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Circulating tumor DNA (ctDNA) is the fraction of cell-free DNA in patient blood that originates from a tumor. Advances in DNA sequencing technologies and our understanding of the molecular biology of tumors have increased interest in exploiting ctDNA to facilitate detection of molecular residual disease (MRD). Analysis of ctDNA as a promising MRD biomarker of solid malignancies has a central role in precision medicine initiatives exemplified by our CIRCULATE-Japan project involving patients with resectable colorectal cancer. Notably, the project underscores the prognostic significance of the ctDNA status at 4 weeks post-surgery and its correlation to adjuvant therapy efficacy at interim analysis. This substantiates the hypothesis that MRD is a critical prognostic indicator of relapse in patients with colorectal cancer. Despite remarkable advancements, challenges endure, primarily attributable to the exceedingly low ctDNA concentration in peripheral blood, particularly in scenarios involving low tumor shedding and the intrinsic error rates of current sequencing technologies. These complications necessitate more sensitive and sophisticated assays to verify the clinical utility of MRD across all solid tumors. Whole genome sequencing (WGS)-based tumor-informed MRD assays have recently demonstrated the ability to detect ctDNA in the parts-per-million range. This review delineates the current landscape of MRD assays, highlighting WGS-based approaches as the forefront technique in ctDNA analysis. Additionally, it introduces our upcoming endeavor, WGS-based pan-cancer MRD detection via ctDNA, in our forthcoming project, SCRUM-Japan MONSTAR-SCREEN-3. [ABSTRACT FROM AUTHOR]

Background: Although nivolumab has a high efficacy, reliable biomarkers are needed to predict the efficacy. We evaluated the nivolumab efficacy according to the TP53 mutation in advanced gastric cancer patients enrolled in the GI-SCREEN project. Methods: Sequence data of tumour specimens and clinicopathological information of 913 patients with advanced gastric cancer who were enrolled between April 2015 and March 2017 were obtained from the GI-SCREEN database. The follow-up information of 266 patients treated with nivolumab was also provided. Results: Among 266 patients treated with nivolumab, the objective response rate (ORR) of TP53 wild type (wt) patients (24.6%) was higher than that of TP53 mutant patients (14.8%). Among TP53 mutant patients, the ORR of the frameshift type tended to be higher than the transition and transversion type (23.1%, 13.6%, and 13.0%, respectively). The median progression-free survival (PFS) was statistically longer in TP53 wt patients than in mutant patients (3.3 vs 2.1 months, HR 1.4, 95% CI 1.1–1.9). Among TP53 mutant patients, PFS was statistically longer in the frameshift type than in the transversion type. Conclusion: Nivolumab showed better efficacy in TP53 wt patients than in mutant patients. Among TP53 mutant patients, the frameshift type may have efficacy from nivolumab treatment. [ABSTRACT FROM AUTHOR]

PURPOSE: Circulating tumor DNA (ctDNA) genotyping on the basis of next-generation sequencing (NGS) may guide targeted therapy for metastatic colorectal cancer (mCRC). However, the validity of NGS-based ctDNA genotyping for RAS/BRAF V600E mutation assessment and the efficacy of anti-EGFR and BRAF-targeted therapies on the basis of ctDNA results remains unclear. PATIENTS AND METHODS: The performance of NGS-based ctDNA genotyping for RAS/BRAF V600E mutation assessment was compared with that of a validated polymerase chain reaction–based tissue testing in patients with mCRC enrolled in the GOZILA study, a nationwide plasma genotyping study. The primary end points were concordance rate, sensitivity, and specificity. The efficacy of anti-EGFR and BRAF-targeted therapies on the basis of ctDNA were also evaluated. RESULTS: In 212 eligible patients, the concordance rate, sensitivity, and specificity were 92.9% (95% CI, 88.6 to 96.0), 88.7% (95% CI, 81.1 to 94.0), and 97.2% (95% CI, 92.0 to 99.4) for RAS and 96.2% (95% CI, 92.7 to 98.4), 88.0% (95% CI, 68.8 to 97.5), and 97.3% (95% CI, 93.9 to 99.1) for BRAF V600E, respectively. In patients with a ctDNA fraction of ≥1.0%, sensitivity rose to 97.5% (95% CI, 91.2 to 99.7) and 100% (95% CI, 80.5 to 100.0) for RAS and BRAF V600E mutations, respectively. In addition to a low ctDNA fraction, previous chemotherapy, lung and peritoneal metastases, and interval between dates of tissue and blood collection were associated with discordance. The progression-free survival of anti-EGFR therapy and BRAF-targeted treatment was 12.9 months (95% CI, 8.1 to 18.5) and 3.7 (95% CI, 1.3 to not evaluated) months, respectively, for matched patients with RAS/BRAF V600E results by ctDNA. CONCLUSION: ctDNA genotyping effectively detected RAS/BRAF mutations, especially with sufficient ctDNA shedding. Clinical outcomes support ctDNA genotyping for determining the use of anti-EGFR and BRAF-targeted therapies in patients with mCRC. Using a large-scale plasma genomic profiling program (SCRUM-Japan GOZILA), we validated ctDNA genotyping for RAS and BRAF V600E in metastatic colorectal cancer comparing with a validated tissue PCR-based testing. [ABSTRACT FROM AUTHOR]

