Bullous Pemphigoid Associated With Dipeptidyl Peptidase-4 Inhibitors: A Case Report and Review of Current Evidence.

Dipeptidyl peptidase-4 inhibitors (DPP-4i), or gliptins, are a widely used glucose-lowering agents. A growing amount of evidence pointed to a possible role of DPP-4i in the induction of bullous pemphigoid (BP), which is an auto-immune skin blistering disease that mainly affects the elderly. In this article we discuss a case of DPP-4i associated BP and we provide an updated review of the current knowledge regarding this emerging entity. Use of DPP-4i, particularly vildagliptin, was found to significantly increase the risk of BP. BP180 would be in the center of the aberrant immune response. DPP-4i induced BP is thought to be associated with male gender, mucosal involvement, and milder inflammatory phenotype especially in Asian population. Generally, patients may not remit fully after DPP-4i withdrawal only and require either topical or systemic glucocorticoid courses.

Novel and recurrent BRCA1/BRCA2 germline mutations in patients with breast/ovarian cancer: a series from the south of Tunisia.

BACKGROUND: The incidence of breast cancer (BC) and/or ovarian cancer (OC) is increasing in Tunisia especially in young women and mostly those with family history. However, the spectrum of BRCA mutations remains little explored in Tunisian patients in particular in the southern region. METHODS: We sequenced the entire coding regions of BRCA1and BRCA2 genes using next generation sequencing (NGS) in 134 selected patients with BC and/or OC. RESULTS: Among the 134 patients, 19 (14.17%) carried pathogenic mutations (10 are BRCA1 mutation carriers and 9 are BRCA2 mutation carriers) that are mainly frameshift index (76.9%). Interestingly, 5 out of the 13 variants (38.46%) were found at least twice in unrelated patients, as the c.1310-1313 delAAGA in BRCA2 and the c.5030_5033 delCTAA that has been identified in 4/98 BC patients and in 3/15 OC patients from unrelated families with strong history of cancer. Besides recurrent mutations, 6 variant (4 in BRCA1 and 2 in BRCA2) were not reported previously. Furthermore, 3 unrelated patients carried the VUS c.9976A > T, (K3326*) in BRCA2 exon 27. BRCA carriers correlated significantly with tumor site (p = 0.029) and TNBC cases (p = 0.008). In the groups of patients aged between 31 and 40, and 41-50 years, BRCA1 mutations occurred more frequently in patients with OC than those with BC, and conversely BRCA2 carriers are mostly affected with BC (p = 0.001, and p = 0.044 respectively). CONCLUSIONS: The overall frequency of the BRCA germline mutations was 14.17% in patients with high risk of breast/ovarian cancer. We identified recurrent mutations as the c.1310_1313 delAAGA in BRCA2 gene and the c.5030_5033 delCTAA in BRCA1 gene that were found in 4% and 20% of familial BC and OC respectively. Our data will contribute in the implementation of genetic counseling and testing for families with high-risk of BC and/or OC.

Bilateral multifocal nodular oncocytic hyperplasia of the parotid gland: a rare entity.

Multifocal nodular oncocytic hyperplasia is an uncommon oncocytic lesion that rarely occurs in the parotid gland. Here, we report a case of a 43-years-old woman who presented with isolated gradual swelling in the 2 parotid regions. She underwent exofacial right parotidectomy. Histologic exam confirmed the diagnosis of oncocytoma arising in a background of multifocal nodular oncocytic hyperplasia with a histological variant of clear cells. Since the lesion was diagnosed as a benign lesion, surgery of the left side was not done. Our case is characterized by: early onset, the histological variant of clear cells and the presence of synchronous oncocytoma. We describe the clinical, histological and therapeutic features of this entity.

Identification of novel candidate genes by exome sequencing in Tunisian familial male breast cancer patients.

Male Breast Cancer (MBC) is a rare and aggressive disease that is associated with genetic factors. Mutations in BRCA1 and BRCA2 account for 10% of all MBC cases suggesting that other genetic factors are involved. The aim of the present study is to screen whole BRCA1 and BRCA2 exons using the Ampliseq BRCA panel in Tunisian MBC patients with family history. Furthermore, we performed exome sequencing using the TruSight One sequencing panel on an early onset BRCA negative patient. We showed that among the 6 MBC patients, only one (MBC-F1) harbored a novel frameshift mutation in exon 2 of the BRCA2 gene (c.17-20delAAGA, p.Lys6Xfs) resulting in a short BRCA2 protein of only 6 amino-acids. We selected 9 rare variants after applying several filter steps on the exome sequencing data. Among these variants, and based on their role in breast carcinogenesis, we retained 6 candidate genes (MSH5, DCC, ERBB3, NOTCH3, DIAPH1, and DNAH11). Further studies are needed to confirm the association of the selected genes with family MBC.

