We aimed to compare overall survival in patients treated with lenvatinib versus sorafenib as a first-line treatment for unresectable hepatocellular carcinoma. Methods: This was an open-label, phase 3, multicentre, non-inferiority trial that recruited patients with unresectable hepatocellular carcinoma, who had not received treatment for advanced disease, at sites in 20 countries throughout the Asia-Pacific, European, and North American regions. The primary endpoint was overall survival, measured from the date of randomisation until the date of death from any cause. The efficacy analysis followed the intention-to-treat principle, and only patients who received treatment were included in the safety analysis. The trial is registered with ClinicalTrials. Findings: Between March 1, and July 30, , patients were recruited.
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They also mediate multi-drug resistance in cancer cells. Different flavonoids are known to interfere with different ABC transporters. Here, the effect of the furanoflavonol karanjin, a potential drug with antiglycaemic, gastroprotective, antifungal, and antibacterial effects, was investigated on ABCB 1 , ABCC 1 , and ABCG2-mediated drug transport in comparison to the flavonoids apigenin, genistein, and naringenin. Moreover, karanjin exerted more pronounced effects than the control flavonoids apigenin, genistein, and naringenin on all three transporters.
Taken together, these findings should be taken into account during further consideration of karanjin as a potential drug for different therapeutic indications. Heavy metals such as cadmium Cd and mercury Hg are toxic pollutants that are detrimental to living organisms. Plants employ a two-step mechanism to detoxify toxic ions. First, phytochelatins bind to the toxic ion, and then the metal-phytochelatin complex is sequestered in the vacuole.
However, it is unclear whether these transporters are also implicated in phytochelatin-dependent detoxification of other heavy metals such as Cd II and Hg II. Here, we show that atabcc1 single or atabcc1 atabcc2 double knockout mutants exhibit a hypersensitive phenotype in the presence of Cd II and Hg II.
Microscopic analysis using a Cd-sensitive probe revealed that Cd is mostly located in the cytosol of protoplasts of the double mutant, whereas it occurs mainly in the vacuole of wild-type cells.
Heterologous expression of the transporters in Saccharomyces cerevisiae confirmed their role in heavy metal tolerance. Together, these results demonstrate that At ABCC 1 and At ABCC 2 are important vacuolar transporters that confer tolerance to cadmium and mercury, in addition to their role in arsenic detoxification.
These transporters provide useful tools for genetic engineering of plants with enhanced metal tolerance and accumulation, which are desirable characteristics for phytoremediation. Blood samples were taken and OXC levels were measured. The therapeutic efficacy of OXC at the 1-year time-point was assessed. However, further studies in larger populations and other ethnic groups are required. Published by Elsevier Ltd. All rights reserved. ABC transporters activity and expression have been associated with the multixenobiotic resistance phenotype MXR.
The activity of these proteins leads to a reduction in the intracellular concentration of several xenobiotics, thus reducing their toxicity. However, little attention has been given to the expression of ABC transporters in marine invertebrates and few studies have investigated their role in immune system cells of sea urchins and shellfish bivalves. Coelomocytes and hemocytes were stained with the ABC transporter substrate calcein-AM and dye accumulation analyzed under flow cytometry.
The treatment with MK increased calcein fluorescence levels in coelomocytes from both species. However, reversin treatment was not able to increase calcein fluorescence in E. The activity of ABCC 1 -like transporter was observed in all cell types from both bivalve species. However, reversin only increased calcein accumulation in hyalinocytes of the oyster C. PubMed Central.
A link between ABCB 1 , high fat diet and gut microbes in relation to colitis was suggested by the animal studies.
The finding that colitis was preceded by altered gut bacterial composition suggests that deletion of Abcb 1 leads to fundamental changes of host-microbiota interaction. Also, high fat diet increases the frequency and severity of colitis in specific pathogen-free Abcb 1 KO mice.
Also, diet and microbes give rise to molecules which are potential substrates for the ABC transporters and which may additionally affect ABC transporter function through nuclear receptors and transcriptional regulation. Another critical role of ABCB 1 was suggested by the finding that. Aquatic organisms, such as bivalves, employ ATP binding cassette ABC transporters for efflux of potentially toxic chemicals.
