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Background Retrospective or single-center prospective studies with relatively small samples have shown that contrast-enhanced US (CEUS) can improve the diagnostic accuracy of percutaneous biopsy, but larger prospective studies are lacking. Purpose To assess the diagnostic performance of CEUS-guided biopsy (CEUS-GB) of focal liver lesions (FLLs) compared with US-guided biopsy (US-GB) in a prospective multicenter study. Materials and Methods In this randomized controlled study conducted in nine hospitals in China between March 2016 and August 2019, adult participants with FLLs detected with US, CT, or MRI and planned for percutaneous biopsy were randomly assigned to undergo either US-GB or CEUS-GB. Lesions diagnosed as malignant at histopathologic analysis were considered true-positive findings. Benign or indeterminate lesions required further confirmation with either repeat biopsy or clinical follow-up at 6 months or later. The primary endpoint was the diagnostic accuracy rate, and comparison between groups was made using the χ2 test. Results In this study, 2056 participants (1297 men, 759 women; mean age, 58 years ± 11 [SD]) were analyzed: 1030 underwent biopsy with US guidance and 1026 underwent biopsy with CEUS guidance. The overall diagnostic accuracy rate of CEUS-GB was 96% (983 of 1026) versus 93% (953 of 1030) for US-GB (P = .002), CEUS-GB enabled correct identification in 96% of participants (983 of 1026) compared with 92% (953 of 1030) with US-GB (P = .002). The negative predictive value (NPV) for both biopsy methods was moderate but significantly higher for CEUS-GB than for US-GB (74% vs 57%, P = .001). The difference was remarkable for lesions smaller than 2.0 cm, with CEUS-GB showing higher diagnostic accuracy (96% vs 88%, P = .004) and sensitivity (95% vs 87%, P = .007) than US-GB. Among lesions smaller than 2.0 cm, the accuracy of CEUS-GB and US-GB for detection of hepatocellular carcinoma was 93% and 80%, respectively (P = .008), while it was comparable for liver metastases (98% vs 95%, P = .63). Conclusion Contrast-enhanced US-guided biopsy of focal liver lesions is an effective and safe procedure with a higher diagnostic accuracy than US-guided biopsy, especially for lesions smaller than 2.0 cm and for hepatocellular carcinoma diagnosis. Clinical trial registration no. NCT02413437 © RSNA, 2022 Online supplemental material is available for this article.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Adulto , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Carcinoma Hepatocelular/patologia , Estudos Prospectivos , Meios de Contraste , Estudos Retrospectivos , Ultrassonografia/métodos , Sensibilidade e Especificidade , Neoplasias Hepáticas/patologia , BiópsiaRESUMO
To investigate the diversity and distribution of rhizobia associated with Sophora davidii in habitats with different light and soil conditions at the Loess Plateau, we isolated rhizobia from root nodules of this plant grown at 14 sites at forest edge or understory in Shaanxi Province. Based on PCR-RFLP and phylogenies of 16S rRNA gene, housekeeping genes (atpD, dnaK, recA), and symbiosis genes (nodC and nifH), a total of 271 isolates were identified as 16 Mesorhizobium genospecies, belonging to four nodC lineages, and three nifH lineages. The dominance of M. waimense in the forest edge and of M. amorphae/Mesorhizobium sp. X in the understory habitat evidenced the illumination as a possible factor to affect the diversity and biogeographic patterns of rhizobia. However, the results of Canonical Correlation Analysis (CCA) among the environmental factors and distribution of rhizobial genospecies illustrated that soil pH and contents of total phosphorus, total potassium and total organic carbon were the main determinants for the community structure of S. davidii rhizobia, while the illumination conditions and available P presented similar and minor effects. In addition, high similarity of nodC and nifH genes between Mesorhizobium robiniae and some S. davidii rhizobia under the forest of Robinia pseudoacacia might be evidence for symbiotic gene lateral transfer. These findings firstly brought an insight into the diversity and distribution of rhizobia associated with S. davidii, and revealed illumination conditions a possible factor with impacts less than the soil traits to drive the symbiosis association between rhizobia and their host legumes.
