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1.
Pediatr Surg Int ; 37(8): 1099-1108, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33966098

RESUMO

OBJECTIVE: To retrospectively assess the value of the combination of conventional ultrasound and shear-wave elastography (SWE) in evaluating the segmental heterogeneity of liver fibrosis in biliary atresia (BA) patients after Kasai portoenterostomy. METHODS: A total of 35 BA patients with liver segmental deformation were enrolled. The segmental deformation was assessed by conventional ultrasound followed with SWE examinations for evaluating the liver stiffness. Liver biopsy was performed in 11 patients in the region of SWE measurement and liver fibrosis was assessed using the Metavir classification. Aminotransferase to platelet ratio index (APRI) was calculated for comparison. The correlations between serum biochemical tests with SWE values were evaluated. Spearman's rank coefficient test was performed to evaluate the correlation between variables. RESULTS: The SWE values of the biopsy segments had significant positive correlations with liver fibrosis severity (r = 0.828, p = 0.001), which was better than APRI (r = 0.366, p = 0.242). The levels of bilirubin and transaminase showed significant correlations with the SWE values at hypertrophic segments in all patients (r from 0.336 to 0.576, all p < 0.05). CONCLUSIONS: Awareness of the segmental heterogeneity of liver fibrosis evaluated by conventional ultrasound and SWE may assist in selecting an appropriate biopsy location and predicting postoperative surveillance for patients with BA.


Assuntos
Técnicas de Imagem por Elasticidade/métodos , Cirrose Hepática/diagnóstico por imagem , Ultrassonografia/métodos , Atresia Biliar/cirurgia , Biópsia/métodos , Estudos de Casos e Controles , Pré-Escolar , Feminino , Humanos , Lactente , Cirrose Hepática/sangue , Cirrose Hepática/patologia , Masculino , Estudos Retrospectivos
2.
Eur Radiol ; 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33877387

RESUMO

OBJECTIVES: Pretreatment evaluation of tumor biology and microenvironment is important to predict prognosis and plan treatment. We aimed to develop nomograms based on gadoxetic acid-enhanced MRI to predict microvascular invasion (MVI), tumor differentiation, and immunoscore. METHODS: This retrospective study included 273 patients with HCC who underwent preoperative gadoxetic acid-enhanced MRI. Patients were assigned to two groups: training (N = 191) and validation (N = 82). Univariable and multivariable logistic regression analyses were performed to investigate clinical variables and MRI features' associations with MVI, tumor differentiation, and immunoscore. Nomograms were developed based on features associated with these three histopathological features in the training cohort, then validated, and evaluated. RESULTS: Predictors of MVI included tumor size, rim enhancement, capsule, percent decrease in T1 images (T1D%), standard deviation of apparent diffusion coefficient, and alanine aminotransferase levels, while capsule, peritumoral enhancement, mean relaxation time on the hepatobiliary phase (T1E), and alpha-fetoprotein levels predicted tumor differentiation. Predictors of immunoscore included the radiologic score constructed by tumor number, intratumoral vessel, margin, capsule, rim enhancement, T1D%, relaxation time on plain scan (T1P), and alpha-fetoprotein and alanine aminotransferase levels. Three nomograms achieved good concordance indexes in predicting MVI (0.754, 0.746), tumor differentiation (0.758, 0.699), and immunoscore (0.737, 0.726) in the training and validation cohorts, respectively. CONCLUSION: MRI-based nomograms effectively predict tumor behaviors in HCC and may assist clinicians in prognosis prediction and pretreatment decisions. KEY POINTS: • This study developed and validated three nomograms based on gadoxetic acid-enhanced MRI to predict MVI, tumor differentiation, and immunoscore in patients with HCC. • The pretreatment prediction of tumor microenvironment may be useful to guide accurate prognosis and planning of surgical and immunological therapies for individual patients with HCC.