Simple Summary: Human epidermal growth factor receptor 2 (HER2) amplification has emerged as a biomarker of metastatic colorectal cancer (mCRC). Prospective clinical trials have demonstrated the efficacy of HER2-targeted therapies for HER2-positive mCRC and explored the underlying mechanisms. To improve the therapeutic efficacy of this strategy, many clinical trials with various HER2-targeted agents are ongoing. This review discusses the molecular basis of HER2-targeted therapeutic strategies for patients with HER2-positive mCRC. Human epidermal growth factor receptor 2 (HER2) amplification has emerged as a biomarker in colorectal cancer (CRC), occurring in 1–4% of metastatic CRC (mCRC). In addition to conventional methods, such as immunohistochemistry and fluorescence in situ hybridization, next-generation sequencing-based tissue or circulating tumor DNA analysis has recently been used to identify HER2 amplification and assess HER2 overexpression. Prospective clinical trials have demonstrated the efficacy of HER2-targeted therapies in HER2-positive mCRC. The TRIUMPH study, a phase II study of dual HER2 antibodies, i.e., pertuzumab plus trastuzumab, demonstrated promising efficacy for patients with HER2-positive mCRC confirmed by tissue-and/or blood-based techniques, which led to the regulatory approval of this combination therapy in Japan. The mechanisms associated with efficacy and resistance have also been explored in translational studies that incorporate liquid biopsy in prospective trials. In particular, HER2 copy number and co-alterations have repeatedly been reported as biomarkers related to efficacy. To improve the therapeutic efficacy of the current strategy, many clinical trials with various HER2-targeted agents are ongoing. This review discusses the molecular basis of HER2-targeted therapeutic strategies for patients with HER2-positive mCRC. [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]

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]

We used a real-world database (GuardantINFORMTM) to analyze the treatment choices for patients with mCRC who underwent next-generation sequencing of circulating tumor DNA (ctDNA) using a commercially available test (Guardant360®) after first- or second-line therapy. From 18,875 patients with claims for CRC, 1064 had confirmed metastatic disease and sufficient histories for analysis (median age 59 years, 44.8% female, 44.5% left-sided). ctDNA was detectable for 997/1064 (93.7%) patients. Clinically actionable molecular profiles were present for 507/1064 (47.7%) patients, including those who had not received targeted therapy in the previous line (410/926, 44.3%). Second- or third-line targeted therapies were administered to 338/1064 patients (31.8%) and were considered matched for 193/338 (57.1%) patients. Therapies administered after testing were informed by the ctDNA results in 56.7% of patients overall (603/1064). Time to treatment discontinuation was most favorable for patients with a clinically actionable ctDNA profile who received matched therapy. This analysis demonstrates the real-world clinical value of plasma-based comprehensive genomic profiling for selecting appropriate molecular-targeted therapies in mCRC patients with disease progression after first- or second-line therapy. [ABSTRACT FROM AUTHOR]

PURPOSE: Circulating tumor DNA (ctDNA) genotyping may guide targeted therapy for patients with advanced GI cancers. However, no studies have validated ctDNA genotyping for microsatellite instability (MSI) assessment in comparison with a tissue-based standard. PATIENTS AND METHODS: The performance of plasma-based MSI assessment using Guardant360, a next-generation sequencing–based ctDNA assay, was compared with that of tissue-based MSI assessment using a validated polymerase chain reaction–based method in patients with advanced GI cancers enrolled in GOZILA study, a nationwide ctDNA profiling study. The primary end points were overall percent agreement, positive percent agreement (PPA), and negative percent agreement. The efficacy of immune checkpoint inhibitor therapy was also evaluated. RESULTS: In 658 patients with advanced GI cancers who underwent both plasma and tissue testing for MSI, the overall percent agreement, PPA, and negative percent agreement were 98.2% (95% CI, 96.8 to 99.1), 71.4% (95% CI, 47.8 to 88.7), and 99.1% (95% CI, 98.0 to 99.7), respectively. In patients whose plasma samples had a ctDNA fraction ≥ 1.0%, the PPA was 100.0% (15/15; 95% CI, 78.2 to 100.0). Three patients with MSI-high (MSI-H) tumors detected only by ctDNA genotyping achieved clinical benefits after receiving anti–programmed cell death 1 therapy with the progression-free survival ranging from 4.3 to 16.7 months. One patient with an aggressive cancer of an unknown primary site benefited from pembrolizumab after rapid detection of MSI-H by ctDNA genotyping. CONCLUSION: ctDNA genotyping was able to detect MSI with high concordance to validated tissue-based MSI testing, especially in patients with tumors that have sufficient ctDNA shedding. Furthermore, ctDNA genotyping enabled identification of patients with MSI-H tumors who benefited from immune checkpoint inhibitor treatment. [ABSTRACT FROM AUTHOR]

Chromosomal instability is one of the characteristics of gastric cancer (GC)[1],[2] associated with frequent amplifications of receptor tyrosine kinase (RTK)-related genes. We present a patient with I EGFR i -amplified GC who acquired substantial numbers of I EGFR i mutations and I MET i amplification during the cetuximab treatment as detected by serial ctDNA sequencing. The number of I EGFR i mutations (range, 1-7; Fig 3C) or known actionable I EGFR i mutations (range, 1-6; Fig 3D) were lower than those seen in our GC patient with 22 I EGFR i mutations, including seven known actionable mutations. [Extracted from the article]