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Rhizobium/classificação , Sophora , China , DNA Bacteriano/genética , Ecossistema , Florestas , Genes Bacterianos , Variação Genética , Filogenia , RNA Ribossômico 16S/genética , Rhizobium/isolamento & purificação , Nódulos Radiculares de Plantas/microbiologia , Solo , Microbiologia do Solo , Sophora/microbiologia , SimbioseRESUMO
Alkyl carboxylic acids as well as primary amines are ubiquitous in all facets of biological science, pharmaceutical science, chemical science and materials science. By chemical conversion to redox-active esters (RAE) and Katritzky's N-alkylpyridinium salts, respectively, alkyl carboxylic acids and primary amines serve as ideal starting materials to forge new connections. In this work, a Mn-mediated reductive decarboxylative/deaminative functionalization of activated aliphatic acids and primary amines is disclosed. A series of C-X (X = S, Se, Te, H, P) and C-C bonds are efficiently constructed under simple and mild reaction conditions. The protocol is applicable to the late-stage modification of some structurally complex natural products or drugs. Preliminary mechanistic studies suggest the involvement of radicals in the reaction pathway.
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Aminas/química , Técnicas de Química Sintética/métodos , Ácidos Graxos/química , Manganês/química , Catálise , Estudos de Viabilidade , OxirreduçãoRESUMO
BACKGROUND: Triple-negative breast cancer (TNBC) patients have relatively poor clinical outcomes. A marker predicting the prognosis of patients with TNBC could help guide treatment. Extensive evidence demonstrates that angiopoietin-like 4 (ANGPTL4) is involved in the regulation of cancer growth, metastasis and angiogenesis. Therefore, its role in TNBC is of interest. METHODS: We tested the ANGPTL4 expression level in tumor tissues by immunohistochemistry (IHC) and detected its association with the clinical features of TNBC patients. Next, the effects and mechanisms of ANGPTL4 on TNBC cell migration and adhesion were investigated. RESULTS: We found that ANGPTL4 overexpression was associated with favorable outcomes in TNBC patients. ANGPTL4 upregulation inhibited cell adhesion, migration and invasion in vitro. Further analyses demonstrated that the possible mechanism might involve suppression of TNBC progression by interacting with extracellular matrix-related genes. CONCLUSIONS: The present findings demonstrated that enhancement of ANGPTL4 expression might inversely correlate with TNBC progression. ANGPTL4 is a promising marker of TNBC and should be evaluated in further studies. TRIAL REGISTRATION: Retrospectively registered.
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Proteína 4 Semelhante a Angiopoietina/genética , Prognóstico , Neoplasias de Mama Triplo Negativas/genética , Adesão Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Progressão da Doença , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/terapiaRESUMO
Immune checkpoint blockade of programmed cell death protein 1 (PD-1) had an impressive long-lasting effect in a portion of advanced-stage melanoma patients, however, this therapy failed to induce responses in several patients; how to increase the objective response rate is very important. Cellular FLICE-inhibitory protein (c-FLIP) could inhibit apoptosis directly at the death-inducing signaling complex of death receptors and is also considered to be the main cause of immune escape. The overexpression of c-FLIPL occurs frequently in melanoma and its expression is associated with the prognosis. We found that the level of c-FLIPL expression was associated with the PD-1 blockade response rate in melanoma patients. Thus, we performed this research to investigate how c-FLIPL regulates immunotherapy in melanoma. We demonstrate that down regulation of c-FLIPL enhances the PD-1 blockade efficacy in B16 melanoma tumor model. Down regulation of c-FLIPL could increase the tumor apoptosis and enhance the antitumor response of T cells in the lymphocyte tumor cells co-culture system. Moreover, knockdown of c-FLIPL could decrease the expression of PD-L1 and recruit more effector T cells in the tumor microenvironment. Our results may provide a new combined therapeutic target for further improving the efficacy of PD-1 blockade in melanoma.