3.
Ann Surg Oncol ; 2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33751300

RESUMO

BACKGROUND: The aim of this work is to explore the impact of the number of sampling sites (NuSS) and sampling location on microvascular invasion (MVI) detection rate and long-term survival of hepatocellular carcinoma (HCC), and determine the minimum NuSS for sufficient MVI detection. PATIENTS AND METHODS: From January 2008 to March 2017, 1144 HCC patients who underwent hepatectomy were retrospectively enrolled. Associations between NuSS and MVI positive rates and overall survival were investigated. NuSS thresholds were determined by Chow test and confirmed prospectively in 305 patients from April 2017 to February 2019. In the prospective cohort, the distribution of MVI in different sampling locations and its prognostic effect was evaluated. RESULTS: MVI positive rates increased as NuSS increased, steadily reaching a plateau when NuSS reached a threshold. A threshold of four, six, eight, and eight sampling sites within paracancerous parenchyma ≤ 1 cm from tumor was required for detecting MVI in solitary tumors measuring 1.0-3.0, 3.1-4.9, and ≥ 5.0 cm and multiple tumors. Patients with adequate NuSS achieved longer survival than those with inadequate NuSS [hazard ratio (HR) = 0.75, P = 0.043]. For all MVI-positive patients, MVI could be detected positive in paracancerous parenchyma ≤ 1 cm from tumor. Patients with MVI positive in paracancerous parenchyma > 1 cm had higher recurrence risk than those with MVI positive only in parenchyma ≤ 1 cm (HR = 6.05, P < 0.001). CONCLUSIONS: Adequate NuSS is associated with higher MVI detection rate and better survival of HCC patients. We recommend four, six, eight, and eight as the cut-points for evaluating MVI sampling quality and patients' prognostic stratification in the subgroups of solitary tumors measuring 1.0-3.0 cm, 3.1-4.9 cm and ≥ 5.0 cm and multiple tumors, respectively.

4.
Korean J Radiol ; 22(6): 959-969, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33569934

RESUMO

OBJECTIVE: This study aimed to evaluate the role of preoperative two-dimensional (2D) shear wave elastography (SWE) in assessing the stages of liver fibrosis in patients with suspected biliary atresia (BA) and compared its diagnostic performance with those of serum fibrosis biomarkers. MATERIALS AND METHODS: This study was approved by the ethical committee, and written informed parental consent was obtained. Two hundred and sixteen patients were prospectively enrolled between January 2012 and October 2018. The 2D SWE measurements of 69 patients have been previously reported. 2D SWE measurements, serum fibrosis biomarkers, including fibrotic markers and biochemical test results, and liver histology parameters were obtained. 2D SWE values, serum biomarkers including, aspartate aminotransferase to platelet ratio index (APRi), and other serum fibrotic markers were correlated with the stages of liver fibrosis by METAVIR. Receiver operating characteristic (ROC) curves and area under the ROC (AUROC) curve analyses were used. RESULTS: The correlation coefficient of 2D SWE value in correlation with the stages of liver fibrosis was 0.789 (p < 0.001). The cut-off values of 2D SWE were calculated as 9.1 kPa for F1, 11.6 kPa for F2, 13.0 kPa for F3, and 15.7 kPa for F4. The AUROCs of 2D SWE in the determination of the stages of liver fibrosis ranged from 0.869 to 0.941. The sensitivity and negative predictive value of 2D SWE in the diagnosis of ≥ F3 was 93.4% and 96.0%, respectively. The diagnostic performance of 2D SWE was superior to that of APRi and other serum fibrotic markers in predicting severe fibrosis and cirrhosis (all p < 0.005) and other serum biomarkers. Multivariate analysis showed that the 2D SWE value was the only statistically significant parameter for predicting liver fibrosis. CONCLUSION: 2D SWE is a more effective non-invasive tool for predicting the stage of liver fibrosis in patients with suspected BA, compared with serum fibrosis biomarkers.

5.
Sci Rep ; 11(1): 1329, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33446724

RESUMO

Higher mortality in asthmatics has been shown previously. However, evidence on different asthma phenotypes on long-term mortality risk is limited. The aim was to evaluate the impact of asthma phenotypes on mortality in general population. Data from the National Health and Nutrition Examination Survey from 2001-2002 to 2013-2014 linked mortality files through December 31, 2015, were used (N = 37,015). Cox proportional hazards regression was used to estimate the risk of all-cause and cause-specific mortality adjusting for sociodemographic characteristics, smoking, body mass index, and chronic conditions. During the mean follow-up time of 7.5 years, 4326 participants died from a variety of causes. Current asthma, but not former asthma was associated with increased all-cause mortality (current asthma: HR = 1.37; 95% CI 1.20-1.58; Former asthma: HR = 0.93; 95% CI 0.73-1.18); as well as mortality from cardiovascular disease (HRCurrent = 1.41; 95% CI 1.08-1.85) and chronic lower respiratory diseases (HRCurrent = 3.17; 95% CI 1.96-5.14). In addition, we found that the HR for cardiovascular disease (CVD) mortality was slightly greater in people with childhood-onset asthma than those with adult-onset asthma. The HR for chronic lower respiratory diseases (CLRD) mortality was greater in people with adult-onset asthma than those with childhood-onset asthma. However, the differences were not statistically significant. Our study suggested that current asthma but not former asthma was associated with increased all-cause, CLRD and CVD mortality. Future well-designed studies with larger sample are required to demonstrate the association and clarify the potential mechanisms involved.

