Advances in the Genetics of Familial Renal Cancer

We discuss recent advances in the diagnosis and management of renal cell cancer (RCC) given the enhanced molecular genetics knowledge in this area. A number of hereditary renal cancer syndromes have been described, including von Hippel-Lindau disease, Birt-Hogg-Dube syndrome, hereditary leiomyomatosis/RCC syndrome, and hereditary papillary renal cancer. Early molecular diagnosis now facilitates the management and prevention of RCC in families. Recommendations for screening in families are discussed. The Oncologist 2010;15:532-538

Hereditary ataxias and paediatric neurology: new movers and shakers enter the field

Over 25 autosomal dominant and autosomal recessive spinocerebellar ataxias have been isolated over the last decade. The recognition of paediatric ataxia phenotypes and, in addition, other movement disorders including hereditary choreiform and parkinsonian syndromes, has improved our knowledge of these diseases. Advances in molecular genetics has allowed fuller delineation and better recognition of these diseases. (C) 2003 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Molecular diagnostic cytopathology: definitions, scope and clinical utility

Molecular diagnosis is the application of molecular biology techniques and knowledge of the molecular mechanisms of disease to diagnosis, prognostication and treatment of diseases. Although it is not widely used in routine molecular cytological practice, some examples are presented here of the application of molecular techniques to the routine cytopathological diagnosis of solid tumours and lymphoreticular malignancies. The term 'molecular diagnostic cytopathology' is proposed to define the application of molecular diagnosis to cytopathology, and the challenges of the introduction of molecular diagnosis into routine diagnostic histopathology and cytopathology are discussed. Finally, the importance of a combined morphological, immunophenotypic and molecular approach to maintain the diagnostic pathologist at the heart of the clinical decision-making process is emphasized.

Prognostic and Predictive Biomarkers in Resected Colon Cancer: Current Status and Future Perspectives for Integrating Genomics into Biomarker Discovery

The number of agents that are potentially effective in the adjuvant treatment of locally advanced resectable colon cancer is increasing. Consequently, it is important to ascertain which subgroups of patients will benefit from a specific treatment. Despite more than two decades of research into the molecular genetics of colon cancer, there is a lack of prognostic and predictive molecular biomarkers with proven utility in this setting. A secondary objective of the Pan European Trials in Adjuvant Colon Cancer-3 trial, which compared irinotecan in combination with 5-fluorouracil and leucovorin in the postoperative treatment of stage III and stage II colon cancer patients, was to undertake a translational research study to assess a panel of putative prognostic and predictive markers in a large colon cancer patient cohort. The Cancer and Leukemia Group B 89803 trial, in a similar design, also investigated the use of prognostic and predictive biomarkers in this setting. In this article, the authors, who are coinvestigators from these trials and performed similar investigations of biomarker discovery in the adjuvant treatment of colon cancer, review the current status of biomarker research in this field, drawing on their experiences and considering future strategies for biomarker discovery in the postgenomic era. The Oncologist 2010; 15: 390-404

BRCA1 and GATA3 corepress FOXC1 to inhibit the pathogenesis of basal-like breast cancers

In this study we describe a novel interaction between the breast/ovarian tumor suppressor gene BRCA1 and the transcription factor GATA3, an interaction, which is important for normal breast differentiation. We show that the BRCA1-GATA3 interaction is important for the repression of genes associated with triple-negative and basal-like breast cancer (BLBCs) including FOXC1, and that GATA3 interacts with a C-terminal region of BRCA1. We demonstrate that FOXC1 is an essential survival factor maintaining the proliferation of BLBCs cell lines. We define the mechanistic basis of this corepression and identify the GATA3-binding site within the FOXC1 distal promoter region. We show that BRCA1 and GATA3 interact on the FOXC1 promoter and that BRCA1 requires GATA3 for recruitment to this region. This interaction requires fully functional BRCA1 as a mutant BRCA1 protein is unable to localize to the FOXC1 promoter or repress FOXC1 expression. We demonstrate that this BRCA1-GATA3 repression complex is not a FOXC1-specific phenomenon as a number of other genes associated with BLBCs such as FOXC2, CXCL1 and p-cadherin were also repressed in a similar manner. Finally, we demonstrate the importance of our findings by showing that loss of GATA3 expression or aberrant FOXC1 expression contributes to the drug resistance and epithelial-to-mesenchymal transition-like phenotypes associated with aggressive BLBCs. Oncogene (2012) 31, 3667-3678; doi:10.1038/onc.2011.531; published online 28 November 2011

