Rachid Jlidi

No Evidence of Correlation between p53 Codon 72 Polymorphism and Risk of Bladder or Breast Carcinoma in Tunisian Patients

Abstract: The TP53 gene, frequently mutated in human cancers, carries several polymorphisms. The one most informative and studied concerns codon 72; a single base changes the CGC (arginine) to CCC (proline). The arginine form was considered to be a significant risk factor in the development of cancer. However, various reports on this polymorphism are controversial. We carried out the same investigation in two groups of patients, a group with bladder cancer and another with breast cancer, and in healthy controls in two regions of our country, using an improved PCR‐RFLP method. The number of Arg/Arg, Arg/Pro, and Pro/Pro genotypes was as follows: 21, 23, 3 and 13, 19, 2 for patients (total 47) and controls (34), respectively, in the first group; 18, 9, 3 and 19, 26, 4 for patients (30) and controls (49), respectively, in the second group. Statistical analysis of the genotype and allele frequencies did not reveal any difference between patients and controls in both groups except for a weak difference between the homozygotes to heterozygotes in the second group with a chi square of 4.1 (P= 0.045); the number of breast cancer patients is actually low (30) and should be increased in order to assess such a conclusion. Our overall results are therefore not consistent with a high risk associated with TP53 codon 72 polymorphism in breast and in bladder cancers.

Apoptosis and TRAF-1 cleavage in Epstein-Barr virus-positive nasopharyngeal carcinoma cells treated with doxorubicin combined with a farnesyl-transferase inhibitor

Epstein-Barr virus (EBV)-associated nasopharyngeal carcinomas (NPC) are much more sensitive to chemotherapy than other head and neck carcinomas. Spectacular regressions are frequently observed after induction chemotherapy. However, these favorable responses are difficult to predict and often of short duration. So far there have been only few experiments to investigate the mechanisms which underline the cytotoxic effects of anti-neoplastic drugs against NPC cells. In addition, these studies were performed almost entirely on EBV-negative cell lines therefore not truly representative of NPC cells. For the first time, we have used two EBV-positive NPC tumor lines derived from a North African (C15) and a Chinese (C666-1) patient as in vitro targets for a panel of anti-neoplastic agents. Doxorubicin, taxol and in a lesser extent cis-platinum efficiently inhibited NPC cell proliferation at clinically relevant concentrations, but all three agents failed to induce apoptosis. However, massive apoptosis of C15 cells was achieved when doxorubicin (1 microM) was combined with a farnesyl-transferase inhibitor, BIM 2001 (5 microM). Moreover, this apoptotic process was associated with a caspase-dependent early cleavage of the TNF-receptor associated factor 1 (TRAF-1) molecule, a signaling adaptor which is specifically expressed in latently EBV-infected cells. TRAF-1 cleavage might become a useful indicator of chemo-induced apoptosis in EBV-associated NPCs.

Merosin-deficient congenital muscular dystrophy with mental retardation and cerebellar cysts, unlinked to the LAMA2, FCMD, MEB and CMD1B loci, in three Tunisian patients

We report three Tunisian patients affected by congenital muscular dystrophy with mental retardation and cerebellar cysts on cranial magnetic resonance imaging. The clinical features were characterized by hypotonia at birth, joint contractures associated with severe psychomotor retardation, absence of speech, inability to walk in three patients, but calf hypertrophy was noted only in two patients. Brain magnetic resonance imaging showed several cerebellar cysts and vermis hypoplasia in all of the patients. Abnormality of the white matter was present in two patients. The pattern of gyration was normal in all cases. Serum creatine kinase was elevated in all three cases and their muscle biopsy showed dystrophic changes compatible with congenital muscular dystrophy. The immunohistochemical analysis of the skeletal muscle revealed partial merosin deficiency, more pronounced for the N-terminal antibody. Linkage analysis excluded congenital muscular dystrophy loci on chromosomes 6q22, 9q31, 1p32 and 1q42. These patients constituted a particular form of congenital muscular dystrophy with a combination of severe motor delay, mental retardation, partial merosin deficiency and cerebellar cysts. Two patients showed white matter abnormalities on magnetic resonance imaging and hypertrophy of the calves. These cases, in addition to those reported previously, confirmed the large phenotypic variability in the group of secondary merosin deficiency congenital muscular dystrophy.