6.
J Affect Disord ; 282: 707-711, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33445097

RESUMO

BACKGROUND: The estimated global burden of suicide is almost 1 million deaths per year, representing 57% of all violent deaths worldwide. In order to better identify at risk individuals and develop effective prevention strategies at the population level, a comprehensive understanding of the biological, psychological and social risk factors is required. METHOD: Data from the National Health Interview Survey (1997- 2004) were analyzed. Multivariable Cox proportional hazards regression models were used to compute hazard ratios (HRs) and accompanying 95% confidence intervals (CI). RESULTS: During a mean 6.3 years of follow-up of 242, 952 people (1.56 million person-years), 180 deaths due to suicide occurred. Of 18 risk factors, eight revealed associations with suicide. Participants who had never been married (HR, 2.58; 95% CI, 1.44-4.62), current smokers (HR, 2.26; 1.49-3.43), current drinkers (HR, 1.93; 1.14-3.27]), participants with serious psychological distress (HR, 3.34; 1.81-6.18), and a history of emphysema (HR, 2.79; 1.18-6.59), liver disease (HR, 4.63; 2.10-10.20), kidney disease (HR, 2.26; 1.00-5.06) and cancer (HR, 2.18; 1.32-3.59) were at increased risk of completed suicide. LIMITATIONS: Due to the observational nature of this study, we cannot exclude the possibility of reverse or bi-directional causality. CONCLUSIONS: This large, prospective cohort study identified a series of biopsychosocial risk factors that may have utility in suicide prevention.


Assuntos
Suicídio Consumado , Suicídio , Estudos de Coortes , Humanos , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco
7.
J Cell Physiol ; 236(8): 5698-5714, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33393109

RESUMO

Our understanding of signaling pathways regulating the cell fate of human embryonic stem cells (hESCs) is limited. Calcineurin-NFAT signaling is associated with a wide range of biological processes and diseases. However, its role in controlling hESC fate remains unclear. Here, we report that calcineurin A gamma and the NFATc3/SRPX2 axis control the expression of lineage and epithelial-mesenchymal transition (EMT) markers in hESCs. Knockdown of PPP3CC, the gene encoding calcineurin A gamma, or NFATC3, downregulates certain markers both at the self-renewal state and during differentiation of hESCs. Furthermore, NFATc3 interacts with c-JUN and regulates the expression of SRPX2, the gene encoding a secreted glycoprotein known as a ligand of uPAR. We show that SRPX2 is a downstream target of NFATc3. Both SRPX2 and uPAR participate in controlling expression of lineage and EMT markers. Importantly, SRPX2 knockdown diminishes the upregulation of multiple lineage and EMT markers induced by co-overexpression of NFATc3 and c-JUN in hESCs. Together, this study uncovers a previously unknown role of calcineurin A gamma and the NFATc3/SRPX2 axis in modulating the fate determination of hESCs.

8.
J Environ Sci (China) ; 100: 90-98, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33279057

RESUMO

Nitrate (NO3-) is known to be actively involved in the processes of mineralization and heavy metal transformation; however, it is unclear whether and how it affects the bioavailability of antimony (Sb) in paddy soils and subsequent Sb accumulation in rice. Here, the effects of NO3- on Sb transformation in soil-rice system were investigated with pot experiments over the entire growth period. Results demonstrated that NO3- reduced Sb accumulation in brown rice by 15.6% compared to that in the control. After amendment with NO3-, the Sb content in rice plants increased initially and then gradually decreased (in roots by 46.1%). During the first 15 days, the soil pH increased, the oxidation of Sb(III) and sulfides was promoted, but the reduction of iron oxide minerals was inhibited, resulting in the release of adsorbed and organic-bound Sb from soil. The microbial arsenite-oxidizing marker gene aoxB played an important role in Sb(III) oxidation. From days 15 to 45, after NO3- was partially consumed, the soil pH decreased, and the reductive dissolution of Fe(III)-bearing minerals was enhanced; consequently, iron oxide-bound Sb was transformed into adsorbed and dissolved Sb species. After day 45, NO3- was completely reduced, Sb(V) was evidently reduced to Sb(III), and green rust was generated gradually. Thus, the available Sb decreased due to its enhanced affinity for iron oxides. Moreover, NO3- inhibited the reductive dissolution of iron minerals, which ultimately caused low Sb availability. Therefore, NO3- can chemically and biologically reduce the Sb availability in paddy soils and alleviate Sb accumulation in rice. This study provides a potential strategy for decreasing Sb accumulation in rice in the Sb-contaminated sites.


