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Purpose: Activated Notch receptor signaling has been implicated in tumor growth and progression in colorectal cancer (CRC). However, the pathogenic relevance of NOTCH gene alterations remains unclear. The aim of this study was to clarify mutational landscapes and assess their clinical significance in patients with metastatic CRC. Methods: Pre-chemotherapy tumor tissues obtained from 1154 metastatic CRC patients in the Nationwide Cancer Genome Screening Project in Japan between April 2017 and March 2019 were studied using the Oncomine Comprehensive Assay. Results: The frequencies of NOTCH1, NOTCH2, and NOTCH3 nonsynonymous sequence variants were 11.5%, 4.4%, and 10.4%, respectively. The majority of variants were missense of unknown significance that were distributed across all domains of all three NOTCH genes. The gain-of-function mutations in NOTCH reported in multiple malignancies were not identified. The NOTCH amplification rate was less than 1%. No NOTCH fusions were detected. In patients who were registered before, or within 1 year of, first-line chemotherapy, overall survival for 51 patients with only NOTCH3 variants was significantly longer than for 540 patients with no NOTCH variants (median, 40.2 months vs 27.7 months; P = 0.04). Multivariate analysis revealed that variant NOTCH3 was an independent prognostic factor for increased survival (hazard ratio 0.61, 95% confidence interval, 0.39–0.94; P = 0.03) besides poor prognostic factors associated with mutant TP53, KRAS, and BRAF, as well as amplified MYC. Conclusion: NOTCH genes are unlikely to harbor driver mutations and amplifications in patients with metastatic CRC. NOTCH3 variant should be further investigated as a favorable prognostic marker. [ABSTRACT FROM AUTHOR]

Background: Although several randomized trials (RCTs) showed survival benefits of immune checkpoint inhibitor (ICI) plus first-line chemotherapy for advanced gastric or gastroesophageal cancer (AGC), these trials could enroll patients who fulfilled the strict eligibility criteria or waited for certain screening period for central assessment of PD-L1 status. Methods: We retrospectively compared characteristics and clinical outcomes of the patients with AGC who received first-line chemotherapy in control arm of RCTs with ICIs (control group) or clinical practice (practice group) at our institution from February 2016 to April 2019. Results: The control group had a better baseline Eastern Cooperative Oncology Group performance status (PS0, 81.2% vs. 51.4%, p < 0.001) and a longer interval from first visit to first-line chemotherapy initiation (19 days vs. 9 days, p < 0.001) than the practice group. Median overall survival (OS) was 20.3 months in control group and 15.7 months in practice group, with a trend of longer OS in control group than that in practice group (hazard ratio, 0.71; p = 0.062). More patients in control group were treated with subsequent chemotherapy including ICIs. Conclusion: Patients with AGC in RCTs of ICIs had a better PS or a higher chance to receive subsequent chemotherapy, resulting in a better prognosis than those treated in clinical practice. This information should be considered when interpreting RCT results and applying new treatments into clinical practice. [ABSTRACT FROM AUTHOR]

In birds, sex is determined through cell-autonomous mechanisms and various factors, such as the dosage of DMRT1. While the sex-determination mechanism in gonads is well known, the mechanism in germ cells remains unclear. In this study, we explored the gene expression profiles of male and female primordial germ cells (PGCs) during embryogenesis in chickens to predict the mechanism underlying sex determination. Male and female PGCs were isolated from blood and gonads with a purity > 96% using flow cytometry and analyzed using RNA-seq. Prior to settlement in the gonads, female circulating PGCs (cPGCs) obtained from blood displayed sex-biased expression. Gonadal PGCs (gPGCs) also exhibited sex-biased expression, and the number of female-biased genes detected was higher than that of male-biased genes. The female-biased genes in gPGCs were enriched in some metabolic processes. To reveal the mechanisms underlying the transcriptional regulation of female-biased genes in gPGCs, we performed stimulation tests. Retinoic acid stimulation of cultured gPGCs derived from male embryos resulted in the upregulation of several female-biased genes. Overall, our results suggest that sex determination in avian PGCs involves aspects of both cell-autonomous and somatic-cell regulation. Moreover, it appears that sex determination occurs earlier in females than in males. [ABSTRACT FROM AUTHOR]