Anthropogenic water contaminants can, as chemosensitizers, disrupt efflux transporter function enabling other, putatively toxic compounds to enter the organism. The assumption that different inhibitors targeted different efflux pump types was confirmed when comparing measured effects of binary inhibitor compound mixtures in dye accumulation assays with predictions from mixture effect models.
The binary mixture approach was further applied to identify the efflux pump type targeted by environmentally relevant chemosensitizing compounds. Pentachlorophenol and musk ketone, which were selected after a pre-screen of twelve compounds that previously had been identified as chemosensitizers, showed mixture effects that corresponded better with concentration addition when combined with reversine but with independent action predictions when combined with MK indicating targeting of an ABCB 1 -type efflux pump by these compounds.
The influence of specific genotypes, alleles and haplotypes on the risk of DILI development and clinical presentations was analysed. None of the individual polymorphisms or haplotypes was found to be associated with DILI development. Hence, this genotype could potentially be associated with increased risk, though its low frequency in our Spanish cohort prevented a final conclusion.
Carmen; Lucena, M. Results None of the individual polymorphisms or haplotypes was found to be associated with DILI development. ABC multidrug transporters are key players in cancer multidrug resistance and in general xenobiotic elimination, thus their functional assays provide important tools for research and diagnostic applications. In this study we have examined the potential interactions of three key human ABC multidrug transporters with PhenGreen diacetate PGD , a cell permeable fluorescent metal ion indicator.
The non-fluorescent, hydrophobic PGD rapidly enters the cells and, after cleavage by cellular esterases, in the absence of quenching metal ions, PhenGreen PG becomes highly fluorescent.
This fluorescence signal in the presence of specific transporter inhibitors is increased to the fluorescence levels in the control cells. Since PG has very low cellular toxicity, the PG accumulation assay also allows the selection, separation and culturing of selected cell populations expressing either of these transporters. Accumulation of unconjugated bilirubin UCB in the brain causes bilirubin encephalopathy. We examined the effect of prolonged exposure to elevated concentrations of UCB on expression of the two transporters in homozygous, jaundiced jj Gunn rats compared to heterozygous, not jaundiced Jj littermates at different developmental stages 2, 9, 17 and 60 days after birth.
The Mrp1 protein down regulation was accompanied by a modest up-regulation of mRNA, suggesting a translational rather than a transcriptional inhibition. In vitro exposure of choroid plexus epithelial cells obtained from normal rats to UCB, also resulted in a down-regulation of Mrp1 protein. These data suggest that down-regulation of Mrp1 protein at the BSCFB, resulting from a direct effect of UCB on epithelial cells, may impact the Mrp1-mediated neuroprotective functions of the blood-cerebrospinal fluid barrier and actually potentiate UCB neurotoxicity.
CBZ is transported by the P-glycoprotein P-gp. A few studies have shown significant association between CBZ resistant epilepsy and Linkage Disequilibrium LD with adjacent polymorphisms of these genes.
DNA was extracted from their blood samples and Taqman technology for allelic discrimination was performed. Results were described as genotype frequencies. The SHEsis analysis platform was used to calculate linkage disequilibrium index and infer haplotype frequencies. Haploview was used to do permutation test to obtain a corrected p-value.
Uncaria alkaloids reverse ABCB 1 -mediated cancer multidrug resistance. Uncaria alkaloids are the major active components isolated from uncaria, which is a common Chinese herbal medicine. In this study, the MDR-reversal activities of uncaria alkaloids, including rhynchophylline, isorhynchophylline, corynoxeine, isocorynoxeine Icory , hirsutine and hirsuteine, were screened; they all exhibited potent reversal efficacy when combined with doxorubicin.
Further mechanistic study revealed that Icory increased the intracellular accumulation of doxorubicin in ABCB 1 -overexpressing cells by blocking the efflux function of ABCB 1. Collectively, these results indicated that Icory reversed ABCB 1 -mediated MDR by suppressing its efflux function, and it would be beneficial to increase the efficacy of these types of uncaria alkaloids and develop them to be selective ABCB 1 -mediated MDR-reversal agents.
