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Radioactive materials were released into the ocean following the Fukushima Daiichi Nuclear Power Plant accident in 2011. Six years after the accident, the radioactive material concentration was markedly increased in the Okhotsk Intermediate Water (OIW) of the Sea of Okhotsk. This material may have been subjected to southward subsurface dispersal by the North Pacific Intermediate Water (NPIW), which originates from the OIW. The spatiotemporal limitations of available methods have made it challenging to track the dispersal paths of radioactive materials in the North Pacific Subpolar region. Here, we performed a tracer experiment using a three-dimensional numerical model to determine the path of 137Cs from Fukushima to the Sea of Okhotsk via surface subpolar gyre currents and subsurface dispersion by OIW and NPIW. The results showed that the 137Cs concentration in the Sea of Okhotsk increased via the surface current and moved progressively southward via OIW six years after the accident and eastward via OIW and NPIW nine years after the accident, indicating that 137Cs transported by NPIW entered the subtropical region. Based on experiments, this temporal change was mainly caused by ocean currents. Thus, subsurface recirculation of radioactive material via the OIW and NPIW should be considered based on the predicted path and travel time of additional materials released from the power plant. [ABSTRACT FROM AUTHOR]

Sea surface temperature (SST) is crucial for understanding the physical characteristics and ecosystems of coastal seas. SST varies near the tidal flat, where exposure and flood recur according to the tidal cycle. However, the variability of SST near the tidal flat is poorly understood owing to difficulties in making in-situ observations. The high resolution of Landsat 8 enabled us to determine the variability of SST near the macro tidal flat. The spatial distribution of the SST extracted from Landsat 8 changed drastically. The seasonal SST range was higher near the tidal flat than in the open sea. The maximum seasonal range of coastal SST exceeded 23 °C, whereas the range in the open ocean was approximately 18 °C. The minimum and maximum horizontal SST gradients near the tidal flat were approximately − 0.76 °C/10 km in December and 1.31 °C/10 km in June, respectively. The heating of sea water by tidal flats in spring and summer, and cooling in the fall and winter might result in a large horizontal SST gradient. The estimated heat flux from the tidal flat to the seawater based on the SST distribution shows seasonal change ranging from − 4.85 to 6.72 W/m2. [ABSTRACT FROM AUTHOR]

Condition monitoring of the stator and rotor problems such as interturn short fault (ITSF) and partial irreversible demagnetization fault (PIDF) in an interior permanent magnet synchronous motor (IPMSM) is essential for achieving high efficiency and reliability. This article presents a torque angle-based inverter-embedded technique for the online detection and identification of ITSF and PIDF. This technique monitors the deviation in the torque angle caused due to ITSF and PIDF at a certain operating point. In steady-state operation, the torque angle decreases from its original value (healthy state) due to ITSF while increases in the case of PIDF. This particular trend of torque angle is used for the detection and identification of ITSF and PIDF. In this article, the torque angle for a healthy IPMSM is first obtained using multivariate regression analysis over the entire operating region and then compared with the torque angle during operation for any potential variation. The proposed method is verified using a finite-element method-based simulation and experiment on a 400-W IPMSM. The results suggest that the proposed method can be a viable candidate for efficient ITSF and PIDF detection and identification in real time. [ABSTRACT FROM AUTHOR]

An inter-turn fault (ITF) is conventionally analyzed by a method that uses negative-sequence components obtained by symmetrical coordinate transformations. However, this method is inefficient because it involves solving complex equations that include many parameters. This paper proposes a simplified d–q equivalent circuit model of a permanent magnet synchronous motor with an ITF. The model is developed by reflecting representative phenomena related to the negative sequence components of the fault in advance of a final model construction, such that the final model does not require the separation of positive and negative sequence components. As a result, the model can rapidly examine the influence of the fault due to the simplicity of the equations, and can help build the detection and tolerance control techniques of the fault. The model is verified by numerical analysis, simulation and experiment. [ABSTRACT FROM AUTHOR]

The development of high-performance concrete using carbon nanotubes (CNTs), which is used in various industries owing to its excellent mechanical properties, has attracted much attention, leading to ongoing research in this area. However, when mixing CNTs into cement paste, there has been limited focus on the dispersibility, and, in most cases, aqueous dispersions of CNTs used in other industrial sectors are used. Because CNTs form the structures of bundles or aggregates owing to their high aspect ratio and van der Waals force between particles, the desired dispersibility cannot be obtained when mixing CNTs in powder form with other materials. Therefore, in this study, we examined the applicability of CNT aqueous dispersions using PC-based plasticizer used in concrete. Aqueous dispersions of CNT using PC-based surfactants are prepared and their properties are compared with those of a PVP-based aqueous dispersion. To analyze the mechanical properties, the compressive strength and flexural strength are measured on the 28th day. Then, the dispersibility and microstructure are analyzed using scanning electron microscopy image analysis, thermogravimetric analysis, and BET (Brunauer–Emmett–Teller) analysis. The analysis results show the enhancement of mechanical properties due to the mixing of the CNT dispersion, and the results confirm the applicability of the proposed CNT aqueous dispersions using PC-based surfactants. [ABSTRACT FROM AUTHOR]

Background: We evaluated the incidence and spectrum of pathogenic and likely pathogenic variants of cancer susceptibility genes in BRCA1/2 mutation-negative Korean patients with a high risk for hereditary breast cancer using a comprehensive multigene panel that included 35 cancer susceptibility genes.Methods: Samples from 120 patients who were negative for BRCA1/2 mutations, but had been diagnosed with breast cancer that was likely hereditary, were prospectively evaluated for the prevalence of high-penetrance and moderate-penetrance germline mutations.Results: Nine patients (7.5%) had at least one pathogenic or likely pathogenic variant. Ten variants were identified in these patients: TP53 in two patients, PALB2 in three patients, BARD1 in two patients, BRIP1 in two patients, and MRE11A in one patient. We also identified 30 types of 139 variants of unknown significance (VUS). High-penetrance germline mutations, including TP53 and PALB2, tended to occur with high frequency in young (< 35 years) breast cancer patients (4/19, 21.1%) than in those diagnosed with breast cancer at ≥35 years of age (1/101, 1.0%; p = 0.003).Conclusions: These combined results demonstrate that multigene panels offer an alternative strategy for identifying veiled pathogenic and likely pathogenic mutations in breast cancer susceptibility genes. [ABSTRACT FROM AUTHOR]

