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Minimal residual disease (MRD) is usually defined as the small number of cancer cells that remain in the body after treatment. The clinical significance of MRD kinetics is well recognized in treatment of hematologic malignancies, particularly acute lymphoblastic leukemia (ALL). Real time quantitative PCR targeting immunoglobulin (Ig) or T-cell receptor (TCR) rearrangement (PCR-MRD), as well as multiparametric flow cytometric analysis targeting antigen expression, are widely used in MRD detection. In this study, we devised an alternative method to detect MRD using droplet digital PCR (ddPCR), targeting somatic single nucleotide variants (SNVs). This ddPCR-based method (ddPCR-MRD) had sensitivity up to 1E-4. We assessed ddPCR-MRD at 26 time points from eight T-ALL patients, and compared it to the results of PCR-MRD. Almost all results were concordant between the two methods, but ddPCR-MRD detected micro-residual disease that was missed by PCR-MRD in one patient. We also measured MRD in stored ovarian tissue of four pediatric cancer patients, and detected 1E-2 of submicroscopic infiltration. Considering the universality of ddPCR-MRD, the methods can be used as a complement for not only ALL, but also other malignant diseases regardless of tumor-specific Ig/TCR or surface antigen patterns.

Liquid biopsy, a method of detecting genomic alterations using blood specimens, has recently attracted attention as a noninvasive alternative to surgical tissue biopsy. We attempted quantitative analysis to detect amplification of MYCN (MYCNamp) and loss of heterozygosity at 11q (11qLOH), which are clinical requisites as prognostic factors of neuroblastoma (NB). In this study, cell-free DNA (cfDNA) was extracted from plasma samples from 24 NB patients at diagnosis. Copy numbers of MYCN and NAGK genes were quantitatively analyzed by droplet digital PCR (ddPCR). 11qLOH was also assessed by detecting allelic imbalances of heterozygous single nucleotide polymorphisms in the 11q region. The results obtained were compared to those of specimens from tumor tissues. The correlation coefficient of MYCN copy number of cfDNA and tumor DNA was 0.88 (p 0.00001). 11qLOH was also accurately detected from cfDNA, except for one case with localized NB. Given the high accuracy of liquid biopsy, to investigate components of cfDNA, the proportion of tumor-derived DNA was estimated by examining the variant allele frequency of tumor-specific mutations in cfDNA. The proportion of tumor-derived DNA in cfDNA was 42.5% (range, 16.9%-55.9%), suggesting sufficient sensitivity of liquid biopsy for NB. In conclusion, MYCN copy number and 11qLOH could be quantitatively analyzed in plasma cfDNA by ddPCR assay. These results suggest that plasma cfDNA can be substituted for tumor DNA and can also be applied for comprehensive genomic profiling analysis.

Translocations of retinoic acid receptor-α (RARA), typically PML–RARA, are a genetic hallmark of acute promyelocytic leukemia (APL). However, because a small fraction of APL lack translocations of RARA, we focused here on APL cases without RARA translocation to elucidate the molecular etiology of RARA-negative APL. We performed whole-genome sequencing, PCR, and FISH for five APL cases without RARA translocations. Four of five RARA-negative APL cases had translocations involving retinoic acid receptor-β (RARB) translocations, and TBL1XR1–RARB was identified as an in-frame fusion in three cases; one case had an RARB rearrangement detected by FISH, although the partner gene could not be identified. When transduced in cell lines, TBL1XR1–RARB homodimerized and diminished transcriptional activity for the retinoic acid receptor pathway in a dominant-negative manner. TBL1XR1–RARB enhanced the replating capacity of mouse bone marrow cells and inhibited myeloid maturation of human cord blood cells as PML–RARA did. However, the response of APL with RARB translocation to retinoids was attenuated compared with that of PML–RARA, an observation in line with the clinical resistance of RARB-positive APL to ATRA. Our results demonstrate that the majority of RARA-negative APL have RARB translocations, thereby forming a novel, distinct subgroup of APL. TBL1XR1–RARB as an oncogenic protein exerts effects similar to those of PML–RARA, underpinning the importance of retinoic acid pathway alterations in the pathogenesis of APL.Significance: These findings report a novel and distinct genetic subtype of acute promyelocytic leukemia (APL) by illustrating that the majority of APL without RARA translocations harbor RARB translocations. Cancer Res; 78(16); 4452–8. ©2018 AACR.

