The role of nuclear factor (NF)-κB in the regulation of apoptosis in normal and cancer cells has been extensively studied in recent years. Constitutive NF-κB activity in B lymphocytes as well as in ...Hodgkin’s disease and breast cancer cells protects these cells against apoptosis. It has also been reported that NF-κB activation by tumor necrosis factor (TNF)-α, chemotherapeutic drugs, or ionizing radiations can protect several cell types against apoptosis, suggesting that NF-κB could participate in resistance to cancer treatment. These observations were explained by the regulation of antiapoptotic gene expression by NF-κB. However, in our experience, inhibition of NF-κB activity in several cancer cell lines has a very variable effect on cell mortality, depending on the cell type, the stimulus, and the level of NF-κB inhibition. Moreover, in some experimental systems, NF-κB activation is required for the onset of apoptosis. Therefore, it is likely that the NF-κB antiapoptotic role in response to chemotherapy is cell type- and signal-dependent and that the level of NF-κB inhibition is important. These issues will have to be carefully investigated before considering NF-κB as a target for genetic or pharmacological anticancer therapies.
Array-CGH is considered as the first-tier investigation used to identify copy number variations. Right now, there is no available data about the genetic etiology of patients with development ...delay/intellectual disability and congenital malformation in East Africa.
Array comparative genomic hybridization was performed in 50 Rwandan patients with development delay/intellectual disability and multiple congenital abnormalities, using the Agilent's 180 K microarray platform.
Fourteen patients (28%) had a global development delay whereas 36 (72%) patients presented intellectual disability. All patients presented multiple congenital abnormalities. Clinically significant copy number variations were found in 13 patients (26%). Size of CNVs ranged from 0,9 Mb to 34 Mb. Six patients had CNVs associated with known syndromes, whereas 7 patients presented rare genomic imbalances.
This study showed that CNVs are present in African population and show the importance to implement genetic testing in East-African countries.
Congenital heart diseases (CHD) are commonly associated with genetic defects. Our study aimed at determining the occurrence and pattern of CHD association with genetic defects among pediatric ...patients in Rwanda.
A total of 125 patients with clinical features suggestive of genetic defects were recruited. Echocardiography and standard karyotype studies were performed in all patients.
CHDs were detected in the majority of patients with genetic defects. The commonest isolated CHD was ventricular septal defect found in many cases of Down syndrome. In total, chromosomal abnormalities represented the majority of cases in our cohort and were associated with various types of CHDs.
Our findings showed that CHDs are common in Rwandan pediatric patients with genetic defects. These results suggest that a routine echocardiography assessment combined with systematic genetic investigations including standard karyotype should be mandatory in patients presenting characteristic clinical features in whom CHD is suspected to be associated with genetic defect.
Abstract After their successful introduction in postnatal testing, genome-wide arrays are now rapidly replacing conventional karyotyping in prenatal diagnostics. While previous studies have ...demonstrated the advantages of this method, we are confronted with difficulties regarding the technology and the ethical dilemmas inherent to genomic arrays. These include indication for testing, array design, interpretation of variants and how to deal with variants of unknown significance and incidental findings. The experiences with these issues reported in the literature are most often from single centres. Here, we report on a national consensus approach how microarray is implemented in all genetic centres in Belgium. These recommendations are subjected to constant re-evaluation based on our growing experience and can serve as a useful tool for those involved in prenatal diagnosis.
Anthracycline drugs are widely used for the treatment of solid tumors and leukemia, but the molecular basis of their biological effect is still poorly understood. In the HCT 116 colon carcinoma cell ...line, which retains a wild-type inducible p53 gene, we show that the anthracycline daunomycin is a potent inducer of p53 and NF-κB transcription factors. Nuclear accumulation of p53 protein occurred because of increased protein stability and enhanced gene expression. In addition, daunomycin induced the p53 promoter through the binding of p50/p65 NF-κB heterodimers to the κB site in the p53 promoter. Under our conditions, the free radical scavengers NAC and PDTC were not able to block NF-κB activation or p53 induction, indicating that reactive oxygen intermediates were not involved in the cellular response to daunomycin stimulation. Overexpression of a stable unresponsive IκBα mutant in HCT116 cells resulted in a complete inhibition of the NF-κB activation but only a partial impairment of the p53 protein accumulation induced by daunomycin. We conclude that the p53-activating signal generated by daunomycin is partially regulated by NF-κB.