Acquisition of sperm capacitation post-ejaculation into the female reproductive tract is an essential step in the fertilization process. Accordingly, during in vitro fertilization, successful fertilization requires the induction of capacitation in epididymis-retrieved sperm. To date, many candidate substances have been considered as capacitation inducers; however, there are no reports on the efficiency of inducing sperm capacitation among the diverse inducers. Therefore, we attempted to determine the inducer with the best capacitation in inbred mouse sperm by comparing the capacitation performance of a variety of inducers and the percentage of in vitro fertilization-generated zygotes. Calcium chloride, progesterone, bovine serum albumin (BSA), heparin, and lysophosphatidylcholine (Lyso-PC) were used as candidate capacitation inducers. Optimized concentrations of each inducer (2.7 mM calcium, 15 μM progesterone, 0.3% (w/v) BSA, 50 mM heparin, and 100 μM Lyso-PC) were determined based on the ratio of sperm showing an acrosome reaction using Coomassie G-250 blue staining. Calcium at 2.7 mM showed the strongest capacitation induction compared to the other inducers. In vitro fertilization was performed using sperm incubated in each inducer and the ratio of fertilized oocytes was determined. Calcium at 2.7 mM and 0.3% (w/v) BSA showed the highest fertilization rates compared to 15 μM progesterone, 50 mM heparin, and 100 μM Lyso-PC. From these results, we found that 2.7 mM calcium and 0.3% (w/v) BSA were the most effective sperm capacitation inducers of mouse sperm for in vitro fertilization. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma has features of both indolent and aggressive non-Hodgkin lymphomas. Repeated relapses leading to treatment failure in patients with mantle cell lymphoma might suggest the presence of cancer stem cells. A small cell population with CD45+/CD19 − was previously reported to represent cancer stem cells. We evaluated the clinical relevance of CD45+/CD19 − cells in bone marrow of patients with mantle cell lymphoma (n= 20). A CD45+/CD19 − cell population was observed in newly diagnosed mantle cell lymphoma, and its percentage correlated with tumor cells in bone marrow (r= 0.832,p= 0.001) and score on the simplified mantle cell lymphoma prognostic index (r =0.675,p= 0.016). After treatment, CD45+/CD19 − cells decreased (mean: 0.012%), and CD45+/CD19 − cells (0.276%) were higher at relapse or progression than at diagnosis. In conclusion, a CD45+/CD19 − cell population in bone marrow aspirates correlated with the clinical outcome of patients with mantle cell lymphoma. [ABSTRACT FROM AUTHOR]

The present study sought to determine the correlation between 2-methoxyestradiol (2-MeO-E 2 )-induced cell cycle arrest and 2-MeO-E 2 -induced apoptosis. Exposure of Jurkat T cell clone (JT/Neo) to 2-MeO-E 2 (0.5–1.0 μM) caused G 2 /M arrest, Bak activation, Δψm loss, caspase-9 and -3 activation, PARP cleavage, intracellular ROS accumulation, and apoptotic DNA fragmentation, whereas none of these events except for G 2 /M arrest were induced in Jurkat T cells overexpressing Bcl-2 (JT/Bcl-2). Under these conditions, Cdk1 phosphorylation at Thr-161 and dephosphorylation at Tyr-15, up-regulation of cyclin B1 expression, histone H1 phosphorylation, Cdc25C phosphorylation at Thr-48, Bcl-2 phosphorylation at Thr-56 and Ser-70, Mcl-1 phosphorylation at Ser-159/Thr-163, and Bim phosphorylation were detected irrespective of Bcl-2 overexpression. Concomitant treatment of JT/Neo cells with 2-MeO-E 2 and the G 1 /S blocking agent aphidicolin resulted in G 1 /S arrest and abrogation of all apoptotic events, including Cdk1 activation, phosphorylation of Bcl-2, Mcl-1 and Bim, and ROS accumulation. The 2-MeO-E 2 -induced phosphorylation of Bcl-2 family proteins and mitochondrial apoptotic events were suppressed by a Cdk1 inhibitor, but not by an Aurora A kinase (AURKA), Aurora B kinase (AURKB), JNK, or p38 MAPK inhibitor. Immunofluorescence microscopic analysis revealed that 2-MeO-E 2 -induced mitotic arrest was caused by mitotic spindle network impairment and prometaphase arrest. Whereas 10–20 μM 2-MeO-E 2 reduced the proportion of intracellular polymeric tubulin to monomeric tubulin, 0.5–5.0 μM 2-MeO-E 2 increased it. These results demonstrate that the apoptogenic effect of 2-MeO-E 2 (0.5–1.0 μM) was attributable to mitotic spindle defect-mediated prometaphase arrest, Cdk1 activation, phosphorylation of Bcl-2, Mcl-1, and Bim, and activation of Bak and mitochondria-dependent caspase cascade. [ABSTRACT FROM AUTHOR]

To report a case of primary vitreoretinal lymphoma (PVRL) showing recurrence after spontaneous regression, diagnosed with the aid of next-generation sequencing (NGS). Retrospective case report. A 61-year-old immunocompetent Korean woman presented with subretinal lesions suspected of PVRL, which resolved spontaneously in 2 months. After 8 months, the lesion recurred and diagnostic vitrectomy was performed. The cytologic examination of the vitreous was indeterminate as there was only minimal vitreous opacity present at the time of surgery. NGS identified significant mutations including single nucleotide variants in MYD88 L265P, which is a unique hallmark of VRL, in vitreous sample, and the diagnosis of PVRL was made. This case showed PVRL can spontaneously regress almost completely, then recur, so careful ophthalmic and systemic follow-ups are warranted. When cytological confirmation is challenging due to the minimal disease involvement in the vitreous, NGS is effective in confirming the mutation profiles of PVRL. [ABSTRACT FROM AUTHOR]

The article reports on cases of in-frame deletion mutation in juxtamembrane domain (JMD) of the FLT3 (Fms-like tyrosine kinase 3). It states that cases include patients with easy bruisability and petechiae and hyperdiploid B cell-acute lymphoblastic leukemia and bone marrow showed increase count in myeloblast cells. It mentions that in one patient the deletion mutation was missing upon relapse, suggesting that mutation may not be driver mutation having different genetic backgrounds.

Introduction: Acute myeloid leukemia (AML) is a complex hematologic malignancy characterized by uncontrolled proliferation of myeloid precursor cells within bone marrow. Despite advances in understanding of its molecular underpinnings, AML remains a therapeutic challenge due to its high relapse rate and clonal evolution. Methods: In this retrospective study, we analyzed data from 24 AML patients diagnosed at a single institution between January 2017 and August 2023. Comprehensive genetic analyses, including chromosomal karyotyping, next-generation sequencing, and gene fusion assays, were performed on bone marrow samples obtained at initial diagnosis and relapse. Clinical data, treatment regimens, and patient outcomes were also documented. Results: Mutations in core genes of FLT3, NPM1, DNMT3A, and IDH2 were frequently discovered in diagnostic sample and remained in relapse sample. FLT3-ITD, TP53, KIT, RUNX1, and WT1 mutation were acquired at relapse in one patient each. Gene fusion assays revealed stable patterns, while chromosomal karyotype analyses indicated a greater diversity of mutations in relapsed patients. Clonal evolution patterns varied, with some cases showing linear or branching evolution and others exhibiting no substantial change in core mutations between diagnosis and relapse. Conclusions: Our study integrates karyotype, gene rearrangements, and gene mutation results to provide a further understanding of AML heterogeneity and evolution. We demonstrate the clinical relevance of specific mutations and clonal evolution patterns, emphasizing the need for personalized therapies and measurable residual disease monitoring in AML management. By bridging the gap between genetics and clinical outcome, we move closer to tailored AML therapies and improved patient prognoses. [ABSTRACT FROM AUTHOR]