Assuntos
Oryza , Poluentes do Solo , Antimônio/análise , Disponibilidade Biológica , Compostos Férricos , Nitratos , Raízes de Plantas/química , Solo , Poluentes do Solo/análise
9.
Hepatol Int ; 14(6): 1034-1047, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33369707

RESUMO

BACKGROUND AND AIMS: Microvascular invasion (MVI) is a key pathological factor that severely affects the postoperative prognosis of patients with hepatocellular carcinoma (HCC). However, no MVI classification schemes based on standardized gross sampling protocols of HCC are available at present. METHODS: 119 HCC specimens were sampled at multiple sites (3-, 7-, and 13 points) for the optimum MVI detection rate. 16,144 resected HCCs were graded as M0, M1 or M2 by adopting three-tiered MVI grading (MVI-TTG) scheme based on the seven-point sampling protocol (SPSP). Survival analyses were performed on 2573 patients to explore the advantages of MVI-TTG. RESULTS: The MVI detection rate determined by SPSP was significantly higher than that determined by the 3-point sampling method (34.5% vs. 47.1%, p = 0.048), but was similar to that determined by the 13-point sampling method (47.1% vs. 51.3%, p = 0.517). Among 16,144 resected HCCs, the proportions of M0, M1 and M2 specimens according to SPSP were 53.4%, 26.2% and 20.4%, respectively. Postoperative survival analysis in 2573 HCC patients showed that the 3-year recurrence rates in M0, M1 and M2 MVI groups were 62.5%, 71.6% and 86.1%, respectively (p < 0.001), and the corresponding 3-year overall survival (OS) rates were 94.1%, 87.5% and 67.0%, respectively (p < 0.001). M1 grade was associated with early recurrence, while M2 grade was associated with both early and late recurrence. MVI-TTG had a larger area under the curve and net benefit rate than the two-tiered MVI grading scheme for predicting time to recurrence and OS. CONCLUSIONS: SPSP is a practical method to balance the efficacy of sampling numbers and MVI detection rates. MVI-TTG based on SPSP is a better prognostic predictor than the two-tiered MVI scheme. The combined use of SPSP and MVI-TTG is recommended for the routine pathological diagnosis of HCC.

10.
Theranostics ; 10(26): 12072-12089, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33204330

RESUMO

Background: Among head and neck squamous cell carcinomas (HNSCCs), hypopharyngeal squamous cell carcinoma (HPSCC) has the worst prognosis. Iron metabolism, which plays a crucial role in tumor progression, is mainly regulated by alterations to genes and post-transcriptional processes. The recent discovery of the N6-methyladenosine (m6A) modification has expanded the realm of previously undiscovered post-transcriptional gene regulation mechanisms in eukaryotes. Many studies have demonstrated that m6A methylation represents a distinct layer of epigenetic deregulation in carcinogenesis and tumor proliferation. However, the status of m6A modification and iron metabolism in HPSCC remains unknown. Methods: Bioinformatics analysis, sample analysis, and transcriptome sequencing were performed to evaluate the correlation between m6A modification and iron metabolism. Iron metabolic and cell biological analyses were conducted to evaluate the effect of the m6A reader YTHDF1 on HPSCC proliferation and iron metabolism. Transcriptome-wide m6A-seq and RIP-seq data were mapped to explore the molecular mechanism of YTHDF1 function in HPSCC. Results: YTHDF1 was found to be closely associated with ferritin levels and intratumoral iron concentrations in HPSCC patients at Sir Run Run Shaw Hospital. YTHDF1 induced-HPSCC tumorigenesis depends on iron metabolism in vivo in vitro. Mechanistically, YTHDF1 methyltransferase domain interacts with the 3'UTR and 5'UTR of TRFC mRNA, then further positively regulates translation of m6A-modified TFRC mRNA. Gain-of-function and loss-of-function analyses validated the finding showing that TFRC is a crucial target gene for YTHDF1-mediated increases in iron metabolism. Conclusion: YTHDF1 enhanced TFRC expression in HPSCC through an m6A-dependent mechanism. From a therapeutic perspective, targeting YTHDF1 and TFRC-mediated iron metabolism may be a promising strategy for HPSCC.


