BSV163/DOPE-mediated TRAIL gene transfection acts synergistically with chemotherapy against cisplatin-resistant ovarian cancer.

Ovarian cancer is the seventh most frequently diagnosed cancer among women worldwide. Most patients experience recurrence and succumb eventually to resistant disease, underscoring the need for an alternative treatment option. In the presented manuscript, we investigated the effect of the TRAIL-gene, transfected by an innovative bioinspired lipid vector BSV163/DOPE in the presence or absence of cisplatin, to fight against sensitive and resistant ovarian cancer. We showed that BSV163/DOPE can transfect ovarian cancer cell lines (Caov3, OVCAR3, and our new cisplatin-resistant, CR-Caov3) safely and efficiently. In addition, TRAIL-gene transfection in association with cisplatin inhibited cellular growth more efficiently (nearly 50% in Caov3 cells after the combined treatment, and 15% or 25% by each treatment alone, respectively) owing to an increase in apoptosis rate, caspases activity and TRAIL's death receptors expression. Most importantly, such synergistic effect was also observed in CR-Caov3 cells demonstrated by an apoptosis rate of 35% following the combined treatment in comparison with 17% after TRAIL-gene transfection or 6% after cisplatin exposition. These results suggest this combination may have potential application for sensitive as well as refractory ovarian cancer patients.

Suicide gene strategies applied in ovarian cancer studies.

Ovarian cancer represents the most lethal gynecological malignancy among women in developed countries. Despite the recent innovations, the improvements in the 5-year survival rate have been insufficient and the management of this disease still remains a challenge. The fact that the majority of patients experience recurrent or resistant disease have substantiated the necessity of an innovative treatment. Among various strategies investigated, the recent strides made in gene delivery techniques have made gene therapy, including suicide gene strategies, a potential alternative for treating ovarian cancer. Various suicide gene candidates, which are capable of promoting cancer cell apoptosis directly after its entry or indirectly by prodrug administration, can be separated into three systems using enzyme-coding, toxin or pro-apoptotic genes. With this review, we aim to provide an overview of different suicide genes depending on therapeutic strategies, the vectors used to deliver these transgenes specifically to malignant cells, and the combined treatments of these genes with various therapeutic regimens.

Antibacterial and transfection activities of nebulized formulations incorporating long n-alkyl chain silver N-heterocyclic carbene complexes.

The development of new antibacterial molecules is essential in view of the emergence of pathogenic strains resistant to multiple antibiotics. Among the infectious pathologies, pulmonary infections are particularly difficult to treat due to the complexity of lung anatomy and the presence of natural barriers such as mucus. At present, the aerosol delivery of antibacterial compounds is still poorly employed. Furthermore, the presence of bacteria in lungs negatively affects aerosolized Cystic Fibrosis gene therapy efficiency. A multi-functional formulation (antibacterial and transfection activities) could increase the therapeutic effect. This work reports the synthesis of new N-heterocyclic carbene silver complexes (Ag-NHC) featuring a lipid chain and the evaluation of their antibacterial potency, especially when delivered following aerosolization. When formulated alone in water, these Ag-NHC displayed remarkable antibacterial activities against some Staphyloccocus aureus strains and Pseudomonas aeruginosa clinical strains. Moreover, combined with cationic lipid and DNA (ternary combination), they could be used to deliver therapeutic genes via aerosolization in infected lungs. Altogether, the data reported herein support n-alkyl chain Ag-NHC as a possible alternative to conventional antibiotics for treating respiratory infections and to combat the emergence of multi-resistant bacteria.

Enhancement of lung gene delivery after aerosol: a new strategy using non-viral complexes with antibacterial properties.

The pathophysiology of obstructive pulmonary diseases, such as cystic fibrosis (CF), leads to the development of chronic infections in the respiratory tract. Thus, the symptomatic management of the disease requires, in particular, repetitive antibiotherapy. Besides these antibacterial treatments, certain pathologies, such as CF or chronic obstructive pulmonary disease (COPD), require the intake of many drugs. This simultaneous absorption may lead to undesirable drug interactions. For example, Orkambi® (lumacaftor/Ivacaftor, Vertex), a pharmacological drug employed to treat F508del patients, cannot be used with antibiotics such as rifampicin or rifabutin (rifamycin family) which are necessary to treat Mycobacteriaceae. As far as gene therapy is concerned, bacteria and/or biofilm in the airways present an additional barrier for gene transfer. Thus, aerosol administration of nanoparticles have to overcome many obstacles before allowing cellular penetration of therapeutic compounds. This review focusses on the development of aerosol formulations adapted to the respiratory tract and its multiple barriers. Then, formulations that are currently used in clinical applications are summarized depending on the active molecule delivered. Finally, we focus on new therapeutic approaches to reduce possible drug interactions by transferring the antibacterial activity to the nanocarrier while ensuring the transfection efficiency.

