Annals of medicine
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The RET proto-oncogene is the major gene involved in the pathogenesis of Hirschsprung (HSCR), a complex genetic disease characterized by lack of ganglia along variable lengths of the gut. Here we present a survey of the different molecular mechanisms through which RET mutations lead to the disease development. Among these, loss of function, gain of function, apoptosis, aberrant splicing and decreased gene expression are exemplified and considered with respect to their pathogenetic impact. ⋯ Notably, gene expression impairment seems to be at the basis of the association of HSCR disease with several RET polymorphisms, allowing us to define a predisposing haplotype spanning from the promoter to exon 2. Putative functional variants, in the promoter and in intron 1, and proposed as low penetrant predisposing alleles, are presented and discussed. Finally, based on the RET mutation effects thus summarized, we attempt to derive conclusions which may be useful for HSCR risk prediction and genetic counselling.
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NPAS3 is a member of the basic helix-loop-helix PAS domain class of transcription factors expressed in the brain. Evidence from a human chromosomal rearrangement and a mouse knock-out strain suggest that it may play a part in the aetiology of psychiatric illness. In this review, we describe evolutionary constraints on the NPAS3 gene, relevant functional studies from a related gene and the behavioural and hippocampal neurogenesis deficit observed in the mutant mouse. In addition, we speculate on the physiological regulation of NPAS3 and whether NPAS3 gene variation contributes to psychiatric illness at the population level.
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Review
Novel approaches to treatment of advanced colorectal cancer with anti-EGFR monoclonal antibodies.
The standard treatment of metastatic colorectal cancer (mCRC) is combination of 5- fluorouracil/folinic acid with irinotecan or oxaliplatin-based chemotherapy. Epidermal growth factor receptor (EGFR) is overexpressed in 70%-80% of colorectal cancers (CRC). EGFR overexpression is known to be involved in carcinogenic processes, such as cell proliferation, apoptosis, angiogenesis and metastasis. ⋯ Anti-EGFR MoAbs are well tolerated and have limited overlapping toxicities in combination with other cytotoxic drugs. The most common side effect of anti-EGFR MoAb is an acneform skin rash, which is a surrogate marker of efficacy of treatment with MoAbs. In this review, we will discuss the use of anti-EGFR MoAbs in the treatment of mCRC, with focus on cetuximab and panitumumab.
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While antidepressant pharmacotherapy is an effective treatment of depression, it still is hampered by a delayed time of onset of clinical improvement and a series of side effects. Moreover, a substantial group of patients has only limited response or fails to respond at all. One source accounting for these variations are genetic differences as currently analysed by single nucleotide polymorphisms (SNP) mapping. ⋯ It is clear, however, that other candidate systems have to be considered in the pharmacogenetics of antidepressant drugs, such as neuropeptidergic systems, the hypothalamus-pituitary adrenal (HPA) axis and neurotrophic systems. There is recent evidence that polymorphisms in genes regulating the HPA axis have an important impact on response to antidepressants. These studies mark the beginning of an emerging standard SNP profiling system that ultimately allows identifying the right drug for the right patient at the right time.
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The anterior pituitary gland is a central regulator of growth, reproduction and homeostasis, and is the end-product of a carefully orchestrated pattern of expression of signalling molecules and transcription factors leading to the development of this complex organ secreting six hormones from five different cell types. Naturally occurring and transgenic murine models have demonstrated a role for many of these molecules in the aetiology of combined pituitary hormone deficiency (CPHD). ⋯ The highly variable phenotype may consist of isolated hypopituitarism, or more complex disorders such as septo-optic dysplasia (SOD) and holoprosencephaly. Since mutations in any one transcription factor are uncommon, and since the overall incidence of mutations in known transcription factors is low in patients with CPHD, it is clear that many genes remain to be identified, and characterization of these will further elucidate the pathogenesis of these complex conditions, and also shed light on normal pituitary development.