Homozygous pArg610del Mutation Unusually Associated With Severe Delay of Growth in 2 Acid Sphingomyelinase Deficiency-affected Sibs.

BACKGROUND: Typically, patients with Acid Sphingomyelinase Deficiency (ASMD) because of p.Arg610del mutation, have mild phenotype with normal linear growth. OBSERVATION: We reported the case of 2 Tunisian brothers who have been referred for splenomegaly, polyadenopathies, pubertal, and growth delay. Molecular testing of SMPD1 gene revealed the presence of a homozygous p.Arg610del mutation. Lysosphingomyelin and its isoform-509 were both increased confirming ASMD for both cases. Growth hormone deficiency was highly suspected but growth hormone response after stimulating tests was acceptable for both patients. CONCLUSIONS: There is no correlation between phenotype-genotype in case of p.Arg610del mutation that could be associated to a severe delay of growth.

Oil from hake (Merluccius merluccius): Characterization, antioxidant activity, wound healing and anti-inflammatory effects.

The aim of this work was to evaluate some biological properties of hake head oil (HHO) as well its lipid composition. The fatty acid profiles showed a dominance of unsaturated fatty acids overtaking 55% of the total fatty acids. Omega-3 polyunsaturated fatty acid profiles exhibited a dominance of EPA (eicosapentaenoic acid) (3.96%) and DHA (docosahexaenoic acid) (25.39%). The antioxidant activity was determined through two different assays: DPPH scavenging activity and ß-carotene bleaching by linoleic acid assay. Eighteen mice were excised on their back and divided into 3 groups, treated with sterile saline, commercial healing cream and HHO, respectively. The wound closure rate, the hydroxyproline contents and the histopathology evolution in skin tissue were elaborated. Also, the anti-inflammatory activity was studied by carrageenan-induced mouse paw edema. Mice were divided into 3 groups treated respectively with sterile saline, anti inflammatory drug reference and HHO. The anti-inflammatory evaluation of HHO in mice exhibited an important inhibition of carrageenan-induced hind paws edema, as confirmed by the histological analysis, the superoxide dismutase (SOD), catalase (CAT) and malondialdehyde (MDA) level. HHO displayed a significant wound healing effect probably due to the anti-inflammatory and antioxidant activities of its EPA and DHA contents. The overall results proved that HHO might be favorable drugs who exert a great therapeutic potential wound healing and anti-inflammatory effects in animal model.

Association of FOXA1 and EMT markers (Twist1 and E-cadherin) in breast cancer.

The transcription factor FOXA1 (forkhead box A1) plays key roles in tumor development and progression. In the present study, we analyzed the expression of FOXA1 in 52 breast tumors and 10 normal tissues, and investigated the relationship between FOXA1 and two EMT markers, namely Twist1 and E-cadherin by RT-PCR and IHC respectively. The expression level of FOXA1 was higher in tumor compared to normal tissues but the difference was not statistically significant (P = 0.138). FOXA1 expression correlated with less aggressive behavior as SBR grade I (P = 0.04), small tumors size (P = 0.05), and longer survival (P = 0.001). Furthermore, estrogen and progesterone positive tumors exhibit high level of FOXA1 (P = 0.002 and P = 0.038 respectively). Survival analysis showed that patients with ER positive/FOXA1 positive (P log rank = 0.001), PR positive/FOXA1 positive (P log rank = 0.044) and HER-2 negative/FOXA1 positive (P log rank = 0.002) tumors have a significant prolonged overall survival. On the other hand, the expression of E-cadherin positively correlated with FOXA1 (P = 0.028), whereas negative association was seen between the expression of Twist1 and FOXA1 (P = 0.016). Kaplan-Meier plots showed that patients with Twist1negative/FOXA1positive tumors have a significant prolonged overall survival (P log rank = 0.001) and FOXA1 appeared as independent predictors of patient survival in multivariate analyses. Overall, our results indicate that FOXA1 could be a useful biomarker to predict prognosis in breast cancer patients.

Glyphosate disrupts redox status and up-regulates metallothionein I and II genes expression in the liver of adult rats. Alleviation by quercetin.

