Duplicate Points Research Articles

Partitioning for Enhanced Statistical Power and Noise Reduction: Comparing One-Way and Repeated Measures Analysis of Variance (ANOVA).

Using simulated data with duplicate observational data points, this researchaims to highlight the notable efficiency of repeated measures analysis of variance (ANOVA) compared to one-way ANOVA as a more powerful statistical model.One of the principal advantages of repeated measures ANOVA is its design, in which each subject acts as their own control. This methodology allows for the statistical mitigation of individual differences among subjects, thereby reducing extraneous variability (noise) that can obscure the effects of the experimental conditions under investigation. By employing identical simulated column values within this analysis, we observe that the F-statistic generated by the repeated measures ANOVA tends to be larger than that derived from the one-way ANOVA. A distinguishing feature of repeated measures ANOVA is its incorporation of an additional dimension of within-subject variation in its partitioning procedure. This acknowledges that measurements taken from the same subject are inherently correlated. This correlation introduces a separate source of partitioned variation, distinct from that attributable to between-subject differences. The term SSBetween x Withinencapsulates the residual variation that remains after accounting for both group differences and individual subject discrepancies. By explicitly recognizing the interrelatedness of measurements collected from the same subjects, repeated measures ANOVA effectively reduces the residual error variation contributing to the denominator in calculating the F-statistic. This reduction in error variation (noise) results in a more sensitive statistical test than one-way ANOVA, thus enhancing the power of the analysis. Consequently, the ability of repeated measures ANOVA to account for the correlated nature of repeated observations not only yields a more robust estimation of the treatment effects but also fortifies the statistical conclusions drawn from the data.

Calibrations without raw data-A response to "Seasonal calibration of the end-cretaceous Chicxulub impact event".

A recent article by DePalma et al. reported that the season of the End-Cretaceous mass extinction was confined to spring/summer on the basis of stable isotope analyses and supplementary observations. An independent study that was concurrently under review reached a similar conclusion using osteohistology and stable isotope analyses. We identified anomalies surrounding the stable isotope analyses reported by DePalma et al. Primary data are not provided, the laboratory where the analyses were performed is not identified, and the methods are insufficiently specified to enable accurate replication. Furthermore, isotopic graphs for carbon and oxygen contain irregularities such as missing data points, duplicate data points, and identical-length error bars for both elements despite different scales, that appear inconsistent with laboratory instrument outputs. A close examination of such methodological omissions and data irregularities can help to raise the standards for future studies of seasonality and prevent inaccurate claims or confirmation bias.

An Improvement Method for Improving the Surface Defect Detection of Industrial Products Based on Contour Matching Algorithms.

Aiming at the problems of the poor robustness and universality of traditional contour matching algorithms in engineering applications, a method for improving the surface defect detection of industrial products based on contour matching algorithms is detailed in this paper. Based on the image pyramid optimization method, a three-level matching method is designed, which can quickly obtain the candidate pose of the target contour at the top of the image pyramid, combining the integral graph and the integration graph acceleration strategy based on weak classification. It can quickly obtain the rough positioning and rough angle of the target contour, which greatly improves the performance of the algorithm. In addition, to solve the problem that a large number of duplicate candidate points will be generated when the target candidate points are expanded, a method to obtain the optimal candidate points in the neighborhood of the target candidate points is designed, which can guarantee the matching accuracy and greatly reduce the calculation amount. In order to verify the effectiveness of the algorithm, functional test experiments were designed for template building function and contour matching function, including uniform illumination condition, nonlinear condition and contour matching detection under different conditions. The results show that: (1) Under uniform illumination conditions, the detection accuracy can be maintained at about 93%. (2) Under nonlinear illumination conditions, the detection accuracy can be maintained at about 91.84%. (3) When there is an external interference source, there will be a false detection or no detection, and the overall defect detection rate remains above 94%. It is verified that the proposed method can meet the application requirements of common defect detection, and has good robustness and meets the expected functional requirements of the algorithm, providing a strong technical guarantee and data support for the design of embedded image sensors in the later stage.

