Clinical relevance of nitrated beta 2-glycoprotein I in antiphospholipid syndrome: Implications for thrombosis risk.

Β-Glycoprotein I (βGPI) is an important anti-thrombotic protein and is the major auto-antigen in the antiphospholipid syndrome (APS). The clinical relevance of nitrosative stress in post translational modification of βGPI was examined.The effects of nitrated (n)βGPI on its anti-thrombotic properties and its plasma levels in primary and secondary APS were determined with appropriate clinical control groups.

Non-CpG methylation biases bisulphite PCR towards low or unmethylated mitochondrial DNA: recommendations for the field.

Mitochondrial DNA (mtDNA) is a circular genome of 16 kb that is present in multiple copies in mitochondria. mtDNA codes for genes that contribute to mitochondrial structure and function. A long-standing question has asked whether mtDNA is epigenetically regulated similarly to the nuclear genome.

Tumour infiltrating lymphocyte status is superior to histological grade, DNA mismatch repair and BRAF mutation for prognosis of colorectal adenocarcinomas with mucinous differentiation.

Mucinous colorectal adenocarcinoma (CRC) is conventionally defined by extracellular mucin comprising >50% of the tumour area, while tumours with ≤50% mucin are designated as having a mucinous component. However, these definitions are largely arbitrary and comparisons of clinico-molecular features and outcomes by proportion of mucinous component are limited. A cohort of 1643 patients with stage II/III cancer was examined for tumour mucinous component, DNA mismatch repair (MMR) status, BRAF mutation and tumour infiltrating lymphocytes (TILs).

Scarcity of Recurrent Regulatory Driver Mutations in Colorectal Cancer Revealed by Targeted Deep Sequencing.

Background: Genetic testing of cancer samples primarily focuses on protein-coding regions, despite most mutations arising in noncoding DNA. Noncoding mutations can be pathogenic if they disrupt gene regulation, but the benefits of assessing promoter mutations in driver genes by panel testing has not yet been established. This is especially the case in colorectal cancer, for which few putative driver variants at regulatory elements have been reported.

JMJD6 is a tumorigenic factor and therapeutic target in neuroblastoma.

Chromosome 17q21-ter is commonly gained in neuroblastoma, but it is unclear which gene in the region is important for tumorigenesis. The JMJD6 gene at 17q21-ter activates gene transcription. Here we show that JMJD6 forms protein complexes with N-Myc and BRD4, and is important for E2F2, N-Myc and c-Myc transcription.

Assessing the Evolutionary Conservation of Protein Disulphide Bonds.

Studying the evolutionary conservation of proteins can be a valuable tool for understanding its function. At the sequence level, the conservation of each residue can be used to infer the importance of the particular regions of proteins. In the case of protein disulphide bonds, the conservation of the cysteines involved can be used to infer the conservation of the disulphide bond itself.

Analysis of 7,815 cancer exomes reveals associations between mutational processes and somatic driver mutations.

Driver mutations are the genetic variants responsible for oncogenesis, but how specific somatic mutational events arise in cells remains poorly understood. Mutational signatures derive from the frequency of mutated trinucleotides in a given cancer sample, and they provide an avenue for investigating the underlying mutational processes that operate in cancer. Here we analyse somatic mutations from 7,815 cancer exomes from The Cancer Genome Atlas (TCGA) across 26 cancer types.

Dual roles of different redox forms of complement factor H in protecting against age related macular degeneration.

Complement Factor H (CFH) is an important inhibitor of the alternate complement pathway in Bruch's membrane (BM), located between the choriocapillaris and the retinal pigment epithelium. Furthermore dysfunction of its activity as occurs with certain polymorphisms is associated with an increased risk of age related macular degeneration (AMD). The retina is a site of high generation of reactive oxygen species (ROS) and dysfunction of redox homeostasis in this milieu also contributes to AMD pathogenesis.

Finding cancer driver mutations in the era of big data research.

In the last decade, the costs of genome sequencing have decreased considerably. The commencement of large-scale cancer sequencing projects has enabled cancer genomics to join the big data revolution. One of the challenges still facing cancer genomics research is determining which are the driver mutations in an individual cancer, as these contribute only a small subset of the overall mutation profile of a tumour.

Identification of allosteric disulfides from labile bonds in X-ray structures.

Protein disulfide bonds link pairs of cysteine sulfur atoms and are either structural or functional motifs. The allosteric disulfides control the function of the protein in which they reside when cleaved or formed. Here, we identify potential allosteric disulfides in all Protein Data Bank X-ray structures from bonds that are present in some molecules of a protein crystal but absent in others, or present in some structures of a protein but absent in others.

The interaction between cytosine methylation and processes of DNA replication and repair shape the mutational landscape of cancer genomes.

