BET inhibitors induce apoptosis through a MYC independent mechanism and synergise with CDK inhibitors to kill osteosarcoma cells

Osteosarcoma (OS) survival rates have plateaued in part due to a lack of new therapeutic options. Here we demonstrate that bromodomain inhibitors (BETi), JQ1, I-BET151, I-BET762, exert potent anti-tumour activity against primary and established OS cell lines, mediated by inhibition of BRD4. Strikingly, unlike previous observations in long-term established human OS cell lines, the antiproliferative activity of JQ1 in primary OS cells was driven by the induction of apoptosis, not cell cycle arrest. In further contrast, JQ1 activity in OS was mediated independently of MYC downregulation. We identified that JQ1 suppresses the transcription factor FOSL1 by displacement of BRD4 from its locus. Loss of FOSL1 phenocopied the antiproliferative effects of JQ1, identifying FOSL1 suppression as a potential novel therapeutic approach for OS. As a monotherapy JQ1 demonstrated significant anti-tumour activity in vivo in an OS graft model. Further, combinatorial treatment approaches showed that JQ1 increased the sensitivity of OS cells to doxorubicin and induced potent synergistic activity when rationally combined with CDK inhibitors. The greater level of activity achieved with the combination of BETi with CDK inhibitors demonstrates the efficacy of this combination therapy. Taken together, our studies show that BET inhibitors are a promising new therapeutic for OS

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Minimum Information Standards in Chemistry: A Call for Better Research Data Management Practices

Research data management (RDM) is needed to assist experimental advances and data collection in the chemical sciences. Many funders require RDM because experiments are often paid for by taxpayers and the resulting data should be deposited sustainably for posterity. However, paper notebooks are still common in laboratories and research data is often stored in proprietary and/or dead-end file formats without experimental context. Data must mature beyond a mere supplement to a research paper. Electronic lab notebooks (ELN) and laboratory information management systems (LIMS) allow researchers to manage data better and they simplify research and publication. Thus, an agreement is needed on minimum information standards for data handling to support structured approaches to data reporting. As digitalization becomes part of curricular teaching, future generations of digital native chemists will embrace RDM and ELN as an organic part of their research

MPS FAIR Hackathon

FAIR Hackathon for Mathematical and Physical Sciences (MPS) Research Communities, Alexandria, VA Feb 27-28, 201

Technique [Volume 88, Issue 5]

2002 Georgia Tech FootballAtlanta offers many options for movie loversAutopilot Off performs positive punk music at the Warped TourBiomedical professor looks to a future without castsBoard of Regents approves new Tech degree programsbubbleCampus housing provides various entertainment outletsChem researchers utilize "shared" computingCity hosts hidden jewels of cultural offeringsCS investigation leads to changesDirty Vegas mixes pop and techno, with good resultsFaces at Georgia TechFerst wall of fame preserves arts historyFor the love of the gameFreshman Survival: 99 things to do before you graduateFreshman Survival: George P. Burdell legend over 80 years oldFreshman Survival: Getting involved can be easy, funFreshman Survival: Music tradition alive todayFreshman Survival: Public transportation provides alternativesFreshman Survival: Students maintain Tech's mechanical mascotFreshman Survival: Tech students change majors frequentlyFreshman Survival: You certainly won't find these in Webster's...Gailey's road leads to homeHightower demolition to take two monthsHinkel's column beneficial to TechInstitute defines 'technological community'Jackets impressed with width of worldLibrary renovations completeNews BriefsNo car? Nearby Midtown eats can fit the stingiest budgetOIT revamps Tech email systemOUR VIEWS Consensus OpinionPresident Massey encourages students to get involved while at TechProgram looks to attract new leadersRegents approve tuition increaseResnet unviels new improvementsSAC undergoes a new faceliftSmog strangles city as Tech profs combat the problemState, Tech wrestle with fake ID issueTechnique CredoTech offers variety of dining options for students living on campusTech profs expose fuzzy accountingThe Aussie heads homeThe year in sports: Tech teams triumph...Two BitsWeis resigns as parking headWhat is the Technique?With new attractions, city may never slee

Hematopoietic stem and progenitor cell-restricted Cdx2 expression induces transformation to myelodysplasia and acute leukemia

The caudal-related homeobox transcription factor CDX2 is expressed in leukemic cells but not during normal blood formation. Retroviral overexpression of Cdx2 induces AML in mice, however the developmental stage at which CDX2 exerts its effect is unknown. We developed a conditionally inducible Cdx2 mouse model to determine the effects of in vivo, inducible Cdx2 expression in hematopoietic stem and progenitor cells (HSPCs). Cdx2-transgenic mice develop myelodysplastic syndrome with progression to acute leukemia associated with acquisition of additional driver mutations. Cdx2-expressing HSPCs demonstrate enrichment of hematopoietic-specific enhancers associated with pro-differentiation transcription factors. Furthermore, treatment of Cdx2 AML with azacitidine decreases leukemic burden. Extended scheduling of low-dose azacitidine shows greater efficacy in comparison to intermittent higher-dose azacitidine, linked to more specific epigenetic modulation. Conditional Cdx2 expression in HSPCs is an inducible model of de novo leukemic transformation and can be used to optimize treatment in high-risk AML