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2.
ACS Appl Bio Mater ; 7(5): 3452-3459, 2024 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-38723150

RESUMO

A two-photon nanoparticle probe was designed and developed based on the principle of intermolecular interaction of the aggregation-induced locally excited emission luminescence mechanism. The probe has the advantages of simple synthesis, convenient use, strong atomic economy, good biocompatibility, and photobleaching resistance. It can produce a specific and sensitive response to formaldehyde, help detect FA in normal cells and cancer cells, and is expected to become a specific detection probe for FA in vitro and in vivo.


Assuntos
Materiais Biocompatíveis , Formaldeído , Teste de Materiais , Nanopartículas , Tamanho da Partícula , Fótons , Formaldeído/química , Formaldeído/análise , Humanos , Nanopartículas/química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/síntese química , Luminescência , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Estrutura Molecular
3.
J Biochem Mol Toxicol ; 38(2): e23646, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38345168

RESUMO

Circular RNAs (circRNAs) exhibit essential regulation in the malignant development of hepatocellular carcinoma (HCC). This study aims to investigate the physiological mechanisms of circ_0029343 encoded by scavenger receptor class B member 1 (SCARB1) involved in the growth and metastasis of HCC. Differentially expressed mRNAs in HCC were obtained, followed by the prediction of target genes of differentially expressed miRNAs and gene ontology and kyoto encyclopedia of genes and genomes analysis on the differentially expressed mRNAs. Moreover, the regulatory relationship between circRNAs encoded by SCARB1 and differentially expressed miRNAs was predicted. In vitro cell experiments were performed to verify the effects of circ_0029343, miR-486-5p, and SRSF3 on the malignant features of HCC cells using the gain- or loss-of-function experiments. Finally, the effects of circ_0029343 on the growth and metastasis of HCC cells in xenograft mouse models were also explored. It was found that miR-486-5p might interact with seven circRNAs encoded by SCARB1, and its possible downstream target gene was SRSF3. Moreover, SRSF3 was associated with the splicing of various RNA. circ_0029343 could sponge miR-486-5p to up-regulate SRSF3 and activate PDGF-PDGFRB (platelet-derived growth factor and its receptor, receptor beta) signaling pathway by inducing p73 splicing, thus promoting the proliferation, migration, and invasion and inhibiting apoptosis of HCC cells. In vivo, animal experiments further confirmed that overexpression of circ_0029343 could promote the growth and metastasis of HCC cells in nude mice. circ_0029343 encoded by SCARB1 may induce p73 splicing and activate the PDGF-PDGFRB signaling pathway through the miR-486-5p/SRSF3 axis, thus promoting the growth and metastasis of HCC cells.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Humanos , Animais , Camundongos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , RNA Circular/genética , RNA Circular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos Nus , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Regulação Neoplásica da Expressão Gênica , Receptores Depuradores Classe B/genética , Receptores Depuradores Classe B/metabolismo , Fatores de Processamento de Serina-Arginina/genética , Fatores de Processamento de Serina-Arginina/metabolismo
4.
J Immunother ; 47(2): 64-76, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38047403

RESUMO

Emerging evidence has validated that extracellular vesicles (EVs) regulate hepatocellular carcinoma (HCC) progression, while its role in HCC immune escape remains to be elucidated. This study investigates the role of EVs-encapsulated lysyl oxidase like-4 (LOXL4) derived from tumor cells in HCC immune escape. HCC-related microarray data sets GSE36376 and GSE87630 were obtained for differential analysis, followed by identifying the essential genes related to the prognosis of HCC patients. Bone marrow-derived macrophages were treated with EVs derived from mouse Hepa 1-6 cells and cocultured with CD8 + T cells to observe the CD8 + T-cell activity. At last, a mouse HCC orthotopic xenograft model was constructed to verify the effects of HCC cell-derived EVs on the immune escape of HCC cells and tumorigenicity in vivo by delivering LOXL4. It was found that ACAT1, C4BPA, EHHADH, and LOXL4 may be the essential genes related to the prognosis of HCC patients. On the basis of the TIMER database, there was a close correlation between LOXL4 and macrophage infiltration in HCC. Besides, STAT1 was closely related to LOXL4. In vitro experiments demonstrated that LOXL4 could induce programmed death-ligand 1 expression in macrophages and immunosuppression by activating STAT1. In vivo experiments also verified that HCC cell-derived EVs promoted the immune escape of HCC cells and tumorigenicity by delivering LOXL4. LOXL4 was delivered into macrophages via EVs to induce programmed death-ligand 1 by activating STAT1 and inhibiting the killing ability of CD8 + T cells to HCC cells, thus promoting immune escape in HCC.


