B7-H1, a recently described member of the B7 family of costimulatory molecules, is thought to be involved in the regulation of cellular and humoral immune responses through the PD-1 receptor on activated T and B cells. We report here that, except for cells of the macrophage lineage, normal human tissues do not express B7-H1. In contrast, B7-H1 is abundant in human carcinomas of lung, ovary and colon and in melanomas. The pro-inflammatory cytokine interferon-gamma upregulates B7-H1 on the surface of tumor cell lines. Cancer cell-associated B7-H1 increases apoptosis of antigen-specific human T-cell clones in vitro, and the apoptotic effect of B7-H1 is mediated largely by one or more receptors other than PD-1. In addition, expression of B7-H1 on mouse P815 tumor increases apoptosis of activated tumor-reactive T cells and promotes the growth of highly immunogenic B7-1(+) tumors in vivo. These findings have implications for the design of T cell-based cancer immunotherapy.
Faithful segregation of replicated chromosomes is essential for maintenance of genetic stability and seems to be monitored by several mitotic checkpoints. Various components of these checkpoints have been identified in mammals, but their physiological relevance is largely unknown. Here we show that mutant mice with low levels of the spindle assembly checkpoint protein BubR1 develop progressive aneuploidy along with a variety of progeroid features, including short lifespan, cachectic dwarfism, lordokyphosis, cataracts, loss of subcutaneous fat and impaired wound healing. Graded reduction of BubR1 expression in mouse embryonic fibroblasts causes increased aneuploidy and senescence. Male and female mutant mice have defects in meiotic chromosome segregation and are infertile. Natural aging of wild-type mice is marked by decreased expression of BubR1 in multiple tissues, including testis and ovary. These results suggest a role for BubR1 in regulating aging and infertility.
Adoptive T cell therapy, involving the ex vivo selection and expansion of antigen-specific T cell clones, provides a means of augmenting antigen-specific immunity without the in vivo constraints that can accompany vaccine-based strategies. A phase I study was performed to evaluate the safety, in vivo persistence, and efficacy of adoptively transferred CD8 ؉ T cell clones targeting the tumor-associated antigens, MART1͞MelanA and gp100 for the treatment of patients with metastatic melanoma. Four infusions of autologous T cell clones were administered, the first without IL-2 and subsequent infusions with low-dose IL-2 (at 0.25, 0.50, and 1.0 ؋ 10 6 units͞m 2 twice daily for the second, third, and fourth infusions, respectively). Forty-three infusions of MART1͞MelanA-specific or gp100-specific CD8 ؉ T cell clones were administered to 10 patients. No serious toxicity was observed. We demonstrate that the adoptively transferred T cell clones persist in vivo in response to low-dose IL-2, preferentially localize to tumor sites and mediate an antigen-specific immune response characterized by the elimination of antigen-positive tumor cells, regression of individual metastases, and minor, mixed or stable responses in 8 of 10 patients with refractory, metastatic disease for up to 21 mo.
PSM was expressed in all cases of prostate adenocarcinoma, with the greatest extent and intensity observed in the highest grades. The expression increased incrementally from benign epithelium to high grade PIN or adenocarcinoma. Conversely, PSA showed the greatest staining in benign epithelium, with decreased expression incrementally from benign epithelium to high grade PIN or adenocarcinoma. Expression of PSM is clinically useful for the identification of prostate epithelium, particularly PIN or adenocarcinoma, and its expression is regulated independent of PSA. The number of PSM immunoreactive cells was not predictive of recurrence, most likely because of the presence of abundant immunoreactivity in most cases, or because of differential expression in primary and metastatic disease.
