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Algal toxins produced by microalgae, such as domoic acid (DA)1, have toxic effects on humans. However, toxicity tests using mice only yield lethal doses of algal toxins without providing insights into the mechanism of action on cells. In this study, a fast segmentation of microfluidic flow cytometry cell images based on the bidirectional background subtraction (BBS)2 method was developed to get the visual evidence of apoptosis in both bright-field and fluorescence images. This approach enables mapping of changes in cell morphology and activity under algal toxins, allowing for fast (within 60 s) and automated biological detection. By combining microfluidics with flow cytometry, the intricate cellular-level reaction process can be observed in micro samples of 293 T cells and mouse spleen cells, offering potential for future in vitro experiments.
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Microalgas , Microfluídica , Humanos , Animais , Camundongos , Citometria de FluxoRESUMO
Diffractive deep neural networks (D2NNs) have demonstrated their importance in performing various all-optical machine learning tasks such as classification and segmentation. However, current D2NNs can only detect spatial domain intensity information. They cannot solve problems that rely on frequency information, such as laser linewidth compression. We propose a new D2NN architecture that fully exploits frequency domain information. We demonstrate that only frequency domain D2NN (OF-D3NN) can be trained using deep learning algorithms and be successfully integrated into a free-space optical communications system (FSO) for information recovery.
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Single image dehazing is a challenging task because of the hue and brightness distortion problems due to the atmospheric scattering. These problems limit the perceptual fidelity, as well as information integrity, of a given image. In this paper, we propose an image dehazing method based on the optical neural networks dehazing by simulating optical diffraction. The algorithm is trained from a large number of hazy images and their corresponding clean images. The experimental results demonstrate that the proposed method has reached an advanced level in both PSNR and SSIM dehazing performance indicators, and the amount of calculation is less than most artificial neural networks.
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Research on the polarization reflection distribution characteristics of wakes on the sea surface can provide a theoretical basis for ocean wake target detection and has important research value in the field of ship and underwater moving target monitoring. The Kelvin wake model and the Cox-Munk model are used to describe a wake on a rough sea surface. Considering the atmospheric Rayleigh scattering and the reflection characteristics of a rough sea surface, a visible spectrum band wake polarization characteristic model based on the Stokes vector and Mueller matrix is established to explore the polarization reflection distribution characteristics of wakes on the sea surface under skylight background at different wind speeds, wind directions, and sun angles. A simulation is done of the airborne polarization reflection imaging of wakes on a rough sea surface. The results show that under the determined observation angle, the polarization distribution characteristics of wakes on a rough sea surface are mainly related to the angle of the sun. The polarization contrast of simulated wakes in typical scenes is acceptable, and it is feasible to detect sea wake targets by the polarization method. The analysis and simulation of the wake polarization characteristics model can provide a theoretical basis for ocean wake target detection.
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The efficacy of anaplastic lymphoma kinase (ALK) positive non-small-cell lung cancer (NSCLC) treatment with small molecule inhibitors is greatly challenged by acquired resistance. A recent study reported the newest generation inhibitor resistant mutation L1198F led to the resensitization to crizotinib, which is the first Food and Drug Administration (FDA) approved drug for the treatment of ALK-positive NSCLC. It is of great importance to understand how this extremely rare event occurred for the purpose of overcoming the acquired resistance of such inhibitors. In this study, we exploited molecular dynamics (MD) simulation to dissect the molecular mechanisms. Our MD results revealed that L1198F mutation of ALK resulted in the conformational change at the inhibitor site and altered the binding affinity of ALK to crizotinib and lorlatinib. L1198F mutation also affected the autoactivation of ALK as supported by the identification of His1124 and Tyr1278 as critical amino acids involved in ATP binding and phosphorylation. Our findings are valuable for designing more specific and potent inhibitors for the treatment of ALK-positive NSCLC and other types of cancer.
