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1.
Emerg Microbes Infect ; 10(1): 1626-1637, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34365904

RESUMO

Coronaviruses (CoVs) can infect a variety of hosts, including humans, livestock and companion animals, and pose a serious threat to human health and the economy. The current COVID-19 pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has killed millions of people. Unfortunately, effective treatments for CoVs infection are still lacking, suggesting the importance of coronavirus vaccines. Our previous work showed that CoV nonstuctural protein 14 (nsp14) functions as (guanine-N7)-methyltransferase (N7-MTase), which is involved in RNA cap formation. Moreover, we found that N7-MTase is well conserved among different CoVs and is a universal target for developing antivirals against CoVs. Here, we show that N7-MTase of CoVs can be an ideal target for designing live attenuated vaccines. Using murine hepatitis virus strain A59 (MHV-A59), a representative and well-studied model of coronaviruses, we constructed N7-MTase-deficient recombinant MHV D330A and Y414A. These two mutants are highly attenuated in mice and exhibit similar replication efficiency to the wild-type (WT) virus in the cell culture. Furthermore, a single dose immunization of D330A or Y414A can induce long-term humoral immune responses and robust CD4+ and CD8+ T cell responses, which can provide full protection against the challenge of a lethal-dose of MHV-A59. Collectively, this study provides an ideal strategy to design live attenuated vaccines for coronavirus by abolishing viral RNA N7-MTase activity. This approach may apply to other RNA viruses that encode their own conservative viral N7-methyltransferase.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Vacinas Atenuadas/imunologia , Animais , Vacinas contra COVID-19/administração & dosagem , Citocinas/biossíntese , Humanos , Imunidade Celular , Imunidade Humoral , Imunogenicidade da Vacina , Interferon Tipo I/biossíntese , Masculino , Camundongos , Mutação , Vacinas Atenuadas/administração & dosagem , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/imunologia
2.
Biomed Pharmacother ; 138: 111532, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34311531

RESUMO

Fufang Zhenzhu Tiaozhi formula (FTZ), a preparation of Chinese herbal medicine, has various pharmacological properties, such as hypoglycemic, hypolipidemic, anticoagulant, and anti-inflammatory activities. Hepatocyte apoptosis is a marker of nonalcoholic steatohepatitis (NASH) and contributes to liver injury, fibrosis, and inflammation. Given the multiple effects of FTZ, we investigated whether FTZ can be a therapeutic agent for NASH and its mechanism. In the present study, we observed that FTZ treatment had an obviously favorable influence on hepatic steatosis and fibrosis in the histopathologic features of type 2 diabetes mellitus (T2DM) and coronary heart disease (CHD) with NASH minipigs. In addition, immunohistochemical analysis showed increased expression of the fibrotic marker α-smooth muscle actin (α-SMA), and a TUNEL assay revealed increased apoptotic positive hepatic cells in the liver tissues of the model group. Furthermore, FTZ administration reduced the increased expression of α-SMA, and FTZ inhibited apoptosis by affecting Bcl-2/Bax and cleaved caspase-3 expression. Mechanistically, our data suggested that FTZ treatment attenuated hepatic steatosis and fibrosis via the adenosine monophosphate-activated protein kinase (AMPK) pathway. In vitro studies showed that FTZ also attenuated intracellular lipid accumulation in HepG2 cells exposed to palmitic acid (PA) and oleic acid (OA). FTZ upregulated the expression levels of P-AMPK and BCL-2 and downregulated BAX. The changes induced by FTZ were reversed by Compound C, an inhibitor of AMPK. In conclusion, FTZ attenuated NASH by ameliorating steatosis and hepatocyte apoptosis, which is attributable to the regulation of the AMPK pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Doença das Coronárias/enzimologia , Doença das Coronárias/etiologia , Doença das Coronárias/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/enzimologia , Células Hep G2 , Humanos , Lipídeos/sangue , Fígado/enzimologia , Fígado/patologia , Cirrose Hepática/enzimologia , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Suínos , Porco Miniatura
3.
Artigo em Inglês | MEDLINE | ID: mdl-34166206

