was found in terms of quantitative flow ratio among three groups. At 5 years follow-up, negative remodeling lesions had a higher rate of composite vessel-oriented clinical event (14.3%), compared to intermediate (1.4%, P=0.004) or positive remodeling lesions (4.8%, P=0.06). After adjusting for multiple covariates, negative remodeling remained an independent determinant for vessel-oriented clinical event (HR: 4.849, 95% CI 1.542-15.251, P=0.007). CONCLUSION: IVUS-derived negative remodeling is associated with adverse long-term clinical outcome in stable patients with intermediate coronary artery stenosis.
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Doença da Artéria Coronariana/epidemiologia , Vasos Coronários/diagnóstico por imagem , Infarto do Miocárdio/epidemiologia , Revascularização Miocárdica/estatística & dados numéricos , Ultrassonografia de Intervenção , Remodelação Vascular , Idoso , Velocidade do Fluxo Sanguíneo , Doença da Artéria Coronariana/terapia , Estenose Coronária/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica/diagnóstico por imagem , Estudos RetrospectivosRESUMO
Cyclization of propargylamines with CO2 to obtain 2-oxazolidone heterocyclic compounds is an essential reaction in industry but it is usually catalyzed by noble-metal catalysts with organic bases as co-catalysts under harsh conditions. We have synthesized a unique CuI /CuII mixed valence copper-based framework {[(CuI 6 I5 )Cu3 II L6 (DMA)3 ](NO3 )â 9DMA}n (1) with good solvent and thermal stability, as well as a high density of uncoordinated amino groups evenly distributed in the large nanoscopic channels. Catalytic experiments show that 1 can effectively catalyze the reaction of propargylamines with CO2 , and the yield can reach 99 %. The turnover frequency (TOF) reaches a record value of 230â h-1 , which is much higher than that of reported noble-metal catalysts. Importantly, this is the first report of heterogeneously catalyzed green conversion of propargylamines with CO2 without solvents and co-catalysts under low temperature and atmospheric pressure. A mechanistic study reveals that a triply synergistic catalytic effect between CuI /CuII and uncoordinated amino groups promotes highly efficient and green conversion of CO2 . Furthermore, 1 directly catalyzes this reaction with high efficiency when using simulated flue gas as a CO2 source.
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BACKGROUND: Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor has become the standard of care to reduce thrombotic events in patients with acute coronary syndrome or after percutaneous coronary intervention (PCI). The role of routine platelet function testing (PFT) in patients treated with DAPT after PCI remains controversial and evidence of PFT-guided antiplatelet therapy for patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI is limited. METHODS: We analyzed 1,353 consecutive STEMI patients undergoing primary PCI. PFT was performed 72 hr postprocedure using a vasodilator-stimulated phosphoprotein assay. The primary endpoint of major adverse cardio-cerebral events (MACCEs) was defined as a composite of all-cause death, cardiac death, nonfatal myocardial infarction, target vessel revascularization, and ischemic stroke. Patients with high platelet reactivity (HPR) were randomized to receive an intensified antiplatelet strategy by switching from clopidogrel to ticagrelor (HPR switch group) or to continue on clopidogrel (HPR nonswitch group). One-year clinical outcomes were compared among the groups. RESULTS: The baseline clinical characteristics were comparable across all groups (all p > .05). At the 1-year clinical follow-up, the primary endpoint of MACCE was significantly higher in the HPR nonswitch group than in the non-HPR and HPR switch groups (19.49% vs. 10.20% or 8.57%, p < .05), which was mainly caused by higher mortality (14.87% vs. 4.51% or 5.71%, p < .05). Major bleeding events were comparable across the groups. CONCLUSIONS: In STEMI patients with HPR, identified by vasodilator stimulated phosphoprotein (VASP)-determined PFT, switching clopidogrel to ticagrelor could significantly improve 1-year clinical outcomes without increasing the risk of bleeding.