Assuntos
Carcinoma Hepatocelular , Vesículas Extracelulares , Neoplasias Hepáticas , Animais , Humanos , Camundongos , Antígeno B7-H1/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Ligantes , Neoplasias Hepáticas/metabolismo , Proteína-Lisina 6-Oxidase/genética , Proteína-Lisina 6-Oxidase/metabolismo , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Evasão Tumoral
5.
J Transl Med ; 21(1): 752, 2023 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-37880710

RESUMO

BACKGROUND: Long non-coding RNA (lncRNA) HOTAIR acts importantly in liver cancer development, but its effect on radioresistance remains poorly understood. Here, our study probed into the possible impact of HOTAIR in radioresistance in liver cancer stem cells (LCSCs) and to elucidate its molecular basis. METHODS: Following sorting of stem and non-stem liver cancer cells, LCSCs were identified and subjected to RNA-seq analysis for selecting differentially expressed genes. Expression of HOTAIR was determined in liver cancer tissues and CSCs. The stemness, proliferation, apoptosis and radioresistance of LCSCs were then detected in response to altered expression of HOTAIR-LSD1-JMJD6-BRD4. RESULTS: Ectopic HOTAIR expression was found to promote radioresistance of LCSCs by maintaining its stemness. Mechanistic investigations indicated that HOTAIR recruited LSD1 to the MAPK1 promoter region and reduced the level of H3K9me2 in the promoter region, thus elevating ERK2 (MAPK1) expression. JMJD6-BRD4 complex promoted HOTAIR transcription by forming a complex and positively regulated ERK2 (MAPK1) expression, maintaining the stemness of LCSCs, and ultimately promoting their radioresistance in vitro and in vivo. CONCLUSION: Collectively, our work highlights the promoting effect of the JMJD6-BRD4 complex on the radioresistance of LCSCs through a HOTAIR-dependent mechanism.


Assuntos
Neoplasias Hepáticas , RNA Longo não Codificante , Humanos , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Histona Desmetilases com o Domínio Jumonji/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas Nucleares/metabolismo , Regiões Promotoras Genéticas/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Fatores de Transcrição/metabolismo
7.
Stem Cells Int ; 2023: 6510571, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36762032

RESUMO

It is becoming increasingly evident that key mechanisms of mesenchymal stem cell (MSC) efficacy appear to associate with paracrine activities, and the delivery of cargos through extracellular vesicles (EVs) controls the mechanistic actions of MSCs. Thus, this study clarified a possible mechanism by which EV-encapsulated NEAT1 from adipose-derived mesenchymal stem cells (ADSCs) might mediate gemcitabine resistance in pancreatic cancer (PCa). Microarray profile suggested a differentially expressed lncRNA NEAT1 in PCa, and we determined its expression in PCa cells. NEAT1 was found to be upregulated in PCa. The binding affinity among NEAT1, miR-491-5p, and Snail was identified through bioinformatic analysis and experimental validation. NEAT1 competitively bound to miR-491-5p to elevate Snail expression and diminish SOCS3 expression. PCa cells were cocultured with EVs extracted from ADSCs, followed by assessment of malignant phenotypes, tumorigenesis, and gemcitabine resistance of PCa cells using gain- or loss-of-function experiments. ADSC-derived EVs carrying NEAT1 promoted PCa cell proliferation, migration, and gemcitabine resistance in vitro and enhanced tumorigenicity in vivo by inhibiting miR-491-5p and SOCS3 and upregulating Snail. Collectively, the findings from our study found a new potential strategy for gemcitabine resistance in PCa by illustrating the mechanistic insights of oncogenic ADSC-derived EVs-loaded NEAT1 via regulating the miR-491-5p/Snail/SOCS3 axis.