Methylated cytosines (5mCs) are frequently mutated in the genome. However, no studies have yet comprehensively analysed mutation-methylation associations across cancer types. Here we analyse 916 cancer genomes, together with tissue type-specific methylation and replication timing data.

The Histone Methyltransferase DOT1L Promotes Neuroblastoma by Regulating Gene Transcription.

Myc oncoproteins exert tumorigenic effects by regulating expression of target oncogenes. Histone H3 lysine 79 (H3K79) methylation at Myc-responsive elements of target gene promoters is a strict prerequisite for Myc-induced transcriptional activation, and DOT1L is the only known histone methyltransferase that catalyzes H3K79 methylation. Here, we show that N-Myc upregulates DOT1L mRNA and protein expression by binding to the DOT1L gene promoter.

Differential DNA repair underlies mutation hotspots at active promoters in cancer genomes.

Promoters are DNA sequences that have an essential role in controlling gene expression. While recent whole cancer genome analyses have identified numerous hotspots of somatic point mutations within promoters, many have not yet been shown to perturb gene expression or drive cancer development. As such, positive selection alone may not adequately explain the frequency of promoter point mutations in cancer genomes.

Carbon-Coated Gold Nanorods: A Facile Route to Biocompatible Materials for Photothermal Applications.

Gold nanorods and their core-shell nanocomposites have been widely studied because of their well-defined anisotropy and unique optical properties and applications. This study demonstrates a facile hydrothermal synthesis strategy for generating carbon coating on gold nanorods (AuNRs@C) under mild conditions (<200 °C), where the carbon shell is composed of polymerized sugar molecules (glucose). The structure and composition of the produced core-shell nanocomposites were characterized using advanced microscopic and spectroscopic techniques.

WDR5 Supports an N-Myc Transcriptional Complex That Drives a Protumorigenic Gene Expression Signature in Neuroblastoma.

MYCN gene amplification in neuroblastoma drives a gene expression program that correlates strongly with aggressive disease. Mechanistically, trimethylation of histone H3 lysine 4 (H3K4) at target gene promoters is a strict prerequisite for this transcriptional program to be enacted. WDR5 is a histone H3K4 presenter that has been found to have an essential role in H3K4 trimethylation.

The search for cis-regulatory driver mutations in cancer genomes.

With the advent of high-throughput and relatively inexpensive whole-genome sequencing technology, the focus of cancer research has begun to shift toward analyses of somatic mutations in non-coding cis-regulatory elements of the cancer genome. Cis-regulatory elements play an important role in gene regulation, with mutations in these elements potentially resulting in changes to the expression of linked genes. The recent discoveries of recurrent TERT promoter mutations in melanoma, and recurrent mutations that create a super-enhancer regulating TAL1 expression in T-cell acute lymphoblastic leukaemia (T-ALL), have sparked significant interest in the search for other somatic cis-regulatory mutations driving cancer development.

Intestinal-specific activatable Myb initiates colon tumorigenesis in mice.

Transcription factor Myb is overexpressed in most colorectal cancers (CRC). Patients with CRC expressing the highest Myb are more likely to relapse. We previously showed that mono-allelic loss of Myb in an Adenomatous polyposis coli (APC)-driven CRC mouse model (Apc(Min/+)) significantly improves survival.

Hope, optimism and survival in a randomised trial of chemotherapy for metastatic colorectal cancer.

Purpose: Psychological responses to cancer are widely believed to affect survival. We investigated associations between hope, optimism, anxiety, depression, health utility and survival in patients starting first-line chemotherapy for metastatic colorectal cancer.

Methods: Four hundred twenty-nine subjects with metastatic colorectal cancer in a randomised controlled trial of chemotherapy completed baseline questionnaires assessing the following: hopefulness, optimism, anxiety and depression and health utility.

Validation of a proxy for estrogen receptor status in breast cancer patients using dispensing data.

Aim: To assess the performance of a proxy for estrogen receptor (ER) status in breast cancer patients using dispensing data.

Methods: We derived our proxy using 167 patients. ER+ patients had evidence of at least one dispensing record for hormone therapy during the lookback period, irrespective of diagnosis date and ER- had no dispensing records for hormone therapy during the period.

Disulfide bond acquisition through eukaryotic protein evolution.

Disulfide bonds play critical roles in protein stability and function. They are generally considered to be strongly conserved among species. Although there is compelling evidence in the literature for this conservation on a case-by-case basis, comparative genomic analyses of disulfide conservation have in the past been limited.

Are antibody deficiency disorders associated with a narrower range of cancers than other forms of immunodeficiency?

Analysis of cancer risk in primary immune deficiency (PID) offers insight into the relationship between immune function and cancer. Data on Australian patients (n = 1132) notified voluntarily to the Australasian Society of Clinical Immunology and Allergy PID Registry (1990-2008) were linked with national death and cancer registries. Person-years of follow-up commenced from up to 15 years before registration on the PID Registry or January 1982, the inception of national cancer registration.