Brentuximab vedotin (BV) monotherapy (BV-M) and combination (BV-C) therapies are safe and effective for classical Hodgkin lymphoma (cHL) and CD30-expressing peripheral T-cell lymphomas (PTCLs). Although the sample sizes have been small (12–29 patients), in clinical studies, response rates of 53–88% have been reported for BV retreatment in patients with an initial BV response. We evaluated the real-world characteristics and treatment patterns of cHL/PTCL patients who received BV and were retreated in the United States. Symphony Health Patient Claims (11/2013–1/2022) were retrospectively analyzed to identify cHL/PTCL patients treated with BV and retreated with BV-M, BV-C, or non-BV therapy. Patient characteristics were described by retreatment, and predictors of BV-M retreatment were identified. Among the cHL and PTCL patients treated with BV (n = 6442 and 2472, respectively), 13% and 12%, respectively, were retreated with BV; the median times from initial BV to BV-M retreatment were 5 and 7 months, respectively; and the numbers of BV-M retreatment doses were 4 and 5, respectively. Among cHL patients, the predictors of BV-M retreatment were age (18–39 vs. ≥60 years), sex (women vs. men), and previous stem cell transplantation (yes vs. no). Among PTCL patients, the only predictor of BV-M retreatment was systemic anaplastic large-cell lymphoma subtype (yes vs. no). Real-world data support clinical study results suggesting earlier BV treatment be considered, as BV retreatment may be an option. [ABSTRACT FROM AUTHOR]

The roles of individual bacteria and their relationship in the development of colorectal cancer (CRC) remain unclear. We aimed to determine the prevalence of CRC-associated bacteria using quantitative real-time PCR (qPCR) or 16S rRNA analysis and the statistical correlations of patient demographics and clinical characteristics comprising alcohol consumption with CRC-associated bacteria. We determined the prevalence of five CRC-associated bacterial species in 38 CRC patients (39 samples) and 21 normal individuals using qPCR, and the relative abundance of bacterial taxa in the gut microbiome was assessed using 16S rRNA analysis. Fusobacterium nucleatum was the only bacterium that was significantly (P < 0.0001) more prevalent in the cancer tissue (82.1%) than in the normal tissue (0%) by qPCR. 16S rRNA analysis showed a significant correlation between six operational taxonomic units (OTUs), namely, the genera Fusobacterium, Peptostreptococcus, Collinsella, Prevotella, Parvimonas, and Gemella, in patients with CRC. An integrated analysis using 16S rRNA data and epidemiological characteristics showed that alcohol consumption was significantly correlated with the abundance of Fusobacterium OTUs. The correlation of alcohol consumption with the abundance of Fusobacterium OTUs in cancer tissue discovered using 16S rRNA analysis suggests a possible link between alcohol metabolism and subsequent tumorigenesis caused by F. nucleatum. [ABSTRACT FROM AUTHOR]

Objective: We aimed to identify common genes and recurrent causative variants in a large group of Asian patients with different epilepsy syndromes and subgroups. Methods: Patients with unexplained pediatric‐onset epilepsy were identified from the in‐house Severance Neurodevelopmental Disorders and Epilepsy Database. All patients underwent either exome sequencing or multigene panels from January 2017 to December 2019, at Severance Children's Hospital in Korea. Clinical data were extracted from the medical records. Results: Of the 957 patients studied, 947 (99.0%) were Korean and 570 were male (59.6%). The median age at testing was 4.91 years (interquartile range, 1.53–9.39). The overall diagnostic yield was 32.4% (310/957). Clinical exome sequencing yielded a diagnostic rate of 36.9% (134/363), whereas the epilepsy panel yielded a diagnostic rate of 29.9% (170/569). Diagnostic yield differed across epilepsy syndromes. It was high in Dravet syndrome (87.2%, 41/47) and early infantile developmental epileptic encephalopathy (60.7%, 17/28), but low in West syndrome (21.8%, 34/156) and myoclonic‐atonic epilepsy (4.8%, 1/21). The most frequently implicated genes were SCN1A (n = 49), STXBP1 (n = 15), SCN2A (n = 14), KCNQ2 (n = 13), CDKL5 (n = 11), CHD2 (n = 9), SLC2A1 (n = 9), PCDH19 (n = 8), MECP2 (n = 6), SCN8A (n = 6), and PRRT2 (n = 5). The recurrent genetic abnormalities included 15q11.2 deletion/duplication (n = 9), Xq28 duplication (n = 5), PRRT2 deletion (n = 4), MECP2 duplication (n = 3), SCN1A, c.2556+3A>T (n = 3), and 2q24.3 deletion (n = 3). Significance: Here we present the results of a large‐scale study conducted in East Asia, where we identified several common genes and recurrent variants that varied depending on specific epilepsy syndromes. The overall genetic landscape of the Asian population aligns with findings from other populations of varying ethnicities. [ABSTRACT FROM AUTHOR]

Clonal hematopoiesis (CH) is a condition in which healthy individuals have somatic mutations in hematopoietic stem cells. It has been reported with increased risk of hematologic malignancy and cardiovascular disease in the general population, but studies of Korean populations with comorbid disease entities are scarce. White blood cells (WBCs) from patients with gastric cancer (GC) (n=121) were analyzed using a DNA-based targeted (531 genes) panel with customized pipeline designed to detect single nucleotide variants and small indels with low-allele-frequency of ≥0.2 %. We defined significant CH variants as having variant allele frequency (VAF) ≥2 % among variants found in WBCs. Matched cell-free DNA (cfDNA) samples were also analyzed with the same pipeline to investigate the false-positive results caused by WBC variants in cfDNA profiling. Significant CH variants were detected in 29.8 % of patients and were associated with age and male sex. The number of CH variants was associated with a history of anti-cancer therapy and age. DNMT3A and TET2 were recurrently mutated. Overall survival rate of treatment-naïve patients with stage IV GC was higher in those with CH, but Cox regression showed no significant association after adjustment for age, sex, anti-cancer therapy, and smoking history. In addition, we analyzed the potential interference of WBC variants in plasma cell-free DNA testing, which has attracted interest as a complementary method for tissue biopsy. Results showed that 37.0 % (47/127) of plasma specimens harbored at least one WBC variant. VAFs of interfering WBC variants in the plasma and WBC were correlated, and WBC variants with VAF ≥4 % in WBC were frequently detected in plasma with the same VAF. This study revealed the clinical impact of CH in Korean patients and suggests the potential for its interference in cfDNA tests. [ABSTRACT FROM AUTHOR]

To report a case of a patient whose MYD88 mutation disappeared from the aqueous humor following treatment with intravitreal methotrexate. A retrospective review of clinical, histopathological and imaging records. A 49-year-old woman presented with bilateral primary vitreoretinal lymphoma confirmed by molecular and next-generation sequencing studies on vitreous biopsy samples. Initially, the MYD88 L265P mutation was detected in aqueous samples of both eyes. Serial testing for MYD88 L265P mutations performed on aqueous samples collected at the time of the weekly intravitreal methotrexate injections showed the mutation ceased to be detected after four weekly injections in the non-vitrectomized right eye and after two weekly injections in the vitrectomized left eye. Clinical improvement accompanied the negativization of the mutation in both eyes. We present a case that demonstrates the possible utilization of serial testing for the MYD88 L265P mutation as a tool for monitoring disease course in vitreoretinal lymphoma. [ABSTRACT FROM AUTHOR]

