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BACKGROUND: Minimal residual disease (MRD) is an important prognostic factor for survival in adults with acute leukemia. The role of pretransplantation MRD status in myelodysplastic syndrome with excess blasts (MDS-EB) is unknown. This study retrospectively analyzed the relationship between pretransplantation MRD status and long-term survival. MATERIALS AND METHODS: Patients with MDS-EB who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) from March 5, 2005, to November 8, 2020, were included. The relationship between pretransplantation MRD status and long-term survival was analyzed using univariate and multivariate logistic regression models. RESULTS: Of 220 patients with MDS-EB who underwent allo-HSCT, 198 were eligible for inclusion in this multicenter, retrospective cohort study. Complete remission was attained in 121 (61.1%) patients, and 103 patients underwent detection of MRD pretransplantation, with 67 patients being MRD-positive and 36 patients being MRD-negative. The median follow-up time was 16 months, the median age was 41 years (6-65 years), and 58% of the patients were men. The 3-year disease-free survival (DFS) and overall survival (OS) probabilities for all patients were 70.1% and 72.9%, respectively. For patients in complete remission, the 3-year DFS and OS probabilities were 72.2% and 74.8%, respectively. Further analysis found that the 3-year DFS rates of MRD-negative and MRD-positive patients were 85.6% and 66.5% (p = .045), respectively, whereas the 3-year OS rates were 91.3% and 66.4% (p = .035), respectively. Univariate and multivariate analyses showed that poor pretransplantation MRD clearance was an independent prognostic risk factor for DFS and OS. CONCLUSION: Poor pretransplantation MRD clearance is an independent prognostic risk factor for long-term survival after allo-HSCT for patients with MDS-EB. PLAIN LANGUAGE SUMMARY: Poor minimal residual disease clearance pretransplanation is an independent prognostic risk factor for long-term survival after allogeneic hematopoietic stem cell transplantation for patients with myelodysplastic syndrome with excess blasts.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Adulto , Masculino , Humanos , Feminino , Prognóstico , Estudos Retrospectivos , Neoplasia Residual/diagnóstico , Síndromes Mielodisplásicas/terapia , Fatores de RiscoRESUMO
INTRODUCTION: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the standard and curative treatment strategy for patients with hematologic malignancies. Recently, decitabine-included regimens have been investigated by several studies including ours, which may prevent relapse of primary malignant diseases. METHODS: This study was to retrospectively evaluate a 7-day decitabine-included regimen with reduced dose of idarubicin for patients with hematologic malignancies who underwent allo-HSCT. RESULTS: A total of 84 patients were enrolled, including 24 cases in 7-day and 60 cases in 5-day decitabine groups, respectively. Patients conditioned with 7-day decitabine regimen showed accelerated neutrophil (12.05 ± 1.97 vs. 13.86 ± 3.15; u = 9.309, p < 0.001) and platelet (16.32 ± 6.27 vs. 21.37 ± 8.57; u = 8.887, p < 0.001) engraftment compared with those treated with 5-day decitabine regimen. Patients in the 7-day decitabine group showed a significantly lower incidence rate of total (50.00% [12/24] versus 78.33% [47/60]; χ2 = 6.583, p = 0.010) and grade III or above (4.17% [1/24] vs. 31.67% [19/60]; χ2 = 7.147, p = 0.008) oral mucositis compared to those in the 5-day decitabine group. However, the occurrence of other major complications post-allo-HSCT and outcomes of patients in these two groups were comparable. CONCLUSION: These results demonstrate that this 7-day decitabine-contained new conditioning regimen seems to be feasible and safe for patients with myeloid neoplasms who receive allo-HSCT, and a large-scale prospective study is needed to confirm the findings of this study.
