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OBJECTIVE: Previous clinical studies and meta-analyses have shown controversial results on the association between C3435T polymorphism of the ABCB1 gene and anti-epileptic drug (AED) resistance. Based on the fact that sample size and confounding factors could contribute to the inconsistency, we performed an updated meta-analysis by including the most recent studies, and subgroup analysis was conducted to evaluate the effect of confounding factors on the association. MATERIALS AND METHODS: We searched articles in 6 electronic databases including PubMed, Medline, Embase, Web of science, Cochrane Library, CNKI (China National Knowledge Infrastructure) for relevant articles up to June 2020. RESULTS: The current analysis showed that the C allele of C3435T variant was a risk factor for drug resistance in the overall populations (C allele vs. T allele, OR: 1.13; 95% CI: 1.02 - 1.25; p = 0.02) and in the Caucasians (C allele vs. T allele, OR: 1.09; 95% CI: 1.09 - 1.43; p = 0.002), while no association was observed in Asians and Indians. Particularly, our study reported for the first time that the 3435T allele was more common in epilepsy patients with drug resistance in the Tunisian population (C allele vs. T allele, OR: 0.31; 95% CI: 0.15 - 0.65; p = 0.002). In addition, our present analysis suggested an association between C3435T and AED resistance in cryptogenic, symptomatic, but not in idiopathic patients. Subgroup studies based on age and gender showed no association. CONCLUSION: AED resistance in Caucasian and Tunisian populations may benefit from ABCB1 C3435T genotyping. We recommend that more details, such as gender and etiology of epilepsy, should be taken into account to draw a reliable conclusion in future studies.
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Anticonvulsivantes , Epilepsia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Anticonvulsivantes/efeitos adversos , Povo Asiático/genética , Resistência a Medicamentos/genética , Epilepsia/tratamento farmacológico , Epilepsia/genética , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Plasmonic metamaterials enable extraordinary manipulation of key constitutive properties of light at a subwavelength scale and thus have attracted significant interest. Here, we report a simple and convenient nanofabrication method for a novel meta-device by glancing deposition of gold into anodic aluminum oxide templates on glass substrates. A methodology with the assistance of ellipsometric measurements to examine the anisotropy and optical activity properties is presented. A tunable polarization conversion in both transmission and reflection is demonstrated. Specifically, giant broadband circular dichroism for reflection at visible wavelengths is experimentally realized by oblique incidence, due to the extrinsic chirality resulting from the mutual orientation of the metamaterials and the incident beam. This work paves the way for practical applications for large-area, low-cost polarization modulators, polarization imaging, displays, and bio-sensing.
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Cancer therapy with tyrosine kinase inhibitors (TKIs) is a rapidly developing field, and several TKIs have been reported to have an impact on the activities of UDP-glucosyltransferases (UGTs), implying a potential risk for drug-drug interaction (DDI). Herein, we investigated the inhibitory effects of two commonly used TKIs, midostaurin and ruxolitinib, on human UGTs and quantitatively evaluated their DDI potential via UGT inhibition. It was found that midostaurin was a potent inhibitor of the majority of human UGTs, including UGT1A3, 1A4, 1A7, 1A8, 1A9, 1A10, 2B7, 2B15, and 2B17, with IC50 values lower than 4 µM (IC50 0.0128-3.85 µM), while ruxolitinib exhibited weak inhibition towards the activity of almost all the tested UGT isoforms. Furthermore, based on reversible inhibition, the co-administration of midostaurin at the clinical available dose was predicted to increase the plasma exposure to sensitive UGT1A3, 1A7, and 1A8 substrates by at least 61.4%, 25.6%, and 651%, respectively. In summary, our data identify that midostaurin is a potent inhibitor of the majority of human UGTs and may bring a potential risk of DDI via inhibition against UGT1A3, 1A7, and 1A8, while ruxolitinib cannot trigger UGT-mediated DDI due to its weak inhibition towards UGTs.