A simple technique is proposed to measure the transmission loss through a panel of arbitrary size. The present technique uses two anechoic rooms to simulate the free acoustic field. Different from the conventional methods, the incident angle, the sound pressure distribution, and the spectral distribution of the incident sound waves can be changed arbitrarily. By the calibration experiments, the reasonable capabilities of the prototype facility are confirmed. In the experiment, a panel is installed in between two anechoic rooms. For the sake of simplicity, quasiplanar sound waves are provided in the sound-source room at uniform sound pressure over the panel. The intensity of the transmitted sound waves is measured in the receiving room. The modal analyses and the transmission loss measurements are completed for three different materials: aluminum, honeycomb sandwich, and carbon composite. The results are useful to verify the numerical analyses. DOI: 10.2514/1.J050404

In hypersonic flow computations, it is a key issue to predict surface heating accurately, though this is still challenging because there always are possibilities of resulting in anomalous solutions. In this paper, three properties for flux functions are proposed: 1) shock stability/robustness, 2) conservation of total enthalpy, and 3) resolving boundary layer. Then, numerical experiments are performed for widely used or recently developed flux functions, and these fluxes are categorized into five major groups based on how they satisfy the three properties. These tests reveal that no flux function investigated here possesses all the three properties. In particular, the first one is not satisfied by any flux functions, including flux-vector-splittings. Finally, contributions of those properties are compared in a two-dimensional, viscous, hypersonic blunt-body problem. Results showed that the first and the third properties are crucial, and the second one is preferred to predict hypersonic heating. A group of flux functions that best satisfies these properties is suggested, and they are recommended either to be used or designed for hypersonic heating computations. DOI: 10.2514/1.41605

This paper studies a computational fluid dynamics validation study of wake-capturing capability for unsteady flow characteristics. The computational fluid dynamics code used in this study is based on the Cartesian grid system with octree mesh refinement and uses a weighted essentially nonoscillatory numerical scheme to achieve higher-order accuracy to preserve unsteady flow characteristics. Flow properties in the flat-plate wake flowfield, such as mean velocity, root mean square of perturbation velocity, and frequency wise power spectrum of flow velocity, were chosen to validate the computational fluid dynamics code. The comparison between computational fluid dynamics results and experimental data showed good agreement for mean velocity and low-frequency fluctuations. DOI: 10.2514/1.33502

Numerical studies were carried out to investigate the effects of turbulent boundary layers on panel flutter at supersonic speeds. In this study, Reynolds-averaged Navier-Stokes equations were solved to take into account the turbulent boundary layer and its viscous effects. First, the fluid-structure coupling code was validated. The computed flutter boundaries agreed well with experimental data. Moreover, the results showed that the viscous effects were important and should be taken into account for flutter computation. Second, the boundary-layer effects were investigated in the Mach number range of 1.0-2.4. We compared the Reynolds-averaged Navier-Stokes computation with the inviscid computation and discussed the differences between them. We found that the boundary layer has not only a stabilizing effect but also a destabilizing effect, depending on the Mach number. The most important finding is that the flutter dynamic pressure slowly increases due to the boundary layer as the Mach number increases. In addition, the design boundary methodology was reviewed in terms of the turbulent boundary-layer effect, which will be helpful for the development of a new boundary-layer correction for the design boundary. DOI: 10.2514/1.35786

The intention of the present work is to relate the theory for vortex breakdown, derived for breakdown observed in simple geometries, to the breakdown over a highly swept delta wing. Specifically, the appearance of negative azimuthal vorticity and the origin of this vorticity are considered. In addition, the helix angle criterion, associated with a change in criticality of the vortex core, is related to the onset of breakdown. Two delta wings are considered: a static delta wing with sweep angle of 76 degrees and a pitching delta wing with sweep angle of 70 degrees; both cases are modeled computationally. In the static case, the existence of breakdown is associated with the presence of an upstream change in sign of the azimuthal vorticity, consistent with analyses for simpler geometries. This negative azimuthal vorticity is shown to arise by a similar mechanism to that proposed for breakdown in a pipe. A transition in criticality of the delta wing vortex is also shown to be linked with the appearance of breakdown. DOI: 10.2514/1.37177