Assuntos
Antígenos CD/genética , Neoplasias Hipofaríngeas/genética , Ferro/metabolismo , Recidiva Local de Neoplasia/epidemiologia , Proteínas de Ligação a RNA/metabolismo , Receptores da Transferrina/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Adenosina/análogos & derivados , Adenosina/metabolismo , Animais , Antígenos CD/metabolismo , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Estudos de Coortes , Imagem de Difusão por Ressonância Magnética , Intervalo Livre de Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hipofaríngeas/patologia , Neoplasias Hipofaríngeas/cirurgia , Hipofaringe/diagnóstico por imagem , Hipofaringe/patologia , Hipofaringe/cirurgia , Ferro/análise , Masculino , Metilação , Camundongos , Recidiva Local de Neoplasia/patologia , RNA Mensageiro/metabolismo , Receptores da Transferrina/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
BMC Musculoskelet Disord ; 21(1): 588, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873274

RESUMO

BACKGROUND: Limb girdle muscular dystrophy type 2Y (LGMD2Y) is a rare subgroup of limb girdle muscular dystrophy featuring limb-girdle weakness, tendon contracture and cardiac involvement. It is caused by the mutation of TOR1AIP1, which encodes nuclear membrane protein LAP1 (lamina-associated polypeptide 1) and comprises heterogeneous phenotypes. The present study reported a patient with a novel homozygous TOR1AIP1 mutation that presented with selective muscle weakness, which further expanded the phenotype of LGMD2Y- and TOR1AIP1-associated nuclear envelopathies. CASE PRESENTATION: A 40-year-old male presented with Achilles tendon contracture and muscle weakness that bothered him from 8 years old. While the strength of his distal and proximal upper limbs was severely impaired, the function of his lower limbs was relatively spared. Muscle pathology showed dystrophic features, and electron microscopy showed ultrastructural abnormalities of disrupted muscle nuclei envelopes. Whole-exome sequencing showed a frameshift mutation in TOR1AIP1 (c.98dupC). CONCLUSION: We reported a novel mild phenotype of LGMD2Y with relatively selective distal upper limb weakness and joint contracture and revealed the heterogeneity of LGDM2Y and the role of the LAP1 isoform by literature review.


Assuntos
Contratura , Distrofia Muscular do Cíngulo dos Membros , Adulto , Criança , Contratura/diagnóstico , Contratura/genética , Humanos , Masculino , Debilidade Muscular , Distrofia Muscular do Cíngulo dos Membros/genética , Mutação , Fenótipo , Tendões
12.
iScience ; 23(9): 101475, 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32905879

RESUMO

Region-specific neural progenitor cells (NPCs) can be generated from human embryonic stem cells (hESCs) by modulating signaling pathways. However, how intrinsic transcriptional factors contribute to the neural regionalization is not well characterized. Here, we generate region-specific NPCs from hESCs and find that SOX1 is highly expressed in NPCs with the rostral hindbrain identity. Moreover, we find that OTX2 inhibits SOX1 expression, displaying exclusive expression between the two factors. Furthermore, SOX1 knockout (KO) leads to the upregulation of midbrain genes and downregulation of rostral hindbrain genes, indicating that SOX1 is required for specification of rostral hindbrain NPCs. Our SOX1 chromatin immunoprecipitation sequencing analysis reveals that SOX1 binds to the distal region of GBX2 to activate its expression. Overexpression of GBX2 largely abrogates SOX1-KO-induced aberrant gene expression. Taken together, this study uncovers previously unappreciated role of SOX1 in early neural regionalization and provides new information for the precise control of the OTX2/GBX2 interface.

13.
Sleep Med ; 73: 217-222, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32858334

RESUMO

OBJECTIVES: To examine the cross-sectional relationship between sleep duration and 11 chronic diseases (risk of obesity, depression, diabetes, asthma, COPD, arthritis, kidney, CHD, stroke, and cancer [excluding skin cancer]) by using data from Behavioral Risk Factor Surveillance System. METHODS: Using data from the 2013, 2014 and 2016 Behavioral Risk Factor Surveillance System, a total sample consisted of 1,191,768 participants. Logistic regression models were constructed to calculate OR and 95% confidence intervals (CI) for the association between sleep duration and 11 chronic diseases. In addition, we also conducted subgroup analysis based on age and gender. RESULTS: In multi-adjusted model, the positive association between extremely short or long sleep duration and risk of chronic diseases was significant (P < 0.05) with the exception of skin cancer (P = 0.14 and P = 0.43). There are stronger association between extremely short or long sleep duration and obesity, diabetes, asthma, chronic obstructive pulmonary disease, arthritis, kidney, coronary heart disease, stroke, and cancer in women and aged 18-64 years old. CONCLUSIONS: Our results indicated a higher risk of common chronic diseases due to short or long sleep duration in women and aged 18-64 years. Further studies are needed to demonstrate these association.


