IntroductionInterferon ␣ (IFN-␣) is an important therapeutic cytokine that exerts antitumor activity in a variety of tumor cells. 1,2 Chronic myelogenous leukemia (CML) is one of the hematologic malignancies that responds well to IFN-␣ therapy. [3][4][5] However, the effect of the therapy is limited because of the development of resistance to IFN-␣, which has often been observed in patients with CML in the late chronic phase, accelerated phase, or blastic phase. 5 Although efforts to understand the molecular basis of the resistance to IFN-␣ have been made, the mechanism is still unknown.Interferon ␣ exerts its biologic actions by binding to the high-affinity cell surface receptor. Receptor-associated Janus family tyrosine kinases Tyk2 and Jak1 are activated on stimulation by IFN-␣, followed by tyrosine phosphorylation of critical tyrosine residues of the cytoplasmic domain of the receptors by Jaks. 6 This allows receptor recruitment and Jak-mediated tyrosine phosphorylation of signal transducer and activator of transcription (STAT) molecules. When STAT1 and STAT2 become tyrosine phosphorylated they bind to each other and, in combination with p48, form a complex called IFN-stimulated gene factor-3 (ISGF3). After translocation into the cell nucleus, this complex binds to the conserved IFN-stimulated responsive element (ISRE) sequence within the promoter of IFN-responsive genes and initiates transcription of these genes. 7 The suppressor of cytokine signaling (SOCS) proteins, 8 also known as STAT-induced STAT inhibitor (SSI) 9 or cytokineinducible src homology (SH)2 domain-containing protein (CIS), 10 are a family of negative regulators of cytokine signaling that are characterized by a central SH2 domain and a C-terminal SOCSbox. 11 Of the family members, SOCS1 and SOCS3 are the most potent inhibitors of cytokine-induced signals. Forced expression of SOCS1 or SOCS3 down-regulates a variety of cytokine signal pathways including Previously, we established a new human CML cell line, KT-1, from the peripheral blood of a patient with CML blast crisis. 13 Although most CML cell lines are resistant to IFN-␣, this cell line is sensitive to the antiproliferative and apoptosis-inducing effects of IFN-␣. Subsequently, we established several sublines of the KT-1 cell line. 14,15 These sublines exhibit significant variation in responsiveness to IFN-␣. One subline, KT-1/A3, is the most sensitive cell line against IFN-␣ treatment. One of the IFN-␣-resistant sublines, KT-1/B7, was isolated by subcloning of KT-1 cells without any selection by IFN-␣ treatment. 14 Another IFN-␣-resistant cell line, KT-1/A3R, was isolated by culturing KT-1/A3 cells with increasing concentrations of IFN-␣. 15 In both of these IFN-␣-resistant sublines, IFN-␣-induced activation of ISGF3 was reduced in comparison with KT-1/A3 cells. In the KT-1/B7 subline, the level of STAT2 protein (one of the ISGF3 components) was reduced and this reduction was responsible for the reduced ISGF3 activation by IFN-␣. In the KT-1/A3R subline, the ISGF3 components were unc...

Twenty-eight patients with Japanese spotted fever were clinically investigated. The diagnosis was determined by confirming an increase of specific antibody. All patients were treated with minocycline, and all recovered, excluding one patient with a fulminant course. Fever and exanthema were observed in all patients, and an eschar was pointed out in 20 (71%) patients. The platelet count was 10 x 10(4)/microl or lower in 8 (28%) patients. The fibrin degradation product (FDP)-level was abnormally high, 10 microg/ml or more, in 16 (57%) patients. The creatine kinase (CK) value was high in 14 of 22 patients, suggesting the presence of myositis. The leukocyte count, FDP, C-reactive protein, and soluble interleukin 2 receptor (sIL2-R) levels were significantly higher in severe cases. In the group without concomitant steroid therapy, mean times of 54.7 h and 101.4 h were required to reduce the temperature to 38 degrees C and 37 degrees C or lower, respectively, after the initiation of tetracycline treatment. There were 6 severe cases: 1 with disseminated intravascular coagulation, 2 with multiorgan failure, 1 with acute respiratory distress syndrome, and 2 with meningoencephalitis. These severe cases formed a group that required 6 or more days to initiate therapy after the onset (P < 0.005 vs non-severe group), showing that delay in diagnosis and therapy is the major cause of aggravation. In the 2 patients complicated by multiorgan failure, the sIL2-R level, produced by activated lymphocytes, was 10,000 U/ml or higher, suggesting that an sIL2-R level of more than 10,000 U/ml can be used as a marker of poor prognosis. It may be better that moderate to severe cases are treated with minocycline plus short-term steroid therapy.

Interferon α (IFNα) has significant clinical activity in the treatment of patients with chronic myelogenous leukaemia (CML), but the mechanisms of its selective efficacy in the treatment of the disease are unknown. The CrkL adaptor protein interacts directly with the BCR–ABL fusion protein that causes the malignant transformation and is constitutively phosphorylated in BCR–ABL‐expressing cells. In the present study, we provide evidence that CrkL was engaged in IFNα‐signalling in the CML‐derived KT‐1 cell line, which expresses BCR–ABL and is sensitive to the growth inhibitory effects of IFNα. CrkL is constitutively associated with BCR–ABL in these cells and treatment with IFNα had no effect on the BCR–ABL/CrkL interaction. After IFNα stimulation, CrkL associated with Stat5, which also underwent phosphorylation in an IFNα‐dependent manner. The interaction of CrkL with Stat5 was facilitated by the function of both the SH2 and the N‐terminus SH3 domains of CrkL. The resulting CrkL–Stat5 complex translocated to the nucleus and could be detected in gel shift assays using elements derived from either the β‐casein promoter or the promoter of the PML gene, an IFNα‐inducible gene that mediates growth inhibitory responses. In addition to its interaction with Stat5, CrkL interacts with C3G in KT‐1 cells and such an interaction regulates the downstream activation of the small GTPase Rap1, which also mediates inhibition of cell proliferation. Thus, despite its engagement by BCR–ABL in CML‐derived cells, CrkL mediates activation of downstream signalling pathways in response to the activated type I IFN receptor and such signals may contribute to the generation of the anti‐proliferative effects of IFNα in CML.

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Endometriosis is a relatively common disorder in women of reproductive age; however, appendiceal endometriosis is rare. Thus, a definitive diagnosis is likely to be established only by histology of the appendix. We report a case of endometriosis of the appendix in a 42-year-old woman who presented with symptoms of acute appendicitis. We treated the patient by performing laparoscopic appendectomy, which resulted in a good outcome.