8.
Microbiol Spectr ; 10(3): e0141722, 2022 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-35695552

RESUMO

In flavivirus, the furin-mediated cleavage of prM is mandatory to produce infectious particles, and the immature particles containing uncleaved prM cannot undergo membrane fusion and release to the extracellular environment. However, the detailed relationship between viral replication or pathogenicity and furin in Japanese encephalitis virus (JEV) hasn't been clarified. Here, JEV with the mutations in furin cleavage sites and its nearby were constructed. Compared with WT virus, the mutant virus showed enhanced cleavage efficiency of prM protein and increased replication ability. Furthermore, we found that the mutations mainly promote genomic replication and assembly of JEV. However, the mutant formed smaller plaques than WT virus in plaque forming assay, indicating the lower cytopathogenicity of mutant virus. To assess the virulence of JEV mutant, an in vivo assay was performed using a mouse model. A higher survival rate and attenuated neuroinflammation were observed in JEV mutant-infected mice than those of WT-infected mice, suggesting the cleavage of prM by furin was closely related to viral virulence. These findings will provide new understanding on JEV pathogenesis and contribute to the development of novel JEV vaccines. IMPORTANCE Japanese encephalitis virus (JEV) is the leading cause of viral encephalitis epidemics in Southeast Asia, affecting mostly children, with high morbidity and mortality. During the viral maturation process, prM is cleaved into M by the cellular endoprotease furin in the acidic secretory system. After cleavage of the prM protein, mature virions are exocytosed. Here, the mutant in furin cleavage sites and its nearby was constructed, and the results showed that the mutant virus with enhanced replication mainly occurred in the process of genomic replication and assembly. Meanwhile, the mutant showed an attenuated virulence than WT virus in vivo. Our study contributes to understanding the function of prM and M proteins and provides new clues for live vaccine designation for JEV.


Assuntos
Vírus da Encefalite Japonesa (Espécie) , Linhagem Celular , Vírus da Encefalite Japonesa (Espécie)/genética , Vírus da Encefalite Japonesa (Espécie)/metabolismo , Furina/metabolismo , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/metabolismo , Virulência , Replicação Viral
9.
Diagn Interv Radiol ; 28(3): 193-199, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35748200

RESUMO

PURPOSE We aimed to assess the performance of quantitative 3D shape analysis in the differential diagno- sis of pancreatic serous oligocystic adenoma (SOA) and mucinous cystic neoplasm (MCN). METHODS Four hundred thirty-two patients diagnosed with serous cystic neoplasms (SCNs) or MCNs were retrospectively reviewed from August 2014 to July 2019 and finally 87 patients with MCNs (n = 45) and SOAs (n = 42) were included. Clinical data and magnetic resonance morphologic fea- tures with 3D shape analysis of lesions (shape sphericity, compacity, and volume) were recorded and compared between MCNs and SOAs according to the pathology. Univariable and multivari- able regression analyses were used to identify independent impact factors for differentiating MCN from SOA. RESULTS The age of MCN patients was younger than SOAs (43.02 ± 10.83 years vs. 52.78 ± 12.31 years; OR = 0.275; 95% CI: 0.098-0.768; P = .014). MCN has a higher female/male ratio than SOA (43/2 vs. 27/15; OR = 40.418; 95% CI: 2.704-604.171; P = .007) and was more often located in the distal of pancreas (OR = 31.403; 95% CI: 2.985-330.342; P = .004). Shape_Sphericity derived from 3D shape analysis was a significant independent factor in the multivariable analysis and the value of MCN was closer to 1 than SOA (OR = 35.153; 95% CI: 5.301-237.585; P < .001). Area under the receiver operating characteristic curve (AUC) of Shape_Sphericity was 0.923 (optimal cutoff value was 0.964876). CONCLUSION Shape_Sphericity in combination with age, sex, and location could help to distinguish MCN from SOA.