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Antineoplásicos/farmacologia , Glucuronosiltransferase/antagonistas & inibidores , Isoenzimas/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Estaurosporina/análogos & derivados , Interações Medicamentosas , Humanos , Nitrilas , Pirimidinas , Proteínas Recombinantes , Estaurosporina/farmacologiaRESUMO
The tumor microenvironment is increasingly acknowledged as a critical contributor to cancer progression, mediating genetic and epigenetic alterations. Beyond diverse cellular interactions from the microenvironment, physicochemical factors such as tumor acidosis also significantly affect cancer dynamics. Recent research has highlighted that tumor acidosis facilitates invasion, immune escape, metastasis, and resistance to therapies. Thus, noninvasive measurement of tumor acidity and the development of targeted interventions represent promising strategies in oncology. Techniques like contrast-enhanced ultrasound (CEUS) can effectively assess blood perfusion, while ultrasound-stimulated microbubble cavitation (USMC) has proven to enhance tumor blood perfusion. We therefore aimed to determine whether CEUS assesses tumor acidity and whether USMC treatment can modulate tumor acidity. Firstly, we tracked CEUS perfusion parameters in MCF7 tumor models and compared them with in vivo tumor pH recorded by pH microsensors. We found that the peak intensity and area under curve of tumor contrast-enhanced ultrasound correlated well with tumor pH. We further conducted USMC treatment on MCF7 tumor-bearing mice, tracked changes of tumor blood perfusion and tumor pH in different perfusion regions before and after the USMC treatment to assess its impact on tumor acidity and optimize therapeutic ultrasound pressure. We discovered that USMC with 1.0 Mpa significantly improved tumor blood perfusion and tumor pH. Furthermore, tumor vascular pathology and PGI2 assays indicated that improved tumor perfusion was mainly due to vasodilation rather than angiogenesis. More importantly, analysis of glycolysis-related metabolites and enzymes demonstrated USMC treatment can reduce tumor acidity by reducing tumor glycolysis. These findings support that CEUS may serve as a potential biomarker to assess tumor acidity and USMC is a promising therapeutic modality for reducing tumor acidosis.
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Numerous nanomedicines have been developed recently that can accumulate selectively in tumours due to the enhanced permeability and retention (EPR) effect. However, the high interstitial fluid pressure (IFP) in solid tumours limits the targeted delivery of nanomedicines. We were previously able to relieve intra-tumoural IFP by low-frequency non-focused ultrasound (LFNFU) through ultrasonic targeted microbubble destruction (UTMD), improving the targeted delivery of FITC-dextran. However, the accumulation of nanoparticles of different sizes and the optimal acoustic pressure were not evaluated. In this study, we synthesised Cy5.5-conjugated mesoporous silica nanoparticles (Cy5.5-MSNs) of different sizes using a one-pot method. The Cy5.5-MSNs exhibited excellent stability and biosafety regardless of size. MCF7 tumour-bearing mice were subjected to UTMD over a range of acoustic pressures (0.5, 0.8, 1.5 and 2.0 MPa), and injected intravenously with Cy5.5-MSNs. Blood perfusion, tumour IFP and intra-tumoural accumulation of Cy5.5-MSNs were analysed. Blood perfusion and IFP initially rose, and then declined, as acoustic pressure intensified. Furthermore, UTMD significantly enhanced the accumulation of differentially sized Cy5.5-MSNs in tumour tissues compared to that of the control group, and the increase was sevenfold higher at an acoustic pressure of 1.5 MPa. Taken together, UTMD enhanced the infiltration and accumulation of Cy5.5-MSNs of different sizes in solid tumours by reducing intra-tumour IFP.