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Plaquetas/efeitos dos fármacos , Terapia Antiplaquetária Dupla , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária/administração & dosagem , Testes de Função Plaquetária , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Idoso , Aspirina/administração & dosagem , Biomarcadores/sangue , Plaquetas/metabolismo , Moléculas de Adesão Celular/sangue , China , Clopidogrel/administração & dosagem , Substituição de Medicamentos , Terapia Antiplaquetária Dupla/efeitos adversos , Terapia Antiplaquetária Dupla/mortalidade , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Proteínas dos Microfilamentos/sangue , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/mortalidade , Fosfoproteínas/sangue , Inibidores da Agregação Plaquetária/efeitos adversos , Valor Preditivo dos Testes , Estudos Prospectivos , Recidiva , Medição de Risco , Fatores de Risco , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Ticagrelor/administração & dosagem , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Patent ductus arteriosus (PDA) complicated by Eisenmenger syndrome (ES) remains to be a major cause of morbidity and mortality worldwide. Giving increasing evidences of benefit from targeted therapies, ES patients once thought to be inoperable may have increasing options for management. This study aims to explore whether PDA in patients with ES can be treated with transcatheter closure (TCC). METHODS: Between August 2014 and July 2016, four of fifteen PDA-ES patients whose Qp/Qs improved significantly and Qp/Qs > 1.5 after acute vasodilator testing with 100% oxygen were selected to receive TCC and pulmonary vasodilator therapy. PAH-targeted drugs were prescribed before and after occlusion for all. Trial occlusion was performed before permanent closure. RESULTS: The first TCC failed after initiation of PAH-targeted drugs for 6 months in four patients. After the medication was adjusted and extended to 12 months, TCC was performed for all without hemodynamic intolerances during perioperative period. Pulmonary artery systolic pressure (PASP) was significantly decreased (≥ 40%) immediately after TCC. During a mean follow-up of 48 ± 14.70 months, there were a further decrease of PASPs in two patients, the other two showed improved pulmonary vascular resistance, WHO functional class and six-minute walking distance despite deteriorated PASP. CONCLUSION: Some selected PDA-ES patients might benefit from TCC and combined PAH-targeted drugs play a crucial role.
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Anti-Hipertensivos/uso terapêutico , Pressão Arterial/efeitos dos fármacos , Cateterismo Cardíaco , Permeabilidade do Canal Arterial/terapia , Complexo de Eisenmenger/terapia , Artéria Pulmonar/efeitos dos fármacos , Vasodilatadores/uso terapêutico , Adulto , Anti-Hipertensivos/efeitos adversos , Cateterismo Cardíaco/efeitos adversos , Terapia Combinada , Quimioterapia Combinada , Permeabilidade do Canal Arterial/diagnóstico por imagem , Permeabilidade do Canal Arterial/fisiopatologia , Complexo de Eisenmenger/diagnóstico por imagem , Complexo de Eisenmenger/fisiopatologia , Feminino , Humanos , Masculino , Artéria Pulmonar/fisiopatologia , Recuperação de Função Fisiológica , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Vasodilatadores/efeitos adversos , Adulto JovemRESUMO
Allograft interstitial fibrosis was characterized by massive extracellular matrix deposition caused by activated fibroblasts and myofibroblasts. Epithelial-mesenchymal transition (EMT) is recognized as an important source of myofibroblasts contributing to the pathogenesis of allograft interstitial fibrosis. Smad ubiquitination regulatory factor 1 (Smurf1) has been recently reported to be involved in the progression of EMT. Our study was to detect the effect of Bortezomib and Smurf1 in the EMT and allograft interstitial fibrosis. Biomarkers of EMT, as well as Smurf1, were examined in human proximal tubular epithelial cells (HK-2) treated with tumour necrosis factor-alpha (TNF-α) in various doses or at various time points by Western Blotting or qRT-PCR. We knockdown or overexpressed Smurf1 in HK-2 cells. Furthermore, rat renal transplant model was established and intervened by Bortezomib. Allograft tissues from human and rats were also collected and prepared for HE, Masson's trichrome, immunohistochemical staining and western blotting assays. As a result, we found that TNF-α significantly promoted the development of EMT in a time-dependent and dose-dependent manner through Smurf1/Akt/mTOR/P70S6K signalling pathway. More importantly, Bortezomib alleviated the progression of EMT and allograft interstitial fibrosis in vivo and in vitro by inhibiting the production of TNF-α and expression of Smurf1. In conclusion, Smurf1 plays a critical role in the development of EMT induced by TNF-α. Bortezomib can attenuate the Sumrf1-mediated progression of EMT and renal allograft interstitial fibrosis, which could be suggested as a novel choice for the prevention and treatment of renal allograft interstitial fibrosis.
