Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 960
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Neuroradiol ; 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32035971

RESUMO

BACKGROUND AND PURPOSE: The aim of the study was to evaluate whether leukoaraiosis (LA) severity is associated with earlier neurological outcome in acute stroke patients undergoing mechanical thrombectomy. MATERIALS AND METHODS: In this retrospective multicenter study, we evaluated 273 acute stroke patients treated with mechanical thrombectomy. LA severity was graded as 0-2 (absent-to-moderate) versus 3-4 (severe) according to the van Swieten scale. The main clinical outcome was the proportion of early neurological improvement and early neurological deterioration. Early neurological improvement was defined as a decrease of ≥4 points on the NIHSS, or an NIHSS score of zero 24 hours after baseline assessment. Early neurological deterioration was defined as an increase of ≥4 points on the NIHSS 24 hours after baseline assessment. RESULTS: There was a significantly lower early neurological improvement rate (17.1% versus 39.2%; P=0.006) and non-significantly higher early neurological deterioration rate (29.3% versus 17.7%; P=0.084) in patients with severe LA (sLA) compared with patients with absent-to-moderate LA. In multivariable analysis, sLA was inversely associated with early neurological improvement (OR, 0.31; 95% CI, 0.13-0.78; P=0.012). There was no significant association of sLA with early neurological deterioration. However, in patients without symptomatic intracranial hemorrhage, sLA was an independent predictor of early neurological deterioration (OR, 2.65; 95% CI, 1.09-6.45; P=0.032). CONCLUSIONS: sLA is a significant negative predictor of early neurological improvement and is an independent predictor of early neurological deterioration in patients without symptomatic intracranial hemorrhage.

2.
Nat Commun ; 11(1): 647, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005830

RESUMO

Providing high performance electrical nano-interconnects for micro-nano electronics that are robust in harsh environments is highly demanded. Today, electrical nano-interconnects based on metallic nanowires, e.g. Ag and Cu, are limited by their positive physicochemical reactivity and ductility under large strain (i.e. irreversible dislocations and local necking-down elongation) at high temperatures or in strong oxidizing and acidic environments. Herein, to overcome these limitations, high-quality millimetre-sized soft manganese-based silicide (Mn5Si3@SiO2) nanowire nanocables are designed via a glassy Si-Mn-O matrix assisted growth. The proposed nanocables exhibit good electrical performance (resistivity of 1.28 to 3.84×10-6 Ωm and maximum current density 1.22 to 3.54×107 A cm-2) at temperatures higher than 317°C in air atmosphere, strongly acidic (HCl, PH=1.0) and oxidizing (H2O2, 10%) ambient, and under complex electric field. The proposed Mn5Si3@SiO2 nanocables, which withstand a strain of 16.7% free of failure, could be exploited for diverse applications in flexible electronics and complex wiring configurations.

3.
Biophys J ; 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-32049055

RESUMO

Metastasis of mesenchymal tumor cells is traditionally considered as a single-cell process. Here, we report an emergent collective phenomenon in which the dissemination rate of mesenchymal breast cancer cells from three-dimensional tumors depends on the tumor geometry. Combining experimental measurements and computational modeling, we demonstrate that the collective dynamics is coordinated by the mechanical feedback between individual cells and their surrounding extracellular matrix (ECM). We find the tissue-like fibrous ECM supports long-range physical interactions between cells, which turn geometric cues into regulated cell dissemination dynamics. Our results suggest that migrating cells in three-dimensional ECM represent a distinct class of an active particle system in which the collective dynamics is governed by the remodeling of the environment rather than direct particle-particle interactions.

4.
Oncol Rep ; 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-32020217

RESUMO

Osteosarcoma is one of the most malignant bone tumors, and its major threats are aggressive invasion and early tumor metastasis, which result in a poor prognosis and high mortality. Accumulating evidence indicates that ginsenoside compound K (CK) has a significant antitumor effect, particularly on the inhibition of proliferation and invasion of numerous human tumors. In the present study, it was revealed that CK inhibited the viability and proliferation of osteosarcoma cells. Moreover, it was demonstrated that CK induced apoptosis and inhibited the migration and invasion of osteosarcoma cells via apoptotic staining, Annexin V/PI staining, and Transwell invasion assays. Furthermore, at the molecular level, the present results confirmed that apoptosis and invasion­related proteins were regulated by CK, which was possibly related to the blockade of the PI3K/mTOR/p70S6K1 signaling pathway. In summary, the present findings indicated that CK inhibited viability and proliferation, induced apoptosis, and inhibited the migration and invasion of osteosarcoma cells through the PI3K/mTOR/p70S6K1 signaling pathway.