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Códon , Resistencia a Medicamentos Antineoplásicos/genética , Mutação , Domínios e Motivos de Interação entre Proteínas , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Receptores Proteína Tirosina Quinases/química , Receptores Proteína Tirosina Quinases/genética , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Aminoácidos/química , Quinase do Linfoma Anaplásico , Sítios de Ligação , Crizotinibe , Humanos , Modelos Moleculares , Conformação Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/química , Pirazóis/química , Piridinas/química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
The authors first present a Rosenthal inequality for sequence of extended negatively dependent (END) random variables. By means of the Rosenthal inequality, the authors obtain some complete moment convergence and mean convergence results for arrays of rowwise END random variables. The results in this paper extend and improve the corresponding theorems by Hu and Taylor (1997).
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Conceitos Matemáticos , Análise de Variância , Computação Matemática , Dinâmica não LinearRESUMO
Glioma is a prevalent brain malignancy associated with poor prognosis. Although chemotherapy serves as the primary treatment for brain tumors, its effectiveness is hindered by the limited ability of drugs to traverse the blood-brain barrier (BBB) and the development of drug resistance linked to tumor hypoxia. Herein, we report the creation of hybrid camouflaged multifunctional nanovesicles comprising membranes of tumor C6 cells (mT) and bacterial outer membrane vesicles (OMVs) and co-loaded with manganese dioxide nanoparticles (MnO2 NPs) and doxorubicin (DOX) to synergistically enhance the chemotherapy/chemodynamic therapy (CDT) of glioma. Owing to OMV-mediated BBB penetration and mT-inherited tumor-homing properties, MnO2-DOX@mT/OMVs can penetrate the BBB and enhance the tumor cell-specific uptake of DOX via "proton sponge effect"-mediated lysosomal escape. This enhances the apoptotic effect induced by DOX and minimizing DOX-associated cardiotoxicity by facilitating the accumulation of DOX at the tumor site. Furthermore, the MnO2 NPs in MnO2-DOX@mT/OMVs can generate potent CDT by accelerating the Fenton-like reaction with DOX-generated H2O2 and achieving glutathione (GSH)-depletion-induced glutathione peroxidase 4 (GPX4) inactivation. These results showed that MnO2-DOX@mT/OMVs, designed for brain tumor targeting, significantly inhibited tumor growth and exhibited favorable biological safety. This innovative approach offers the augmentation of anticancer treatment efficacy via a potential combination of chemotherapy and CDT.
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Neoplasias Encefálicas , Doxorrubicina , Glioma , Compostos de Manganês , Nanopartículas , Óxidos , Compostos de Manganês/química , Compostos de Manganês/farmacologia , Óxidos/química , Óxidos/farmacologia , Glioma/tratamento farmacológico , Glioma/patologia , Glioma/metabolismo , Doxorrubicina/farmacologia , Doxorrubicina/química , Animais , Nanopartículas/química , Camundongos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Antibióticos Antineoplásicos/farmacologia , Antibióticos Antineoplásicos/química , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Membrana Celular/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/química , Linhagem Celular Tumoral , Humanos , Tamanho da Partícula , Ensaios de Seleção de Medicamentos Antitumorais , Sobrevivência Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Propriedades de Superfície , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Apoptose/efeitos dos fármacos , RatosRESUMO
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and is a serious threat to human health; thus, early diagnosis and adequate treatment are essential. However, there are still great challenges in identifying the tipping point and detecting early warning signals of early HCC. In this study, we aimed to identify the tipping point (critical state) of and key molecules involved in hepatocarcinogenesis based on time series transcriptome expression data of HCC patients. The phase from veHCC (very early HCC) to eHCC (early HCC) was identified as the critical state in HCC progression, with 143 genes identified as key candidate molecules by combining the DDRTree (dimensionality reduction via graph structure learning) and DNB (dynamic network