Facioscapulohumeral muscular dystrophy (FSHD) is caused by the loss of repression at the D4Z4 locus leading to aberrant double homeobox 4 (DUX4) expression in skeletal muscle. Activation of this early embryonic transcription factor results in the expression of its target genes causing muscle fiber death. Although progress toward understanding the signals driving DUX4 expression has been made, the factors and pathways involved in the transcriptional activation of this gene remain largely unknown. Here, we describe the identification and characterization of p38a as a novel regulator of DUX4 expression in FSHD myotubes. By using multiple highly characterized, potent, and specific inhibitors of p38a/b, we show a robust reduction of DUX4 expression, activity, and cell death across patient-derived FSHD1 and FSHD2 lines. RNA-seq profiling reveals that a small number of genes are differentially expressed upon p38a/b inhibition, the vast majority of which are DUX4 target genes. Our results reveal a novel and apparently critical role for p38a in the aberrant activation of DUX4 in FSHD and support the potential of p38a/b inhibitors as effective therapeutics to treat FSHD at its root cause. SIGNIFICANCE STATEMENT Using patient-derived facioscapulohumeral muscular dystrophy (FSHD) myotubes, we characterize the pharmacological relationships between p38a/b inhibition, double homeobox 4 (DUX4) expression, its downstream transcriptional program, and muscle cell death. p38a/b inhibition results in potent and specific DUX4 downregulation across multiple genotypes without significant effects in the process of myogenesis in vitro. These findings highlight the potential of p38a/b inhibitors for the treatment of FSHD, a condition that today has no approved therapies.
This paper presents the results of two experimental evaluations of transitional jobs programs for recently released former prisoners: the Evaluation of the Center for Employment Opportunities (CEO) and the Transitional Jobs Reentry Demonstration (TJRD). The analysis assesses the effects of these programs on employment and recidivism. We find that the programs in both studies led to a large increase in employment driven by the transitional jobs themselves. However, the programs did not increase employment in non-program jobs. In addition, the CEO transitional jobs program reduced recidivism, but the TJRD programs did not. These results have implications for policy and research.
JEL Classification Code: J24
Keywords: 12FSHD, facioscapulohumeral dystrophy, muscular dystrophy, DUX4, p38, p38 alpha, mitogen-13 activated protein kinase, MAPK14, MAPK, SAPK, myogenesis, microsatellite, D4Z4 repeats, 14 small molecule, inhibitor. 15 16 SUMMARY 17 FSHD is caused by the loss of repression at the D4Z4 locus leading to DUX4 expression in 18 skeletal muscle, activation of its early embryonic transcriptional program and muscle fiber death. 19While progress toward understanding the signals driving DUX4 expression has been made, the 20 factors and pathways involved in the transcriptional activation of this gene remain largely 21 unknown. Here, we describe the identification and characterization of p38α as a novel regulator 22 of DUX4 expression in FSHD myotubes. By using multiple highly characterized, potent and 23 specific inhibitors of p38α/β, we show a robust reduction of DUX4 expression, activity and cell 24 death across FSHD1 and FSHD2 patient-derived lines. RNA-seq profiling reveals that a small 25 number of genes are differentially expressed upon p38α/β inhibition, the vast majority of which 26 are DUX4 target genes. Our results reveal a novel and apparently critical role for p38a in the 27 aberrant activation of DUX4 in FSHD and support the potential of p38α/β inhibitors as effective 28 therapeutics to treat FSHD at its root cause. 29
3587 Background: KRAS mutated metastatic colorectal cancer (mCRC) is inherently resistant to EGFR targeted therapy and carries an inferior prognosis to wild-type disease with a median survival of approximately 16 months. Methods: The activity of dalotuzumab (Dz) has been investigated in KRAS mutant pre-clinical colon cancer models. In addition efficacy data relating to a sub-set of KRAS mutant mCRC patients enrolled in a randomized phase II/III study (initiated prior to the introduction of KRAS genotyping) of Dz in combination with cetuximab (Cx) and irinotecan (Ir) are reported. All patients had received Cx and Ir with either placebo (n=20), weekly Dz (n=18), or 2 weekly Dz (n=31). Results: In pre-clinical models, Dz was found to be effective in inhibiting IGF-1 mediated cellular growth. Furthermore, in colorectal cancer xenograft models high IGF-1 was found to identify a sub-set of Dz responsive tumours. Combination studies demonstrated that Irinotecan exposure resulted in the activation of IGF-1R and PI3K signaling pathways, representing a possible cellular survival mechanism. In xenograft models the combination of Dz with irinotecan produced lasting tumor growth inhibition that persisted even after treatment withdrawal. Outcome data are reported for 69 patients with KRAS mutant mCRC enrolled in the randomized study. Efficacy data demonstrated differential activity between colon versus rectal tumours with evidence of activity in the rectal subgroup. Molecular analysis suggests that this observation may be mediated by differential IGF-1 expression. Conclusions: These data suggest that Dz in combination with irinotecan may have utility in the treatment of KRAS mutated colorectal cancer patients. Based on these data Dz is being further evaluated in a molecularly selected population of mCRC. [Table: see text]
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.