RESUMO

To interprete the importance of clinical features and genotypes for warfarin daily dose prediction, we developed a post-hoc interpretable framework based on an ensemble predictive model. This framework includes permutation importance for global interpretation and local interpretable model-agnostic explanation (LIME) and shapley additive explanations (SHAP) for local explanation. The permutation importance globally ranks the importance of features on the whole data set. This can guide us to build a predictive model with less variables and the complexity of final predictive model can be reduced. LIME and SHAP together explain how the predictive model give the predicted dosage for specific samples. This help clinicians prescribe accurate doses to patients using more effective clinical variables. Results showed that both the permutation importance and SHAP demonstrated that VKORC1, age, serum creatinine (SCr), left atrium (LA) size, CYP2C9 and weight were the most important features on the whole data set. In specific samples, both SHAP and LIME discovered that in Chinese patients, wild-type VKORC1-AA, mutant-type CYP2C9*3, age over 60, abnormal LA size, SCr within the normal range, and using amiodarone definitely required dosage reduction, whereas mutant-type VKORC1-AG/GG, small age, SCr out of normal range, normal LA size, diabetes and heavy weight required dosage enhancement.

4.
JCI Insight ; 6(12)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34156031

RESUMO

PDCD10, also known as CCM3, is a gene found to be associated with the human disease cerebral cavernous malformations (CCMs). PDCD10 forms a complex with GCKIII kinases including STK24, STK25, and MST4. Studies in C. elegans and Drosophila have shown a pivotal role of the PDCD10-GCKIII complex in maintaining epithelial integrity. Here, we found that mice deficient of Pdcd10 or Stk24/25 in the kidney tubules developed polyuria and displayed increased water consumption. Although the expression levels of aquaporin genes were not decreased, the levels of total and phosphorylated aquaporin 2 (Aqp2) protein in the apical membrane of tubular epithelial cells were decreased in Pdcd10- and Stk24/25-deficient mice. This loss of Aqp2 was associated with increased expression and membrane targeting of Ezrin and phosphorylated Ezrin, Radixin, Moesin (p-ERM) proteins and impaired intracellular vesicle trafficking. Treatment with Erlotinib, a tyrosine kinase inhibitor promoting exocytosis and inhibiting endocytosis, normalized the expression level and membrane abundance of Aqp2 protein, and partially rescued the water reabsorption defect observed in the Pdcd10-deficient mice. Our current study identified the PDCD10-STK-ERM signaling pathway as a potentially novel pathway required for water balance control by regulating vesicle trafficking and protein abundance of AQP2 in the kidneys.

5.
J Am Chem Soc ; 143(24): 8993-9001, 2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34106720

RESUMO

The enantioselective synthesis of axially chiral biaryls by a copper-catalyzed Diels-Alder/retro-Diels-Alder reaction of 2-pyrones with alkynes is reported herein. Using electron-deficient 2-pyrones and electron-rich 1-naphthyl acetylenes as the reaction partners, a broad range of axially chiral biaryl esters are obtained in excellent yields (up to 97% yield) and enantioselectivities (up to >99% ee). DFT calculations reveal the reaction mechanism and provide insights into the origins of the stereoselectivities. The practicality and robustness of this reaction are showcased by gram-scale synthesis. The synthetic utilizations are demonstrated by the amenable transformations of the products.

6.
Anal Chim Acta ; 1166: 338596, 2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34023003

RESUMO

Rapid, quantitative, and sensitive assays for the multiplexed detection of bacterial pathogens are urgently needed for public health. Here, we report the generation of dual-modified phage sensors for the simultaneous detection of multiple pathogenic bacteria. The M13KE phage was dual modified to display the targeting peptide on the minor coat protein pIII (∼5 copies) and the streptavidin-binding (StrB) peptide on the major coat protein pVIII (∼2700 copies). The targeting peptide specifically recognizes the target bacteria, and the StrB peptide acts as the efficient signal amplification and transduction unit upon binding with fluorescently tagged streptavidin. The bright fluorescence emitted from individual target bacteria can be clearly distinguished from the background via both the flow cytometry and fluorescence microscopy. Three different dual-modified phages targeting E. coli O157:H7, Salmonella Typhimurium, and Pseudomonas aeruginosa were constructed, and high specificity was verified via a large excess of other non-target bacteria. Using a 40 mL sample volume, the target bacteria detection limit was approximately 102 cells/mL via flow cytometry measurement in the presence of other non-target bacteria. By combining these three dual-modified phages into a cocktail, simultaneous detection and quantification of three target bacterial pathogens was demonstrated with good linearity. The strategy of constructing dual-modified phage represents a promising tool in the detection of bacterial pathogens.