Assuntos
Adenoma , Neoplasias Pancreáticas , Adenoma/diagnóstico por imagem , Adulto , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Pâncreas/patologia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Estudos Retrospectivos
10.
ACS Omega ; 7(12): 10458-10468, 2022 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-35382336

RESUMO

Accurate diagnosis of cancer subtypes is a great guide for the development of surgical plans and prognosis in the clinic. Raman spectroscopy, combined with the machine learning algorithm, has been demonstrated to be a powerful tool for tumor identification. However, the analysis and classification of Raman spectra for biological samples with complex compositions are still challenges. In addition, the signal-to-noise ratio of the spectra also influences the accuracy of the classification. Herein, we applied the variational autoencoder (VAE) to Raman spectra for downscaling and noise reduction simultaneously. We validated the performance of the VAE algorithm at the cellular and tissue levels. VAE successfully downscaled high-dimensional Raman spectral data to two-dimensional (2D) data for three subtypes of non-small cell lung cancer cells and two subtypes of kidney cancer tissues. Gaussian naïve bayes was applied to subtype discrimination with the 2D data after VAE encoding at both the cellular and tissue levels, significantly outperforming the discrimination results using original spectra. Therefore, the analysis of Raman spectroscopy based on VAE and machine learning has great potential for rapid diagnosis of tumor subtypes.

11.
J Magn Reson Imaging ; 56(4): 1009-1017, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35119776

RESUMO

BACKGROUND: Recently, a prototype 5.0 T whole-body MRI scanner was developed. A 5.0 T diffusion-weighted imaging (DWI) may help overcome the issues that limit 3.0 T DWI. PURPOSE: To evaluate the feasibility of 5.0 T high-field DWI in the upper abdomen and assess the agreement of the apparent diffusion coefficient (ADC) with that from 3.0 T abdominal DWI. STUDY TYPE: Prospective proof of concept. POPULATION: Nine volunteers (mean ± SD age: 37.3 ± 7.0 years, 8 M), eight healthy and one with liver and kidney cysts. FIELD STRENGTH/SEQUENCE: 3.0 T and 5.0 T; respiratory-triggered spin-echo echo-planar-imaging (SE-EPI)-based DWI sequence. ASSESSMENT: Subjective image quality scores. The ADC values in abdominal organs (liver, pancreas, spleen, and kidney) were measured by two observers for evaluating the interobserver and interfield agreement. STATISTICAL TESTS: Wilcoxon-rank sum test, Bland-Altman analysis, intraclass correlation coefficients (ICCs), and coefficients of variation (CVs). RESULTS: The 5.0 T DWI displayed an increase in subjective image quality score compared to 3.0 T DWI without the significant difference (3.0 T DWI: 3.50 ± 0.47, 5.0 T DWI: 3.72 ± 0.42, P = 0.157). Both the interfield and interobserver agreements of ADC values were substantial to excellent (ICCs = 0.640-0.902). For all four upper abdominal organs, there were no significant differences between the ADC values measured by two observers and between the ADC values of 3.0 T and 5.0 T DWI (P = 0.134-1.000). The CVs of ADC measurements from 3.0 T and 5.0 T DWI were all less than 15.0% (6.7%-14.2%). DATA CONCLUSION: The substantial to excellent agreements between the ADC values measured with 3.0 T and 5.0 T DWI for liver, pancreas, spleen, and kidney suggested that 5.0 T DWI can be applied for abdominal imaging. The ADC values from 5.0 T abdominal DWI hold the potential to serve as the quantitative markers for clinical investigations. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.


Assuntos
Imagem de Difusão por Ressonância Magnética , Imagem Ecoplanar , Abdome/diagnóstico por imagem , Adulto , Imagem de Difusão por Ressonância Magnética/métodos , Imagem Ecoplanar/métodos , Humanos , Imageamento por Ressonância Magnética , Estudos Prospectivos , Reprodutibilidade dos Testes
12.
Eur Radiol ; 32(6): 4198-4209, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35079885