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Bortezomib/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibrose/tratamento farmacológico , Nefropatias/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular , Fibrose/metabolismo , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Nefropatias/metabolismo , Transplante de Rim/métodos , Masculino , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Nerve guidance conduits (NGCs) are tubular tissue engineering scaffolds used for nerve regeneration. The poor mechanical properties and porosity have always compromised their performances for guiding and supporting axonal growth. Therefore, in order to improve the properties of NGCs, the computational design approach was adopted to investigate the effects of different NGC structural features on their various properties, and finally, design an ideal NGC with mechanical properties matching human nerves and high porosity and permeability. Three common NGC designs, namely hollow luminal, multichannel, and microgrooved, were chosen in this study. Simulations were conducted to study the mechanical properties and permeability. The results show that pore size is the most influential structural feature for NGC tensile modulus. Multichannel NGCs have higher mechanical strength but lower permeability compared to other designs. Square pores lead to higher permeability but lower mechanical strength than circular pores. The study finally selected an optimized hollow luminal NGC with a porosity of 71% and a tensile modulus of 8 MPa to achieve multiple design requirements. The use of computational design and optimization was shown to be promising in future NGC design and nerve tissue engineering research.
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BACKGROUND: Plant viruses in agricultural crops are of great concern worldwide, and over 75% of them are transmitted from infected to healthy plants by insect vectors. Tomato yellow leaf curl virus (TYLCV) is a begomovirus, which is the largest and most economically important group of plant viruses, transmitted by the whitefly Bemisia tabaci. The circulation of TYLCV in the insect involves complex insect-virus interactions, whereas the molecular mechanisms of these interactions remain ambiguous. The insect gut as a barrier for viral entry and dissemination is thought to regulate the vector specificity. However, due to its tiny size, information for the responses of whitefly gut to virus infection is limited. METHODS: We investigated the transcriptional response of the gut of B. tabaci Middle East-Asia Minor 1 species to TYLCV infection using Illumina sequencing. RESULTS: A total of 5207 differentially expressed genes (DEGs) between viruliferous and non-viruliferous whitefly guts were identified. Enrichment analyses showed that cargo receptor and ATP-binding cassette (ABC) transporters were enriched in DEGs, and might help the virus to cross gut barrier. TYLCV could perturb cell cycle and DNA repair as a possible result of its replication in the whitefly. Our data also demonstrated that TYLCV can activate whitefly defense responses, such as antimicrobial peptides. Meanwhile, a number of genes involved in intracellular signaling were activated by TYLCV infection. CONCLUSIONS: Our results reveal the complex insect-virus relationship in whitefly gut and provide substantial molecular information for the role of insect midguts in virus transmission.
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Begomovirus , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/virologia , Hemípteros/genética , Hemípteros/virologia , Interações Hospedeiro-Patógeno/genética , Transcriptoma , Animais , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Ontologia Genética , Sequenciamento de Nucleotídeos em Larga Escala , Anotação de Sequência Molecular , Vírus de Plantas , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Surgical approaches for Chiari malformation type I (CM-I) complicated with syringomyelia (SM) are controversial, so we assessed the efficacy and safety of two widely used procedures. METHODS: We retrospectively analyzed results from posterior fossa decompression (PFD) using bony decompression with dura-splitting or a combined technique (duraplasty with arachnoid dissection and coagulation of the herniated tonsils) for CM-I associated with SM between Jan 2008 and Feb 2016. Patients were followed up for at least one year. General data, primary outcomes (symptom improvement, syrinx reductions, and complications) and secondary outcomes (operating time, blood loss, postoperative hospital stay) for each procedure were compared. RESULTS: Of the 49 patients treated, 17 had dura-splitting decompression and 32 had the combined technique. There were no significant differences in general data. The combined technique was significantly superior to dura-splitting for long-term syrinx reductions (length, 100.03 ± 44.79 vs 72.73 ± 34.79 mm, p = 0.040; diameter, 8.09 ± 3.46 vs 5.73 ± 3.02 mm, p = 0.026) and symptom improvement (75.00% vs 47.06%, p = 0.036). No postoperative complications occurred during dura-splitting cases; however, complications occurred in 9 combined technique cases (31.25%, p = 0.010) and surgical time was longer for the combined technique (248.03 ± 60.12 vs 167.94 ± 60.11 min, p < 0.001). CONCLUSIONS: The combined technique improved long-term symptoms and reduced syringes compared to dura-splitting; however, postoperative complications are more likely.