Assuntos
Bacteriófagos , Escherichia coli O157 , Bactérias , Salmonella typhimurium , Estreptavidina
7.
World J Surg Oncol ; 19(1): 134, 2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33888125

RESUMO

BACKGROUND: Medulloblastoma (MB) is the most common pediatric embryonal tumor. Accurate identification of cerebral spinal fluid (CSF) dissemination is important in prognosis prediction. Both MRI of the central nervous system (CNS) and CSF cytology will appear false positive and negative. Our objective was to investigate the added value of preoperative-enhanced T1-weighted image-based radiomic features to clinical characteristics in predicting preoperative CSF dissemination for children with MB. MATERIALS AND METHODS: This retrospective study included 84 children with histopathologically confirmed MB between November 2006 and November 2018 (training cohort, n=60; internal validation cohort, n=24). A set of cases between December 2018 and February 2020 were used for external validation (n=40). The children with normal head and spine magnetic resonance images (MRI) and no subsequent dissemination in 1 year were diagnosed as non-CSF dissemination. The CSF dissemination was manifested as intracranial or intraspinal nodular-enhanced lesions. Clinical features were collected, and conventional MRI features of preoperative head MRI examinations were evaluated. A total of 385 radiomic features were extracted from preoperative-enhanced T1-weighted images. Minimum redundancy, maximum correlation, and least absolute shrinkage and selection operator were performed to select the features with the best performance in predicting preoperative CSF dissemination. A combined clinical-MRI radiomic prediction model was developed using multivariable logistic regression. Receiver operating curve analysis (ROC) was used to validate the predictive performance. Nomogram and decision curve analysis (DCA) were developed to evaluate the clinical utility of the combined model. RESULTS: One clinical and nine radiomic features were selected for predicting preoperative CSF dissemination. The combined model incorporating clinical and radiomic features had the best predictive performance in the training cohort with an AUC of 0.89. This was validated in the internal and external cohorts with AUCs of 0.87 and 0.73. The clinical utility of the model was confirmed by a clinical-MRI radiomic nomogram and DCA. CONCLUSIONS: The combined model incorporating clinical, conventional MRI, and radiomic features could be applied to predict preoperative CSF dissemination for children with MB as a noninvasive biomarker, which could aid in risk evaluation.


Assuntos
Neoplasias Cerebelares , Meduloblastoma , Neoplasias Cerebelares/diagnóstico por imagem , Neoplasias Cerebelares/cirurgia , Criança , Humanos , Imageamento por Ressonância Magnética , Meduloblastoma/diagnóstico por imagem , Meduloblastoma/cirurgia , Prognóstico , Estudos Retrospectivos
8.
Circulation ; 143(20): 2007-2022, 2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-33663221

RESUMO

BACKGROUND: Heart failure (HF) is among the leading causes of morbidity and mortality, and its prevalence continues to rise. LARP7 (La ribonucleoprotein domain family member 7) is a master regulator that governs the DNA damage response and RNAPII (RNA polymerase II) pausing pathway, but its role in HF pathogenesis is incompletely understood. METHODS: We assessed LARP7 expression in human HF and in nonhuman primate and mouse HF models. To study the function of LARP7 in heart, we generated global and cardiac-specific LARP7 knockout mice. We acutely abolished LARP7 in mature cardiomyocytes by Cas9-mediated LARP7 somatic knockout. We overexpressed LARP7 in cardiomyocytes using adeno-associated virus serotype 9 and ATM (ataxia telangiectasia mutated protein) inhibitor. The therapeutic potential of LARP7-regulated pathways in HF was tested in a mouse myocardial infarction model. RESULTS: LARP7 was profoundly downregulated in failing human hearts and in nonhuman primate and murine hearts after myocardial infarction. Low LARP7 levels in failing hearts were linked to elevated reactive oxygen species, which activated the ATM-mediated DNA damage response pathway and promoted LARP7 ubiquitination and degradation. Constitutive LARP7 knockout in mouse resulted in impaired mitochondrial biogenesis, myocardial hypoplasia, and midgestational lethality. Cardiac-specific inactivation resulted in defective mitochondrial biogenesis, impaired oxidative phosphorylation, elevated oxidative stress, and HF by 4 months of age. These abnormalities were accompanied by reduced SIRT1 (silent mating type information regulation 2 homolog 1) stability and deacetylase activity that impaired SIRT1-mediated transcription of genes for oxidative phosphorylation and energy metabolism and dampened cardiac function. Restoring LARP7 expression after myocardial infarction by either adeno-associated virus-mediated LARP7 expression or small molecule ATM inhibitor substantially improved the function of injured heart. CONCLUSIONS: LARP7 is essential for mitochondrial biogenesis, energy production, and cardiac function by modulating SIRT1 homeostasis and activity. Reduction of LARP7 in diseased hearts owing to activation of the ATM pathway contributes to HF pathogenesis and restoring LARP7 in the injured heart confers myocardial protection. These results identify the ATM-LARP7-SIRT1 pathway as a target for therapeutic intervention in HF.

