Neutrophil neutral endopeptidase variation and its regulation by opioid peptides

The opioid peptide methionine-enkephalin (MENK) has significant immunomodulatory ability in addition to its neurotransmitter function. Since neutral endopeptidase (NEP, CD10, enkephalinase EC 3.4.24.11) cleaves opioid peptides, the presence and activity of NEP in neutrophils from different persons might be responsible for the diverse, neuropeptide-induced, responses of neutrophils from different donors [Ann. N. Y. Acad. Sci. 650 (1992) 146]. The results obtained showed statistically significant differences in NEP activity among donors (high, medium and low). A 10-fold higher NEP activity in neutrophils (160-280 nmol/10(6) cells/h) and in their corresponding membrane preparations (550 nmol/mg protein/min) in our study, as compared to literature data, was a result of high specificity and affinity of Suc-Ala-Ala-Phe-pNA as substrate. In control nontreated neutrophils, the number of CD10 positive cells were not correlated with NEP activity. However, in neutrophils treated with a physiological (10(-10) M) concentration of MENK, two main events occurred; not only did the number of CD10 positive cells correlate with NEP activity, but contrary to control samples, MENK upregulated the expression of CD10 marker as demonstrated by an increase of mean florescence intensity (F-mean) in donors with low NEP activity. Taken together, these data add some clarity to the diverse activity of enkephalins in association with enzyme cleavage of those molecules.     

Localization of occult breast lesions: practical solutions to problems of triangulation

The preoperative triangulation and localization of some occult breast lesions can be complicated if the lesion is located deep in the breast. Based on the authors' experience of 1,400 localization procedures, standard breast positions were modified to help locate lesions that were difficult to see in two projections. Standard compression plates were also modified, allowing placement of fenestrations over deep lesions--especially those in the axillary tail of the breast--to facilitate safe, accurate localization.     

Radiation shielding design of a new tomotherapy facility

It is expected that intensity modulated radiation therapy (IMRT) and image guided radiation therapy (IGRT) will replace a large portion of radiation therapy treatments currently performed with conventional MLC-based 3D conformal techniques. IGRT may become the standard of treatment in the future for prostate and head and neck cancer. Many established facilities may convert existing vaults to perform this treatment method using new or upgraded equipment. In the future, more facilities undoubtedly will be considering de novo designs for their treatment vaults. A reevaluation of the design principles used in conventional vault design is of benefit to those considering this approach with a new tomotherapy facility. This is made more imperative as the design of the TomoTherapy system is unique in several aspects and does not fit well into the formalism of NCRP 49 for a conventional linear accelerator.     

Ketotifen reverses MDR1-mediated multidrug resistance in human breast cancer cells in vitro and alleviates cardiotoxicity induced by doxorubicin in vivo

PURPOSE: To investigate the effect of the antihistamine ketotifen on multidrug resistance in human breast cancer cells and doxorubicin toxicity in mice. METHODS: Clonogenicity assays were used to test the effect of ketotifen on human multidrug resistant breast cancer cell lines exposed to chemotherapeutic agents. Flow cytometry was used to measure accumulation of doxorubicin in cells. Fluorimetry was used to measure accumulation of doxorubicin in cardiac tissues. Histological analysis and toxicity studies in mice were used to test the effect of ketotifen on doxorubicin-induced toxicity. RESULTS: Ketotifen was found to restore the sensitivity of P-glycoprotein-overexpressing multidrug-resistant MCF-7/adr cells to doxorubicin, mitoxantrone, VP-16 and vinblastine, but not to methotrexate or camptothecin. Ketotifen, however, was unable to restore sensitivity of BCRP-overexpressing MCF-7/mx cells or MRP-overexpressing MCF-7/vp cells to mitoxantrone or VP-16, respectively. In vivo, pretreatment of mice with ketotifen caused an increased accumulation of doxorubicin in cardiac tissue, consistent with a block in drug clearance. However, unlike verapamil, ketotifen pretreatment did not enhance doxorubicin toxicity but in fact provided protection, both at the level of cardiac tissue damage and in terms of survival. CONCLUSIONS: Taken together, these observations show that ketotifen is unique in its ability both to reverse multidrug resistance due to P-glycoprotein overexpression and to provide cardioprotection to doxorubicin.