Supplementary Methods: IRB approval, Genomic analysis, Identification of translocations and determination of their breakpoints, Plasmids Construct, Cell line and reagent, Co-immunoprecipotation and immunoblotting analysis, Luciferase assay, Retrovirus production and transduction, FCM and Morphologic analysis, Human CB cell culture, and Colony replating assay. Supplementary Tables: Table 1. Clinical characteristics of RARA translocation negative APL cases. Table 2. BAC clones for FISH used in this study. Table 3. Primer sequences. Table 4. Somatic mutations observed in RARA-negative APL cases. Supplementary Figures: Figure 1. Morphologic feature and FISH analyisis for RARB translocations. Figure 2. Event-free survival of RARA-negative APL. Figure 3. Determination of TBL1XR1 mutated allele by allele-specific PCR. Figure 4. Constructs of TBL1XR1-RARB and other RARA fusions. Figure 5. Morphologic change in U937. Figure 6. Colony replating assay with mouse bone marrow. Figure 7. Colony replating assay with human cord blood.

An inclined flow channel instrument that can be developed to be a structurally simple and easy-to-use rheometer was applied to control the thickness, specifically the viscosity and elasticity, of liquids thickened to support swallowing in nursing-care practice. Aqueous solutions containing salt or acid, which might be used as ingredients in drinks, were thickened with a commercial thickener. The thickener efficacy decreased because of the salt or acid in liquid phase. Analysis of the flows in the instrument by experimentation yielded a dimensionless relation representing changes of the Deborah number in the flow process, as indicated by the relative flow length, considering the shear rate in oral processing. One unique methodology to evaluate the viscoelasticities of thickened liquids during the swallowing process was presented utilizing the measurements such as elapsed time and velocity in the instrument.

Inconsistency in maturation of saccharinan kelp due to changes in the marine environment is a problem in terms of securing seedlings for aquaculture. In Hokkaido, the main producing area of Saccharina japonica, it has become a challenge to stably secure the parental algae of the species for aquaculture. When maturation was induced by short-day conditions in naturally collected S. japonica sporophytes as well as in the sporophytes collected from them and cultivated, sorus formation began in approximately 3 weeks and spread to 0.4%-16.8% on the upper side area and 23.2%-41.1% on the underside area after about 5 weeks, with the highest rates, 23.2%-59.5%, observed around the base part of the underside. Sorus formation began from the base and middle parts in the top-intact thalli and from the marginal part in the top-cut thalli. The released zoospore germlings grew steadily as aquaculture seedlings, and the blade width and wet weight of the seedlings collected in August and subjected to mariculture in November were significantly larger after approximately five and a half months compared to those of thalli cultivated using a conventional method (i.e. thalli collected just prior to the mariculture). Seedling production through maturation induction in sporophytes would be a feasible option for seedling production facilities and would be helpful for stably producing seedlings without the effect of the natural environment.

本研究は、美術系造形教育へ三次元デジタイズ技術を取り入れていくことを目的としている。複数種類の機器を導入して実験と教材開発を行い、各機器の特性、価格のバランスを含めて、実際の授業への導入実現性、継続性を分析していく。 5年計画の2年目にあたる本研究では、3Dスキャン4機種の運用実験に加えて、実際の授業でのシステムを利用した演習を行った。Photo Booth型システムでは、3Dメッシュとテクスチャの生成から、オートリギングとアニメーション設定を行った。また、一眼レフ型システムを構築して、複数種類の対象物を用いてスキャン実験を行った。, The goal of this project is to integrate 3D digitizing technologies into the curriculum of art educational institutions. We conduct experiments and develop teaching materials with several types of equipment. Based on the comparison between the characteristics of each equipment and its price, we analyze the feasibility and sustainability using the system in the classroom. In the second year of the five-year plan, we conducted operational experiments of four 3D scanning systems and exercises using this system in the classroom. Using Photo Booth system, students generated 3D mesh and texture, and then set up auto-rigging and animation. In addition, we built a SLR (Single-lens reflex camera) system and conducted scanning experiments with multiple types of objects.

6-Mercaptopurine (6-MP) is widely used for the treatment of paediatric leukaemia and lymphoma. Recently, germline variants in the NUDT15 gene have been identified as one of the major genetic causes for 6-MP-associated adverse effects such as myelosuppression. Patients with hypomorphic NUDT15 variants accumulate excessive levels of DNA-incorporated thioguanine in white blood cells, resulting in severe myelosuppression. Although preclinical studies suggest that these variants may influence the protein stability of NUDT15, this has not been directly characterised in patients. In this study, we report the development of a series of novel monoclonal antibodies against NUDT15, using which we quantitatively assessed NUDT15 protein levels in 37 patients with acute lymphoblastic leukaemia treated with 6-MP, using sandwich enzyme-linked immunosorbent assay (ELISA). The NUDT15 genotype was highly correlated with its protein levels (p 0.0001), with homozygous and compound heterozygous patients showing exceedingly low NUDT15 expression. There was a positive correlation between NUDT15 protein level and 6-MP tolerance (r = 0.631, p 0.0001). In conclusion, our results point to low NUDT15 protein abundance as the biochemical basis for NUDT15-mediated 6-MP intolerance, thus providing a phenotypic readout of inherited NUDT15 deficiency.