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Besides genome editing, CRISPR-Cas12a has recently been used for DNA detection applications with attomolar sensitivity but, to our knowledge, it has not been used for the detection of small molecules. Bacterial allosteric transcription factors (aTFs) have evolved to sense and respond sensitively to a variety of small molecules to benefit bacterial survival. By combining the single-stranded DNA cleavage ability of CRISPR-Cas12a and the competitive binding activities of aTFs for small molecules and double-stranded DNA, here we develop a simple, supersensitive, fast and high-throughput platform for the detection of small molecules, designated CaT-SMelor (CRISPR-Cas12a- and aTF-mediated small molecule detector). CaT-SMelor is successfully evaluated by detecting nanomolar levels of various small molecules, including uric acid and p-hydroxybenzoic acid among their structurally similar analogues. We also demonstrate that our CaT-SMelor directly measured the uric acid concentration in clinical human blood samples, indicating a great potential of CaT-SMelor in the detection of small molecules.
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Proteínas Associadas a CRISPR , Sistemas CRISPR-Cas , Endodesoxirribonucleases , Fatores de Transcrição , Regulação Alostérica , Bioensaio , Clostridiales , Humanos , Limite de Detecção , Motivos de Nucleotídeos , Parabenos , Biologia Sintética , Ácido Úrico/sangueRESUMO
AIM: To study the expression and prognostic significance of CD80 in patients with gastric adenocarcinoma. Materials & methods: Real-time quantitative PCR, western blot and immunohistochemistry were performed to detect the expression of CD80 in gastric cancer tissues and matched adjacent normal tissues. Double immunohistochemical staining was performed to preliminary examine the relationship between CD80+ cells and CD8+ cytotoxic T lymphocytes. RESULTS: The expression of CD80 was downregulated in tumor tissues compared with normal tissues (p = 0.002). Immunohistochemistry analysis showed that 49 (39.8%) of 123 patients with gastric cancer demonstrated reduced CD80 expression, which was correlated with the tumor differentiation grade. CONCLUSION: Our data suggest that reduced CD80 expression independently predicts a poor prognosis in patients with gastric adenocarcinoma.
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Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Antígeno B7-1/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Antígeno B7-1/genética , Biomarcadores Tumorais , Feminino , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Neoplasias Gástricas/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
Coenzyme Q10 (CoQ10) is an important component of the respiratory chain in humans and some bacteria. As a high-value-added nutraceutical antioxidant, CoQ10 has excellent capacity to prevent cardiovascular disease. The content of CoQ10 in the industrial Rhodobacter sphaeroides HY01 is hundreds of folds higher than normal physiological levels. In this study, we found that overexpression or optimization of the synthetic pathway failed CoQ10 overproduction in the HY01 strain. Moreover, under phosphate- limited conditions (decreased phosphate or in the absence of inorganic phosphate addition), CoQ10 production increased significantly by 12% to220 mg/L, biomass decreased by 12%, and the CoQ10 productivity of unit cells increased by 27%. In subsequent fed-batch fermentation, CoQ10 production reached 272 mg/L in the shake-flask fermentation and 1.95 g/L in a 100-L bioreactor under phosphate limitation. Furthermore, to understand the mechanism associated with CoQ10 overproduction under phosphate- limited conditions, the comparatve transcriptome analysis was performed. These results indicated that phosphate limitation combined with glucose fed-batch fermentation represented an effective strategy for CoQ10 production in the HY01. Phosphate limitation induced a pleiotropic effect on cell metabolism, and that improved CoQ10 biosynthesis efficiency was possibly related to the disturbance of energy metabolism and redox potential.
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As the first fungal quorum sensing molecule, farnesol-induced morphological transition is usually studied in dimorphic fungi, but in basidiomycetes the morphological changes regulated by farnesol are rarely investigated. In this study, we found that farnesol made the basidiomycete Coriolus versicolor develop into a hyperbranched morphology with short hyphae and bulbous tips. Farnesol treatment resulted in a significant increase of intracellular oxidative stress level, which influenced the expression of several morphogenesis-related genes, and thereby led to the morphological changes. High oxidative stress level significantly stimulated the expression of laccase genes for improving intracellular laccase biosynthesis. The resulted hyperbranched morphology further accelerated the secretion of intracellular laccase into culture medium. As a result, extracellular laccase production reached a maximum of 2189.2 ± 54.7 U/L in farnesol-induced cultures, which was 6.8-fold greater than that of control cultures. SDS-PAGE and native-PAGE showed that farnesol increased laccase production by promoting the biosynthesis of three laccase isoforms. Together these results provide new opportunities in not only understanding the farnesol-regulated mycelial morphology in basidiomycetes, but also developing novel strategies for enhancing the production of secreted enzymes of biotechnological interest.