Le carcinome nasopharyngé en Afrique du Nord et dans le Sud-Est asiatique : entre similitude et différence

Nasopharyngeal carcinoma (NPC) is an unusual head and neck cancer because of its unequal geographical distribution and its consistent association with the Epstein-Barr virus (EBV). This malignant tumor poses a serious public health problem in many countries, especially in Southeast Asia and North Africa where the recorded incidence are highest. During the past decade, a growing number of studies were undertaken to define the molecular basis of NPC. However, the analysis of several clinical and biological parameters of North African and Southeast Asian NPCs has shown notable differences, suggesting that they could result from a distinct combination of etiological factors. One intriguing characteristic of North African NPC, concerns its bimodal age distribution with a secondary peak of incidence in the range of 15-25 years, not observed in Asian NPC. In this juvenile form of NPC, immuno-histochemistry assay has shown that the two key proteins controlling the apoptotic-survival balance p53 and Bcl-2 are less frequently expressed whereas the transmembrane tyrosine-kinase receptor c-kit and the main EBV oncoprotein LMP1 were more abundant. In addition, the EBV serological alterations are less informative for the diagnosis of the juvenile compared to the adult form. In addition, most North African NPCs contain EBV strains with genetic polymorphisms distinct from those described in the Southeast Asia series (predominance of F, D, H1-H2, XhoI+ and f, C, H, XhoI- respectively). In contrast, studies relating on tumor chromosomal alterations or aberrant promoter methylation result in data very similar to those obtained from the Southeast Asia series, supporting the concept of a common molecular basis for all NPC regardless of patient geographic origin.

Wegener’s granulomatosis presenting as multiple bilateral renal masses: case report and literature review

Wegener’s granulomatosis (WG) is a disease of unknown etiology characterized by necrotizing granulomatous vascularitis. The upper and lower respiratory tract and kidney involvements are very common; however, its presentation as bilateral renal masses is unusual. We report a case of a 59-year-old female patient who presented with multiple bilateral renal masses. The patient presented with sinusal and ocular symptoms suggestive of WG, and positive antineutrophil cytoplasmic antibodies (c-ANCA) with an anti-PR3 pattern. Histopathologic examination of the renal biopsy specimen revealed granulomatous inflammation with vasculitis and fibrinoid necrosis. The patient management, including prednisone and cyclophosphamid, induced a marked improvement of the renal masses. This case illustrates that WG should be considered in the differential diagnosis of renal masses.

A more accurate detection of codon 72 polymorphism and LOH of the TP53 gene

The polymorphism at codon 72 of the TP53 gene has been extensively studied for its involvement in cancerogenesis and loss of heterozygosity (LOH) detection. Usually, the exon 4 of the TP53 gene is amplified by polymerase chain reaction (PCR) on DNA extracted from blood and tumor tissues, then digested by AccII. In the case of heterozygosity, the comparison of AccII profile from blood and tumor DNA PCR products allowed the identification of a potential LOH in the TP53 locus. This method can be hindered by a partial AccII digestion and/or DNA contamination of non-tumor cells. To circumvent these problems, we have developed a new approach by using the AccII restriction site between exon 4 and exon 6. The PCR amplification of exon 4-6, followed by AccII digestion allowed us to detect without ambiguity any LOH case.

Prognostic significance of p16INK4a/p53 in Tunisian patients with breast carcinoma.