Activation of Wnt signaling through beta-catenin mutations contributes to the development of hepatocellular carcinoma (HCC) and hepatoblastoma (HB). To explore the contribution of additional Wnt pathway molecules to hepatocarcinogenesis, we examined beta-catenin, AXIN1 and AXIN2 mutations in 73 HCCs and 27 HBs. beta-catenin mutations were detected in 19.2% (14 out of 73) HCCs and 70.4% (19 out of 27) HBs. beta-catenin mutations in HCCs were primarily point mutations, whereas more than half of the HBs had deletions. AXIN1 mutations occurred in seven (9.6%) HCCs and two (7.4%) HBs. The AXIN1 mutations included seven missense mutations, a 1 bp deletion, and a 12 bp insertion. The predominance of missense mutations found in the AXIN1 gene is different from the small deletions or nonsense mutations described previously. Loss of heterozygosity at the AXIN1 locus was present in four of five informative HCCs with AXIN1 mutations, suggesting a tumor suppressor function of this gene. AXIN2 mutations were found in two (2.7%) HCCs but not in HBs. Two HCCs had both AXIN1 and beta-catenin mutations, and one HCC had both AXIN2 and beta-catenin mutations. About half the HCCs with AXIN1 or AXIN2 mutations showed beta-catenin accumulation in the nucleus, cytoplasm or membrane. Overall, these data indicate that besides the approximately 20% of HCCs and 80% of HBs with beta-catenin mutations contributing to hepatocarcinogenesis, AXIN1 and AXIN2 mutations appear to be important in an additional 10% of HCCs and HBs.
The islet in non-insulin-dependent diabetes mellitus (NIDDM) is characterized by loss of ,B cells and large local deposits of amyloid derived from the 37-amino acid protein, islet amyloid polypeptide (IAPP Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by (3-cell destruction and islet amyloid derived from islet amyloid polypeptide (IAPP) (1, 2). IAPP is a 37-amino acid protein that possesses amyloidogenic properties in species that spontaneously develop NIDDM (humans, monkeys, cats), but is non-amyloidogenic in mice that do not develop NIDDM (3, 4). Overexpression of human IAPP (h-IAPP), but not rat IAPP, in COS cells resulted in intracellular IAPP amyloidosis that was associated with cell death (5). Thus far, hemizygous transgenic mice for h-IAPP have not been reported to develop islet amyloid or diabetes mellitus spontaneously (6-8). Induction of marked insulin resistance in hemizygous mice transgenic for h-IAPP provokes intra-and extracellular IAPP amyloid formation, which is associated with 13-cell death and hyperglycemia (9).Based on these observations, we hypothesized that sufficiently increased rates of h-IAPP expression and synthesis results in intracellular IAPP amyloidosis and (3-cell death, which results in diabetes mellitus (10). To examine this further, we developed a homozygous line of mice transgenic for h-IAPP, thereby doubling the h-IAPP gene copy number. We report here that these mice spontaneously developed diabetes mellitus due to (3-cell death, which was associated with abnormal intra-and extracellular aggregates of h-IAPP. We conclude that overproduction of IAPP in vulnerable species (humans, monkeys, cats) may cause (3-cell destruction and diabetes mellitus. MATERIALS AND METHODSPreparation of Transgenic Construct. The RIPHAT transgene (2395 bp) is described elsewhere (9). It consists of a PCR-generated cDNA encompassing the h-IAPP coding sequence (270 bp) under the regulation of the rat insulin II promoter/5' untranslated region and followed by intron I (728 bp) from the human albumin gene and the polyadenylylation site/RNA termination region (525 bp) from the human glyceraldehyde-3-phosphate gene (GAPDH). Use of the albumin intron I and GAPDH polyadenylylation site in transgenic constructs has been described (11).Generation of Transgenic Mice. Hemizygotes of the RHF line described in Couce et al. (9) were self-crossed to generate Fl offspring. Transgenic offspring were identified by PCR amplification of RIPHAT from tail DNA. Hemizygotes were distinguished from homozygotes by backcross breeding to nontransgenic FVB/N mice. Homozygotes were defined as those mice that generated more than 20 transgenic and no nontransgenic offspring. Four such homozygotes were used to establish the core RHF breeding colony.Northern Blot Analysis. Total RNA was prepared from whole pancreata of FVB/N, RHF hemizygote, and RHF homozygote males and females. Gels and blots were prepared and hybridized as described (9)
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