Fast subsampling strategy for point cloud based on novel octree coding

Owing to the continuous expansion in data scale, the calculation, storage, and transmission of 3D data have been plagued by numerous issues. The point cloud data, in particular, often contain duplicated and anomalous points, which can hinder tasks such as measurement. To address this issue, it is crucial to utilize point cloud pre-processing methods that combine subsampling and denoising. These methods help obtain clean, evenly distributed, and compact points to enhance the accuracy of the data. In this study, an efficient point cloud subsampling method is proposed that combines point cloud denoising capabilities. This method can effectively preserve salient features while improving the quality of point cloud data. By constructing the octree structure of the point cloud, the corresponding node code is obtained according to the spatial coordinates of the point cloud, and the feature vector of the node is calculated based on the analysis of covariance. Node feature similarity is introduced to distinguish the node into feature and non-feature nodes, forming the node feature code, and the layer threshold is introduced to filter outliers. Experimental results demonstrate that our proposed algorithm has a time ratio of over four compared to the curvature-based algorithm. Additionally, it exhibits an average grey entropy that is 1.6×e−3 lower than that of the random sampling method. And considering both time cost and subsampling effectiveness, proposed algorithm outperforms the state-of-the-art subsampling strategies, such as Approximate Intrinsic Voxel Structure and SampleNet. This approach is effective in removing noise while preserving important features, thereby reducing overall size of the point cloud. The high computational efficiency of our algorithm makes it a valuable reference for fast and precise measurements that require timeliness. It successfully addresses the challenges posed by the continuous expansion of data scale and offers significant advantages over existing subsampling methods. By improving the quality of point cloud data, our algorithm contributes to reducing complexity, enables efficient and accurate measurements.

Spatial pattern consistency and repeatability of proximal soil sensor data for digital soil mapping

AbstractData from proximal soil sensors can facilitate digital soil mapping at high spatial resolutions. However, their use for predicting static soil properties, such as texture, is affected by spatio‐temporal changes in environmental and measurement conditions. In this research study, seasonal changes in spatial patterns and repeatability of data provided by a platform that simultaneously measures the red (Red) and near infrared (NIR) reflectance, apparent soil electrical conductivity (ECa), temperature, and volumetric moisture content of topsoil (at 3–6 cm depth) were assessed. Test fields are located in Southern Finland with textures dominated by clay and fine sandy till. During single scans, mean relative differences between the data from duplicated measurement points ranged from ~4% to 6% and were the highest for temperature and Red values. The consistency of spatial patterns across seasons (spring and autumn 2021 and 2022) was the highest for ECa values, and the lowest for NIR. ECa and moisture were significant for predicting the clay contents at a cereal grain crop site, whereas temperature was significant at grass ley sites. Errors were generally lower when using spring data compared with autumn data (RMSE ranging from 4.8% to 11.1% for the data from different fields and measurement dates). For the fields, where static soil properties change at small spatial scales, spatially detailed moisture and temperature data support the understanding of seasonal changes in the spatial patterns derived from multi‐sensor data, and the corresponding changes in the performance of calibration models.

A 3D shape measurement method for high-reflective surface based on dual-view multi-intensity projection

Phase shifting profilometry has been commonly used in three-dimensional shape measurement with the advantages of high-precision and non-contact. However, it is still challenging to measure high-reflective surface because image saturation will lead to absolute phase errors and reconstruction errors. In this paper, a dual-view multi-intensity projection method was proposed. Compared with the single-view method, the proposed method can reconstruct more points at each projection intensity especially for pixels around the specular angle and reduce the number of projections to reduce the time consumption. First, we established the dual-view structured light system consisting of two monocular systems that share the same projector. Subsequently, a dual-view saturated pixel judging method was proposed that enables the reconstruction results under two views to be combined without duplicate points. The multi-intensity projection method was adopted by reducing the input projection intensity step by step and reconstructing the remaining pixels around the specular angle. Finally, the reconstruction result can be obtained by stitching point clouds at each projection intensity. Experiments verified that the proposed method could improve the integrity of reconstructed point clouds and measurement efficiency.

Retraction: Cajanonic acid A regulates the ratio of Th17/Treg via inhibition of expression of IL-6 and TGF-β in insulin-resistant HepG2 cells.

This Retraction follows an Expression of Concern relating to this article previously published by Portland Press.This article is being retracted from Bioscience Reports at the request of the Editor-in-Chief and the Editorial following receipt of a notification from a reader, alerting the Editorial Board to multiple duplicate data points in the images from Figure 3A. Upon further examination by the Editorial Office, additional clusters of duplicated data points were also noted in in Figure 3F and 4C.The authors have been contacted in regards to the retraction, and were unable to provide the Editorial Office with the original data which they stated was obtained using equipment from another laboratory, which can no longer be accessed/retrieved due to equipment issues. Given the extent of the issues raised, the Editorial Board stand by the decision to retract the article. The authors agree to the Retraction.