Background: Immune checkpoint inhibitors may enhance the efficacy of radiotherapy (RT) in cancer treatment but the effect remains unknown in metastatic gastric cancer (mGC). This study aimed to compare the tumor shrinkage by palliative RT for mGC patients with or without previous exposure to anti-PD-1 therapy. Methods: Data of 36 mGC patients who had received palliative RT from April 2013 to May 2019 were analyzed. Primary tumor responses were evaluated through a volumetric measurement-based method using computed tomography (CT) and endoscopic responses were evaluated in patients who underwent endoscopy before and after RT. Tumor microenvironment (TME) immune status was investigated by analyzing tumor-infiltrating lymphocytes by flow cytometry. Results: Among 36 patients, 18 had previous exposure to anti-PD-1 before RT showing no significant differences in baseline characteristics with the other 18 patients without exposure to anti-PD-1 treatment. Tumor responses were observed in 28% (5/18) and none (0/18) in the anti-PD-1-exposed vs. naïve group, respectively (P = 0.045). Five out of eight patients in the anti-PD-1-exposed group, who underwent endoscopy after RT showed partial response, but none in the anti-PD-1-naïve patients showed response (P = 0.026). Increase in the CD8+ T cell/effector regulatory T cell ratio in TILs after anti-PD-1 therapy was noted in three responders to RT, but not in the other three non-responders. Conclusions: Prior exposure to anti-PD-1 therapy increases tumor response to RT. Immune profiling suggests that anti-PD-1 therapy may enhance the efficacy of RT by immunoactivation in the TME. [ABSTRACT FROM AUTHOR]

Background: Hyperprogressive disease (HPD) during treatment with anti-programmed death-1/programmed death-ligand 1 monoclonal antibodies has anecdotally been reported in some types of cancers, but is not well-characterized in patients with advanced gastric cancer (AGC). Methods: Total 62 AGC patients treated with nivolumab in a single institution from September 2017 to April 2018 were enrolled in this study. Tumor responses were assessed according to Response Evaluation Criteria in Solid Tumors version 1.1, and HPD was defined as ≥ two fold increase in tumor growth rate. Clinicopathological and molecular characteristics associated with HPD were also investigated. Results: Thirteen of 62 patients (21%) developed HPD after nivolumab treatment. Overall survival (OS) and progression-free survival (PFS) were significantly shorter in patients with HPD than in patients without HPD (median OS: 2.3 months vs. not reached, P < 0.001; median PFS: 0.7 months vs. 2.4 months, P < 0.001). Liver metastases (77% vs. 41%), Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or 2 (77% vs. 29%), and a large sum of target lesion diameters at baseline (median 104.2 mm vs. 44.9 mm) were significantly associated with HPD. Absolute neutrophil count (ANC) and C-reactive protein (CRP) level significantly increased in the first 4 weeks in only patients with HPD. Conclusions: HPD was observed in AGC patients treated with nivolumab and correlated with some clinicopathological characteristics. Elevations in ANC and CRP levels upon treatment might indicate HPD. [ABSTRACT FROM AUTHOR]

This work reports the study of ion dynamics produced by ablation of Al, Cu, Ag, Au, and Bi targets using nanosecond laser pulses at 193 nm as a function of the laser fluence from threshold up to 15 J cm-2. An electrical (Langmuir) probe has been used for determining the ion yield as well as kinetic energy distributions. The results clearly evidence that ablation of Al shows unique features when compared to other metals. The ion yield both at threshold (except for Al, which shows a two-threshold-like behavior) and for a fixed fluence above threshold scale approximately with melting temperature of the metal. Comparison of the magnitude of the yield reported in literature using other wavelengths allows us to conclude its dependence with wavelength is not significant. The evolution of the ion yield with fluence becomes slower for fluences above 4-5 J cm-2 with no indication of saturation suggesting that ionization processes in the plasma are still active up to 15 J cm-2 and production of multiple-charged ions are promoted. This dependence is mirrored in the proportion of ions with kinetic energies higher than 200 eV. This proportion is not significant around threshold fluence for all metals except for Al, which is already 20%. The unique features of Al are discussed in terms of the energy of laser photons (6.4 eV) that is enough to induce direct photoionization from the ground state only in the case of this metal. [ABSTRACT FROM AUTHOR]

We observed strong 1.5 μm photoluminescence (PL) from Si-capped Ge1-xSnx nanodots on Si (001) substrates formed using ultrathin SiO2 films. The lack of the quantum size effect in the PL revealed that the PL came from Si capping layers with radiative defects and not from the nanodots. The PL intensities were strongly enhanced when the Sn composition x increased in Ge1-xSnx nanodots or the nanodot size decreased. These results indicate that the formation of the radiative defects in Si is strongly correlated with the nanodot structures such as its geometry and strain states. This study demonstrates a new formation technique for light-emitting Si structures with high controllability and compatibility with Si technology. [ABSTRACT FROM AUTHOR]

We developed a technique for forming epitaxial GaSb quantum dots on Si substrates using ultrathin SiO2 films that contain epitaxial Ge nuclei. Unlike Volmer–Weber-type GaSb quantum dots on Si, the dot density was higher (109–1012 cm-2) and the dot size was controlled in the range of approximately 10–100 nm. The nucleation of quantum dots was initiated by trapping Ga atoms on the Ge nuclei. Photoluminescence spectroscopy measurement at 5 K revealed the quantum-confinement effect in GaSb dots causing the photoluminescence peak to be continuously blueshifted from 0.76 eV by ∼30 meV when the base length of the dots decreases from 100 to 17 nm. [ABSTRACT FROM AUTHOR]

