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Background: Deregulated Notch signaling is implicated in T‐cell acute lymphoblastic leukemia (T‐ALL)/T‐cell lymphoblastic lymphoma (T‐LBL). Crenigacestat (LY3039478) prevents cleavage of Notch proteins and may benefit patients with relapsed/refractory T‐ALL/T‐LBL. Methods: JJCB was a multicenter, nonrandomized, open‐label, dose‐escalation, phase 1 study in adult patients with relapsed/refractory T‐ALL/T‐LBL. Eligible patients received Crenigacestat orally 3 times per week plus dexamethasone at 24 mg twice daily on days 1 to 5 every other week in a 28‐day cycle. The starting level of Crenigacestat was 50 mg, and dose escalation was performed with a modified 3+3 scheme for the estimation of dose‐limiting toxicity (DLT) at the recommended dose level. Results: In total, 36 patients with T‐ALL (n = 31 [86.1%]) or T‐LBL (n = 5 [13.9%]) were treated with Crenigacestat and dexamethasone. Six patients (16.7%) experienced DLTs: 2 of 12 (16.7%) in the 75‐mg cohort (grade 4 gastrointestinal hemorrhage and grade 3 nausea, vomiting, and diarrhea), 1 of 15 (6.7%) in the 100‐mg cohort (grade 3 diarrhea), and 3 of 3 (100%) in the 125‐mg cohort (grade 3 diarrhea, nausea, and vomiting). The maximum tolerated dosewas 75 mg plus 24 mg of dexamethasone daily on days 1 to 5. Twenty‐eight patients (77.8%) experienced 1 or more treatment‐emergent adverse events related to the study treatment. The best overall response was a confirmed response, with 1 patient (2.8%) having a duration of response of 10.51 months. Six patients (16.7%) achieved stable disease, and 12 patients (33.3%) experienced progressive disease. The remaining 17 patients (47.2%) were not evaluable. The median event‐free survival was 1.18 months (95% confidence interval, 0.76‐2.14 months) among all groups. A pharmacodynamic analysis showed decreased plasma amyloid β levels. Conclusions: Crenigacestat demonstrated limited clinical activity at the recommended dose in adult patients with relapsed/refractory T‐ALL/T‐LBL. This report describes the clinical activity of a highly potent and selective Notch inhibitor, Crenigacestat, in combination with dexamethasone in adult patients with relapsed/refractory T‐cell acute lymphoblastic leukemia (T‐ALL)/T‐cell lymphoblastic lymphoma (‐LBL). In this study, the recommended phase 2 dose of 75 mg of Crenigacestat 3 times per week is established for patients with T‐ALL/T‐LBL in combination with dexamethasone. [ABSTRACT FROM AUTHOR]

The k‐means algorithm is arguably the most popular nonparametric clustering method but cannot generally be applied to datasets with incomplete records. The usual practice then is to either impute missing values under an assumed missing‐completely‐at‐random mechanism or to ignore the incomplete records, and apply the algorithm on the resulting dataset. We develop an efficient version of the k‐means algorithm that allows for clustering in the presence of incomplete records. Our extension is called km‐means and reduces to the k‐means algorithm when all records are complete. We also provide initialization strategies for our algorithm and methods to estimate the number of groups in the dataset. Illustrations and simulations demonstrate the efficacy of our approach in a variety of settings and patterns of missing data. Our methods are also applied to the analysis of activation images obtained from a functional magnetic resonance imaging experiment. [ABSTRACT FROM AUTHOR]

Seminal roots of maize are pivotal for early seedling establishment. The maize mutant rootless concerning crown and seminal roots (rtcs) is defective in seminal root initiation during embryogenesis. In this study, the transcriptomes of wild-type and rtcs embryos were analyzed by RNA-Seq based on histological results at three stages of seminal root primordia formation. Hierarchical clustering highlighted that samples of each genotype grouped together along development. Determination of their gene activity status revealed hundreds of genes specifically transcribed in wildtype or rtcs embryos, while K-mean clustering revealed changes in gene expression dynamics between wild-type and rtcs during embryo development. Pairwise comparisons of rtcs and wild-type embryo transcriptomes identified 131 transcription factors among 3526 differentially expressed genes [false discovery rate (FDR) <5% and llog2Fcl≥1]. Among those, functional annotation highlighted genes involved in cell cycle control and phytohormone action, particularly auxin signaling. Moreover, in silico promoter analyses identified putative RTCS target genes associated with transcription factor action and hormone metabolism and signaling. Significantly, non-syntenic genes that emerged after the separation of maize and sorghum were over-represented among genes displaying RTCS-dependent expression during seminal root primordia formation. This might suggest that these non-syntenic genes came under the transcriptional control of the syntenic gene rtcs during seminal root evolution. Taken together, this study provides first insights into the molecular framework underlying seminal root initiation in maize and provides a starting point for further investigations of the molecular networks underlying RTCS-dependent seminal root initiation. [ABSTRACT FROM AUTHOR]