Assessment of the Influence of Sulfuric Acid/Hydrogen Peroxide Mixture on Organic Sulfur Reduction of High Sulfur Coals and Their Chemical Composition

One of the contaminants in coal is sulphur. The adverse impact of sulfur on coal, such as environmental pollution, degradation of steel quality, and reduction of coal’s thermal value, has led to the attention of sulfur separation methods in recent decades. Leaching (chemical dissolution) is one of the best methods for desulfurising coal, reducing sulfur in coal. In this study, hydrogen peroxide as an oxidising agent on sulfuric acid yield in reducing sulfur types of coal and chemical structure and the organic texture of high sulfur coal was investigated. The experiments were designed using a three-level response surface methodology with four duplicate points and 27 experiments. The independent variables studied were temperature, time, stirring speed and ratio of sulfuric acid to hydrogen peroxide. Dependent variables included reduction percentage of total, pyritic and organic sulfur. This study showed that 99.99% of total sulfur, 30.11% of pyritic sulfur and 69.08% of organic sulfur were reduced. These values were obtained at a temperature of 60°C, time 120 min, stirring speed 200 rpm and 3:1 ratio of sulfuric acid to hydrogen peroxide. Significant changes were observed by infrared spectroscopy (FTIR) of the coal structure before and after desulphurisation. On the other hand, the studies showed no specific changes in the bonds related to the organic coal matrix. The results showed that this method could be used as a secure process for removing inorganic and organic sulfur without destroying the organic coal matrix.

FLT3-Mutated Acute Myeloid Leukemia Using a Novel Regimen of Gemtuzumab Ozogamicin and Midostaurin in Combination with Standard Cytarabine and Daunorubicin Induction Therapy

FLT3-Mutated Acute Myeloid Leukemia Using a Novel Regimen of Gemtuzumab Ozogamicin and Midostaurin in Combination with Standard Cytarabine and Daunorubicin Induction Therapy

Identity and access management using distributed ledger technology: A survey

SummaryAs the basic building block of any information security system, identity and access management (IAM) solutions play vital role in enterprise's security programmes. Providing centric solutions for IAM is inefficient in terms of having single point of failure, high cost, duplication and complexity to the users. Recently, emerging the distributed ledger technology (DLT) has attracted significant scientific interests in research areas like identity management, authentication and access control processes. In these contexts, Blockchain can offer greater data and rule confidentiality and integrity, as well as increasing the availability of the system by removing the single point of failure in the procedure. In this paper, we provide a comprehensive overview of the IAM solutions based on their basic components including identity management, authentication and access control. In the identity concept, we discuss about self‐sovereign identity which enhances privacy and security of distributed digital identities by providing individual's consolidated digital identity and verified attributes for enabling them to utilize their ownership. To offer a clearer understanding of the state of the art, we propose taxonomy to categorize them based on their features. For the conclusion of the paper, we compare the existing methods based on proposed taxonomy. Also, considering the advantages and disadvantages of existing methods, we discussed about the possible future directions.

Nanopore sequencing sheds a light on the FLT3 gene mutations complexity in acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) patients carry in 27% of cases an activating mutation of the fms-like tyrosine kinase-3 (FLT3) gene: internal tandem duplication (ITD) or tyrosine kinase domain (TKD) point mutation. The simultaneous presence of both types of mutations, so-called FLT3 dual mutations, has been reported in 2% of APL, but this circumstance has never been studied. We studied a cohort of 74 APL cases, performing an in-depth analysis of three FLT3 dual mutant cases. Nanopore sequencing (NS) allowed us to characterize their complex mutational profile, showing the occurrence of multiple activating FLT3 mutations on different alleles in the leukemic promyelocytes and suggesting a cumulative impact of these events on the constitutive activation of the FLT3 pathway in APL cells. NS approach not only sheds light on the FLT3 mutational complexity in APL, but may also be useful to better clarify the FLT3 mutations landscape in acute myeloid leukemia.