Infiltrating ductal carcinoma (IDC) of the breast is a result of genetic alterations that affect the regulation of the cell cycle check-point and apoptosis. The aim of the present study was analysis using immunohistochemical localization of mouse double minute-2 (mdm2), p16INK4a, p53, bax and bcl-2 markers in Tunisian patients with breast IDC and to determine if there was correlation with the major clinico-pathological parameters and with survival of patients. We showed that the expression of p53, p16INK4a, mdm2, bcl-2, and bax was observed in 46.3%, 20.7%, 38%, 50% and 11.9% of cases, respectively. Statistical analysis revealed that positive expression of mdm2 was associated with larger tumors (P=0.013), whereas bax positivity was more prevalent in younger patients and in tumors of smaller size (P=0.008 and P=0.012 respectively). Furthermore, the expression of p16INK4a correlated with advanced grade (P<0.0001), triple negative tumors (ER-/PR-/HER2-, P=0.001) and mdm2 expression (P=0.017). The absence of nuclear p53 accumulation was predictive of good prognosis as well as when it was associated with negative expression of p16INK4a. Our findings suggest that among the biomarkers tested, p16INK4a might have a useful clinical and prognostic significance in infiltrating ductal carcinoma of the breast.

Le carcinome nasopharyngé en Afrique du Nord et dans le Sud-Est asiatique : entre similitude et différenceNorth African and Southeast Asian nasopharyngeal carcinomas: between the resemblance and the dissemblance

Nasopharyngeal carcinoma (NPC) is an unusual head and neck cancer because of its unequal geographical distribution and its consistent association with the Epstein-Barr virus (EBV). This malignant tumor poses a serious public health problem in many countries, especially in Southeast Asia and North Africa where the recorded incidence are highest. During the past decade, a growing number of studies were undertaken to define the molecular basis of NPC. However, the analysis of several clinical and biological parameters of North African and Southeast Asian NPCs has shown notable differences, suggesting that they could result from a distinct combination of etiological factors. One intriguing characteristic of North African NPC, concerns its bimodal age distribution with a secondary peak of incidence in the range of 15-25 years, not observed in Asian NPC. In this juvenile form of NPC, immuno-histochemistry assay has shown that the two key proteins controlling the apoptotic-survival balance p53 and Bcl-2 are less frequently expressed whereas the transmembrane tyrosine-kinase receptor c-kit and the main EBV oncoprotein LMP1 were more abundant. In addition, the EBV serological alterations are less informative for the diagnosis of the juvenile compared to the adult form. In addition, most North African NPCs contain EBV strains with genetic polymorphisms distinct from those described in the Southeast Asia series (predominance of F, D, H1-H2, XhoI+ and f, C, H, XhoI- respectively). In contrast, studies relating on tumor chromosomal alterations or aberrant promoter methylation result in data very similar to those obtained from the Southeast Asia series, supporting the concept of a common molecular basis for all NPC regardless of patient geographic origin.

Amylose bronchique localisée : Une observation

Resume L’amylose pulmonaire localisee est exceptionnelle. Les manifestations treacheobronchiques sont les plus frequentes. Nous rapportons l’observation d’un homme de 68 ans qui avait consulte pour toux et dyspnee. La fibroscopie bonchique avait montre une infiltation sous-muqueuse avec stenose des bronches lobaires superieure et inferieure gauches. Des biopsies bronchiques etagees etaient realisees et avaient conclu a une amylose de type AL. Notre objectif est de decrire les caracteristiques anato-imocliniques de l’amylose pulmonaire localisee et de discuter sa pathogenie.

Cellular Interactions in Nasopharyngeal Carcinomas

Tumor cell population in nasopharyngeal carcinomas (NPC) is highly heterogeneous. In addition of being heavily infiltrated by nonmalignant leucocytes, malignant NPC cells can display various phenotypes in terms of epithelial maturation and viral gene expression. These various cell sub-populations communicate through membrane contacts, secretion of cytokines and exosomes. Understanding their interactions is crucial for the elucidation of tumor growth and immune escape as well as for designing better therapeutic approaches. This chapter deals with three major questions. (1) What are the local factors responsible for leucocyte attraction and retention in NPC tumors? (2) What are the suspected autocrine and paracrine mechanisms of tumor growth? (3) What are the mechanisms of tumor immune evasion which could explain the growth of malignant epithelial cells containing viral antigenic proteins in a context of local inflammation?