5.
J Clin Lab Anal ; : e23215, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32020674

RESUMO

BACKGROUND: CircMAN2B2 is a newly discovered circRNA that has been found to be an oncogene in lung cancer and glioma. The present study was designed to reveal the role of circMAN2B2 in gastric carcinoma (GC). METHODS: qRT-PCR method was utilized to examine circMAN2B2 expression in GC tissues and paracancerous tissues. Next, circMAN2B2 expression in SNU-16 and AGS cells was silenced by transfection. CCK-8 assay, colony formation assay, flow cytometer, Transwell assay, and Western blot were conducted for testing cell phenotype changes. Further, the downstream genes and signaling were uncovered by qRT-PCR and Western blot. RESULTS: As relative to paracancerous tissues, circMAN2B2 was high-expressed in GC tissues. Silence of circMAN2B2 clearly declined SNU-16 and AGS cells viability, survival, migration but enhanced apoptosis. Meanwhile, silence of circMAN2B2 induced the cleavage of caspases (-3 and -9), down-regulation of MMPs (-2 and -9), and up-regulation of miR-145. The impacts of circMAN2B2 silence toward SNU-16 and AGS cells were attenuated by miR-145 silence. Moreover, circMAN2B2 silence deactivated PI3K, AKT while activated JNK through regulating miR-145. CONCLUSION: This work presented the oncogenic function of circMAN2B2 in GC cells growth and migration. CircMAN2B2 exerted its function possibly through regulating miR-145 as well as PI3K/AKT and JNK pathways.

6.
J Biochem Mol Toxicol ; : e22458, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32020707

RESUMO

Gastric cancer (GC) is the third leading cause of cancer-related death worldwide. Circular RNA circHIAT1 has been proved to play an antitumor role. We aimed to explore the function and mechanism of circHIAT1 in GC. MKN28 and MKN45 cells were transfected with PLCDH-circHIAT1, miR-21 mimic, and relative control. Cell viability and apoptosis were examined through Cell Counting Kit-8 and flow cytometry, respectively. CircHIAT1 expression and other relative factors were tested through quantitative reverse transcription-polymerase chain reaction and Western blot analysis, respectively. Our findings demonstrated that circHIAT1 was lowly expressed in GC tissues. After transfection with PLCDH-circHIAT1 in MKN28 and MKN45 cells, cell viability was decreased, while the expression levels of p53 and p21 were raised, as well as apoptosis. Besides this, the epithelial-mesenchymal transition process was inhibited by PLCDH-circHIAT1 transfection. Mechanistically, miR-21 expression was upregulated in GC tissues and could be negatively regulated by circHIAT1. Further experiments showed that the addition of miR-21 mimic reversed the growth inhibition effects of circHIAT1 overexpression. Moreover, circHIAT1 inhibited the activation of phosphatase and tensin homolog/phosphatidylinositol 3 kinase/protein kinase B and extracellular signal-regulated kinase signal pathways via downregulating miR-21. CircHIAT1 functioned as a tumor inhibitor in GC cells through downregulating miR-21, and could be a novel target for GC treatment.

7.
J Hazard Mater ; 391: 122201, 2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-32045804

RESUMO

Dissolved organic matter (DOM), ubiquitously co-present in micropollutant-impaired water, significantly decreases micropollutant removal in UV-based AOPs through consuming radicals and filtering UV light. In this study, pre-ozonation was proposed to alleviate the negative effects of DOM on UV-based AOPs. After ozone treatment of DOM-containing water at ozone dosages of 0.1-1 mg O3/mg DOC, the degradation rate of benzoic acid (BA) in UV/H2O2 process increased by 7-34% mainly due to the enhanced transmission of UV light. The degradation rate of BA in UV/S2O82- process varied from -11% to 25% at ozone dosages of 0.1-1 mg O3/mg DOC because of the increased photolysis rate of S2O82- and the altered reactivity of DOM towards SO4-. Pre-ozonation of DOM at ozone dosage of 1 mg O3/mg DOC enhanced the oxidation rate of BA in UV/chlorine process by 35% due to the increased rate of chlorine photolysis and the decreased reactivity of DOM towards Cl. The influence of pre-ozonation on the formation potential of disinfection by-products (DBPs) depends on the kind of AOPs and the species of DBPs. The energy cost analysis suggests that pre-ozonation of DOM is an economic process for enhancing pollutant abatement by UV-based AOPs.

