Developing site-specific guidelines for orchard soils based on bioaccessibility – Can it be done?

Horticultural land within the periurban fringe of NZ towns and cities increasingly is being developed for residential subdivision. Recent surveys have shown that concentrations of As, Cd, Cu, Pb, and ΣDDT (sum of DDT and its degradation products DDE and DDD) in such soils can exceed criteria protective of human health.¹ Soil ingestion is a key exposure pathway for non-volatile contaminants in soil. Currently in NZ, site-specific risk assessments and the derivation of soil guidelines protective of human health assume that all of the contaminant present in the soil is available for uptake and absorption by the human gastrointestinal tract. This assumption can overestimate health risks and has implications for the remediation of contaminated sites.² In comparison, the bioavailability of contaminants is considered when estimating exposure via dermal absorption and by ingestion of home-grown produce.³ Dermal absorption factors and plant uptake factors are included in the calculations for estimating exposures via these routes

Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition

SummarySmoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant

Chromatin loop anchors are associated with genome instability in cancer and recombination hotspots in the germline

Abstract Background Chromatin loops form a basic unit of interphase nuclear organization, with chromatin loop anchor points providing contacts between regulatory regions and promoters. However, the mutational landscape at these anchor points remains under-studied. Here, we describe the unusual patterns of somatic mutations and germline variation associated with loop anchor points and explore the underlying features influencing these patterns. Results Analyses of whole genome sequencing datasets reveal that anchor points are strongly depleted for single nucleotide variants (SNVs) in tumours. Despite low SNV rates in their genomic neighbourhood, anchor points emerge as sites of evolutionary innovation, showing enrichment for structural variant (SV) breakpoints and a peak of SNVs at focal CTCF sites within the anchor points. Both CTCF-bound and non-CTCF anchor points harbour an excess of SV breakpoints in multiple tumour types and are prone to double-strand breaks in cell lines. Common fragile sites, which are hotspots for genome instability, also show elevated numbers of intersecting loop anchor points. Recurrently disrupted anchor points are enriched for genes with functions in cell cycle transitions and regions associated with predisposition to cancer. We also discover a novel class of CTCF-bound anchor points which overlap meiotic recombination hotspots and are enriched for the core PRDM9 binding motif, suggesting that the anchor points have been foci for diversity generated during recent human evolution. Conclusions We suggest that the unusual chromatin environment at loop anchor points underlies the elevated rates of variation observed, marking them as sites of regulatory importance but also genomic fragility

Prevalence of visits to five types of complementary and alternative medicine practitioners by the general population: A systematic review

Objective To systematically review surveys of 12-month prevalence of visits to complementary and alternative medicine (CAM) practitioners for five therapies: acupuncture, homeopathy, osteopathy, chiropractic, and medical herbalism. Methods Studies were identified via database searches to 2011. Study quality was assessed using a six-item tool. Results Forty-one surveys across 12 countries were included. Twenty-five (61%) met four of six quality criteria. Prevalence of visits by adults were (median, range): acupuncturists 1.4% (0.2–7.5%, N = 27 surveys), homeopaths 1.5% (0.2–2.9%, N = 20 surveys), osteopaths 1.9% (0.2–4.4%, N = 9 surveys), chiropractors 7.5% (0.3–16.7, N = 33 surveys), medical herbalists 0.9% (0.3–4.7%, N = 14 surveys). Estimates were slightly lower for children and higher for older adults. There was little change over the past 15–20 years. Conclusions This review summarises 12-month prevalence of visits to CAM practitioners in Europe, North America, Australia, East Asia, Saudi Arabia and Israel. A small but significant percentage of these general populations visit CAM practitioners each year

Signal transduction underlying the control of urinary bladder smooth muscle tone by muscarinic receptors and β-adrenoceptors

The normal physiological contraction of the urinary bladder, which is required for voiding, is predominantly mediated by muscarinic receptors, primarily the M3 subtype, with the M2 subtype providing a secondary backup role. Bladder relaxation, which is required for urine storage, is mediated by β-adrenoceptors, in most species involving a strong β3-component. An excessive stimulation of contraction or a reduced relaxation of the detrusor smooth muscle during the storage phase of the micturition cycle may contribute to bladder dysfunction known as the overactive bladder. Therefore, interference with the signal transduction of these receptors may be a viable approach to develop drugs for the treatment of overactive bladder. The prototypical signaling pathway of M3 receptors is activation of phospholipase C (PLC), and this pathway is also activated in the bladder. Nevertheless, PLC apparently contributes only in a very minor way to bladder contraction. Rather, muscarinic-receptor-mediated bladder contraction involves voltage-operated Ca2+ channels and Rho kinase. The prototypical signaling pathway of β-adrenoceptors is an activation of adenylyl cyclase with the subsequent formation of cAMP. Nevertheless, cAMP apparently contributes in a minor way only to β-adrenoceptor-mediated bladder relaxation. BKCa channels may play a greater role in β-adrenoceptor-mediated bladder relaxation. We conclude that apart from muscarinic receptor antagonists and β-adrenoceptor agonists, inhibitors of Rho kinase and activators of BKCa channels may have potential to treat an overactive bladder

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Organic compounds in the environment:Validation of procedures to quantify nonextractable polycyclic aromatic hydrocarbon residues in soil

This study was conducted to optimize butanol solvent shake extraction, dichloromethane soxtec extraction, and methanolic saponification extraction for the selective extraction of aged polycyclic aromatic hydrocarbons from soil. Extraction kinetics for these methods was established to determine the optimal time necessary to achieve exhaustive compound extraction. This resulted in times of 12, 6, and 5 h, respectively, for butanol, dichloromethane, and saponification, to extract polycyclic aromatic hydrocarbons from previously spiked, then aged soil. Increasing the soil mass to butanol volume ratio reduced the proportion of polycyclic aromatic hydrocarbon extracted by butanol, highlighting the importance of determining and maintaining a constant soil to solvent ratio for comparative purposes. Drying soil samples before dichloromethane soxtec extraction reduced by 30 to 76% the amount of polycyclic aromatic hydrocarbons extracted. The effect of sample drying is discussed with relevance to enhancing the formation of nonextractable compounds in soil and compound losses previously assumed by volatilization. The optimized extraction procedures provided low variability with relative standard deviations ≤ 5.2% for analysis of multiple replicates. The results obtained by the optimized procedures provided equivalent or improved reproducibility to those obtained by other methods reported in the literature