Defective stem cell factor expression in c-myb null fetal liver stroma.

High levels of c-Myb are observed in immature precursor myeloid and lymphoid cells, while downregulation of c-myb accompanies terminal differentiation to a mature phenotype. This has established c-Myb as a crucial transcription factor for hematopoiesis. Further evidence for this is the embryonic death of the c-myb homozygous mutant mouse at ED15 due to defective fetal liver erythropoiesis. Cells from fetal liver of wild-type and c-myb-/- embryos were examined in detail for their hematopoietic potential and the capacity of the stroma to support wild-type hematopoiesis. The c-myb-/- fetal liver was shown to harbor sevenfold fewer spleen focus-forming cells and a similarly lower number of cells with long-term repopulating capacity (high proliferative potential cells). However, shorter term repopulating cells were not substantially reduced. c-myb-/- stromal cells were unable to support the proliferation of wild-type bone marrow lineage-negative cells. This was found to be partly due to a decrease in stem cell factor (SCF) expression while partial rescue of the stromal cell cultures was achieved through the addition of exogenous SCF. DNA binding studies for two sites within the SCF promoter demonstrated an in vitro interaction between the SCF promoter and c-Myb and transient transfection studies demonstrated that c-Myb could substantially transactivate the SCF promoter in HEK293 cells. These data explain why the c-myb-/- embryos are so impaired in their ability to establish hematopoiesis.

Cyclooxygenase-2, a colorectal cancer nonsteroidal anti-inflammatory drug target, is regulated by c-MYB.

Cyclooxygenase-2 (COX-2) is an important pharmacological target with great promise in the prevention and treatment of colorectal cancer (CRC). The mechanism underlying COX-2 overexpression in CRC is unresolved. On the basis of the coincident high levels of the transcription factor c-MYB and COX-2 in CRC, we hypothesized that c-MYB is a candidate activator of COX-2 transcription. We identified 13 c-Myb binding sites in the human COX-2 promoter. Eight of these sites were moderate to high-affinity DNA binding targets. Promoter studies indicated that c-Myb can activate COX-2 transcription, whereas dominant-negative Myb mediated repression. These data provide the first rational basis for overexpression of COX-2 in CRC and offer an additional potential target for managing this disease.

c-Myb is critical for murine colon development.

The mammalian colon develops from a simple tube of undifferentiated cells into a complex, highly ordered organ, with a continuously self-renewing epithelial layer. We have previously described c-Myb expression in the epithelia of murine and human colon crypts and documented increased expression in colorectal adenocarcinoma cells. To investigate the role of c-Myb in colonic epithelium development, we have used embryos with a disrupted c-myb gene. Prior to the in utero death of these embryos at E15, we excised colon tissue and transplanted it under the kidney capsule of recipient mice to allow further development and cyto-differentiation. Compared to the colons of wildtype and heterozygous littermates, the c-myb homozygous knockout colon is highly irregular with a disordered epithelium and abnormal crypts. In addition, the expression of Bcl-2, a known target of c-Myb, is reduced and apoptosis is increased, indicating a critical requirement for c-Myb in normal colon development.

Evaluation of the fine needle aspiration biopsy in the preoperative selection of cold thyroid nodules.

From 1980 to 1988 the authors examined by fine needle aspiration biopsy (FNAB) 4609 patients with solitary thyroid nodules or multinodular goiters. A total of 5605 "cold" thyroid nodules were evaluated and classified, on the basis of the cytologic findings, as malignant, follicular lesions (probably malignant and probably benign) and benign. Then the authors compared the preoperative cytologic findings with the postoperative histologic results in 827 nodules from patients who underwent surgery. In the 805 thyroid nodules in which an adequate cytologic specimen was obtained, false-negative results were 2.3% and false-positive findings were 1.1% By comparing cytologic and histologic diagnoses, preoperative FNAB resulted in the ability to accurately assess the risk of cancer in a thyroid nodule; since 250 nodules were identified as malignant, the risk of a "cold" thyroid nodule being cancer was 4.46% in this series.

[Receptor status and ovarian function in carcinoma of the breast]. / Status recettoriale e funzione ovarica nel carcinoma della mammella.

The Authors have evaluated the relationship between the presence of estrogen (ER) and progesterone (PgR) receptors and the ovarian function in 321 consecutive and unselected women who have undergone surgery for breast cancer. A significant relationship was found between the presence and the concentration of steroid receptors (ER and PgR) in the neoplastic tissue and the ovarian function. The Authors confirm the importance of considering the menopausal status in the evaluation of the results of steroid receptor assay.