Clinical symptoms and chemotherapy completion in elderly patients with newly diagnosed acute leukemia: a retrospective comparison study with a younger cohort

<p>Abstract</p> <p>Background</p> <p>Cancer affects older adults disproportionately. The disease is often difficult to diagnose and treat due to co-morbidities and performance status, and patients tend to discontinue chemotherapy prematurely. There are no systemic studies of the reasons and factors that create a higher withdrawal rate in older acute leukemia patients. This study tried to understand the initial characteristics, blood counts and bone marrow measurements in older acute leukemia patients by comparing them with a younger group to provide information and assistance in early clinical diagnosis, treatment and reasons for treatment withdrawal.</p> <p>Methods</p> <p>Using retrospective medical record reviews, we examined clinical characteristics and chemotherapy completion status in the patients of two groups (age ≥ 60, n = 183 and age <60, n = 183) who were diagnosed with acute leukemia for the first time and were hospitalized in Union Hospital Affiliated with Fujian Medical University from 2004 to 2008.</p> <p>Results</p> <p>There were no statistical differences in initial presenting symptoms of fatigue (67.2% vs. 57.9%, <it>P</it>>0.05) and pallor (53% vs. 59.6%, <it>P</it>>0.05) between the two groups, but older patients demonstrated more underlying diseases including lung infections (25.7%, <it>P </it>= <0.001), cardiovascular disease (4.4%, <it>P </it>= 0.007), and hypertension (20.8%, <it>P </it>=< 0.001). The complete remission rate after chemotherapy (1 to 2 courses) was 49.5% in the older group and 66.7% in the younger group (χ²= 6.202, <it>P </it>= 0.013). The percentage of patients age 60 and older who prematurely discontinued chemotherapy (50.3%), mainly due to the influences of traditional Chinese concept of critical illness, financial difficulties, and intolerance to adverse reactions to chemotherapy, was significantly higher than that of younger patients (37.7%) (χ²= 5.866, <it>P </it>= 0.015).</p> <p>Conclusions</p> <p>A comprehensive approach to diagnosis, treatment selection, and toxicity management, and implementing strategies to enhance treatment compliance may improve outcomes in older adults with acute leukemia.</p

Cytochrome P450 1 genes in birds : evolutionary relationships and transcription profiles in chicken and Japanese quail embryos

© The Author(s), 2011. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in PLoS One 6 (2011): e28257, doi:10.1371/journal.pone.0028257.Cytochrome P450 1 (CYP1) genes are biomarkers for aryl hydrocarbon receptor (AHR) agonists and may be involved in some of their toxic effects. CYP1s other than the CYP1As are poorly studied in birds. Here we characterize avian CYP1B and CYP1C genes and the expression of the identified CYP1 genes and AHR1, comparing basal and induced levels in chicken and quail embryos. We cloned cDNAs of chicken CYP1C1 and quail CYP1B1 and AHR1. CYP1Cs occur in several bird genomes, but we found no CYP1C gene in quail. The CYP1C genomic region is highly conserved among vertebrates. This region also shares some synteny with the CYP1B region, consistent with CYP1B and CYP1C genes deriving from duplication of a common ancestor gene. Real-time RT-PCR analyses revealed similar tissue distribution patterns for CYP1A4, CYP1A5, CYP1B1, and AHR1 mRNA in chicken and quail embryos, with the highest basal expression of the CYP1As in liver, and of CYP1B1 in eye, brain, and heart. Chicken CYP1C1 mRNA levels were appreciable in eye and heart but relatively low in other organs. Basal transcript levels of the CYP1As were higher in quail than in chicken, while CYP1B1 levels were similar in the two species. 3,3′,4,5,5′-Pentachlorobiphenyl induced all CYP1s in chicken; in quail a 1000-fold higher dose induced the CYP1As, but not CYP1B1. The apparent absence of CYP1C1 in quail, and weak expression and induction of CYP1C1 in chicken suggest that CYP1Cs have diminishing roles in tetrapods; similar tissue expression suggests that such roles may be met by CYP1B1. Tissue distribution of CYP1B and CYP1C transcripts in birds resembles that previously found in zebrafish, suggesting that these genes serve similar functions in diverse vertebrates. Determining CYP1 catalytic functions in different species should indicate the evolving roles of these duplicated genes in physiological and toxicological processes.Funding to MEJ and BB was from the Carl Tryggers Stiftelse and The Swedish Research Council Formas. Funding for BRW and JJS was from the United States National Institutes of Health (National Institute of Environmental Health Sciences), grants R01ES015912 and P42ES007381 to JJS

