IL-15 ex vivo overcomes CD4+ T cell deficiency for the induction of human antigen-specific CD8+ T cell responses

CD4(+) Th cells are important for the induction and maintenance of antigen-specific CD8(+) T cell function, so their loss or dysfunction in HIV-infected or cancer patients could reduce the patients' ability to control viral infection. Previous work in murine systems indicated that IL-15 codelivered with vaccines could overcome CD4(+) Th cell deficiency for induction of functionally efficient CD8(+) T cells and maintenance of viral-specific CTLs, but its efficacy in helping primary human CD8(+) T cell responses is unknown. In the present study, a peptide-pulsed, DC-based human coculture ex vivo system was used to study the role of IL-15 in overcoming CD4(+) Th deficiency to elicit CD8(+) T cell responses in CD4-depleted PBMCs from healthy individuals and PBMCs from HIV-1-infected patients. We found that IL-15 could overcome CD4(+) Th deficiency to induce primary and recall memory CD8(+) T cell responses in healthy individuals. Moreover, in CD4-deficient, HIV-1-infected patients with diminished CD8(+) T cell responses, IL-15 greatly enhanced CD8(+) T cell responses to alloantigen. These results suggest that IL-15 may be useful in the development of therapeutic and preventive vaccines against cancers and viral infections in patients defective in CD4(+) Th cell.     

Evaluation of solid lipid microparticles produced by spray congealing for topical application of econazole nitrate

Objectives The aims of this study were to evaluate the suitability of the spray congealing technique to produce solid lipid microparticles (SLMs) for topical administration and to study the skin permeation of a drug from SLMs compared with solid lipid nanoparticles (SLNs). Methods Econazole nitrate was used as model drug and Precirol ATO 5 as the lipidic carrier. SLMs and SLNs were both prepared at 5: 1, 10: 1 and 12.5: 1 lipid: drug weight ratios and characterised in terms of particle size, morphology, encapsulation efficiency and chemical analysis of the particle surface. SLMs and SLNs were also incorporated into HPMC K 100M hydrogels for ex‐vivo drug permeation tests using porcine epidermis. Key findings SLMs had particle sizes of 18–45 μm, while SLNs showed a mean diameter of 130–270 nm. The encapsulation efficiency was 80–100%. Permeation profiles of econazole nitrate were influenced by both particle size (significant difference until 9 h) and the amount of lipid. Conclusions The results confirm the usefulness of SLNs as carriers for topical administration and suggest the potential of SLMs for the delivery of drugs to the skin.     

Functional modulation of Crohn's disease myofibroblasts by anti-tumor necrosis factor antibodies

BACKGROUND & AIMS: Infliximab induces immune cell apoptosis by outside-to-inside signaling through transmembrane tumor necrosis factor-alpha (mTNF). However, in inflamed gut, myofibroblasts also produce TNF-alpha, and the affects of anti-TNF antibodies on these structural cells are unknown. We investigated the action of infliximab on apoptosis, the production of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMP)-1, and migration of Crohn's disease (CD) myofibroblasts. METHODS: Colonic myofibroblasts were isolated from patients with active CD and controls. mTNF was evaluated by Western blotting and flow cytometry. Infliximab-treated myofibroblasts were analyzed for apoptosis by Annexin V staining and caspase-3. TIMP-1 and MMPs were measured by Western blotting, and fibroblast migration was assessed by using an in vitro wound-healing scratch assay. RESULTS: CD myofibroblasts showed higher mTNF expression than control myofibroblasts. Infliximab had no effect on CD myofibroblast apoptosis, caspase-3 activation, and production of MMP-3 and MMP-12. However, infliximab induced a significant dose-dependent increase in TIMP-1 production, which was inhibited by the p38 mitogen-activated protein kinase inhibitor SB 203580. The anti-TNF agents adalimumab, etanercept, and p55 TNF-receptor-human IgG fusion protein also increased TIMP-1 production. The migration of CD myofibroblasts was enhanced significantly by infliximab and recombinant human TIMP-1, and infliximab-induced migration was inhibited by anti-TIMP-1 neutralizing antibody. Infliximab also decreased CD myofibroblast collagen production. CONCLUSIONS: Our findings show a novel therapeutic pathway for anti-TNF therapies in enhancing TIMP-1 production and myofibroblast migration, which may reduce MMP activity and facilitate the wound healing.     

