Vadlamudi R.K.,CTRC |
Rajhans R.,CTRC |
Chakravarty D.,CTRC |
Nair B.C.,CTRC |
And 4 more authors.
Journal of Steroid Biochemistry and Molecular Biology | Year: 2010
Estradiol (E2), estrogen receptor (ER), ER-coregulators have been implicated in the development and progression of breast cancer. In situ E2 synthesis is implicated in tumor cell proliferation through autocrine or paracrine mechanisms, especially in post-menopausal women. Several recent studies demonstrated activity of aromatase P450 (Cyp19), a key enzyme that plays critical role in E2 synthesis in breast tumors. The mechanism by which tumors enhance aromatase expression is not completely understood. Recent studies from our laboratory suggested that PELP1 (Proline, Glutamic acid, Leucine rich Protein 1), a novel ER-coregulator, functions as a potential proto-oncogene and promotes tumor growth in nude mice models without exogenous E2 supplementation. In this study,wefound that PELP1 deregulation contributes to increased expression of aromatase, local E2 synthesis and PELP1 cooperates with growth factor signaling components in the activation of aromatase. PELP1 deregulation uniquely up-regulated aromatase expression via activation of aromatase promoter I.3/II. Analysis of PELP1 drivenmammarytumors in xenograft as well as in transgenic mouse models revealed increased aromatase expression. PELP1-mediated induction of aromatase requires functional Src and PI3K pathways. Chromatin immuno precipitation (ChIP) assays revealed that PELP1 is recruited to the Aro 1.3/II aromatase promoter. HER2 signaling enhances PELP1 recruitment to the aromatase promoter and PELP1 plays a critical role in HER2-mediated induction of aromatase expression. Mechanistic studies revealed that PELP1 interactions with orphan receptor ERRα, and histone demethylases play a role in the activation of aromatase promoter. Accordingly, ChIP analysis showed alterations in histone modifications at the aromatase promoter in the model cells that exhibit local E2 synthesis. Immunohistochemical analysis of breast tumor progression tissue arrays suggested that deregulation of aromatase expression occurs in advanced-stage and node-positive tumors, and that cooverexpression of PELP1 and aromatase occur in a sub set of tumors. Collectively, our results suggest that PELP1 regulation of aromatase represent a novel mechanism for in situ estrogen synthesis leading to tumor proliferation by autocrine loop and open a new avenue for ablating local aromatase activity in breast tumors. © 2009 Elsevier Ltd. All rights reserved.
Lapusan S.,Saint Antoine Hospital |
Vidriales M.B.,Hospital Universitario Of Salamanca |
Thomas X.,Edouard Herriot Hospital |
De Botton S.,Institute Gustave Roussy |
And 15 more authors.
Investigational New Drugs | Year: 2012
The efficacy of anti-CD33 immunoconjugates had been previously demonstrated for gemtuzumabozogamicin. AVE9633 is an anti-CD33-maytansine conjugate created by ImmunoGen Inc. Phase I trials of AVE9633 were performed in patients with AML to evaluate tolerability, pharmacokinetics and pharmacodynamics. Three phase I studies of AVE9633 were performed in 54 patients with refractory/relapsed AML, evaluating drug infusion on day 1 of a 21-day cycle (Day 1 study), day 1 and 8 (Day 1/8 study) and day 1, 4 and 7 (Day 1/4/7 study) of a 28-day cycle. Toxicitywasmainly allergic reaction during infusion (3 grade 3 bronchospasms). DLT was reached for the D1-D7 schedule at 150 mg/sqm (1 keratitis, 1 liver toxicity), and the MTD was set at 130 mg/sqm for this schedule. In the two other phases I, the DLT was not reached. In the Day 1/8 study, CD33 on peripheral blasts was saturated and down-modulated for doses of 75 mg/m2 × 2 or higher, which was correlated with WBC kinetics and plasma levels of AVE9633. Decrease of DM4/CD33 ratio on the blasts surface between day 1 and 8 was the rational for evaluating day 1/4/7 schedule. This induced relatively constant DM4/CD33 levels over the first 8 days, however no activity was noted. One CRp, one PR and biological activity in five other patients were observed in this study. The Day 1 and Day 1/4/7 studies were early discontinued because of drug inactivity at doses significantly higher than CD33 -saturating doses. No myelossuppression was observed at any trial of AVE9633. The pharmacokinetics/ pharmacodynamics data obtained in these studies will provide very useful information for the design of the next generation of immunoconjugates. © 2012 Springer Science+Business Media, LLC.