biomarker) methods. Then, we ranked the candidate genes to verify their mRNA levels using the diethylnitrosamine (DEN)-induced HCC mouse model and identified five early warning signals, namely, CCT3, DSTYK, EIF3E, IARS2 and TXNRD1; these signals can be regarded as the potential early warning signals for the critical state of HCC. We identified CCT3 as an independent prognostic factor for HCC, and functions of CCT3 involving in the "MYCtargets_V1" and "E2F-Targets" are closely related to the progression of HCC. The predictive method combining the DDRTree and DNB methods can not only identify the key critical state before cancer but also determine candidate molecules of critical state, thus providing new insight into the early diagnosis and preemptive treatment of HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Camundongos , Humanos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/patologia , Carcinogênese/genética , Carcinogênese/patologia , Biomarcadores , Transcriptoma , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Chaperonina com TCP-1/genética , Chaperonina com TCP-1/metabolismoRESUMO
Objective: To provide a systematic review of existing meta-analysis on the efficacy, safety and pharmacokinetics of the novel Polo-like kinase-1 (Plk1) inhibitors in various tumor treatments, and assess the methodological quality and the strength of evidence of the included meta-analysis. Methods: The Medline, PubMed, Embase, etc. were searched and updated on 30 June 2022. 22 eligible clinical trials involving a total of 1256 patients were included for analyses. Randomised controlled trials (RCTs) compared the efficacy or safety, or both of any Plk1 inhibitors with placebo (active or inert) in participants. To be included, studies had to be RCTs, quasi-RCTs, and nonrandomized comparative studies. Results: A meta-analysis of two trials reported progression-free survival (PFS) of the overall population (effect size (ES), 1.01; 95% confidence intervals (CIs), 0.73-1.30, I2 =0.0%, P<0.001) and overall survival (OS) of the overall population (ES, 0.91; 95% CIs, 0.31-1.50, I2 =77.6%, P=0.003). 18 adverse events (AEs) reflected that the possibility of occurrence of AEs in the Plk1 inhibitors group was 1.28 times higher than in the control group (odds ratios (ORs), 1.28; 95% CIs,1.02-1.61). The results of meta-analysis showed that the incidence of AEs in the nervous system was the highest (ES, 0.202; 95% CIs, 0.161-0.244), followed by blood system (ES, 0.190; 95% CIs, 0.178-0.201) and digestive system (ES, 0.181; 95% CIs, 0.150-0.213). Rigosertib (ON 01910.Na) was associated with a decreased risk of AEs in digestive system (ES, 0.103; 95% CIs, 0.059-0.147), but BI 2536 and Volasertib (BI 6727) increased risk of AEs in blood system (ES, 0.399; 95% CIs, 0.294-0.504). Five eligible studies reported the pharmacokinetic parameters of the low dosage (100 mg) cohort and the high dosage (200 mg) cohort, and there was no statistical difference in the total plasma clearance, terminal half-life and apparent volume of distribution at steady state. Conclusions: Plk1 inhibitors work better in improving OS and they are well tolerated, effective and safe in reducing the severity of illness while improving the quality of life, especially in patients with non-specific tumors, respiratory system tumors, musculoskeletal system tumors, and urinary system tumors. However, they fail to prolong the PFS. From the vertical whole level analysis, compared to other systems in the body, Plk1 inhibitors should be avoided as far as possible for the treatment of tumors related to the blood circulatory system, digestive system and nervous system, which were attributed to the intervention of Plk1 inhibitors associated with an increased risk of AEs in these systems. The toxicity caused by immunotherapy should be carefully considered. Conversely, a horizontal comparison of three different types of Plk1 inhibitors suggested that Rigosertib (ON 01910.Na) might be relatively suitable for the treatment of tumors associated with the digestive system, while Volasertib (BI 6727) might be even less suitable for the treatment of tumors associated with the blood circulation system. Additionally, in the dose selection of Plk1 inhibitors, the low dose of 100 mg should be preferred, and meanwhile, it can also ensure the pharmacokinetic efficacy that is indistinguishable from the high dose of 200 mg. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022343507.
