Megakaryocyte expansion and macrophage infiltration in bone marrow of rats subchronically treated with MNX, N-nitroso environmental degradation product of munitions compound RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine).

Hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), environmental degradation product of munitions hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), causes seizures in rats with acute oral exposure like parent RDX. Our previous studies have additionally reported hematotoxicity with acute MNX exposure manifested as myelosuppression, anemia and splenic hemosiderosis. This study explored whether MNX administered subchronically continued to target bone marrow to elicit peripheral blood cytopenia. Female Sprague-Dawley rats were gavaged daily for 4 or 6 weeks with 47 mg kg-1 day-1 MNX (» LD50 ) or vehicle (5% dimethyl sulfoxide in corn oil) and hematological and clinical chemistry parameters, spleen weights, spleen and bone marrow histopathology and immunohistochemistry with ED1 anti-CD68 macrophage marker were evaluated 24 h after the last dose. Unexpectedly, no decrease in blood erythroid parameters was seen with subchronic MNX and convulsions and tremors ceased after 2 weeks of treatment. Toxicological effects observed were MNX-induced increases in blood granulocyte and platelet counts and in bone marrow megakaryocyte and ED1+ -macrophage density. MNX was without effect on bone marrow cellularity and picrosirius red stained/collagen fiber deposition. Spleen weight increased modestly with extramedullary hematopoiesis evident, but hemosiderin and relative red and white pulp areas were unaffected. Collectively, this study demonstrated that erythroid effects characteristic of acute MNX exposure were not evident with subchronic exposure. However, megakaryocyte proliferation in bone marrow coincident with thrombocytosis after subchronic MNX exposure suggested continued hematotoxicity, but with a qualitatively different outcome. Granulocytosis and increased bone marrow macrophages implicated an inflammatory component in MNX hematotoxicity. Copyright © 2017 John Wiley & Sons, Ltd.

The opposite effects of doxorubicin on bone marrow stem cells versus breast cancer stem cells depend on glucosylceramide synthase.

Myelosuppression and drug resistance are common adverse effects in cancer patients with chemotherapy, and those severely limit the therapeutic efficacy and lead treatment failure. It is unclear by which cellular mechanism anticancer drugs suppress bone marrow, while drug-resistant tumors survive. We report that due to the difference of glucosylceramide synthase (GCS), catalyzing ceramide glycosylation, doxorubicin (Dox) eliminates bone marrow stem cells (BMSCs) and expands breast cancer stem cells (BCSCs). It was found that Dox decreased the numbers of BMSCs (ABCG2(+)) and the sphere formation in a dose-dependent fashion in isolated bone marrow cells. In tumor-bearing mice, Dox treatments (5mg/kg, 6 days) decreased the numbers of BMSCs and white blood cells; conversely, those treatments increased the numbers of BCSCs (CD24(-)/CD44(+)/ESA(+)) more than threefold in the same mice. Furthermore, therapeutic-dose of Dox (1mg/kg/week, 42 days) decreased the numbers of BMSCs while it increased BCSCs in vivo. Breast cancer cells, rather than bone marrow cells, highly expressed GCS, which was induced by Dox and correlated with BCSC pluripotency. These results indicate that Dox may have opposite effects, suppressing BMSCs versus expanding BCSCs, and GCS is one determinant of the differentiated responsiveness of bone marrow and cancer cells.

Implementing a referral to telephone tobacco cessation services in Louisiana community pharmacies: a pilot study.

BACKGROUND: With one of the highest rates of tobacco dependence in the nation, Louisiana has been searching for economical and effective methods for assisting patients in cessation efforts. Community pharmacists are in an excellent position to promote tobacco cessation due to their availability to patients. The "Ask-Advise-Refer" model is a short intervention in which patients desiring to quit smoking are referred to free tobacco cessation telephone counseling services. OBJECTIVE: To evaluate the implementation of the Ask-Advise-Refer model in a sample of Louisiana pharmacies and identify barriers experienced by pharmacists when identifying and referring appropriate patients. METHODS: Nine pharmacists from across the state implemented the Ask-Advise-Refer model in their community pharmacies. Each pharmacist submitted a weekly tally sheet consisting of number of patients asked about tobacco dependence, number of patients not ready to quit, number referred to tobacco cessation telephone counseling, number enrolled in study, and amount of time involved with interventions. Additionally, participating pharmacists completed a self-administered survey at the completion of the pilot study to determine opinions on barriers to widespread implementation of the program. RESULTS: Over a 6-month period, the 9 pharmacists asked 5429 patients about tobacco dependence. Of the 657 self-identified tobacco-dependent patients, 478 (72.8%) were not ready to quit, and 179 (27.2%) indicated that they were ready to quit tobacco in the next 30 days. Of the patients ready to quit, 169 (94.4%) were referred to telephone counseling services to assist in their cessation efforts. CONCLUSIONS: Louisiana community pharmacists have the ability to screen and identify tobacco-dependent patients ready to quit tobacco use, but barriers exist that prevent a large number of these patients from being referred to available, free cessation counseling.