Although intratumor heterogeneity has been inferred in multiple myeloma (MM), little is known about its subclonal phylogeny. To describe such phylogenetic trees in a series of patients with MM, we ...perform whole-exome sequencing and single-cell genetic analysis. Our results demonstrate that at presentation myeloma is composed of two to six different major clones, which are related by linear and branching phylogenies. Remarkably, the earliest myeloma-initiating clones, some of which only had the initiating t(11;14), were still present at low frequencies at the time of diagnosis. For the first time in myeloma, we demonstrate parallel evolution whereby two independent clones activate the RAS/MAPK pathway through RAS mutations and give rise subsequently to distinct subclonal lineages. We also report the co-occurrence of RAS and interferon regulatory factor 4 (IRF4) p.K123R mutations in 4% of myeloma patients. Lastly, we describe the fluctuations of myeloma subclonal architecture in a patient analyzed at presentation and relapse and in NOD/SCID-IL2Rγ(null) xenografts, revealing clonal extinction and the emergence of new clones that acquire additional mutations. This study confirms that myeloma subclones exhibit different survival properties during treatment or mouse engraftment. We conclude that clonal diversity combined with varying selective pressures is the essential foundation for tumor progression and treatment resistance in myeloma.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Wildfires produce smoke that can carry organic compounds to a vineyard, which are then absorbed by the grape berry and result in wines with elevated levels of smoke-related phenols. These phenols ...have been found to have a large impact on the flavor of wines, being the cause of a smokey flavor with a lasting ashy aftertaste. When evaluating the sensory profile of these wines, there is an observed problem due to the lasting nature of these undesirable attributes and potential flavor carryover between samples. Through the use of standard and temporal attribute check-all-that-apply, this research desires to better understand the impact of smoke on the sensorial profiles of wines with various levels of smoke phenols (high, moderate, and low). Additionally, through the employment of different interstimulus protocols, the effectiveness of rinses on diminishing the smoke flavor in wines and optimal time separation were investigated. It was determined that a 1 g/L pectin rinse in between samples with a 120 s separation is optimal to ensure the removal of smoke attribute perception. This work also indicated the need to look deeper at the effects of the in-mouth hydrolysis of glyconjugate phenols that impact overall smoke flavor.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Non-coding RNAs (ncRNAs) are transcribed throughout the genome and provide regulatory inputs to gene expression through their interaction with chromatin. Yet, the genomic targets and functions of ...most ncRNAs are unknown. Here we use chromatin-associated RNA sequencing (ChAR-seq) to map the global network of ncRNA interactions with chromatin in human embryonic stem cells and the dynamic changes in interactions during differentiation into definitive endoderm. We uncover general principles governing the organization of the RNA-chromatin interactome, demonstrating that nearly all ncRNAs exclusively interact with genes in close three-dimensional proximity to their locus and provide a model predicting the interactome. We uncover RNAs that interact with many loci across the genome and unveil thousands of unannotated RNAs that dynamically interact with chromatin. By relating the dynamics of the interactome to changes in gene expression, we demonstrate that activation or repression of individual genes is unlikely to be controlled by a single ncRNA.
BACKGROUND AND PURPOSE Asthma is characterized by reversible bronchoconstriction and airway hyperreactivity. Although M3 muscarinic receptors mediate bronchoconstriction, non‐selective muscarinic ...receptor antagonists are not currently recommended for chronic control of asthma. We tested whether selective blockade of M3 receptors, at the time of antigen challenge, blocks subsequent development of airway hyperreactivity in antigen‐challenged guinea‐pigs.
EXPERIMENTAL APPROACH Ovalbumin‐sensitized guinea‐pigs were pretreated with 1 µg·kg−1 of a kinetically selective M3 receptor antagonist, tiotropium, or 1 mg·kg−1 of a non‐selective muscarinic receptor antagonist, atropine, and challenged with inhaled ovalbumin. Animals were anaesthetized, paralyzed, ventilated and vagotomized 24 h later. We measured vagally mediated bronchoconstriction and i.v. ACh‐induced bronchoconstriction.