Projections released by the U.S. Department of Education paint a bright future for jobs in the science, technology, engineering and mathematics (STEM) fields. As populations grow, natural resources diminish, disease prevention and treatment become more complex and evolutionary and universal mysteries continue to be explored, science and technology will remain critical to expanding human knowledge and solving challenges of today and for the future. Opportunities abound for STEM graduates today, but preparing enough STEM graduates to drive the scientific breakthroughs and technological innovations of tomorrow will be a daunting task for colleges and universities across the country. The U.S. President’s Council of Advisors on Science and Technology predicts that in the next decade, we will need approximately 1 million more STEM professionals than we will produce at our current rate. Currently, about 300,000 graduates obtain Bachelor and Associate degrees in STEM fields every year. In order to create this new workforce of 1 million additional STEM experts, that number needs to increase by 100,000 annually. The challenge is clear: Universities must attract more students to STEM programs. However, once these students have enrolled, another challenge begins to unfold: Only about 40 percent of students who enroll in STEM programs graduate with STEM degrees. The remaining 60 percent switch to non-STEM fields or drop out of college entirely. To address the challenges of attraction and retention, educational institutions throughout the country are trading in traditional teaching methods for new pedagogical techniques. These new methods move beyond a model where students passively listen to lectures and cram for tests, to methods that engage students in activities, enable collaboration across STEM disciplines and encourage students to use their hands just as much as their heads. With these new approaches to learning and teaching come new approaches to designing learning environments. These new spaces are eliminating the stereotypes associated with traditional STEM classrooms and fostering the type of creative brilliance that can help us educate and prepare one million new STEM graduates. Here are three ideas every university should consider when rethinking their STEM learning spaces to better recruit and retain students for the future. Get out of the basement Traditionally, STEM teaching labs and research spaces were located in building cores or basements. These underground “lairs” were uncomfortable and uninviting to students and faculty using these facilities. They featured little to no windows, no natural light and the overall environment felt more institutional than educational. For students that didn’t have a class assigned to these spaces, the labs were relatively unknown, and were considered untouchable and intimidating. Countless studies show the design of classroom environments influence students’ motivation and learning, and universities are seeing the value in encouraging the student body to observe the scientific process to raise curiosity and interest. From a design perspective, we use the term “putting science on display” pretty regularly. The general idea is to place science classrooms and labs in public, high-traffic areas. Instead of solid walls, expansive floor-to-ceiling windows celebrate the sciences and allow passersby the opportunity to observe research and watch it unfold. This helps make science an approachable, open process, and as an added benefit, it gives universities the chance to show off their cool research equipment. The University of Buffalo has embraced this idea with its Clinical Translational Research Center (CTRC). Embedded in the same building as Kaleida Health’s Gates Vascular Institute, the CTRC uses interior glass throughout the building to show science in an open, transparent process. Embrace startup culture A key component of successful STEM programs is experimentation. For example, if you look at the most successful technology startups over the last 10 years, very few started in a formal academic settings. More often than not, they started in garages or coffee shops—places with more sofas than fixed bench space. There’s a lot STEM learning environments can learn from these spaces, specifically in how they encourage free thinking and experimentation. Taking inspiration from startups, our team at CannonDesign is seeing an increase in makerspace, hackerspace and innovation hubs within STEM buildings. These spaces serve a pretty basic purpose: nurturing creativity, encouraging experimentation and stimulating intellectual inquiry in an informal setting. They don’t act exclusively as labs, garages or workshops, but they do include many of the tools found in these space (3-D printers, welding machines, computers, building materials). The Univ. of Utah sees the value in such spaces with their new Lassonde Studios Entrepreneurial building that features a 20,000-sf making/planning/hacking space to foster interdisciplinary and cross-disciplinary “mash-ups” extending beyond STEM disciplines and including others, such as business majors. Infuse appropriate technology into S&T academic environments Millennials and Generation Z grew up in a digital world and expect to take full advantage of technology in every aspect of life, especially college. However, technology hasn’t revolutionized education the way it has other industries. STEM learning environments can be leading examples for how using technology can enhance learning by making it more engaging and accessible. The flipped classroom is a good example of an effective use of technology for enhanced learning. The flipped classroom is a pedagogical model that has students watch video lectures and complete homework prior to class. Doing this creates richer face-to-face interactions when students are actually in class; instead of listening to a lecture, they spend their time asking questions, participating in hands-on activities and even getting involved in real university research efforts. On the most dramatic end of the spectrum, some universities are using virtual reality, simulation and gaming to inspire and educate future STEM innovators. These tools allow students to quite literally take part in technology. For example, CAVE environments, which are rooms wrapped in screens that project 3D virtual environments, allow students to immerse themselves in a setting and actually interact with what they’re seeing. From an infrastructure design standpoint, these technology-rich spaces require a building that provides enhanced server space, room for complex computing platforms, and the power and cooling sources to keep everything up and running. One interesting trend our team is also seeing related to technology is a decrease in dedicated computer labs. Prior to the days of constant connectivity, computer labs acted as the hub of higher education buildings. But today, 90 percent of students own a laptop, 86 percent of students own a smartphone and 47 percent of students own a tablet. The need to access university-owned equipment is dwindling, and the need to plug in personal devices and work anywhere is the new norm. There’s no denying universities need to prove themselves up to the challenge of attracting and retaining the much needed next generation of STEM professionals. How they choose to design their STEM learning environments can play a big role in helping them meet this challenge and exceed current projections. Stephen Blair leads CannonDesign’s global science and technology practice, focused on helping academic and corporate institutions design solutions that turn challenges into opportunities for success. www.cannondesign.com