Despite 35 years of clinical trials, there is little improvement in one-year survival rates for patients with metastatic melanoma, and the disease is essentially untreatable if not cured surgically. The paucity of chemotherapeutic agents that are effective for treating metastatic melanoma indicates a dire need to develop new therapies. Here, we found a previously unrecognized role for c-Abl and Arg in melanoma progression. We demonstrate that the kinase activities of c-Abl and Arg (c-Abl, Arg) are elevated in primary melanomas (60%), in a subset of benign nevi (33%), and in some human melanoma cell lines. Using siRNA and pharmacological approaches, we show that c-Abl/Arg activation is functionally relevant because it is required for melanoma cell proliferation, survival, and invasion. Significantly, we identify the mechanism by which activated c-Abl promotes melanoma invasion by showing that it transcriptionally upregulates MMP-1, and using rescue approaches we demonstrate that c-Abl promotes invasion via a STAT3→MMP-1 pathway. Additionally, we show that c-Abl and Arg are not merely redundant, as active Arg drives invasion in a STAT3-independent manner, and upregulates MMP-3 and MT1-MMP, in addition to MMP-1. Most importantly, c-Abl and Arg not only promote in vitro processes important for melanoma progression, but also promote metastasis in vivo, as inhibition of c-Abl/Arg kinase activity with the c-Abl/Arg inhibitor, nilotinib, dramatically inhibits metastasis in a mouse model. Taken together, these data identify c-Abl and Arg as critical, novel, drug targets in metastatic melanoma, and indicate that nilotinib may useful in preventing metastasis in patients with melanomas harboring active c-Abl and Arg.

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To investigate the etiologies for discrepancies between cervicovaginal smear and corresponding cervical biopsy results, 615 patients with cytologic diagnoses of dysplasia or malignancy during 1 year were reviewed. Sixty-nine patients (11%) were identified in which the cytologic and histologic diagnoses differed. Utilizing an algorithm developed for the study, these cases were assigned an etiologic category for discrepancy: colposcopic biopsy or cytologic sampling, cytologic screening, histotechnical processing, histologic or cytologic interpretation. The most common cause for a discrepancy was colposcopic biopsy sampling (36 cases, 51%). There were nine errors (13%) in biopsy interpretation, with seven underdiagnoses and two overdiagnoses. Eight errors (11%) in cytologic interpretation occurred with half of these representing underdiagnoses. The other causes for discrepancy were less common--cytologic sampling (6 cases), histotechnical processing (3 cases), cytologic screening (2 cases), and a combination of factors (5 cases). Use of this algorithm allows laboratories to identify problem areas and design specific corrective protocols to improve diagnostic accuracy and patient care.

This study characterized infections in BALB/c mice by the nonpigmented Yersinia pestis KIM and its derivatives lacking the low-Ca2+-response virulence plasmid pCD1 or failing to express selected yersinial outer membrane proteins (YOPs). The parent Y. pestis showed net growth in the spleen by 2 h and in the liver after 7 h; exponential growth in both the liver and spleen culminated in death of the mice starting on day 4, with total bacterial numbers of less than 108 in the blood, liver, and spleen together. The histopathology progressed from microabscesses to extensive coagulative necrosis unaccompanied by further immigration of inflammatory cells. This, together with the relatively low bacterial numbers, suggests a toxigenic mechanism. YopEor YopK-YopLyersiniae were cleared from the spleen but grew in the liver after an initial lag. Their growth was curbed after 1 to 2 days and entered a plateau that lasted 5 to 6 days; viable numbers then declined rapidly. This suggests that these Yopmutations distinguish, at least kinetically, between host responses in liver and spleen. Both strains caused acute inflammation in liver that evolved into structured lesions surrounded by progressively mononuclear inflammation suggestive of a granulomatous response. Accordingly, YOP E and YOPs K and L are necessary in the early days of the infection for net growth in spleen and prolonged growth in the liver; their absence is reflected morphologically by the emergence of cell-mediated immunity in the liver. The YopEand YopK-YopLmutants bound only slightly increased amounts of C3, suggesting that YOPs E, K, and L are protective through mechanisms other than interfering with the binding of complement.