8.
Clin Respir J ; 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32052554

RESUMO

BACKGROUND: This study assessed predictors of pulmonary thromboembolism (PE) resolution and their implications for clinical outcome. METHOD: A total of 150 patients with acute PE diagnosed by computed tomography pulmonary angiography (CTPA) were included. All patients received anticoagulant therapy for 3-6 months and were followed-up for at least 2 years. D-dimer levels in plasma were assayed at the first admission and during follow-up. RESULTS: The rate of CTPA-confirmed PE resolution was 48.67% at 6 months, 68% at 12 months, and 78.67% at 24 months. Thirty-nine patients had recurrent thrombosis after anticoagulation therapy was stopped, whereas 93 patients had complete resolution. The initial D-dimer level positively correlated with the pulmonary artery obstruction index (PAOI) (r = 0.21; P = 0.015), but did not significantly differ between patients experiencing resolution or recurrence. In contrast, the follow-up mean D-dimer level was significantly higher in the recurrent group (P < 0.001), and this level was an independent risk factor for recurrent PE after termination of anticoagulation treatment (OR 1.003, 95%CI 1.002 to 1.004; P < 0.001). Higher initial thromboembolic burden measured by PAOI was associated with residual thromboemboli (P = 0.004) and recurrence (P = 0.03), but was not an independent risk factor for either. CONCLUSIONS: Elevated D-dimer is an independent risk factor for PE recurrence. A higher initial thromboembolic burden may be associated with unresolved thromboemboli or recurrence.

9.
Food Chem ; 315: 126275, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32004982

RESUMO

The effects of individual epi-brassinolide (eBL) and NaCl, as well as their combination on contents of main phytochemicals and antioxidant capacity of Chinese kale sprouts were investigated. Our results showed that the application of 100 nM eBL decreased the contents of individual and total glucosinolates, while treatments of 160 mM NaCl both alone and combined with 100 nM eBL enhanced the glucosinolates accumulation by promoting the expression of genes involved in glucosinolate biosynthesis in Chinese kale sprouts and the combined treatment led to significantly higher content of most glucosinolate profiles. Moreover, it also elevated the contents of ascorbic acid and total carotenoids, whereas did not influence the total phenolics and antioxidant capacity. These findings indicated that the combined treatment of 100 nM eBL plus 160 mM NaCl could provide a new strategy to improve the main health promoting compounds in Chinese kale sprouts.

10.
FEMS Microbiol Ecol ; 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32005997

RESUMO

Phyllosphere harbor diverse microorganisms, which influence plant growth and health. In order to understand the extent to which environmental factors affect epiphytic microbial communities, we characterized microbial communities on leaves of three separate tree species present on the college campus, and also present within a forest park over two seasons. Quantitative PCR analysis showed the quantity of 16S rRNA genes was lower in May compared with October, while the abundances of functional genes (nifH and bacterial amoA genes) were extremely high in May. High-throughput sequencing revealed a large variation in the diversity and composition of bacterial and diazotrophic communities over the two seasons, and showed the abundance of functional genera, such as Nocardioides, Bacillus and Zoogloea were significantly elevated in May. In addition, xenobiotic biodegradation pathways of bacterial communities were clearly elevated in May. Network analysis showed the correlations between phyllospheric bacteria in May were more complex than that in October and showed greater negative correlations. These results were consistent in all tree species in this study. This study showed that phyllospheric bacteria varied greatly in different seasons, which implies that different growing seasons should be considered in the exploitation of the interactions between phyllospheric microorganisms and host plants.

11.
Gen Physiol Biophys ; 39(1): 1-12, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32039820

RESUMO

Gastric cancer (GC) is a high mortality disease. We studied the function and mechanism of long non-coding RNA prostate cancer-associated transcript 6 (lncRNA PCAT6) on cell proliferation and epithelial-mesenchymal transition (EMT) in GC cells. CCK-8, flow cytometry and colony formation assay were respectively used to detect the cell viability, apoptosis and colony formation. PCAT6 and miR-15a expression were changed by cell transfection. Moreover, the level of Cyclin D1, p53, Bax, Cleaved caspase-3 and relate-proteins of EMT and cell pathways were investigated by Western blot. Besides, the level of miR-15a and PCAT6 was tested by RT-qPCR. Besides, the target relation between miR-15a and PCAT6 were tested by luciferase assay. PCAT6 was highly expressed in GC cells and tissues. Silencing of PCAT6 restrained the relate-proteins of cell proliferation and EMT. Furthermore, PCAT6 reversely regulated miR-15a and miR-15a inhibitor reversed the efficacy of sh-PCAT6 in cell proliferation and EMT. PCAT6 restrained the relate-proteins of RB/E2F and Wnt/ß-catenin pathways and miR-15a reverse this progress. Finally, PCAT6 was a target of miR-15a. Silencing of lncRNA PCAT6 restrained proliferation and EMT of GC cells by targeting miR-15a via RB/E2F and Wnt/ß-catenin pathways.