9.
Theranostics ; 11(4): 1609-1625, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33408770

RESUMO

Aims: Pathological cardiac fibrosis and hypertrophy are common features of left ventricular remodeling that often progress to heart failure (HF). Endothelial cells (ECs) are the most abundant non-myocyte cells in adult mouse heart. Simvastatin, a strong inducer of Krüppel-like Factor 2 (Klf2) in ECs, ameliorates pressure overload induced maladaptive cardiac remodeling and dysfunction. This study aims to explore the detailed molecular mechanisms of the anti-remodeling effects of simvastatin. Methods and Results: RGD-magnetic-nanoparticles were used to endothelial specific delivery of siRNA and we found absence of simvastatin's protective effect on pressure overload induced maladaptive cardiac remodeling and dysfunction after in vivo inhibition of EC-Klf2. Mechanism studies showed that EC-Klf2 inhibition reversed the simvastatin-mediated reduction of fibroblast proliferation and myofibroblast formation, as well as cardiomyocyte size and cardiac hypertrophic genes, which suggested that EC-Klf2 might mediate the anti-fibrotic and anti-hypertrophy effects of simvastatin. Similar effects were observed after Klf2 inhibition in cultured ECs. Moreover, Klf2 regulated its direct target gene TGFß1 in ECs and mediated the protective effects of simvastatin, and inhibition of EC-Klf2 increased the expression of EC-TGFß1 leading to simvastatin losing its protective effects. Also, EC-Klf2 was found to regulate EC-Foxp1 and loss of EC-Foxp1 attenuated the protective effects of simvastatin similar to EC-Klf2 inhibition. Conclusions: We conclude that cardiac microvasculature ECs are important in the modulation of pressure overload induced maladaptive cardiac remodeling and dysfunction, and the endothelial Klf2-TGFß1 or Klf2-Foxp1-TGFß1 pathway mediates the preventive effects of simvastatin. This study demonstrates a novel mechanism of the non-cholesterol lowering effects of simvastatin for HF prevention.


Assuntos
Cardiomegalia/tratamento farmacológico , Células Endoteliais/efeitos dos fármacos , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Proteínas Repressoras/metabolismo , Sinvastatina/farmacologia , Fator de Crescimento Transformador beta/metabolismo , Remodelação Ventricular/efeitos dos fármacos , Animais , Anticolesterolemiantes/farmacologia , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Sobrevivência Celular , Células Cultivadas , Células Endoteliais/metabolismo , Fatores de Transcrição Forkhead/genética , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Fatores de Transcrição Kruppel-Like/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Repressoras/genética , Fator de Crescimento Transformador beta/genética
10.
Eur Radiol ; 31(8): 5902-5912, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33496829

RESUMO

OBJECTIVES: To investigate the value of full-field digital mammography-based deep learning (DL) in predicting malignancy of Breast Imaging Reporting and Data System (BI-RADS) 4 microcalcifications. METHODS: A total of 384 patients with 414 pathologically confirmed microcalcifications (221 malignant and 193 benign) were randomly allocated into the training, validation, and testing datasets (272/71/71 lesions) in this retrospective study. A combined DL model was developed incorporating mammography and clinical variables. Model performance was evaluated by using areas under the receiver operating characteristic curve (AUC) and compared with the clinical model, stand-alone DL image model, and BI-RADS approach. The predictive performance for malignancy was also compared between the combined model and human readers (2 juniors and 2 seniors). RESULTS: The combined DL model demonstrated favorable AUC, sensitivity, and specificity of 0.910, 85.3%, and 91.9% in predicting BI-RADS 4 malignant microcalcifications in the testing dataset, which outperformed the clinical model, DL image model, and BI-RADS with AUCs of 0.799, 0.841, and 0.804, respectively. The combined model achieved non-inferior performance as senior radiologists (p = 0.860, p = 0.800) and outperformed junior radiologists (p = 0.155, p = 0.029). The diagnostic performance of two junior radiologists was improved after artificial intelligence assistance with AUCs increased to 0.854 and 0.901 from 0.816 (p = 0.556) and 0.773 (p = 0.046), while the interobserver agreement was improved with a kappa value increased to 0.843 from 0.331. CONCLUSIONS: The combined deep learning model can improve the malignancy prediction of BI-RADS 4 microcalcifications in screening mammography and assist junior radiologists to achieve better performance, which can facilitate clinical decision-making. KEY POINTS: • The combined deep learning model demonstrated high diagnostic power, sensitivity, and specificity for predicting malignant BI-RADS 4 mammographic microcalcifications. • The combined model achieved similar performance with senior breast radiologists, while it outperformed junior breast radiologists. • Deep learning could improve the diagnostic performance of junior radiologists and facilitate clinical decision-making.