Assuntos
Diabetes Mellitus , Adolescente , Adulto , Sistema de Vigilância de Fator de Risco Comportamental , Doença Crônica , Estudos Transversais , Diabetes Mellitus/epidemiologia , Feminino , Humanos , Pessoa de Meia-Idade , Fatores de Risco , Sono , Adulto Jovem
14.
Exp Ther Med ; 20(2): 1030-1038, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32742345

RESUMO

Mast cells (MCs) are the major effector cells of allergic rhinitis (AR). The present study aimed to investigate the effects of C-C chemokine receptor type 3 (CCR3) on the proliferation, apoptosis, chemotaxis and activated degranulation of mouse MCs. Mouse bone marrow-derived MCs were cultured in vitro, purified and identified using toluidine blue staining and flow cytometry. Three different CCR3-short hairpin (shRNA) lentiviral vectors were constructed and transfected into MCs, and the mRNA and protein expression levels of CCR3 were assessed by reverse transcription-quantitative PCR and western blotting. Proliferation and apoptosis of the MCs were measured using Cell Counting kit-8 (CCK-8) assays and flow cytometry, respectively. MC chemotaxis was assessed by Transwell assay and quantified using flow cytometry. The activation of MC degranulation was examined using ELISAs. The results demonstrated that MCs were appropriately isolated, and identified that CCR3-shRNA2 presented the higher knockdown effect among the three shRNAs tested. Following 96 h of transfection, the results of CCK-8 and flow cytometry assays demonstrated that CCR3-shRNA2 inhibited MC proliferation and promoted MC apoptosis. The results from the Transwell assay indicated that CCR3-shRNA2 restrained MC chemotaxis, whereas ELISA results demonstrated that CCR3-shRNA2 suppressed MC degranulation. In conclusion, CCR3-shRNA2 effectively downregulated CCR3 mRNA and protein expression levels in mouse MCs. In addition, CCR3-shRNA2 promoted MC apoptosis and suppressed the proliferation, chemotaxis and degranulation of mouse MCs, suggesting that CCR3-shRNA2 may serve as a therapeutic tool for the treatment of allergic rhinitis.

15.
Oncologist ; 25(10): e1552-e1561, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32663354

RESUMO

BACKGROUND: The predictive model of postsurgical recurrence for solitary early hepatocellular carcinoma (SE-HCC) is not well established. The aim of this study was to develop a novel model for prediction of postsurgical recurrence and survival for patients with hepatitis B virus (HBV)-related SE-HCC ≤10 cm. PATIENTS AND METHODS: Data from 1,081 patients with HBV-related SE-HCC ≤10 cm who underwent curative liver resection from 2003 to 2016 in our center were collected retrospectively and randomly divided into the derivation cohort (n = 811) and the internal validation cohort (n = 270). Eight hundred twenty-three patients selected from another four tertiary hospitals served as the external validation cohort. Postsurgical recurrence-free survival (RFS) and overall survival (OS) predictive nomograms were generated. The discriminatory accuracies of the nomograms were compared with six conventional hepatocellular carcinoma (HCC) staging systems. RESULTS: Tumor size, differentiation, microscopic vascular invasion, preoperative α-fetoprotein, neutrophil-to-lymphocyte ratio, albumin-to-bilirubin ratio, and blood transfusion were identified as the risk factors associated with RFS and OS. RFS and OS predictive nomograms based on these seven variables were generated. The C-index was 0.83 (95% confidence interval [CI], 0.79-0.87) for the RFS-nomogram and 0.87 (95% CI, 0.83-0.91) for the OS-nomogram. Calibration curves showed good agreement between actual observation and nomogram prediction. Both C-indices of the two nomograms were substantially higher than those of the six conventional HCC staging systems (0.54-0.74 for RFS; 0.58-0.76 for OS) and those of HCC nomograms reported in literature. CONCLUSION: The novel nomograms were shown to be accurate at predicting postoperative recurrence and OS for patients with HBV-related SE-HCC ≤10 cm after curative liver resection. IMPLICATIONS FOR PRACTICE: This multicenter study proposed recurrence or mortality predictive nomograms for patients with hepatitis B virus-related solitary early hepatocellular carcinoma ≤10 cm after curative liver resection. A close postsurgical surveillance protocol and adjuvant therapy should be considered for patients at high risk of recurrence.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Trombose , Carcinoma Hepatocelular/cirurgia , Hepatectomia , Vírus da Hepatite B , Humanos , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia , Nomogramas , Prognóstico , Estudos Retrospectivos
16.
Chem Pharm Bull (Tokyo) ; 68(4): 369-379, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32238654

