Differential copy number aberrations in novel candidate genes associated with progression from in situ to invasive ductal carcinoma of the breast.

Only a minority of intraductal carcinomas of the breast give rise to stromally invasive disease. We microdissected 206 paraffin blocks representing 116 different cases of low-grade ductal carcinoma in situ (DCIS). Fifty-five were pure DCIS (PD) cases without progression to invasive carcinoma.

The cytoskeletal regulatory scaffold protein GIT2 modulates mesenchymal stem cell differentiation and osteoblastogenesis.

G protein-coupled receptor kinase interacting protein 2 (GIT2) is a signaling scaffold protein involved in the regulation of cytoskeletal structure, membrane trafficking, and G protein-coupled receptor internalization. Since dynamic cytoskeletal reorganization plays key roles both in osteoblast differentiation and in the maintenance of osteoclast polarity during bone resorption, we hypothesized that skeletal physiology would be altered in GIT2(-/-) mice. We found that adult GIT2(-/-) mice have decreased bone mineral density and bone volume in both the trabecular and cortical compartments.

The genomic relationship between primary breast carcinomas and their nodal metastases.

We screened the whole tumor genome to identify DNA copy number gains and losses that discriminate between primary breast carcinomas (MP) and their nodal metastases (ML). Six candidate genes were confirmed by quantitative PCR to have differentially distributed copy number changes. Three of the genes (ERRγ, DDX6, and TIAM1) were more commonly amplified in nodal metastases.

Identification of metastasis-associated breast cancer genes using a high-resolution whole genome profiling approach.

Purpose: We employed a whole genome tumor profiling approach in an attempt to identify DNA copy number alterations (CNAs) and new candidate genes that are correlated with the metastatic potential of a primary breast carcinoma and with progression at the metastatic site.

Methods: Fifty-four small (≤ 2 cm), high grade, ER-positive, formalin-fixed invasive ductal carcinomas were suitable for whole genome profiling analysis. Twenty-four of them did not form metastases within 5-10 years (unmatched primaries, UP).

Fully deleted adenovirus persistently expressing GAA accomplishes long-term skeletal muscle glycogen correction in tolerant and nontolerant GSD-II mice.

Glycogen storage disease type II (GSD-II) patients manifest symptoms of muscular dystrophy secondary to abnormal glycogen storage in cardiac and skeletal muscles. For GSD-II, we hypothesized that a fully deleted adenovirus (FDAd) vector expressing hGAA via nonviral regulatory elements (PEPCK promoter/ApoE enhancer) would facilitate long-term efficacy and decrease propensity to generate anti-hGAA antibody responses against hepatically secreted hGAA. Intravenous delivery of FDAdhGAA into GAA-tolerant or nontolerant GAA-KO mice resulted in long-term hepatic secretion of hGAA.

Identification of OTX2 as a medulloblastoma oncogene whose product can be targeted by all-trans retinoic acid.

Through digital karyotyping of permanent medulloblastoma cell lines, we found that the homeobox gene OTX2 was amplified more than 10-fold in three cell lines. Gene expression analyses showed that OTX2 transcripts were present at high levels in 14 of 15 (93%) medulloblastomas with anaplastic histopathologic features. Knockdown of OTX2 expression by siRNAs inhibited medulloblastoma cell growth in vitro, whereas pharmacologic doses of all-trans retinoic acid repressed OTX2 expression and induced apoptosis only in medulloblastoma cell lines that expressed OTX2.

Growth arrest and apoptosis in adult T cell leukemia cell lines following IL-2 deprivation.

Adult T-cell leukemia (ATL) is a peripheral T-cell neoplasm caused by human T-cell leukemia virus type-I (HTLV-I). Since ATL cells often require IL-2 for their proliferation and survival, we examined the effect of IL-2 deprivation on the IL-2-dependent ATL cells established from ATL patients. After IL-2 withdrawal, these cells were arrested in the G1 phase and then underwent apoptosis.

Tumor growth suppression by a retroviral vector displaying scFv antibody to CEA and carrying the iNOS gene.

Background: In a recent in vitro study we demonstrated a specifically-targeted killing of CEA-expressing cells by a recombinant bifunctional retrovector displaying an scFv antibody to CEA and carrying the iNOS gene. In this study, we tested whether a gene therapy using the recombinant retrovirus could inhibit the growth of CEA-expressing tumors in mice.

Materials And Methods: SCID mice were inoculated s.

Targeting of interleukin-2 to human MK-1-expressing carcinoma by fusion with a single-chain Fv of anti-MK-1 antibody.

Background: Targeting of cytokines into the tumor sites using antibody-cytokine fission proteins represents a novel approach in cancer immunotherapy. We previously reported a novel monoclonal antibody, FU-MK-1, which recognizes a glycoprotein antigen (termed MK-1 antigen) that is overexpressed on the surface of a majority of carcinomas.

Materials And Methods: To target IL-2 and cytotoxicity of effector cells to MK-1-expressing tumor cells, we genetically fused recombinant human interleukin-2 (rhIL-2) to a single chain variable fragment (scFv) antibody derived from FU-MK-1.