RESUMO

OBJECTIVES: To explore the importance of three-dimensional (3D) quantitative analysis during gadoxetic acid-enhanced magnetic resonance imaging (MRI) of microvascular invasion (MVI) and early recurrence (< 2 years) after surgery of single hepatocellular carcinoma (HCC) ≤ 3 cm. METHODS: Two hundred fourteen patients with pathologically confirmed HCC (training cohort: n = 169; validation cohort: n = 45) were included retrospectively. The 3D quantitative parameters (volume, sphericity, and compacity) and conventional MRI features were analyzed. The significant predictors for MVI were identified using univariate and multivariate logistic regression analyses. Nomograms were constructed from the prediction model, and the relationship between the significant predictors and early recurrence rates was evaluated using the Kaplan-Meier method. RESULTS: Tumor sphericity (odds ratio [OR] = 0.000; p < 0.001), non-smooth tumor margin (OR = 3.353; p = 0.015), and peritumoral hypointensity on hepatobiliary phase (HBP) (OR = 14.067; p = 0.003) were independent significant factors for MVI. When these three factors were combined, the diagnostic specificity of the training and validation cohorts was 97.0 (128/132) and 87.9 (29/33), respectively. The nomogram based on the predictive model performed satisfactorily in the training (C-index: 0.885) and validation (C-index: 0.869) cohorts. Early recurrence rates of patients with two or three significant factors were significantly higher than those with none in the training (29.1% vs. 10.2%, p = 0.007) and validation (36.4% vs. 6.7%, p = 0.037) cohorts. CONCLUSIONS: Lower sphericity combined with non-smooth tumor margin and peritumoral hypointensity on HBP are potential predictive factors for MVI and associated with early recurrence after surgery of HCC ≤ 3 cm. KEY POINTS: • Lower sphericity, non-smooth tumor margin, and peritumoral hypointensity on HBP were important indicators of the occurrence of MVI in HCC. • The combinational model prepared from these findings satisfactorily predicted MVI, and the presence of these predictors was associated with an early recurrence rate after surgical resection in HCC patients. • This model could help clinicians in the preoperative management of small HCC ≤ 3 cm.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Imageamento por Ressonância Magnética/métodos , Invasividade Neoplásica/patologia , Estudos Retrospectivos
13.
Acta Radiol ; 63(6): 734-742, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33969700

RESUMO

BACKGROUND: Gadoxetic acid-enhanced magnetic resonance imaging (MRI) has been widely used in clinical practice. However, scientific evidence is lacking for recommending a particular sequence for measuring tumor size. PURPOSE: To retrospectively compare the size of hepatocellular carcinoma (HCC) measured on different gadoxetic acid-enhanced MRI sequences using pathology as a reference. MATERIAL AND METHODS: A total of 217 patients with single HCC who underwent gadoxetic acid-enhanced MRI before surgery were included. The size of the HCC was measured by two abdominal radiologists independently on the following sequences: T1-weighted; T2-weighted; b-500 diffusion-weighted imaging (DWI); and arterial, portal venous, transitional, and hepatobiliary phases. Tumor size measured on MRI was compared with pathological size by using Pearson correlation coefficient, independent-sample t test, and Bland-Altman plot. Agreement between two readers was evaluated with intraclass correlation coefficient (ICC). RESULTS: Correlation between the MR images and pathology was high for both readers (0.899-0.955). Absolute error between MRI and pathologic assessment was lowest on hepatobiliary phase images for both readers (reader 1, 2.8±4.2 mm; reader 2, 3.2±3.4 mm) and highest on arterial phase images for reader 1 (4.9±4.4 mm) and DWI phase images for reader 2 (5.1±4.9 mm). Absolute errors were significantly different for hepatobiliary phase compared with other sequences for both readers (reader 1, P≤0.012; reader 2, P≤0.037). Inter-reader agreements for all sequence measurements were strong (0.971-0.997). CONCLUSION: The performance of gadoxetic acid-enhanced MRI sequences varied with HCC size, and the hepatobiliary phase may be optimal among these sequences.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/patologia , Meios de Contraste , Gadolínio DTPA , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Imageamento por Ressonância Magnética/métodos , Estudos Retrospectivos , Sensibilidade e Especificidade
14.
Cancer Manag Res ; 13: 5751-5759, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34305409