DTOF-ANN: An Artificial Neural Network phishing detection model based on Decision Tree and Optimal Features

Recently, phishing emerges as one of the biggest threats to human’s daily networking environments. Phishing attackers disguise illegal URLs as normal ones to steal user’s private information with the social engineering techniques, such as emails and SMS, which calls for an effective method of preventing phishing attacks to relieve the loss by them. Neural networks can be used to detect and prevent phishing attacks because of their strong active learning abilities from massive datasets and high accuracy in data classification. However, duplicate points in the public datasets and negative and useless features in the feature vectors will trap the training of the neural networks into the problem of over-fitting, which will make the trained classifier weak when detect phishing websites. This paper proposes DTOF-ANN (Decision Tree and Optimal Features based Artificial Neural Network) to tackle this shortcoming, which is a neural-network phishing detection model based on decision tree and optimal feature selection. First, the traditional K-medoids clustering algorithm is improved with an incremental selection of initial centers to remove the duplicate points from the public datasets. Then, an optimal feature selection algorithm based on the new defined feature evaluation index, decision tree and local search method is designed to prune out the negative and useless features. Finally, the optimal structure of the neural network classifier is constructed through properly adjusting parameters and trained by the selected optimal features. Experimental results have demonstrated that DTOF-ANN exhibits higher performance than many of the existing methods.

Environmental Assessment of Imiringi River in South-South Nigeria: The Water Quality Index Approach

The water quality index (WQI) is important because it aids in understanding complex water quality data. Hence, WQI of Imiringi River was evaluated in order to classify quality grade of the water in unambiguous terms. Apart from seepages emanating from oil installations that are located further upstream of Oswan community, dumpsite leachates and agricultural run-offs are some of the likely nonpoint sources of pollution. Because the river ebbs away during the dry term, samples were collected in the rainy period of August 2019 at duplicate points across five field locations. Physical and chemical tests were carried out for ten (10) water samples following standard analytical protocols. Results obtained are: conductivity (32.7 ± 2.7 µs/cm), iron (2.57 ± 0.53 mg/L), dissolved solids (18.1 ± 1.4 mg/L), pH (5.2 ± 0.1), alkalinity (1.1 ± 0.1 mg/L), hardness (1.4 ± 0.2 mg/L), calcium (0.34 ± 0.03 mg/L), magnesium (2.08 ± 0.32 mg/L), dissolved oxygen (10.5 ± 0.7 mg/L), chloride (9.8 ± 0.7 mg/L), nitrate (0.12 ± 0.04 mg/L) and biochemical oxygen demand (0.36 ± 0.08 mg/L). Generally, iron and pH values fell short of regulatory standards while pH represented the most significantly varying parameter (p < 0.05) across all locations owing to human influences and dilution effects across the watercourse. Also, conductivity and dissolved solids depicted the strongest inter-parameter association. Overall, the downstream section of river revealed the poorest water quality condition while the entire river stretch was classified as being unsuitable for drinking even though it can support aquatic life.

Abstract 1293: HM43239, a novel FLT3 inhibitor in overcoming resistance for acute myeloid leukemia

