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Notch receptors and their ligands play important roles in both normal animal development and pathogenesis. We show here that the F-box/WD40 repeat protein SEL-10 negatively regulates Notch receptor activity by targeting the intracellular domain of Notch receptors for ubiquitin-mediated protein degradation. Blocking of endogenous SEL-10 activity was done by expression of a dominant-negative form containing only the WD40

Candidemia continues to be associated with a high mortality. Preventative measures should be targeted against high-risk hospitalized patients, especially those in ICUs, the elderly, and those undergoing major surgery. Local surveillance of candidemia is important to optimize management.

Notch signaling is required for vascular development and tumor angiogenesis.

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The Notch family of cell-surface receptors has been proposed to regulate cell-fate decisions by modulating the ability of each cell to respond to environmental cues. In vertebrates, gain-of-function and loss-of-function studies have demonstrated a requirement for Notch signaling for proper patterning of the vasculature during embryogenesis. To examine the molecular mechanisms by which Notch regulates vascular development, we analyzed changes in gene expression in response to Notch signaling. Notch signal transduction and function were assessed in primary human endothelial cells isolated from the dermal microvasculature of neonates, HMVECd. We demonstrate that HMVECd cells express a heterodimeric form of endogenous Notch4 on their cell surface. Using an in vitro coculture assay, we found that Delta4 can function as a ligand for Notch4 in HMVECd cells. Moreover, ectopic expression of an activated allele of Notch4 upregulated the expression of Delta4, suggesting that there may be a regulatory loop between Notch4 and its ligand, Delta4. Notch4 activation also induced the expression of the transcriptional repressors, HES1, HERP1, and HERP2, as well as ephrinB2, an angiogenic factor proposed to be involved in arterial/venous endothelial cell specification.

Background:Cytological grading is a useful tool for selection of therapy and prognosis in breast carcinoma. Despite having many cytological grading systems, there is still no agreement among pathologists to accept one of them as a gold standard.Aim:This study was undertaken to evaluate six such three-tier cytological grading systems to determine which system corresponds best to histological grading done by Nottingham modification of Scarff Bloom Richardson (SBR)'s method.Materials and Methods:In a double-blind study, preoperative cytological grades obtained by six systems on fine-needle aspiration cytology (FNAC) smears were compared by testing concordance, association and correlation with histological grade derived postoperatively by the SBR's method in 57 patients of breast carcinoma. Bivariate correlation studies and multiple linear regressions were done to assess the significance of the different cytological parameters to predict final cytological grades.Results:Robinson's system demonstrated the best correlation (ρ = 0.799; P = 0.000 and τ = 0.765; P = 0.000), maximum percent agreement (77.19%) and a substantial kappa value of agreement (κ = 0.62) with the SBR's grading system. All the six cytological grading systems correlated with histological grading strongly and positively. In multiple regression analysis, all of the cytological parameters of Robinson's system except cell size and nucleoli had significance in predicting the final cytological grade.Conclusions:Robinson's grading system is simple, more objective and reproducible, and demonstrated the best concordance with histological grading. So, Robinson's system should be used routinely for breast carcinoma aspirates.

During normal development Notch receptor signaling is important in regulating numerous cell fate decisions.Mutations that truncate the extracellular domain of Notch receptors can cause aberrant signaling and promote unregulated cell growth. We have examined two types of truncated Notch oncoproteins that arise from proviral insertion into the Notch4 gene (Notch4/int-3) or a chromosomal translocation involving the Notch1 gene (TAN-1). Both Notch4/int-3 and TAN-1 oncoproteins lack most or all of their ectodomain. Normal Notch signaling requires ␥-secretase/presenilin-mediated proteolytic processing, but whether Notch oncoproteins are also dependent on ␥-secretase/presenilin activity is not known. We demonstrate that Notch4/int-3-induced activation of the downstream transcription factor, CSL, is abrogated in cells deficient in presenilins or treated with a pharmacological inhibitor of ␥-secretase/presenilins. Furthermore, we find that both Notch4/int-3 and TAN-1 accumulate at the cell surface, where presenilindependent cleavage occurs, when ␥-secretase/presenilin activity is inhibited. ␥-Secretase/presenilin inhibition effectively blocks cellular responses to Notch4/int-3, but not TAN-1, apparently because some TAN-1 polypeptides lack transmembrane domains and do not require ␥-secretase/presenilin activity for nuclear access. These studies highlight potential uses and limitations of ␥-secretase/presenilin inhibitors in targeted therapy of Notch-related neoplasms.