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Background: Secondary acute myeloid leukemia (S-AML) patients generally have a poor prognosis, but the chromosomal aberrations of S-AML have been rarely reported. We aimed to explore the chromosomal aberrations and clinical significance in patients with S-AML. Patients and methods: The clinical characteristics and karyotypes of 26 patients with S-AML were retrospectively analyzed. The overall survival (OS) was measured from the time of the patients' transition to AML (i.e., at S-AML diagnosis). Results: The study included 26 S-AML patients (13 males and 13 females), with a median age of 63 years (range, 20-77 years). They transformed from various hematologic malignancies or solid tumors; most of them were secondary to myelodysplastic syndrome (MDS). About 62% of the S-AML patients showed chromosomal aberrations. The serum lactate dehydrogenase (LDH) level in S-AML patients with abnormal karyotype was higher than those with normal karyotype. Apart from the differences in treatment regimens, S-AML patients with chromosomal aberrations had shorter OS (P < 0.05). Conclusion: S-AML patients with abnormal karyotype have higher LDH levels and shorter OS than normal karyotype patients, and the OS of hypodiploidy was much shorter than hyperdiploid.
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Leucemia Mieloide Aguda , Masculino , Feminino , Humanos , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Prognóstico , Leucemia Mieloide Aguda/diagnóstico , Aberrações Cromossômicas , Aneuploidia , Cariótipo AnormalRESUMO
Clinical cancer immunotherapies are usually impeded by tumor immunosuppression driven by tumor associated macrophages (TAMs). Thus, TAMs can be considered as a promising therapeutic target for improved immunotherapy, and TAMs-focused molecular targeting agents have made ideal progress in clinical practice. Even so, most TAMs-targeting agents still cannot cover up their own shortcomings as free drugs. The emergence of multifunctional nanomaterials can expectedly endow these therapeutic cargoes with high solubility, favorable pharmacokinetic distribution, cell-specific delivery, and controlled release. Here, the underlying mechanisms of tumor immunosuppression caused by TAMs are first emphatically elucidated, and then the basic design of TAMs-focused immune-nanomedicines are discussed, mainly including diverse categories of nanomaterials, targeted and stimulus-responsive modifications, and TAM imaging in nanomedicines. A summary of current TAMs-targeting immunotherapeutic mechanisms based on functional nanomedicines for TAMs elimination and/or repolarization is further presented. Lastly, some severe challenges related to functional nanomedicines for TAMs-focused cancer immunotherapy are proposed, and some feasible perspectives on clinical translation of TAMs-associated anticancer immunonanomedicines are provided. It is hoped that, with rapid development of nanomedicine in cancer immunotherapy, TAMs-focused therapeutic strategies may be anticipated to become an emerging immunotherapeutic modality for future clinical cancer treatment.
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Nanoestruturas , Neoplasias , Nanomedicina , Macrófagos Associados a Tumor , Imunoterapia , Terapia de Imunossupressão , Neoplasias/terapiaRESUMO
Clinically, the conventional treatments of cancer are still often accompanied by tumor recurrence, metastasis and other poor prognosis. Nowadays, more attention has been paid to photodynamic therapy (PDT), which is regarded as an adjuvant antineoplastic strategy with superiorities in great spatiotemporal selectivity and minimal invasiveness. In addition to eliminating tumor cells via reactive oxygen species (ROS), more meaningfully, this phototherapy can trigger immunogenic cell death (ICD) that plays a vital role in photodynamic immunotherapy (PDIT). ICD-based PDIT holds some immunotherapeutic potential due to further enhanced antitumor efficacy by utilizing various combined therapies to increase ICD levels. To help the PDIT-related drugs improve pharmacokinetic properties, bioavailability and system toxicity, multifunctional nanocarriers can be reasonably designed for enhanced PDIT. In further consideration of severe hypoxia, low immunity and immune checkpoints in tumor microenvironment (TME), advanced nanotherapeutics-mediated PDIT has been extensively studied for boosting antitumor immunity by oxygen-augment, ICD-boosting, adjuvant stimulation and combined checkpoints blockade. Herein, this review will summarize different categories of nanocarriers consisting of their material type, targeting and stimuli-responsiveness. Moreover, we will focus on the latest progress of various strategies to enhance the antitumor immune effect for PDIT and elucidate their corresponding immune-activation mechanisms. Nevertheless, there are several thorny challenges in PDIT, including limited light penetration, tumor hypoxia, immune escape and the development of novel small-molecule compounds that replace immune checkpoint inhibitors (ICIs) for easy integration into nanosystems. It is hoped that these issues raised will be helpful to the preclinical study of nanotherapeutics-based PDIT, thus accelerating the transformation of PDIT to clinical practice.