Abstract Introduction: Acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 (FLT3) mutation is associated with poor prognosis with a high risk of relapse after therapy and reduced overall survival. Currently, FLT3 inhibitors have shown clinical benefits in the corresponding AML patients. Activating mutations within internal tandem duplication (ITD) and tyrosine kinase domain (TKD) point mutations of FLT3 have been reported as oncogenic driver mutations in about 30% of AML. The acquired D835Y and F691L point mutations of FLT3-TKD are associated with resistance to FLT3-targeted AML therapy. In this study, we have characterized HM43239, a novel FLT3 inhibitor, and assessed its potential as a novel therapy in overcoming resistance for AML patients. Materials and Methods: In vitro site-directed competition binding assay was performed to measure interactions between HM43239 and FLT3 mutations. Standard proliferation assay, immunoblotting, and apoptosis analysis were carried out to validate the potency of HM43239 in AML resistance cell lines. In vivo study, HM43239 was evaluated in Ba/F3 cells expressing FLT3 ITD/F691L or FLT3 ITD/D835Y xenograft mice models. Combination studies were evaluated in Acute Myeloid Leukemia xenograft mice models. Results: HM43239 potently inhibited both FLT3 ITD/D835Y and FLT3 ITD/F691L mutations in preclinical evaluation. It showed high in vitro binding affinity to both mutations, and exhibited potent inhibitory activity in in vitro and in vivo models using Ba/F3 cells expressing FLT3 ITD/D835Y or FLT3 ITD/F691L. Moreover, HM43239 could overcome the FL-induced drug resistance with a higher cytotoxic potency in MOLM-14 cells harboring FLT3 ITD. In KG-1a cells, HM43239 potently inhibited phosphorylation of SYK, STAT3 and STAT5. In addition, it inhibited the proliferation and induced the apoptosis of leukemic stem cell (LSC) marker-expressing KG1a cells (CD34+/CD38- cells), suggesting the possibility of targeting LSC. Also, HM43239 significantly inhibited p-FLT3 and p-STAT5 under normal human plasma milieu in a dose-dependent manner in Ba/F3 and MOLM-14 cell line harboring FLT3 ITD. Furthermore, the combination treatment of HM43239 with various reagents (e.g., IAP inhibitor, chemotherapy, etc) demonstrated synergistic efficacy in mouse models, xenografted with both MV-4-11 and MOLM-13 cell lines without any significant toxicity. Conclusion: Taken together, HM43239 demonstrated the potential therapeutic efficacy for the treatment of AML patients, and implicated the mechanism of overcoming resistance and preventing relapse. Citation Format: JiSook Kim, InHwan Bae, JaeYul Choi, MinJeong Kim, JooYun Byun, MiJin Moon, EunYoung Lee, Yu-Yon Kim, Hyun Jeong Kang, Eunyoung Kim, SunYoung Jung, YoungGil Ahn, YoungHoon Kim, Kwee Hyun Suh. HM43239, a novel FLT3 inhibitor in overcoming resistance for acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1293.

Evaluation of gilteritinib in combination with chemotherapy in preclinical models of FLT3-ITD+ acute myeloid leukemia.

Activating internal tandem duplication (ITD) and tyrosine kinase domain (TKD) point mutations in Fms-like tyrosine kinase 3 (FLT3) occur in approximately 30% of patients with acute myeloid leukemia (AML), and confer a poor prognosis with standard cytarabine/anthracycline or azacitidine-based chemotherapy regimens. Gilteritinib is a highly-specific, potent FLT3/AXL inhibitor with demonstrated activity against FLT3-ITD and FLT3-TKD mutations. Compared with salvage chemotherapy, treatment with once-daily oral gilteritinib demonstrated a clinical benefit in patients with FLT3-mutated relapsed/refractory AML, which led to its recent approval in Japan and the United States. We investigated the effects of gilteritinib combined with cytarabine plus daunorubicin/idarubicin, or combined with azacitidine in human FLT3-ITD–positive (FLT3-ITD+) AML cell lines and xenografted mouse models. Gilteritinib induced G1 arrest and apoptosis in a dose-dependent manner. The addition of cytarabine, daunorubicin, idarubicin, or azacitidine potentiated apoptosis. Gilteritinib alone or combined with cytarabine, daunorubicin, idarubicin, or azacitidine, inhibited anti-apoptotic protein expression in MV4-11 cells. In xenografted mice, administration of cytarabine, idarubicin, or azacitidine in combination with gilteritinib had little impact on plasma or intratumor PK profiles of gilteritinib, cytarabine, idarubicin, or azacitidine. Gilteritinib combined with chemotherapy reduced tumor volume to a greater extent than either gilteritinib or chemotherapy alone. Of note, the addition of cytarabine plus daunorubicin/idarubicin led to tumor regression in mice, with complete regression observed in six out of eight mice in both triple combination groups. These findings support the investigation of gilteritinib combined with chemotherapy in patients with FLT3-ITD+ AML, including those who are ineligible for intensive chemotherapy.