12.
Genes (Basel) ; 11(1)2020 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-31968559

RESUMO

Accurate analysis of gene expression requires selection of appropriate reference genes. In this study, we report analysis of eight candidate reference genes (ACTIN, UBQ, EF-1α, UBC, IF-4α, TUB, PP2A, and HIS), which were screened from the genome and transcriptome data in Brassica juncea. Four statistical analysis softwares geNorm, NormFinder, BestKeeper, and RefFinder were used to test the reliability and stability of gene expression of the reference genes. To further validate the stability of reference genes, the expression levels of two CYCD3 genes (BjuB045330 and BjuA003219) were studied. In addition, all genes in the xyloglucan endotransglucosylase/hydrolase (XTH) family were identified in B. juncea and their patterns at different periods of stem enlargement were analyzed. Results indicated that UBC and TUB genes showed stable levels of expression and are recommended for future research. In addition, XTH genes were involved in regulation of stem enlargement expression. These results provide new insights for future research aiming at exploring important functional genes, their expression patterns and regulatory mechanisms for mustard development.

13.
Br J Nutr ; : 1-41, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31959268

RESUMO

Taurine plays important roles in the metabolism of bile acid, cholesterol and lipid. However, little relevant information has been available in fish where taurine has been identified as a conditionally essential nutrient. The present study aimed to investigate the effects of dietary taurine on the metabolism of bile acid, cholesterol, and lipid in tiger puffer, which is both an important aquaculture species and a good research model having a unique lipid storage pattern. An 8-week feeding trial was conducted in a flow-through seawater system. Three experimental diets differed only in taurine level, i.e., 1.7, 8.2, and 14.0 mg kg-1. Taurine supplementation increased the total bile acid content in liver, but decreased the content in serum. Taurine supplementation also increased the contents of total cholesterol (TC) and HDL-C in both liver and serum. The hepatic bile acid profile mainly includes taurocholic acid (94.48%), taurochenodeoxycholic acid (4.17%), and taurodeoxycholic acid (1.35%), and the contents of all these conjugated bile acids were increased by dietary taurine. The hepatic lipidomics analysis showed that taurine tended to decrease the abundance of individual phospholipids, and increase those of some individual triglycerides and ceramides. The hepatic mRNA expression study showed that taurine stimulated the biosynthesis of both bile acid and cholesterol, possibly via regulation of FXR and HDL metabolism. Taurine also stimulated the hepatic expression of lipogenic genes. In conclusion, dietary taurine stimulated the hepatic biosynthesis of both bile acid and cholesterol, and tended to regulate the lipid metabolism in multiple ways.

14.
J Nanobiotechnology ; 18(1): 10, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31918721

RESUMO

BACKGROUND: 5-Fluorouracil (5-FU) has been commonly prescribed for patients with colorectal cancer (CRC), but resistance to 5-FU is one of the main reasons for failure in CRC. Recently, microRNAs (miRNAs) have been established as a means of reversing the dilemma by regulating signaling pathways involved in initiation and progression of CRC. However, how to safely and effectively deliver miRNA to target cells becomes a main challenge. RESULTS: In this study, Engineered exosomes were exploited to simultaneously deliver an anticancer drug 5-FU and miR-21 inhibitor oligonucleotide (miR-21i) to Her2 expressing cancer cells. Purified engineered exosomes from the donor cells loaded with 5-FU and miR-21i via electroporation to introduce into 5-FU-resistant colorectal cancer cell line HCT-1165FR. Furthermore, systematic administration of 5-FU and miR-21i loaded exosomes in tumor bearing mice indicated a significantly anti-tumor effect. The results showed that the engineered exosome-based 5-FU and miR-21i co-delivery system could efficiently facilitate cellular uptake and significantly down-regulate miR-21 expression in 5-FU resistant HCT-1165FR cell lines. Consequently, the down-regulation of miR-21 induced cell cycle arrest, reduced tumor proliferation, increased apoptosis and rescued PTEN and hMSH2 expressions, regulatory targets of miR-21. Of particular importance was the significant reduction in tumor growth in a mouse model of colon cancer with systematic administration of the targeting miR-21i. More excitedly, the combinational delivery of miR-21i and 5-FU with the engineered exosomes effectively reverse drug resistance and significantly enhanced the cytotoxicity in 5-FU-resistant colon cancer cells, compared with the single treatment with either miR-21i or 5-FU. CONCLUSION: The strategy for co-delivering the functional small RNA and anticancer drug by exosomes foreshadows a potential approach to reverse the drug resistance in CRC and thus to enhance the efficacy of the cancer treatment.

