Endosomal Escape of Bioactives Deployed via Nanocarriers: Insights Into the Design of Polymeric Micelles

Pharmaceutical Research - Cytoplasmic delivery of bioactives requires the use of strategies such as active transport, electroporation, or the use of nanocarriers such as polymeric nanoparticles,...     

The molecular basis of familial hypercholesterolemia in Lebanon: Spectrum of LDLR mutations and role of PCSK9 as a modifier gene

Autosomal dominant hypercholesterolemia (ADH), a major risk for coronary heart disease, is associated with mutations in the genes encoding the low‐density lipoproteins receptor (LDLR), its ligand apolipoprotein B (APOB) or PCSK9 (Proprotein Convertase Subtilin Kexin 9). Familial hypercholesterolemia (FH) caused by mutation in the LDLR gene is the most frequent form of ADH. The incidence of FH is particularly high in the Lebanese population presumably as a result of a founder effect. In this study we characterize the spectrum of the mutations causing FH in Lebanon: we confirm the very high frequency of the LDLR p.Cys681X mutation that accounts for 81.5 % of the FH Lebanese probands recruited and identify other less frequent mutations in the LDLR. Finally, we show that the p.Leu21dup, an in frame insertion of one leucine to the stretch of 9 leucines in exon 1 of PCSK9, known to be associated with lower LDL‐cholesterol levels in general populations, is also associated with a reduction of LDL‐cholesterol levels in FH patients sharing the p.C681X mutation in the LDLR. Thus, by studying for the first time the impact of PCSK9 polymorphism on LDL‐cholesterol levels of FH patients carrying a same LDLR mutation, we show that PCSK9 might constitute a modifier gene in familial hypercholesterolemia. © 2009 Wiley‐Liss, Inc.     

Trends in the incidence of cancer in the Sousse region,Tunisia, 1993–2006

In this article, we analyzed trends in incidence rates of the major cancer sites for a 14‐year period, 1993–2006, in the Sousse region localized in the centre of Tunisia. Five‐year age‐specific rates, crude incidence rates (CR), world age‐standardized rates (ASR), percent change (PC) and annual percent change (APC) were calculated using annual data on population size and its estimated age structure. A total of 6,975 incident cases of cancer were registered, with a male to‐female sex ratio of 1.4:1. ASRs showed stable trends (?0.1% in males, and +1.0% in females). The leading cancer sites in rank were lung, breast, lymphoma, colon‐rectum, bladder, prostate, leukemia, stomach and cervix uteri. For males, the incidence rates of lung, bladder and prostate cancers remained stable over time. While, cancers of colon‐rectum showed a marked increase in incidence (APC: +4.8%; 95% CI: 1.2%, 8.4%) and non‐Hodgkin's lymphoma (NHL) showed a notable decline (APC: ?4.4%; 95% CI: ?8.2, ?0.6). For females, cancers of the breast (APC: +2.2%; 95% CI: 0.4%, 4.0%) and corpus uteri (APC: +7.4%; 95% CI: 2.8%, 12.0%) showed a marked increase in incidence during the study period, while the cervix uteri cancer decreased significantly (APC: ?6.1%; 95% CI: ?9.2%, ?3.0%). The results underline the increasing importance of cancer as a cause of mortality and morbidity in Tunisia. Our findings justify the need to develop effective program aiming at the control and prevention of the spread of cancer amongst Tunisian population.     

Loss of INK4a/Arf gene enhances ultraviolet radiation‐induced cutaneous tumor development

The CDKN2A locus encodes for tumor suppressor genes p16^INK4a and p14^Arf which are frequently inactivated in human skin tumors. The purpose of this study was to determine the relationship between loss of INK4a/Arf activity and inflammation in the development of ultraviolet (UV) radiation‐induced skin tumors. Panels of INK4a/Arf^‐/? mice and wild‐type (WT) mice were treated with a single dose of UVB (200 mJ/cm²). For long‐term studies, these mice were irradiated with UVB (200 mJ/cm²) three times weekly for 30 weeks. At the end of the experiment, tissues were harvested from mice and assayed for inflammatory biomarkers and cytokines. A single dose of UVB resulted in a significant increase in reactive oxygen species (ROS) and 8‐dihydroxyguanosine (8‐oxo‐dG) lesions in INK4a/Arf^?/? mice compared to WT mice. When subjected to chronic UVB, we found that 100% of INK4a/Arf^?/‐ mice had tumors, whereas there were no tumors in WT controls after 24 weeks of UVB exposure. The increase in tumor development correlated with a significant increase in nuclear factor (NF)‐κB, cyclooxygenase‐2 (COX‐2), prostaglandin E₂ (PGE₂) and its receptors both in UVB‐exposed skin and in the tumors. A significant increase was seen in inflammatory cytokines in skin samples of INK4a/Arf^‐/‐ mice following treatment with chronic UVB radiation. Furthermore, significantly more CD11b⁺Gr1⁺ myeloid cells were present in UVB‐exposed INK4a/Arf^‐/‐ mice compared to WT mice. Our data indicate that by targeting UVB‐induced inflammation, it may be possible to prevent UVB‐induced skin tumors in individuals that carry CDKN2A mutation.     

Lobular idiopathic granulomatos mastitis. About 10 cases

Our retrospective study was performed on 10 cases of granulomatous mastitis registered in Obstetric Gynaecology Department and Pathology Department of CHU F. Hached, Sousse, during 8 years period. The mean age was 36.4 years (range 32-59). Among these 10 cases. 8 were observed in reproductive-age women and 2 were noted in menopausal women. Clinical findings showed unilateral breast nodule associated with inflammatory signs in 4 cases, mammelonary retraction in 2 cases and serous or sero-purulent mamelonnary flow in 4 cases. Mamnmographic examination suggested a malignant tumor in 5 patients. In all cases, the diagnosis is made by histopathology. Surgical treatment consisted in wide excision with drainage or radical mastectomy, eventually with combination with antibiotic therapy and non steroid anti-inflammatory drugs. Prognostic features showed a good cicatrization in 4 cases, local recurrence and cutaneous fistulization in one patient. Granulomatous mastitis aetiology is still unclear, auto-immune aetio-pathogenesis appears more interesting and should be clarified.