In addition to somatic mutations, germline genetic predisposition to hematologic malignancies is currently emerging as an area attracting high research interest. In this study, we investigated genetic alterations in Korean acute lymphoblastic leukemia/lymphoma (ALL) patients using targeted gene panel sequencing. To this end, a gene panel consisting of 81 genes that are known to be associated with 23 predisposition syndromes was investigated. In addition to sequence variants, gene-level copy number variations (CNVs) were investigated as well. We identified 197 somatic sequence variants and 223 somatic CNVs. The IKZF1 alteration was found to have an adverse effect on overall survival (OS) and relapse-free survival (RFS) in childhood ALL. We found recurrent somatic alterations in Korean ALL patients similar to previous studies on both prevalence and prognostic impact. Six patients were found to be carriers of variants in six genes associated with primary immunodeficiency disorder (PID). Of the 81 genes associated with 23 predisposition syndromes, this study found only one predisposition germline mutation (TP53) (1.1%). Altogether, our study demonstrated a low probability of germline mutation predisposition to ALL in Korean ALL patients. [ABSTRACT FROM AUTHOR]

In vivo, mammalian oocytes are surrounded by granulosa cells (GCs) that exist in a three-dimensional (3D) microenvironment with soft stiffness. The GCs play an important role for the in vivo growth and development of oocytes, through bidirectional communication between oocytes and GCs. To mimic the cellular microenvironment of a 3D organized follicle, this study designed a co-culture system using porcine ovarian GCs (pGCs) encapsulated in agarose matrix for in vitro maturation (IVM) of pig oocytes. We report the effects of our newly designed co-culture system on IVM and development of pig oocytes. Immature cumulus-oocyte-complexes (COCs) were matured on a 1% (w/v) agarose matrix encapsulated without or with pGCs. The number of pGCs within the agarose matrix was optimized by analyzing the in vitro development of parthenogenetic embryos. Moreover, the role of the ovarian stromal pGCs as feeder cells was assessed by analyzing the PA embryonic development. Subsequently, the effect of pGCs encapsulated in a 3D agarose matrix was evaluated for the developmental competence of pig oocytes by analyzing blastocyst formation after parthenogenetic activation (PA), intra-oocyte GSH and ROS contents, expression levels of BMP15 and BAX , TUNEL (terminal deoxynucleotidyl transferase-mediated d-UTP nick end-labeling) assay, protein expression levels of BMP15, and intra-oocyte ATP levels. The optimized number of pGCs (5 × 104 cells/well) in a 3D agarose matrix led to a significantly higher blastocyst formation, increased BMP15 gene and protein expression, and intra-oocyte ATP levels; moreover, it induced significantly lower intra-oocyte ROS contents, pro-apoptotic BAX gene expression, and apoptotic index, compared to control. Our results demonstrate that application of pGCs as feeder cells encapsulated in the agarose matrix for IVM effectively increases the developmental competence of porcine oocytes. • Effects of IVM on agarose matrix with granulosa cells on oocyte maturation and embryonic development were evaluated in pigs. • IVM under the granulosa cells (pGCs) in a 3D agarose matrix significantly increased BMP15 gene and protein expression. • IVM under the pGCs in agarose matrix increased intra-oocyte ATP levels and reduced ROS contents and apoptotic index. • Application of the agarose matrix with pGCs for IVM effectively increased the developmental competence of pig oocytes. [ABSTRACT FROM AUTHOR]

The North Pacific is a crucial region in decadal climate changes like the El-Ninõ Southern Oscillation (ENSO) and the Pacific decadal oscillation (PDO), which influence critically not only oceans but also atmosphere. Despite of the importance of ocean data in the North Pacific, available data have been rare due to limitation of accessibility. Data assimilation have been used to produce more reliable ocean data. The North Pacific is comprised of several distinctive areas, including the equatorial and tropical regions, subtropical regions, and the boreal Bering Sea region. Each region demonstrates various ocean current characteristics. Appropriate assimilation method considering the characteristics of the sea area might be selected. In this study, we compared the performance of Ensemble Optimal Interpolation (EnOI), a simplified version of Ensemble Kalman Filter (EnKF), according to ensemble composition and assimilation time interval and compared the regional performance difference between EnOI and EnKF in each region. Ocean circulation model in the North Pacific was conducted using ROMS from 2006 to 2015. Assimilation of sea surface temperature for 2015 using EnKF and EnOI methods with satellite data from the Operational Sea Surface Temperature and Sea Ice Analysis (OSTIA) was applied respectively. The RMSE of the Sea Surface Temperature of EnKF was lower than that of EnOI in the Northwest Pacific where the spatial SST correlation structure was complex. But, the RMSE of EnOI was lower than EnKF in the Equator area with simple SST correlation structure in SST. The efficiency of each method in terms of accuracy, resources and time was also compared. EnOI was faster by about 7 times than EnKF. [ABSTRACT FROM AUTHOR]

Previously, we reported that endometrial stromal (ES) and endometrial epithelial (EE) cells did not attach to tenascin C, indicating the absence of active integrin α9β1 on the surface of mouse ES and EE cells. However, that study used recombinant tenascin C without fibronectin (FN) type III repeats interacting with integrin heterodimers. Therefore, we re-evaluated the presence of integrin α9β1 actively functioning on the surface of mouse ES and EE cells using full-length native tenascin C with FN type III repeats. The functionality of integrin α9β1 was confirmed using attachment and antibody inhibition assays. Both mouse ES and EE cells showed significantly increased adhesion to native tenascin C, and functional blocking of integrin α9β1 significantly inhibited adhesion to native tenascin C. These results demonstrate that the integrin α9 and β1 subunits function as active heterodimers on the plasma membrane of mouse ES and EE cells, respectively. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding a rare case of CD5-positive mature B-cell neoplasm with t(10;14)(q24;q11.2) and trisomy 12 in a 62-year-old male.

Background: Hereditary hemolytic anemia (HHA) refers to a heterogeneous group of genetic disorders that share one common feature: destruction of circulating red blood cells (RBCs). The destruction of RBCs may be due to membranopathies, enzymopathies, or hemoglobinopathies. Because these are genetic disorders, incorporation of next-generation sequencing (NGS) has facilitated the diagnostic process of HHA. Method: Genetic data from 29 patients with suspected hereditary anemia in a tertiary hospital were retrospectively reviewed to evaluate the efficacy of NGS on hereditary anemia diagnosis. Targeted NGS was performed with custom probes for 497 genes associated with hematologic disorders. After genomic DNA was extracted from peripheral blood, prepared libraries were hybridized with capture probes and sequenced using NextSeq 550Dx (Illumina, San Diego, CA, USA). Result: Among the 29 patients, ANK1 variants were detected in five, four of which were pathogenic or likely pathogenic variants. SPTB variants were detected in six patients, five of which were classified as pathogenic or likely pathogenic variants. We detected g6pd pathogenic and spta1 likely pathogenic variants in two patients and one patient, respectively. Whole-gene deletions in both HBA1 and HBA2 were detected in two patients, while only HBA2 deletion was detected in one patient. One likely pathogenic variant in PLKR was detected in one patient, and one likely pathogenic variant in ALAS2 was detected in another. Conclusion: Here, NGS played a critical role in definitive diagnosis in 18 out of 29 patients (62.07%) with suspected HHA. Thus, its incorporation into the diagnostic workflow is crucial. [ABSTRACT FROM AUTHOR]

