Lysophosphatidate Induces Chemo-Resistance by Releasing Breast Cancer Cells from Taxol-Induced Mitotic Arrest

Taxol is a microtubule stabilizing agent that arrests cells in mitosis leading to cell death. Taxol is widely used to treat breast cancer, but resistance occurs in 25-69% of patients and it is vital to understand how Taxol resistance develops to improve chemotherapy. The effects of chemotherapeutic agents are overcome by survival signals that cancer cells receive. We focused our studies on autotaxin, which is a secreted protein that increases tumor growth, aggressiveness, angiogenesis and metastasis. We discovered that autotaxin strongly antagonizes the Taxol-induced killing of breast cancer and melanoma cells by converting the abundant extra-cellular lipid, lysophosphatidylcholine, into lysophosphatidate. This lipid stimulates specific G-protein coupled receptors that activate survival signals.In this study we determined the basis of these antagonistic actions of lysophosphatidate towards Taxol-induced G2/M arrest and cell death using cultured breast cancer cells. Lysophosphatidate does not antagonize Taxol action in MCF-7 cells by increasing Taxol metabolism or its expulsion through multi-drug resistance transporters. Lysophosphatidate does not lower the percentage of cells accumulating in G2/M by decreasing exit from S-phase or selective stimulation of cell death in G2/M. Instead, LPA had an unexpected and remarkable action in enabling MCF-7 and MDA-MB-468 cells, which had been arrested in G2/M by Taxol, to normalize spindle structure and divide, thus avoiding cell death. This action involves displacement of Taxol from the tubulin polymer fraction, which based on inhibitor studies, depends on activation of LPA receptors and phosphatidylinositol 3-kinase.This work demonstrates a previously unknown consequence of lysophosphatidate action that explains why autotaxin and lysophosphatidate protect against Taxol-induced cell death and promote resistance to the action of this important therapeutic agent

A survey of clinical features of allergic rhinitis in adults

Background: Allergic rhinitis (AR) has high prevalence and substantial socio-economic burden. Material/Methods: The study included 35 Italian Centers recruiting an overall number of 3383 adult patients with rhinitis (48% males, 52% females, mean age 29.1, range 18\u201345 years). For each patient, the attending physician had to fill in a standardized questionnaire, covering, in particular, some issues such as the ARIA classification of allergic rhinitis (AR), the results of skin prick test (SPT), the kind of treatment, the response to treatment, and the satisfaction with treatment. Results: Out of the 3383 patients with rhinitis, 2788 (82.4%) had AR: 311 (11.5%) had a mild intermittent, 229 (8.8%) a mild persistent, 636 (23.5%) a moderate-severe intermittent, and 1518 (56.1%) a moderate-severe persistent form. The most frequently used drugs were oral antihistamines (77.1%) and topical corticosteroids (60.8%). The response to treatment was judged as excellent in 12.2%, good in 41.3%, fair in 31.2%, poor in 14.5%, and very bad in 0.8% of subjects. The rate of treatment dissatisfaction was significantly higher in patients with moderate-to-severe AR than in patients with mild AR (p<0.0001). Indication to allergen immunotherapy (AIT) was significantly more frequent (p<0.01) in patients with severe AR than with mild AR. . Conclusions: These fndings confirm the appropriateness of ARIA guidelines in classifying the AR patients and the association of severe symptoms with unsuccessful drug treatment. The optimal targeting of patients to be treated with AIT needs to be reassessed

Cypress pollen: an unexpected major sensitizing agent in different regions of Italy.

Abstract OBJECTIVES: In this multicenter survey, we assessed the impact of sensitization to cypress in atopic patients in Italy and determined whether cypress pollen concentration changed over time. METHODS: Allergists were required to collect the results of 100-200 consecutive skin prick tests (SPTs) performed during 2012. Seasonal symptoms were also recorded, as were airborne cypress pollen concentrations (data from the Italian Aerobiology Association) in 1998-2000 and 2010-2012. RESULTS: We examined 2258 atopic outpatients (56% females; age, 2-84 years) sensitized to at least 1 of the aeroallergens tested (Dermatophagoides species, grass, pellitory, olive, cypress, birch, Alternaria tenuis, and dog and cat dander). We found that 62.9%, 16.1%, and 32.7% of patients living in central, northern, and southern Italy, respectively, were sensitized to cypress (P < .0001). The cypress pollen concentration peak was delayed from February to March in 1998-2000 and 2010-2012 in all 3 regions, with a shift in pollination towards spring. Patients who were monosensitized to cypress reported mainly rhinitis (90.7%-97.6%) and conjunctivitis (38.1%-100%). In polysensitized patients, the prevalence of rhinitis, conjunctivitis, and asthma increased progressively (P < .0001) from southern to northern Italy. The same trend was observed for the prevalence of reported winter symptoms typical of cypress allergy (28%-65%). CONCLUSIONS: Today, cypress pollen is the most frequent sensitizing aeroallergen (assessed by SPT) in several areas of central Italy. Variations in the timing of the cypress pollination period may have favored this increased sensitization. Rhinitis and conjunctivitis are the predominant symptoms. The clinical impact of this allergy was poor in southern Italy and increased in central areas before reaching its peak in northern region

Cypress pollen: an unexpected major sensitizing agent in different regions of Italy.

In this multicenter survey, we assessed the impact of sensitization to cypress in atopic patients in Italy and determined whether cypress pollen concentration changed over time