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Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective therapy for children with high-risk acute lymphoblastic leukemia (ALL). Human leukocyte antigen (HLA)-haploidentical HSCT (haplo-HSCT) or umbilical cord blood transplantation (UCBT) are both important alternative sources of stem cells for those without an HLA-identical sibling donor or unrelated matched donor. We aimed to compare the therapeutic effects of single UCBT and unmanipulated haplo-HSCT in high-risk ALL children (n = 129). Hematopoietic recovery was significantly faster in haplo-HSCT recipients than in UCBT recipients. The 2-year cumulative incidences of relapse in the haplo-HSCT and UCBT groups were 16.1% and 24.1%, respectively (p = 0.169). The 2-year cumulative incidences of non-relapse mortality in the haplo-HSCT and UCBT groups were 12.8% and 18.8%, respectively (p = 0.277). The 2-year probabilities of overall survival in the haplo-HSCT and UCBT groups were 82.0% and 69.6%, respectively (p = 0.071), and the 2-year probability of disease-free survival in the haplo-HSCT group was higher than in the UCBT group (71.0% vs. 57.2%, p = 0.040). However, several variables (such as leukocyte count and cytogenetics at diagnosis) were different between the groups, and a possible center effect should also be considered. In addition, only mild and moderate chronic graft-versus-host disease (GVHD) was associated with significantly improved survival compared to those without chronic GVHD in multivariate analysis. Thus, our results show that both unmanipulated haplo-HSCT and UCBT are valid for high-risk ALL children lacking a HLA matched donor, and both strategies expand the donor pool for children in need.
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Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Doença Enxerto-Hospedeiro/epidemiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Recidiva Local de Neoplasia/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Recidiva , Análise de Sobrevida , Resultado do TratamentoRESUMO
This research is to study the electrical stimulation characteristics of orbicularis oculi muscle and the characteristics of the mechanical contraction. We observed the stimulus current diffusion regularity and its relationship with mechanical contraction in the orbicularis oculi muscle using an electrode gathering line. Under different stimulus intensities of 2 or 4 mA, the closer the recording electrodes were to the stimulating electrode, the larger was the amplitude. When the recording electrode and stimulating electrode distance increased, the amplitude declined linearly with decreasing function. In addition, current conduction across the muscle fiber was studied. Under different stimulus intensities of 2 or 4 mA, it was found that the closer the recording electrodes were to the stimulating electrode, the larger was the amplitude. When the recording electrode and stimulating electrode distance increased, the amplitude declined linearly with decreasing function. The transverse current reached a maximum 4 mA range, and increasing the current intensity did not increase the propagation range. Under different stimulation intensities, the larger the stimulus intensity, the greater is the potential change and the faster is the attenuation. Longitudinal current, even in the range of 6 mm, can still record electrical activity. While a transverse current diffuser has a maximum range of 4 mm, increasing the current intensity does not increase the propagation range.
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Estimulação Elétrica , Músculos Faciais/fisiopatologia , Traumatismos do Nervo Facial/fisiopatologia , Animais , Biofísica , Modelos Animais de Doenças , Eletrodos Implantados , Eletromiografia , Potencial Evocado Motor/fisiologia , Traumatismos do Nervo Facial/patologia , Feminino , Masculino , CoelhosRESUMO
The therapeutic goal of cancer treatment is now geared towards triggering tumour-selective cell death with autophagic cell death being required for the chemotherapy of apoptosis-resistant cancer. In this study, Carnosic acid (CA), a polyphenolic diterpene isolated from Rosemary (Rosemarinus officinalis), significantly induced autophagic cell death in HepG2 cells. Ca treatment caused the formation of autophagic vacuoles produced an increasing ratio of LC3-II to LC3-I in a time- and dose-dependent manner but had no effect on the levels of autophagy-related protein ATG6 and ATG13 expression. Autophagy inhibitors, 3-methyladenine (3-MA), chloroquine and bafilomycin A1, or ATG genes silencing in HepG2 cells significantly inhibited CA-induced autophagic cell death. The CA treatment decreased the levels of phosphorylated Akt and mTOR without any effects on PI3K or PTEN. Most importantly, overexpression of Akt and knockdown of PTEN attenuated autophagy induction in CA-treated cells. Taken together, our results indicated that CA induced autophagic cell death through inhibition of the Akt/mTOR pathway in human hepatoma cells. These findings suggest that CA has a great potential for the treatment of hepatoma via autophagic induction.
