To characterize the differences between second trimester Down syndrome (DS) and euploid fetuses, we used Affymetrix microarrays to compare gene expression in uncultured amniotic fluid supernatant samples. Functional pathway analysis highlighted the importance of oxidative stress, ion transport, and G protein signaling in the DS fetuses. Further evidence supporting these results was derived by correlating the observed gene expression patterns to those of small molecule drugs via the Connectivity Map. Our results suggest that there are secondary adverse consequences of DS evident in the second trimester, leading to testable hypotheses about possible antenatal therapy for DS.antenatal therapy ͉ Connectivity Map ͉ gene expression ͉ prenatal diagnosis ͉ trisomy 21

Loss of the adenomatous polyposis coli (APC) protein is a common initiating event in colon cancer. Here we show that thymocyte-specific loss of APC deregulated β-catenin signaling and suppressed Notch-dependent transcription. These events promoted the proliferation of cells of the double-negative 3 and 4 stages and reduced rearrangements between the variable, diversity and joining regions of the gene encoding T cell receptor (TCR) β, encouraging developmental progression of aberrant thymocytes lacking pre-TCR and αβ TCR. Simultaneously, the loss of APC prolonged the mitotic metaphase-to-anaphase checkpoint and impaired chromosome segregation, blocking development beyond the double-negative 4 stage. The result was extensive thymic atrophy and increased frequencies of thymocytes with chromosomal abnormalities. Thus, loss of APC in immature thymocytes has consequences distinct from those of deregulation of β-catenin signaling and is essential for T cell differentiation.Adenomatous polyposis coli (APC) is a tumor suppressor whose loss is intimately linked with colon cancer. APC is an essential component of the Wnt signaling pathway and is required for the formation of a cytoplasmic complex containing β-catenin, the kinase GSK-3β and axin. In this complex, β-catenin is phosphorylated by GSK-3β and is 'tagged' for degradation 1 . When Wnt signaling is activated by the binding of Wnt soluble proteins to frizzled receptors, this complex is disrupted and nonphosphorylated β-catenin is stabilized. The non-phospholylated β-catenin binds to the Tcf-Lef family of transcription factors and activates Wnt-dependent gene transcription by providing a transcription activation domain to the complex 1 .Correspondence should be addressed to F.G. (fgounari@tufts-nemc.org) or K.K. (khashayarsha_khazaie@dfci.harvard.edu). COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests.Supplementary information is available on the Nature Immunology website. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptMost human colorectal tumors contain mutations in APC, although in rare instances those with an intact APC contain activating mutations of the gene encoding β-catenin that alter the functionally important phosphorylation sites [2][3][4] . The APC mutations result in truncated proteins that lack all axin-binding motifs and a variable number of the 20-amino acid repeats that are associated with down-regulation of intracellular β-catenin [5][6][7] . Those findings led to the idea that the main tumor-suppressing function of APC resides in its capacity to properly regulate intracellular β-catenin 2,3,8 . However, APC encodes a multifunctional protein that participates in several cellular processes, including cell adhesion and migration, signal transduction, microtubule assembly and chromosome segregation. In dividing cells, APC is localized at the kinetochore and interacts with the microtubule end-binding protein EB1 as well as the cell cycle checkpoint proteins...

Objective To prospectively study the addition of array comparative genomic hybridization (CGH) to the prenatal evaluation of fetal structural anomalies. Methods Pregnant women carrying fetuses with a major structural abnormality were recruited at the time of invasive procedure for chromosome analysis. Only women whose fetuses had a normal karyotype (n = 50) were subsequently evaluated by array CGH using one of two arrays (1887 clones covering 622 loci or subsequently 4685 clones covering 1500 loci). Results The mean gestational age of the fetuses was 24.5 weeks (range 11–38 weeks). The most prevalent anomalies were cardiac, central nervous system, skeletal, and urogenital. The median turnaround time for culturing and array CGH diagnosis was 18 days (range 2–72). Four of 50 fetuses had abnormal array results. One (2%) was clinically significant and three (6%) were inherited or benign variants. Conclusions Array CGH studies in fetuses with sonographic anomalies and normal metaphase karyotype detected clinically significant copy number alterations in 1 of 50 cases. This percentage (2%) is consistent with prior prenatal reports. Further studies are warranted to more precisely identify which fetal anomalies are associated with copy number alterations of clinical significance.

Although BRCA1 function is essential for maintaining genomic integrity in all cell types, it is unclear why increased risk of cancer in individuals harbouring deleterious mutations in BRCA1 is restricted to only a select few tissues. Here we show that human mammary epithelial cells (HMECs) from BRCA1-mutation carriers (BRCA1mut/+) exhibit increased genomic instability and rapid telomere erosion in the absence of tumour-suppressor loss. Furthermore, we uncover a novel form of haploinsufficiency-induced senescence (HIS) specific to epithelial cells, which is triggered by pRb pathway activation rather than p53 induction. HIS and telomere erosion in HMECs correlate with misregulation of SIRT1 leading to increased levels of acetylated pRb as well as acetylated H4K16 both globally and at telomeric regions. These results identify a novel form of cellular senescence and provide a potential molecular basis for the rapid cell- and tissue- specific predisposition of breast cancer development associated with BRCA1 haploinsufficiency.