A genome-wide association study of upper aerodigestive tract cancers conducted within the INHANCE consortium

Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p≤5×10⁻⁷). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10⁻⁸) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2×10⁻⁸) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5×10⁻⁸; rs1229984-ADH1B, p = 7×10⁻⁹; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.     

A mighty small heart: the cardiac proteome of adult Drosophila melanogaster

Drosophila melanogaster is emerging as a powerful model system for the study of cardiac disease. Establishing peptide and protein maps of the Drosophila heart is central to implementation of protein network studies that will allow us to assess the hallmarks of Drosophila heart pathogenesis and gauge the degree of conservation with human disease mechanisms on a systems level. Using a gel-LC-MS/MS approach, we identified 1228 protein clusters from 145 dissected adult fly hearts. Contractile, cytostructural and mitochondrial proteins were most abundant consistent with electron micrographs of the Drosophila cardiac tube. Functional/Ontological enrichment analysis further showed that proteins involved in glycolysis, Ca(2+)-binding, redox, and G-protein signaling, among other processes, are also over-represented. Comparison with a mouse heart proteome revealed conservation at the level of molecular function, biological processes and cellular components. The subsisting peptidome encompassed 5169 distinct heart-associated peptides, of which 1293 (25%) had not been identified in a recent Drosophila peptide compendium. PeptideClassifier analysis was further used to map peptides to specific gene-models. 1872 peptides provide valuable information about protein isoform groups whereas a further 3112 uniquely identify specific protein isoforms and may be used as a heart-associated peptide resource for quantitative proteomic approaches based on multiple-reaction monitoring. In summary, identification of excitation-contraction protein landmarks, orthologues of proteins associated with cardiovascular defects, and conservation of protein ontologies, provides testimony to the heart-like character of the Drosophila cardiac tube and to the utility of proteomics as a complement to the power of genetics in this growing model of human heart disease.     

Burden of podoconiosis in poor rural communities in Gulliso woreda, West Ethiopia

Background

Podoconiosis is an environmental lymphoedema affecting people living and working barefoot on irritant red clay soil. Podoconiosis is relatively well described in southern Ethiopia, but remains neglected in other parts of the Ethiopian highlands. This study aimed to assess the burden of podoconiosis in rural communities in western Ethiopia.

Methodology/Principal Findings

A cross-sectional study was conducted in Gulliso woreda (district), west Ethiopia. A household survey in the 26 rural kebeles (villages) of this district was conducted to identify podoconiosis patients and to measure disease prevalence. A more detailed study was done in six randomly selected kebeles to describe clinical features of the disease, patients'' experiences of foot hygiene, and shoe wearing practice. 1,935 cases of podoconiosis were registered, giving a prevalence of 2.8%. The prevalence was higher in those aged 15–64 years (5.2%) and in females than males (prevalence ratio 2.6∶1). 90.3% of patients were in the 15–64 year age group. In the detailed study, 335 cases were interviewed and their feet assessed. The majority of patients were farmers, uneducated, and poor. Two-third of patients developed the disease before the age of thirty. Almost all patients (97.0%) had experienced adenolymphangitis (ALA - red, hot legs, swollen and painful groin) at least once during the previous year. Patients experienced an average of 5.5 ALA episodes annually, each of average 4.4 days, thus 24 working days were lost annually. The incidence of ALA in podoconiosis patients was higher than that reported for filariasis in other countries. Shoe wearing was limited mainly due to financial problems.

Conclusions

We have documented high podoconiosis prevalence, frequent adenolymphangitis and high disease-related morbidity in west Ethiopia. Interventions must be developed to prevent, treat and control podoconiosis, one of the core neglected tropical diseases in Ethiopia.     

A cladistic analysis reveals an eastern Tibetan occurrence of Taiwanoserica (Coleoptera: Scarabaeidae)

The systematic position of some newly discovered Serica species from the eastern margin of the Tibetan Plateau (Sichuan, China) is explored through a phylogenetic analysis based on 117 morphological characters using the parsimony criterion. The resulting consensus tree of this analysis reveals that three of these taxa belong to the lineage of Taiwanoserica as supposed initially due to their general external appearance. Based on the occurrence of related taxa and on the topology of Taiwanoserica taxa as well, it must be assumed that Taiwanoserica originated also in the eastern Tibetan mountains. Four new species are described: Serica (sensu lato) silviae n. sp., Serica (Taiwanoserica) wenchuanensis n. sp., Serica (Taiwanoserica) sigipinensis n. sp., Serica (Taiwanoserica) chengtuensis n. sp.     