The adaptability of root system architecture to unevenly distributed mineral nutrients in soil is a key determinant of plant performance. The molecular mechanisms underlying nitrate dependent plasticity of lateral root branching across the different root types of maize are only poorly understood. In this study, detailed morphological and anatomical analyses together with cell type-specific transcriptome profiling experiments combining laser capture microdissection with RNA-seq were performed to unravel the molecular signatures of lateral root formation in primary, seminal, crown, and brace roots of maize (Zea mays) upon local high nitrate stimulation. The four maize root types displayed divergent branching patterns of lateral roots upon local high nitrate stimulation. In particular, brace roots displayed an exceptional architectural plasticity compared to other root types. Transcriptome profiling revealed root type-specific transcriptomic reprogramming of pericycle cells upon local high nitrate stimulation. The alteration of the transcriptomic landscape of brace root pericycle cells in response to local high nitrate stimulation was most significant. Root type-specific transcriptome diversity in response to local high nitrate highlighted differences in the functional adaptability and systemic shoot nitrogen starvation response during development. Integration of morphological, anatomical, and transcriptomic data resulted in a framework underscoring similarity and diversity among root types grown in heterogeneous nitrate environments. [ABSTRACT FROM AUTHOR]

Maize develops a complex root system composed of embryonic and post-embryonic roots. Spatio-temporal differences in the formation of these root types imply specific functions during maize development. A comparative transcriptomic study of embryonic primary and seminal, and post-embryonic crown roots of the maize inbred line B73 by RNA sequencing along with anatomical studies were conducted early in development. Seminal roots displayed unique anatomical features, whereas the organization of primary and crown roots was similar. For instance, seminal roots displayed fewer cortical cell files and their stele contained more meta-xylem vessels. Global expression profiling revealed diverse patterns of gene activity across all root types and highlighted the unique transcriptome of seminal roots. While functions in cell remodeling and cell wall formation were prominent in primary and crown roots, stress-related genes and transcriptional regulators were over-represented in seminal roots, suggesting functional specialization of the different root types. Dynamic expression of lignin biosynthesis genes and histochemical staining suggested diversification of cell wall lignification among the three root types. Our findings highlight a cost-efficient anatomical structure and a unique expression profile of seminal roots of the maize inbred line B73 different from primary and crown roots. [ABSTRACT FROM AUTHOR]

Copy-number alterations are widespread in animal and plant genomes, but their immediate impact on gene expression is still unclear. In animals, copy-number alterations usually exhibit dosage effects, except for sex chromosomes which tend to be dosage compensated. In plants, genes within small duplications (,100 kb) often exhibit dosage-dependent expression, whereas large duplications (.50 Mb) are more often dosage compensated. However, little or nothing is known about expression in moderately-sized (1-50 Mb) segmental duplications, and about the response of small RNAs to dosage change. Here, we compared maize (Zea mays) plants with two, three, and four doses of a 14.6-Mb segment of chromosome 1 that contains ∼300 genes. Plants containing the duplicated segment exhibit dosage-dependent effects on ear length and flowering time. Transcriptome analyses using GeneChip and RNA-sequencing methods indicate that most expressed genes and unique small RNAs within the duplicated segments exhibit dosage-dependent transcript levels. We conclude that dosage effect is the predominant regulatory response for both genes and unique small RNA transcripts in the segmental dosage series we tested. To our knowledge this is the first analysis of small RNA expression in plant gene dosage variants. Because segmental duplications comprise a significant proportion of eukaryotic genomes, these findings provide important new insight into the regulation of genes and small RNAs in response to dosage changes. [ABSTRACT FROM AUTHOR]