Assuntos
Neoplasias da Mama , Calcinose , Aprendizado Profundo , Inteligência Artificial , Neoplasias da Mama/diagnóstico por imagem , Calcinose/diagnóstico por imagem , Detecção Precoce de Câncer , Feminino , Humanos , Mamografia , Estudos Retrospectivos
11.
Cardiovasc Res ; 117(2): 585-599, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-32091582

RESUMO

AIMS: Endothelial cell (EC) homoeostasis plays an important role in normal physiological cardiac functions, and its dysfunction significantly influences pathological cardiac remodelling after myocardial infarction (MI). It has been shown that the sphingosine 1-phosphate receptor 1 (S1pr1) was highly expressed in ECs and played an important role in maintaining endothelial functions. We thus hypothesized that the endothelial S1pr1 might be involved in post-MI cardiac remodelling. METHODS AND RESULTS: Our study showed that the specific loss of endothelial S1pr1 exacerbated post-MI cardiac remodelling and worsened cardiac dysfunction. We found that the loss of endothelial S1pr1 significantly reduced Ly6clow macrophage accumulation, which is critical for the resolution of inflammation and cardiac healing following MI. The reduced reparative macrophages in post-MI myocardium contributed to the detrimental effects of endothelial S1pr1 deficiency on post-MI cardiac remodelling. Further investigations showed that the loss of endothelial S1pr1-reduced Ly6clow macrophage proliferation, while the pharmacological activation of S1pr1-enhanced Ly6clow macrophage proliferation, thereby ameliorated cardiac remodelling after MI. A mechanism study showed that S1P/S1pr1 activated the ERK signalling pathway and enhanced colony-stimulating factor 1 (CSF1) expression, which promoted Ly6clow macrophage proliferation in a cell-contact manner. The blockade of CSF1 signalling reversed the enhancing effect of S1pr1 activation on Ly6clow macrophage proliferation and worsened post-MI cardiac remodelling. CONCLUSION: This study reveals that cardiac microvascular endothelium promotes reparative macrophage proliferation in injured hearts via the S1P/S1PR1/ERK/CSF1 pathway and thus ameliorates post-MI adverse cardiac remodelling.

12.
Clin Cardiol ; 44(1): 20-26, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33219708

RESUMO

BACKGROUND: Although the European Medicines Agency and the US Food and Drug Administration have, respectively, approved rivaroxaban for the prevention of recurrent major adverse cardiovascular events in patients with myocardial infarction and stable coronary artery disease, its efficacy and safety is unclear. This meta-analysis aimed to evaluate the benefit and risk of adding rivaroxaban in coronary artery disease (CAD) patients, focusing on treatment effects stratified by different baseline clinical presentations. HYPOTHESIS: There are differences in treatment effects of adding rivaroxaban among CAD patients with different baseline clinical presentations. METHODS: Medline, EMBASE, and Cochrane Databases were systematically searched from inception to 21 July 2020 for randomized controlled trials (RCTs) comparing rivaroxaban in CAD patients. The primary efficacy endpoint and safety endpoint were assessed by using Mantel-Haenszel pooled risk ratios (RRs) and 95% confidence intervals (CIs). RESULTS: Five RCTs that included 43 650 patients were identified. Patients receiving rivaroxaban had a significantly lower risk of the primary efficacy endpoint (RR, 0.86; 95% CI, 0.76-0.97, p = .01) accompanied by increased risk of the primary safety endpoint (RR, 1.83; 95% CI, 1.10-3.05, p = .02). Subgroup analyses showed that in males the risk-benefit appears to be more favorable while in patients ≥65 years, in females, in patients with diabetes, those with mild to moderate impaired renal function, and region of Asia/other seems unfavorable. CONCLUSION: Rivaroxaban may provide an additional choice for secondary prevention in CAD patients. However, careful estimation of the risk of ischemic and bleeding events using patient characteristics are critical to achieving net benefit.