KEY RESULTS Electrical stimulation of both vagus nerves induced frequency‐dependent bronchoconstriction in sensitized animals that was significantly increased after antigen challenge. Antigen‐induced hyperreactivity was completely blocked by tiotropium pretreatment but only partially blocked by atropine pretreatment. Surprisingly, although tiotropium blocked bronchoconstriction induced by i.v. ACh, it did not inhibit vagally‐induced bronchoconstriction in sensitized controls, suggesting that tiotropium does not block hyperreactivity by blocking receptors for vagally released ACh. Rather, tiotropium may have worked through an anti‐inflammatory mechanism, since it inhibited eosinophil accumulation in the lungs and around nerves.
CONCLUSIONS AND IMPLICATIONS These data confirm that testing M3 receptor blockade with exogenous ACh does not predict vagal blockade. Our data also suggest that selective blockade of M3 receptors may be effective in asthma via mechanisms that are separate from inhibition of bronchoconstriction.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The loci encoding the glutathione-S-transferase (GST) enzymes comprise a large supergene family located on at least seven chromosomes. The function of the GST enzymes has traditionally been ...considered to be the detoxication of electrophiles by glutathione conjugation. A wide variety of endogenous (e.g. by-products of reactive oxygen species activity) and exogenous (e.g. polycyclic aromatic hydrocarbons) electrophilic substrates have been identified. Interestingly, recent data has suggested a role, at least for the pi class gene product, in jun kinase inhibition. Since many GST genes are polymorphic, there has been considerable interest in determining whether particular allelic variants are associated with altered risk (or outcome) of a variety of diseases. We describe recent studies in patients with asthma and cutaneous basal cell carcinoma that demonstrate associations between GSTP1 and GSTT1 genotypes and disease phenotypes. Thus, GSTP1val(105)/val(105) was protective against asthma symptoms and GSTT1 null was associated with a subgroup of basal cell carcinoma patients who develop large numbers of primary tumours in clusters. Importantly, these associations were characterised by relatively large odds ratios (0.11 and 7.4, respectively) implying that the allelic variants exert a substantial biological effect. These and other data indicate the importance of GST polymorphism in determining disease phenotype.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Inappropriate DNA methylation is frequently associated with human tumour development, and in specific cases, is associated with clinical outcomes. Previous reports of DNA methylation in ...low/intermediate grade non-muscle invasive bladder cancer (NMIBC) have suggested that specific patterns of DNA methylation may have a role as diagnostic or prognostic biomarkers. In view of the aggressive and clinically unpredictable nature of high-grade (HG) NMIBC, and the current shortage of the preferred treatment option (Bacillus:Calmette-Guerin), novel methylation analyses may similarly reveal biomarkers of disease outcome that could risk-stratify patients and guide clinical management at initial diagnosis.
Promoter-associated CpG island methylation was determined in primary tumour tissue of 36 initial presentation high-grade NMIBCs, 12 low/intermediate-grade NMIBCs and 3 normal bladder controls. The genes HOXA9, ISL1, NKX6-2, SPAG6, ZIC1 and ZNF154 were selected for investigation on the basis of previous reports and/or prognostic utility in low/intermediate-grade NMIBC. Methylation was determined by Pyrosequencing of sodium-bisulphite converted DNA, and then correlated with gene expression using RT-qPCR. Methylation was additionally correlated with tumour behaviour, including tumour recurrence and progression to muscle invasive bladder cancer or metastases.
The ISL1 genes' promoter-associated island was more frequently methylated in recurrent and progressive high-grade tumours than their non-recurrent counterparts (60.0% vs. 18.2%, p = 0.008). ISL1 and HOXA9 showed significantly higher mean methylation in recurrent and progressive tumours compared to non-recurrent tumours (43.3% vs. 20.9%, p = 0.016 and 34.5% vs 17.6%, p = 0.017, respectively). Concurrent ISL1/HOXA9 methylation in HG-NMIBC reliably predicted tumour recurrence and progression within one year (Positive Predictive Value 91.7%), and was associated with disease-specific mortality (DSM).