15.
Microbiome ; 8(1): 4, 2020 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-31954405

RESUMO

BACKGROUND: Stress-induced hormones are essential for plants to modulate their microbiota and dynamically adjust to the environment. Despite the emphasis of the role of the phytohormone ethylene in the plant physiological response to heterospecific neighbour detection, less is known about how this activated signal mediates focal plant rhizosphere microbiota to enhance plant fitness. Here, using 3 years of peanut (Arachis hypogaea L.), a legume, and cyanide-containing cassava (Manihot esculenta Crantz) intercropping and peanut monocropping field, pot and hydroponic experiments in addition to exogenous ethylene application and soil incubation experiments, we found that ethylene, a cyanide-derived signal, is associated with the chemical identification of neighbouring cassava and the microbial re-assemblage in the peanut rhizosphere. RESULTS: Ethylene production in peanut roots can be triggered by cyanide production of neighbouring cassava plants. This gaseous signal alters the microbial composition and re-assembles the microbial co-occurrence network of peanut by shifting the abundance of an actinobacterial species, Catenulispora sp., which becomes a keystone in the intercropped peanut rhizosphere. The re-assembled rhizosphere microbiota provide more available nutrients to peanut roots and support seed production. CONCLUSIONS: Our findings suggest that root ethylene acts as a signal with a dual role. It plays a role in perceiving biochemical cues from interspecific neighbours, and also has a regulatory function in mediating the rhizosphere microbial assembly, thereby enhancing focal plant fitness by improving seed production. This discovery provides a promising direction to develop novel intercropping strategies for targeted manipulations of the rhizosphere microbiome through phytohormone signals. Video abstract.

16.
Small ; : e1906360, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31972070

RESUMO

Hepatotoxicity is a key concern in the clinical translation of nanotherapeutics because preclinical studies have consistently shown that nanotherapeutics accumulates extensively in the liver. However, clinical-stage nanotherapeutics have not shown increased hepatotoxicity. Factors that can contribute to the hepatotoxicity of nanotherapeutics beyond the intrinsic hepatotoxicity of nanoparticles (NPs) are poorly understood. Because of this knowledge gap, clinical translation efforts have avoided hepatotoxic molecules. By examining the hepatotoxicity of nanoformulations of known hepatotoxic compounds, it is demonstrated that nanotherapeutics are associated with lower hepatotoxicity than their small-molecule counterparts. It is also found that the reduced hepatotoxicity is related to the uptake of nanotherapeutics by macrophages in the liver. These findings can facilitate further development and clinical translation of nanotherapeutics.

17.
Dig Dis Sci ; 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31993894

RESUMO

BACKGROUND AND AIMS: The objective of this study was to construct and authenticate nomograms to project overall survival (OS) and cancer-specific survival (CSS) in primary gastrointestinal non-Hodgkin lymphomas (PGINHL). METHODS: Suitable patients were chosen from the Surveillance, Epidemiology and End Results database and Wannan Medical College Yijishan Hospital. The Cox regression model was used to acquire independent predictive factors to develop nomograms for projecting OS and CSS. The performance of the nomograms was validated using the Harrell's concordance index (C-index), calibration curves, and decision curve analysis (DCA) and was compared with that of the AJCC 7th staging system. Survival curves were obtained using the Kaplan-Meier method, while the log-rank test was used to compare the difference among the groups. RESULTS: The C-index of the nomograms for OS and CSS was 0.735 (95% CI = 0.719-0.751) and 0.761 (95% CI = 0.739-0.783), respectively, signifying substantial predictive accuracy. These outcomes were reproducible when the nomograms were used for the internal and external validation cohorts. Moreover, assessments of the C-index, AUC, and DCA between the nomogram results and the AJCC 7th staging system showed that the former was better for evaluation and was more clinically useful. CONCLUSIONS: We constructed the nomogram which could predict 1-, 3-, and 5-year OS and CSS of patients with PGINHL. Our nomogram showed good performance, suggesting that it can be used as an efficacious instrument for predictive assessment of patients with PGINHL.