13.
14.
Mol Ther Nucleic Acids ; 22: 251-262, 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33230431

RESUMO

Adult hearts are hard to recover after cardiac injury due to the limited proliferative ability of cardiomyocytes. Emerging evidence indicates the induction of cell cycle reentry of cardiomyocytes by special treatment or stimulation, which offers adult heart regenerative potential. Herein, a microRNA (miRNA) screening in cardiomyocytes identified miR-301a enriched specially in the neonatal cardiomyocytes from rats and mice. Overexpression of miR-301a in primary neonatal cardiomyocytes and H9C2 cells induced G1/S transition of the cell cycle, promoted cellular proliferation, and protected cardiomyocytes against hypoxia-induced apoptosis. Adeno-associated virus (AAV)9-mediated cardiac delivery of miR-301a to the mice model with myocardial infarction (MI) dramatically promoted cardiac repair post-MI in vivo. Phosphatase and tensin homolog (PTEN)/phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway was confirmed to mediate miR-301a-induced cell proliferation in cardiomyocytes. Loss of function of PTEN mimicked the miR-301a-induced phenotype, while gain of function of PTEN attenuated the miR-301a-induced cell proliferation in cardiomyocytes. Application of RG7440, a small molecule inhibitor of AKT, blocked the function of miR-301a in cardiomyocytes. The current study revealed a miRNA signaling in inducing the cell cycle reentry of cardiomyocytes in the injured heart, and it demonstrated the miR-301a/PTEN/AKT signaling as a potential therapeutic target to reconstitute lost cardiomyocytes in mammals.

15.
J Clin Neurosci ; 79: 74-79, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33070923

RESUMO

BACKGROUND: Primary central nervous system T-cell lymphoma (PCNSTCL) is a rare neoplasm with few data regarding its common features and survival characteristics. OBJECTIVE: To explore the Surveillance, Epidemiology, and End Results 18 (SEER 18) database to determine the epidemiology of PCNSTCL. METHODS: The SEER 18 registry database was queried to identify patients diagnosed with PCNSTCL from 1973 to 2014 and extract their information. Age-specific rates and Kaplan-Meier overall survival (OS) were calculated. A Cox proportional hazards model was applied to investigate relationships between various demographic/treatment variables and OS. RESULTS: The age-specific incidence rates were higher in the older population (≥60 years). Among 59 PCNSTCL cases from the SEER 18, the mean age at presentation was 55.8 years (SD, ±17.95), with a male predominance (1.36:1.00). The median follow-up was 8 months, and the median OS was 8 months (SE, ±4.162). The 1-, 3-, and 5-year OS was 46.3% [95% CI, 33.4%-59.2%], 32.8% [20.3%-45.3%], and 32.8% [20.3%-45.3%], respectively. Seventeen of the 59 patients survived at last follow-up. Patients < 60 years had a greater 3-year OS compared with patients ≥ 60 years (52.6% [33.6%-71.6%] vs 13.9% [1.4%-26.4%]. Multivariate analysis has demonstrated that only age at diagnosis (≥60/<60 years) exhibited a significant relationship with OS (HR, 3.495 [1.688-7.235];p = 0.001). Sex (female/male) was observed to have a doubted trend towards significance (HR, 0.487 [0.231-1.030]; p = 0.060). CONCLUSIONS: PCNSTCL is generally of poor prognosis but younger age at diagnosis (<60 years) predicts a better prognosis.