Erythroid sarcoma is very rare form of pure erythroid leukemia with undetermined biological features. Here, we present an infant with a multifocal erythroid sarcoma, diagnosed because the tumor cells were positive for glycophorin A. After acute myeloid leukemia-oriented chemotherapy and surgical resection followed by cord blood transplantation, he has successfully maintained complete remission without any late effects. Total transcriptome analysis of the tumor identified a novel fusion gene, RCC1-LCK, and high LCK expression levels, suggesting that LCK overexpression was involved in leukemogenesis in this case.

We aimed to examine the effects of cannabidiol (CBD)-containing hemp oil without delta-9-tetrahydrocannabinol (THC) as a supplemental treatment for canine atopic dermatitis (CAD), as well as its adverse effects, and effects on concurrent drug use in dogs.In this retrospective case series, 8 dogs with CAD were diagnosed by veterinary dermatologists certified by the Japanese Society of Veterinary Dermatology.The medical records of dogs supplemented with CBD-containing hemp oil were evaluated with respect to signalment, physical examination, plasma C-reactive protein concentrations, pharmacologic management, the CAD Extent and Severity Index (4th iteration), and the Pruritus Visual Analog Scale.Overall, CBD, used as a supplement in combination with other drugs, was well-tolerated over a wide dose range and decreased the occurrence of pruritus in dogs with CAD when ingested twice a day.This study provides the first report of supplementation with CBD without THC that was effective in controlling pruritic behavior in dogs with CAD.Further controlled studies are required to investigate the dose range, efficacy, and safety.Effets du cannabidiol sans delta-9-tétrahydrocannabinol sur la dermatite atopique canine : évaluation rétrospective de huit cas.Nous avons cherché à examiner les effets de l’huile de chanvre contenant du cannabidiol (CBD) sans delta-9-tétrahydrocannabinol (THC) en tant que traitement complémentaire de la dermatite atopique canine (CAD), ainsi que ses effets indésirables et ses effets sur les médicaments concomitants utilisés chez le chien.Dans cette étude rétrospective de cas, huit chiens atteints de CAD ont été diagnostiqués par des dermatologues vétérinaires certifiés par la Société japonaise de dermatologie vétérinaire.Les dossiers médicaux des chiens supplémentés avec de l’huile de chanvre contenant du CBD ont été évalués en ce qui concerne le signalement, l’examen physique, les concentrations plasmatiques de protéine C-réactive, la gestion pharmacologique, l’indiceDans l’ensemble, le CBD, utilisé comme supplément en association avec d’autres médicaments, a été bien toléré sur une large gamme de doses et a diminué l’apparition de prurit chez les chiens atteints de CAD lorsqu’il est ingéré deux fois par jour.Cette étude fournit le premier rapport de supplémentation en CBD sans THC efficace pour contrôler le comportement prurigineux chez les chiens atteints de CAD.D’autres études contrôlées sont nécessaires pour étudier la gamme de doses, l’efficacité et l’innocuité.(Traduit par D

Monosomy 7 (-7) occurs in various types of paediatric myeloid disorders and has a poor prognosis. Recent studies have demonstrated that patients with germline gain-of-function SAMD9/9L variants and loss-of-function GATA2 variants are prone to developing myelodysplastic syndrome (MDS) associated with -7. However, the prevalence of the genetic variants among paediatric haematologic disorders with -7 is unknown. The present study screened germline variants of GATA2 and SAMD9/9L in 25 patients with various types of paediatric haematological disorders associated with -7. The diagnoses of the 25 patients included MDS (n = 10), acute myeloid leukaemia (AML) and myeloid sarcomas (n = 9), juvenile myelomonocytic leukaemia (n = 3) and other disorders (n = 3). Seven patients with a germline pathogenic GATA2 variant were found. For SAMD9/9L screening, next-generation sequencing was used to detect low-abundance variants and found four novel germline variants. Functional analysis revealed that three out of the four variants showed growth-restricting capacity in vitro and thus, were judged to be pathogenic. Cases with GATA2 mutation tended to be older, compared to those with SAMD9/9L mutations. In conclusion, GATA2 and SAMD9/9L were sequenced in 25 patients with paediatric haematologic disorders associated with -7, and 40% of them were found to have some pathogenic germline variants in the three genes.