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Líquido Extracelular , Microbolhas , Nanopartículas , Dióxido de Silício , Animais , Nanopartículas/química , Camundongos , Humanos , Feminino , Dióxido de Silício/química , Líquido Extracelular/metabolismo , Carbocianinas/química , Carbocianinas/administração & dosagem , Células MCF-7 , Tamanho da Partícula , Sistemas de Liberação de Medicamentos , Pressão , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/patologia , Neoplasias da Mama/patologia , AcústicaRESUMO
RATIONALE AND OBJECTIVES: To develop and validate a clinical-radiomics model of dynamic contrast-enhanced MRI (DCE-MRI) for the preoperative discrimination of Vessels encapsulating tumor clusters (VETC)- microvascular invasion (MVI) and prognosis of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: 219 HCC patients from Institution 1 were split into internal training and validation groups, with 101 patients from Institution 2 assigned to external validation. Histologically confirmed VETC-MVI pattern categorizing HCC into VM-HCC+ (VETC+/MVI+, VETC-/MVI+, VETC+/MVI-) and VM-HCC- (VETC-/MVI-). The regions of intratumor and peritumor were segmented manually in the arterial, portal-venous and delayed phase (AP, PP, and DP, respectively) of DCE-MRI. Six radiomics models (intratumor and peritumor in AP, PP, and DP of DCE-MRI) and one clinical model were developed for assessing VM-HCC. Establishing intra-tumoral and peri-tumoral models through combining intratumor and peritumor features. The best-performing radiomics model and the clinical model were then integrated to create a Combined model. RESULTS: In institution 1, pathological VM-HCC+ were confirmed in 88 patients (training set: 61, validation set: 27). In internal testing, the Combined model had an AUC of 0.85 (95% CI: 0.76-0.93), which reached an AUC of 0.75 (95% CI: 0.66-0.85) in external validation. The model's predictions were associated with early recurrence and progression-free survival in HCC patients. CONCLUSIONS: The clinical-radiomics model offers a non-invasive approach to discern VM-HCC and predict HCC patients' prognosis preoperatively, which could offer clinicians valuable insights during the decision-making phase.
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Introduction: As one of the most common malignant tumors in clinical practice, hepatocellular carcinoma (HCC) is a major threat to human health, where alpha-fetoprotein (AFP) is widely used for early screening and diagnoses. However, the level of AFP would not elevate in about 30-40% of HCC patients, which is clinically referred to as AFP-negative HCC, with small tumors at an early stage and atypical imaging features, making it difficult to distinguish benign from malignant by imaging alone. Methods: A total of 798 patients, with the majority being HBV-positive, were enrolled in the study and were randomized 2:1 to the training and validation groups. Univariate and multivariate binary logistic regression analyses were used to determine the ability of each parameter to predict HCC. A nomogram model was constructed based on the independent predictors. Results: A unordered multicategorical logistic regression analyses showed that the age, TBIL, ALT, ALB, PT, GGT and GPR help identify non-hepatic disease, hepatitis, cirrhosis, and hepatocellular carcinoma. A multivariate logistic regression analyses showed that the gender, age, TBIL, GAR, and GPR were independent predictors for the diagnosis of AFP-negative HCC. And an efficient and reliable nomogram model (AUC=0.837) was constructed based on independent predictors. Discussion: Serum parameters help reveal intrinsic differences between non-hepatic disease, hepatitis, cirrhosis, and HCC. The nomogram based on clinical and serum parameters could be used as a marker for the diagnosis of AFP-negative HCC, providing an objective basis for the early diagnosis and individualized treatment of hepatocellular carcinoma patients.