RESUMO

INTRODUCTION: Circular RNA (CircRNA) SCARB1 plays an oncogenic role in renal cell carcinoma, while its role in other cancers is unclear. The aim of this study was to explore the role of circRNA SCARB1 in hepatocellular carcinoma (HCC). METHODS: The expression of circRNA SCARB1, mature miR-497 and miR-497 precursor in HCC and paired non-tumor tissues from 64 HCC patients were analyzed by RT-qPCR. CircRNA SCARB1 was overexpressed in HCC cells, followed by the measurement of the expression levels of both mature miR-497 and miR-497 precursor to evaluate the effects of overexpression of circRNA SCARB1 on the maturation of miR-497. The effects of circRNA SCARB1 and miR-497 on the proliferation and migration of HCC cells were assessed by CCK-8 assay and Transwell assay, respectively. RESULTS: We found that circRNA SCARB1 was upregulated in HCC. In addition, mature miR-497 and miR-497 were downregulated in HCC. Correlation analysis showed that circRNA SCARB1 was inversely correlated with mature miR-497 but not miR-497 precursor. Consistently, in HCC cells, downregulated mature miR-497, but not miR-497 precursor, was observed in HCC cells transfected with circRNA SCARB1 expression vector. Analysis of cellular behaviors showed that overexpression of circRNA SCARB1 increased the proliferation and migration of HCC cells, while overexpression of miR-497 decreased cell proliferation and migration. Moreover, overexpression of miR-497 reduced the effects of overexpression of circRNA SCARB1. DISCUSSION: Therefore, circRNA SCARB1 is upregulated in HCC and promotes HCC cell proliferation and migration by suppressing the maturation of miR-497.

15.
Microbiol Spectr ; 9(1): e0032121, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34160280

RESUMO

Candida albicans is a prevalent opportunistic human fungal pathogen for which treatment is limited to only four main classes of antifungal drugs, with the azole and echinocandin classes being used most frequently. Drug tolerance, the ability of some cells to grow slowly in supra-MIC drug concentrations, decreases the number of available treatment options. Here, we investigated factors affecting tolerance and resistance to ketoconazole in C. albicans. We found both temperature and the composition of growth medium significantly affected tolerance with little effect on resistance. In deletion analysis of known efflux pump genes, CDR1 was partially required for azole tolerance, while CDR2 and MDR1 were dispensable. Tolerance also required Hsp90 and calcineurin components; CRZ1, which encodes a transcription factor downstream of calcineurin, was required only partially. Deletion of VMA11, which encodes a vacuolar ATPase subunit, and concanamycin A, a V-ATPase inhibitor, abolished tolerance, indicating the importance of vacuolar energy transactions in tolerance. Thus, tolerance to ketoconazole is regulated by multiple factors, including physiological and genetic mechanisms. IMPORTANCE Due to the ever-expanding range of invasive medical procedures and treatments, invasive fungal infections now pose a serious global threat to many people living in an immunocompromised status. Like humans, fungi are eukaryotic, which significantly limits the number of unique antifungal targets; the current arsenal of antifungal agents is limited to just three frontline drug classes. Additional treatment complexities result from the development of drug tolerance and resistance, which further narrows therapeutic options; however, the difference between tolerance and resistance remains largely unknown. This study demonstrates that tolerance and resistance are regulated by multiple genetic and physiological factors. It is prudent to note that some factors affect tolerance only, while other factors affect both tolerance and resistance. The complex underlying mechanisms of these drug responses are highlighted by the fact that there are both shared and distinct mechanisms that regulate tolerance and resistance.


Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Farmacorresistência Fúngica/efeitos dos fármacos , Tolerância a Medicamentos , Cetoconazol/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Proteínas Fúngicas , Proteínas de Choque Térmico HSP90 , Humanos , Proteínas de Membrana Transportadoras , Testes de Sensibilidade Microbiana , Proteínas do Tecido Nervoso , Proteolipídeos , ATPases Translocadoras de Prótons , Temperatura
16.
Onco Targets Ther ; 13: 9407-9417, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33061427

RESUMO

OBJECTIVE: The aim of this study was to estimate the relevance of the epidermal growth factor receptor (EGFR) between serum vascular endothelial growth factor (VEGF) and matrix metalloproteinase 9 (MMP-9) in primary hepatocellular carcinoma (HCC) patients with transarterial chemoembolization (TACE). METHODS: The pre-treatment and post-treatment concentrations of the serum VEGF and MMP­9 were detected with Luminex assay in 80 EGFR-negative patients and 59 EGFR-positive patients who received TACE therapy with different chemotherapeutic drugs. RESULTS: The serum concentration of MMP-9 in the EGFR-positive patients with primary HCC was significantly higher than that in the EGFR-negative patients (P < 0.05). In EGFR-positive patients with primary HCC, differences in stage, metastasis, and differentiation were significant (P < 0.05). Serum VEGF level significantly decreased at the second course of treatment in the EGFR-negative patients from the P group (P < 0.05), while serum MMP-9 level significantly decreased at the second course of treatment in the EGFR-negative patients from the E group (P < 0.05). Serum VEGF level in the EGFR-positive patients among three groups slightly decreased at the first, second and third courses of treatments; however, the differences were not significant (P > 0.05). Serum MMP-9 level in the EGFR-positive patients among three groups showed mild decrease at the first and second courses of treatments; however, the decreases at the third course of treatment were significant (P < 0.05). CONCLUSION: Serum VEGF and MMP-9 are potential biomarkers for the treatment monitoring of EGFR-positive and -negative patients after TACE therapy with different chemotherapeutic drugs.