A STUDY OF CARBON-MONOXIDE AND NEUTRAL CARBON IN THE S106 MOLECULAR CORE

Maps are presented of J=2-1 and J=3-2 (CO)-O-18 emission from the molecular environment of the bipolar nebula S106, together with complementary observations of the P-3(1)-P-3(0), C I emission. Line splitting observed extensively over the E molecular cloud suggests that it is best explained as the expanding remnant of a thick toroid surrounding the optical lobes. The poor correlation between the observed molecular line emission and dust continuum emission in the E cloud is probably due to a large temperature gradient. Strong C I emission from the protostellar candidate S106 FIR suggests the nearby presence of a powerful source of far-UV radiation, whose energy supply is unlikely to arise from gravitational contraction of a protostar. It is probable that this source is the star S106 LR, which also heats S106 FIR. There is evidence, in both C I and (CO)-O-18, for a predominantly blueshifted outflow from S106 IR, best interpreted as a stellar wind-driven shock into the toroidal remnant. (CO)-O-18 and (CO)-C-13 appear to be depleted, relative to canonical values for their abundances, in S106 FIR, despite its high optical extinction, which should discourage selective photodissociation. Elsewhere in the cloud the C I line profiles show a resemblance to those of (CO)-O-18, with intensity equivalent to a few photodissociation regions (PDRs) along the line of sight.

Identification and molecular cloning of a novel amphibian Bowman Birk-type trypsin inhibitor from the skin of the Hejiang Odorous Frog; Odorrana hejiangensis.

In this study, an amphibian (Odorrana hejiangensis) skin extract was fractionated by reverse phase HPLC and fractions were screened for trypsin inhibitory activity. Using this initial approach, a novel trypsin inhibitory peptide was detected with an apparent protonated molecular mass of 1804.83Da, as determined by MALDI-TOF mass spectrometry. It was named Hejiang trypsin inhibitor (HJTI) in accordance. The primary structure of the biosynthetic precursor of HJTI was deduced from a cDNA sequence cloned from a skin-derived cDNA library. The primary structure of the encoded predicted mature active peptide was established as: GAPKGCWTKSYPPQPCS (non-protonated monoisotopic molecular mass - 1802.81Da). On the basis of this unequivocal amino acid sequence, a synthetic replicate was synthesized by solid phase Fmoc chemistry. This replicate displayed a moderately potent trypsin inhibition with a K(i) of 388nM. Bioinformatic analysis of the primary structure of this peptide indicated that it was a member of the Bowman-Birk family of protease inhibitors. The substitutions of Gln-14 and Ser-17 by Lys, resulted in an increase in cationicity and a small increase in potency to a K(i) value of 218nM. Neither HJTI nor its synthetic analog, possessed any significant antimicrobial activity.

Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration

Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P = 1.1 × 10(-8)] and rs4711751 on 6p12 near VEGFA (OR 1.15; P = 8.7 × 10(-9)). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genome-wide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD.

Zoonotic helminth infections with particular emphasis on fasciolosis and other trematodiases

Zoonotic infections are among the most common on earth and are responsible for >60 per cent of all human infectious diseases. Some of the most important and well-known human zoonoses are caused by worm or helminth parasites, including species of nematodes (trichinellosis), cestodes (cysticercosis, echinococcosis) and trematodes (schistosomiasis). However, along with social, epidemiological and environmental changes, together with improvements in our ability to diagnose helminth infections, several neglected parasite species are now fast-becoming recognized as important zoonotic diseases of humans, e.g. anasakiasis, several fish-borne trematodiasis and fasciolosis. In the present review, we discuss the current disease status of these primary helminth zoonotic infections with particular emphasis on their diagnosis and control. Advances in molecular biology, proteomics and the release of helminth genome-sequencing project data are revolutionizing parasitology research. The use of these powerful experimental approaches, and their potential benefits to helminth biology are also discussed in relation to the future control of helminth infections of animals and humans.