Assuntos
Neoplasias do Sistema Nervoso Central/epidemiologia , Linfoma de Células T/epidemiologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Programa de SEER
16.
BMC Med Genomics ; 13(Suppl 10): 152, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-33087117

RESUMO

BACKGROUND: Vitamin K antagonist (warfarin) is the most classical and widely used oral anticoagulant with assuring anticoagulant effect, wide clinical indications and low price. Warfarin dosage requirements of different patients vary largely. For warfarin daily dosage prediction, the data imbalance in dataset leads to inaccurate prediction on the patients of rare genotype, who usually have large stable dosage requirement. To balance the dataset of patients treated with warfarin and improve the predictive accuracy, an appropriate partition of majority and minority groups, together with an oversampling method, is required. METHOD: To solve the data-imbalance problem mentioned above, we developed a clustering-based oversampling technique denoted as DBCSMOTE, which combines density-based spatial clustering of application with noise (DBCSCAN) and synthetic minority oversampling technique (SMOTE). DBCSMOTE automatically finds the minority groups by acquiring the association between samples in terms of the clinical features/genotypes and the warfarin dosage, and creates an extended dataset by adding the new synthetic samples of majority and minority groups. Meanwhile, two ensemble models, boosted regression tree (BRT) and random forest (RF), which are built on the extended dataset generateed by DBCSMOTE, accomplish the task of warfarin daily dosage prediction. RESULTS: DBCSMOTE and the comparison methods were tested on the datasets derived from our Hospital and International Warfarin Pharmacogenetics Consortium (IWPC). As the results, DBCSMOTE-BRT obtained the highest R-squared (R2) of 0.424 and the smallest mean squared error (mse) of 1.08. In terms of the percentage of patients whose predicted dose of warfarin is within 20% of the actual stable therapeutic dose (20%-p), DBCSMOTE-BRT can achieve the largest value of 47.8% among predictive models. The more important thing is that DBCSMOTE saved about 68% computational time to achieve the same or better performance than the Evolutionary SMOTE, which was the best oversampling method in warfarin dose prediction by far. Meanwhile, in warfarin dose prediction, it is discovered that DBCSMOTE is more effective in  integrating BRT than RF  for warfarin dose prediction. CONCLUSION: Our finding is that the genotypes, CYP2C9 and VKORC1, no doubt contribute to the predictive accuracy. It was also discovered left atrium diameter, glutamic pyruvic transaminase and serum creatinine included in the model actually improved the predictive accuracy; When congestive heart failure, diabetes mellitus and valve replacement were absent in DBCSMOTE-BRT/RF, the predictive accuracy of DBCSMOTE-BRT/RF decreased. The oversampling ratio and number of minority clusters have a large impact on the effect of oversampling. According to our test, the predictive accuracy was high when the number of minority clusters was 6 ~ 8. The oversampling ratio for small minority clusters should be large (> 1.2) and for large minority clusters should be small (< 0.2). If the dataset becomes larger, the DBCSMOTE would be re-optimized and its BRT/RF model should be re-trained. DBCSMOTE-BRT/RF outperformed the current commonly-used tool called Warfarindosing. As compared to Evolutionary SMOTE-BRT and RF  models, DBCSMOTE-BRT and RF models take only a small computational time to achieve the same or higher performance in many cases. In terms of predictive accuracy, RF is not as good as BRT. However, RF still has a powerful ability in generating a highly accurate model as the dataset increases; the software "WarfarinSeer v2.0" is a test version, which packed DBCSMOTE-BRT/RF. It could be a convenient tool for clinical application in warfarin treatment.

17.
Dermatol Ther ; 33(6): e14410, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33052606

RESUMO

Although various factors were reported to be related to post-herpetic neuralgia (PHN), studies based on adequate and comprehensive data were absent. Data was extracted from cases of hospitalized patients with herpes zoster in dermatology department, Sichuan hospital of traditional Chinese medicine range from December, 2011 to February, 2018, and then cleaned to build prediction model with TREENET algorithms. Following evaluated the prediction model by ROC and confusion matrix, variables importance ranking and variables dependency analysis were performed, resulting in the importance ranking of factors for PHN and the dependency between factors and PHN. Based on strict inclusion and exclusion criteria, 1303 (571 PHN and 732 normal controls) cases and 2958 indicators were selected. Model evaluation showed high ROC value (training sample = 0.985, test samples = 0.752) and high accuracy value (70.27%), which indicated that the model was predictive. After variables importance ranking and variables dependency analysis, 62 variables in the model were associated with the occurrence of PHN. Our study identified 62 variables related to PHN and revealed that various variables were the important risk factors for PHN, including age, MCHC, sodium and UA.