The present work evaluated the possible protective effects of quercetin against glyphosate-induced hepatotoxicity in adult rats. Rats were randomly divided into three groups: a control group (C), a glyphosate-treated group (Gly) and a group treated with both glyphosate and quercetin (Gly+QE). During the experimental period (15 days), glyphosate (50 mg/kg b.w.) was administered every two days by intraperitoneal way while quercetin (20 mg/kg b.w./day) was administered daily by gavage. Glyphosate-induced hepatic oxidative stress was evidenced by the increased levels of malondialdehyde, hydrogen peroxide, advanced oxidation protein products and protein carbonyls with a significant decrease in enzymatic (superoxide dismutase, catalase, glutathione peroxidase) and non-enzymatic (non-protein thiols, glutathione, vitamin C) antioxidants. Plasma biomarkers of hepatotoxicity (AST, ALT, ALP, γ-GT, albumin) were also altered. Moreover, glyphosate induced DNA damage, up-regulated metallothionein (MT I and MT II) genes expression and provoked histopathological changes in rats' liver. Quercetin supplementation to glyphosate-treated rats markedly ameliorated all the parameters indicated above as well as the liver histoarchitecture. Therefore, quercetin might have beneficial effects against glyphosate-induced hepatotoxicity in rats.

Potential benefits of polysaccharides derived from marine alga Ulva lactuca against hepatotoxicity and nephrotoxicity induced by thiacloprid, an insecticide pollutant.

The present study aimed to evaluate the potential protective and antioxidant effect of polysaccharides (PS) extracted from Ulva lactuca against thiacloprid (THC) induced nephrotoxicity and hepatotoxicity. The antioxidant capacity of PS was tested in vitro using ABTS radical scavenging activity and plasmid DNA cleavage assays andin vivo on adult male rats treated for 30 days. Animals were allocated into four groups: control; THC (22.5 mg/kg); THC (22.5 mg/kg) + PS1 (100 mg/kg diet); and THC (22.5 mg/kg) + PS2 (200 mg/kg diet). The structural features of PS were determined by Fourier transformed infrared (FT-IR), UV absorption peak detection, high performance liquid chromatography (HPLC) and gel permeation chromatography, and also functional properties were investigated. Overall, results indicated that THC increased significantly malondialdehyde, advanced oxidation protein products, glutathione levels, which is correlated with severe histological and plasmatic biochemical injuries in both liver and kidney tissues. However, cotreatment PS induced a significant protective and healing affects against the nephrotoxicity and hepatotoxcity induced by THC.

Fermented camel milk prevents carbon tetrachloride induced acute injury in kidney of mice.

Fermented milk is known to possess potent antioxidant activity. The present study was undertaken to assess the preventive effect of fermented camel milk (FCM) prepared using lactococcus lactis subsp. cremoris against CCl4 induced kidney damage in mice. Nephrotoxicity was induced in mice by a single dose of CCl4 (10 ml/kg 0·3% olive oil, ip). Female mice were pretreated daily with FCM for 15 d. Renal damage was associated with an increase in oxidative stress parameters (lipid peroxidation, protein carbonyl and changes in antioxidant enzyme activities and non-enzymatic antioxidant) and nephropathology markers.The renal injury induced by CCl4 was confirmed by the histological study of the CCl4-intoxicated mice. Pretreatment with FCM significantly prevented renal dysfunction by reducing oxidative stress, while mice recovered normal kidney histology. Moreover, FCM prevented toxicity biomarker changes by reducing creatinine, urea, uric acid, lactate dehydrogenase (LDH) and electrolytes levels in plasma. These data indicate that FCM is efficient in inhibiting oxidative stress induced by CCl4, and suggests that the administration of this milk may be helpful in the prevention of kidney damage.

Tuberculosis and non-pulmonary malignancies : study of ten cases.