A Neutron Diffraction and Molecular Dynamics Investigation of Acetate-based Ionic Liquids as Solvents for Glucose

The liquid state structure of the ionic liquid, 1-ethyl-3-methylimidazolium acetate, and the solute/solvent structure of glucose dissolved in the ionic liquid at a 1: 6 molar ratio have been investigated at 323 K by molecular dynamics simulations and neutron diffraction experiments using H/D isotopically substituted materials. Interactions between hydrogen-bond donating cation sites and polar, directional hydrogen-bond accepting acetate anions are examined. Ion-ion radial distribution functions for the neat ionic liquid, calculated from both MD and derived from the empirical potential structure refinement model to the experimental data, show the alternating shell-structure of anions around the cation, as anticipated. Spatial probability distributions reveal the main anion-to-cation features as in-plane interactions of anions with imidazolium ring hydrogens and cation-cation planar stacking. Interestingly, the presence of the polarised hydrogen-bond acceptor anion leads to increased anion-anion tail-tail structuring within each anion shell, indicating the onset of hydrophobic regions within the anion regions of the liquid.

A molecular photoionic AND gate based on fluorescent signalling

MOLECULES that perform logic operations are prerequisites for molecular information processing and computation. We and others have previously reported receptor molecules that can be considered to perform simple logic operations by coupling ionic bonding or more complex molecular-recognition processes with photonic (fluorescence) signals: in these systems, chemical binding (the 'input') results in a change in fluorescence intensity (the 'output') from the receptor. Here we describe a receptor (molecule (1) in Fig. 1) that operates as a logic device with two input channels: the fluorescence signal depends on whether the molecule binds hydrogen ions, sodium ions or both. The input/output characteristics of this molecular device correspond to those of an AND gate.

Haplotypes spanning SPEC2, PDZ-GEF2 and ACSL6 genes are associated with schizophrenia

Chromosome 5q22-33 is a region where studies have repeatedly found evidence for linkage to schizophrenia. In this report, we took a stepwise approach to systematically map this region in the Irish Study of High Density Schizophrenia Families (ISHDSF, 267 families, 1337 subjects) sample. We typed 289 SNPs in the critical interval of 8 million basepairs and found a 758 kb interval coding for the SPEC2/PDZ-GEF2/ACSL6 genes to be associated with the disease. Using sex and genotype-conditioned transmission disequilibrium test analyses, we found that 19 of the 24 typed markers were associated with the disease and the associations were sex-specific. We replicated these findings with an Irish case-control sample (657 cases and 414 controls), an Irish parent-proband trio sample (187 families, 564 subjects), a German nuclear family sample (211 families, 751 subjects) and a Pittsburgh nuclear family sample (247 families, 729 subjects). In all four samples, we replicated the sex-specific associations at the levels of both individual markers and haplotypes using sex- and genotype-conditioned analyses. Three risk haplotypes were identified in the five samples, and each haplotype was found in at least two samples. Consistent with the discovery of multiple estrogen-response elements in this region, our data showed that the impact of these haplotypes on risk for schizophrenia differed in males and females. From these data, we concluded that haplotypes underlying the SPEC2/PDZ-GEF2/ACSL6 region are associated with schizophrenia. However, due to the extended high LD in this region, we were unable to distinguish whether the association signals came from one or more of these genes.

CNV analysis in a large schizophrenia sample implicates deletions at 16p12.1 and SLC1A1 and duplications at 1p36.33 and CGNL1

Large and rare copy number variants (CNVs) at several loci have been shown to increase risk for schizophrenia. Aiming to discover novel susceptibility CNV loci, we analysed 6,882 cases and 11,255 controls genotyped on Illumina arrays, most of which have not been used for this purpose before. We identified genes enriched for rare exonic CNVs among cases, and then attempted to replicate the findings in an additional 14,568 cases and 15,274 controls. In a combined analysis of all samples, 12 distinct loci were enriched among cases with nominal levels of significance (P500kb), rare CNVs showed a 1.2% excess in cases after excluding known schizophrenia-associated loci, suggesting that additional susceptibility loci exist. However, even larger samples are required for their discovery.