Combination of radiotherapy and targeted therapies in the treatment of locally advanced non-small cell lung cancer

Lung cancer is the most common cancer in the world. One third of patients with non-small cell lung cancer (NSCLC) are diagnosed with locally or regionally advanced unresectable disease at presentation. Currently, in this stage of disease, a combination of chemotherapy and radiotherapy is the standard treatment approach for patients with good performance status, and concomitant chemo-radiotherapy has demonstrated to be the best therapeutic approach. However, despite improvements in treatment, local tumor control remains suboptimal and distant metastases remain the major site of failure. The diversity of molecular abnormalities in NSCLC may partly contribute to its resistance to therapy. It is therefore widely accepted that one approach to improve the efficacy of cancer therapy is the development of rational combinations of anticancer agents that may exhibit synergistic interactions. The introduction of several biologic agents represents an important advance in the management of NSCLC and some of them have shown to have a synergistic effect when given in combination with radiotherapy and chemotherapy in preclinical and in clinical models. In the present review we discuss the rationale and the feasibility of these combinations and the first results available from clinical trials.     

Disparities in mammography use among US women aged 40-64 years, by race, ethnicity, income, and health insurance status, 1993 and 2005

OBJECTIVE: To examine current disparities in mammography use, and changes in disparities over time by race, ethnicity, income, insurance, and combinations of these characteristics. RESEARCH DESIGN: Comparison of cross-sectional surveys of mammography use using the 1993 and 2005 National Health Interview Survey. SUBJECTS: Women aged 40-64 (1993, n = 4167; 2005, n = 7434). MEASURES: Mammogram within prior 2 years. RESULTS: In 2005, uninsured women reported the lowest mammography use (38.3%). Though screening increased 6.9 percentage points among low-income, uninsured women, the overall disparity between insured and uninsured women did not change significantly between 1993 and 2005. Screening seems to have declined among middle-income, uninsured women, increasing the gap compared with middle-income, insured women. The lower mammography use in 1993 among American Indian/Alaska Native compared with white women was not present in 2005; however, lower use among Asian compared with white women emerged in 2005. We found no differences between African American and white women. Hispanic women were less likely than non-Hispanic women to report screening in 2005 (58.1% vs. 69.0%). CONCLUSIONS: Although mammography use increased for some groups between 1993 and 2005, low-income, uninsured women continued to have the lowest screening rates in 2005 and the disparity for this group was not reduced. The gap in screening use for middle-income, uninsured women increased, resulting from possible declines in mammography even for uninsured women not in poverty. Asian women became less likely to receive screening in 2005. Continuing efforts are needed to eliminate disparities. Increased efforts are especially needed to address the large persistent disparity for uninsured women, including middle-income uninsured women.     

Activated ERK1/2 expression in glioblastoma multiforme and in peritumor tissue

Anomalies of growth factor signaling have been reported in malignant human gliomas. The extracellular signal-regulated kinases (ERKs) play a crucial role in transducing growth factor signals to the nucleus and are involved in a wide range of biological responses, including cell proliferation, differentiation and motility. ERK1/2 is expressed and activated in glioblastoma multiforme (GBM). However, no information is available in literature concerning the presence and activity of ERK1/2 in the peritumor tissue. In the present study, we evaluated by immunohistochemistry total and phosphorylated (t and p) ERK1/2 expression in 31 cases of primary GBM and in tissue surrounding the enhanced lesion at different distances up to 3.5 cm from the tumor margin. Total ERK1/2 was, as expected, uniformly expressed not only in GBM but in the areas around the tumor also, which showed higher levels of immunolabeling. ERK1/2 activation was observed in GBM as well as in peritumor tissue, with no statistical difference in the level of the enzymatic activities. In particular, in the peritumor tissue pERK1/2 was present independently of neoplastic cells not only in reactive astrocytes, but in apparently normal glial cells also. These results indicate that ERK1/2 pathway may participate in GBM growth and progression. In addition, they strongly suggest that ERK1/2 stimulation may be linked not only to tissue reactivity to tumor invasion, but also to cell motility or represent per se a sign of transformation. Finally, our findings highlight the meaning of the extension of neoplasm fingers beyond the outer margin of GBM. Patients with neoplastic cells at <10% or without neoplastic cells in peritumor areas showed a higher survival time compared with those with neoplastic elements at > or = 10%. In addition, a percentage > or = 10 of neoplastic elements in peritumor tissue was associated with an approximately 4-fold increased death risk.