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BACKGROUND: This study aimed to evaluate the efficacy and safety of dapagliflozin as a monotherapy glucose-lowering drug treatment for older adults with diabetes. RESEARCH DESIGN & METHODS: Randomized controlled trial reports were retrieved from PubMed, Embase Cochrane Library, and Web of Science from database inception to 8 May 2021. Publication bias and heterogeneity were assessed using the Cochrane risk-of-bias tool and the Cochrane Q statistic, respectively. RESULTS: Compared with placebo, dapagliflozin as a monotherapy glucose-lowering drug did improve the control of glycosylated hemoglobin and fasting plasma glucose levels in older adults. Our analysis also confirmed that the body weight of older adults was well controlled under treatment of dapagliflozin as a monotherapy glucose-lowering drug. Patients in older adults with diabetes took a higher risk of genital infection and renal impairment or failure after treatment of dapagliflozin. In addition, treatment with dapagliflozin reduced the risk of hypoglycemia, and did not reveal increased risk of urinary tract infection and developing fractures compared to placebo in older adults. CONCLUSIONS: Dapagliflozin as a monotherapy glucose-lowering drug appeared to be an effective treatment for older adults with diabetes, although it might increase risk of genital infection and renal impairment or failure.
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Diabetes Mellitus Tipo 2 , Humanos , Idoso , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/efeitos adversos , Glucosídeos/efeitos adversos , Compostos Benzidrílicos/efeitos adversos , Resultado do Tratamento , Glucose , Glicemia , Método Duplo-CegoRESUMO
Mesenchymal stem cells have shown noticeable potential for unlimited self-renewal. They can differentiate into specific somatic cells, integrate into target tissues via cell-cell contact, paracrine effects, exosomes, and other processes and then regulate the target cells and tissues. Studies have demonstrated that transplantation of MSCs could decrease the expression and concentration of collagen in the liver, thereby reducing liver fibrosis. A growing body of evidence indicates that apoptotic MSCs could inhibit harmful immune responses and reduce inflammatory responses more effectively than viable MSCs. Accumulating evidence suggests that mitochondrial transfer from MSCs is a novel strategy for the regeneration of various damaged cells via the rescue of their respiratory activities. This study is aimed at reviewing the functions of MSCs and the related roles of the programmed cell death of MSCs, including autophagy, apoptosis, pyroptosis, and ferroptosis, as well as the regulatory pathogenic mechanisms of MSCs in liver fibrosis. Research has demonstrated that the miR-200B-3p gene is differentially expressed gene between LF and normal liver samples, and that the miR-200B-3p gene expression is positively correlated with the degree of liver fibrosis, suggesting that MSCs could inhibit liver fibrosis through pyroptosis. It was confirmed that circulating monocytes could deliver MSC-derived immunomodulatory molecules to different sites by phagocytosis of apoptotic MSCs, thereby achieving systemic immunosuppression. Accordingly, it was suggested that characterization of the programmed cell death-mediated immunomodulatory signaling pathways in MSCs should be a focus of research.
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Sonodynamic therapy (SDT) is a promising treatment method for solid tumors. However, the high interstitial fluid pressure (IFP) in tumor tissues limits the accumulation of sonosensitizers. In the present study, microbubbles ultrasonic cavitation was used to regulate the tumor's IFP and evaluate SDT effects. Rabbit VX2 tumor tissues were treated with microbubbles ultrasonic cavitation. The IFP of different tumor parts before and after cavitation was measured by the WIN method. The accumulation of the sonosensitizers hematoporphyrin monomethyl ether (HMME) in tumor tissues was observed using an ultramicro spectrophotometer and laser confocal microscope. Then, tumor-bearing rabbits were treated with SDT once a week for eight weeks and the therapeutic effect was evaluated. After microbubbles ultrasonic cavitation treatment, the tumor's IFP decreased and the HMME concentration increased. We concluded that microbubbles ultrasonic cavitation can increase HMME accumulation in rabbit VX2 tumors and increase SDT therapeutic effects.