Background: Hereditary hemolytic anemia (HHA) refers to a heterogeneous group of genetic disorders that share one common feature: destruction of circulating red blood cells (RBCs). The destruction of RBCs may be due to membranopathies, enzymopathies, or hemoglobinopathies. Because these are genetic disorders, incorporation of next-generation sequencing (NGS) has facilitated the diagnostic process of HHA. Method: Genetic data from 29 patients with suspected hereditary anemia in a tertiary hospital were retrospectively reviewed to evaluate the efficacy of NGS on hereditary anemia diagnosis. Targeted NGS was performed with custom probes for 497 genes associated with hematologic disorders. After genomic DNA was extracted from peripheral blood, prepared libraries were hybridized with capture probes and sequenced using NextSeq 550Dx (Illumina, San Diego, CA, USA). Result: Among the 29 patients, ANK1 variants were detected in five, four of which were pathogenic or likely pathogenic variants. SPTB variants were detected in six patients, five of which were classified as pathogenic or likely pathogenic variants. We detected g6pd pathogenic and spta1 likely pathogenic variants in two patients and one patient, respectively. Whole-gene deletions in both HBA1 and HBA2 were detected in two patients, while only HBA2 deletion was detected in one patient. One likely pathogenic variant in PLKR was detected in one patient, and one likely pathogenic variant in ALAS2 was detected in another. Conclusion: Here, NGS played a critical role in definitive diagnosis in 18 out of 29 patients (62.07%) with suspected HHA. Thus, its incorporation into the diagnostic workflow is crucial. [ABSTRACT FROM AUTHOR]

Background We evaluated the clinical accuracy and utility of whole-genome sequencing (WGS) of plasma microbial cell-free DNA (cfDNA) as a novel noninvasive method in diagnosing invasive aspergillosis (IA) in patients with hematologic malignancy (HM) or coronavirus disease 2019 (COVID-19). Methods Adults with HM or COVID-19 and suspected IA were recruited. IA cases were retrospectively diagnosed according to EORTC/MSG definitions and ECMM/ISHAM criteria for HM and COVID-19 patients, respectively. The results of cfDNA WGS were compared with the conventional diagnosis. Results Microbial cfDNA WGS was performed 53 times from 41 participants (19 from HM, 16 from COVID-19, and 7 from the control group). In participants with HM, Aspergillus cfDNA was detected in 100% of proven IA and 91.7% of probable IA cases. In participants with COVID-19, 50.0% of probable IA were positive for Aspergillus in cfDNA WGS. Concordance between Aspergillus cfDNA detection and proven/probable IA conventional diagnosis was significantly higher in participants with HM than in those with COVID-19. IA diagnosed using EORTC/MGS definitions showed significantly high concordance between Aspergillus cfDNA detection and proven/probable IA. Conclusions Aspergillus cfDNA detection strongly correlated with proven/probable IA diagnosed using EORTC/MSG definitions and could be used as an additional diagnostic tool for IA. [ABSTRACT FROM AUTHOR]

The exposure of cumulus cells to nuclear matured oocytes can be regulated through the forced delay of nuclear maturation or the alteration of in vitro maturation (IVM) time in cumulus-oocyte complexes (COCs). However, to date, no evidence has been presented for the enhancement of cytoplasmic maturation by them, indicating irrelevance of cumulus cells in cytoplasmic maturation. Therefore, in order to identify the requirement of cumulus cells in achieving the cytoplasmic maturation of immature oocytes, this study investigated the effects of cumulus cells on the in vitro cytoplasmic maturation of oocytes within COCs derived from porcine medium antral follicles (MAFs) post-the completion of nuclear maturation. For these, with IVM of COCs for 44 h (control), cumulus cell-free oocytes with completed nuclear maturation were in - vitro -matured additionally for 0, 6, or 12 h, and then a variety of factors representing the cytoplasmic maturation of oocytes were analyzed and compared. As the results, the IVM of COCs for 32 h showed complete nuclear maturation and incomplete cytoplasmic maturation. Moreover, after the removal of cumulus cells from COCs with the completion of nuclear maturation, IVM for an additional 6 or 12 h resulted in significant increases in the size of the perivitelline space, the proportion of oocytes with a normal intracellular mitochondrial distribution and a normal round first polar body, and the preimplantation development into the 2-cell and blastocyst stages after parthenogenetic activation. Simultaneously, they showed significant reduction in the level of intracellular reactive oxygen species and no significant differences in the total number of blastocysts. Furthermore, oocytes obtained by this approach did not significantly differ from control oocytes produced by IVM of COCs for 44 h. Our results demonstrate that the cumulus cells enclosing COCs derived from porcine MAFs are not essential for the completion of cytoplasmic maturation after complete nuclear maturation by COCs. [ABSTRACT FROM AUTHOR]

Simple Summary: In our study, we found genetic mutations in the DNA of cancer cells obtained from the blood of many patients with metastatic prostate cancer. These changes were more common in patients whose cancer was progressing and aggressive in nature, often unresponsive to conventional treatment strategies. Additionally, these genetic mutation findings were more sensitive than the conventional method of checking the prostate-specific antigen (PSA) level in the blood for detecting prostate cancer progression. This means a simple blood test could help us track genetic mutations, detect aggressive cancer subtypes, determine the progression of the disease, and manage advanced prostate cancer more effectively. The positivity rate of circulating tumor DNA (ctDNA) next-generation sequencing (NGS) varies among patients with metastatic prostate cancer (mPC), complicating its incorporation into regular practice. This retrospective study analyzed the ctDNA sequencing results of 100 mPC patients from May 2021 to March 2023 to identify the factors associated with positive ctDNA. Three custom gene panels were used for sequencing. Overall, 63% of the patients exhibited tier I/II somatic alterations, while 12% had pathogenic/likely pathogenic germline alterations. The key genes that were altered included AR, TP53, RB1, PTEN, and APC. Mutations in BRCA1/2, either germline or somatic, were observed in 21% of the patients. Among the metastatic castration-resistant prostate cancer (mCRPC) patients, the ctDNA-positive samples generally showed higher median prostate-specific antigen (PSA) levels and were more likely to be at the radiographic and clinical progressive disease stages, although they were not significantly associated with PSA progression. Our results suggest that ctDNA analysis could detect meaningful genetic changes in mPC patients, especially during disease progression. [ABSTRACT FROM AUTHOR]

Simple Summary: Circulating tumor DNA (ctDNA) has emerged as a potential biomarker for clear cell renal cell carcinoma (ccRCC). However, the ctDNA characteristics have not been demonstrated in small ccRCC. The aim of our pilot study is to explore the characteristics of ctDNA in pT1a ccRCC (ccRCC less than 4 cm in diameter). We included 53 patients with pT1a ccRCC, a greater number than in previous studies using next-generation sequencing. We found that the ctDNA detection rate was low in pT1a ccRCC. The relationship between ctDNA and clinicopathological features, such as tumor size, tumor grade, and patient age, was not clear. Increasing the sensitivity and removing background noise in ctDNA analysis may aid in further understanding the characteristics of ctDNA, thereby enhancing its clinical utility in pT1a ccRCC. Circulating tumor DNA (ctDNA) is a promising biomarker for clear cell renal cell carcinoma (ccRCC); however, its characteristics in small renal masses of ccRCC remain unclear. In this pilot study, we explored the characteristics of ctDNA in pT1a ccRCC. Plasma samples were collected preoperatively from 53 patients with pT1a ccRCC. The ctDNA of pT1a ccRCC was profiled using next-generation sequencing and compared with that of higher-stage ccRCC. The association of ctDNA in pT1a ccRCC with clinicopathological features was investigated. The positive relationship of mutations between ctDNA and matched tissues was evaluated. In pT1a ccRCC, the ctDNA detection rate, cell-free DNA concentration, and median variant allele frequency were 20.8%, 5.8 ng/mL, and 0.38%, respectively, which were significantly lower than those in metastatic ccRCC. The ctDNA gene proportions in pT1a samples differed from those in metastatic ccRCC samples. The relationships between ctDNA and tumor size, tumor grade, and patient age were not elucidated. The positive concordance between ctDNA and matched tissues was poor for pT1a ccRCC. Strategies are needed to increase sensitivity while eliminating noise caused by clonal hematopoiesis to increase the clinical utility of ctDNA analysis in small renal masses of ccRCC. [ABSTRACT FROM AUTHOR]