本研究は、美術系造形教育へ三次元デジタイズ技術を取り入れていくことを目的としている。複数種類の機器を導入して実験と教材開発を行い、各機器の特性、価格のバランスを含めて、実際の授業への導入実現性、継続性を分析していく。 5 年計画の初年度では、Photo Booth 型、Hand Held 型、赤外線360 度カメラ型の3 種の機器を導入した。それぞれ、システム開発、運用実験、教材開発を進めた。特に、赤外線360 度カメラ型では、学生の卒業作品に利用することができた。夜の大学全体を三次元スキャンすることで、ウェブ上で体験できる作品「バーチャルナイトユニバーシティ」が完成した。, The goal of this project is to integrate 3D digitizing technologies into the curriculum of art educational institutions. We conduct experiments and develop teaching materials with several types of equipment. Based on the comparison between the characteristics of each equipment and its price, we analyze the feasibility and sustainability using the system in the classroom. In the first year of the five-year plan, we introduced three types of equipment: Photo Booth, Hand Held, and Infrared 360-degree camera. For each equipment, we developed systems and teaching materials, and conducted operational experiments. In particular, the infrared 360-degree camera was used for the students’ graduation project. By scanning the entire university at night, the student has created “Virtual Night University” that can be experienced on the web.

Background An atypical form of Burkitt leukemia/lymphoma (BL), BL with a phenotype of precursor B-cells (preBLL), is listed in the WHO Classification. Recent reports suggested that preBLL and classical BL could be distinguished by the differences in IG-MYC translocation architecture and an additional mutated genes profile. The characteristics of classical BL are IG-MYC by aberrant somatic hypermutation or class switch recombination, and BL-specific gene mutations such as MYC, ID3, and CCND3. Meanwhile, preBLL is characterized by IG-MYC due to aberrant VDJ recombination and mutations in NRAS and KRAS. However, it is not clear whether all preBLL cases can be differentiated. This report investigated the molecular characteristics of an infant preBLL case, with a more advanced stage of maturity than typical preBLL. Case The patient showed BL-like morphology with IGH-MYC rearrangement. In the immunophenotyping, CD20 and surface immunoglobulin were negative, whereas other markers were consistent with BL. To evaluate the genetic contribution, we performed whole-exome sequencing. The breakpoint analysis revealed the IG-MYC occurred due to an aberrant VDJ recombination. Meanwhile, additional somatic mutations were detected in FBXO11, one of the mutant genes specific to BL. In the analysis of the specimen in complete remission, mutation in KRAS, frequently mutated in preBLL, was detected with low frequency, suggesting somatic mosaicism. Conclusion The present case showed the characteristics of both typical preBLL and classical BL. Because preBLL includes atypical cases such as the present case, further studies are required to elucidate preBLL features.

Background Lymphoblastic lymphoma (LBL) and acute lymphoblastic leukemia (ALL) are categorized as the same entity under precursor lymphoid neoplasms in the World Health Organization classification. However, compared to B-cell ALL, the molecular genetic makeup of B-cell LBL remains to be understood, mainly due to its rarity. We performed whole exome sequencing (WES) on seven patients with TCF3-PBX1-positive B-cell LBL. Methods WES was performed using DNA extracted from tumor specimens and paired blood samples at remission for six patients, and tumor-only analysis was performed for one patient whose remission sample was not available. For one patient, a relapsed sample was also analyzed. Results KMT2D variants and 6q LOH were found as recurrent alterations. Somatic variants of KMT2D were identified in three of the seven patients. Of note, the two patients with heterozygous nonsense variant of KMT2D were at stage III, without bone marrow infiltration. 6q LOH was also identified in two others, out of the seven patients. The common 6q deleted region of the two patients ranged from 6q12 to 6q16.3. Both patients had bone marrow infiltration. Analysis of recurrent case also revealed that the relapsed clone might be derived from a minor clone of the bone marrow at diagnosis. Conclusion In this study, through WES for seven patients with TCF3-PBX1-positive B-LBL, we identified KMT2D mutations and 6q LOH as recurrent alterations. In order to elucidate the relationship between these recurrent alterations and disease specificity or outcomes, further studies comparing with TCF3-PBX1-positive B-ALL are required.

