A series of experiments was performed to characterize the nature of local tissue reactions to cocaine. The time‐course of tissue injury was assessed over a 21‐day period by gross and microscopic examination of the skin of rats administered 0.1–2.0% cocaine hydrochloride by i.e. or s.c. injection. Pronounced blanching, progressively severe hemorrhage, delayed extravasation of Evans blue dye, and eventual scar formation were seen grossly at injection sites. Marked engorgement of blood vessels, small hemorrhagic foci, and hyalinization of scattered muscle bundles of the pannieulus carnosus were apparent microscopically at 15 min post‐injection. Subsequent changes during (he next 3 h included progressively severe hemorrhage and loss of muscle bundles, degeneration of hair follicles and necrosis of the vascular endothelium and epidermis. Healing of cocaine‐induced lesions, as monitored for 21 days, was relatively rapid and complete. A hyperplastic epidermis covered formerly ulcerated areas by 6 days. Destroyed cellular structures in the derm is were replaced by collagen. Since cocaine's local tissue toxicity has been ascribed to vasoconstriction, the toxic potential of cocaine was contrasted with that of a potent vasoconstrictor, epinephrine (EPI). Although 0.1% EPI produced greater vasoconstriction than did cocaine, s.c. injection of EPI did not result in skin damage. The slight acidity of cocaine hydrochloride solutions appeared to be of little consequence, since s.c. injection of pH 5 and 6 saline had little effect on tissues. Our results suggest that cocaine is directly cytotoxic, though ischemia resulting from vascular injury and vasoconstriction may contribute to the local tissue injury caused by the drug.
Tumor relapse and drug resistance are major factors that limit the curability of multiple myeloma (MM). New regimens have improved overall MM survival rates, but patients with high-risk features continue to have inferior outcomes. Chromosome 17p13 deletion (del17p) which includes the loss of the TP53 gene is a high-risk cytogenetic abnormality and is associated with poor clinical outcomes due to relatively short remissions and the development of pan-drug resistant disease. Increased relapse rates suggest that del17p enhances clonogenic growth, and we found that the loss of p53 increased both the frequency and drug resistance of tumor-initiating MM cells (TICs). Subsequent RNA sequencing (RNA-seq) studies demonstrated significant activation of the Notch signaling pathway and upregulation of inhibitor of DNA binding (ID1/ID2) genes in p53-knock out (p53-KO) cells. We found that the loss of ID1 or HES-1 expression or treatment with a gamma-secretase inhibitor (GSI) significantly decreased the clonogenic growth of p53-KO, but not p53 wild-type cells. GSI treatment in a small set of MM specimens also reduced the clonogenic growth in del17p samples but not in non-del17p samples. This effect was specific as overexpression of the Notch intracellular domain (NICD) rescued the effects of GSI treatment. Our study demonstrates that the Notch signaling and ID1 expression are required for TIC expansion in p53-KO MM cells. These findings also suggest that GSI may be specifically active in patients with p53 mutant MM.
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