Background: PPM1D (Protein phosphatase magnesium-dependent 1δ) is known as a damage response regulator, a part of the p53 negative feedback loop. Truncating mutations of PPM1D, resulting in overexpression, are frequently found in the blood of patients with breast or ovarian cancer. To identify whether the PPM1D mutation predisposes patients to such cancers or if it results from the cancer and therapy, somatic PPM1D mutations in association with previous cancer and chemotherapy need to be explored. Methods: We performed next-generation sequencing (NGS) analysis of blood samples from patients suspected to have hereditary cancer. We grouped the patients according to their diagnoses and history of chemotherapy. For the patients with PPM1D mutations in blood, tumor tissue specimens were examined for the PPM1D mutation using conventional sequencing. Results: A total of 1,195 patients, including 719 patients with breast cancer and 240 with ovarian cancer, were tested, and four (~0.3%) had the truncating mutation in PPM1D. All truncating mutations were in exon 6, in mosaic form, with a mean allele fraction of 11.15%. While 395 out of the 1,195 patients had undergone chemotherapy, the four with the truncating mutation had a history of cisplatin-based chemotherapy. No corresponding mutations were identified in the tumor tissues. Conclusions: We investigated the frequency of the somatic mosaic PPM1D mutation, in patients with breast or ovarian cancer, which is suggested to be low and related to a history of cisplatin-based chemotherapy. It may be a marker of previous exposure to selective pressure for cells with an impaired DNA damage response. [ABSTRACT FROM AUTHOR]

Background: BCR::ABL1 fusion has significant prognostic value and is screened for chronic myeloid leukemia (CML) disease monitoring as a part of routine molecular testing. To overcome the limitations of the current standard real-time quantitative polymerase chain reaction (RQ-PCR), we designed and validated a next-generation sequencing (NGS)-based assay to quantify BCR::ABL1 and ABL1 transcript copy numbers. Methods: After PCR amplification of the target sequence, deep sequencing was performed using an Illumina Nextseq 550Dx sequencer and in-house–designed bioinformatics pipeline. The Next-generation Quantitative sequencing (NQ-seq) assay was validated for its analytical performance, including precision, linearity, and limit of detection, using serially diluted control materials. A comparison with conventional RQ-PCR was performed with 145 clinical samples from 77 patients. Results: The limit of detection of the NQ-seq was the molecular response (MR) 5.6 [BCR::ABL1 0.00028% international scale (IS)]. The NQ-seq exhibited excellent precision and linear range from MR 2.0 to 5.0. The IS value from the NQ-seq was highly correlated with conventional RQ-PCR. Conclusions: We conclude that the NQ-seq is an effective tool for monitoring BCR::ABL1 transcripts in CML patients with high sensitivity and reliability. Prospective assessment of the unselected large series is required to validate the clinical impact of this NGS-based monitoring strategy. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigated the effect of various growth factors and hormones in an in vitro growth medium on in vitro maturation and the developmental competence of oocytes derived from small antral follicles in pigs. Cumulus–oocyte complexes derived from small antral follicles (<3 mm) were cultured in an in vitro growth medium supplemented with epidermal growth factor (EGF), insulin-like factor-1 (IGF-1), insulin, or growth hormone (GH). The effects on oocyte growth, nuclear progression, oocyte maturation, and embryonic development after parthenogenesis were examined. Insulin treatment during oocyte growth was found to have a positive effect on nuclear maturation, embryonic development after parthenogenesis, and the expansion of cumulus cells. Insulin showed positive results by enhancing cytoplasmic maturation, decreasing free radical content, and increasing maturation-promoting factor activity. This study evaluated the effect of various growth factors and hormones in an in vitro growth (IVG) medium on the in vitro maturation (IVM) and developmental competence of oocytes derived from small antral follicles (SAFs) in pigs. Cumulus–oocyte complexes (COCs) derived from SAFs were either untreated or treated with epidermal growth factor (EGF), insulin-like factor-1 (IGF-1), insulin, or growth hormone (GH) for 2 days of IVG. Following IVG, COCs were cultured for maturation, and IVM oocytes were induced for parthenogenesis (PA). During IVG, the nuclear maturation of oocytes was significantly increased by the insulin treatment compared to other treatments. Moreover, the insulin treatment significantly increased blastocyst formation after PA relative to the No-IVG, control, EGF, and GH treatments. The cumulus expansion score after IVG-IVM was significantly higher in the insulin group than in the other groups. The glutathione (GSH) contents in IVM oocytes were increased through treatment with IGF, insulin, and GH compared to those of No-IVG oocytes. The level of reactive oxygen species (ROS) in IVM oocytes in all treatment groups was significantly lower after IVG culture than in the No-IVG group. The maturation-promoting factor (MPF) activity after IVM in the insulin-treated oocytes was significantly higher than that of the oocytes treated with EGF, IGF-1, and GH. In conclusion, this study demonstrates that insulin treatment during IVG culture improves the maturational and developmental competence of oocytes derived from SAFs in pigs through its effect on cumulus cell expansion and cytoplasmic microenvironments, such as GSH, ROS, and MPF activity. [ABSTRACT FROM AUTHOR]

