Branching on multi-aggregated variables

open5siopenGamrath, Gerald; Melchiori, Anna; Berthold, Timo; Gleixner, Ambros M.; Salvagnin, DomenicoGamrath, Gerald; Melchiori, Anna; Berthold, Timo; Gleixner, Ambros M.; Salvagnin, Domenic

Spitzer, Near-Infrared, and Submillimeter Imaging of the Relatively Sparse Young Cluster, Lynds 988e

We present {\it Spitzer} images of the relatively sparse, low luminosity young cluster L988e, as well as complementary near-infrared (NIR) and submillimeter images of the region. The cluster is asymmetric, with the western region of the cluster embedded within the molecular cloud, and the slightly less dense eastern region to the east of, and on the edge of, the molecular cloud. With these data, as well as with extant H$\alpha$ data of stars primarily found in the eastern region of the cluster, and a molecular $^{13}$CO gas emission map of the entire region, we investigate the distribution of forming young stars with respect to the cloud material, concentrating particularly on the differences and similarities between the exposed and embedded regions of the cluster. We also compare star formation in this region to that in denser, more luminous and more massive clusters already investigated in our comprehensive multi-wavelength study of young clusters within 1 kpc of the Sun.Comment: 21 pages, 6 tables, 13 figures. Full resolution figures at: http://astro.pas.rochester.edu/~tom/Preprints/L988e.pd

Participatory Rulemaking in State Government: A Managed Care Success Story

In June 1997, the Missouri Department of Insurance ( DOI ) was presented with a massive undertaking: implementation of Senate Substitute for Senate Committee Substitute for House Substitute for House Committee Substitute for House Bill 335 ( HB 335 ). The bill enacted sweeping reforms of the managed health care system, incorporating some of the strongest consumer protections in the country. Prior to 1997, the DOI\u27s authority over managed care, and hence its expertise, was limited. Furthermore, the bill contained a variety of controversial and complex issues, so implementation of the legislation was certain to be difficult both politically and technically. This Comment examines the rulemaking process as established by the Missouri Administrative Procedure Act and the costs and benefits that an extensive, participatory process for rulemaking may have for state agencies, the public, and the regulated industry. Specifically, this Comment will focus on the participatory process leading up to the promulgation of three rules generated as a result of the passage of HB 335. The participatory process for the three rules-concerning a standardized credentialing form, the delivery of prescription drugs, and the adequacy of a Health Maintenance Organization\u27s ( HMO\u27s ) network of health care providers-yielded very different experiences. In general, the process was invaluable to the DOI in the development of implementing rules and is highly recommended to agencies considering rules to put into effect legislative enactments

Enteric Neurospheres Are Not Specific to Neural Crest Cultures: Implications for Neural Stem Cell Therapies

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited

DHODH modulates transcriptional elongation in the neural crest and melanoma

Melanoma is a tumour of transformed melanocytes, which are originally derived from the embryonic neural crest. It is unknown to what extent the programs that regulate neural crest development interact with mutations in the BRAF oncogene, which is the most commonly mutated gene in human melanoma1. We have used zebrafish embryos to identify the initiating transcriptional events that occur on activation of human BRAF(V600E) (which encodes an amino acid substitution mutant of BRAF) in the neural crest lineage. Zebrafish embryos that are transgenic for mitfa:BRAF(V600E) and lack p53 (also known as tp53) have a gene signature that is enriched for markers of multipotent neural crest cells, and neural crest progenitors from these embryos fail to terminally differentiate. To determine whether these early transcriptional events are important for melanoma pathogenesis, we performed a chemical genetic screen to identify small-molecule suppressors of the neural crest lineage, which were then tested for their effects on melanoma. One class of compound, inhibitors of dihydroorotate dehydrogenase (DHODH), for example leflunomide, led to an almost complete abrogation of neural crest development in zebrafish and to a reduction in the self-renewal of mammalian neural crest stem cells. Leflunomide exerts these effects by inhibiting the transcriptional elongation of genes that are required for neural crest development and melanoma growth. When used alone or in combination with a specific inhibitor of the BRAF(V600E) oncogene, DHODH inhibition led to a marked decrease in melanoma growth both in vitro and in mouse xenograft studies. Taken together, these studies highlight developmental pathways in neural crest cells that have a direct bearing on melanoma formation

Ponatinib in patients with refractory acute myeloid leukaemia: findings from a phase 1 study

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99099/1/bjh12382.pd

Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML

Occurrence of the BCR-ABL[superscript T315I] gatekeeper mutation is among the most pressing challenges in the therapy of chronic myeloid leukemia (CML). Several BCR-ABL inhibitors have multiple targets and pleiotropic effects that could be exploited for their synergistic potential. Testing combinations of such kinase inhibitors identified a strong synergy between danusertib and bosutinib that exclusively affected CML cells harboring BCR-ABL[superscript T315I]. To elucidate the underlying mechanisms, we applied a systems-level approach comprising phosphoproteomics, transcriptomics and chemical proteomics. Data integration revealed that both compounds targeted Mapk pathways downstream of BCR-ABL, resulting in impaired activity of c-Myc. Using pharmacological validation, we assessed that the relative contributions of danusertib and bosutinib could be mimicked individually by Mapk inhibitors and collectively by downregulation of c-Myc through Brd4 inhibition. Thus, integration of genome- and proteome-wide technologies enabled the elucidation of the mechanism by which a new drug synergy targets the dependency of BCR-ABL[superscript T315I] CML cells on c-Myc through nonobvious off targets