RESUMO

Tyrosinase plays important roles in many different disease related processes, and the development of its inhibitors is particularly important in biotechnology. In this study, thirty-nine 3-/4-alkoxyphenylethylidenethiosemicarbazides were synthesized as novel tyrosinase inhibitors based on structure-based molecular design. Our experimental results demonstrated that thirty-one of them possess remarkable tyrosinase inhibitory activities with IC50 value below 1 µM, and 5a, 6e, 6g and 6t did not display any toxicity to 293T cell line at the concentration of 1000 µmol/L. According to the inhibitory activities, several compounds were selected for detail investigation on the structure-activity relationships (SARs), mechanisms of enzyme inhibition, inhibitory kinetics and cytotoxicity. In particular, the interaction between the selected inhibitors and the active center of tyrosinase was considered and discussed in detail based on their structural characteristics. Taken together, the results presented here demonstrated that the newly designed compounds are promising candidates for the treatment of tyrosinase-related disorders and further development of them may have significant contribution in biomedical science.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Semicarbazidas/farmacologia , Agaricales/enzimologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Células HEK293 , Humanos , Cinética , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Semicarbazidas/síntese química , Semicarbazidas/química , Relação Estrutura-Atividade
17.
Clin Cancer Res ; 26(14): 3760-3770, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32234760

RESUMO

PURPOSE: Adults with T-cell lymphoblastic lymphoma (T-LBL) generally benefit from treatment with acute lymphoblastic leukemia (ALL)-like regimens, but approximately 40% will relapse after such treatment. We evaluated the value of CpG methylation in predicting relapse for adults with T-LBL treated with ALL-like regimens. EXPERIMENTAL DESIGN: A total of 549 adults with T-LBL from 27 medical centers were included in the analysis. Using the Illumina Methylation 850K Beadchip, 44 relapse-related CpGs were identified from 49 T-LBL samples by two algorithms: least absolute shrinkage and selector operation (LASSO) and support vector machine-recursive feature elimination (SVM-RFE). We built a four-CpG classifier using LASSO Cox regression based on association between the methylation level of CpGs and relapse-free survival in the training cohort (n = 160). The four-CpG classifier was validated in the internal testing cohort (n = 68) and independent validation cohort (n = 321). RESULTS: The four-CpG-based classifier discriminated patients with T-LBL at high risk of relapse in the training cohort from those at low risk (P < 0.001). This classifier also showed good predictive value in the internal testing cohort (P < 0.001) and the independent validation cohort (P < 0.001). A nomogram incorporating five independent prognostic factors including the CpG-based classifier, lactate dehydrogenase levels, Eastern Cooperative Oncology Group performance status, central nervous system involvement, and NOTCH1/FBXW7 status showed a significantly higher predictive accuracy than each single variable. Stratification into different subgroups by the nomogram helped identify the subset of patients who most benefited from more intensive chemotherapy and/or sequential hematopoietic stem cell transplantation. CONCLUSIONS: Our four-CpG-based classifier could predict disease relapse in patients with T-LBL, and could be used to guide treatment decision.

18.
Leukemia ; 34(9): 2392-2404, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32080345

RESUMO

We aimed to establish a discriminative gene-expression-based classifier to predict survival outcomes of T-cell lymphoblastic lymphoma (T-LBL) patients. After exploring global gene-expression profiles of progressive (n = 22) vs. progression-free (n = 28) T-LBL patients, 43 differentially expressed mRNAs were identified. Then an eleven-gene-based classifier was established using LASSO Cox regression based on NanoString quantification. In the training cohort (n = 169), high-risk patients stratified using the classifier had significantly lower progression-free survival (PFS: hazards ratio 4.123, 95% CI 2.565-6.628; p < 0.001), disease-free survival (DFS: HR 3.148, 95% CI 1.857-5.339; p < 0.001), and overall survival (OS: HR 3.790, 95% CI 2.237-6.423; p < 0.001) compared with low-risk patients. The prognostic accuracy of the classifier was validated in the internal testing (n = 84) and independent validation cohorts (n = 360). A prognostic nomogram consisting of five independent variables including the classifier, lactate dehydrogenase levels, ECOG-PS, central nervous system involvement, and NOTCH1/FBXW7 status showed significantly greater prognostic accuracy than each single variable alone. The addition of a five-miRNA-based signature further enhanced the accuracy of this nomogram. Furthermore, patients with a nomogram score ≥154.2 significantly benefited from the BFM protocol. In conclusion, our nomogram comprising the 11-gene-based classifier may make contributions to individual prognosis prediction and treatment decision-making.