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Quantification of endogenous steroids and their precursors is essential for diagnosis of a wide range of causes for female infertility. However, immunoassays often overestimate concentrations due to assay interference by other endogenous steroids, especially at low concentrations. In addition, it still lacks of diagnostic reference intervals for five sex steroid hormones, including estradiol (E2), 11-deoxycorticosterone (DOC), 17-hydroxyprogesterone (17-OHP4), pregnenolone (P5) and progesterone (P4), which are crucial for distinguishing between normal individuals and female infertility. Therefore, we developed and validated a reliable and rapid ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for simultaneous determination and quantification of five sex hormones, giving the reference intervals to accurately evaluate and diagnose female infertility. Our results showed that the developed UPLC-MS/MS assay was fast, high throughput, reproducible, specific, accurate, highly sensitive, and fully validated for simultaneous determination of P5, P4, 17-OHP4, DOC and E2 in human follicular fluid. The simple sample preparation procedure in the current study gave reproducible and consistent recoveries. The validation results show that the UPLC-MS/MS assay has acceptable accuracy and precision at low concentrations, which permits their use in clinical study. In addition, our data gave the concentration range of five steroid hormones quantification in patients with female infertility and normal individuals. Our data can be used to accurately evaluate and diagnose female infertility.
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Infertilidade Feminina , Espectrometria de Massas em Tandem , Cromatografia Líquida/métodos , Feminino , Hormônios Esteroides Gonadais , Hormônios , Humanos , Infertilidade Feminina/diagnóstico , Esteroides/química , Espectrometria de Massas em Tandem/métodosRESUMO
Importance: Although BCR-ABL fusion oncoprotein tyrosine kinase inhibitors (BCR-ABL TKIs) can substantially improve the survival rate of chronic myeloid leukemia (CML), they are clinically accompanied by severe hepatotoxicity. Objective: To compare the relative risk (RR) of hepatotoxicity of new-generation BCR-ABL TKIs with that of imatinib, and to provide an overall assessment of the clinical benefit. Data Sources: PubMed, Embase, Cochrane library databases, and ClinicalTrials.gov were searched for clinical trials published between January 2000 and April 2020. Study Selection: Study selection was conducted independently by 2 investigators according to the inclusion and exclusion criteria published previously in the protocol: only randomized phase 2 or phase 3 clinical trials that compared bosutinib, dasatinib, nilotinib, or ponatinib with imatinib were included. Among the 2666 records identified, 9 studies finally fulfilled the established criteria. Data Extraction and Synthesis: Two investigators extracted study characteristics and data independently using a standardized data extraction form. Data were extracted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. When substantial heterogeneity was observed, pooled estimates were calculated based on the random-effect model; otherwise, the fixed-effect model was used. Main Outcomes and Measures: Data extracted included study characteristics, baseline patient information, interventions and data on all-grade and high-grade (grades 3 and 4) elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, overall survival, and major molecular response (MMR). The RRs and 95% CIs were calculated using the inverse variance method. Results: Nine trials involving 3475 patients were analyzed; the median (range) age was 49 (18-91) years; 2059 (59.2%) were male patients. Increased risks were observed for each new-generation TKI except for dasatinib. Patients receiving new-generation TKIs were more likely to experience all grades of ALT elevation (pooled RR, 2.89; 95% CI, 1.78-4.69; P < .001) and grades 3 and 4 ALT elevation (pooled RR, 4.36; 95% CI, 2.00-9.50; P < .001) compared with those receiving imatinib. Patients receiving new-generation TKIs were also more likely to experience all grades of AST elevation (pooled RR, 2.20; 95% CI, 1.63-2.98; P < .001) and grades 3 and 4 AST elevation (pooled RR, 2.65; 95% CI, 1.59-4.42; P < .001) compared with those receiving imatinib. New-generation TKIs were associated with a significantly higher rate of MMR at 1 year compared with imatinib (pooled RR, 1.59; 95% CI, 1.44-1.75; P < .001). No statistical difference in overall survival at 1 year was found between new-generation TKIs and imatinib (pooled RR, 1.00; 95% CI, 1.00-1.01; P = .33). Conclusions and Relevance: When compared to imatinib, bosutinib, nilotinib, and ponatinib had higher relative risks of hepatotoxicity. Treatment with new-generation TKIs was associated with a higher MMR rate at 1 year but not with 1-year overall survival.