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Abietanos/efeitos adversos , Autofagia/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Extratos Vegetais/efeitos adversos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adenina/análogos & derivados , Adenina/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células , Cloroquina/farmacologia , Inativação Gênica , Células Hep G2 , Humanos , Macrolídeos/farmacologia , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
OBJECTIVE: Although hypertension is the most common risk factor for thoracic aortic diseases, it is not understood how increased pressures on the ascending aorta lead to aortic aneurysms. We investigated the role of angiotensin II type 1 receptor activation in ascending aortic remodeling in response to increased biomechanical forces using a transverse aortic constriction (TAC) mouse model. APPROACH AND RESULTS: Two weeks after TAC, the increased biomechanical pressures led to ascending aortic dilatation and thickening of the medial and adventitial layers of the aorta. There was significant adventitial hyperplasia and inflammatory responses in TAC ascending aortas were accompanied by increased adventitial collagen, elevated inflammatory and proliferative markers, and increased cell density attributable to accumulation of myofibroblasts and macrophages. Treatment with losartan significantly blocked TAC-induced vascular inflammation and macrophage accumulation. However, losartan only partially prevented TAC-induced adventitial hyperplasia, collagen accumulation, and ascending aortic dilatation. Increased Tgfb2 expression and phosphorylated-Smad2 staining in the medial layer of TAC ascending aortas were effectively blocked with losartan. In contrast, the increased Tgfb1 expression and adventitial phospho-Smad2 staining were only partially attenuated by losartan. In addition, losartan significantly blocked extracellular signal-regulated kinase activation and reactive oxygen species production in the TAC ascending aorta. CONCLUSIONS: Inhibition of the angiotensin II type 1 receptor using losartan significantly attenuated the vascular remodeling associated with TAC but did not completely block the increased transforming growth factor-ß1 expression, adventitial Smad2 signaling, and collagen accumulation. These results help to delineate the aortic transforming growth factor-ß signaling that is dependent and independent of the angiotensin II type 1 receptor after TAC.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Anti-Hipertensivos/farmacologia , Aorta/efeitos dos fármacos , Aneurisma da Aorta Torácica/prevenção & controle , Hipertensão/tratamento farmacológico , Losartan/farmacologia , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Animais , Aorta/metabolismo , Aorta/patologia , Aorta/fisiopatologia , Aorta/cirurgia , Aneurisma da Aorta Torácica/etiologia , Aneurisma da Aorta Torácica/metabolismo , Aneurisma da Aorta Torácica/patologia , Aneurisma da Aorta Torácica/fisiopatologia , Pressão Arterial , Fenômenos Biomecânicos , Colágeno/metabolismo , Constrição , Dilatação Patológica , Modelos Animais de Doenças , Ecocardiografia Doppler , Hipertensão/complicações , Hipertensão/metabolismo , Hipertensão/patologia , Hipertensão/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor Tipo 1 de Angiotensina/metabolismo , Proteína Smad2/metabolismo , Fatores de Tempo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
BACKGROUND: Lung cancer is one of the leading causes of cancer-related mortality worldwide. Conventional chemotherapy and radiotherapy are the primary therapeutic methods for lung cancer with the use of combination therapies gaining popularity. The frequency and duration of treatment, as well as, managing lung cancer by targeting multiple aspects of cancer biology is often limited by toxicity to the patient. There are many naturally occurring anticancer agents that have a high degree of efficacy and low toxicity, offering a viable and safe approach for the treatment of lung cancer. The herbs traditionally used in Chinese medicine for anticancer treatment offer great potential to enhance the efficacy of conventional therapy. In this study, we evaluated the synergistic effects of Fei-Liu-Ping (FLP) ointment in treating lung cancer; a known anticancer Chinese herbal based formula. METHODS: In this study, A549 human lung carcinoma cell line and Lewis lung