18.
ChemMedChem ; 15(2): 182-187, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31755225

RESUMO

A new class of pyrimidine derivatives were identified as potent protein tyrosine kinase (PTK) inhibitors for the treatment of idiopathic pulmonary fibrosis (IPF). Most of these small-molecule inhibitors displayed strong enzymatic activity against BTK and JAK3 kinases at concentrations lower than 10 nM. The representative compound N-(3-((5-chloro-2-(4-((1-morpholino)acetylamino)phenylamino)-4-pyrimidinyl)amino)phenyl)acrylamide (6 a) also exhibited high inhibitory potency toward both BTK and JAK kinase families, as well as ErbB4, at a concentration of 10 nM, achieving rates of inhibition higher than 57 %. Additionally, in vivo biological evaluations showed that 6 a can remarkably decrease the severity of IPF disease. All these investigations suggested that the multi-PTK inhibitor 6 a may serve as a promising agent for the treatment of IPF.

19.
J Immunol Methods ; 477: 112688, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31676342

RESUMO

Biologics are potentially immunogenic and can elicit immune response. Complex biologics, such as bispecific antibodies or multi-domain molecules can induce anti-drug antibodies (ADA) with specificity to different domains. Domain specific ADAs may differently affect drug efficacy and safety, and thus, characterization of ADA domain specificity has become a regulatory expectation for multi-domain biologics. Unlike well-established methods for screening, confirmation, titer and neutralizing ADA detection, characterization of ADA domain specificity is an emerging field. The conventional approach for determination of ADA domain specificity is a competitive inhibition with domain-containing molecules. When developing a conventional domain specificity assay for moxetumomab pasudotox, a recombinant anti-CD22 immunotoxin, comprised of two functional domains (CD22-binding fragment and truncated Pseudomonas exotoxin A (PE38), we encountered a bioanalytical challenge. The method was able to detect immunodominant anti-PE38 (ADA-PE) but generated false negative results for low abundant CD22-binding domain ADA (ADA-BD) in a polyclonal sample. Troubleshooting experiments using control samples with varying levels of each ADA subtype demonstrated that a major factor for successful ADA identification was the ratio of the ADA signals contributed by each ADA subtype. To overcome this unique bioanalytical challenge, we developed a novel approach, which ensures detection of a domain-specific ADA subtype regardless of its relative level in a polyclonal ADA sample by evaluating signal inhibition by a respective domain-containing molecule at the condition when signals from all other ADAs are fully blocked. The method has been used for characterization of ADA domain specificity in moxetumomab pasudotox clinical trials, including study 1053, the pivotal Phase III study in hairy cell leukemia patients. It allowed for successful detection of ADA-BD in the presence of immunodominant ADA-PE, enabling accurate determination of domain specificity for moxetumomab pasudotox. The results demonstrated that the method was superior than the conventional approach. The method could be applied broadly to other biologics with two or more domains when there is a need to detect a minor ADA subtype in polyclonal samples.

20.
Surg Radiol Anat ; 42(2): 137-141, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31486863

RESUMO

BACKGROUND: Transverse ligament tubercles are unique structures that maintain the stability of the upper cervical spine. However, the density variations of tubercles in different clinical contexts or populations have not been carefully studied through multidetector computed tomography (MDCT). PURPOSE: This study aimed to evaluate the relationship between density variations in the transverse ligament tubercles, as measured through multidetector computed tomography (MDCT), with age, gender, or laterality. METHODS: A cohort of 339 Chinese patients that underwent MDCT in the head or neck were recruited. The patients were divided into eight age groups. The densities of the bilateral transverse ligament tubercles were classified through MDCT, and the potential relationship between the density of the tubercles and the age, gender, or laterality was analyzed. RESULTS: Based on MDCT findings, four different density types of tubercles were identified (type 0-III). Our data suggest that the density of tubercles increased with age (χ2 = 637.7, p < 0.05). However, the density of tubercles did not correlate with laterality (male: t = 0.217, p > 0.05, female: t = 1.448, p > 0.05) or gender (χ2 = 5.706, p > 0.05). CONCLUSIONS: The density of the transverse ligament tubercles, as measured through MDCT, shows a stereotyped dynamic pattern, i.e., it apparently increases with age, but neither gender nor laterality significantly contribute to these changes.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA