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Senescent cells accumulate in aging tissues, impairing their ability to undergo repair and regeneration following injury. Previous research has demonstrated that targeting tissue senescence with senolytics can enhance tissue regeneration and repair by selectively eliminating SnCs in specific aged tissues. In this study, we focused on eliminating senescent skin cells in aged mice to assess the effects on subsequent wound healing. We applied ABT-263 directly to the skin of 24-month-old mice over a 5-day period. Following topical ABT-263, aged skin demonstrated decreased gene expression of senescence markers p16 and p21, accompanied by reductions in SA-β-gal- and p21-positive cells compared to DMSO controls. However, ABT-263 also triggered a temporary inflammatory response and macrophage infiltration in the skin. Bulk RNA sequencing of ABT-263-treated skin revealed prompt upregulation of genes associated with wound healing pathways, including hemostasis, inflammation, cell proliferation, angiogenesis, collagen synthesis, and extracellular matrix organization. Aged mice skin pre-treated with topical ABT-263 exhibited accelerated wound closure. In conclusion, topical ABT-263 effectively reduced several senescence markers in aged skin, thereby priming the skin for improved subsequent wound healing. This enhancement may be attributed to ABT-263-induced senolysis which in turn stimulates the expression of genes involved in extracellular matrix remodeling and wound repair pathways.

Objective: Rarefaction of blood and lymphatic vessels in the skin has been reported in systemic sclerosis (SSc) (scleroderma). E26 transformation-specific-related factor (ERG) and Friend leukemia virus-induced erythroleukemia 1 (FLI-1) are important regulators of angiogenesis, but their role in lymphatic vasculature is lesser known. The goal of this study was to determine the role of ERG and FLI-1 in postnatal lymphangiogenesis and SSc lymphatic system defects., Methods: Immunofluorescence was used to detect ERG and FLI-1 in skin biopsy samples from patients with SSc and healthy controls. Transcriptional analysis of ERG or FLI-1-silenced human dermal lymphatic endothelial cells (LECs) was performed using microarrays. Effects of ERG and FLI-1 deficiency on in vitro tubulogenesis in human dermal LECs were examined using a Matrigel assay. ERG and FLI-1 endothelial-specific knockouts and ERG lymphatic-specific knockouts were generated to examine vessel regeneration in mice., Results: ERG and FLI-1 protein levels were reduced in the blood and lymphatic vasculature in SSc skin biopsy samples. ERG levels were shown to regulate genes involved in lymphatic vessel specification, including vascular endothelial growth factor receptor 3/FLT-4, lymphatic vessel endothelial hyaluronan receptor 1, SOX-18, and prospero homeobox 1 (PROX-1), whereas FLI-1 enhanced the function of ERG. The ERG-FLT-4 pathway regulated in vitro tubulogenesis in human LECs. Deficiency of ERG or FLI-1 similarly impaired the function of blood vessels in mice. However, only ERG deficiency affected the regeneration of lymphatic vessels during wound healing., Conclusion: ERG and FLI-1 are essential regulators of blood and lymphatic vessel regeneration. Deficiency of ERG and FLI-1 in SSc endothelial cells may contribute to the impairment of blood and lymphatic vasculature in patients with SSc., (© 2024 American College of Rheumatology.)

We aim to assess the clinical impact of circulating levels of sCD163, FoxP3, IGF-1 in LSCC patients (Laryngeal Squamous Cell Carcinoma). The concentrations of sCD163, FoxP3, and IGF-1 were measured using ELISA test in the serum samples collected from 70 pretreatment LSCC patients and 70 age and sex-matched healthy controls. Statistical analysis was performed using ANOVA to compare the two groups, and the correlation between markers and clinical parameters. Receiver-Operator Characteristic (ROC) curve analysis was conducted to determine the optimal cutoff values and evaluate the diagnostic impact of these markers. Significant differences in the levels of sCD163, FoxP3, and IGF-1 were observed between LSCC patients and the control group, with respective p-values of 0.01, 0.022, <0.0001. The determined cutoff values for sCD163, FoxP3, IGF-1 concentrations were 314.55 ng/mL, 1.69 ng/mL, and 1.69 ng/mL, respectively. The corresponding area under the curve (AUC) values were 0.67 (95% CI: 0.57-0.76), 0.70 (95% CI: 0.61-0.80), 0.84 (95% CI: 0.76-0.92), respectively. Furthermore, it was found that IGF-1 concentrations exceeding 125.20 ng/mL were positively correlated with lymph node metastasis. Elevated serum levels of sCD163, FoxP3 and IGF-1 are associated with the diagnosis of LSCC. IGF-1 appears to be the most promising indicator for the LSCC progression.

Tracheal hemangioma is a very rare benign vascular tumor. Few cases of tracheal hemangioma in children are reported in the literature. Chronic cough is the main symptom of the disease; however, hemoptysis is rarely reported as a symptom of tracheal hemangioma in children. Here, we report a case of tracheal hemangioma in an eight-year-old girl admitted to our pediatric department for recurrent hemoptysis. Routine biological and radiological investigations were normal. Diagnosis was made using computed tomography and bronchoscopy. Beta-blocker therapy was not efficient. Bronchoscopic treatment by electrical excision enables complete recovery. Tracheal hemangioma should be considered a cause of recurrent hemoptysis when routine biological and radiological investigations are negative., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Upregulated signal flow through RAS and the mitogen-associated protein kinase (MAPK) cascade is the unifying mechanistic theme of the RASopathies, a family of disorders affecting development and growth. Pathogenic variants in more than 20 genes have been causally linked to RASopathies, the majority having a dominant role in promoting enhanced signaling. Here, we report that SPRED2 loss of function is causally linked to a recessive phenotype evocative of Noonan syndrome. Homozygosity for three different variants-c.187C>T (p.Arg63 ∗ ), c.299T>C (p.Leu100Pro), and c.1142&#95;1143delTT (p.Leu381Hisfs ∗ 95)-were identified in four subjects from three families. All variants severely affected protein stability, causing accelerated degradation, and variably perturbed SPRED2 functional behavior. When overexpressed in cells, all variants were unable to negatively modulate EGF-promoted RAF1, MEK, and ERK phosphorylation, and time-course experiments in primary fibroblasts (p.Leu100Pro and p.Leu381Hisfs ∗ 95) documented an increased and prolonged activation of the MAPK cascade in response to EGF stimulation. Morpholino-mediated knockdown of spred2a and spred2b in zebrafish induced defects in convergence and extension cell movements indicating upregulated RAS-MAPK signaling, which were rescued by expressing wild-type SPRED2 but not the SPRED2 Leu381Hisfs ∗ 95 protein. The clinical phenotype of the four affected individuals included developmental delay, intellectual disability, cardiac defects, short stature, skeletal anomalies, and a typical facial gestalt as major features, without the occurrence of the distinctive skin signs characterizing Legius syndrome. These features, in part, characterize the phenotype of Spred2 -/- mice. Our findings identify the second recessive form of Noonan syndrome and document pleiotropic consequences of SPRED2 loss of function in development., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Malignant tumors of the temporal bone are rare. They include a wide histological variety. They are mostly primary tumors with an estimated incidence of 0.8-1.0 per 1,000,000 inhabitants per year [1]. Metastases form an uncommon subgroup. The clinical features of these temporal bone metastases are nonspecific and predominantly consist of hearing loss, vertigo, facial palsy, tinnitus, headache, otalgia or otorrhoea [2]. The aim of our publication is to report a rare case of metastasis in the temporal bone as initial manifestation of lung cancer. Our patient was a 44-year-old man who presented for a right mastoid swelling with a grade VI right facial nerve palsy. Imaging and biopsy confirmed the diagnosis of small cell lung carcinoma petrous metastasis. The treatment was palliative. An osteolytic lesion of the temporal bone in an elderly patient may fit with a primary tumor of the temporal bone. It must, also, suggest the diagnosis of metastasis. The malignant tumor most frequently responsible is breast cancer, but lung cancer must also be considered in smoking patients.

Background: By virtue of their multiple functions, lips are essential organs. Thus, lip cancers represent a distinct entity in head and neck surgery. Their treatment is fundamentally surgical. We aimed, in this study, to define modalities of repairing techniques of lip defects after surgical resection and post-operative complications., Methods: We conducted a 4 years retrospective descriptive study including 70 adult patients admitted with lip cancers., Results: Suture, local and regional flaps were the performed techniques for repairing defects (respectively n=28, 35 and 7). The most common postoperative complications were wound dehiscence (n=4), and surgical site necrosis (n=2) and infection (9 patients). Functional sequelae were dominated by microstomia (n=26), (food leakage) (n=9) and gingival exposure (n=11). Aesthetic results were good, fair or poor respectively in 54.3%; 32.9% and 12.8% of patients., Conclusion: Lip cancers surgery is relatively well-codified. However, it may be difficult to choose the best repairing technique, especially in case of large lip defect considering functional and aesthetic prejudices.

Objectives: Tunisia is in the endemic area of nasopharyngeal carcinoma. Epstein-Barr virus (EBV) based assays have been commonly used as standard markers for screening and monitoring the disease. So, it is very important to find novel factors for the early diagnostic and prognostic evaluation of this cancer. The aim of the study was to evaluate the expression of IGF-1R (Insulin Growth Factor Receptor 1), LMP 1 (Latent Membrane Protein 1) and EBERs (EBV encoded RNAs) in order to determine their correlation with clinicopathologic parameters and survival rates in patients with nasopharyngeal carcinoma (NPC). We also looked for the relationship between these biomarkers., Methods: IGF-1R and LMP1 expression was performed by means of immunohistochemical method and EBERs were detected using in situ hybridization of paraffin embedded tumor tissues of 94 patients with nasopharyngeal carcinoma and 45 non-cancerous nasopharyngeal mucosa samples., Results: Our findings demonstrated that IGF-1R was over expressed in 47.87% of NPC patients and only in 2.22% of controls. Positive LMP1 expression was detected in 56.38% of NPC patients and all NPC patients were positive for the EBV-encoded RNAs staining. A statistically significant positive correlation was observed between IGF-1R expression and the tumor size ( P < .001). Kaplan-Meier survival curves showed that NPC patients with a strong IGF-1R expression level have shorter median and 5-year Overall Survival than those with weak expression rates (100.15 vs 102.68 months, P = .08). In addition, median and 5-year Disease-Free Survival was significantly lower in the LMP1 positive NPC patients than in the LMP1 negative ones (53.38 vs 93.37 months, P = .03). Moreover, LMP1 expression correlated strongly with IGF-1R expression ( P = .018). The relationship between these two biomarkers could influence patient survival., Conclusion: IGF1-R and LMP1 could be valuable prognostic markers in Tunisian NPC patients.

Introduction: The contribution of transoral laser microsurgery (TLM) in the management of early glottic cancer is now well established. The anterior commissure (AC) is a delicate anatomic subsite due to its difficult access and the high risk of tumour spread from this site to the thyroid cartilage, the subglottis and the pre epiglottic space. These reasons make the endoscopic approach controversial in case of AC involvement., Methods: This is a single centre retrospective study performed between the years 2012 and 2015. Eighteen patients treated with advanced Va laser cordectomies were included., Results: All tumours were staged T1 (78% were T1a and 12% T1b). After laser surgery 4 patients (22.22%) had positive margins. These patients were candidate to second look procedure allowing detection and treatment of residual disease.  Oncologic outcomes were studied. Two patients experienced local relapses within a mean delay of 7 months. The local control rate was 88.9% while the local control using laser only was 83.33%. One patient underwent a total laryngectomy (TL) followed by adjuvant radiation therapy (RT) after a massive recurrence in the AC with infiltration of the thyroid cartilage. The laryngeal preservation rate was 94.44%. The 3 years overall survival rate reached 100% while the 3 years disease free survival was 88.9%., Conclusion: the TLM offers acceptable oncologic outcomes in the treatment of T1 laryngeal cancer with AC involvement.

Laryngocele is a rare benign lesion of the larynx caused by an abnormal dilatation of the laryngeal saccule. We report the case of a 78-year-old man presenting bilateral cervical painless soft mass. Bilateral external laryngocele diagnosis was confirmed by CT scan and the patient underwent a surgical resection.

Introduction: Pharyngocutaneous fistula is the most frequent complication of primary and secondary laryngectomy and pharyngolaryngectomy. It has an important impact on the patient, his entourage and the healthcare team. The risk factors for pharyngostoma are multiple and its treatment is not codified., Aim: To identify the various factors that may predispose to this complication and to describe the different therapeutic means to control it., Methods: This retrospective study examined 68 cases of laryngeal cancer treated by total laryngectomy or pharyngolaryngectomy at Salah Azaїez's head and neck oncologic surgery department between 2015 and 2017., Results: Most of our patients were male (97%) who were major consumer of tobacco and alcohol. The most common stage were T4aN0M0 (34%) and T4aN1M0 (22%). Regarding treatment, we found that 73.5% of patients were operated on by total laryngectomy, 17.7% of patients were operated on by total pharyngolaryngectomy and 8.8% of patients were operated on by square laryngectomy. Pharyngostoma was diagnosed in 20.5% of cases within an average of 15 days. Among the risk factors studied, those that were statistically correlated with the occurrence of CPF in univariate studies were pre-laryngeal infiltration (p = 0.006), postoperative CRP level (p= 0.017), extension to piriform recess (p = 0.009), TNM stage (p=0.039), an associated thyroid surgery (p = 0.020) and pharyngeal closure under tension (p=0.000). In multivariate studies, five of the risk factors identified in the univariate analysis were found. This testifies to their major role as a risk factor for pharyngostoma. These factors were pre-laryngeal infiltration (p=0.001), postoperative CRP level (p=0.000), piriform recess involvement (p=0.004) Associated thyroid surgery (p=0.012) and pharyngeal closure under tension (p = 0.000)., Conclusion: By identifying predictive factors for pharyngostoma, we can identify patients in which this complication may occur and manage the medical care means to prevent it more efficiently.

Tuberculosis, a human infectious disease caused by Mycobacterium tuberculosis ( M.tb ), is still a major cause of morbidity and mortality worldwide. The success of M.tb as a pathogen relies mainly on its ability to divert the host innate immune responses. One way by which M.tb maintains a persistent infection in a "silent" granuloma is to inhibit inflammation and induce an immunoregulatory phenotype in host macrophages (MΦs). However, M.tb effectors governing the switch of MΦs from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype remain to be determined. The E arly S ecreted A ntigenic T arget 6 kDa or ESAT-6, has been implicated in the virulence and pathogenesis of tuberculosis. Here, we investigated roles of ESAT-6 in MΦ differentiation and polarization. We found that treatment of human monocytes with ESAT-6 did not interfere with differentiation of M1 MΦs. However, ESAT-6 promoted differentiation of M0 and M2 MΦs toward the M1 phenotype, as indicated by secretion of pro-inflammatory cytokines IL-6, IL-12, and TNF-α, and induction of a typical M1 transcriptional signature. Interestingly, we found that ESAT-6 switched terminal full activation of M1 polarized MΦs to the M2 phenotype. Indeed, in the pro-inflammatory M1 MΦs, ESAT-6 was able to inhibit IL-12 and TNF-α secretion and stimulate that of IL-10. Moreover, gene expression profiling of these cells showed that ESAT-6 induced downregulation of M1 MΦ cell surface molecules CD80 and CD86 , transcription factors IRF5 and c-MAF , cytokines IL-12, IL-10 , and IL-6 , as well as chemokines CXCL10 and CXCL1 . Overall, our findings suggest ESAT-6 as being one of the effectors used by M.tb to induce the pro-inflammatory M1 phenotype at the primo-infection; a prerequisite step to promote granuloma formation and subsequently drive the phenotype switch of MΦ polarization from M1 to M2 at a later stage of the infection. Our study improves current knowledge regarding mechanisms of virulence of M.tb and may be helpful to develop novel tools targeting ESAT-6 for a better and more efficient treatment of tuberculosis.

Purpose: The transcription factor Krüppel-like factor 6 (KLF6) regulates various cellular functions, such as metabolism, cell proliferation, and differentiation. KLF6 plays a key role in the development and progression of multiple human cancers., Methods: Fifty primary biopsies and 10 normal nasopharyngeal mucosae were used to analyze by RT-QPCR the expression and the copy number of wtKLF6 and the spliced variants (KLF6-SV1, KLF6-SV2, and KLF6-SV3) in Tunisian patients with nasopharyngeal carcinoma. The expression analysis of E-cadherin and cyclin D1 was conducted by RT-QPCR and Western blot, respectively., Results: The wtKLF6 was significantly downexpressed in tumors compared to normal tissues ( p = 0.0015), whereas KLF6-SV1 and KLF6-SV2 were overexpressed in tumors compared to wtKLF6 and KLF6-SV3 ( p < 0.0001). Copy number variation was reduced in tumors compared to normal tissues ( p = 0.0071). Interestingly, KLF6-SV1 is associated with the juvenile form ( p = 0.0003) which is more aggressive than the adult form of NPC. Furthermore, the oncogenic variant KLF6-SV1 was overexpressed in tumors lacking the expression of E-cadherin ( p = 0.0022) suggesting its role in metastasis and tumor progression. The wtKLF6 is associated negatively with cyclin D1 in tumor tissues ( p = 0.048)., Conclusion: The wtKLF6 was downexpressed in contrast with the oncogenic variants. Overexpression of KLF6-SV1 is associated with young patients, and loss of E-cadherin suggests that this variant correlated with the aggressiveness of NPC.

We investigated human leukocyte antigen (HLA) profiles for Tunisians with nasopharyngeal carcinoma (NPC), their families, and a sample of unrelated healthy Tunisians in order to identify HLA specificities associated with familial NPC. HLA-A, -B, and -DRB1 typing was successful for 36 NPC patients, 72 unaffected family members, and 130 community controls, and the chi square or Fisher exact test was used to compare allele frequencies between cases and controls. We observed a consistent protective effect of HLA-DRB1*10 on NPC development. However, none of the NPC patients or their family members had a positive result for this HLA marker (0% vs 9.2% in controls, P = 0.047). In addition, HLA-A*26 was probably an induction marker, as its allelic frequency was significantly higher among NPC patients than among controls (P = 0.003) and among NPC patients than among at-risk family members (P = 0.067). Logistic regression analysis of the joint effect of selected HLA specificities showed that HLA-A*26 and HLA-A*30 were co-associated and have an important effect on NPC risk. Despite the small size of our cohort, we showed that HLA-A*26-A*30 and HLA-DRB1*10 might be predictive markers for NPC screening of Tunisian families with a high risk of NPC.

Background: The role of IGF-1 in promoting cancer has been investigated for many years. The aim of this study is to explore the relationship between rates of IGF-1 and NPC and to evaluate association of IGF-1 with clinical parameters., Materials and Methods: IGF-1 levels was measured by Elisa test among 82 NPC patients and 60 healthy controls, Results: Our results showed, for the first time, a significant increased levels of IGF-I in NPC by in comparison with healthy controls (p<0.01). According to the age, sex and tumor size of NPC patients, we demonstrated that IGF-1 concentrations are significantly higher in NPC aged over 30 years compared to patients aged less than 30 years (p<0.01). The IGF-1 levels are, also, higher among women compared to men (p<0.01). The concentrations of IGF-1 were positively correlated with tumor size of NPC patients (p<0.01)., Conclusion: IGF-I could be a good nasopharyngeal cancer diagnostic marker., (Copyright © 2016 Elsevier GmbH. All rights reserved.)

Leishmania-specific cytotoxic T cell response is part of the acquired immune response developed against the parasite and contributes to resistance to reinfection. Herein, we have used an immune-informatic approach for the identification, among Leishmania major potentially excreted/secreted proteins previously described, those generating peptides that could be targeted by the cytotoxic immune response. Seventy-eight nonameric peptides that are predicted to be loaded by HLA-A*0201 molecule were generated and their binding capacity to HLA-A2 was evaluated. These peptides were grouped into 20 pools and their immunogenicity was evaluated by in vitro stimulation of peripheral blood mononuclear cells from HLA-A2+-immune individuals with a history of zoonotic cutaneous leishmaniasis. Six peptides were identified according to their ability to elicit production of granzyme B. Furthermore, among these peptides 3 showed highest affinity to HLA-A*0201, one derived from an elongation factor 1-alpha and two from an unknown protein. These proteins could constitute potential vaccine candidates against leishmaniasis.

Background: During a blood meal, female sand flies, vectors of Leishmania parasites, inject saliva into the host skin. Sand fly saliva is composed of a large variety of components that exert different pharmacological activities facilitating the acquisition of blood by the insect. Importantly, proteins present in saliva are able to elicit the production of specific anti-saliva antibodies, which can be used as markers for exposure to vector bites. Serological tests using total sand fly salivary gland extracts are challenging due to the difficulty of obtaining reproducible salivary gland preparations. Previously, we demonstrated that PpSP32 is the immunodominant salivary antigen in humans exposed to Phlebotomus papatasi bites and established that humans exposed to P. perniciosus bites do not recognize it., Methodology/principal Findings: Herein, we have validated, in a large cohort of 522 individuals, the use of the Phlebotomus papatasi recombinant salivary protein PpSP32 (rPpSP32) as an alternative method for testing exposure to the bite of this sand fly. We also demonstrated that screening for total anti-rPpSP32 IgG antibodies is sufficient, being comparable in efficacy to the screening for IgG2, IgG4 and IgE antibodies against rPpSP32. Additionally, sera obtained from dogs immunized with saliva of P. perniciosus, a sympatric and widely distributed sand fly in Tunisia, did not recognize rPpSP32 demonstrating its suitability as a marker of exposure to P. papatasi saliva., Conclusions/significance: Our data indicate that rPpSP32 constitutes a useful epidemiological tool to monitor the spatial distribution of P. papatasi in a particular region, to direct control measures against zoonotic cutaneous leishmaniasis, to assess the efficiency of vector control interventions and perhaps to assess the risk of contracting the disease.

The most common inherited haemoglobin disorders encountered in Tunisia are β-thalassemia and sickle cell disease, which result from mutations in the β-globin gene. Few studies focused on δ-globin gene variations responsible for δ-thalassemia or HbA2 variants. HbA2' [δ16 (A13) Gly→Arg (GGC→CGC)] is a δ-chain variant that has been identified in several populations of African origin. We report herein for the first time the description of HbA2' in the Tunisian population. Identification of HbA2' in the studied family was carried out by high-performance liquid chromatography and confirmed by sequencing analyses of the whole δ-globin gene. Haplotypes of the β-globin gene cluster were constructed by mapping the restriction sites using polymerase chain reaction followed by enzymatic digestion. Compound heterozygosity of HbA2' with HbO-Arab was identified in the proband. The mother and two other siblings showed heterozygous HbA2' whereas the father showed heterozygous HbO-Arab. The sum of HbA2 and HbA2' in all cases was less than 4%, thus excluding β-thalassemia. β-cluster haplotype analysis revealed that this mutation was associated with the F haplotype (-+--+++). The unique origin of this mutation in Africa is likely since the linked β-cluster haplotype is one of the major haplotypes found in African populations.

Background: The cyclooxygenase-2 (cox-2) pathway is now recognized to be important in human cancer development and progression. The gene for cox-2 carries a common single nucleotide polymorphism, T8473C, located within a potential functional region in the 3'-UTR of cox-2 gene was identified. We have investigated the frequencies of cox-2 genotypes in Tunisian population to determine whether that polymorphism was associated with the risk of nasopharyngeal carcinoma (NPC) in Tunisian population., Material and Methods: One hundred and eighty-nine NPC patients were compared to 237 healthy controls., Results: The cox-2 T8473C polymorphism was significantly associated with NPC (P=0.031). The CC-genotype and C allele were more frequent in control compared to patients group [CC: OR=0.37; P=0.013; 95% CI: 0.17-0.81; C: OR=0.72; P=0.032; 95% CI: 0.53-0.97]. Multivariate logistic regression analyses revealed that the CC-genotype was associated with a significantly decreased risk of NPC (P=0.013). Tumor sizes, histologic grade, presence of primary lymph node metastases, age or sex were not associated with cox-2 genotypes., Conclusion: We conclude that the CC-genotype and C allele of cox-2 T8473C gene polymorphism are associated with decreased risk of nasopharyngeal carcinoma in a Tunisian population., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Nasopharyngeal carcinoma (NPC) is a complex multifactorial disorder involving both genetic and environmental factors. Polymorphisms of genes encoding nitric oxide synthase (NOS) and antioxidant glutathione-S transferases (GSTs) have been associated with various tumors. We examined the combined role of NOS3, NOS2 and GST polymorphisms in NPC risk in Tunisians. We found that NOS3−786C allele and −786 CC genotype, NOS3+894T allele and +894 GT+TT genotypes, NOS2−277 G allele and −277 GG genotype, and GSTT1 del/del genotype, are more prevalent in NPC patients as compared to healthy controls. Our results suggest that genetically driven dysfunction in red–ox stress pathway could augment the risk in NPC-susceptible individuals.