Purpose: Primary central nervous system (CNS) rhabdomyosarcomais a rare mesenchymal tumor predominantly seen in children and associated with a poor outcome. We report a case of primary CNS rhabdomyosarcoma with PAX3-NCOA2 fusion and presenta systematic meta-review of primary CNS rhabdomyosarcoma to characterize this rare tumor.Methods: We present the case of a 6-year-old boy with primary CNS rhabdomyosarcoma in the posterior fossa. In a systematic meta-review, we compare the demographic data of primary CNS rhabdomyosarcoma with data of rhabdomyosarcoma at all sites from the SEER database and analyze clinical factors associated with survival outcome.Results: Our patient underwent gross total resectionand receivedvincristine, actinomycin-D, cyclophosphamide with early introduction of concurrent focal radiation and remained alive with no evidence of disease for 2 years after the end of therapy. Histopathological review revealed embryonal-type rhabdomyosarcoma, and whole-transcriptome analysis revealed PAX3 (EX6)-NCOA2 (EX12) fusion. In all, 77 cases of primary CNS rhabdomyosarcoma were identified through the meta-review. The demographic data of primary CNS rhabdomyosarcoma were similar to dataof rhabdomyosarcoma at all sites. Overall and event-free survival outcomes were available for 64 and 56 patients, respectively, with a 3-year OS of 29.5%and a 3-year EFS of 26.2%. The group that received trimodal treatment exhibited better survival outcomes, with a 3-year OS of 57.4%and a 3-year EFS of 46.3%.Conclusions: Primary CNS rhabdomyosarcoma shares common histological, molecular, and demographic features with non-CNS rhabdomyosarcoma. A trimodal treatment approach with early introduction of radiation therapy may result in favorable survival outcomes.

The effect of genetic variation on second malignant neoplasms (SMNs) remains unclear. First, we identified the pathogenic germline variants in cancer-predisposing genes among 15 children with SMNs after childhood leukemia/lymphoma using whole-exome sequencing. Because the prevalence was low, we focused on the association between SMNs and NUDT15 in primary acute lymphoblastic leukemia (ALL) cases. NUDT15 is one of the 6-mercaptopurine (6-MP) metabolic genes, and its variants are common in East Asian individuals. The prevalence of NUDT15 hypomorphic variants was higher in patients with SMNs (n = 14; 42.9%) than in the general population in the gnomAD database (19.7%; P = .042). In the validation study with a cohort of 438 unselected patients with ALL, the cumulative incidence of SMNs was significantly higher among those with (3.0%; 95% confidence interval [CI], 0.6% to 9.4%) than among those without NUDT15 variants (0.3%; 95% CI, 0.0% to 1.5%; P = .045). The 6-MP dose administered to patients with ALL with a NUDT15 variant was higher than that given to those without SMNs (P = .045). The 6-MP–related mutational signature was observed in SMN specimens after 6-MP exposure. In cells exposed to 6-MP, a higher level of 6-MP induced DNA damage in NUDT15-knockdown induced pluripotent stem cells. Our study indicates that NUDT15 variants may confer a risk of SMNs after treatment with 6-MP in patients with ALL.

Acute promyelocytic leukemia (APL) is cytogenetically characterized by the t(15;17) (q24;q21), although cases without this translocation exist. These cases are referred to as "cryptic" or "masked" translocations. Additionally, fewer than 5% of APL cases have another partner gene fused to the RARA gene. The TBL1XR1-RARA fusion gene has recently been reported as a novel RARA-associated fusion gene. We report a case with TBL1XR1-RARA and a masked translocation that was not detected by conventional tests for RARA-associated translocations. Three-year-old girl was diagnosed with APL based morphological findings, although conventional tests for RARA-associated chimeric genes were negative. She received all-trans retinoic acid treatment, but that was not effective. She achieved a complete remission (CR) by conventional multidrug chemotherapy, but had extramedullary relapse 2 years after onset. She underwent cord blood transplantation (CBT) in her second CR and is currently alive. To investigate the underlying pathogenesis of this unique case, we performed whole-genome sequencing and found a cryptic insertion of RARA gene into the TBL1XR1 gene. The transcript of the chimeric gene, TBL1XR1-RARA, was confirmed as an in-frame fusion by RT-PCR. In conclusion, we found using next-generation sequencing (NGS) a TBL1XR1-RARA fusion in a child with variant APL without the classic karyotype. Cryptic insertion could also occur in cases other than APL with PML-RARA. Variant APL has many variants and NGS analysis should therefore be considered for APL variant cases, even for those without RARA translocation detected by conventional analysis.