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Agaricales/fisiologia , Farneseno Álcool/farmacologia , Hifas/fisiologia , Agaricales/efeitos dos fármacos , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Genes Fúngicos , Dissulfeto de Glutationa/metabolismo , Hifas/efeitos dos fármacos , Hifas/crescimento & desenvolvimento , Lacase/metabolismo , Morfogênese/efeitos dos fármacos , Morfogênese/genética , Espécies Reativas de Oxigênio/metabolismo , Fatores de TempoRESUMO
Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is an uncommon extranodal non-Hodgkin's lymphoma (NHL), which was traditionally treated with anthracycline-containing regimens followed by consolidative radiation therapy (RT) to add therapeutic benefits. The introduction of anti-CD20 antibody rituximab for the treatment of B-cell NHLs has significantly improved the clinical outcome of these malignant diseases. It is unclear, however, whether consolidative RT could still add therapeutic benefits for PB-DLBCL patients treated with rituximab. To answer this important question, we used the Surveillance, Epidemiology, and End Results (SEER) database to evaluate the impact of RT on the clinical outcomes of PB-DLBCL patients in the rituximab era. Information on patient age, year of diagnosis, stage, race, laterality, and RT status for PB-DLBCL patients diagnosed between 2001 and 2014 were extracted. Kaplan-Meier survival curves were plotted, and log-rank test was used to compare the potential survival difference. Multivariate analysis using Cox proportional hazards model was employed to determine the impact of RT and other factors such as age, race, tumor laterality, stage, and year of diagnosis on survival. Among the 386 patients identified, the median follow-up time was 45 months (range, 0-167 months); the median age was 64 years (range, 19-93 years); 33.9% of the patients were younger than 60 years of age; 69.9% of the patients were stage I; 79.0% were white; 51.8% received RT. The 5-year OS and cause-specific survival (CSS) for the whole cohort were 72.3% and 82.5%, respectively. The 5-year OS was significantly superior for patients who received RT compared to those who did not receive RT (78.1% vs. 66.0%, P = 0.031). In multivariable analysis, RT remained significantly associated with improved OS (P = 0.026). In summary, our study suggests that RT still adds significant therapeutic benefits for patients with PB-DLCBL in the rituximab era.
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Antineoplásicos Imunológicos/administração & dosagem , Neoplasias da Mama/terapia , Quimiorradioterapia/métodos , Linfoma Difuso de Grandes Células B/terapia , Rituximab/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/uso terapêutico , Quimiorradioterapia/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Rituximab/uso terapêutico , Programa de SEER , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
2,5-Furandicarboxylic acid (FDCA) is a bio-based platform chemical for the production of polyethylene furanoate (PEF) and other valuable furanic chemicals. A magnetic laccase catalyst with (2,2,6,6-tetramethyl-piperidin-1-yl)oxyl (TEMPO) as the mediator has the remarkable capability of oxidizing 5-hydroxymethylfurfural (HMF) to 2,5-furandicarboxylic acid (FDCA). Under optimal reaction conditions, a quantitative yield (90.2 %) of FDCA with complete HMF conversion was obtained after 96â h of reaction. More importantly, the magnetic laccase catalyst exhibited good recyclability and stability, maintaining 84.8 % of its original activity following six reuse cycles. This is the first report on the efficient catalytic oxidation of HMF to FDCA by using an immobilized enzyme catalyst.
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Ácidos Dicarboxílicos/síntese química , Enzimas Imobilizadas/química , Furaldeído/análogos & derivados , Furanos/síntese química , Lacase/química , Nanopartículas de Magnetita/química , Biocatálise , Óxidos N-Cíclicos/química , Furaldeído/química , Química Verde/métodos , Oxirredução , Dióxido de Silício/químicaRESUMO
Graphene as a 2-dimentional material has been widely used in the field of biomedical applications. In this study, molecular dynamics simulations are carried out on the fibrinopeptide-A and graphene surfaces with N and O modifications. A new set of parameters for the CHARMM force field are developed to describe the behaviors of the surfaces. Our results indicate that the existence of most oxygen and nitrogen groups may enhance the interaction between the surfaces and the peptide, whereas the substitutional nitrogen on the graphene surface does not make a big difference. The improvement of interaction is not only because of the functional group on the surface, but also the defective morphology. The defective morphology also clears away the surface water layer. Our results suggest that the interactions between graphene biomolecules can be affected by functionalizing the surface with different types of functional groups, which is in accordance with the theory of material design.