The nature of effector cells and the potential immunogenicity of Leishmania major excreted/secreted proteins (LmES) were evaluated using peripheral blood mononuclear cells (PBMCs) from healed zoonotic cutaneous leishmaniasis individuals (HZCL) and healthy controls (HC). First, we found that PBMCs from HZCL individuals proliferate and produce high levels of IFN-γ and granzyme B (GrB), used as a marker of activated cytotoxic T cells, in response to the parasite antigens. IFN-γ is produced by CD4(+) T cells, but unexpectedly GrB is also produced by CD4(+) T cells in response to stimulation with LmES, which were found to be as effective as soluble Leishmania antigens to induce proliferation and cytokine production by PBMCs from immune individuals. To address the question of regulatory T cell (Tregs) involvement, the frequency of circulating Tregs was assessed and found to be higher in HZCL individuals compared to that of HC. Furthermore, both CD4(+)CD25(+) and CD4(+)CD25(-) T cells, purified from HZCL individuals, produced IFN-γ and GrB when stimulated with LmES. Additional experiments showed that CD4(+)CD25(+)CD127(dim/-) Tregs were involved in GrB production. Collectively, our data indicate that LmES are immunogenic in humans and emphasize the involvement of CD4(+) T cells including activated and regulatory T cells in the immune response against parasite antigens.

We studied epidermal growth factor receptor (EGFR) expression profile with the aim of an individualized therapy for patients with non-small cell lung cancer (NSCLC) from whom tumor materials are not sufficient for molecular investigations. Using immunohistochemistry, we found a markedly increased EGFR expression with significant difference in term of intensity and distribution from normal mucosa to primary tumors (p < 0.05). Furthermore, patients with EGFR positive tumors had significantly shorter survival than those with EGFR negative tumors (p = 0.0001). Thus, EGFR over-expression is a valuable prognostic marker to predict poor outcome in Tunisian patients with NSCLC.

Mediterranean area (MA) represents a zone of intermediate incidence (1-5/100,000) for NPC, the highest frequency being observed in North Africa (NA) where it is characterized by a bimodal age repartition due to a first adolescence peak. In MA and NA, NPC remain diagnosed at advanced stages which impact poorly on overall and disease-free survival. It's therapy in MA followed the progresses and standardisation of protocols, based on concomitant chemoradiotherapy (CCRT) alone or preceded by induction chemotherapy (ICT) in advanced (N2-3, T3-4) stages, while localized cases are managed irradiation alone. NPC overall an disease-free survival improved, due to the use of combined chemo and radiotherapy., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Because nasopharyngeal carcinoma (NPC) has a close association with Epstein-Barr virus (EBV), measuring serum EBV DNA and anti-EBV serum marker concentrations could be a feasible method for NPC diagnosis, monitoring and probably screening especially in a community at risk. The aim of this study was to determine the EBV pattern in sporadic NPC and in high risk NPC Tunisian families in order to evaluate their risk factors and help for NPC screening. The rates of anti-EBV antibodies and EBV DNA were determined in the serum of 47 healthy members randomly selected from 23 NPC multiplex families with two or more affected members, 93 healthy Tunisian community controls chosen with the same age, sex and geographic origin as unaffected individuals and 66 EBV positive sporadic NPC patients whose serum was available before and after treatment. Unexpectedly, significant lower concentrations of anti-EA (Early Antigen) IgG and anti-VCA (Viral Capsid Antigen) IgG were found in unaffected members from NPC families than in healthy controls while viral loads were negative in all the tested sera. For sporadic NPC patients, anti-EA IgG and anti-VCA IgA concentrations were significantly higher than in healthy controls and these rates decreased after treatment. The level of EBV DNA load varied according to the condition of the tumour. This study suggests that in the Tunisian NPC families, screening for malignancy is based on serum concentrations but not on EBV DNA load while in the sporadic NPC group, serologic markers and EBV DNA load are complementary for diagnosis and follow-up.

Papillary thyroid carcinoma is the most common form of differentiated thyroid carcinoma. It is generally confined to the neck with or without spread to regional lymph nodes. Metastatic thyroid carcinomas are uncommon and mainly include lung and bone. Metastases involving oral and maxillofacial region are extremely rare. We described a case of malar metastasis revealing a follicular variant of papillary thyroid carcinoma, presenting with pain and swelling of the left cheek in a 67-years-old female patient with an unspecified histological left lobo-isthmectomy medical history. To our knowledge, this is the first recorded instance of a malar metastasis from a follicular variant of papillary thyroid carcinoma.