Subsequent malignant neoplasms (SMNs) are one of the most serious late complications in pediatric patients with cancer, with more than 10% of long-term cancer survivors developing SMNs. Germline mutations in cancer predisposition genes have been recently highlighted as a risk factor. For example, germline mutations in the TP53 gene were reported to be a risk factor for SMNs. A comprehensive genomic analysis for a large cohort of long-term survivors of childhood cancer showed that variants in cancer predisposition genes were correlated with the higher cumulative incidence of SMNs. As another genetic risk, previous reports suggested that polymorphisms in genes regulating thiopurine pathway such as TPMT gene might contribute to SMN development after acute lymphoblastic leukemia treatment. Considering improved survival probability, attention should be paid for late complications. Thus, therapeutic strategy should be optimized based on a risk for SMNs of each individual.

IntroductionGiven an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research Network for Diabetes Registry: J-BRAND Registry) to elucidate the safety and efficacy profile of long-term usage of alogliptin.Research design and methodsWe registered 5969 patients from April 2012 through September 2014, who started receiving alogliptin (group A) or other classes of oral hypoglycemic agents (OHAs; group B), and were followed for 3 years at 239 sites nationwide. Safety was the primary outcome. Symptomatic hypoglycemia, pancreatitis, skin disorders of non-extrinsic origin, severe infections, and cancer were collected as major adverse events (AEs). Efficacy assessment was the secondary outcome and included changes in hemoglobin A1c (HbA1c), fasting blood glucose, fasting insulin and urinary albumin.ResultsOf the registered, 5150 (group A: 3395 and group B: 1755) and 5096 (3358 and 1738) were included for safety and efficacy analysis, respectively. Group A patients mostly (>90%) continued to use alogliptin. In group B, biguanides were the primary agents, while DPP-4 inhibitors were added in up to ~36% of patients. The overall incidence of AEs was similar between the two groups (42.7% vs 42.2%). Kaplan-Meier analysis revealed the incidence of cancer was significantly higher in group A than in group B (7.4% vs 4.8%, p=0.040), while no significant incidence difference was observed in the individual cancer. Multivariate Cox regression analysis revealed that the imbalanced patient distribution (more elderly patients in group A than in group B), but not alogliptin usage per se, contributed to cancer development. The incidence of other major AE categories was with no between-group difference. Between-group difference was not detected, either, in the incidence of microvascular and macrovascular complications. HbA1c and fasting glucose decreased significantly at the 0.5-year visit and nearly plateaued thereafter in both groups.ConclusionsAlogliptin as a representative of DPP-4 inhibitors was safe and durably efficacious when used alone or with other OHAs for patients with type 2 diabetes in the real world setting.

To evaluate the non-Newtonian viscosities of liquid foods thickened for assistance of swallowing in nursing-care practice, an inclined flow channel instrument was investigated for development into a structurally simple and easy-to-use viscometer. Experimental analysis of the flows of Newtonian and non-Newtonian test liquids in the instrument derived a dimensionless relation expressing changes of the friction coefficient in the flow process which was indicated by the relative flow length, considering the shear rate level in the swallowing process. A methodology to evaluate uniquely the viscosities of liquid foods undergoing the swallowing process was presented using the measurements such as the flow length and velocity in the instrument.

Translocations of retinoic acid receptor-α (RARA), typically PML–RARA, are a genetic hallmark of acute promyelocytic leukemia (APL). However, because a small fraction of APL lack translocations of RARA, we focused here on APL cases without RARA translocation to elucidate the molecular etiology of RARA-negative APL. We performed whole-genome sequencing, PCR, and FISH for five APL cases without RARA translocations. Four of five RARA-negative APL cases had translocations involving retinoic acid receptor-β (RARB) translocations, and TBL1XR1–RARB was identified as an in-frame fusion in three cases; one case had an RARB rearrangement detected by FISH, although the partner gene could not be identified. When transduced in cell lines, TBL1XR1–RARB homodimerized and diminished transcriptional activity for the retinoic acid receptor pathway in a dominant-negative manner. TBL1XR1–RARB enhanced the replating capacity of mouse bone marrow cells and inhibited myeloid maturation of human cord blood cells as PML–RARA did. However, the response of APL with RARB translocation to retinoids was attenuated compared with that of PML–RARA, an observation in line with the clinical resistance of RARB-positive APL to ATRA. Our results demonstrate that the majority of RARA-negative APL have RARB translocations, thereby forming a novel, distinct subgroup of APL. TBL1XR1–RARB as an oncogenic protein exerts effects similar to those of PML–RARA, underpinning the importance of retinoic acid pathway alterations in the pathogenesis of APL. Significance: These findings report a novel and distinct genetic subtype of acute promyelocytic leukemia (APL) by illustrating that the majority of APL without RARA translocations harbor RARB translocations. Cancer Res; 78(16); 4452–8. ©2018 AACR.

