Immune senescence: significance of the stromal microenvironment.

The immune system undergoes age-associated changes known as immunosenescence, resulting in increased susceptibility to infections, cancers and autoimmunity in the aged. The basis of our understanding of immunosenescence has been derived primarily from studies examining intrinsic defects within many of the cells of the immune system. While these studies have provided insight into the mechanisms of immunosenescence, a picture is now emerging that the stromal microenvironment within lymphoid organs also contributes significantly to the age-associated decline of immune function. These extrinsic defects appear to impact the functional activity of immune cells and may offer a potential target to recover immune activity. Indeed, rejuvenation studies which have targeted the stromal niche have restored immune function in aged successfully, highlighting the impact of the microenvironment towards the aetiology of immunosenescence.

Phase I clinical trial and pharmacokinetics of intravesical mitomycin C in dogs with localized transitional cell carcinoma of the urinary bladder.

BACKGROUND: Transitional cell carcinoma (TCC) is the most common cancer of the urinary tract in dogs. The most frequent cause of death is urinary obstruction from the primary tumor. Standard medical therapy for TCC is only partially effective. HYPOTHESIS/OBJECTIVES: Intravesical administration of mitomycin C (MMC) in dogs with invasive TCC will result in antitumor activity against the primary tumor and minimal systemic drug absorption. ANIMALS: Thirteen privately owned dogs with naturally occurring, histopathologically diagnosed TCC of the urinary bladder. METHODS: A prospective phase I trial was performed. MMC was given intravesically (600 µg/mL initial concentration) for 1 h/d for 2 consecutive days each month. The MMC concentration was escalated to a maximum of 800 µg/mL in groups of 3 dogs until the maximum tolerated dose (MTD) was determined. Serum assays for MMC were performed to determine the extent of systemic absorption of the MMC. RESULTS: The MTD of MMC based on local toxicoses was 700 µg/mL (1-h dwell time, 2 consecutive days). In addition, 2 dogs had severe myelosuppression and appeared to have systemic absorption of MMC. Five dogs had partial remission, and 7 dogs had stable disease. CONCLUSIONS: Intravesical MMC has antitumor activity in dogs with invasive TCC. Further study is needed to determine the cause of the myelosuppression associated with MMC administration, and to develop strategies to minimize this risk.

Dual role of pyrrolizidine alkaloids in nectar.

Pyrrolizidine alkaloids occur in several plant families, attracting ithomiine and danaine butterflies that specialize on the flowers. I show that pyrrolizidine alkaloids in artificial nectar also inhibit at least one butterfly,Agraulis vanillae (Nymphalidae: Heliconiinae), a more general forager. Inhibition was demonstrated in two ways: quantity of nectar consumed and number of artificial flowers visited. The amount of sucrose solution consumed by individual butterflies was measured using a microcapillary tube. Number of flower visits was determined using an array of artificial orange and yellow flowers.A. vanillae drank less sucrose solution with monocrotaline, a pyrrolizidine alkaloid, than without. When monocrotaline was placed into yellow flowers,A. vanillae learned to visit predominantly orange flowers. Evolutionarily, pyrrolizidine alkaloids in nectar may represent an adaptation to exclude butterflies. Ithomiines and danaines, seeking these compounds in larval food plants, were not excluded. Alternatively, ithomiines and danaines overcame the nectar defense. In either case, the plant effectively increased floral constancy by inhibiting generalist butterflies and attracting specialists.