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Doença Enxerto-Hospedeiro , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Mucosite , Humanos , Decitabina/efeitos adversos , Mucosite/complicações , Estudos Retrospectivos , Recidiva Local de Neoplasia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/complicações , Prognóstico , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Doença Enxerto-Hospedeiro/etiologiaRESUMO
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for patients with myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). However, post-HSCT relapse remains a major cause of treatment failure. Here we assessed the efficacy of a new conditioning regimen comprising decitabine (Dec), busulfan (Bu), cyclophosphamide (Cy), fludarabine (Flu), and cytarabine (Ara-c) for allo-HSCT in patients with MDS and MDS/MPN. A total of 48 patients were enrolled, including 44 with MDS and 4 with chronic myelomonocytic leukemia (CMML). Patients received Dec 20 mg/m2/day on days -9 to -5, combined with a Bu/Cy/Flu/Ara-c-modified preparative regimen. At a median follow-up of 522 days (range, 15 to 1313 days), the overall survival (OS) was 86%, relapse incidence was 12%, and nonrelapse mortality was 12%. The incidence of severe acute (grade III-IV) graft-versus-host disease (GVHD) was 23% and that of chronic GVHD was 15%. At 2 years, OS was 74% and 86%, respectively for high-risk and very-high-risk patients with MDS. Survival was promising in patients with poor-risk gene mutations, such as TP53 and ASXL1 (88%), and in those with ≥3 gene mutations (79%). Results of immunomonitoring studies revealed that proper natural killer cells made essential contributions to these favorable clinical outcomes. Overall, this new regimen was associated with a low relapse rate, low incidence and severity of GVHD, and satisfactory survival in allo-HSCT recipients with MDS and MDS/MPN.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Bussulfano/uso terapêutico , Decitabina/uso terapêutico , Doença Enxerto-Hospedeiro/etiologia , Humanos , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Condicionamento Pré-Transplante , Transplante HomólogoRESUMO
The generalized oscillator strengths of the low-lying valence-shell excitations of N2, O2, and C2H2 have been studied by the high-energy electron scattering, the high-resolution inelastic X-ray scattering, and the multireference single- and double-excitation configuration-interaction methods. Good agreement between the present electron-scattering results and the X-ray-scattering ones for the a''1Σg +v'=0 and a''1Σg +v'=1+b1Πuv'=0 excitations of N2 and the A'3Δu excitation of O2 is achieved in the small squared momentum transfer region, while obvious discrepancies among them are observed in the large squared momentum transfer region. This phenomenon indicates that the first Born approximation is satisfied in the small squared momentum transfer region, while it does not hold in the large squared momentum transfer region at an incident electron energy of 1500 eV, in view of the fact that the first Born approximation is satisfied in the X-ray scattering. In addition, the present calculation for the a''1Σg + excitation shows that the traditional assigned v' = 0 and 1 of the aâ³1Σg + excitation correspond to v' = 9 and 13 of the 21Σg + excitation and reproduces the X-ray-scattering results of the a''1Σg +v'=0 excitation very well except the ones in the small squared momentum transfer region. We also report the generalized oscillator strengths of the à + BÌ excitations of C2H2, and its profile shows that the bending geometry has great influence on the transition feature.
RESUMO
K-vacancy Auger states of N(q+) (q = 2-5) ions are studied by using the complex multireference single- and double-excitation configuration interaction (CMRD-CI) method. The calculated resonance parameters are in good agreement with the available experimental and theoretical data. It shows that the resonance positions and widths converge quickly with the increase of the atomic basis sets in the CMRD-CI calculations; the standard atomic basis set can be employed to describe the atomic K-vacancy Auger states well. The strong correlations between the valence and core electrons play important roles in accurately determining those resonance parameters, Rydberg electrons contribute negligibly in the calculations. Note that it is the first time that the complex scaling method has been successfully applied for the B-like nitrogen. CMRD-CI is readily extended to treat the resonance states of molecules in the near future.
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Background: Self-expanding stents (SES) are reemerging as therapeutic alternatives to treat coronary artery disease. It has been proposed that SES can improve clinical outcomes by inducing less injury at implantation and achieving better vessel wall apposition.To date, little data exists comparing the vascular response to both methods of deployment in a controlled experimental setting. Objective: To quantify differences in vascular injury and healing between second-generation SES and balloon-expandable stents (BES) and the effects of balloon post-dilatation in a porcine coronary model. Methods: Seventy-five bare SES (AXXESS or vProtect) and 42 BES (Vision) were implanted in porcine coronaries. A subset of these received balloon post-dilatation(SES 1 D 5 22, BES 1 D 5 20). Follow-up was scheduled at 30 (BES 5 10, BES 1 D 56, SES 5 19, SES 1 D 5 8), 90 (BES 5 6, BES 1 D 5 8, SES 5 19, SES 1 D 5 8), and 180 days (BES 5 6, BES 1 D 5 6, SES 5 15, SES 1 D 5 6). Results: In vivo imaging and histological analysis showed that neointimal formation peaks early (30 days) in BES. Conversely, for SES, the peak occurred later (90 days). However, the neointimal formation achieved in either group equalized at 180 days. For SES, post-dilatation shortened the peak of neointimal formation to 30 days. Conversely, for BES, post-dilatation delayed the peak of neointimal formation to 90 days. At 30 days, histology showed that SES had significantly less injury. However, at 90 days, injury scores tended to be higher for SES. By 180 days, injury scores were comparable between both groups. Conclusions: The mechanism of stent expansion influences the degree of vascular injury and healing. The synergistic use of balloon post dilatation changes the dynamics of healing and may impact the potential beneficial effects inherent to SES technologies.