BAFF-induced changes in B cell antigen receptor-containing lipid rafts in Sjögren's syndrome.

OBJECTIVE: To determine the effect of excessive production of BAFF on the distribution and function of B cell subsets in patients with primary Sjögren's syndrome (SS). METHODS: The phenotype of B lymphocytes was analyzed by flow cytometry. Differences in the expression level of membrane IgD and CD38 were used to identify B lymphocyte subsets evolving from naive Bm1 through memory Bm5 cells. Based on our finding of a low expression of CD45RA, we sorted Bm2/Bm2' cells to determine the time course of translocation of the CD19 molecule and the B cell receptor into lipid rafts, by confocal microscopy. Serum levels of BAFF were measured by an enzyme-linked immunosorbent assay developed in-house. RESULTS: "Circulating" Bm2/Bm2' cells were expanded in patients with primary SS compared with rheumatic disease controls and with normal controls. In addition, these B cell subsets were functionally abnormal. Prolonged residency of the B cell receptor in lipid rafts in these cells was associated with elevated CD19 expression in B cells, most notably, Bm2 and Bm2' cells, obtained from the patients with primary SS. BAFF levels were higher in the patients than in the normal controls and correlated with the percentage of Bm2/Bm2' cells and their expression of CD19 in primary SS patients. These correlations were confirmed by placing sorted Bm1 or Bm2 cells from normal controls in culture in the presence or absence of BAFF. CONCLUSION: Bm2/Bm2' cells express more CD19 molecules in primary SS patients than in normal controls. BAFF might participate in this elevated expression of CD19. These patients might be suitable candidates for treatment with BAFF antagonists.

Is periodontal disease mediated by salivary BAFF in Sjögren's syndrome?

OBJECTIVE: To correlate the periodontal status of 15 patients with primary Sjögren's syndrome (SS) with their salivary levels of BAFF. METHODS: The periodontal status of 15 patients who fulfilled the criteria for primary SS was compared with that of 15 controls with xerostomia who did not fulfill the criteria for primary SS but had similar symptoms of dry mouth. The level of BAFF was measured in paired samples of saliva and serum using in-house enzyme-linked immunosorbent assays. Periodontitis was assessed by the plaque index, the modified gingival index, the papillary bleeding index, and the periodontal pocket depth. RESULTS: Notwithstanding the better oral hygiene practices of the patients with primary SS compared with those of the xerostomia controls and the subsequent reduction of their plaque index scores, complications of periodontitis, such as bleeding, gingival hypertrophy, and periodontal pockets, were not improved. This failure to ameliorate the complications of periodontitis in patients with primary SS was associated with high levels of BAFF in their saliva compared with the levels in xerostomia controls (7.4 +/- 2.1 versus 1.0 +/- 0.4 ng/ml [P < 0.002]). The levels of BAFF in saliva did not correlate with the levels in sera but did correlate with the periodontal pocket depth (P < 0.002). CONCLUSION: These findings are similar to the bone resorption observed in patients with rheumatoid arthritis. They suggest that the known effect of B cells in periodontitis would be partly mediated by salivary BAFF in patients with primary SS.

Thyroid dysfunction in primary Sjögren's syndrome: a long-term followup study.

OBJECTIVE: To evaluate the prevalence of thyroid dysfunction and related autoantibodies in patients with primary Sjögren's syndrome (pSS), and to determine whether these abnormalities develop over time. METHODS: pSS patients (n = 137) and controls (n = 120) were investigated for thyroid dysfunction and for the presence of anti-thyroid peroxidase antibody (anti-TPO) and antithyroglobulin antibody (ATG). Followup time for patients was 1-16 years, and 72 of the 120 controls were reevaluated 3 years after initial evaluation. RESULTS: Thyroid disease was more frequent in the pSS patients than in the controls (30% versus 4%; P < 10(-4)), as were anti-TPO and ATG (11% versus 3%; P < 0.02, and 3% versus 1%, not significant). Ten of 107 euthyroid pSS patients dropped out of the study, and thyroid dysfunction became apparent at followup in 12 of the remaining 97. Most of the patients with thyroid-related autoantibodies at entry developed autoimmune thyroid disease thereafter. CONCLUSION: Thyroid dysfunction is frequent in pSS patients, and those prone to develop thyroid disorders are identified by thyroid-related autoantibodies, or by rheumatoid factor and anti-Ro/SSA activity.