Systemic Epstein-Barr virus (EBV)-positive T-cell lymphoma (TCL) of childhood has no effective, standard treatment. CHOP-like regimens or immunosuppressive therapies are options, but almost all pat...

Herein, we propose methods that use three-dimensional trajectory data (one-dimensional time × two-dimensional space) acquired from probe vehicles to detect damaged spots on roads caused by natural disasters. Detecting road damages immediately after a disaster is essential to ensure quick and safe evacuations, rescue and relief operations, and efficient road repairs. However, road damages are currently monitored only by closed-circuit television, administrators patrolling the roads, and reports from users of the roads. Consequently, the number of locations that are being monitored is limited, and damage detection is delayed. Our proposed methods automatically estimate the locations of widespread damages on general roads. After analyzing and extracting the features of probe data obtained during a disaster, our proposed methods were verified using the data of past disasters. Our methods can identify anomalous vehicle behaviors and indicate various possibilities for detecting road damages.

BACKGROUND Genetic hallmark of atypical teratoid/rhabdoid tumor (AT/RT) is loss-of-function variants or deletions in SMARCB1 gene on 22q11.2 chromosome, which is common to extracranial malignant rhabdoid tumors (MRT). Previous studies demonstrated that approximately one-thirds of AT/RT and extracranial MRT patients harbored germline SMARCB1 variants as the rhabdoid tumor predisposing syndrome. We studied herein intensive analysis of the SMARCB1 gene in AT/RT and extracranial MRT patients focusing on prevalence of germline genetic variants. PROCEDURE: In total, 16 patients were included. Both tumor-derived DNA and germline DNA were obtained from all patients. First, screening for SMARCB1 alterations in the tumor specimens was done by direct sequencing, ddPCR and SNP array analysis. Then, analysis of germline DNA samples focusing on the genomic abnormalities detected in the paired tumors in each case was performed. RESULTS In eight of 16 cases (50%), genomic alterations observed in the tumor-derived DNA were also detected in the germline DNA. It is worth noting that three patients had germline mosaicism. Two of three patients had mosaic deletion, including SMARCB1 region, and the average copy number of the deleted region in the SMARCB1 gene in the germline was 1.60 and 1.76. For another patient, the fraction of SMARCB1 variants in normal cells was as low as 1.7%. CONCLUSIONS Approximately half the MRT cases in this study had SMARCB1 germline alterations. Considering the presence of low-frequency mosaicisms which conventional methods might overlook, inherited germline variants in predisposition genes are more important than previously assumed for the pathogenesis of pediatric cancers.

Enantioselective α-allylation of α-substituted β-ketoesters with simple allyl alcohols was successfully performed by synergistic catalysis with the catalyst combination of a chiral primary amino acid and an achiral palladium complex without additional promotors like acids or bases. The allylation reaction and generation of a chiral quaternary carbon stereocenter proceeded smoothly to produce α,α-disubstituted β-ketoesters in high yields (91-99%) with high enantioselectivities (90-99% ee).

本稿は科学研究費助成事業16K00731「地域博物館の有する骨格標本を3D プリンターを用いて活用する手法の開発と実践」及び、その成果発表としての「動物のからだ展」の実施報告である。研究においては美術・デザイン系大学の取り組みとして、地域の自然史博物館や動物園資料館に収蔵されている骨格標本のデジタルデータ化と3D プリンターを用いたレプリカ制作、及びそれらを展示、教育目的として活用する一連の試みを実践した。3D スキャンの手法としてはフォトグラメトリーを採用している。フォトグラメトリーのデータ取得において、館外への持ち出しが難しい貴重な標本については、撮影条件を整えるのが困難な出張先においても成功率を高めるノウハウも確立した。本稿においてはそれらについても報告している。 「動物のからだ展」ではこれまでに無い試みとして、美術と博物の垣根を越え、人工物である美術作品や標本のレプリカを同じ会場で比較して展示をしている。多くの展示・発表の機会も創出し、「動物のからだ展」では9 日間で2,700 名の動員を得た。, This report is the implementation report of Grants-in-Aid for Scientific Research 16K00731 "Development and practice of a method to use skeletal specimens owned by the natural history museum with a 3D printer" and "Animal Body Exhibition” of the research's result announcement. In this research , as a study of art design university, we did digitalization of skeletal specimens and replica production using 3D printer. The replicas were produced using skeletal specimens stored in the museum of natural history and the zoo's museum, and those collected by ourselves. I adopted photogrammetry as a method of 3D scanning. It is very difficult to acquire data of valuable samples that are difficult to take out outside because it is difficult to set up the imaging conditions. We have also established a way to increase the success rate of data acquisition under such difficult shooting conditions. In “Animal Body Exhibition”, we made an unprecedented attempt. We display replicas of works of art and specimens, which are artefacts, across the boundaries of art and museums at the same venue. At the “Animal Body Exhibition”, 2,700 people were mobilized on the 9days.