Assuntos
Angioplastia Coronária com Balão/instrumentação , Doença da Artéria Coronariana/cirurgia , Stents , Túnica Íntima/fisiopatologia , Lesões do Sistema Vascular/prevenção & controle , Cicatrização , Angioplastia Coronária com Balão/métodos , Animais , Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/fisiopatologia , Modelos Animais de Doenças , Desenho de Equipamento , Escala de Gravidade do Ferimento , Stents/efeitos adversos , Stents/normas , Suínos , Fatores de Tempo , Túnica Íntima/lesões , Grau de Desobstrução Vascular , Lesões do Sistema Vascular/etiologiaRESUMO
SERCA2a gene therapy improves contractile and energetic function of failing hearts and has been shown to be associated with benefits in clinical outcomes, symptoms, functional status, biomarkers, and cardiac structure in a phase 2 clinical trial. In an effort to enhance the efficiency and homogeneity of gene uptake in cardiac tissue, we examined the effects of nitroglycerin (NTG) in a porcine model following AAV1.SERCA2a gene delivery. Three groups of Göttingen minipigs were assessed: (i) group A: control intracoronary (IC) AAV1.SERCA2a (n = 6); (ii) group B: a single bolus IC injection of NTG (50 µg) immediately before administration of intravenous (IV) AAV1.SERCA2a (n = 6); and (iii) group C: continuous IV NTG (1 µg/kg/minute) during the 10 minutes of AAV1.SERCA2a infusion (n = 6). We found that simultaneous IV infusion of NTG and AAV1.SERCA2a resulted in increased viral transduction efficiency, both in terms of messenger RNA (mRNA) as well as SERCA2a protein levels in the whole left ventricle (LV) compared to control animals. On the other hand, IC NTG pretreatment did not result in enhanced gene transfer efficiency, mRNA or protein levels when compared to control animals. Importantly, the transgene expression was restricted to the heart tissue. In conclusion, we have demonstrated that IV infusion of NTG significantly improves cardiac gene transfer efficiency in porcine hearts.
Assuntos
Dependovirus/genética , Técnicas de Transferência de Genes , Vetores Genéticos/administração & dosagem , Miocárdio/metabolismo , Nitroglicerina/administração & dosagem , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Animais , Células Cultivadas , Circulação Coronária/efeitos dos fármacos , Expressão Gênica , Hemodinâmica/efeitos dos fármacos , Infusões Intra-Arteriais , Infusões Intravenosas , Masculino , Miócitos Cardíacos/metabolismo , Nitroglicerina/farmacologia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Suínos , Transdução GenéticaRESUMO
OBJECTIVE: To investigate the clinical efficacy of Shuganyiyang Capsule combined with conventional Western medicine (tamsulosin hydrochloride sustained release tablets + prostat tablets) for the treatment of type III prostatitis complicated by erectile dysfunction (ED). METHODS: Eighty patients with type III prostatitis complicated by ED were equally randomized to an experimental and a control group, the former treated with Shuganyiyang Capsule combined with tamsulosin hydrochloride sustained release tablets and prostat tablets, while the latter with tamsulosin hydrochloride and prostat only, both for 8 weeks. Then the prostatitis symptoms, erectile function and psychological conditions of the patients were evaluated using NIH-CPSI, IIEF-5, and hospital anxiety and depression scale (HADA and HADD) respectively. The rates of recovery, excellence, effectiveness and ineffectiveness were calculated. RESULTS: The scores on NIH-CPSI, IIEF-5, HADA and HADD obtained at 4 and 8 weeks after treatment showed statistically significant differences between the two time points as well as from the baseline (P < 0.01). At 8 weeks, the scores on NIH-CPSI, IIEF-5, HADA and HADD were 6.83 +/- 4.96, 21.03 +/- 2.54, 6.05 +/- 1.62, and 5.35 +/- 3.30 in the experimental group, as compared with 7.55 +/- 4.89, 17.68 +/- 4.15, 6.88 +/- 2.45, and 7.85 +/- 3.77 in the control (P < 0.05). The rate of effectiveness was significantly higher in the experimental than in the control group (90% [36/40] vs 70% [28/40], P < 0.05). CONCLUSION: Shuganyiyang Capsule combined with conventional Western medicine, such as alpha blockers and galenica, produces definite effect on chronic prostatitis complicated by ED, improves the psychological conditions of the patient, and enhances the therapeutic efficiency of chronic prostatits.