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Neoplasias , Fotoquimioterapia , Linhagem Celular Tumoral , Humanos , Morte Celular Imunogênica , Imunoterapia , Neoplasias/tratamento farmacológico , Microambiente TumoralRESUMO
OBJECTIVE: To investigate the bacteriostatic effect of platelet-rich plasma (PRP) and its derivative platelet gel (PG) supernatant on Escherichia coli in vitro and its relationship with platelet factor 4 (PF4). METHODS: Apheresis platelets donated by healthy volunteers were obtained from the Blood station of Lu an Blood Center as the source of PRP. The counts of platelet, white blood cell and red blood cell in PRP and its derivative PG supernatant were detected by automatic hematology analyzer. Bacterial growth of PRP and PG supernatants co-cultured with bacteria for different time was observed by plate coating culture method, and the contents of PF4 in PRP and PG supernatants were detected by ELISA. RESULTS: Apheresis platelets were collected from 28 healthy volunteers with a median age of 33 (21-56) years old. PRP can inhibit the growth of escherichia coli, but there were individual differences in antibacterial effect within 24 hours. PRP of 13 healthy volunteers had strong antibacterial effect at 24 hours, 7 cases had weak antibacterial effect at 24 hours, and 8 cases had no antibacterial effect at 24 hours. PG supernatant showed no significant individual difference, and all of them had bacteriostatic effect within 12 hours, but no bacteriostatic effect after 12 hours. There was no statistical difference in the bacteriostatic effect of PRP at 24 hours between healthy volunteers aged ≤30 years and >30 years (P>0.05), and there was no statistical difference between the white blood cell count ≤0.1×109/L and (0.1-1) ×109/L groups (P>0.05). There was significant difference in the bacteriostatic effect of PRP between the two groups with platelet content ≤1 000×109/L and >1 000×109/L (P<0.05). The platelet count in PRP was higher than that in PG supernatant ï¼»(911.57±160.52) ×109/L vs 0ï¼½. The PF4 level in PRP was higher than that in PG supernatant (23623.34±9822.14 vs 6664.74±4065.83, P<0.05). CONCLUSION: Both PRP and PG supernatant have antibacterial effects in Escherichia coli. The bacteriostatic effect of PRP was better than that of PG supernatant, and the platelet and PF4 contents in PRP were higher than those in PG supernatant, suggesting that the platelet and PF4 levels play an important role in bacteriostasis.
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Fator Plaquetário 4 , Plasma Rico em Plaquetas , Adulto , Humanos , Pessoa de Meia-Idade , Escherichia coliRESUMO
OBJECTIVE: The aim of this study was to examine effect of parental arterial stiffness in offspring. METHODS: The individuals who participated in the second or subsequent follow-up and had parent-offspring relationship and completed measurements of brachial-ankle pulse wave velocity (baPWV) from the Kailuan study were recruited. The individuals were divided into groups by the 10-year intervals and sex. Arterial stiffness was defined as the 75th percentiles in each age category. Multivariable generalized estimating equations was used to analyse the effect of parental baPWV and blood pressure in offspring. Multivariable logistic regression using generalized estimating equations was used to analyse the effect of parental arterial stiffness in offspring. RESULTS: A total of 4514 parents and offspring who met the inclusion criteria, including 1785 paternal offspring and 625 maternal offspring was recruited. Mean age of paternal offspring and maternal offspring were 36.26 (SD 7.86) and 36.42 (SD 7.57) years, while their mean baPWV were 1294.40 (SD 225.32) and 1270.74 (SD 241.42) cm/s, respectively. In multivariate linear regression analyses, after adjusted for the covariate risk factors, an increase of 1âcm/s in the paternal and maternal baPWV of resulted in an increase of 0.05 and 0.30âcm/s in offspring, respectively. In multivariate logistic regression analyses, the risk of arterial stiffness in the offspring of paternal and maternal arterial stiffness increased by 50 and 77%, respectively. CONCLUSION: Paternal and maternal baPWV are linear positively correlated with baPWV in offspring. Parental arterial stiffness is a risk factor for arterial stiffness of offspring and is independent of traditional risk factors of offspring arterial stiffness.