Quantitative cross-species extrapolation between humans and fish: The case of the anti-depressant fluoxetine

This article has been made available through the Brunel Open Access Publishing Fund.Fish are an important model for the pharmacological and toxicological characterization of human pharmaceuticals in drug discovery, drug safety assessment and environmental toxicology. However, do fish respond to pharmaceuticals as humans do? To address this question, we provide a novel quantitative cross-species extrapolation approach (qCSE) based on the hypothesis that similar plasma concentrations of pharmaceuticals cause comparable target-mediated effects in both humans and fish at similar level of biological organization (Read-Across Hypothesis). To validate this hypothesis, the behavioural effects of the anti-depressant drug fluoxetine on the fish model fathead minnow (Pimephales promelas) were used as test case. Fish were exposed for 28 days to a range of measured water concentrations of fluoxetine (0.1, 1.0, 8.0, 16, 32, 64 μg/L) to produce plasma concentrations below, equal and above the range of Human Therapeutic Plasma Concentrations (HTPCs). Fluoxetine and its metabolite, norfluoxetine, were quantified in the plasma of individual fish and linked to behavioural anxiety-related endpoints. The minimum drug plasma concentrations that elicited anxiolytic responses in fish were above the upper value of the HTPC range, whereas no effects were observed at plasma concentrations below the HTPCs. In vivo metabolism of fluoxetine in humans and fish was similar, and displayed bi-phasic concentration-dependent kinetics driven by the auto-inhibitory dynamics and saturation of the enzymes that convert fluoxetine into norfluoxetine. The sensitivity of fish to fluoxetine was not so dissimilar from that of patients affected by general anxiety disorders. These results represent the first direct evidence of measured internal dose response effect of a pharmaceutical in fish, hence validating the Read-Across hypothesis applied to fluoxetine. Overall, this study demonstrates that the qCSE approach, anchored to internal drug concentrations, is a powerful tool to guide the assessment of the sensitivity of fish to pharmaceuticals, and strengthens the translational power of the cross-species extrapolation

Identification and developmental expression of the full complement of Cytochrome P450 genes in Zebrafish

© The Authors, 2010. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in BMC Genomics 11 (2010): 643, doi:10.1186/1471-2164-11-643.Increasing use of zebrafish in drug discovery and mechanistic toxicology demands knowledge of cytochrome P450 (CYP) gene regulation and function. CYP enzymes catalyze oxidative transformation leading to activation or inactivation of many endogenous and exogenous chemicals, with consequences for normal physiology and disease processes. Many CYPs potentially have roles in developmental specification, and many chemicals that cause developmental abnormalities are substrates for CYPs. Here we identify and annotate the full suite of CYP genes in zebrafish, compare these to the human CYP gene complement, and determine the expression of CYP genes during normal development. Zebrafish have a total of 94 CYP genes, distributed among 18 gene families found also in mammals. There are 32 genes in CYP families 5 to 51, most of which are direct orthologs of human CYPs that are involved in endogenous functions including synthesis or inactivation of regulatory molecules. The high degree of sequence similarity suggests conservation of enzyme activities for these CYPs, confirmed in reports for some steroidogenic enzymes (e.g. CYP19, aromatase; CYP11A, P450scc; CYP17, steroid 17a-hydroxylase), and the CYP26 retinoic acid hydroxylases. Complexity is much greater in gene families 1, 2, and 3, which include CYPs prominent in metabolism of drugs and pollutants, as well as of endogenous substrates. There are orthologous relationships for some CYP1 s and some CYP3 s between zebrafish and human. In contrast, zebrafish have 47 CYP2 genes, compared to 16 in human, with only two (CYP2R1 and CYP2U1) recognized as orthologous based on sequence. Analysis of shared synteny identified CYP2 gene clusters evolutionarily related to mammalian CYP2 s, as well as unique clusters. Transcript profiling by microarray and quantitative PCR revealed that the majority of zebrafish CYP genes are expressed in embryos, with waves of expression of different sets of genes over the course of development. Transcripts of some CYP occur also in oocytes. The results provide a foundation for the use of zebrafish as a model in toxicological, pharmacological and chemical disease research.This work was supported by NIH grants R01ES015912 and P42ES007381 (Superfund Basic Research Program at Boston University) (to JJS). MEJ was a Guest Investigator at the Woods Hole Oceanographic Institution (WHOI) and was supported by grants from the Swedish research council Formas and Carl Trygger's foundation. AK was a Post-doctoral Fellow at WHOI, and was supported by a fellowship from the Japanese Society for Promotion of Science (JSPS). JZ and TP were Guest Students at the WHOI and were supported by a CAPES Ph.D. Fellowship and CNPq Ph.D. Sandwich Fellowship (JZ), and by a CNPq Ph.D. Fellowship (TP), from Brazil