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Medicamentos de Ervas Chinesas/uso terapêutico , Disfunção Erétil/tratamento farmacológico , Fitoterapia , Prostatite/tratamento farmacológico , Cápsulas , Disfunção Erétil/complicações , Humanos , Masculino , Prostatite/complicações , Sulfonamidas/uso terapêutico , Tansulosina , Resultado do TratamentoRESUMO
BACKGROUND: In recent years, intervertebral disc (IVD) degeneration (IDD) has increased in age. There is still a lack of effective treatment in clinics, which cannot improve the condition of IDD at the level of etiology. OBJECTIVE: To explore IDD pathogenesis at the cellular and gene levels and investigate lactotransferrin (LTF) expression in IDD patients and its possible mechanism. METHODS: We downloaded the IDD data set from the Gene Expression Omnibus (GEO) database, screened the differentially expressed genes (DEGs) and hub genes and performed Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis to construct a protein-protein interaction (PPI) network. Subsequently, we verified LTF's regulatory mechanism through cell experiments. IL-1ß was used to intervene in nucleus pulposus cells (NPCs) to construct the IDD cell model, and LTF and Fas expression was detected by qRT-PCR. LTF inhibitor, Fas inhibitor, LTF mimic, and Fas mimic were used to intervene in each group. Western blotting was used to detect Fas, Caspase-3, Bax, and Bcl-2 expression. RESULTS: A total of 131 DEGs and 10 hub genes were screened. LTF mRNA in the IDD model was significantly higher than that in the control group, while Fas' mRNA was significantly lower. When LTF was upregulated or downregulated in NPCs, apoptosis marker expression showed the opposite trend. The rescue test showed that LTF and Fas' overexpression greatly enhanced NPC apoptosis. CONCLUSION: LTF promotes IDD progression by regulating Fas in NPCs, and it may be an effective gene therapy target.
Assuntos
Degeneração do Disco Intervertebral , MicroRNAs , Núcleo Pulposo , Apoptose/genética , Células Cultivadas , Humanos , Degeneração do Disco Intervertebral/metabolismo , Lactoferrina/genética , Lactoferrina/metabolismo , MicroRNAs/metabolismo , Núcleo Pulposo/metabolismo , RNA Mensageiro/metabolismoRESUMO
The study assessed chronic myocardial, coronary and systemic effects of intracoronary supersaturated oxygen (SSO2) therapy. Left anterior descending coronary arteries of 40 swine were stented and randomized to 90-min selective intracoronary infusion of SSO2 (pO2 760-1000 mmHg) or normoxemic saline. In 20 out of 40 animals, SSO2 delivery followed a 60-min balloon occlusion to induce myocardial infarction (MI). In both normal and MI models, intracoronary treatment with hyperoxemic SSO2 therapy showed no evidence of coronary thrombosis. There were no biologically relevant differences between treatments at either time point in regard to coronary intervention site healing and neointimal growth. No signs of any myocardial or systemic toxicity were observed after 7 or 30 days. A trend was observed toward reduced incidence of microscopic MI scars and reduced infarct size in histopathology, as well as toward better recovery of echocardiographically evaluated global and regional contractility at 30 days. No treatment related infarcts or thromboemboli were observed in the downstream organs.
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Trombose Coronária , Infarto do Miocárdio , Animais , Vasos Coronários/patologia , Infarto do Miocárdio/patologia , Miocárdio/patologia , Oxigênio , SuínosRESUMO
BACKGROUND: Embolic stroke is a major cause of morbidity in aortic and cardiac interventional procedures. Although cerebral embolic protection devices have been developed for carotid interventions and for open heart surgery, a percutaneous device for cerebral embolic protection during aortic and cardiac interventions would be desirable. METHODS: The Embrella Embolic Deflector (Embrella Cardiovascular Inc, Wayne, Pa) is a percutaneously placed embolic protection device, inserted by a 6F access in the pig's right forelimb, and deployed in the aorta, covering the brachiocephalic vessel origins. The device functions by deflecting embolic debris downstream in the aortic circulation. A swine model (n = 3) was developed for testing the deployment, retrieval, and efficacy of the device using a carotid filtration circuit for collection of emboli. Human atheromatous material was prepared as embolization particles with diameters between 150 and 600 µm. Deflection efficiency of the device was calculated by comparing numbers of embolic particles in the carotid circulation during protected and unprotected injections. RESULTS: The device was reliably deployed, positioned, and retrieved (n = 24). There was no significant drop in blood pressure across the membrane of the device to suggest reduction of cerebral blood flow. The device did not become occluded by embolic debris despite an embolic load many times that encountered in the clinical situation. Particles entering the carotid circulation after aortic injection of emboli were reduced from 19% of total (unprotected) to 1.3% (protected, P < .0001), with 98.7% of all injected particles being deflected downstream. There was no evidence of arterial injury related to the device found at necropsy. CONCLUSION: The Embrella Embolic Deflector performs safely and reliably in the swine model of human atheroembolism. It effectively deflects almost all emboli downstream, away from the carotid circulation. The deflector shows promise as an aortic embolic protection device and merits further investigation.