17.
Diagn Interv Radiol ; 26(5): 396-402, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32815521

RESUMO

PURPOSE: We aimed to evaluate which morphologic features on magnetic resonance imaging (MRI) could predict the progression of pancreatic cystic lesions (PCLs) that are suitable for follow-up. METHODS: A total of 2176 MRI findings of PCLs were retrospectively reviewed between January 2009 and December 2016. The study population was composed of 223 patients. Clinical data and morphologic features of PCLs were recorded. We divided the individuals into two sub-groups according to the final features on MRI. Univariable and multivariable regression analyses were performed to identify independent risk factors for progression of PCLs. RESULTS: A total of 84 PCLs (37.7%) progressed during follow-up, while 139 PCLs (62.3%) were stable. Age (odds ratio [OR], 1.042; P = 0.017), number of lesions (OR, 0.491; P = 0.048), communication to pancreatic duct (PD) (OR, 2.425; P = 0.007) and presence of septa (OR, 6.105; P < 0.001) were significant independent factors for progression of PCLs. Among 84 lesions that progressed, 23 lesions (27.4%) increased to ≥ 30 mm in diameter or showed worrisome imaging features at the end of follow-up that needed clinical intervention. The initial size and communication to PD were independent factors for progression of PCLs necessitating clinical intervention (P < 0.001 and P = 0.011, respectively). CONCLUSION: Age, number of the lesions, communication to PD and presence of septa were independent risk factors for the progression of PCLs, and the initial size and communication to PD could potentially predict PCLs needing clinical interventions.


Assuntos
Cisto Pancreático , Neoplasias Pancreáticas , Seguimentos , Humanos , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Pâncreas , Cisto Pancreático/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Estudos Retrospectivos
18.
Liver Transpl ; 26(6): 751-763, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31901208

RESUMO

Small recurrent hepatocellular carcinoma (HCC) can show atypical imaging patterns, and a specific diagnostic algorithm for HCC is lacking. This study aimed to better characterize postoperative recurrent HCCs <20 mm in size with gadoxetic acid-enhanced magnetic resonance imaging (MRI). We evaluated 373 newly developed nodules after hepatectomy in 204 HCC patients with chronic hepatitis B virus infection. The diagnostic performance of Liver Imaging Reporting and Data System (LI-RADS) version 2018 was calculated with gadoxetic acid-enhanced MRI to characterize recurrent HCC. Modified diagnostic algorithms were proposed by combining significant imaging biomarkers related to subcentimeter and 10-19 mm recurrence, and the algorithms were then compared with the LI-RADS system. A total of 256 recurrent HCCs (108 recurrent HCCs <10 mm in size; 148 recurrent HCCs 10-19 mm in size) were confirmed via histology or follow-up imaging. Nonrim arterial phase hyperenhancement (APHE) and 3 LI-RADS ancillary features (AFs; hepatobiliary phase hypointensity, mild-moderate T2 hyperintensity, and restricted diffusion) were significantly related to recurrent HCCs <20 mm in size according to a multivariate analysis. For subcentimeter recurrence, combining at least 2 of the 3 AFs only achieved better specificity (sensitivity, 83.3%; specificity, 87.7%) than the LR-4 category (sensitivity, 88.9%, P = 0.21; specificity, 70.8%, P = 0.006). For 10-19 mm recurrences, combining nonrim APHE and at least 1 of the 3 AFs achieved only a significantly enhanced sensitivity of 85.1% but a lower specificity of 86.5% compared with the LR-5 category (sensitivity: 63.5%, P < 0.001; specificity: 94.2%, P = 0.13). In conclusion, the diagnostic algorithms for subcentimeter and 10-19 mm recurrent HCCs should be stratified. Combining at least 2 AFs demonstrated comparable sensitivity with significantly enhanced specificity compared with the LR-4 category for characterizing subcentimeter recurrence.