Molecular Evolution and Functional Divergence of the Cytochrome P450 3 (CYP3) Family in Actinopterygii (Ray-Finned Fish)

The cytochrome P450 (CYP) superfamily is a multifunctional hemethiolate enzyme that is widely distributed from Bacteria to Eukarya. The CYP3 family contains mainly the four subfamilies CYP3A, CYP3B, CYP3C and CYP3D in vertebrates; however, only the Actinopterygii (ray-finned fish) have all four subfamilies and detailed understanding of the evolutionary relationship of Actinopterygii CYP3 family members would be valuable.Phylogenetic relationships were constructed to trace the evolutionary history of the Actinopterygii CYP3 family genes. Selection analysis, relative rate tests and functional divergence analysis were combined to interpret the relationship of the site-specific evolution and functional divergence in the Actinopterygii CYP3 family. The results showed that the four CYP3 subfamilies in Actinopterygii might be formed by gene duplication. The first gene duplication event was responsible for divergence of the CYP3B/C clusters from ancient CYP3 before the origin of the Actinopterygii, which corresponded to the fish-specific whole genome duplication (WGD). Tandem repeat duplication in each of the homologue clusters produced stable CYP3B, CYP3C, CYP3A and CYP3D subfamilies. Acceleration of asymmetric evolutionary rates and purifying selection together were the main force for the production of new subfamilies and functional divergence in the new subset after gene duplication, whereas positive selection was detected only in the retained CYP3A subfamily. Furthermore, nearly half of the functional divergence sites appear to be related to substrate recognition, which suggests that site-specific evolution is closely related with functional divergence in the Actinopterygii CYP3 family.The split of fish-specific CYP3 subfamilies was related to the fish-specific WGD, and site-specific acceleration of asymmetric evolutionary rates and purifying selection was the main force for the origin of the new subfamilies and functional divergence in the new subset after gene duplication. Site-specific evolution in substrate recognition was related to functional divergence in the Actinopterygii CYP3 family

Category label and response location shifts in category learning

The category shift literature suggests that rule-based classification, an important form of explicit learning, is mediated by two separate learned associations: a stimulus-to-label association that associates stimuli and category labels, and a label-to-response association that associates category labels and responses. Three experiments investigate whether information–integration classification, an important form of implicit learning, is also mediated by two separate learned associations. Participants were trained on a rule-based or an information–integration categorization task and then the association between stimulus and category label, or between category label and response location was altered. For rule-based categories, and in line with previous research, breaking the association between stimulus and category label caused more interference than breaking the association between category label and response location. However, no differences in recovery rate emerged. For information–integration categories, breaking the association between stimulus and category label caused more interference and led to greater recovery than breaking the association between category label and response location. These results provide evidence that information–integration category learning is mediated by separate stimulus-to-label and label-to-response associations. Implications for the neurobiological basis of these two learned associations are discussed

Toxic Diatom Aldehydes Affect Defence Gene Networks in Sea Urchins.

Marine organisms possess a series of cellular strategies to counteract the negative effects of toxic compounds, including the massive reorganization of gene expression networks. Here we report the modulated dose-dependent response of activated genes by diatom polyunsaturated aldehydes (PUAs) in the sea urchin Paracentrotus lividus. PUAs are secondary metabolites deriving from the oxidation of fatty acids, inducing deleterious effects on the reproduction and development of planktonic and benthic organisms that feed on these unicellular algae and with anti-cancer activity. Our previous results showed that PUAs target several genes, implicated in different functional processes in this sea urchin. Using interactomic Ingenuity Pathway Analysis we now show that the genes targeted by PUAs are correlated with four HUB genes, NF-κB, p53, δ-2-catenin and HIF1A, which have not been previously reported for P. lividus. We propose a working model describing hypothetical pathways potentially involved in toxic aldehyde stress response in sea urchins. This represents the first report on gene networks affected by PUAs, opening new perspectives in understanding the cellular mechanisms underlying the response of benthic organisms to diatom exposure