Assuntos
Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Transcriptoma , Adulto , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nomogramas , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Estudos Retrospectivos
19.
Hepatol Int ; 14(2): 190-201, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32078141

RESUMO

BACKGROUND: Two-dimensional shear wave elastography (2D-SWE) is the latest generation of ultrasound elastography for the non-invasive assessment of liver fibrosis in chronic hepatitis B (CHB). We aimed to identify confounders of 2D-SWE in fibrosis grading. METHODS: A prospective cohort of 440 CHB patients (286 with liver biopsy and 154 with clinical decompensated cirrhosis) was consecutively enrolled from a clinical trial (registration number: ChiCTR-DCD-15006000) aimed at optimizing 2D-SWE assessments from 2015 to 2018. All patients underwent 2D-SWE examination, anthropometric measurement, and serum biomarker assessment. Steatosis was graded by the magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF). RESULTS: Overall, the prevalence of incorrect fibrosis staging by 2D-SWE was 26.1% (n = 115), with 43.5% of patients under-staged and 56.5% over-staged. In multivariate analysis, the steatosis degree was an independent predictor of 2D-SWE discordance in the overall cohort, with moderate-severe steatosis for underestimation (odds ratio, [OR] = 4.3, 95% confidence interval [CI] 1.2-18.2, p = 0.049) and overestimation (OR = 8.2, 95% CI 2.9-23.5, p < 0.001), and mild steatosis for overestimation (OR = 3.7, 95% CI 1.5-9.0, p = 0.004). In patients with liver biopsy, both histological inflammation activity over 2 (OR = 5.0, 95% CI 2.0-25.3, p = 0.048) and moderate-severe steatosis (OR = 5.2, 95% CI 2.1-13.4, p < 0.001) were independent factors associated with discordance. For the risk of 2D-SWE mis-staging, a nomogram that integrated these confounders was established and the area under the receiver operating characteristic curve of the model was 0.861. CONCLUSIONS: Steatosis and inflammation activities were confounders for 2D-SWE. The combination of these confounders could predict mis-staging risks of CHB-related fibrosis with 2D-SWE and may be valuable to decision-making on liver biopsy for fibrosis staging.


Assuntos
Hepatite B Crônica , Cirrose Hepática/diagnóstico por imagem , Adulto , Estudos de Coortes , Técnicas de Imagem por Elasticidade , Feminino , Humanos , Masculino , Valor Preditivo dos Testes , Estudos Prospectivos , Índice de Gravidade de Doença
20.
Exp Ther Med ; 19(2): 1121-1128, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32010278

RESUMO

The present study aimed to evaluate the utility of the extent of change (C) and change rate (Cr) of cardiac troponin I (cTnI) and hypersensitive C-reactive protein (hs-CRP) prior to and after treatment in evaluating the early therapeutic efficacy of acute myocardial infarction (AMI) treatment. A total of 145 patients with AMI who received regular MI treatment were enrolled in the present study. Patients were divided into the effective group and the ineffective group based on the early therapeutic efficacy. The values of two parameters, namely the serum levels of cTnI and hs-CRP, were collected prior to and after AMI treatment. Data were analyzed by using the t-test, Chi-squared test, logistic regression and receiver operating characteristic (ROC) curve analysis. Compared with those in the ineffective group, the values of cTnI and hs-CRP after treatment [cTnI(post) and hs-CRP(post)], as well as their C and Cr values, were significantly decreased in the effective group (P<0.01). Furthermore, the positive rates (PR) of cTnI(post), hs-CRP(post), (cTnI+hs-CRP)(post), C(cTnI), C(hs-CRP) and C(cTnI+hs-CRP) were significantly lower in the effective group compared with those in the ineffective group (P<0.01). It was indicated that hs-CRP(post) and C(hs-CRP), as well as the PR-cTnI(post) and the PR-C(cTnI), may be used as independent factors for early therapeutic efficacy evaluation (P<0.05). In addition, the area under the ROC curve, as well as the associated sensitivity and specificity analysis for cTnI(post), hs-CRP(post), C(cTnI or hs-CRP) and Cr(cTnI or hs-CRP), all indicated that these parameters were able to distinguish between the effective and the ineffective groups. The present study revealed that compared with the cTnI(post) and hs-CRP(post), the C and the Cr of cTnI and hs-CRP may have enhanced value for evaluating the early therapeutic efficacy of AMI treatment.

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