Inhibition of Lck enhances glucocorticoid sensitivity and apoptosis in lymphoid cell lines and in chronic lymphocytic leukemia.

Glucocorticoids are used as part of front-line therapy to treat lymphoid malignancy because of their remarkable ability to induce apoptosis. Yet, in T cells, glucocorticoid-induced apoptosis is readily inhibited by lymphocyte activation and signaling. We have previously shown that the Src family kinase, Lck (lymphocyte cell-specific tyrosine kinase), which is predominantly expressed in T cells, interacts with IP3 receptors to facilitate calcium signaling. Here, we discovered that dexamethasone downregulates Lck, which, in turn, suppresses lymphocyte activation by inhibiting pro-survival calcium oscillations. Moreover, stable expression of shRNAs that selectively targeted Lck or treatment with the Src inhibitor dasatinib (BMS-354825) enhanced apoptosis induction by dexamethasone. To investigate the effect of Lck inhibition in a primary leukemia model, we employed chronic lymphocytic leukemia (CLL) cells that aberrantly expressed Lck and were relatively insensitive to dexamethasone. Lck expression was correlated with resistance to dexamethasone in CLL cells, and its inhibition by dasatinib or other inhibitors markedly enhanced glucocorticoid sensitivity. Collectively, these data indicate that Lck protects cells from glucocorticoid-induced apoptosis and its inhibition enhances sensitivity to dexamethasone. Small-molecule inhibitors of Lck, such as dasatinib, may function to reverse glucocorticoid resistance in some lymphoid malignancies.

Fatal haemorrhage following a low-energy fracture of the pubic ramus.

We report a case of fatal haemorrhage following a low-energy fracture of the pubic ramus in an 85-year-old woman.

Hippocampal tissue transplants reverse lesion-induced spatial memory deficits in zebra finches (Taeniopygia guttata).

The avian hippocampal formation (Hf) plays an important role in spatial memory for food storing. Here we examined the effects of excitotoxic lesions of the Hf and subsequent neural transplantation on a one-trial associative memory task in zebra finches. The results showed (1) that small ibotenic acid lesions of the dorsal Hf of zebra finches produced significant spatial memory impairments compared with controls, sham-lesioned birds, and prelesion performance; and (2) that Hf-lesioned birds given transplants of embryonic hippocampal (H) tissue, but not those given transplants of embryonic anterior telencephalon (AT) tissue, showed a significant reversal of the performance deficits on the spatial memory task. Lesioned-only birds and lesioned birds given H or AT transplants that did not survive did not show behavioral improvement. Sham-lesioned and untreated control birds maintained good performance throughout the experiment. The H and AT transplants were found to be growing partially within the Hf and partially within the underlying ventricle. The transplants appeared healthy and contained neurons with beaded and unbeaded fibers (shown by immunohistochemistry with antibodies to parvalbumin, substance P, and a 200 kDa neurofilament protein). Blood vessels and erythrocytes were also present within the transplants. The results show that neural transplants can survive within the bird brain and that small lesions of the Hf produce significant spatial memory deficits that can only be reversed by surviving homologous H transplants, and not by heterologous telencephalon transplants.