Completeness of Impact Monitoring

The completeness limit is a key quantity to measure the reliability of an impact monitoring system. It provides the impact probability threshold for which every virtual impactor (VI) with impact probability above this value has to be detected. The completeness limit depends on the confidence region sampling: a goal of this paper is to increase the completeness without increasing the computational load, thus we propose a new method to sample the Line Of Variations (LOV) with respect to the previously one used in NEODyS. The step-size of the sampling is not uniform in the LOV parameter, since the probability of each LOV segment between consecutive points is kept constant. Moreover, the sampling interval has been extended to the larger interval [−5,5] in the LOV parameter and a new decomposition scheme in sub-showers and sub-returns is provided to deal with the problem of duplicated LOV points appearing in the same return.The impact monitoring system clomon-2 has been upgraded with all these new features, resulting in a decrease of the impact probability IP* corresponding to the generic completeness limit by a factor ≃ 4 and in an increase of the computational load by a factor ≃ 2. Moreover, since the generic completeness limit is an analytic approximation, we statistically investigate the completeness actually reached by the system. For this we used two different methods: a direct comparison with the results of the independent system Sentry at JPL and an empirical power-law to model the number of virtual impactors as a function of the impact probability. We found empirically that the number of detected virtual impactors with IP > IP* appears to grow according to a power-law, proportional to IP−2/3. An analytical model explaining this power-law is currently an open problem, but we think it is related to the way the number of virtual impactors within a time trel from the first observed close approach accumulates. We give an analytical model and we prove that this cumulative number grows with a power-law proportional to trel3. The power-law allows us to detect a loss of efficiency in the virtual impactors search for impact probabilities near the generic completeness limit. The outcome of the comparison with Sentry shows that the two histograms of the number of VIs as a function of IP are very consistent for IP > IP*, which supports the confidence in the reliability of both systems.

Abstract 804: Antitumor activity of the potent and novel FLT3 inhibitor HM43239 in acute myeloid leukemia

Abstract Introduction: Acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 (FLT3) mutations is associated with poor prognosis with a high risk of relapse after therapy and reduced overall survival. Activating mutations of internal tandem duplication (ITD) and tyrosine kinase domain point mutations (TKD) of FLT3 have been reported in approximately 30% of AML as oncogenic driver mutations. Currently, FLT3 inhibitors showed clinical benefits in the corresponding AML patients. In this study, we have characterized a novel FLT3 inhibitor, HM43239, and assessed the potential as a novel therapy for AML patients. Materials and Methods: HM43239 is a novel, highly potent FLT3 kinase inhibitor. This compound showed tight binding to FLT3 kinase in in silico docking model as a reversible Type I inhibitor. In vitro kinase assay was performed to identify kinase selectivity of HM43239. Standard proliferation assay, immunoblotting, and apoptosis analysis were carried out to validate the potency of HM43239 in AML cell lines. HM43239 was evaluated in MV-4-11 and MOLM-13 xenograft mice models. Tumor sizes were measured and tumor samples were analyzed of the mechanisms of action. Results: Among 191 kinases biochemically assayed, HM43239 showed the high selectivity toward FLT3 and AML associated other kinases (e.g. SYK, JAK and TAK1). IC50s' of HM43239 against FLT3 WT, FLT3 ITD and FLT3 D835Y kinases were 1.1 nM, 1.8 nM and 1.0 nM, respectively. HM43239 potently inhibited the growth of AML cell lines harboring FLT3 ITD mutation, such as MV4-11 (IC50: 1.3 nM), MOLM-13 (5.1 nM) and MOLM-14 (2.9 nM). Furthermore, HM43239 effectively inhibited the phosphorylation levels of FLT3 and of downstream kinases related with cell proliferation. In addition, caspase 3/7-dependent apoptosis was induced by HM43239 in AML cell lines expressing FLT3 ITD mutant. And HM43239 inhibited proliferation and induced apoptosis of leukemic stem cell (LSC) marker-expressing KG1a cells (CD34+/CD38- cells) suggesting that the possibility for targeting LSC. HM43239 showed the excellent dose proportional antitumor activity in mouse models xenografted with both MV4-11 and MOLM-13 cell line without any significant toxicity. Moreover, we identified in vivo modulation of related targets (p-FLT3 & p-STAT5) in AML cell with FLT3 mutant. Conclusion: Taken together, HM43239 has demonstrated the potential therapeutic efficacy for the treatment of AML patients and implicated the mechanism of overcoming resistance and preventing relapse. Citation Format: Miyoung Lee, Young Eun Ha, Mi Jin Moon, Joo-Yun Byun, HyunKyung Yu, SeokJong Kang, JaeHo Lee, Kyuhang Lee, Eunkyung Kim, Eunyoung Kim, Ho Jeong Lee, YoungHoon Kim, YoungGil Ahn, KweeHyun Suh, Sun-Jin Kim. Antitumor activity of the potent and novel FLT3 inhibitor HM43239 in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 804.