Monitoring of 7α-hydroxy-4-cholesten-3-one during therapy of cerebrotendinous xanthomatosis: a case report

Cerebrotendinous xanthomatosis (CTX) is a rare, inherited autosomal-recessive lipid-storage disorder caused by 27-hydroxylase deficiency. In this study, we report of a 30-year old man with this disorder who was treated using chenodeoxycholic acid, simvastatin, and low-density lipoprotein (LDL) apheresis. The LDL apheresis was performed weekly for nine months. The first subjective improvement was reported by the patient after his fourth LDL-apheresis. Spasticity, gait disturbances, and his entire psychomotoric test results had improved tremendously. His fine motoric skills have been regained. The efficacy of LDL-apheresis was monitored using quantitative determination of 7α-OH-4-cholesten-3-one in plasma based on a LC–MS/MS method. The clearance efficacy of 7α-hydroxy-4-cholesten-3-one from the patient's plasma per LDL-apheresis varied between 8% and 53% but returned to the initial high levels after seven days (mean value 241 ng/mL). A slight negative trend in the plasma concentration could be derived over the period of nine months.     

Engineered Mitochondrial Ferritin as a Magnetic Resonance Imaging Reporter in Mouse Olfactory Epithelium

We report the design of a MRI reporter gene with applications to non-invasive molecular imaging. We modified mitochondrial ferritin to localize to the cell cytoplasm. We confirmed the efficient cellular processing of this engineered protein and demonstrated high iron loading in mammalian cells. The reporter’s intracellular localization appears as distinct clusters that deliver robust MRI contrast. We used this new reporter to image in vivo and ex vivo the gene expression in native olfactory sensory neurons in the mouse epithelium. This robust MRI reporter can facilitate the study of the molecular mechanisms of olfaction and to monitor intranasal gene therapy delivery, as well as a wide range of cell tracking and gene expression studies in living subjects.     

Colonic eosinophilic inflammation in experimental colitis is mediated by Ly6C(high) CCR2(+) inflammatory monocyte/macrophage-derived CCL11

Recent genome-wide association studies of pediatric inflammatory bowel disease have implicated the 17q12 loci, which contains the eosinophil-specific chemokine gene CCL11, with early-onset inflammatory bowel disease susceptibility. In the current study, we employed a murine model of experimental colitis to define the molecular pathways that regulate CCL11 expression in the chronic intestinal inflammation and pathophysiology of experimental colitis. Bone marrow chimera experiments showed that hematopoietic cell-derived CCL11 is sufficient for CCL11-mediated colonic eosinophilic inflammation. We show that dextran sodium sulfate (DSS) treatment promotes the recruitment of F4/80(+)CD11b(+)CCR2(+)Ly6C(high) inflammatory monocytes into the colon. F4/80(+)CD11b(+)CCR2(+)Ly6C(high) monocytes express CCL11, and their recruitment positively correlated with colonic eosinophilic inflammation. Phenotypic analysis of purified Ly6C(high) intestinal inflammatory macrophages revealed that these cells express both M1- and M2-associated genes, including Il6, Ccl4, Cxcl2, Arg1, Chi3l3, Ccl11, and Il10, respectively. Attenuation of DSS-induced F4/80(+)CD11b(+)CCR2(+)Ly6C(high) monocyte recruitment to the colon in CCR2(-/-) mice was associated with decreased colonic CCL11 expression, eosinophilic inflammation, and DSS-induced histopathology. These studies identify a mechanism for DSS-induced colonic eosinophilia mediated by Ly6C(high)CCR2(+) inflammatory monocyte/macrophage-derived CCL11.     

DNA-based taxonomy for associating adults and larvae in multi-species assemblages of chafers (Coleoptera: Scarabaeidae)

DNA sequences provide a universal character system in taxonomy for associating all developmental stages of organisms, but ambiguity arises due to genetic variation within species. The problem is compounded where target groups are less well studied or incompletely represented in DNA databases. Here we investigate the utility of DNA for larval-adult species associations within chafer (Coleoptera: Scarabaeidae) communities from four sites in the tropical lowlands of Nepal. We sequenced ca. 1600 bp of mitochondrial cox1 and rrnL and 700 bp of nuclear 28S rRNA from 250 larval and adult specimens. Individuals were grouped into putative species using statistical parsimony analysis and population aggregation analysis (PAA), whereby specimens from each locality were grouped according to the presence of diagnostic nucleotides. In addition, species membership was determined based on shifts in branching rates on clock-constrained trees to detect the putative transition from speciation to population coalescence patterns. Using these two methods we delineated between 48 and 56 groups, of which 16-20 were composed of larval and adult individuals. Nuclear and mtDNA-based groups were highly congruent; variation of 28S rRNA within groups was very low, while one widespread 28S rRNA genotype was universally found in a paraphyletic group of five mtDNA clusters. Linnean names could be assigned to 19 groups, and hence between 86.1% and 92.7% of larval specimens could be associated to species by their membership in clearly delineated groups that contained fully identified adults. The remaining larvae were delineated as five species, four of which could be assigned to Anomala or Adoretus based on their phylogenetic position. We conclude that the sequence variation was highly structured in this complex assemblage of chafers and that any given individual (larva or adult) can be readily associated with a particular DNA group using the criterion of diagnos ability. The association of different developmental stages therefore becomes a matter of determining the extent of the DNA-based groups, rather than matching of sequences from adult and larval individuals. This indicates the need for a purely sequence-based taxonomic system when associating different life stages via DNA.