Synthesis and Biological Evaluation of Tyrphostins As Anticancer Agents

Recent developments in molecular biology have led to a greater understanding of signalling mechanisms which are overexpressed or distorted in the cancer cell, resulting in the identification of a number of new molecular targets for cancer chemotherapy. Protein Tyrosine Kinases (PTKs) are enzymes which play an important role in the signal transduction pathways leading to mitogenesis. Growth factors, such as epidermal growth factor (EGF) are responsible for stimulating cells to synthesise DNA prior to mitosis. The EGF receptor, which is present at elevated levels in certain cancer cells, has been shown to display PTK activity. Tyrphostins are low molecular weight molecules which are structurally similar to tyrosine. These have been shown to display PTK inhibition activity. The earliest reported tyrphostins such as (a) were based upon a benzylidenemalononitile nucleus, but more recently a number of tyrphostins containing a 5-membered heterocyclic nucleus (b) have been reported. Tyrphostins containing a nitrothiophene fragment (c) were prepared using standard methodology. These compounds were shown to display excellent in vitro growth inhibition in cells with a high EGF concentration. More detailed studies later showed that a number of these compounds were not selective for the EGF receptor, and instead displayed wide-spectrum cytotoxicity by an unknown mechanism. The crystal structure of one tyrphostin was solved, showing that the aromatic and cyano groups are cis across the extra-annular double bond. Previous studies had shown that analogues of misonidazole (d) which contained a nitrothiophene group (e) possessed the ability to become reduced to cytotoxic species in hypoxic tumour cells, which have a low oxygen saturation. The reduction potentials of a number of nitrothienyl tyrphostins were measured, and some of these fell within the parameters required for in vivo bioreduction. Pyridyl and quinolyl tyrphostins such as (f) and (g) have been reported to display interesting biological profiles. In particular, 2- and 4-substituted quinolines were particularly active, and this may be perhaps due at least in part to substitution at these electropositive centres. Substitution at the 3-position gave rise to a series of inactive compounds. In order to extend the study of this structure-activity relationship, a series of 6-, 7- and 8-quinolyl tyrphostins (h) were synthesised. Antibody-Directed Enzyme Prodrug Therapy (ADEPT) is a sophisticated method to deliver cytotoxic agents at their preferred site of action. An antibody which recognises surface antigens on a cancer cell also possesses an enzyme which hydrolyses a prodrug molecule such as (i) and leads to the release of the drug molecule. A methodology to synthesise such a prodrug was investigated, but it was not possible to complete the urea linkage between L-glutamate and the benzene ring by attempting to generate an isocyanate at either of the amino groups in the starting materials

Canopy spectral reflectance detects oak wilt at the landscape scale using phylogenetic discrimination

The oak wilt disease caused by the invasive fungal pathogen Bretziella fagacearum is one of the greatest threats to oak-dominated forests across the Eastern United States. Accurate detection and monitoring over large areas are necessary for management activities to effectively mitigate and prevent the spread of oak wilt. Canopy spectral reflectance contains both phylogenetic and physiological information across the visible near-infrared (VNIR) and short-wave infrared (SWIR) ranges that can be used to identify diseased red oaks. We develop partial least square discriminant analysis (PLS-DA) models using airborne hyperspectral reflectance to detect diseased canopies and assess the importance of VNIR, SWIR, phylogeny, and physiology for oak wilt detection. We achieve high accuracy through a three-step phylogenetic process in which we first distinguish oaks from other species (90% accuracy), then red oaks from white oaks (Quercus macrocarpa) (93% accuracy), and, lastly, infected from non-infected trees (80% accuracy). Including SWIR wavelengths increased model accuracy by ca. 20% relative to models based on VIS-NIR wavelengths alone; using a phylogenetic approach also increased model accuracy by ca. 20% over a single-step classification. SWIR wavelengths include spectral information important in differentiating red oaks from other species and in distinguishing diseased red oaks from healthy red oaks. We determined the most important wavelengths to identify oak species, red oaks, and diseased red oaks. We also demonstrated that several multispectral indices associated with physiological decline can detect differences between healthy and diseased trees. The wavelengths in these indices also tended to be among the most important wavelengths for disease detection within PLS-DA models, indicating a convergence of the methods. Indices were most significant for detecting oak wilt during late August, especially those associated with canopy photosynthetic activity and water status. Our study suggests that coupling phylogenetics, physiology, and canopy spectral reflectance provides an interdisciplinary and comprehensive approach that enables detection of forest diseases at large scales. These results have potential for direct application by forest managers for detection to initiate actions to mitigate the disease and prevent pathogen spread

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Genome-wide meta-analysis of common variant differences between men and women

The male-to-female sex ratio at birth is constant across world populations with an average of 1.06 (106 male to 100 female live births) for populations of European descent. The sex ratio is considered to be affected by numerous biological and environmental factors and to have a heritable component. The aim of this study was to investigate the presence of common allele modest effects at autosomal and chromosome X variants that could explain the observed sex ratio at birth. We conducted a large-scale genome-wide association scan (GWAS) meta-analysis across 51 studies, comprising overall 114 863 individuals (61 094 women and 53 769 men) of European ancestry and 2 623 828 common (minor allele frequency >0.05) single-nucleotide polymorphisms (SNPs). Allele frequencies were compared between men and women for directly-typed and imputed variants within each study. Forward-time simulations for unlinked, neutral, autosomal, common loci were performed under the demographic model for European populations with a fixed sex ratio and a random mating scheme to assess the probability of detecting significant allele frequency differences. We do not detect any genome-wide significant (P < 5 × 10−8) common SNP differences between men and women in this well-powered meta-analysis. The simulated data provided results entirely consistent with these findings. This large-scale investigation across ∼115 000 individuals shows no detectable contribution from common genetic variants to the observed skew in the sex ratio. The absence of sex-specific differences is useful in guiding genetic association study design, for example when using mixed controls for sex-biased trait

Meta-analysis identifies seven susceptibility loci involved in the atopic March

Eczema often precedes the development of asthma in a disease course called the a 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10 a'8) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10 a'9). Additional susceptibility loci identified

An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype

AbstractBackgroundThe genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder.MethodsWe analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures.ResultsThe SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10–9) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10–9).ConclusionsThis large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression

Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.Peer reviewe

Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.</p

Формирование эмоциональной культуры как компонента инновационной культуры студентов

Homozygosity has long been associated with rare, often devastating, Mendelian disorders1 and Darwin was one of the first to recognise that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity, ROH), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3,4. Here we use ROH to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts and find statistically significant associations between summed runs of homozygosity (SROH) and four complex traits: height, forced expiratory lung volume in 1 second (FEV1), general cognitive ability (g) and educational attainment (nominal p<1 × 10−300, 2.1 × 10−6, 2.5 × 10−10, 1.8 × 10−10). In each case increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing convincing evidence for the first time that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5,6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein (LDL) cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been

Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels.

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Variant annotation was supported by software resources provided via the Caché Campus program of the InterSystems GmbH to Alexander Teumer