The uptake of the two essential ingredients for life, oxygen and nutrients, occurs primarily through the oral cavity, but these two lifelines need to be separated with high accuracy once inside the body. The two syste...The uptake of the two essential ingredients for life, oxygen and nutrients, occurs primarily through the oral cavity, but these two lifelines need to be separated with high accuracy once inside the body. The two systems, the gas exchange pulmonary system and the gastro-intestinal feeding system, are derived from the same primitive embryonic structure during development, the foregut, which need to be separated before birth. In certain newborns, this separation occurs not or insufficiently, leading to life threatening conditions, sometimes incompatible with life. The development of the foregut, trachea and lungs is influenced and coordinated by a multitude of signaling cascades and transcription factors. In this review, we will highlight the development of the foregut and pulmonary system and focus on associated congenital abnormalities in light of known genetic alterations with specific attention to the transcription factor SOX2.展开更多
Natural and synthetic glucocorticoids (GCs) are widely employed in a number of inflammatory, autoimmune and neoplastic diseases, and, despite the introduction of novel therapies, remain the first-line treatment for in...Natural and synthetic glucocorticoids (GCs) are widely employed in a number of inflammatory, autoimmune and neoplastic diseases, and, despite the introduction of novel therapies, remain the first-line treatment for inducing remission in moderate to severe active Crohn’s disease and ulcerative colitis. Despite their extensive therapeutic use and the proven effectiveness, considerable clinical evidence of wide inter-individual differences in GC efficacy among patients has been reported, in particular when these agents are used in inflammatory diseases. In recent years, a detailed knowledge of the GC mechanism of action and of the genetic variants affecting GC activity at the molecular level has arisen from several studies. GCs interact with their cytoplasmic receptor, and are able to repress inflammatory gene expression through several distinct mechanisms. The glucocorticoid receptor (GR) is therefore crucial for the effects of these agents: mutations in the GR gene (NR3C1, nuclear receptor subfamily 3, group C, member 1) are the primary cause of a rare, inherited form of GC resistance; in addition, several polymorphisms of this gene have been described and associated with GC response and toxicity.However, the GR is not self-standing in the cell and the receptor-mediated functions are the result of a complex interplay of GR and many other cellular partners. The latter comprise several chaperonins of the large cooperative hetero-oligomeric complex that binds the hormonefree GR in the cytosol, and several factors involved in the transcriptional machinery and chromatin remodeling, that are critical for the hormonal control of target genes transcription in the nucleus. Furthermore, variants in the principal effectors of GCs (e.g. cytokines and their regulators) have also to be taken into account for a comprehensive evaluation of the variability in GC response. Polymorphisms in genes involved in the transport and/or metabolism of these hormones have also been suggested as other possible candidates of interest that could play a role in the observed inter-individual differences in efficacy and toxicity. The best-characterized example is the drug efflux pump P-glycoprotein, a membrane transporter that extrudes GCs from cells, thereby lowering their intracellular concentration. This protein is encoded by the ABCB1/ MDR1 gene; this gene presents different known polymorphic sites that can influence its expression and function. This editorial reviews the current knowledge on this topic and underlines the role of genetics in predicting GC clinical response. The ambitious goal of pharmacogenomic studies is to adapt therapies to a patient’s specific genetic background, thus improving on efficacy and safety rates.展开更多
The XX/XY sex chromosomal system of mammals, including human, challengesthe chromosome pairing mechanism during male meiosis. Pairing and subsequent separation of homologous chromosomes generates haploid cells from di...The XX/XY sex chromosomal system of mammals, including human, challengesthe chromosome pairing mechanism during male meiosis. Pairing and subsequent separation of homologous chromosomes generates haploid cells from diploid cells during the meiotic divisions. One of the basic requirements for recognition between homologous chromosomes is DNA sequence identity.展开更多
文摘The uptake of the two essential ingredients for life, oxygen and nutrients, occurs primarily through the oral cavity, but these two lifelines need to be separated with high accuracy once inside the body. The two systems, the gas exchange pulmonary system and the gastro-intestinal feeding system, are derived from the same primitive embryonic structure during development, the foregut, which need to be separated before birth. In certain newborns, this separation occurs not or insufficiently, leading to life threatening conditions, sometimes incompatible with life. The development of the foregut, trachea and lungs is influenced and coordinated by a multitude of signaling cascades and transcription factors. In this review, we will highlight the development of the foregut and pulmonary system and focus on associated congenital abnormalities in light of known genetic alterations with specific attention to the transcription factor SOX2.
文摘Natural and synthetic glucocorticoids (GCs) are widely employed in a number of inflammatory, autoimmune and neoplastic diseases, and, despite the introduction of novel therapies, remain the first-line treatment for inducing remission in moderate to severe active Crohn’s disease and ulcerative colitis. Despite their extensive therapeutic use and the proven effectiveness, considerable clinical evidence of wide inter-individual differences in GC efficacy among patients has been reported, in particular when these agents are used in inflammatory diseases. In recent years, a detailed knowledge of the GC mechanism of action and of the genetic variants affecting GC activity at the molecular level has arisen from several studies. GCs interact with their cytoplasmic receptor, and are able to repress inflammatory gene expression through several distinct mechanisms. The glucocorticoid receptor (GR) is therefore crucial for the effects of these agents: mutations in the GR gene (NR3C1, nuclear receptor subfamily 3, group C, member 1) are the primary cause of a rare, inherited form of GC resistance; in addition, several polymorphisms of this gene have been described and associated with GC response and toxicity.However, the GR is not self-standing in the cell and the receptor-mediated functions are the result of a complex interplay of GR and many other cellular partners. The latter comprise several chaperonins of the large cooperative hetero-oligomeric complex that binds the hormonefree GR in the cytosol, and several factors involved in the transcriptional machinery and chromatin remodeling, that are critical for the hormonal control of target genes transcription in the nucleus. Furthermore, variants in the principal effectors of GCs (e.g. cytokines and their regulators) have also to be taken into account for a comprehensive evaluation of the variability in GC response. Polymorphisms in genes involved in the transport and/or metabolism of these hormones have also been suggested as other possible candidates of interest that could play a role in the observed inter-individual differences in efficacy and toxicity. The best-characterized example is the drug efflux pump P-glycoprotein, a membrane transporter that extrudes GCs from cells, thereby lowering their intracellular concentration. This protein is encoded by the ABCB1/ MDR1 gene; this gene presents different known polymorphic sites that can influence its expression and function. This editorial reviews the current knowledge on this topic and underlines the role of genetics in predicting GC clinical response. The ambitious goal of pharmacogenomic studies is to adapt therapies to a patient’s specific genetic background, thus improving on efficacy and safety rates.
文摘The XX/XY sex chromosomal system of mammals, including human, challengesthe chromosome pairing mechanism during male meiosis. Pairing and subsequent separation of homologous chromosomes generates haploid cells from diploid cells during the meiotic divisions. One of the basic requirements for recognition between homologous chromosomes is DNA sequence identity.