Assuntos
Herpes Zoster , Neuralgia Pós-Herpética , Análise de Dados , Herpes Zoster/diagnóstico , Herpes Zoster/epidemiologia , Hospitais , Humanos , Medicina Tradicional Chinesa , Neuralgia Pós-Herpética/diagnóstico , Neuralgia Pós-Herpética/epidemiologia
18.
Expert Opin Pharmacother ; 21(17): 2137-2151, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32772741

RESUMO

INTRODUCTION: Statins are the first-line treatment to reduce cardiovascular (CV) events, mainly by reducing low-density-lipoprotein cholesterol (LDL-C), but many patients need additional treatments to reach the current lipid goals. AREAS COVERED: Herein, the authors review the published literature on the efficacy and safety of the therapies that are most often added to statins to achieve lipid targets. EXPERT OPINION: Ezetimibe is usually the first additional treatment to achieve LDL-C targets. It reduces LDL-C by about a further 20% and has an excellent safety and tolerability profile. The monoclonal antibody proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, evolocumab, and alirocumab, can reduce LDL-C by ≥50% when added to statins and they also have a well-established safety and tolerability record. The recently approved bempedoic acid is well tolerated and appears to be free of skeletal muscle-related problems, but the CV outcome study with this drug has not been completed. Inclisiran, a small-interfering RNA targeting PCSK9 is at an advanced stage of development and the available data indicate a satisfactory safety profile and LDL-C lowering efficacy similar to the PCSK9 monoclonal antibodies with the advantage of less frequent administration.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Ezetimiba/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , LDL-Colesterol/sangue , Ensaios Clínicos como Assunto , Quimioterapia Combinada , Ezetimiba/administração & dosagem , Ezetimiba/efeitos adversos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hipercolesterolemia/sangue , Pró-Proteína Convertase 9/antagonistas & inibidores , Resultado do Tratamento
19.
Plant Signal Behav ; 15(9): 1785668, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32662739

RESUMO

The NAC transcription factor (TF) is one of the largest families of TFs in plants and plays an important role in plant growth, development, and response to environmental stress. The structural and functional characteristics of NAC TFs have been uncovered in the past years, including sequence binding features of the DNA-binding domain located in the N-terminus and dynamic interplay between the domain located at the C-terminus and other proteins. Studies on NAC TF are increasing in number; these studies distinctly contribute to our understanding of the regulatory networks of NAC-mediated complex signaling and transcriptional reprogramming. Previous studies have indicated that NAC TFs are key regulators of the plant stress response. However, these studies have been for six years so far and mainly focused on drought and salt stress. There are relatively few reports about NAC TFs in plant cold signal pathway and no related reviews have been published. In this review article, we summarize the structural features of NAC TFs, the target genes, upstream regulators and interaction proteins of stress-responsive NAC TFs, and the roles NAC TFs play in plant cold stress signal pathway.


Assuntos
Proteínas de Plantas/metabolismo , Fatores de Transcrição/metabolismo , Temperatura Baixa , Regulação da Expressão Gênica de Plantas , Estresse Fisiológico/fisiologia
20.
Am J Hypertens ; 33(12): 1127-1135, 2020 12 31.
Artigo em Inglês | MEDLINE | ID: mdl-32484231

RESUMO

BACKGROUND: Hyperhomocysteinemia (HHcy) plays a synergistic role with hypertension in vascular injury; however, the relationship between HHcy and hypertension in renal injury remains unclear. Here, we sought to evaluate the relationship between HHcy and hypertension in the context of renal injury and to elucidate the mechanism of action underlying this relationship. METHODS: Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were randomized into WKY, WKY + HHcy, SHR, and SHR + HHcy groups. Blood pressure, plasma homocysteine, serum malondialdehyde (MDA), serum superoxide dismutase (SOD), urinary albumin creatinine ratio (UACR), and glomerular filtration rate (GFR) were measured. Renal histopathology and expression levels of NOX2, NOX4, and nephrin in the kidneys were examined. RESULTS: The WKY + HHcy and SHR groups exhibited lower serum SOD and GFR levels, relative to the WKY group, along with higher levels of both serum MDA and UACR. Higher mRNA and protein expression levels of NOX2 and NOX4, along with lower expression levels of nephrin, were observed in the kidneys of WKY + HHcy and SHR rats, relative to WKY controls, respectively. Similar effects were observed in the SHR + HHcy group, relative to the SHR group and WKY + HHcy group, respectively. Periodic acid-Schiff staining showed an increase in the glomerular extracellular matrix in the WKY + HHcy and SHR + HHcy groups compared with their respective controls. CONCLUSIONS: HHcy appears to synergistically increase hypertensive renal damage by enhancing oxidative stress.

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