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Doença Hepática Induzida por Substâncias e Drogas/etiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Tirosina Quinases/antagonistas & inibidores , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/sangue , Compostos de Anilina/efeitos adversos , Aspartato Aminotransferases/sangue , Dasatinibe/efeitos adversos , Feminino , Humanos , Mesilato de Imatinib/efeitos adversos , Imidazóis/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Pessoa de Meia-Idade , Nitrilas/efeitos adversos , Proteínas Oncogênicas v-abl/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcr/efeitos dos fármacos , Piridazinas/efeitos adversos , Pirimidinas/efeitos adversos , Quinolinas/efeitos adversos , Risco , Adulto JovemRESUMO
OBJECTIVES: To assess the efficiency and safety profiles of levetiracetam and (fos)phenytoin (phenytoin or fosphenytoin) for second-line treatment of seizures by performing a meta-analysis of RCTs. METHODS: We systematically searched PubMed, Embase, Cochrane, FDA.gov, and ClinicalTrials.gov for RCTs (published before July 31, 2020; no language restrictions). Two independent reviewers screened abstracts and titles against inclusion and exclusion criteria published previously in the PROSPERO: CRD42020202736. Eleven studies fulfilled the established criteria. We assessed pooled data by using a random-effects model. Quality analysis was performed by using version 2 of the Cochrane risk-of-bias tool (RoB 2). RevMan v.5.3 was used to perform statistical analyses, and publication bias (egger's test) was assessed with Stata MP v.14.0. RESULTS: Levetiracetam was similar to (fos)phenytoin in seizure termination rate (risk ratio [RR] 0.94; 95% CI 0.87 to 1.01), time of seizure termination (mean difference [MD] 0.44; -0.60 to 1.49), and drug resistance ([RR] 1.12, 0.86 to 1.45). The safety outcome showed a significant statistical difference between fosphenytoin group and levetiracetam group ([RR] 1.44, 1.14 to 1.81), while there was no significant difference observed between phenytoin treatment and levetiracetam treatment ([RR] 1.26, 0.99 to 1.60). CONCLUSION: Levetiracetam was similar to (fos)phenytoin in cessation rate convulsive status epilepticus, and drug resistance, while it was superior (fos)phenytoin in pooled safety outcome. Further exploration is still needed as to whether it is the first choice for second-line drugs.
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Fenitoína , Estado Epiléptico , Anticonvulsivantes/uso terapêutico , Humanos , Levetiracetam/uso terapêutico , Fenitoína/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Estado Epiléptico/tratamento farmacológicoRESUMO
Osimertinib is the only third-generation epidermal growth factor receptor tyrosine-kinase inhibitor (EGFR-TKI) approved by Food and Drug Administration (FDA). This study aimed to know the inhibitory effect of osimertinib on human UDP-glucosyltransferases (UGTs) and human liver microsomes (HLMs), as well as to identify its potential to cause drug-drug interaction (DDI) arising from the modulation of UGT activity. High inhibitory effect of osimertinib was shown towards UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A10, 2B7 and 2B15. Especially, osimertinib exhibited competitive inhibition against UGT1A1 with a Ki,u of 0.87 ± 0.12 µM. It also noncompetitively inhibited SN-38 glucuronidation in pooled HLMs with a Ki,u of 3.32 ± 0.25 µM. Results from quantitative prediction study indicated that osimertinib administered at 80 mg/day may result in a 4.83 % increase in the AUC of drugs mainly metabolized by UGT1A1, implying low risk of DDI via liver metabolism. However, the ratios of [I]gut/Ki,u are much higher than 11 in HLMs and recombinant UGT1A1, indicating a risk for interaction in intestine. The effects of osimertinib on intestinal UGT should be paid more attention on to avoid unnecessary clinical DDI risks.