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Fibrinopeptídeo A/química , Grafite/química , Simulação de Dinâmica Molecular , Nitrogênio/química , Oxigênio/química , Propriedades de SuperfícieRESUMO
Acral melanoma is a rare disease, but is common in Asia. Knowledge of its prognostic indicators is limited. Growing evidence indicates that inflammation plays a critical role in the development and progression of acral melanoma. We developed a novel prognostic model on the basis of preoperative inflammatory markers and examined its prognostic value in a cohort of patients. This retrospective study included 232 acral melanoma patients who underwent radical surgical resection between 2000 and 2010 at the Sun Yat-sen University Cancer Center. Significant predictive factors were identified by multivariate Cox regression analyses, and a prognostic model on the basis of these variables was constructed to predict survival. Kaplan-Meier curves were plotted to estimate overall survival. Multivariate analyses showed that C-reactive protein, albumin/globulin ratio, age, lactic dehydrogenase, and lymph node positivity were related independently to survival. After analyzing these variables, we classified patients into three risk groups. The new prognostic model identified three categories of patients with different prognoses (P<0.001) and significantly stratified patient prognosis into different tumor stages. The area under the curve of the new prognostic model was 0.684 (95% confidence interval: 0.620-0.743), which was significantly higher than that of the other variables (P<0.001). C-reactive protein and albumin/globulin ratio were independently related to survival in our study population and the prognostic model developed using inflammatory-based scores was useful in stratifying patients into different risk groups. Thus, this model will be a valuable complement to the 2009 American Joint Committee on Cancer staging for Asian patients with acral melanoma.
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Inflamação/genética , Melanoma/genética , Neoplasias Cutâneas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Neoplasias Cutâneas/patologia , Adulto JovemRESUMO
A novel strategy of exposing 2-day-old mycelia cultures to 0.8mM farnesol was developed to stimulate extracellular polysaccharide (EPS) production in Trametes versicolor submerged cultures. Farnesol, a quorum sensing molecule in fungi, could significantly increase EPS production by promoting polysaccharide biosynthesis and regulating mycelial morphology. EPS yield reached a maximum of 2.56g/L that was 2.7-fold greater than that of control cultures. Farnesol made T. versicolor develop into fluffy, loose and multi-hyphae morphology, which facilitated the excretion of intracellular polysaccharide into culture medium. Moreover, EPS from farnesol-induced cultures (EPS-F) with higher carbohydrate and uronic acid contents mainly contained high molecular weight polysaccharide (134kDa, 85%), and comprised glucose, mannose and galactose in a molar ratio of 34.2:2.1:1.0. These physicochemical properties led to stronger antioxidant and antitumor activities of EPS-F. This is the first report that farnesol can significantly improve the production of polysaccharide with higher biological activities. It provides a novel strategy to enhance the production and bioactivity of mushroom polysaccharide using microbial quorum sensing molecules.
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Espaço Extracelular/efeitos dos fármacos , Farneseno Álcool/farmacologia , Polissacarídeos Fúngicos/biossíntese , Polissacarídeos Fúngicos/farmacologia , Percepção de Quorum , Trametes/citologia , Trametes/efeitos dos fármacos , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Espaço Extracelular/metabolismo , Células HeLa , Humanos , Percepção de Quorum/efeitos dos fármacos , Trametes/metabolismoRESUMO
The aim of this study is to investigate the incidence and clinical outcomes of primary mediastinal large B-cell lymphoma (PMBL).Here we did a retrospective analysis using the surveillance, epidemiology, and end results (SEER) database to analyze the incidences and survival of patients with PMBL diagnosed during 2001-2012 among major ethnic groups.During 2001-2012, a total of 426 PMBL patients were identified, including 336 whites, 46 blacks, and 44 others. The incidence rates of female to male ratios in white, black, and other were 1.4938, 1.1202, and 1.7303 respectively, suggesting that the female-prominent disease occurrence was seen only in whites and others, but not in black population. Compared to white, the other had a worse 5-year overall survival (OS); however, factors including age, race, socioeconomic status, and stage associated with OS showed no significant difference among ethnic groups; thus, biology factors should be explored to explain the racial difference in OS.In conclusion, our findings revealed diversities in demographic features and prognosis among different racial groups.