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Rigidez Vascular , Índice Tornozelo-Braço , Pressão Sanguínea , Criança , Humanos , Pais , Análise de Onda de Pulso , Fatores de RiscoRESUMO
Effective classification of flies is beneficial to prevent the spread of disease and protect agricultural production. It is important to prevent the invasion of fly species. Aiming at the problem of similar morphology and difficulty in the classification of fly species in the natural environment, this paper proposes a fine-grained classification method for fly species in the complex natural environment based on deep convolutional neural network. Firstly, the specific position of the fly in the image is located by the gradient-weighted class activation graph method, and the object region of the fly is obtained. Then, the local region containing the most abundant information in the image is extracted. When extracting features from the local region, the attention module and cross-layer bilinear pooling are combined. The feature information of different convolutional layers is integrated. Finally, the global and local feature information is integrated for classification. We experimentally compared the proposed method with other state-of-the-art methods on the established dataset. Experimental results show that the accuracy of the proposed method on the three datasets is 84.34%, 89.53% and 93.26%, respectively. Compared with other state-of-the-art methods, this method has a good classification effect on fly species.
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Dípteros , Animais , Atenção , Meio Ambiente , Redes Neurais de ComputaçãoRESUMO
BACKGROUND: Epigenetic modifications have recently attracted much attention in the study of the biological mechanisms of Acute Myelocytic Leukemia (AML) for therapy and prognosis. However, studies on DNA methylation changes during AML treatment are limited. OBJECTIVE: The comprehensive DNA methylation-transcriptome profiles association analysis in this study aimed to establish whole-genome DNA methylation profiles and explore DNA methylation-related genes and their potential functions before and after treatment. And more appropriate biomarkers are expected to be identified for therapy strategies in AML. METHODS: Illumina 450K and RNA-Seq data were obtained from the Cancer Genome Atlas. We performed comprehensive DNA methylation-transcriptome profiles association analysis, pathway analysis, correlation analysis, and survival analyses. The StarBase database was utilized to predict interactions between lncRNAs, miRNAs and target mRNAs. RESULTS: In total, 1592 distinct CpG sites and 2419 different expression transcripts were identified between pretreatment and post-treatment AML. The significantly enriched functions of methylated genes were stem cell differentiation, cell population maintenance, and cell development. The expression of UGT3A2, MOG, and VSTM1 was correlated with DNA methylation levels (r2 >0.5). Lastly, we identified 4 lncRNAs, 9 miRNAs and 142 mRNAs to construct a lncRNA-miRNA-mRNA ceRNA network. CONCLUSION: Our results revealed that DNA methylation was altered before and after treatment. Alterations in DNA methylation affected target gene expression and participated in the key biological processes of AML. Therefore, ceRNA networks may provide further insight into the study of favorable therapeutic markers in AML.
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Leucemia Mieloide Aguda , MicroRNAs , RNA Longo não Codificante , Biomarcadores Tumorais/metabolismo , Metilação de DNA/genética , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Transcriptoma/genéticaRESUMO
Clinically, the primary cause of chemotherapy failure belongs to the occurrence of cancer multidrug resistance (MDR), which directly leads to the recurrence and metastasis of cancer along with high mortality. More and more attention has been paid to multifunctional nanoplatform-based dual-therapeutic combination to eliminate resistant cancers. In addition to helping both cargoes improve hydrophobicity and pharmacokinetic properties, increase bioavailability, release on demand and enhance therapeutic efficacy with low toxic effects, these smart co-delivery nanocarriers can even overcome drug resistance. Here, this review will not only present different types of co-delivery nanocarriers, but also summarize targeted and stimuli-responsive combination nanomedicines. Furthermore, we will focus on the recent progress in the co-delivery of dual-drug using such intelligent nanocarriers for surmounting cancer MDR. Whereas it remains to be seriously considered that there are some knotty issues in the fight against MDR of cancers via using co-delivery nanoplatforms, including limited intratumoral retention, the possible changes of combinatorial ratio under complex biological environments, drug release sequence from the nanocarriers, and subsequent free-drug resistance after detachment from the nanocarriers. It is hoped that, with the advantage of continuously developing nanomaterials, two personalized therapeutic agents in combination can be better exploited to achieve the goal of cooperatively combating cancer MDR, thus advancing the time to clinical transformation.
