Biomedical subjects

N J Maughan

Publications and source records attributed to N J Maughan.

6 recordsLinked to original sources

PubMed2006

Achaete-scute like 2 (ascl2) is a target of Wnt signalling and is upregulated in intestinal neoplasia.

Achaete-scute like (ASCL)2 is a basic helix-loop-helix transcription factor essential for the maintenance of proliferating trophoblasts during placental development. Using oligonucleotide microarrays we identified ascl2 as a gene significantly upregulated in colorectal adenocarcinomas (n=36 cancers, n=16 normals; 15-fold, P<0.0001). This finding was confirmed by quantitative reverse transcriptase (RT)-PCR on large intestinal cancers (n=29 cancers, n=16 normals; 10-fold, P<0.0001). In situ hybridization for ascl2 demonstrated expression at the base of small and large intestinal crypts (n=304), but in no other normal tissues excepting placenta. By in situ hybridization, 52-71% of colorectal adenomas (n=187), 50-73% of large (n=327) and 33-64% of small intestinal adenocarcinomas (n=124) were positive for ascl2 expression. Upregulation of murine ascl2 was also observed using oligonucleotide microarrays, quantitative RT-PCR and in situ hybridization on apcmin/+ and apc1638N/+ smad4-/+ tumours. Tumour cell lines stably transfected with LEF1(DN) or APC2, or transiently transfected with short-interfering RNA (siRNA) against beta-catenin showed a significant downregulation of ascl2. Colocalization of ascl2 with nuclear beta-catenin was observed in 73 small intestinal adenocarcinomas (P=0.0008) and apcmin/+ tumours. Preliminary in vitro data suggest ascl2 may promote progression through the G2/M cell cycle checkpoint. In summary, ascl2 is a putative regulator of proliferation that is overexpressed in intestinal neoplasia.

Animals↗

PubMed2003

Genomics in colorectal cancer: godsend or gimmick?

Genomics and the new techniques it embraces, such as cDNA and tissue arrays, comparative genomic hybridization and single nucleotide polymorphism analysis, offer the opportunity to generate massive amounts of data relating to screening, aetiology, diagnosis, prognostication and optimal treatment in colorectal cancer. To make progress, studies must be designed to stringently test these new technologies and compare them to the tried and tested gold standards. This is best done in the form of large randomized controlled trials. Genomics undoubtedly offers the prospect of exciting new developments in the field of colorectal cancer but these should be regarded with caution until they are proved superior to present practices and models.

Colorectal Neoplasms↗

PubMed2003

Modern management of colorectal cancer--a pathologist's view.

Colorectal cancer is an increasingly significant cause of both mortality and morbidity due to wider adoption of the Western lifestyle and a progressively ageing population. Recently steps forward have been made both in surgical and chemoradiotherapeutic management of this disease. Well performed total mesorectal excision surgery has now become the gold standard for rectal cancer resection. Several prognostic markers, both clinicopathological and molecular, have been identified allowing better patient counselling and targeting of treatment. The rationale for patient selection, timing and dose of radiotherapy has been further elucidated. New chemotherapy agents are under trial and predictive factors allowing selection of those patients most likely to respond to them have been identified. Many of these factors will increase in importance as colorectal cancer becomes a chronic disease with lengthening survival times. As we will discuss the pathologist has important roles in all of these developments and at all stages of colorectal cancer management.

Colorectal Neoplasms↗

PubMed2002

Pathology--a molecular prognostic approach.

Colorectal cancer affects 29,000 people and kills approximately 15,000 in England and Wales each year, most of these deaths resulting from the effects of local or distant recurrence. There is a need to give these patients accurate prognoses and individualised treatment regimens. At present, the best prognostic markers are clinicopathological. Post-genomic science and the new high throughput technologies offer unrivalled opportunities to understand the biology and molecular pathology of colorectal cancer. These technologies should be used in the context of large randomised controlled trials to identify new molecular prognostic and predictive markers and also new targets for therapy.

Biomarkers, Tumor↗

PubMed2001

Unlocking the archive--gene expression in paraffin-embedded tissue.

The histopathology archive represents a vast, well-characterized source of specimens covering virtually every disease and is available for molecular biological investigation. The archive has in recent years become widely used for molecular genetic analysis and DNA can be routinely extracted from formalin-fixed, paraffin-embedded tissue. More recently, archival specimens have become a source of material for extensive analysis of mRNA expression utilizing DNA microarrays, real-time quantitative reverse transcriptase polymerase chain reaction (PCR), and in situ hybridization and amplification techniques. These techniques will enable a greater understanding of the changes that occur in gene function during every stage of the development of disease and will lead to better diagnosis, better evaluation of prognosis, and better treatment through targeted therapeutic regimes.

Biological Specimen Banks↗

PubMed2001

An introduction to arrays.

DNA microarrays are a new technology that allows the analysis of large numbers of genes at a high resolution by the hybridization of labelled DNA, which may be reverse-transcribed from mRNA, to a substrate containing thousands of spotted cDNAs or oligonucleotides. The amount of hybridized target is analysed, giving information on gene expression, polymorphisms or mutations present and allowing the gene profiling of different subtypes of disease. This technique has massive implications for the further understanding of the complicated genetic alterations involved in tumourigenesis and other disease processes and also for the generation of accurate prognostic information and optimization of treatment in these situations.

Computational Biology↗