carcinoma xenograft mouse model were used. In addition, we utilized an in vitro co-culture system to simulate the tumor microenvironment in order to evaluate the molecular mechanisms of FLP treatment. RESULTS: FLP treatment significantly inhibited tumor growth in the Lewis lung xenograft by 40 percent, compared to that of cyclophosphamide (CTX) of 62.02 percent. Moreover, combining FLP and CTX inhibited tumor growth by 83.23 percent. Upon evaluation, we found that FLP treatment reduced the concentration of serum pro-inflammatory cytokines IL-6, TNF-α, and IL-1ß. In addition, we also found an improvement in E-cadherin expression and inhibition of N-cadherin and MMP9. We found similar findings in vitro when we co-cultured A549 cells with macrophages. FLP treatment inhibited A549 cell growth, invasion and metastasis, in part, through the regulation of NF-κB and altering the expression of E-cadherin, N-cadherin, MMP2 and MMP9. CONCLUSIONS: FLP exerts anti-inflammatory properties in the tumor microenvironment, which may contribute to its anticancer effects. FLP treatment may be a promising therapy for inflammation associated lung cancer treatment alone, or in combination with conventional therapies and may prevent lung cancer metastasis.
Assuntos
Antineoplásicos/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Inflamação/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Caderinas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Interleucina-6/metabolismo , Macrófagos , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Pomadas , Fator de Necrose Tumoral alfa/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
N-Acyl-4-phenylthiazole-2-amines were designed and synthesized, moreover their effects on acetylcholinesterase activities were tested. N-Acyl-4-phenylthiazole-2-amines were prepared from substituted 2-bromo-1-acetophenones by three steps reaction, and their AChE inhibitory activities were measured by Ellman method in vitro. The results showed that the target compounds had a certain inhibitory activity on AChE in vitro. Among them, 8c was the best, and IC50 of 8c was 0.51 micromol x L(-1), better than that of rivastigmine and Huperzine-A. The inhibitory activities of N-acyl-4-phenylthiazole-2-amines on acetylcholinesterase are worth while to be further studied.
Assuntos
Aminas/farmacologia , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Tiazóis/farmacologia , Acetilcolinesterase/metabolismo , Alcaloides/farmacologia , Aminas/síntese química , Inibidores da Colinesterase/síntese química , Rivastigmina/farmacologia , Sesquiterpenos/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of novel N-acyl-thiochromenothiazol-2-amine derivatives were designed and synthesized, furthermore, their inhibition effect on acetylcholinesterase was investigated. N-Acyl-thiochromenothiazol-2-amines were prepared from thiophenol by Hantzsch reaction, acylation reaction and substitution reaction. Moreover, their bioactivities as AChE inhibitors in vitro were measured with Ellman spectrophotometry. The results showed that most of them had a certain inhibition activity on AChE, and the compound 10a was the best in them. The IC50 of 10a to AChE is 7.92 µmol x L(-1), and the value is better than that of rivastigmine. N-Acyl-thiochromenothiazol-2-amine derivatives showed a certain bioactivity in vitro, which were worth further investigation.
Assuntos
Aminas/farmacologia , Benzopiranos/síntese química , Benzopiranos/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Tiazóis/síntese química , Tiazóis/farmacologia , Acetilcolinesterase/metabolismo , Aminas/síntese química , Rivastigmina , Relação Estrutura-AtividadeRESUMO
A series of novel 2-amino-4-phenylthiazole derivatives were designed and synthesized, furthermore, their inhibition effect on acetylcholinesterase were investigated. 2-Amino-4-phenylthiazoles were prepared from alpha-bromoacetophenones by Hantzsch reaction, acylation reaction and substitution reaction. Moreover, their bioactivities as AChE inhibitors in vitro were measured with Ellman spectrophotometry. The results showed that most of them had a certain inhibition activity on AChE, and the compound 8a was the best of them. The IC50 of 8a to AChE is 3.54 micromol x L(-1), and the value was better than that of rivastigmine. 2-Amino-4-phenylthiazole derivatives showed a certain bioactivity in vitro, which were worth further investigation.