Objectives: Detection of ovarian cancer progression is crucial in improving patient prognosis. However, existing tests based on biomarker and radiological imaging are insufficient for the early detection of recurrent ovarian cancer. Blood sample-based ctDNA samples are easily obtained and can be used for disease monitoring in ovarian cancer patients undergoing primary surgery. Methods: Patients diagnosed with epithelial ovarian carcinoma and control patients undergoing surgery for benign ovarian mass with CA-125 above 35 were enrolled. For ctDNA analysis, 10 mL of Whole blood samples were collected before surgery and 3, 6, 9, 12 months after surgery. Library preparation and target capture were done using a commercial kit and custom target gene panel targeting nine genes (ARID1A, BRCA1, BRCA2, CCNE1, KRAS, MYC, PIK3CA, PTEN, and TP53). Next-generation sequencing (NGS) was done with the NextSeq 550Dx System (Illumina, USA). Data analysis was performed using the custom analysis pipeline (Dxome, Korea). Variants are classified into four tiers based on their clinical significance in cancer diagnosis, prognosis, and therapeutics following the standards and guidelines established by the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. We curated only tier I/II variants as a meaningful variation. Results: We analyzed 352 whole blood samples from 172 patients, including 93 patients with carcinoma (high or low-grade serous, mucinous, clear cell, or endometrioid) and 79 patients with the benign or borderline ovarian disease. Among 93 patients with carcinoma, 69.9% (65/93) were identified with tier I/II (pathogenic) somatic mutations (TP53, BRCA1, BRCA2, ARID1A, MYC, PIK3CA, PTEN, KRAS) from preoperatively collected samples at baseline. No pathogenic mutations were identified in benign/borderline tumor patients (0/79). For the genes covered by ctDNA and tissue-NGS assays, a total number of 76 tier I/II somatic mutations were detected in 42 patients' tissue samples, of which 90.8% (69/76) were also detected temporally matched whole blood samples. Of the 42 tissue samples with mutations, 92.9% (39/42) had at least one concordant genomic mutation in ctDNA analysis. Among ten patients with cancer progression, 80.0% (8/10) patients were identified with the same list of mutations as the baseline. In these eight patients, ctDNA enabled early detection of future progression by an average of 41 days (maximum of 143 days) than the conventional methods. Based on three months of follow-up ctDNA, persistently elevated group patients had a worse prognosis than other groups (zero conversion, non-detectable) (figure 1). [Display omitted] Conclusions: Our preliminary analysis suggests that ctDNA-based surveillance may serve an important role in detecting disease progression in ovarian cancer, providing genetic characteristics of cancer. Further applicability of ctDNA in clinical decision-making should be explored. [ABSTRACT FROM AUTHOR]

Background: Nuclear hormone receptor gene, NR2F1, plays a key role in brain and eye development. Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS, MIM #615772) is an autosomal dominant hereditary disorder caused by mutations in this gene. However, there have been few studies describing fundus and optical coherence tomography findings on BBSOAS. Materials and methods: The patient underwent a detailed clinical evaluation and ophthalmic imaging followed by targeted panel next-generation sequencing analysis. Results: A 7-year-old Korean boy, with a history of delayed development and borderline intellectual functioning, was referred to our clinic for evaluation of low vision. He was born full-term with no perinatal insults. Best-corrected visual acuity was 20/100 in both eyes, and latent nystagmus was noted. Dilated fundus examinations revealed optic atrophy in both eyes, and optical coherence tomography showed diffuse thinning of retinal nerve fiber layers. Targeted panel next-generation sequencing showed novel c.513C>G; p.Tyr171Ter (NM_005654.4) in NR2F1 gene. This stop-gain mutation was predicted to be deleterious by in silico prediction programs, and was absent in the current population genomic database. Conclusions: We highlighted the value of genetic testing in definite diagnosis of BBSOAS in patients with unexplained optic atrophy. [ABSTRACT FROM AUTHOR]

The phenotype of the 5α-reductase type 2 deficiency (5αRD2) by the SRD5A2 gene mutation varies, and although there have been many attempts, the genotype-phenotype correlation still has not yet been adequately evaluated. Recently, the crystal structure of the 5α-reductase type 2 isozyme (SRD5A2) has been determined. Therefore, the present study retrospectively evaluated the genotype-phenotype correlation from a structural perspective in 19 Korean patients with 5αRD2. Additionally, variants were classified according to structural categories, and phenotypic severity was compared with previously published data. The p.R227Q variant, which belongs to the NADPH-binding residue mutation category, exhibited a more masculine phenotype (higher external masculinization score) than other variants. Furthermore, compound heterozygous mutations with p.R227Q mitigated phenotypic severity. Similarly, other mutations in this category showed mild to moderate phenotypes. Conversely, the variants categorized as structure-destabilizing and small to bulky residue mutations showed moderate to severe phenotypes, and those categorized as catalytic site and helix-breaking mutations exhibited severe phenotypes. Therefore, the SRD5A2 structural approach suggested that a genotype-phenotype correlation does exist in 5αRD2. Furthermore, the categorization of SRD5A2 gene variants according to the SRD5A2 structure facilitates the prediction of the severity of 5αRD2 and the management and genetic counseling of patients affected by it. [ABSTRACT FROM AUTHOR]

Next‐generation sequencing (NGS) facilitates comprehensive molecular analyses that help with diagnosing unsolved disorders. In addition to detecting single‐nucleotide variations and small insertions/deletions, bioinformatics tools can identify copy number variations (CNVs) in NGS data, which improves the diagnostic yield. However, due to the possibility of false positives, subsequent confirmation tests are generally performed. Here, we introduce Copy‐number Analysis by BAse‐level NormAlization (CABANA), a visualization tool that allows users to intuitively identify candidate CNVs using the normalized single‐base‐level read depth calculated from NGS data. To demonstrate how CABANA works, NGS data were obtained from 474 patients with neuromuscular disorders. CNVs were screened using a conventional bioinformatics tool, ExomeDepth, and then we normalized and visualized those data at the single‐base level using CABANA, followed by manual inspection by geneticists to filter out false positives and determine candidate CNVs. In doing so, we identified 31 candidate CNVs (7%) in 474 patients and subsequently confirmed all of them to be true using multiplex ligation‐dependent probe amplification. The performance of CABANA was deemed acceptable by comparing its diagnostic yield with previous data about neuromuscular disorders. Despite some limitations, we expect CABANA to help researchers accurately identify CNVs and reduce the need for subsequent confirmation testing. [ABSTRACT FROM AUTHOR]

Context: Despite the absence of light within the body, the application of microscopy during stages of in vitro embryo production has led to the discovery of light irradiation effects on embryo preimplantation development. Aims: To determine the optimal light irradiation wavelengths at various embryo stages for improving the preimplantation development of mouse embryos and the quality (total cell number) of blastocysts. Method: All in vitro procedures of zygote or 2-cell embryo manipulation, embryo monitoring, and culture medium exchange were conducted under visible (390–750 nm), blue (445–500 nm), green (500–575 nm), yellow (575–585 nm), or red (620–750 nm) light irradiation wavelength. Key results: We found that blue, green, and yellow light irradiation during in vitro blastocyst production from zygotes significantly improved blastocyst production and quality, compared to visible and red light irradiation. However, 2-cell embryos exposed to yellow light during in vitro blastocyst production produced significantly more high-quality blastocysts than did 2-cell embryos exposed to visible, blue, green, or red light. After exposure to blue and green – but not yellow – light during in vitro zygote manipulation, yellow light irradiation during embryo monitoring and culture medium exchange triggered significant retardation of preimplantation development. Conclusion: These results demonstrate that yellow light irradiation during in vitro blastocyst production, regardless of embryo stage, improves preimplantation development of mouse embryos. Implications: The present study will contribute to produce greater high-quality blastocysts and reduce experimental errors generated by light exposure during mouse embryo-related studies. Despite the absence of light within the body, light is an essential factor in the in vitro production of embryos using a microscope. However, light irradiation can adversely affect the embryos. This study demonstrates that yellow light irradiation during in vitro mouse embryo production can do the least damage to the embryos, and the finding will contribute to greater in vitro production of high-quality embryos and reduce experimental errors generated by light exposure during mouse embryo-related studies. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PCa) is characterized by complex genomic rearrangements such as the ETS oncogene family fusions, yet the clinical relevance is not well established. While paneled genetic tests of DNA repair genes are recommended in advanced PCa, conventional genomic or cytogenetic tools are not ideal for genome-wide screening of structural variations (SVs) such as balanced translocation due to cost and/or resolution issues. Methods: In this study, we tested the feasibility of whole-genome optical genomic mapping (OGM), a newly developed platform for genome-wide SV analysis to detect complex genomic rearrangements in consecutive unselected PCa samples from MRI/US-fusion targeted biopsy. Results: We tested ten samples, and nine (90%) passed quality check. Average mapping rate and coverage depth were 58.1 ± 23.7% and 157.3 ± 97.7×, respectively (mean ± SD). OGM detected copy number alterations such as chr6q13 loss and chr8q12-24 gain. Two adjacent tumor samples were distinguished by inter/intra-chromosomal translocations, revealing that they're from the same ancestor. Furthermore, OGM detected large deletion of chr13q13.1 accompanied by inter-chromosomal translocation t(13;20)(q13.1;p13) occurring within BRCA2 gene, suggesting complete loss of function. Conclusion: In conclusion, clinically relevant genomic SVs were successfully detected in PCa samples by OGM. We suggest that OGM can complement panel sequencing of DNA repair genes BRCA1/2 or ATM in high-risk PCa. [ABSTRACT FROM AUTHOR]