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Linfoma Difuso de Grandes Células B/etnologia , Neoplasias do Mediastino/etnologia , Adolescente , Adulto , Idoso , China/epidemiologia , China/etnologia , Feminino , Humanos , Incidência , Linfoma Difuso de Grandes Células B/epidemiologia , Masculino , Neoplasias do Mediastino/epidemiologia , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Programa de SEER , Taxa de SobrevidaRESUMO
An efficient strategy for laccase production in Trametes versicolor cultures was developed using vanillic acid as the inducer. The optimized vanillic acid treatment strategy consisted of exposing 2-day-old mycelia cultures to 80 mg/L vanillic acid. After 4 days, laccase activity of 588.84 U/L was achieved in flasks which represented a 1.79-fold increase compared to the control. In 200-L airlift bioreactor, the maximal laccase activity reached up to 785.12 U/L using the optimized vanillic acid treatment strategy. The zymograms of culture supernatants revealed three bands with laccase activity, among which Lac1 and Lac2 were abundant laccase isoforms constitutively expressed, and Lac3 was an inducible isozyme by vanillic acid. The results of real-time quantitative PCR showed that the transcription level of lcc in T. versicolor cultures grown with vanillic acid for 7 days was about 5.64-fold greater than that without vanillic acid in flasks. In 200-L airlift bioreactor cultures of T. versicolor with addition of vanillic acid, the transcript level of lcc at day 7 was 2.62-fold higher than that in flasks with vanillic acid due to the good mass transfer and oxygen supply in the bioreactor system. This study provides a basis for understanding the induction mechanism of vanillic acid for laccase production and has good potential for industrial applications.
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Lacase/biossíntese , Trametes/efeitos dos fármacos , Ácido Vanílico/farmacologia , Biomassa , Reatores Biológicos , Eletroforese em Gel de Poliacrilamida Nativa , Reação em Cadeia da Polimerase em Tempo Real , Trametes/metabolismoRESUMO
In recent years, asparaginase-based chemotherapy regimens have produced excellent short-term efficacy in patients with extranodal natural killer/T-cell lymphoma (ENKTL). However, few long-term outcomes have been reported to date. A phase II clinical trial evaluating the efficacy and safety of a combination of gemcitabine, oxaliplatin and asparaginase (GELOX), followed by radiotherapy (RT) in the treatment of localized ENKTL, was reported by this group in 2012. By the time of the present analysis, detailed information had been collected for all 27 patients in the phase II trial, over an extended follow-up period. The median follow-up time was 63.15 months. The 5-year overall survival and progression-free survival were 85.0 and 74.0%, respectively. Recurrence within the RT field was observed in three patients, and the planning target-volume control rate at 5 years was 88.9%. One patient with confirmed lung invasion who did not respond to autologus stem cell transplantation (ASCT) was successfully treated by salvage therapy with lenalidomide monotherapy, and the EBV DNA load in this individual reflected disease progression and treatment response. No clinically significant late toxicities were identified during follow-up visits. In conclusion, this updated analysis confirmed the long-term benefit of the GELOX regimen followed by RT, and demonstrated a good safety profile for this treatment. This strategy may be one of the most suitable options for the treatment of early stage ENKTL.