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Aorta Torácica , Procedimentos Cirúrgicos Cardíacos/instrumentação , Dispositivos de Proteção Embólica , Embolia Intracraniana/prevenção & controle , Procedimentos Cirúrgicos Vasculares/instrumentação , Animais , Aorta Torácica/diagnóstico por imagem , Aorta Torácica/fisiopatologia , Aortografia , Cadáver , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Artérias Carótidas/fisiopatologia , Castração , Circulação Cerebrovascular , Modelos Animais de Doenças , Feminino , Humanos , Embolia Intracraniana/etiologia , Embolia Intracraniana/fisiopatologia , Masculino , Teste de Materiais , Desenho de Prótese , Fluxo Sanguíneo Regional , Sus scrofa , Fatores de Tempo , Procedimentos Cirúrgicos Vasculares/efeitos adversosRESUMO
CD8+ T cells constitute an essential component of the adaptive immune system. They are activated through T cell receptor (TCR) recognizing antigenic peptides presented by MHC class I molecules expressed by antigen-presenting cells, such as dendritic cells (DCs). Harvesting a large number of activated, antigen-specific human CD8+ T cells for functional studies has been a laborious task for immunologists, largely because of the variables associated with DC preparations. Here we describe a robust, cost-effective DC-free antigen-presenting system capable of generating a large number of antigen-specific CD8+ T cells in vitro.
Assuntos
Linfócitos T CD8-Positivos/metabolismo , Antígenos de Histocompatibilidade Classe I/genética , Microglobulina beta-2/genética , Apresentação de Antígeno , Células Cultivadas , Técnicas de Cocultura , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Ativação Linfocitária , Proteínas Recombinantes/metabolismo , Microglobulina beta-2/metabolismoRESUMO
B-type natriuretic peptide (BNP) is an established first-line therapy for acute decompensated heart failure (HF), but its efficacy in preventing left ventricular (LV) remodeling after myocardial injury is unknown. The goal of this study was to evaluate the effects of BNP therapy on remodeling after ischemic injury in an awake canine model. Dogs were chronically instrumented for hemodynamics. Ischemia was created by daily coronary embolization (Embo; 3.1 x 10(4) beads/day) for 3 wk; 60 min after the first embolization, BNP (100 ng x kg(-1) x min(-1); n = 6) or saline (control; n = 6) was continuously infused via a left atrial catheter for 3 wk. Hemodynamics and echocardiography were performed in an awake state at baseline, 3 wk after Embo + BNP infusion, and 4 wk after stopping Embo + BNP infusion. End-systolic elastance (E(es)) and LV change in pressure over time (dP/dt) were preserved throughout Embo + BNP therapy versus control therapy (E(es): 3.76 +/- 1.01 vs. 1.41 +/- 0.16 mmHg/ml; LV dP/dt: 2,417 +/- 96 vs. 2,068 +/- 95 mmHg/s; both P < 0.05 vs. control). LV end-diastolic dimension was significantly smaller in BNP-treated dogs compared with control dogs (4.29 +/- 0.10 vs. 4.77 +/- 0.17 cm), and ejection fraction was maintained in treated dogs vs. control dogs (53 +/- 1% vs. 46 +/- 2%) (both P < 0.05 vs. control). Cyclooxygenase (COX)-2 expression in terminal LV tissue was significantly reduced after BNP therapy. Treatment with continuous infusion of BNP preserved LV geometry, improved systolic function, and prevented the progression of systolic HF after persistent ischemic injury.
