Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma

The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a pediatric cancer in which MYCN amplification is strongly associated with unfavorable outcome. Here, we show that CYC065 (fadraciclib), a clinical inhibitor of CDK9 and CDK2, selectively targeted MYCN-amplified neuroblastoma via multiple mechanisms. CDK9 — a component of the transcription elongation complex P-TEFb — bound to the MYCN-amplicon superenhancer, and its inhibition resulted in selective loss of nascent MYCN transcription. MYCN loss led to growth arrest, sensitizing cells for apoptosis following CDK2 inhibition. In MYCN-amplified neuroblastoma, MYCN invaded active enhancers, driving a transcriptionally encoded adrenergic gene expression program that was selectively reversed by CYC065. MYCN overexpression in mesenchymal neuroblastoma was sufficient to induce adrenergic identity and sensitize cells to CYC065. CYC065, used together with temozolomide, a reference therapy for relapsed neuroblastoma, caused long-term suppression of neuroblastoma growth in vivo, highlighting the clinical potential of CDK9/2 inhibition in the treatment of MYCN-amplified neuroblastoma

SCENARIO BUILDING AS A TOOL FOR PLANNING A SUSTAINABLE TRANSPORTATION SYSTEM

This paper suggests a scenario approach to identify policies that will result in a sustainable transportation system and applies the approach to explore the future development of the Tel-Aviv metropolitan area (TAMA). The authors have constructed two scenarios for the future development of the TAMA: an expected scenario and a desired scenario. The scenarios were constructed by means of a two-round Delphi expert-based survey. Based on the opinion of the experts, the research examines potential policy measures, which may contribute to a sustainable transportation system in Tel-Aviv. The development of both expected and desired scenarios helped to analyze the feasibility of the desired scenario and assess the likelihood of implementation of its different elements. Results show that a combination of policy measures is necessary in order to achieve a sustainable transportation system for the TAMA, with land uses and technological measures being vital elements, and economic and governmental measures playing a secondary role. Key elements in the desired scenario are a highly developed public transportation system, better coordination between the spatial development and the transportation system, high parking fees, congestion pricing and maintaining the functional role of the central business district. The main elements in the desired scenario are also probable, as indicated by the expected scenario. This suggests that a sustainable development of the transportation system in Tel-Aviv is a realistic vision. The Delphi method used in this study appears to be an efficient tool for long range planning

Time-series model for vehicle speeds

This paper presents a time-series model for the spot speeds of vehicles on a road section. Based on time-series analysis techniques, the model incorporates information on the extent of existing dependency between the speeds of successive vehicles. The model for the data is chosen while relying heavily on the data, and thus emphasis is given to their special characteristics. The advantages of using the model are examined with regard to the relative speed of two successive vehicles along a road section. The results are compared with those obtained by using a model of independent observations; fewer errors are obtained with the time-series model. Therefore, it is concluded that the sequence of speed observations contains valuable information which should be incorporated into speed models.