INTRODUCTION: Tuberculosis (TBC) is a major public health problem with high mortality especially in developing countries. It is associated with a higher risk of developing pulmonary and non-pulmonary malignancies including solid and hematologic cancers. Association between TBC and nonpulmonary malignancies is rarely described in the literature. AIM: To describe the epidemiological, clinical, therapeutic modalities and the evolutive aspects of patients treated for cancer and TBC. METHODS: This is a retrospective study conducted over a period of 19 years (between 1993 and 2012), including 10 patients followed up for cancer and tuberculosis at the department of oncology and the department of infectious disease, CHU Habib Bourguiba Hospital and CHU HediChaker, Sfax, Tunisia. RESULTS: The average age of patients was 55 years old. The sex ratio was 1. The different locations of cancer were represented by the breast (4 cases), the nasopharynx (1 case), the colon (1 case), the kidney (1 case) the gum (1 case), the endometrium (1 case) and the blood (1 case).TBC and cancer were synchronous in 5 cases. Concerning the metachronous presentation that interested 5 patients, the average time betweenthe onset of TBC after cancer diagnosis was 3.5 years. Three of these patients were treated by chemotherapy with radiation therapy. TBClocalization was nodal in 6 cases, spinal one case, nasopharyngeal in one case, peritoneal in one case and urogenital in one case. The diagnosisof TBC was made incidentally in two cases during axillary lymph node dissection. The therapeutic management of cancer was based on surgery,chemotherapy and / or radiotherapy. All patients received anti TBC treatment for at least six months. Surgery was indicated in one case(laminectomy). A complete remission of cancer was observed in 9 patients. Concerning TBC, recovery was observed in 8 patients, 1 patient hada spinal recurrence and 1 patient is being treated. CONCLUSION: Chronic inflammation during TBC can lead to cancer development. The etiopathogenesis of this association is still imperfectly known. Association between TBC and non-pulmonary cancer, although rare, should be always kept in mind in order to handle in time these two diseases in order provide the best chances of recovery for patients.

Overexpression of miR-10b in colorectal cancer patients: Correlation with TWIST-1 and E-cadherin expression.

MicroRNAs are emergent players of epigenetics that function as oncogenes or tumor suppressors and that have been implicated in regulating diverse cellular pathways. MiR-10b is an oncogenic microRNA involved in tumor invasion and metastasis in various cancers. Our data have shown that miR-10b is overexpressed in colorectal cancer samples in comparison with non-tumorous adjacent mucosa (p = 0.0025) and that it is associated with severe features such as tumor size >5 cm (p = 0.023), distant metastasis (p = 0.0022), non-differentiated tumors (p = 0.016), and vascular invasion (p = 0.01). Regarding the regulation of its expression, positive correlation between the loss of miR-10b and aberrant DNA methylation (p = 0.02) as well as a loss of TWIST-1 messenger RNA (p = 0.018) have been observed. Furthermore, expression analysis of the downstream miR-10b targets has shown that there are associations between low HOXD10 messenger RNA and E-cadherin protein levels (p < 0.0001, p = 0.0008, respectively) and overexpression of miR-10b. Our data suggests that overexpression of miR-10b results from high levels of TWIST-1 and may induce a decrease of E-cadherin membranous protein levels, thus contributing to the acquisition of metastatic phenotypes in colorectal cancer.

Flavonoid compounds from the red marine alga Alsidium corallinum protect against potassium bromate-induced nephrotoxicity in adult mice.

Potassium bromate (KBrO3 ), an environmental pollutant, is a well-known human carcinogen and a potent nephrotoxic agent. Currently, natural products have built a well-recognized role in the management of many diseases induced by pollutants. As potent natural sources of bioactive compounds, marine algae have been demonstrated to be rich in novel secondary metabolites with a broad range of biological functions. In this study, adults male mice were orally treated for 15 days with KBrO3 (0.5 g/L) associated or not with extract of Alsidium corallinum, a red Mediterranean alga. In vitro study demonstrated that algal extract has antioxidant efficacy attributable to the presence of flavonoids and polyphenols. Among these, Liquid chromatography-mass spectrometry analysis showed A. corallinum is rich in kaempferol, apigenin, catechin, and quercetin flavonoids. In vivo study showed that supplementation with the alga significantly prevented KBrO3 -induced nephrotoxicity as indicated by plasma biomarkers (urea, uric acid, and creatinin levels) and oxidative stress related parameters (malondialdehyde, superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione, vitamin C, hydrogen peroxide, protein oxidation products) in kidney tissue. The corrective effect of A. corallinum on KBrO3 -induced kidney injury was also supported by molecular and histopathological observations. In conclusion, it was established that the red alga, thanks to its bioactive compounds, effectively counteracts toxic effects of KBrO3 and could be a useful coadjuvant agent for treatment of this pollutant poisonings. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1475-1486, 2017.

Olive oil abrogates acrylamide induced nephrotoxicity by modulating biochemical and histological changes in rats.