A method to form epitaxial Ge1-xSnx quantum dots (QDs) on Si (111) substrates has been developed by codeposition of Ge and Sn on ultrathin SiO2 films with predeposited Ge nuclei. Hemispherical Ge1-xSnx QDs with an ultrahigh density (∼1012 cm-2) were epitaxially grown in the nanometer-size range. The QD size was controlled by changing the GeSn deposition amount. High-resolution transmission electron microscopy observations revealed that the main formed Ge1-xSnx QDs had less strain and no misfit dislocations. [ABSTRACT FROM AUTHOR]

We studied the formation of β-FeSi2 nanodots by codeposition at disilicide stoichiometric deposition rates of Fe and Si on Si (111) substrates covered with ultrathin SiO2 films. Hemispherical β-FeSi2 nanodots with an ultrahigh density (>1012 cm-2) and with a narrow size distribution at the average size of ∼5 nm diameter were epitaxially grown by the codeposition at 500 °C on ultrathin SiO2 films with predeposited Si. High-resolution transmission electron microscope observations showed that the formed nanodots were strained with a main configuration of β-FeSi2 (110)/Si (111). We propose the formation mechanism that a reaction between the SiO2 films and deposited Si atoms formed voids in the SiO2 films to work as nucleation sites, followed by direct β-FeSi2 formation from Fe and Si without passing through other iron silicide phases. [ABSTRACT FROM AUTHOR]

Ge nanodots with a typical size of ∼4 nm and ultrahigh density (>1012 cm-2) were grown on ultrathin SixGe1-x oxide films made by oxidizing Ge wetting layers grown on Si (111)–(7×7) surfaces. The density of the nanodots was independent of the Ge deposition rate, indicating that the chemical reaction between Ge atoms and the oxide films determined the nucleation of Ge nanodots. The size and density of Ge nanodots grown on the ultrathin SixGe1-x oxide films depended on the growth temperature and deposition amount. These dependences indicate that we can form the Ge nanodots with ultrahigh density controllably by using ultrathin SixGe1-x oxide films. © 2004 American Institute of Physics. [ABSTRACT FROM AUTHOR]

The blue‐breasted quail (Coturnix chinensis), the smallest species of quail with short generation interval and excellent reproductive performance, is a potential avian research model. A normal series of skeletal development of avian embryos could be served as a reference standard in the fields of developmental biology and teratological testing as well as in the investigation of mutation with skeletal abnormalities and in the study of the molecular mechanisms of skeletal development through genome manipulation. Furthermore, ossification sequence shows a species‐specific pattern and has potential utility in phylogeny. However, data on the skeletal development of blue‐breasted quail embryos are scarce. Here, we established a series of normal stages for the skeletal development of blue‐breasted quail embryos. Cartilage and ossified bones of blue‐breasted quail embryos were stained blue and red with Alcian blue 8GX and Alizarin red S, respectively. The time and order of chondrification and calcification of their skeletons were documented every 24 hr from 3 to 17 days of incubation, and a 15‐stage series of skeletal development was created. Moreover, a comparative study with the Japanese quail (Coturnix japonica) demonstrated that ossification sequence differed significantly between these two species. [ABSTRACT FROM AUTHOR]

Chickens and Japanese quail (Coturnix japonica) have traditionally been the primary avian models in developmental biology research. Recently, the blue‐breasted quail (Coturnix chinesis), the smallest species in the order Galliformes, has been proposed as an excellent candidate model in avian developmental studies owing to its precocious and prolific properties. However, data on the embryonic development of blue‐breasted quail are scarce. Here, we developed a normal developmental series for the blue‐breasted quail based on developmental features. The blue‐breasted quail embryos take 17 days to reach the hatching period at 37.7°C. We documented specific periods of incubation in which significant development occurred, and created a 39‐stage developmental series. The developmental series for the blue‐breasted quail was almost identical to that for chickens and Japanese quail in the earlier stages of development (stages 1–16). Our staging series is especially useful at later stages of development (stages 34–39) of blue‐breasted quail embryos as a major criterion of staging in this phase of development was the weight of embryos and the length of third toes. [ABSTRACT FROM AUTHOR]

Chickens and Japanese quail (Coturnix japonica) have traditionally been the primary avian models in developmental biology research. Recently, the blue‐breasted quail (Coturnix chinesis), the smallest species in the order Galliformes, has been proposed as an excellent candidate model in avian developmental studies owing to its precocious and prolific properties. However, data on the embryonic development of blue‐breasted quail are scarce. Here, we developed a normal developmental series for the blue‐breasted quail based on developmental features. The blue‐breasted quail embryos take 17 days to reach the hatching period at 37.7°C. We documented specific periods of incubation in which significant development occurred, and created a 39‐stage developmental series. The developmental series for the blue‐breasted quail was almost identical to that for chickens and Japanese quail in the earlier stages of development (stages 1–16). Our staging series is especially useful at later stages of development (stages 34–39) of blue‐breasted quail embryos as a major criterion of staging in this phase of development was the weight of embryos and the length of third toes. [ABSTRACT FROM AUTHOR]