Assuntos
Carcinoma Hepatocelular , Hepatite B Crônica , Neoplasias Hepáticas , Transplante de Fígado , Algoritmos , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/cirurgia , Meios de Contraste , Gadolínio DTPA , Vírus da Hepatite B , Hepatite B Crônica/complicações , Hepatite B Crônica/diagnóstico por imagem , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/cirurgia , Imageamento por Ressonância Magnética , Recidiva Local de Neoplasia/diagnóstico por imagem , Estudos Retrospectivos , Sensibilidade e Especificidade
19.
BMC Med Imaging ; 19(1): 43, 2019 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-31126251

RESUMO

BACKGROUND: The purpose was to investigate the difference of detection rate of incidental pancreatic cystic lesions (PCLs) with computed tomography (CT) and magnetic resonance imaging (MRI) and to compare the difference between CT and MRI and to explore the effect of this difference on surgical resection. METHODS: We reviewed the diagnostic reports for incidental PCLs between 2013 and 2016. Images of PCLs would be re-evaluated. Clinical and imaging data were recorded. The chi-square and independent t-test were conducted for categorical and continuous variables. RESULTS: The prevalence of PCLs was 1.91% (1038/54210) and 3.36% (1282/38099) on CT and MRI respectively, and increased with increasing age (P < 0.001). No significant differences were found in the annual prevalence of PCLs on CT (P = 0.796) and MRI (P = 0.213) from 2013 to 2016 while the number of examinations was increasing every year. The annual detection rate of MRI for small PCLs (< 20 mm) was significantly higher than CT (P < 0.001), but was not significantly different for large PCLs (≥20 mm). The rate of surgical resection of PCLs (≥20 mm) in MRI group was higher than CT (55.2% vs. 37.0%, P < 0.001). CONCLUSIONS: The detection rate of PCLs on CT and MRI tended to be stable despite increasing scan volumes. Female had a slightly more frequency of PCLs than male. MRI detected more small PCLs(< 20 mm) and had higher impact on surgical resection of large PCL(≥20 mm) compared with CT.


Assuntos
Imageamento por Ressonância Magnética/métodos , Cisto Pancreático/diagnóstico por imagem , Cisto Pancreático/cirurgia , Tomografia Computadorizada por Raios X/métodos , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , China , Feminino , Humanos , Achados Incidentais , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Sensibilidade e Especificidade , Fatores Sexuais , Adulto Jovem
20.
Eur J Radiol ; 103: 25-31, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29803381

RESUMO

PURPOSE: Our purpose was to demonstrate the prognostic significance of T1 mapping on gadoxetic acid-enhanced MR imaging in prediction of recurrence of single HCC after hepatectomy. MATERIALS AND METHODS: One hundred and seven patients with single nodular HCC (≤3 cm) who underwent preoperative gadoxetic acid-enhanced MRI were included in the study. T1 mapping with syngo MapIt was obtained on a 1.5 T scanner. Radiological features and reduction rate of T1 relaxation time (Δ%) of tumors were assessed by two radiologists. Cumulative recurrence rates were compared between groups of low and high reduction rate of T1 relaxation time. A further classified cumulative recurrence rate of the overall cohort was based on the numbers of independent predictive factors. RESULTS: Reduction rate of T1 relaxation time (P = 0.001) and non-hypervascular hypointense nodules (P = 0.042) in preoperative gadoxetic acid-enhanced MRI were independently related to recurrence of HCC after hepatectomy. Patients of lower reduction rates group had higher cumulative recurrence rates (P < 0.0001) than patients of higher reduction rates group. A combination of the two risk factors in patients with single HCC had significantly higher recurrence rates compared to those with either or none of the two risk factors. CONCLUSIONS: Reduction rate of T1 relaxation time combined with non-hypervascular hypointense nodules can be reliable biomarkers in the preoperative prediction of recurrence of HCC after hepatectomy.


Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Gadolínio DTPA , Aumento da Imagem/métodos , Neoplasias Hepáticas/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Recidiva Local de Neoplasia/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Meios de Contraste , Feminino , Hepatectomia , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
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