Acrylamide (ACR) is one of the most important contaminants occurring in foods heated at high temperatures. The aim of this study is to investigate the protective efficacy of extra virgin olive oil (EVOO), a main component of the Mediterranean diet, against nephrotoxicity induced by ACR. Rats have received by gavage during 21 days either ACR (40 mg/kg body weight) or ACR-associated with EVOO (300 µl) or only EVOO (300 µl). Acrylamide induced nephrotoxicity as evidenced by an increase in malondialdehyde (MDA), hydrogen peroxide (H2O2), protein carbonyls (PCOs) and a decrease in glutathione, non-protein thiols (NPSHs), and vitamin C levels. Activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) were also decreased. Lactate dehydrogenase (LDH) activity, creatinine, urea, and uric acid, urinary volume and creatinine clearance levels were modified. EVOO supplementation improved all the parameters indicated above. Kidney histoarchitecture confirmed the biochemical parameters and the beneficial role of EVOO. EVOO, when added to the diet, may have a beneficial role against kidney injury by scavenging free radicals and by its potent antioxidant power.

Effects of barium graded doses on redox status, membrane bound ATPases and histomorphological aspect of the liver in adult rats.

Nowadays, liver diseases constitute a major health problem in the world. The objective of the present study was to elucidate the hepatotoxicity induced by barium chloride (BaCl2) administered at graded doses in order to evaluate redox state and membrane-bound ATPases in the liver of adult rats. Our results showed, after 21 days of treatment with barium at doses 67 150 and 300 ppm, an increase in hepatic biomarkers such as AST, ALT and GGT activities and in bilirubin and albumin levels. A significant increase in MDA, LOOHs, H2O2, AOPP and PCO levels in liver of treated rats with graded doses of BaCl2 was also observed suggesting the implication of oxidative stress with a significant relation between dose and response. Moreover, LDH activity increased in plasma and decreased in liver of all treated groups. Antioxidant activities of glutathione peroxidase and catalase decreased, especially with the highest dose of barium, indicating a failure of antioxidant system defense. Additionally, the activities of Na+K+-ATPase and Mg2+-ATPase significantly decreased in all treated groups. Our biochemical findings were supported by histological observations. These results highlight the subchronic hepatotoxicity of barium.

Increasing maneb doses induces reactive oxygen species overproduction and nephrotoxicity in adult mice.

BACKGROUND AND PURPOSE: The aim of this study was to elucidate the biochemical, molecular and histopathological aspects of the kidney injuries as well as the hematological perturbations induced after adult mice exposure to increasing doses of maneb (MB). MATERIAL AND METHOD: Adult mice were intraperitoneally treated for seven days with four graded doses of MB, corresponding to 1/8, 1/6, 1/4 and 1/2 of its lethal dose (LD50=1500 mg/kg body weight). RESULTS: Hematological analysis revealed a significant disruption in total white blood cells and platelets and a significant decrease in the plasmatic levels of ferrozine in mice treated with 1/8, 1/6 and 1/4 of MB LD50. However, the ferrozine levels increased significantly in the group treated with 1/2 of MB LD50. Evenly, our results showed a significant increase in the levels of malondialdehyde, lipid hydroperoxides, hydrogen peroxide and advanced oxidation protein products in all treated groups. The activities of catalase and glutathione peroxidase decreased significantly in all MB treated mice. Additionally, all treated groups exhibited strong nephrotoxicity signs, including increases in plasma urea, creatinine and albumin levels and lactate dehydrogenase activity, as well as a significant decrease in uric acid levels. Electrophoresis analysis revealed nucleic acid degradation, testifying the genotoxicity of MB. Moreover, the histopathological observations showed severe renal injuries, which could be related to the above mentioned data. CONCLUSIONS: Our data showed, for the first time, that the MB tested doses led to oxidative stress installation causing renal cell damages and lowering all defense systems capacities.

Nitraria retusa fruit prevents penconazole-induced kidney injury in adult rats through modulation of oxidative stress and histopathological changes.

