TSPY expression is variably altered in transgenic mice with testicular feminization.

TSPY (testis-specific protein, Y-encoded) genes are expressed in premeiotic germ cells and round spermatids. The topology and timing of TSPY expression, and also its homology to members of the TTSN-family, suggest that TSPY is a proliferation factor for germ cells. There is also evidence for a role of TSPY in the aetiology of testis cancer.

Telomerase deletion limits progression of p53-mutant hepatocellular carcinoma with short telomeres in chronic liver disease.

Background & Aims: During early stages of carcinogenesis most human epithelial cancers including hepatocellular carcinoma (HCC) have been observed to transit through a "crisis" stage characterized by telomere shortening, loss of p53 checkpoint function, and a sharp increase in aneuploidy. The function of telomerase during in vivo hepatocarcinogenesis has not been studied in this genetic context.

Methods: Here we generated a mouse model in which HCC was induced by chronic organ damage (HBs-AG transgene) in the presence of telomere shortening and p53 deletion.

Cryopreservation and orthotopic transplantation of rat ovaries as a means of gamete banking.

Besides the exponentially increasing number of mouse strains, the rising number of rat strains, due to the establishment of transgenic and coisogenic strains in this species, surpasses the capacity of most animal houses. Cryopreservation of gametes may be a means of solving these problems. Here we describe an easy and fast method for the cryopreservation and transplantation of frozen-thawed ovaries of the rat.

Insertional mutagenesis by replication-deficient retroviral vectors encoding the large T oncogene.

Insertion sites of replication-deficient retroviral vectors may trigger clonal dominance of hematopoietic cells in vivo. Here, we tested whether this would also be the case when using vectors that express powerful oncogenes, such as the large tumor antigen (TAg) of simian virus 40. TAg inactivates the tumor-suppressor proteins p53 and Rb by virtue of a chaperone-like activity.

Testing the importance of p27 degradation by the SCFskp2 pathway in murine models of lung and colon cancer.

Decreased expression of the CDK inhibitor p27kip1 in human tumors directly correlates with increased resistance to chemotherapies, increased rates of metastasis, and an overall increased rate of patient mortality. It is thought that decreased p27 expression in tumors is caused by increased proteasomal turnover, in particular activation of the pathway governed by the SCFskp2 E3 ubiquitin protein ligase. We have directly tested the importance of the SCFskp-mediated degradation of p27 in tumorigenesis by analyzing the tumor susceptibility of mice that express a form of p27 that cannot be ubiquitinated and degraded by this pathway (p27T187A).

Inhibition of lupus disease by anti-double-stranded DNA antibodies of the IgM isotype in the (NZB x NZW)F1 mouse.

Objective: In systemic lupus erythematosus (SLE), immune complexes (ICs) containing pathogenic IgG anti-double-stranded DNA (anti-dsDNA) autoantibodies are deposited in renal capillaries and initiate glomerulonephritis (GN) by the activation of complement and effector cells. In contrast, it has been demonstrated that the presence of IgM anti-dsDNA antibodies correlates negatively with the development of GN in SLE. The aim of this study was to determine whether anti-dsDNA antibodies of the IgM isotype protect against IC-mediated organ damage in SLE.

Nephroblastomatosis and loss of WT1 expression associated with trisomy 13.

Trisomy 13 (Patau's syndrome) is a rare finding in newborns. The life span of babies affected by this chromosome abnormality is severely shortened, and multiple, partly severe malformations occur. In this study, we report on an unborn with trisomy 13 (artificially aborted on the 24th week) which showed, among other typical deformities, bilateral nephrogenic rests (nephroblastomatosis).

HOXB4 enforces equivalent fates of ES-cell-derived and adult hematopoietic cells.

Genetic manipulation of hematopoietic stem and progenitor cells is an important tool for experimental and clinical applied hematology. However, techniques that allow for gene targeting, subsequent in vitro selection, and expansion of genetically defined clones are available only for ES cells. Such molecularly defined and, hence, "safe" clones would be highly desirable for somatic gene therapy.

Clonal dominance of hematopoietic stem cells triggered by retroviral gene marking.

Gene marking with replication-defective retroviral vectors has been used for more than 20 years to track the in vivo fate of cell clones. We demonstrate that retroviral integrations themselves may trigger nonmalignant clonal expansion in murine long-term hematopoiesis. All 29 insertions recovered from clones dominating in serially transplanted recipients affected loci with an established or potential role in the self-renewal or survival of hematopoietic stem cells.

Leukemias following retroviral transfer of multidrug resistance 1 (MDR1) are driven by combinatorial insertional mutagenesis.

Previous studies have demonstrated leukemic complications in mice after high-copy retroviral gene transfer of the multidrug resistance 1 (MDR1) cDNA, encoding a membrane-located efflux pump expressed in hematopoietic stem cells. In contrast, no such complications or MDR1-associated alterations of hematopoiesis were observed in numerous other studies exploring MDR1 gene transfer into cell lines, mice, dogs, nonhuman primates, and human subjects. Here, we show that leukemias associated with retroviral expression of MDR1 depend on high vector dose, and involve the selection of clones with combinatorial insertional mutagenesis of proto-oncogenes or other signaling genes.

Contrasting effects of telomere shortening on organ homeostasis, tumor suppression, and survival during chronic liver damage.

Telomere shortening limits the regenerative capacity of cells during aging and chronic disease but at the same time inhibits tumor progression, and it has yet to be determined which of these mechanisms is dominantly affecting organismal survival. Here we show that telomere shortening in telomerase knockout (mTERC-/-) mice in combination with chronic liver damage significantly reduced organismal survival even though telomere shortening strongly inhibited liver tumor formation. Decreased survival induced by telomere shortening correlated with an imbalance between liver cell proliferation and liver cell apoptosis.

Significant differences in the effects of magnetic field exposure on 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis in two substrains of Sprague-Dawley rats.

We have shown previously (S. Thun-Battersby et al., Cancer Res.

Lack of effects of sodium 2-mercaptoethane sulfonate (mesna) on Ochratoxin A induced renal tumorigenicity following life-time oral administration of Ochratoxin A in DA and Lewis rats.

Sodium 2-mercaptoethane sulfonate (Mesna) reacts with urotoxic metabolites of oxazaphosphorine drugs (e.g. cyclophosphamide or ifosfamide) and has been used clinically to protect against damage induced by these aggressive anti-neoplastic drugs in the kidney and lower urinary and genital tracts.

Strain-specific mammary proliferative lesion development following lifetime oral administration of ochratoxin A in DA and Lewis rats.

OTA, a potent nephrotoxin in several species, is a renal carcinogen in animals and is implicated in the etiology of BEN. The NTP classified OTA as having clear evidence of carcinogenic activity, based on uncommon tubular adenomas and tubular cell carcinomas of the kidney and multiple fibroadenomas of the mammary gland, seen in the rat. As shown previously (Castegnaro et al.