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There are numerous studies that demonstrate the anti-neoplastic activity of phosphatidylinositol 3-kinase (PI3K) inhibitors and the mechanisms of inducing autophagy in cancer cells. The new anticancer drug puquitinib mesylate (XC-302) is a molecular-targeted drug, which suppresses the activity of PI3K directly. However, it remains unclear whether XC302 can develop an antitumor effect by inducing autophagy in nasopharyngeal cancer cells. The MTT assay was used to study the anti-proliferative effects of XC-302. Subsequently, autophagy was determined by monodansylcadaverine (MDC) staining, punctate localization of green fluorescent protein (GFP)-light chain 3 (LC3), LC3 protein blotting and electron microscopy. The expression levels of beclin 1, p62, protein kinase B (AKT), phospho (p)AKT, mechanistic target of rapamycin (mTOR) and pmTOR in XC-302induced autophagy were detected. Autophagy inhibition was assayed by 3-methyladenine (3MA) or small interfering RNA (siRNA) silencing of beclin 1. XC-302 inhibited the viability of CNE2 in a dose-dependent manner and the IC50 of 72 h was 5.2 µmol/l. After cells were exposed to XC-302 for 24 h, MDC-labeled autophagolysosomes were evident in CNE-2 cells by fluorescence microscope. Autophagosomes and autolysosomes were identified by transmission electron microscopy. Following transfection with GFPLC3, XC-302 induced a significant accumulation of GFPLC3, as monitored by a confocal microscope, which was reduced by 3-MA. XC-302 induced the formation of LC3II, increased beclin 1 levels and decreased the expression of p62. Additionally, the expression levels of pAKT and pmTOR were reduced with the elevation of XC-302. Knockdown of beclin 1 with siRNA or co-treatment with 3-MA enhanced significantly the survival of CNE-2 and promoted the ability of clone formation. XC-302 also induced apoptosis in CNE-2, and when autophagy was inhibited by 3-MA, the apoptosis rate was decreased. The present data provides the evidence that XC-302 can induce autophagy in CNE-2, which promotes the program of cell death and inhibits the PI3K/AKT/mTOR signaling pathway. Furthermore, XC-302 also promoted apoptosis in CNE-2 cells, which could be reduced when autophagy was suppressed, meaning that autophagy may interact with apoptosis to induce cell death.
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Adenina/análogos & derivados , Aminoquinolinas/farmacologia , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Adenina/química , Adenina/farmacologia , Aminoquinolinas/química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteína Beclina-1 , Western Blotting , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Relação Dose-Resposta a Droga , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Estrutura Molecular , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/ultraestrutura , Interferência de RNARESUMO
Biomaterial surfaces and interfaces are intrinsically complicated systems because they involve biomolecules, implanted biomaterials, and complex biological environments. It is difficult to understand the interaction mechanism between biomaterials and biomolecules through conventional experimental methods. Computer simulation is an effective way to study the interaction mechanism at the atomic and molecular levels. In this review, we summarized the recent studies on the interaction behaviors of biomolecules with three types of the most widely used biomaterials: hydroxyapatite (HA), titanium oxide (TiO2), and graphene(G)/graphene oxide(GO). The effects of crystal forms, crystallographic planes, surface defects, doping atoms, and water environments on biomolecules adsorption are discussed in detail. This review provides valuable theoretical guidance for biomaterial designing and surface modification.
Assuntos
Materiais Biocompatíveis/química , Aminoácidos/química , Fosfatos de Cálcio/química , Simulação por Computador , Cristalografia , Durapatita/química , Grafite/química , Teste de Materiais , Modelos Moleculares , Estrutura Molecular , Peptídeos/química , Polímeros/química , Proteínas/química , Propriedades de Superfície , Titânio/químicaRESUMO
In patients with multiple myeloma (MM), once-weekly intravenous injection or twice-weekly subcutaneous injection (SC) of bortezomib has been proven to offer non-inferior efficacy to standard twice-weekly intravenous administration, with an improved safety profile. However, whether once-weekly SC bortezomib can further reduce the incidence rate of peripheral neuropathy (PN) and not compromise the efficacy remains to be investigated. 25 patients of MM treated with once-weekly SC bortezomib were reviewed in this study. The median treatment cycles were 4 (range, 2-9 cycles). Complete response (CR) rate was 52%, ≥very good partial response (VGPR) rate was 72%, and ≥partial response (PR) rate was 84%. 1-year and 2-year PFS rate was 63.0% and 34.3%, respectively, and 2-year OS rate was 100%. Any grade of PN was reported in 9 patients (36.0%), with 7 patients (28.0%) had grade 1 PN, and 2 patients (8.0%) had grade 2 PN. No patients reported grade 3/4 PN in this cohort. In conclusion, once-weekly subcutaneous administration of bortezomib offers excellent efficacy with a further improved safety profile, especially with regard to PN. It needs to be validated in future prospective randomized trials.