The tumor suppressor p53 plays a pivotal role in the cellular response to DNA damage as it controls DNA repair, cell cycle arrest and apoptosis. We studied the autoregulation of human p53 gene ...transcription in colon cancer cell lines. Wild-type p53 has been shown to autoregulate its own transcription either positively or negatively and probably in a cell-type-specific manner. Indeed, a p53 binding site has been described in the human and murine p53 promoters, but a direct binding of wild-type p53 protein to this site has never been reported. In this study, we demonstrated a transactivation of human p53 promoter by wild-type p53 in human colon cancer cells. We identified in the human p53 promoter a novel potential p53-responsive element that binds wild-type p53. Moreover, wild-type p53 protein transactivated a reporter plasmid containing a luciferase gene driven by a minimal promoter harboring this p53 binding site. Finally, as the p53 promoter contains an NF-κB binding site, we demonstrated an additive effect when NF-κB subunits and p53 protein combined to transactivate the human p53 promoter.
Aminopyropheophorbide (APP) is a second generation of photosensitizer for photodynamic therapy (PDT). We demonstrated that APP strongly absorbed red light and, after being taken up by colon cancer ...cells (HCT-116 cells), was localized in cytoplasmic and internal membranes but not in mitochondria. The APP-mediated photosensitization was cytotoxic for HCT-116 cells through an induction of apoptosis. Indeed, DNA fragmentation (DNA laddering and terminal deoxyuridine nick-end labeling) and chromatin condensation (4',6-diamidine-2'-phenylindole staining) could be visualized soon after photosensitization. Because nuclear factor (NF)-kappa B is involved in the response to many photosensitizers, we also demonstrated its nuclear translocation in two waves: a rapid and transient one, followed by a slow and sustained phase. The NF-kappa B turned out to be involved in an antiapoptotic response to APP-mediated photosensitization because the HCT-116 cell line expressing the dominant negative mutant of inhibitor-kappa B alpha was more sensitive to apoptosis as measured by DNA fragmentation and caspase activation. These data unambiguously show that a membrane-located photosensitizer can lead to effective apoptosis, reinforcing the idea that PDT can be an effective means to eradicate colon cancer cells.
Gene therapy is a novel therapeutic approach that might soon improve the prognosis of some cancers. We investigated the feasibility of cytosine deaminase (CD) suicide gene therapy in a model of ...peritoneal carcinomatosis. DHD/K12 colorectal adenocarcinoma cells transfected in vitro with the CD gene were highly sensitive to 5-fluorocytosine (5-FC), and a bystander effect could also be observed. Treating CD+ cells with 5-FC resulted in apoptosis as detected by terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick-end labeling. In vitro, several human cell lines derived from ovarian or colorectal carcinomas, as well as the rat glioblastoma 9 L cell line, responded to CD/5-FC and showed a very strong bystander effect. 5-FC treatment of peritoneal carcinomatosis generated in syngeneic BDIX rats by CD-expressing DHD/K12 cells led to a complete and prolonged response and to prolonged survival. Our study thus demonstrated the efficacy of CD suicide gene therapy for the treatment of peritoneal carcinomatosis.
While the XYY and XXYY syndromes have been several time described in patients, the combination of both syndromes in an individual is a rare event and may result in a severe phenotype. In the present ...observation, a boy with congenital scoliosis due to segmented thoracic hemivertebra associated with radioulnar synostosis and congenital heart disease is described. Chromosome G-banding and FISH analysis demonstrated a de novo mosaic karyotype 48, XXYY/47, XYY in this patient. To the best of our knowledge, this is the first report of a combination of XYY and XXYY syndromes.
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