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Insuficiência Cardíaca/tratamento farmacológico , Isquemia Miocárdica/tratamento farmacológico , Natriuréticos/farmacologia , Peptídeo Natriurético Encefálico/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Animais , GMP Cíclico/sangue , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Cães , Ecocardiografia , Embolia/complicações , Fator VIII/metabolismo , Feminino , Fibrose , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/etiologia , Bombas de Infusão , Macrófagos/patologia , Masculino , Isquemia Miocárdica/diagnóstico por imagem , Isquemia Miocárdica/etiologia , Miocárdio/patologia , Natriuréticos/sangue , Peptídeo Natriurético Encefálico/sangue , Volume Sistólico/efeitos dos fármacos , Pressão Ventricular/efeitos dos fármacosRESUMO
The type 1 ryanodine receptor (RyR1) on the sarcoplasmic reticulum (SR) is the major calcium (Ca2+) release channel required for skeletal muscle excitation-contraction (EC) coupling. RyR1 function is modulated by proteins that bind to its large cytoplasmic scaffold domain, including the FK506 binding protein (FKBP12) and PKA. PKA is activated during sympathetic nervous system (SNS) stimulation. We show that PKA phosphorylation of RyR1 at Ser2843 activates the channel by releasing FKBP12. When FKB12 is bound to RyR1, it inhibits the channel by stabilizing its closed state. RyR1 in skeletal muscle from animals with heart failure (HF), a chronic hyperadrenergic state, were PKA hyperphosphorylated, depleted of FKBP12, and exhibited increased activity, suggesting that the channels are "leaky." RyR1 PKA hyperphosphorylation correlated with impaired SR Ca2+ release and early fatigue in HF skeletal muscle. These findings identify a novel mechanism that regulates RyR1 function via PKA phosphorylation in response to SNS stimulation. PKA hyperphosphorylation of RyR1 may contribute to impaired skeletal muscle function in HF, suggesting that a generalized EC coupling myopathy may play a role in HF.
Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Insuficiência Cardíaca/enzimologia , Músculo Esquelético/enzimologia , Miocárdio/enzimologia , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Animais , Cálcio/metabolismo , Sinalização do Cálcio/genética , Proteínas Quinases Dependentes de AMP Cíclico/genética , Modelos Animais de Doenças , Cães , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Músculo Esquelético/fisiopatologia , Fosforilação , Estrutura Terciária de Proteína/fisiologia , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Retículo Sarcoplasmático/enzimologia , Retículo Sarcoplasmático/genética , Frações Subcelulares , Proteína 1A de Ligação a Tacrolimo/genética , Proteína 1A de Ligação a Tacrolimo/metabolismoRESUMO
Skeletal myoblast (SM) implantation promotes recovery of myocardial function after ischemic injury. Clinical observations suggest an association of SM implantation and ventricular arrhythmias. Support for this link has been sought in animal studies, but none employing models of congestive heart failure. In a canine model of postinfarction congestive heart failure (CHF) we compared the frequency of rhythm disturbances using ambulatory electrocardiography monitoring following skeletal myoblast or saline (SAL) implantation. In 19 mongrel dogs ischemic injury and CHF were induced by intracoronary microsphere infusions. Direct intramyocardial injection of autologous skeletal myoblasts (ASM) (2.7-8.3 x 10(8) cells) or SAL controls was administered to 11 and 8 dogs, respectively. Serial echocardiography and 24-h ambulatory electrocardiography were recorded at baseline (after CHF induction) and at 4 weeks and at 8-10 weeks after injection. Comparisons between groups of left ventricular ejection fraction (LVEF) and the frequency of ventricular arrhythmias, supraventricular arrhythmias, and measures of heart rate variability (HRV) were made at each of the three time points. LVEF increased from 41 +/- 6% to 47 +/- 2% (p < 0.03) in the ASM group, and did not change (42 +/- 6% to 40 +/- 2%, p = ns) in SAL. After injection, no differences were seen in the number of dogs demonstrating ventricular tachycardia (n = 3 vs. n = 2, p = ns) or frequent PVCs (n = 3 vs. n = 3, p = ns) in the ASM versus SAL groups, respectively. Significant changes were observed in a time-domain measure of HRV, standard deviation of normal-to-normal RR interval (in ms: 4 weeks 174 +/- 95 vs. 242 +/- 19; 8 weeks 174 +/- 78 vs. 276 +/- 78, ASM vs. SAL), but not in other time domain parameters. In this canine model of ischemic CHF, ASM implantation did not result in a significant increase in ventricular arrhythmias compared to controls animals. The potential for ASM implantation to affect time-domain parameters of HRV merits further study.