Moderate neonatal jaundice is the most common clinical condition during newborn life. However, a combination of factors may result in acute hyperbilirubinemia, placing infants at risk of developing bilirubin encephalopathy and death by kernicterus.
While most risk factors are known, the mechanisms acting to reduce susceptibility to bilirubin neurotoxicity remain unclear. The presence of modifier genes modulating the risk of developing bilirubin-induced brain damage is increasingly being recognised.
The Abcb 1 and Abcc 1 members of the ABC family of transporters have been suggested to have an active role in exporting unconjugated bilirubin from the central nervous system into plasma. However, their role in reducing the risk of developing neurological damage and death during neonatal development is still unknown. Interestingly, Abcc 1 role appeared to be less important. We demonstrated a critical role of Abcb 1 in protecting the cerebellum from bilirubin toxicity during neonatal development, the most clinically relevant phase for human babies, providing further understanding of the mechanisms regulating bilirubin neurotoxicity in vivo.
Pharmacological treatments aimed to increase Abcb 1 and Abcc 1 expression, could represent a therapeutic option to reduce the risk of bilirubin neurotoxicity. Published by Oxford University Press. For Permissions, please email: journals. Despite long-term clinical experience with docetaxel, unpredictable severe adverse reactions remain an important determinant for limiting the use of the drug.
This prediction system correctly classified Unfortunately, alike most chemotherapeutic agents, the development of acquired resistance to BI is prone to present a significant therapeutic challenge.
Taken together, our findings indicate that in order to circumvent ABCB 1 or ABCG2-mediated acquired resistance to BI , a combined regimen of BI and inhibitors or clinically active drugs that potently inhibit the function of ABC drug transporters, should be considered as a potential treatment strategy in the clinic. To evaluate the breed distribution of the ABCB 1 -1Delta polymorphism in a large number of dogs in North America, including dogs of several herding breeds in which this polymorphism has been detected and other breeds in which this polymorphism has not yet been identified.
Cross-sectional study. These data were reviewed, and results for each dog were recorded in a spreadsheet, along with the dog's breed. The genotypes for each breed were tallied by use of a sorting function. The ABCB 1 -1Delta polymorphism is associated with increased susceptibility to many adverse drug reactions and with suppression of the hypothalamic-pituitary-adrenal axis and is present in many herding breeds of dog.
Veterinarians should be familiar with the breeds that have the ABCB 1 -1Delta polymorphism to make appropriate pharmacologic choices for these patients. ABCB 1 gene polymorphisms and violent suicide attempt among survivors. Those suicide attempters that choose violent methods dramatically diminish the possibility of survival.
Completed suicide using violent means, which is common among first-time suicide attempters, was recently found to be more likely among T allele carriers in the three most common ABCB 1 SNPs, encoding for P-gp. Thus, this study examined, for the first time, whether these ABCB 1 SNPs were associated with the use of violent means among survivors of a suicide attempt. The relations of the three genotypes and of the TTT haplotype with the use of a violent suicide method were evaluated separately.
The impact of confounds on these variables was controlled. Since gender and number of previous suicide attempts were identified as confounds, the relation was tested in the subset of women who were first-time attempters or second- and more-time attempters.
Upregulation of ABCC 1 is thought to improve lung function in patients with cystic fibrosis CF ; the mechanism underlying this effect is unknown. In conclusion, we show that ABCB 1 expression represents the primary sometimes exclusive resistance mechanism in neuroblastoma cells with acquired resistance to SNS Virtual screening of ABCC 1 transporter nucleotidebinding domains as a therapeutic target in multidrug resistant cancer.
Clinically, ABCC 1 expression is linked to cancer multidrug resistance. Substrate efflux is energised by ATP binding and hydrolysis at the nucleotide-binding domains NBDs and inhibition of these events may help combat drug resistance. GLIDE was employed in molecular docking studies for all hit compounds identified by pharmacophore screening. The best potential inhibitors were identified as compounds possessing predicted binding affinities greater than ATP.
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