The design and fabrication of nanostructured materials to control both thermal and electrical properties are demonstrated for high-performance thermoelectric conversion. We have focused on silicon (Si) because it is an environmentally friendly and ubiquitous element. High bulk thermal conductivity of Si limits its potential as a thermoelectric material. The thermal conductivity of Si has been reduced by introducing grains, or wires, yet a further reduction is required while retaining a high electrical conductivity. We have designed two different nanostructures for this purpose. One structure is connected Si nanodots (NDs) with the same crystal orientation. The phonons scattering at the interfaces of these NDs occurred and it depended on the ND size. As a result of phonon scattering, the thermal conductivity of this nanostructured material was below/close to the amorphous limit. The other structure is Si films containing epitaxially grown Ge NDs. The Si layer imparted high electrical conductivity, while the Ge NDs served as phonon scattering bodies reducing thermal conductivity drastically. This work gives a methodology for the independent control of electron and phonon transport using nanostructured materials. This can bring the realization of thermoelectric Si-based materials that are compatible with large scale integrated circuit processing technologies. [ABSTRACT FROM AUTHOR]

The supersonic flows around a typical parachute-like two-body system are numerically studied at a freestream Mach number of 2.0. Both rigid and flexible models, composed of a capsule and a canopy, are considered. The objective is to analyze the effects of angle of attack (AoA) on the unsteady flow produced by the parachute-like two-body system and the difference in flow behaviors between the rigid and flexible systems. The following two model configurations are examined for the rigid canopy case: (1) the canopy is connected to the capsule with a rigid rod and (2) the canopy is separate from the capsule. It is found that at a moderate capsule AoA, the most unstable flow field is generated in the interior of the canopy and the connecting rod has a significant effect on the flow field. For the flexible case, the supersonic flows over the model (2) configuration and the canopy alone are investigated. An area oscillation phenomenon is observed in the flexible canopy. When the capsule AoA is increased, the flexible canopy has greater deformation, which results in a lower drag coefficient. The effect of the canopy AoA is also examined for the flexible canopy alone. A small deformation in the canopy shape is observed. [ABSTRACT FROM AUTHOR]

Bromodomain and extra-terminal (BET) inhibitors suppress super-enhancers and show cytotoxicity against multiple types of tumors. However, early clinical trials with BET inhibitors showed severe hematopoietic toxicities, highlighting the need for sensitive tumors and rational combination strategies to enhance their therapeutic potential. Here, we identified colon cancer-specific super-enhancers that were associated with multiple oncogenic pathways, including the mitogen-activated protein kinase (MAPK) signaling pathway. Among the 14 colon cancer cell lines tested, their sensitivity to JQ1, a BET inhibitor, was not correlated with c-MYC expression. Three of four BRAFV600E-mutant cell lines were sensitive. Addition of JQ1 to vemurafenib, a specific mutant BRAF inhibitor, suppressed cell growth by arresting cell cycle progression and inducing apoptosis in the BRAFV600E-mutant cells. Mechanistically, the feedback activation of MAPK signaling pathway by vemurafenib was repressed by JQ1. Further, the addition of JQ1 to a BRAF inhibitor enhanced the in vivo anti-tumor effect. Thus, this study indicates the therapeutic potential of targeting of super-enhancers and mutant BRAF in patients with BRAFV600E-mutant colorectal cancer. [ABSTRACT FROM AUTHOR]

Phonon diffraction and interference patterns are observed at the atomic scale, using molecular dynamics simulations in systems containing crystalline silicon and nanometric obstacles, such as voids or amorphous inclusions. The diffraction patterns due to these nano-architectured systems of the same scale as the phonon wavelengths are similar to the ones predicted by the simple Fresnel–Kirchhoff integral. The few differences between the two approaches are attributed to the nature of the interface and the anisotropy of crystalline silicon. Based on the wave description of phonons, these findings can provide insights into the interaction of phonons with nano-objects and can have applications in smart thermal energy management. [ABSTRACT FROM AUTHOR]

A 27-year-old female was referred to our hospital with a chief complaint of removal of an impacted right mandibular third molar. Panoramic radiography showed two small circular radiolucencies on the right mandibular ramus. Computed tomography revealed that one of the radiolucencies was an accessory foramen located lateral to the mandibular ramus, and the other radiolucency was an accessory foramen located medial to the ramus; it was also connected to the mylohyoid groove. Continuity with the mandibular canal was confirmed for both accessory foramina. After explaining the risks of extraction, the patient decided against surgery and the impacted tooth was left in situ. Most patients have at least one or more accessory foramina in the mandible; however, accessory foramina of the lateral aspect of the mandibular ramus have not been reported. The high resolution of cone-beam computed tomography and three-dimensional reconstructed images enable improved detection of accessory foramina. Therefore, additional accessory foramina that are similar to those found in the present case could be found in the future using such imaging modalities. [ABSTRACT FROM AUTHOR]

Ge thin films were epitaxially grown on Si(1 1 1) substrates using ultrathin SiO 2 film technique called nanocontact epitaxy. The key to this technique was the use of high density spherical nanodots (NDs) as seed crystals for the epitaxial growth of the Ge films. The seed crystal NDs were elastically strain-relaxed without misfit dislocations so that highly crystalline Ge thin films could be formed. The Ge films were ≈140 nm in thickness and were composed of island-shaped domains with flat Ge(1 1 1) surfaces. The domains had an average size of ≈1 μm and flat surfaces with root mean square of a surface roughness of ≈3 nm. The films had a photoluminescence peak at 0.8 eV, which meant that the films were highly crystalline. [ABSTRACT FROM AUTHOR]