Defensome against Toxic Diatom Aldehydes in the Sea Urchin Paracentrotus lividus

Many diatom species produce polyunsaturated aldehydes, such as decadienal, which compromise embryonic and larval development in benthic organisms. Here newly fertilized Paracentrotus lividus sea urchins were exposed to low concentration of decadienal and the expression levels of sixteen genes, implicated in a broad range of functional responses, were followed by Real Time qPCR in order to identify potential decadienal targets. We show that at low decadienal concentrations the sea urchin Paracentrotus lividus places in motion different classes of genes to defend itself against this toxic aldehyde, activating hsp60 and two proteases, hat and BP10, at the blastula stage and hsp56 and several other genes (14-3-3ε, p38 MAPK, MTase, and GS) at the prism stage. At this latter stage all genes involved in skeletogenesis (Nec, uni, SM50 and SM30) were also down-expressed, following developmental abnormalities that mainly affected skeleton morphogenesis. Moreover, sea urchin embryos treated with increasing concentrations of decadienal revealed a dose-dependent response of activated target genes. Finally, we suggest that this orchestrated defense system against decadienal represents part of the chemical defensome of P. lividus affording protection from environmental toxicants

Environmental sensing and response genes in cnidaria : the chemical defensome in the sea anemone Nematostella vectensis

Author Posting. © The Author(s), 2008. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Cell Biology and Toxicology 24 (2008): 483-502, doi:10.1007/s10565-008-9107-5.The starlet sea anemone Nematostella vectensis has been recently established as a new model system for the study of the evolution of developmental processes, as cnidaria occupy a key evolutionary position at the base of the bilateria. Cnidaria play important roles in estuarine and reef communities, but are exposed to many environmental stressors. Here I describe the genetic components of a ‘chemical defensome’ in the genome of N. vectensis, and review cnidarian molecular toxicology. Gene families that defend against chemical stressors and the transcription factors that regulate these genes have been termed a ‘chemical defensome,’ and include the cytochromes P450 and other oxidases, various conjugating enyzymes, the ATP-dependent efflux transporters, oxidative detoxification proteins, as well as various transcription factors. These genes account for about 1% (266/27200) of the predicted genes in the sea anemone genome, similar to the proportion observed in tunicates and humans, but lower than that observed in sea urchins. While there are comparable numbers of stress-response genes, the stress sensor genes appear to be reduced in N. vectensis relative to many model protostomes and deuterostomes. Cnidarian toxicology is understudied, especially given the important ecological roles of many cnidarian species. New genomic resources should stimulate the study of chemical stress sensing and response mechanisms in cnidaria, and allow us to further illuminate the evolution of chemical defense gene networks.WHOI Ocean Life Institute and NIH R01-ES01591

Molecular Evidence of the Toxic Effects of Diatom Diets on Gene Expression Patterns in Copepods

Diatoms are dominant photosynthetic organisms in the world's oceans and are considered essential in the transfer of energy through marine food chains. However, these unicellular plants at times produce secondary metabolites such as polyunsaturated aldehydes and other products deriving from the oxidation of fatty acids that are collectively termed oxylipins. These cytotoxic compounds are responsible for growth inhibition and teratogenic activity, potentially sabotaging future generations of grazers by inducing poor recruitment in marine organisms such as crustacean copepods.Here we show that two days of feeding on a strong oxylipin-producing diatom (Skeletonema marinoi) is sufficient to inhibit a series of genes involved in aldehyde detoxification, apoptosis, cytoskeleton structure and stress response in the copepod Calanus helgolandicus. Of the 18 transcripts analyzed by RT-qPCR at least 50% were strongly down-regulated (aldehyde dehydrogenase 9, 8 and 6, cellular apoptosis susceptibility and inhibitor of apoptosis IAP proteins, heat shock protein 40, alpha- and beta-tubulins) compared to animals fed on a weak oxylipin-producing diet (Chaetoceros socialis) which showed no changes in gene expression profiles.Our results provide molecular evidence of the toxic effects of strong oxylipin-producing diatoms on grazers, showing that primary defense systems that should be activated to protect copepods against toxic algae can be inhibited. On the other hand other classical detoxification genes (glutathione S-transferase, superoxide dismutase, catalase, cytochrome P450) were not affected possibly due to short exposure times. Given the importance of diatom blooms in nutrient-rich aquatic environments these results offer a plausible explanation for the inefficient use of a potentially valuable food resource, the spring diatom bloom, by some copepod species