Objective: The aim of this review is to study natural history, presentation, treatment and prognosis of head and neck liposarcomas., Methods: We carry a retrospective study about 15 patients diagnosed and treated in our department between 1969 and 2001. Therapeutic modalities included surgery, radiotherapy and chemotherapy., Results: Tumors were mostly localized at the neck (4 cases) and the scalp (3 cases). Cervical lymphadenopathy was found in 1 case. Chest X-ray found showed metastases in 2 cases. Histological types of liposarcomas were the following: myxoid (5 cases), well differentiated (4 cases), pleomorphic (4 cases), round cell (1 case) and dedifferentiated (1 case). Twelve patients underwent surgery. Complete excision was performed in 7 cases. In the other 5 cases, exeresis was incomplete and 4 of them received postoperative radiotherapy. Three patients were not operated because of vascular involvement (1 case) or metastasis (2 cases), and they all received radiotherapy alone. After initial treatment, complete remission was achieved in 7 cases (46.7%). A recurrence occurred in 8 cases (53.3%). Two of these patients were reoperated and another one received chemotherapy. In the other 5 cases, the tumor was uncontrollable and no additional treatment has been proposed. Five-year survival rate was 87% for patients who underwent surgery alone, 75% for those who underwent surgery and postoperative radiotherapy, and 0% for those treated by radiotherapy alone., Conclusion: The mainstay of treatment of head and neck liposarcomas is surgical excision and the prognosis is largely determined by the histological grade and the clinical stage., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)

We report on the long QT syndrome occurring in conjunction with nontoxic multinodular goiter and sensorineural deafness in several siblings of a large family. Autosomal and X-linked recessive and dominant modes of inheritance are possible for the different phenotypes. The affected family members had various phenotype combinations, suggesting variable expressivity and incomplete penetrance., (Copyright 2010. Published by Elsevier Inc.)

Major histocompatibility complex (MHC) class I chain-related A (MICA) molecules mediate natural killer (NK) cell activation and T lymphocyte co-stimulation. A polymorphic methionine (met) to valine (val) variation at amino acid position 129 of the alpha2 heavy chain domain is in linkage disequilibrium with other allelic changes and seems to categorize MICA alleles into strong and weak binder of NKG2D receptor and thereby to influence effector cell function. We investigated here whether MICA-129 dimorphism is associated with susceptibility to/or resistance against developing nasopharyngeal cancer (NPC). DNA from 130 NPC patients and 180 healthy individuals from Tunisia were genotyped for MICA-129 variation. We found a higher frequency of MICA-129 val/val genotype in patients than in controls (corrected p value = 0.02) that could suggest a tumor escape mechanism because of failure to activate NK cells by MICA-129 val allele or absence of NK cell activation because of absence of MICA-129 met allele in individuals otherwise predisposed to viral/environmental factors.

HLA-DRB1, -DQB1, TNFalpha, TNFbeta, HSP70-2 and HSP70-hom genetic polymorphisms were analyzed in 156 unrelated patients who developed mediterranean visceral leishmaniasis (MVL) due to Leishmania infantum, and 154 unrelated healthy controls, who have got asymptomatic infection with this parasite and were selected on the basis of a positive leishmanin skin test (LST). A significantly reduced frequency of HLA-DR2 was observed among MVL patients (16.1%), compared with controls (26.3%) (relative risk = 0.54; p = 0.04). HLA-DR2/DR13 as well as HLA-DQB1*0201/- genotype frequencies were significantly lower in patients vs controls (relapse rate = 0.17 and 0.46, respectively; p < 0.05). However, using Bonferroni correction, none of these associations remained significant. No association was found, between either the -308 base pair TNFalpha gene polymorphism or the NcoI polymorphism in the first intron of the TNFbeta gene and susceptibility to MVL. Analysis of PstI and NcoI polymorphisms in the coding region of HSP70-2 and HSP70-hom genes, respectively, revealed a significantly higher frequency of homozygotes for the HSP70-2/PstI negative allele, among patients (21.8%) vs controls (12.6%) (relapse rate = 1.94; p = 0.04). Again, this result was not significant after using Bonferroni correction. These results do not support association between susceptibility to MVL and the MHC class II and class III loci analyzed in this study.

Thiamine-responsive megaloblastic anaemia (TRMA) syndrome with diabetes and deafness was found in two patients from a Tunisian kindred. The proband was homozygous for a novel mutation, 287delG, in the high-affinity thiamine transporter gene, SLC19A2. We demonstrated that fibroblasts from this patient exhibited defective thiamine transport. These data confirm that the SLC19A2 gene is the high-affinity thiamine carrier and that this novel mutation is responsible for TRMA syndrome.