Assuntos
Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca/fisiologia , Mioblastos/transplante , Isquemia Miocárdica/terapia , Animais , Arritmias Cardíacas/diagnóstico por imagem , Arritmias Cardíacas/fisiopatologia , Cães , Eletrocardiografia Ambulatorial , Insuficiência Cardíaca/diagnóstico por imagem , Hemodinâmica , Isquemia Miocárdica/diagnóstico por imagem , Taquicardia Ventricular/diagnóstico por imagem , Taquicardia Ventricular/fisiopatologia , Ultrassonografia , Função Ventricular EsquerdaRESUMO
Acute myocardial infarction (AMI) has become the leading cause of death in cardiovascular diseases. Myocardial ischemia and reperfusion (MI/R) occurs when myocardial blood circulation is reconstructed after blood supply is limited or lack, often after myocardial infarction, and is the main cause of acute myocardial injury. According to the length of ischemia time, arrhythmia, myocardial inhibition, and myocardial infarction may occur in sequence in MI/R. Mitochondria are the key organelles involved in MI/R injury. Mitochondrial ROS eruption, Ca2+ imbalance, mPTP opening, mitochondrial swelling, and release of pro-apoptotic proteins all lead to mitochondrial dysfunction and myocardial function impairment. Exercise is an effective intervention to prevent myocardial ischemia-reperfusion injury, and its protective effect is closely related to the intensity of exercise, the length of exercise time, the type of exercise and the internal exercise ability. The mitochondrial mechanism of exercise protection against myocardial ischemia-reperfusion injury is determined by many factors. During reperfusion, the heart after trained is better able to maintain energy homeostasis, maintain ΔΨm and limit mPTP activation, maintain ATP synthesis. Activation of the sarcoKATP and/or mitoKATP channels by exercise induces cellular and/or myocardial hyperpolarization, protecting the mitochondria and myocardium during MI/R. Exercise-trained hearts can regulate calcium homeostasis during MI/R and limit mitochondrial Ca2+ overload. Exercise training can improve the activity of mitochondrial antioxidant enzymes to clear ROS and regulate mitochondrial Ca2+ concentration during MI/R. Exercise can increase the bioavailability of NO near mitochondria and indirectly achieve exercise-induced myocardial protection through protein S-nitrosylation and the eNOS-NO pathway is related to mitochondrial biogenesis after exercise training. Exercise training can also affect mitochondrial dynamics during MI/R by preventing mitochondrial division and promoting mitochondrial fusion. Exercise training can promote autophagy of damaged mitochondria and reduces apoptosis through mitochondria too, thus helping to maintain the function of mitochondrial bank. Besides these, exercise training leads to the production of motor factors (mainly from the muscles, but also from the brain, red blood cells, and other tissues) that contribute to remote regulation of the heart. This paper reviews the mitochondrial mechanism of MI/R, the protective effect of exercise on MI/R and the role of mitochondria in it, in order to provide more theoretical basis and new therapeutic targets for the diagnosis and treatment of heart disease, and provide new targets for drug research and development. In future clinical treatment, it is expected that sports pills targeted mitochondria can treat MI/R injury for bedridden people who cannot exercise or people who do not want to exercise through new technological means such as nanoparticle packaging.
RESUMO
Coenzyme CoQ10 (CoQ10), a ubiquinone compound, has been reported to inhibit tyrosinase activity and melanin production in melanoma B16F10 cells. However, the molecular mechanism underlying this inhibitory effect is poorly understood. In this paper we aimed to investigate the molecular mechanisms involved in the anti-melanogenic activity of CoQ10 (1-2⯵M) in UVA (5â¯J/cm2)-irradiated keratinocyte HaCaT cells and α-MSH stimulated B16-F10 cells. It was observed that CoQ10 suppressed p53/POMC, α-MSH production as well as inhibited ROS generation in UVA-irradiated keratinocyte HaCaT cells. CoQ10 down-regulated the melanin synthesis in α-MSH-stimulated B16-F10 cells by suppressing the MITF expression by down regulating the cAMP mediated CREB signaling cascades. Furthermore, in vivo evidence demonstrated the inhibitory effect of CoQ10 on endogenous pigmentation in zebrafish. Increased nuclear Nrf2 translocation accompanied by the induction of HO-1 and γ-GCLC genes were observed in CoQ10 treated keratinocyte HaCaT cells. Notably, silencing of Nrf2 (siRNA transfection) significantly diminished CoQ10-mediated anti-melanogenic activity, as evidenced by impaired antioxidant HO-1 gene, uncontrolled ROS generation, and α-MSH production following UVA irradiation. To conclude, CoQ10 is an effective de-pigmention or skin-whitening agent and could be used in cosmetics for topical application.
