(http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Breast cancer-model expression

Comparison of mammary tumor gene-expression profiles from thirteen murine models using microarrays and with that of human breast tumors showed that many of the defining characteristics of human subtypes were conserved among mouse models.

Noninvasive prenatal genetic testing (NIPT) is an advance in the detection of fetal chromosomal aneuploidies that analyzes cell-free fetal DNA in the blood of a pregnant woman. Since its introduction to clinical practice in Hong Kong in 2011, NIPT has quickly spread across the globe. While many professional societies currently recommend that NIPT be used as a screening method, not a diagnostic test, its high sensitivity (true positive rate) and specificity (true negative rate) make it an attractive alternative to the serum screens and invasive tests currently in use. Professional societies also recommend that NIPT be accompanied by genetic counseling so that families can make informed reproductive choices. If NIPT becomes more widely adopted, States will have to implement regulation and oversight to ensure it fits into existing legal frameworks, with particular attention to returning fetal sex information in areas where sex-based abortions are prevalent. Although there are additional challenges for NIPT uptake in the developing world, including the lack of health care professionals and infrastructure, the use of NIPT in low-resource settings could potentially reduce the need for skilled clinicians who perform invasive testing. Future advances in NIPT technology promise to expand the range of conditions that can be detected, including single gene disorders. With these advances come questions of how to handle incidental findings and variants of unknown significance. Moving forward, it is essential that all stakeholders have a voice in crafting policies to ensure the ethical and equitable use of NIPT across the world.

Transforming growth factor ␤ (TGF-␤) causes growth arrest in the G 1 phase in many cell types. One probable pathway for this growth inhibition is through the TGF-␤-mediated up-regulation of the cyclin-dependent kinase (CDK) inhibitor p15 INK4B, which specifically inhibits the enzymatic activities of CDK4 and CDK6. An active cyclin D-CDK4/6 complex is required for pRb phosphorylation to allow the cell cycle to progress from G 1 to S phase. To study the molecular mechanism of the p15 INK4B induction by TGF-␤, we isolated a 780-base pair promoter sequence of the human p15 gene and inserted this fragment upstream of a luciferase reporter gene. When this construct was transiently transfected into HaCaT cells, luciferase activity was induced more than 10-fold upon TGF-␤ treatment, indicating that the induction of p15 INK4B expression by TGF-␤ is partly exerted at the transcription level. Promoter deletion analysis revealed that the sequence from ؊110 to ؊40 relative to the transcription start site is capable of conferring the 10-fold induction by TGF-␤. Within this region there are three Sp1 consensus sites. Mutation of one of these sites, GGGGCGGAG, substantially reduced both the induction by TGF-␤ and the basal promoter activity, whereas mutations in the other two Sp1 sites and the spacer sequences had little effect. In addition, gel mobility shift assay indicates that the transcription factors Sp1 and Sp3 bind to this Sp1 site. Taken together, these data suggest that a specific Sp1 consensus site is involved in the mediation of TGF-␤ induction as well as the basal promoter activity of the p15 gene and that Sp1 and Sp3 transcription factors might be involved in this regulation.Transforming growth factor ␤s (TGF-␤s) 1 represent a large family of cytokines with diverse activities in the regulation of cell growth, differentiation, and morphogenesis (1-3). TGF-␤ causes growth inhibition of most epithelial, endothelial, fibroblast, neuronal, lymphoid, and hematopoietic cell types (3). TGF-␤ treatment induces growth arrest in the G 1 phase of the cell cycle, and this effect has been attributed largely to an inhibition of phosphorylation of the retinoblastoma susceptibility gene product, pRb (4). Progression through the G 1 phase of the cell cycle requires phosphorylation of pRb by G 1 cyclin-dependent kinase (CDK) complexes, particularly the cyclin D-CDK4 and cyclin D-CDK6 complexes (5). Phosphorylation of pRb releases transcription factors, including members of the E2F transcription factor family, required for the G 1 to S phase transition of the cell cycle (6).Two distinct families of CDK inhibitors, represented by p16 and p21, have been identified recently and shown to be capable of binding to and inhibiting the activities of various CDK enzymes (for a recent review, see Ref. 5). The p16INK4 family of CDK inhibitors specifically interacts with two closely related CDK proteins, CDK4 and CDK6, both of which have been strongly implicated as the physiological pRb kinases. One member of this family, p15 INK4B, was specifica...

Objective The goals of this study were to assess global trends in clinical implementation of Noninvasive Prenatal Testing (NIPT) as commercial tests are marketed increasingly worldwide, and to identify potential challenges for current or future use. Methods We surveyed clinicians from 46 countries about the availability of NIPT; their experiences with using NIPT; and their views on clinical, ethical, and legal issues affecting implementation in their countries. Results Forty-nine respondents from 28 countries completed the survey. The majority reported that NIPT is available in their country (n=43) and that they offer NIPT in their current practice (n=38). Eighteen respondents from 14 countries reported that there are plans to introduce NIPT into routine antenatal care in their country. Test prices varied widely, ranging from $350–$2900, and several respondents observed that high test prices limited or restricted widespread use of NIPT. Responses varied both across and within countries regarding who is offered NIPT, and what the overall screening protocol should be. Conclusion This study provides a snapshot of current use and experiences with NIPT globally. It also highlights differences in service provision that exists both across and within countries, emphasizing the need for developing national and international implementation guidelines for NIPT.