The screech-tone characteristics of an underexpanded jet in the vicinity of a flat plate in which the jet is emitted from a circular sonic nozzle and interacts with a flat plate placed parallel to the jet axis have been investigated experimentally. The flow is visualized using the schlieren technique, and the unsteady pressure on the flat plate as well as the sound pressure level in the far field are measured for different jet-plate separation distances. It is found that screech tone vanishes when the flat plate comes close to the jet axis. However, there is an azimuthal directivity in its propagation, which depends on jet-plate separation distance. In addition, the highly oscillating baseline jet flow is suppressed by the jet-plate interaction, and screech tone completely disappears when the jet-plate separation distance becomes less than 0.61 of the jet diameter. DOI: 10.2514/1.37077

Mammalian spermatogenesis is a heat-vulnerable process that occurs at low temperatures, and elevated testicular temperatures cause male infertility. However, the current reliance on in vivo assays limits their potential to detail temperature dependence and destructive processes. Using ex vivo cultures of mouse testis explants at different controlled temperatures, we found that spermatogenesis failed at multiple steps, showing sharp temperature dependencies. At 38 °C (body core temperature), meiotic prophase I is damaged, showing increased DNA double-strand breaks (DSBs) and compromised DSB repair. Such damaged spermatocytes cause asynapsis between homologous chromosomes and are eliminated by apoptosis at the meiotic checkpoint. At 37 °C, some spermatocytes survive to the late pachytene stage, retaining high levels of unrepaired DSBs but do not complete meiosis with compromised crossover formation. These findings provide insight into the mechanisms and significance of heat vulnerability in mammalian spermatogenesis. High temperatures lead to DNA double-strand break accumulation and asynapsis that trigger the meiotic checkpoint and apoptosis of spermatocytes in ex vivo cultures, providing a rationale for the heat sensitivity of sperm production in mammals. [ABSTRACT FROM AUTHOR]

PURPOSE: Low concordance between plasma-based and tissue-based tests for determining the RAS mutational status have been reported in some but not all patients with limited-extent metastatic colorectal cancer (mCRC). In this study, we investigated the relationship between metastatic site and circulating tumor DNA (ctDNA) detection using ctDNA genotyping, an alternative to tissue genotyping for precision oncology. MATERIALS AND METHODS: We investigated the relationship between metastatic site and ctDNA detection using Guardant360, a next-generation sequencing ctDNA assay, in mCRC patients with single-organ metastasis in the SCRUM-Japan GOZILA study (UMIN000029315). RESULTS: Of 1,187 patients with mCRC enrolled in GOZILA, 138 were eligible (49 with liver-only, 15 with lymph node-only, 27 with peritoneum-only, and 47 with lung-only metastases). The concordance of RAS / BRAF status between Guaradant360 and tissue in vitro diagnostic tests was 95.9% in patients with liver-only, 80.0% in lymph node-only, 56.0% in peritoneum-only, and 65.9% in lung-only metastases. ctDNA fraction, as measured by the median maximum variant allelic fraction (max VAF), and median number of detected variants were 23.1% and five in liver-only, 6.0% and five in lymph node-only, 0.4% and three in peritoneum-only, and 0.4% and three in lung-only metastases, respectively (all P <.001, Kruskal-Wallis test). Few patients with liver-only (2.0%) and lymph node-only metastasis (13.3%) had a max VAF < 0.2%, which is required to ensure a detection limit of 95%, but max VAF was more frequently < 0.2% in patients with lung-only (27.7%) or peritoneum-only metastasis (29.6%). CONCLUSION: Patients with lung-only and peritoneum-only metastatic disease have significantly lower levels of ctDNA, suggesting decreased clinical sensitivity for subclonal variants. This observation suggests that such patients may benefit from concurrent tissue and plasma testing to provide optimal genotyping for subsequent therapy selection. [ABSTRACT FROM AUTHOR]