LGG-26. TYPE II BRAF INHIBITOR TAK-580 SHOWS PROMISE FOR UPCOMING CLINAL TRIAL AS EVIDENCED BY SINGLE PATIENT IND STUDY

Abnormal signaling of the RAS/RAF pathway predominates in pediatric low-grade gliomas (PLGGs). Most (85%) non-NF1 low-grade gliomas have RAS-independent BRAF activation, either due to KIAA1549:BRAF truncated fusion duplication or V600E point mutation. We previously identified two different type II BRAF inhibitors capable of inhibiting downstream activation of pERK and tumor progression in vivo for multiple point mutations and BRAF truncated fusion forms. One compound, in particular, known as TAK-580 was active on authentic human PLGG cells ex vivo and showed excellent CNS penetration. We conducted a single patient IND study for a patient with refractory, progressive LGG. Patient was initially diagnosed at age 2 years and treated with 9 different chemotherapy regimens up until age 15 years prior to starting TAK-580. Study drug was begun orally on a QOD schedule; one cycle was comprised of 28 days. Based on both tolerance and pharmacokinetic analyses, the treatment schedule and dosing were adjusted to weekly, comparable to the adult dosing schedule. MR imaging of her tumor burden has remained stable, and patient has recently started her 33rd cycle of once weekly TAK-580. TAK-580 was well tolerated. Grade 3 and 4 likely or possibly related toxicities included acneiform rash, hyperglycemia, elevated creatinine kinase, elevated ALT and decreased phosphorus. TAK-580 posess a unique mechanism of action targeting the BRAF/MEK complex and inhibiting both BRAF point mutations and common structural abnormalities in PLGGs. These initial results support the upcoming phase I/0/II trial of TAK-580 for children with LGG and other RAS/RAF/MEK/ERK pathway activated tumors.

Regulatory remodeling in the allo-tetraploid frog Xenopus laevis

BackgroundGenome duplication has played a pivotal role in the evolution of many eukaryotic lineages, including the vertebrates. A relatively recent vertebrate genome duplication is that in Xenopus laevis, which resulted from the hybridization of two closely related species about 17 million years ago. However, little is known about the consequences of this duplication at the level of the genome, the epigenome, and gene expression.ResultsThe X. laevis genome consists of two subgenomes, referred to as L (long chromosomes) and S (short chromosomes), that originated from distinct diploid progenitors. Of the parental subgenomes, S chromosomes have degraded faster than L chromosomes from the point of genome duplication until the present day. Deletions appear to have the largest effect on pseudogene formation and loss of regulatory regions. Deleted regions are enriched for long DNA repeats and the flanking regions have high alignment scores, suggesting that non-allelic homologous recombination has played a significant role in the loss of DNA. To assess innovations in the X. laevis subgenomes we examined p300-bound enhancer peaks that are unique to one subgenome and absent from X. tropicalis. A large majority of new enhancers comprise transposable elements. Finally, to dissect early and late events following interspecific hybridization, we examined the epigenome and the enhancer landscape in X. tropicalis × X. laevis hybrid embryos. Strikingly, young X. tropicalis DNA transposons are derepressed and recruit p300 in hybrid embryos.ConclusionsThe results show that erosion of X. laevis genes and functional regulatory elements is associated with repeats and non-allelic homologous recombination and furthermore that young repeats have also contributed to the p300-bound regulatory landscape following hybridization and whole-genome duplication.

Measurement of protein backbone 13CO and 15N relaxation dispersion at high resolution

Peak overlap in crowded regions of two-dimensional spectra prevents characterization of dynamics for many sites of interest in globular and intrinsically disordered proteins. We present new three-dimensional pulse sequences for measurement of Carr-Purcell-Meiboom-Gill relaxation dispersions at backbone nitrogen and carbonyl positions. To alleviate increase in the measurement time associated with the additional spectral dimension, we use non-uniform sampling in combination with two distinct methods of spectrum reconstruction: compressed sensing and co-processing with multi-dimensional decomposition. The new methodology was validated using disordered protein CD79A from B-cell receptor and an SH3 domain from Abp1p in exchange between its free form and bound to a peptide from the protein Ark1p. We show that, while providing much better resolution, the 3D NUS experiments give the similar accuracy and precision of the dynamic parameters to ones obtained using traditional 2D experiments. Furthermore, we show that jackknife resampling of the spectra yields robust estimates of peak intensities errors, eliminating the need for recording duplicate data points.