We investigated the electrical properties of non-doped wafer-bonded germanium-on-insulator substrates (Ge(001)-OI) post-annealed in various ambiences using a pseudo-metal-oxide-semiconductor field effect transistor. The transistor operation in the Ge(001)-OI without post-annealing was observed in the n-channel mode with hysteresis in the channel conductance versus gate voltage curves. The n-channel transistor operation was depletion type, with a large threshold voltage shift from the ideal threshold voltage (∼0 eV). Upon post-annealing the Ge(001)-OI, the behavior of the hysteresis and threshold voltage shift caused by interface defects was improved, which strongly depended on the post-annealing condition. Post-annealing in a N2 ambience yielded the most effective improvement, which included some O2 gas. This improvement is presumably because oxygen vacancies near the Ge/SiO2 interfaces are reduced by the oxygen supply during the post-annealing treatment. [ABSTRACT FROM AUTHOR]

β-FeSi2 flat islands have been fabricated on ultra-thin oxidized Si(111) surfaces by Fe deposition on Si nanodots. The microstructure and interdiffusion behaviour of the β-FeSi2/Si(111) system at the atomic level were studied by using spherical aberration-corrected high-angle annular dark-field scanning transmission electron microscopy and energy dispersive X-ray spectroscopy. The formed β-FeSi2 flat islands had a disc shape with an average size of 30-150 nm width and 10-20 nm height, and were epitaxically grown on high-quality single-phase Si with a crystallographic relationship (110)β-FeSi2/(111)Si and [001]β-FeSi2/Si. Moreover, the heterojunction between the β-FeSi2(110) flat islands and the Si(111) substrate was an atomically and chemically abrupt interface without any irregularities. It is believed that these results are caused by the use of ultra-thin SiO2 films in our fabrication method, which is likely to be beneficial particularly for fabricating practical nanoscaled devices. [ABSTRACT FROM AUTHOR]

Germ cells are the only cell type capable of transmitting genetic information to the next generation. During development, they are set aside from all somatic cells of the embryo. In many species, germ cells form at the fringe of the embryo proper and then traverse through several developing somatic tissues on their migration to the emerging gonads. Primordial germ cells ( PGCs) are the only cells in developing embryos with the potential to transmit genetic information to the next generation. Unlike other species, in avian embryos, PGCs use blood circulation for transport to the future gonadal region. This unique accessibility of avian PGCs during early development provides an opportunity to collect and transplant PGCs. The recent development of methods for production of germline chimeras by transfer of PGCs, and long-term cultivation methods of chicken PGCs without losing their germline transmission ability have provided important breakthroughs for the preservation of germplasm , for the production of transgenic birds and study the germ cell system. This review will describe the development, migration, differentiation and manipulation of germ cells, and discuss the prospects that germ cell technologies offer for agriculture, biotechnology and academic research. [ABSTRACT FROM AUTHOR]

We performed a comparative study of the superconducting gap in the new filled skutterudite superconductors LaPt4Ge12 and LaPt4Ge12 using high-resolution photoemission spectroscopy. We succeeded in observing spectral changes across Tc that reflect the opening of the superconducting gap in both compounds and also in observing a noticeable difference in their respective superconducting spectral shapes near the Fermi level, pointing toward a more complex superconducting gap structure in LaPt4Ge12. In addition, we found that the two-gap model is more suitable for describing the superconducting-state spectrum of LaPt4Ge12 than the single-isotropic-gap and single-anisotropic-gap models, which suggests an explanation that multiband effects may possibly induce the anomalous superconducting properties of LaPt4Ge12. [ABSTRACT FROM AUTHOR]

Broad photoluminescence (PL) around 1.5µm (∼0.8 eV) from Si/GeSn nanodot (ND)/Si structures was enhanced by high temperature post-annealing. This PL was related to radiative electronic states created in the Si-capping layer owing to the underlying GeSn NDs. A light-emitting diode was fabricated containing the Si-capped GeSn NDs as an active layer. Broad electroluminescence (EL) was observed even at room temperature (RT) near 0.8 eV which is consistent with the optical fibre communication wavelength (∼1.5µm). The temperature dependence of the integrated EL intensity revealed two activation energies of 3 and 33 meV. The light emission with a higher activation energy of 33 meV leading to the RT luminescence was considered to have the same origin as that of broad PL. This demonstrates that the Si/GeSn ND/Si structures are promising as a group IV-based light-emitting material compatible with Si technology. [ABSTRACT FROM AUTHOR]

Abstract: Ultrahigh density (>1012 cm−2) Fe3Si nanodots (NDs) are epitaxially grown on Si(111) substrates by codeposition of Fe and Si on the ultrathin SiO2 films with ultrahigh density nanovoids. We used two kinds of methods for epitaxial growth: molecular beam epitaxy (MBE) and solid phase epitaxy. For MBE, low temperature (<300°C) growth of the Fe3Si NDs is needed to suppress the interdiffusion between Fe atoms deposited on the surfaces and Si atoms in the substrate. These epitaxial NDs exhibited the ferromagnetism at low temperatures, which were expected in terms of the application to the magnetic memory device materials. [Copyright &y& Elsevier]