Intensive analysis of the SMARCB1 gene in malignant rhabdoid tumors (MRT) revealed eight of 16 patients with constitutional genetic variants. Three patients had mosaicism of deletion/variant of the SMARCB1 gene, which conventional methods might overlook. The prevalence of cancer predisposition in MRT may thus be higher than previously reported.

Infant acute lymphoblastic leukemia with lysine (K)-specific methyltransferase 2A (KMT2A) rearrangements usually has a poor prognosis regardless of the fusion partners of KMT2A. However, the prognosis of pediatric acute myeloid leukemia (AML) with KMT2A rearrangements depends on its translocation partners. We herein report the case of a 9-month-old boy with a KMT2A-USP2 fusion, which required diagnosis by whole transcriptome sequencing after the failure of detection of known translocation partners by conventional screening approaches. As this first report of a patient with AML with a KMT2A-USP2 fusion illustrates, identification of the partners in all patients with KMT2A-rearranged AML is critical to elucidate the outcomes associated with specific rearrangements and to develop appropriate treatment strategies. Moreover, development of additional methods to detect specific translocation partners of KMT2A and leukemia-specific targeting drugs is important to improve further the outcomes of KMT2A-rearranged AML.

AIM To retrospectively evaluate the outcomes of conventional transarterial chemoembolization (cTACE) for hepatocellular carcinoma (HCC) ≥10 cm. METHODS Twenty-five patients with naive HCC ≥10 cm (mean maximum tumor diameter, 130 ± 27.6 mm; single [n = 12], 2-9 [n = 6], and ≥10 [n = 7]) without extrahepatic spread treated with cTACE were eligible. Five (20%) had vascular invasion. Two to three stepwise cTACE sessions using iodized oil ≤10 mL in one cTACE session were scheduled. When the tumor recurred, additional cTACE was repeated on demand, if possible. Overall survival (OS) rates were calculated using the Kaplan-Meier method. The prognostic factors were evaluated using uni- and multivariate analyses. RESULTS Stepwise cTACE sessions were completed for 20 (80%) patients, but could not be completed for four (16%). In the remaining (4%) patient, the whole tumor was embolized in one session. Additional treatment, mainly cTACE, was undertaken for 19 (76%) patients. The OS rates at 1, 3, and 5 years were 68, 34.7, and 23.1%, respectively. A tumor number of three was a significant prognostic factor (P = 0.020) and the 1-, 3-, and 4-year OS rates in patients with ≤3 and ≥4 tumors were 81.3 and 33.3, 55.6 and 11.1, and 38.9% and 0%, respectively. Whole tumor embolization and the serum level of protein induced by vitamin K absence or antagonist-II were also significant prognostic factors (P

Maritime Autonomous Surface Ship (MASS) has been developed recently, and demonstration projects have been carried out internationally. Considering the full autonomous level is unlikely to be addressed shortly, remote control centre and Remote Operator (RO) will play a vital role in the MASS system. Although competence of watchkeeping at the ship&rsquo, s bridge is inevitable for RO to avoid ship accidents caused by human errors, international requirements have not been introduced yet. This paper presents a way to develop the regulatory framework on the competence of RO based on the International Convention on Standards of Training, Certification and Watchkeeping for Seafarers (STCW) by exploring the concept of Situation Awareness (SA). Goal-Based Gap Analysis (GBGA) is constructed based on the human-behaviour model and the required information for SA. A case study through the mini focus group discussion with interviews by a total of three (3) veteran instructors of training ships is conducted utilising the information including the results of previous demonstration projects on the remote control. The results show the relationship between required information and ship sense, shortage of these factors when RO is operating, additional competence and possible regulatory requirements for RO. The findings support the usefulness of GBGA and pave the way to develop a regulatory framework for RO further.

In this study, the highly enantioselective α-allylation of α-substituted β-ketoesters, particularly 2-oxocycloalkanecarboxylates, is achieved by synergistic catalysis with an achiral palladium complex and a chiral primary amino acid. Various α-allylated β-ketoesters containing a quaternary carbon stereogenic center are synthesized in high yields (up to 97%) with excellent enantioselectivity (up to 99% ee).