In this study we report methylation differences and similarities between clinical sub-types of high-grade NMIBC. We report the potential ability of methylation biomarkers, at initial diagnosis, to predict tumour recurrence and progression within one year of diagnosis. We found that specific biomarkers reliably predict disease outcome and therefore may help guide patient treatment despite the unpredictable clinical course and heterogeneity of high-grade NMIBC. Further investigation is required, including validation in a larger patient cohort, to confirm the clinical utility of methylation biomarkers in high-grade NMIBC.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Epigenetic control of fetal gene expression NAFEE, T. M; FARRELL, W. E; CARROLL, W. D ...
BJOG : an international journal of obstetrics and gynaecology,
2008, 2008-Jan, 20080101, Volume:
115, Issue:
2
Journal Article
Peer reviewed
Each differentiated cell type has its own epigenetic signature, which reflects its genotype, developmental history, and environmental influences, and is ultimately reflected in the phenotype of the ...cell and organism. Some cells undergo major epigenetic 'reprogramming' during fetal development. The proper, or improper, handling of these highly sensitive periods may have significant short-term and long-term effects on the newborn and his/her progeny. This review highlights the impact of environmental and nutritional factors on the epigenome and the potential effect of epigenetic dysregulation on maternal and fetal pregnancy outcomes, as well as possible long-term implications.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
•Acetyl cedrene; a safety assessment based on RIFM's criteria.•A safety assessment based on 7 human health endpoints plus environmental.•All endpoints were cleared using target data, read-across, ...and/or TTC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
The Duality of Smell hypothesis suggests odorants delivered orthonasally elicit different sensations compared with those delivered retronasally despite activating the same receptors in the ...olfactory epithelium. Presently, we investigated this further using a matching paradigm free from odorant or semantic memory bias. Subjects were asked to evaluate an aroma delivered in one condition (orthonasal or retronasal delivery) and match the same aroma from 4 unknowns evaluated in the same or different delivery conditions. Panelists matched flavors in 4 delivery conditions: orthonasal-orthonasal, retronasal-retronasal, retronasal-orthonasal, and orthonasal-retronasal. For orthonasal presentation, panelists smelled samples using their nostrils, and for retronasal presentation, panelists swallowed aqueous flavors. In Experiment 1, panelists were instructed to match familiar flavors (banana, grape, orange, raspberry). In Experiments 2 and 3, panelists used the same experimental design with either 4 unfamiliar flavors (kinnow, longan, pawpaw, prunus) or 4 distinct subtypes of a strawberry flavor (woody, green, ripe, candy). In Experiment 1, the number of correct matches in each condition did not significantly differ suggesting stability in the perceptual construct across delivery routes. However, in Experiments 2 and 3, significantly more samples were correctly matched in the orthonasal-orthonasal and retronasal-retronasal conditions compared with the retronasal-orthonasal or orthonasal-retronasal conditions suggesting aroma perception is dependent on delivery route. Additionally, across the 4 delivery methods, the ability to correctly match flavors decreased as flavor familiarity decreased or similarity increased and may reflect the different cognitive strategies employed by subjects when matching these stimuli. Our results suggest odorant percepts are route-dependent and consistent with the Duality of Smell phenomenon.
Several recent reports have described associations between gestational diabetes (GDM) and changes to the epigenomic landscape where the DNA samples were derived from either cord or placental sources. ...We employed genome-wide 450K array analysis to determine changes to the epigenome in a unique cohort of maternal blood DNA from 11 pregnant women prior to GDM development relative to matched controls. Hierarchical clustering segregated the samples into 2 distinct clusters comprising GDM and healthy pregnancies. Screening identified 100 CpGs with a mean β-value difference of ≥0.2 between cases and controls. Using stringent criteria, 5 CpGs (within COPS8, PIK3R5, HAAO, CCDC124, and C5orf34 genes) demonstrated potentials to be clinical biomarkers as revealed by differential methylation in 8 of 11 women who developed GDM relative to matched controls. We identified, for the first time, maternal methylation changes prior to the onset of GDM that may prove useful as biomarkers for early therapeutic intervention.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
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