The administration of a busulfan solubilised sustained-release emulsion was used to improve the efficiency of endogenous primordial germ cell (PGC) depletion in early chicken embryos. Busulfan was solubilised in N,N-dimethylformamide and diluted 10-fold in phosphate-buffered saline [PBS(-)]. The sustained-release emulsion was prepared by mixing equal amounts of busulfan solubilised solution and sesame oil using a filter. The appropriate time and dose of busulfan sustained-release emulsion administration were established to optimise our novel germline replacement technique. Injecting busulfan sustained-release emulsion into the yolk of recipient embryos at zero hours of incubation did not disturb the movement and proliferation of donor cells during the generation of germline chimeras. A dose of 100 μg of busulfan resulted in the greatest reduction of endogenous PGCs in embryonic gonads and the most successful hatchability of sterilised embryos. Test-cross analysis revealed that the germline transmission rate in busulfan treated chickens was significantly higher than in non-treated controls (99.5 versus 6.0%). This unique and efficient germline transmission system has potential applications in the conservation of endangered and y or rare avian species. [ABSTRACT FROM AUTHOR]

We report a case of HER-2-positive advanced inflammatory breast cancer with invasive micropapillary component showing a complete response to trastuzumab and paclitaxel treatment. A 37-year-old woman was referred to our hospital for right breast swelling with broad skin redness and right axillary tumor. Ipsilateral infraclavicular and contralateral axillary lymph nodes swelling were also recognized. The histopathological findings of core-needle biopsy specimens from primary breast tumor and ipsilateral axillary lymph node were invasive ductal carcinoma with a micropapillary component. Immunohistochemical examination gave a negative result for estrogen receptor (ER)/progesterone receptor (PgR), and overexpression of HER-2 (Hercep Test 3+). Advanced inflammatory breast cancer with an invasive micropapillary component was diagnosed (T4d N3 M1 (LYM), stage IV). The patient was treated with combination chemotherapy using weekly paclitaxel and trastuzumab. After administration of three courses, the breast swelling, skin redness, and lymph node swelling disappeared completely. She maintained complete remission of disease for 12 months and was judged to have a clinically complete response by the RECIST criteria. Invasive micropapillary carcinoma is known to be an aggressive histological type associated with a high incidence of lymph node metastasis and poor prognosis. This is the first reported case of advanced inflammatory breast cancer with an invasive micropapillary component showing a clinically complete response to trastuzumab-containing treatment. This report suggests trastuzumab-containing chemotherapy is a promising therapy for HER-2-positive advanced invasive micropapillary carcinoma. [ABSTRACT FROM AUTHOR]

Abstract: Epitaxial iron-silicide (α-FeSi2, ε-FeSi and β-FeSi2) nanodots were grown on Si(111) substrates with SiO2 ultrathin films by Fe deposition on Si nanodots. The nanodots were characterized in-situ by reflection high-energy electron diffraction and scanning tunneling microscopy, and ex-situ high resolution transmission electron microscopy (HRTEM). For the β-FeSi2 nanodots, the HRTEM images and the corresponding fast Fourier transform patterns analyses revealed that the coherent β-FeSi2 nanodots with a relation of β-FeSi2(110)/Si(111) had a compressive strain of ~0.8% in the [001] β -FeSi2 direction and a tensile strain of ~2.6% in the direction normal to (110) β -FeSi2 plane. [Copyright &y& Elsevier]

Abstract: It has been found that spherical large clusters of carbon atoms are formed by irradiation of crystalline C60 films grown on Si(111)-(7×7) surfaces with electrons field-emitted from a scanning tunneling microscope probe tip. The size distribution of the clusters deduced from surface profile measurements suggests that the dominant clusters were not necessarily C60n (n =2–4) expected from the simple fusion of C60 molecules. It was proposed that electronic excitations of C60 molecules caused the fragment and coalescence of the molecules to form the giant fullerenes as in the photo-induced similar effects. [Copyright &y& Elsevier]

Abstract: We obtained the luminescence image of the GaAs (110) surface by scanning tunneling microscope-cathodoluminescence (STM-CL) spectroscopy, where low-energy (∼100eV) electrons field emitted from the STM tip were used as a bright excitation source. The STM-CL image with high photon signal (1.25×104 cps) showed the dark image corresponding to the surface contamination in the STM image working as the nonradiative recombination centers of carriers. This dark image demonstrated the spatial resolution of about 100nm in STM-CL spectroscopy of the GaAs (110) surface, which was determined by the field-emitted electron beam diameter. [Copyright &y& Elsevier]

• SiGe crystal growth by the traveling liquidus-zone method was carried out in ISS. • The transport phenomena and solidification were investigated by numerical simulation. • Numerical concentration distributions were coincident with the experimental results. • Axial Ge distribution became U-shaped due to the change in cartridge emissivity. • Radial Ge distributions remained relatively uniform throughout the entire crystal. The second and third microgravity experiments on SiGe crystal growth by the traveling liquidus-zone (TLZ) method were carried out aboard the Japanese Experiment Module (JEM) "Kibo" in the International Space Station (ISS) in July 2013 and February 2014. In this study, we numerically investigated the details of transport phenomena and solidification in these two experiments. We found that the deformation of the melt/SiGe crystal interface shape increased with time, and that the growth rate near the crystal edge was much larger than that near the central axis. Comparing the numerical and experimental results of the concentration distribution of Ge, the numerical concentration distributions are reasonably coincident with the experimental ones in both the axial and radial directions. In addition, both numerical and experimental results show that the radial distributions of the Ge concentration remain relatively uniform throughout the entire crystal, although the mean values depend on the growth length. [ABSTRACT FROM AUTHOR]

