Diabetes in non-obese diabetic (NOD) mice is mediated by pathogenic T-helper type 1 (Th1) cells that arise because of a deficiency in regulatory or suppressor T cells. V alpha 14-J alpha 15 natural killer T (NKT) cells recognize lipid antigens presented by the major histocompatibility complex class I-like protein CD1d (refs. 3,4). We have previously shown that in vivo activation of V alpha 14 NKT cells by alpha-galactosylceramide (alpha-GalCer) and CD1d potentiates Th2-mediated adaptive immune responses. Here we show that alpha-GalCer prevents development of diabetes in wild-type but not CD1d-deficient NOD mice. Disease prevention correlated with the ability of alpha-GalCer to suppress interferon-gamma but not interleukin-4 production by NKT cells, to increase serum immunoglobulin E levels, and to promote the generation of islet autoantigen-specific Th2 cells. Because alpha-GalCer recognition by NKT cells is conserved among mice and humans, these findings indicate that alpha-GalCer might be useful for therapeutic intervention in human diseases characterized by Th1-mediated pathology such as Type 1 diabetes.

Immunization of BALB/c mice with alum-adsorbed OVA, followed by three bronchoprovocations with aerosolized OVA, resulted in the development of airway hyperresponsiveness (AHR) and allergic inflammation in the lung accompanied by severe infiltration of eosinophils into airways. In this murine asthma model, administration of monoclonal anti-IL-5 Ab before each Ag challenge markedly inhibited airway eosinophilia, but the treatment did not affect the development of AHR. Immunization and aerosol challenges with OVA following the same protocol failed to induce AHR in the mast cell-deficient W/Wv mice, but induced AHR in their congenic littermates, i.e., WBB6F1 (+/+) mice. No significant difference was found between the W/Wv mice and +/+ mice with respect to the IgE and IgG1 anti-OVA Ab responses and to the airway eosinophilia after Ag provocations. It was also found that reconstitution of W/Wv mice with bone marrow-derived mast cells cultured from normal littermates restored the capacity of developing Ag-induced AHR, indicating that lack of mast cells was responsible for the failure of W/Wv mice to develop Ag-induced AHR under the experimental conditions. However, the OVA-immunized W/Wv mice developed AHR by increasing the frequency and Ag dose of bronchoprovocations. The results suggested that AHR could be developed by two distinct cellular mechanisms. One would go through mast cell activation and the other is IgE/mast cell independent but an eosinophil/IL-5-dependent mechanism.

Characteristic features regarding growth direction and T2 signal intensity can be identified for GH-producing adenomas.

A large variety of human tumours manifest a heterozygous or homozygous deletion in the 9p21 chromosome region. The list includes malignant melanoma, glioma, lung, bladder, pancreatic and renal cancers (Kamb et al, 1994;Nobori et al, 1994), as well as gynaecological tumours (reviewed by Wong et al, 1997). Two putative tumour suppressor genes have been identified in this region: p16 (also known as p16 INK4A , cyclin-dependent kinase 4 inhibitor, CDK4I, CDKN2, and MTS1), and p15 (p15 INK4B ).The p16 gene makes two different proteins, p16 and p19 ARF (p19 alternative reading frame), using different overlapping reading frames, starting with different first exons. The p16 protein uses exon 1α, and p19 ARF uses exon 1β; these two exons are alternatively spliced to the same second and third exons. The p16 and p15 proteins belong to a family of negative regulators of the cell cycle. Specific binding of p16 protein to the CDK4 or CDK6 cyclindependent protein kinases inhibits the phosphorylation activity of CDK-cyclin D complexes towards the nuclear RB/E2F protein complex (Serrano et al, 1993). p16 normally prevents phosphorylation of RB, resulting in RB's retention of E2F. Failure to release E2F at the late G1 checkpoint blocks the cell from entering the S phase (Hengstschläger et al, 1996;Lukas et al, 1996). The p19 ARF protein, although it has an unrelated amino acid sequence, has cell cycle arresting functions. It is the p16 protein that now appears to be the major target of mutations and deletions at the 9p21 loci.The p15 (MTS2) putative tumour suppressor gene is located 25 kb centromeric of the p16 gene on 9p. p15 contains sequences highly homologous to exon 2 of p16 and, like p16, inhibits both CDK4 and CDK6 kinase activities (Guan et al, 1994;Hannon and Beach, 1994). Homozygous deletions of p15 and hypermethylation-associated loss of p15 expression have been reported in glioblastomas (Jen et al, 1994).The p16/p19 ARF and p15 genes appear to play variably important roles in human tumorigenesis, with critical tissue specificities and uncertain implications for clinical prognoses. Little is currently known about the potential role of these genes in reproductive tract biology, and specifically in uterine tumours. We have begun to examine the expression of the p16 gene at the level of mRNA and protein, the methylation status of the 5′-CpG island of p16 exon 1α, and for p16 point mutations and homozygous deletions in these tumours. We have also analysed the p15 gene for mutations and homozygous deletions. We report that the inactivation of the p16 gene, either by homozygous gene deletion, mutation or loss of protein expression, occurs in a small but significant subset of these uterine tumours. Summary The roles of the p16 and p15 inhibitor of cyclin-dependent kinase tumour suppressor genes were examined in human uterine cervical and endometrial cancers. p16 mRNA, examined by reverse transcription polymerase chain reaction (RT-PCR), was significantly reduced in five of 19 (26%) cervical and four of 25 (16%) endometrial tu...

BACKGROUNDThe clinical differential diagnosis between uterine sarcoma and benign leiomyoma is difficult even with magnetic resonance imaging (MRI). Therefore, a considerable number of patients have undergone hysterectomies due to an indication of “suspected malignancy” based on tumor size alone. However, approximately 80% of these hysterectomies have been judged to have been recommended inappropriately. In such situations, reliable preoperative diagnostic tests are required. The authors have evaluated the accuracy of needle biopsy for uterine myoma‐like tumors, a procedure that to the authors' knowledge has been performed infrequently.METHODSTranscervical needle biopsy was performed in 435 patients with uterine myoma‐like tumors. The biopsy specimens were scored for degree of malignancy according to the histopathologic criteria proposed by Bell et al. Histopathologic evaluation of surgical specimens and clinical outcome after 2 years of follow‐up were used as the reference standards.RESULTSOf 435 patients, 7 had uterine sarcomas, 4 of which were scored as ≥ 4 points and were diagnosed as “sarcoma” by needle biopsy alone. No sarcoma cases were included in the group of patients with a score of 0. The cutoff score combining the highest sensitivity and specificity with respect to distinguishing uterine leiomyosarcoma from uterine leiomyoma was 2; sensitivity, specificity, and positive and negative predictive values were 100%, 98.6%, 58%, and 100.0%, respectively.CONCLUSIONSTranscervical needle biopsy using histopathologic scoring is a reliable diagnostic test for the differential diagnosis between uterine sarcoma and leiomyoma. This diagnostic method, combined with MRI screening, could reduce the number of patients currently undergoing unnecessary surgery. Cancer 2002;94:1713–20. © 2002 American Cancer Society.DOI 10.1002/cncr.10382