Assuntos
Hidrolases de Éster Carboxílico/biossíntese , Queratinócitos/metabolismo , Fator 2 Relacionado a NF-E2/biossíntese , Preparações Clareadoras de Pele/farmacologia , Ubiquinona/análogos & derivados , Raios Ultravioleta , alfa-MSH/metabolismo , Animais , Antioxidantes/farmacologia , Hidrolases de Éster Carboxílico/genética , Linhagem Celular Transformada , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/efeitos da radiação , Melanoma Experimental/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/efeitos da radiação , Ubiquinona/farmacologia , Peixe-Zebra , alfa-MSH/antagonistas & inibidoresRESUMO
Elizabethkingia miricola is a Gram-negative rod which has been incriminated in severe infections in humans. Recently, a serious infectious disease was identified in Chinese spiny frogs (Quasipaa spinosa), in the Sichuan Province of China; the disease was characterized by corneal opacity, the presence of ascites and neurological symptoms. A Gram-negative bacillus was isolated from the liver, spleen and kidney of the diseased frogs. Experimental infection test revealed that the bacillus could infect the frogs Q. spinosa and the LD50 value was 1.19 × 106 cfu per frog. The isolated Gram-negative bacillus was identified as E. miricola according to phenotypic characteristics, 16S rRNA and gyrB gene sequence analysis. The isolated strain was only susceptible to florfenicol among all investigated chemotherapeutic agents. Histological examination revealed that E. miricola infection caused pathological lesions to multiple organs and tissues, especially in the liver, brain, kidney. These results confirmed that E. miricola is an emerging pathogen of Chinese spiny frogs.
Assuntos
Chryseobacterium/isolamento & purificação , Infecções por Flavobacteriaceae/veterinária , Ranidae/microbiologia , Animais , Antibacterianos/farmacologia , China/epidemiologia , Chryseobacterium/efeitos dos fármacos , Chryseobacterium/genética , DNA Girase/genética , Infecções por Flavobacteriaceae/tratamento farmacológico , Infecções por Flavobacteriaceae/epidemiologia , Infecções por Flavobacteriaceae/microbiologia , Humanos , Rim/microbiologia , Fígado/microbiologia , Testes de Sensibilidade Microbiana , RNA Ribossômico 16S/genética , Análise de Sequência , Baço/microbiologia , Tianfenicol/análogos & derivados , Tianfenicol/farmacologiaRESUMO
Objective To propose a total time prediction method of MRI examination based on BP neural network.Methods The clinical data of MRI equipment in some tertiary grade A hospital was mined deeply.Totally 63 examination sites and 26 examination methods were combined into several examination sequences,and the examination sequence vector and total examination time were used as the input and output of BP neural network,respectively,so as to construct a BP neural network model.The BP neural network model established was compared with the ridge regression model and Lasso regression model with the mean absolute error(MAE)as the evaluation index when used for predicting MRI examinations.Results The BP neural network model behaved better than the ridge regression model and Lasso regression model with the predicted value close to the measured value and MAE being 53.14 s.Conclusion The proposed method accurately predicts the total MRI examination time and can assist hospital staff in scheduling patient examinations.[Chinese Medical Equipment Journal,2023,44(10):13-16]
RESUMO
Staphylococcus aureus (S. aureus), an important opportunistic pathogen in human and animal, causes a series of diseases in the impairing of immunity of host and even then death. Alpha-hemolysin (Hla), a primary virulence factor, plays a major role in the pathogenic progress of S. aureus, especially in pneumonia. Prim-O-glucosylcimifugin (POG), a nature chromone compound, is an active ingredient in many Chinese Medicines. In this study, POG investigated the inhibitory effect of the secretion of Hla in S. aureus strain USA300 at the subinhibitory concentrations. The hemolysis assays and western blotting assays showed that POG can decrease the production of Hla in the USA300 growth cell cultures in a dose-dependent manner. The results of RT-PCR revealed that reduction of Hla was related to inhibit the transcription of hla and RNAIII. In the cells experiment, POG was proved to protect A549 cells from Hla-medicated injury. In conclusion, POG was shown the capacity of decreased the production of S. aureus Hla. POG can be developed as a candidate agent to treat S. aureus infections against Hla.