Abstract: We investigated desorption of chlorine atoms on Si (111)-(7×7) surfaces induced by hole injection from scanning tunneling microscope tips. The hole-induced desorption of chlorine atoms had a threshold bias voltage corresponding to the energy position of the S3 surface band originated in Si backbonds. The chlorine atom desorption rate was almost proportional to the square of the tunneling current. We have discussed possible mechanisms that two holes injected into Si surface states get localized at the backbonds of chlorinated Si adatoms, which induces the rupture of Cl–Si bonds to result in chlorine atom desorption. [Copyright &y& Elsevier]

Characteristic boundary algorithms coupled with high-order modified-flux-approach ENO (essentially non-oscillatory) schemes are proposed in generalized coordinates for the computation of aeroacoustic problems. So far most of the characteristic algorithms have been used along with high-order finite difference schemes. Here in this study finite volume MFA-ENO schemes with characteristic boundary conditions are proposed, and examined to validate the accuracy by applying to several test problems, including the problem of acoustic waves scattered by a circular cylinder and the problem of vortex convection through the outlet boundary. Non-reflecting boundary conditions to prevent acoustic and vorticity waves to be reflected at the boundary are also analysed. [ABSTRACT FROM AUTHOR]

Abstract: Germanium quantum dots (QDs) were extracted from ultrathin Si x Ge1−x oxide films using scanning tunneling microscope (STM) tips. The extraction was most efficiently performed at a positive sample bias voltage of +5.0V. The tunneling current dependence of the extraction efficiency was explained by the electric field evaporation transfer mechanism for positive Ge ions from QDs to STM tips. Ge QDs (∼7nm) were formed and isolated spatially by extracting the surrounding Ge QDs with an ultrahigh density of >1012 cm−2. Scanning tunneling spectroscopy of the spatially-isolated QDs revealed that QDs with an ultrahigh density are electrically-isolated from the adjacent dots. [Copyright &y& Elsevier]

The normal mode linear analysis is applied to investigate the stability of a circular isolated compressible vortex with the emphasis on studying the effect of entropy stratification of the basic flow on stability properties. We study a family of vortices that have zero total circulation, with the swirl velocity being presented by a Taylor-type distribution in the radial direction. The stratification of entropy is modeled by a Gaussian two-parametric profile whose parameters control the maximal deviation from the homentropic distribution and the extent of the entropic zone. Results presented concern the effect of these parameters and the vortex intensity on instability characteristics. In particular, in the case of homentropic flow, vortices considered are found to be stable only for sufficiently high intensities and cease to be stable as the intensity weakens. As an example of the situation where unstable normal modes can be excited, the scattering of sound waves by the vortex flow is considered. By simulating this process numerically, we show that the scattered field becomes unstable in the course of time and acquires a typical periodical pattern in polar angle. The characteristics of this instability (viz., the growth rate and the azimuthal phase frequency) coincide with those of the linear analysis very closely. This fact shows conclusively that the instability is caused by the induction of unstable normal modes in the vortex by means of sound irradiation. [ABSTRACT FROM AUTHOR]

In this study, computational fluid dynamics (CFD) simulation is performed to clarify the mechanism of rolling moment generation due to a delta wing with a microflap. As a result, it was found that a leading-edge separation vortex is displaced by changing the location of the microflap at the leading edge. The positive rolling moment was produced for installation of the flap in the lower part of the leading edge, whereas the negative rolling moment was produced in the upper part. These characteristics are similar to experimental data. Detailed observation of simulated results in turbulent case shows that the leading-edge separation vortex slightly moves toward the outboard direction in the former case, whereas it does not move toward inboard, but becomes diffusive, in the latter case. The mechanism of the rolling moment generation seems to have a slight discrepancy between CFD results and the explanation based on the experimental data. The rolling moment actually depends not only on the vortex location, but also on its magnitude and size. Finally, there were no large differences in rolling moment between calculated results with and without a turbulence model. [ABSTRACT FROM AUTHOR]

A variable explicit-implicit scheme was proposed by Collins et al. [(CCG) scheme] (Collins, J. E, Colella, P., and Glaz, H. M., "An Implicit-Explicit Eulerian Godunov Scheme for Compressible Flows" Journal of Computational Physics, Vol. 116, 1995, pp. 195-211) for one-dimensional hyperbolic systems. By suitable blending of explicit and implicit schemes, this approach aims to ensure a maximum norm diminishing (MND) property at all Courant numbers. Although proven for linear equations, however, the CCG scheme, fails to maintain this property unconditionally for non-linear equations and requires a specific time-step restriction. The remedy for this limitation of the CCG scheme is shown, and a new general method for the design of unconditionally MND hybrid schemes for nonlinear hyperbolic equations is proposed. An extension to the compressible Navier-Stokes equations is also discussed. The method is tested and verified by calculation of the Burgers equation on a highly stiff nonuniform grid. It is also applied to simulate the reflection of a normal shock wave from the end wall of a two-dimensional channel, which is attended with unsteady, viscous interaction processes including shock bifurcation. [ABSTRACT FROM AUTHOR]