CONTEXT: Nitraria retusa (Forssk.) Asch. (Nitrariaceae) is a medicinal plant which produces edible fruits whose antioxidant activity has been demonstrated. OBJECTIVE: The current study elucidates the potential protective effect of N. retusa fruit aqueous extract against nephrotoxicity induced by penconazole, a triazole fungicide, in the kidney of adult rats. MATERIALS AND METHODS: Adult Wistar rats were exposed either to penconazole (67 mg/kg body weight), or to N. retusa extract (300 mg/kg body weight) or to their combination. Penconazole was administered by intra-peritoneal injection every 2 days from day 7 until day 15, the sacrifice day, while N. retusa extract was administered daily by gavage during 15 days. Oxidative stress parameters, kidney biomarkers and histopathological examination were determined. RESULTS: Nitraria retusa extract administration to penconazole treated rats decreased kidney levels of malondialdehyde (-10%), hydrogen peroxide (-12%), protein carbonyls (PCOs, -11%) and advanced oxidation protein products (AOPP, -16%); antioxidant enzyme activities: catalase (-13%), superoxide dismutase (-8%) and glutathione peroxidase (GPx, -14%), and the levels of non-enzymatic antioxidants: non-protein thiols (-9%), glutathione (-7%) and metallothionein (-12%). Furthermore, this plant extract prevented kidney biomarker changes by reducing plasma levels of creatinine, urea, uric acid and LDH and increasing those of ALP and GGT. Histopathological alterations induced by penconazole (glomeruli fragmentation, Bowman's space enlargement, tubular epithelial cells necrosis and infiltration of inflammatory leucocytes) were attenuated following N. retusa administration. DISCUSSION AND CONCLUSION: Our results indicated that N. retusa fruit extract had protective effects against penconazole-induced kidney injury, which could be attributed to its phenolic compounds.

Cardiac metastases: 4 cases report.

Cardiac metastases are rare. They are found in one to 10% of autopsies of patients withmalignant neoplasm. Adenocarcinoma represents the most common histologicaltype. The most common neoplasms that metastasize to the heart are lung andbreast cancers, melanoma, mesothelioma and lymphoma. However, Cardiacinvolvement is unusual in Hepatic, cutaneous and gastric cancer. We reportedthese three primary localizations in our cases.

Quantitative measurement of iNOS expression in melanoma, nasopharyngeal, colorectal, and breast tumors of Tunisian patients: comparative study and clinical significance.

Chronic inflammation increases the risk of development of human malignancies. iNOS is an enzyme dominantly expressed during inflammatory reactions and seems to play a critical role in tumorigenesis. Our aim was to assess the iNOS expression in four types of human tumors: breast, colorectal, nasopharyngeal, and melanoma, of Tunisian patients. The level of iNOS was measured by RT-QPCR in tumor specimens. We showed that the expression of iNOS was higher in breast compared to colorectal and nasopharyngeal tumors, whereas in melanoma, the level of iNOS expression was low. Significant associations were found when comparing the iNOS expression in cancers pairs such as melanoma versus colorectal (p < 0.0001), colorectal versus nasopharyngeal (p = 0.0072), and melanoma versus breast (p < 0.0001). Furthermore, iNOS expression correlated with the Breslow thickness, Clark level, and histological subtype in melanoma, while in nasopharyngeal carcinoma, significant association was seen with age at diagnosis, TNM, metastasis, response to treatment, and expression of COX-2. Furthermore, the expression of iNOS correlated with tumor size, TNM, tumor location, and histological type in colorectal cancer, and with tumor size, tumor stage, SBR grade, and triple negative cases in breast cancer. On the other hand, immunohistochemistry analysis shows that the expression of iNOS is observed in the stroma and tumor cells as well. Overall, our results highlight that iNOS is a reliable marker for advanced stage and aggressive behavior for the four types of cancer and might be a potential promising therapeutic target.

CpG methylation of ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) and P53 mutation pattern in sporadic colorectal cancer.

The ubiquitin-proteasome system plays an essential regulatory role in various cellular processes. Besides its involvement in normal cellular functions, the alteration of proteasomal activity contributes to the pathological states of several clinical disorders, including cancer. Aberrant methylation of the CpG islands has been reported as an alternative way to inactivate gene expression involved in the ubiquitination process and thus protein degradation in tumor tissues. In this study, we aimed to determine the CpG methylation pattern of the UCHL1 promoter, as well as the mutation spectrum and the expression pattern of P53 in sporadic colorectal cancer (CRC) from Tunisian patients. We found that UCHL1 was methylated in 68.57 % and correlated significantly with lymph node metastasis (P = 0.029) and transcriptional silencing in tumor tissues (P = 0.013). Mutation screening of exons 5-9 of P53 showed that 42.85 % of cases harbor somatic mutation and are positively correlated with the methylated pattern of UCHL1 (P = 0.001). Furthermore, cytoplasmic accumulation of P53 was strongly associated with the unmethylated UCHL1 profile (P = 0.006), supporting the relationship between these two proteins in CRC.