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Portadores de Fármacos/administração & dosagem , Sistemas de Liberação de Medicamentos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Nanoestruturas/administração & dosagem , Nanomedicina Teranóstica/métodos , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Gases/administração & dosagem , Humanos , Concentração de Íons de Hidrogênio , Proteínas de Neoplasias/antagonistas & inibidores , Oxirredução , Peptídeos/administração & dosagem , RNA Interferente Pequeno/administração & dosagem , Tensoativos/administração & dosagem , Tensoativos/uso terapêuticoRESUMO
BACKGROUND: Vascular endothelial growth factor (VEGF) is one of the angiogenesis regulators, which plays an important role in tumor angiogenesis and tumor progression. Current studies have found that VEGF plays an important role in hematologic diseases including acute myeloid leukemia (AML). However, the circulating levels of VEGF in AML were still controversial among published studies. METHODS: Three databases including PubMed, EMBASE, and Cochrane Library databases were searched up to February 2020. All articles included in the meta-analysis met our inclusion and exclusion criteria. Studies will be screened and data extracted by two independent investigators. The Newcastle-Ottawa Scale (NOS) and the Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool were applied to evaluate the quality of the included studies. A random-effects model was applied to pool the standardized mean difference (SMD). Heterogeneity test was performed by the Q statistic and quantified using I2. All statistical analysis was conducted in Stata 12.0 software. RESULTS: Fourteen case-control studies were finally included in this systematic review and meta-analysis. Heterogeneity was high in our included studies (I2 = 91.1%, P < 0.001). Sensitivity analysis showed no significant change when any one study was excluded using random-effect methods (P > 0.05). Egger's linear regression test showed that no publication bias existed (P > 0.05). Patients with AML, mainly those newly diagnosed and untreated, have higher VEGF levels (SMD = 0.85, 95% CI 0.28-1.42). Moreover, AML patients in n ≥ 40 group, plasma group, Asia and Africa group, and age ≥ 45 group had higher circulating VEGF levels (all P < 0.05). CONCLUSIONS: Compared to healthy controls, our meta-analysis shows a significantly higher level of circulating VEGF in AML patients, and it is associated with sample size, sample type, region, and age.
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Leucemia Mieloide Aguda , Fator A de Crescimento do Endotélio Vascular , África , Ásia , Humanos , Fatores de Crescimento do Endotélio VascularRESUMO
Background: Basic fibroblast growth factor (bFGF) plays an important role in the pathogenesis of acute myeloid leukemia (AML). Whether the levels of circulating bFGF are increased or not in untreated AML patients is still not clear. In order to acquire a more definite evaluation, a meta-analysis was performed.Material and methods: We searched PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, and VIP databases for possible eligible articles. Forest plot was used to present the combined effect values and 95% confidence intervals (CI) through the random-effect model. Subgroup analysis was performed based on sample size, sample type, and region. All statistical analysis was performed in STATA12.0 software.Results: After excluding the articles that did not meet the inclusion criteria, 11 studies that met the inclusion conditions were included in this meta-analysis. Overall, AML patients probably had higher circulating levels of bFGF (SMD = 1.15, 95% CI: 0.35-1.94). The results of sensitivity analysis indicated that the results were stable. Moreover, the trim and fill analysis showed that publication bias had little effect and the results were relatively robust. In addition, AML patients with N < 30 group, serum group, and Asia group (all P < 0.05) had higher circulating bFGF levels, whereas other subgroups showed no significant change.Conclusion: The results of current meta-analysis revealed that AML patients had higher circulating bFGF levels, and it was associated with sample type, sample size, and region. Considering the possible pathogenic role of bFGF in AML, drug development targeting bFGF is very promising for AML patients.