Purpose: Liquid biopsy has emerged as a promising tool for minimally invasive and accurate detection of various malignancies. We aimed to apply molecular barcode sequencing to circulating tumour DNA (ctDNA) from liquid biopsies of hepatocellular carcinoma (HCC). Study Design: Patients with HCC or benign liver disease were enrolled between 2017 and 2018. Matched tissue and serum samples were obtained from these patients. Plasma cell‐free DNA was extracted and subjected to targeted sequencing with ultra‐high coverage and molecular barcoding. Results: The study included 143 patients: 102 with HCC, 7 with benign liver tumours and 34 with chronic liver disease. No tier 1/2 or oncogenic mutations were detected in patients with benign liver disease. Among the HCC patients, 49 (48%) had tier 1/2 mutations in at least one gene; detection rates were higher in advanced stages (75%) than in early stages (26%–33%). TERT was the most frequently mutated gene (30%), followed by TP53 (16%), CTNNB1 (14%), ARID2 (5%), ARID1A (4%), NFE2L2 (4%), AXIN1 (3%) and KRAS (1%). Survival among patients with TP53 mutations was significantly worse (p = 0.007) than among patients without these mutations, whereas CTNNB1 and TERT mutations did not affect survival. ctDNA testing combined with α‐fetoprotein and prothrombin induced by vitamin K absence‐II analyses improved HCC detection, even in early stages. Conclusions: ctDNA detection using molecular barcoding technology offers dynamic and personalized information concerning tumour biology, such information can guide clinical diagnosis and management. This detection also has the potential as a minimally invasive approach for prognostic stratification and post‐therapeutic monitoring. [ABSTRACT FROM AUTHOR]

The diagnostic criteria of antibody-mediated rejection (ABMR) has been significantly changed since Banff 2013. The most important revision was adopting microvascular inflammation (MVI) as immunopathologic evidence for ABMR even in C4d-negative cases. In this study, we retrospectively reviewed previous allograft biopsy results and evaluated the impact of this change. We reviewed results of 536 renal allograft biopsies at Severance Hospital during 2011 to 2013, which were diagnosed according to the Banff 2009 criteria. All biopsy results were reassessed according to the Banff 2017 criteria. According to the Banff 2009 criteria, antibody-mediated changes were observed in 48 cases out of the 536 allograft biopsies (9.0%). According to the Banff 2017 criteria, 28 additional cases (5.2%) were reclassified as antibody-mediated changes. Twenty-six of these cases were C4d-negative ABMR. The most frequent diagnostic finding in these cases was MVI comprising glomerulitis and peritubular capillaritis. Donor-specific antibodies were investigated in 14 of these cases, which revealed positive results in 12 cases. The incidence rate of ABMR has increased after the recent revision of the Banff criteria. The MVI in C4d-negative ABMR cases is the major cause for this increase. • The diagnostic criteria for ABMR has been changed significantly. • The microvascular inflammation is the most frequent histology in C4d-negative ABMR. [ABSTRACT FROM AUTHOR]

This open-label, multicenter, single-arm, phase 2 study assessed the safety and efficacy of blinatumomab consolidation therapy in adult patients with newly diagnosed, high-risk diffuse large B-cell lymphoma (DLBCL; International Prognostic Index 3–5 and/or double-/triple-hit or double MYC/BCL-2 expressors) who achieved complete response (CR), partial response (PR), or stable disease (SD) following run-in with 6 cycles of R-chemotherapy (NCT03023878). Of the 47 patients enrolled, 28 received blinatumomab. Five patients (17.9%) experienced grade 4 treatment-emergent adverse events of interest (neutropenia, n = 4; infection, n = 1). Two deaths reported at the end of the study were unrelated to treatment with blinatumomab (disease progression, n = 1; infection, n = 1). 3/4 patients with PR and 4/4 patients with SD after R-chemotherapy achieved CR following blinatumomab. Consolidation with blinatumomab in patients with newly diagnosed, high-risk DLBCL who did not progress under R-chemotherapy was better tolerated than in previous studies where blinatumomab was used for treatment of patients with lymphoma. [ABSTRACT FROM AUTHOR]

Sweet syndrome (SS), or acute febrile neutrophilic dermatosis, is a rare painful skin condition that is characterized by hyperpyrexia, peripheral blood and skin neutrophilia, and edematous skin lesions. Necrotizing SS (NSS) is a severe and locally aggressive condition that histopathologically resembles a necrotizing soft tissue infection. As opposed to necrotizing soft tissue infections, NSS responds to systemic steroids. SS is divided into three subtypes: classical SS, malignancy-associated SS, and drug-induced SS. Within the malignancy-associated SS subtype, both solid tumor and hematologic malignancies have been precursors to developing SS. Here, we present a case of acute myeloid leukemia-associated NSS. [ABSTRACT FROM AUTHOR]

Summary: Measurable residual disease (MRD) negativity is a strong prognostic indicator in multiple myeloma (MM). However, the optimal use of MRD in daily clinical practice has been hampered by the limited feasibility of MRD testing. Therefore, we examined the clinical relevance of commercially available MRD modalities based on clonality assays by fragment analysis with IdentiClone® (n = 73 patients) and next‐generation sequencing (NGS) with LymphoTrack® (n = 116 patients) in newly diagnosed patients with MM who received autologous stem cell transplantation (ASCT). MRD was assessed at the end of induction (pre‐ASCT) and/or at 100 days after ASCT (post‐ASCT). MRD could not predict survival when assessed by fragment analysis. However, NGS‐based MRD negativity at pre‐ or post‐ASCT was beneficial in terms of progression‐free and overall survival. Moreover, NGS‐based MRD negativity was independently associated with improved progression‐free and overall survival, and MRD‐positive patients both pre‐ and post‐ASCT had worst outcome. Indeed, initial adverse prognostic features by high‐risk cytogenetics could be mitigated upon achieving MRD negativity by NGS. We demonstrate the feasibility and clinical benefit of achieving MRD negativity by commercially available clonality‐based MRD assays in MM and support incorporating NGS, but not fragment analysis, to tailor therapeutic strategies in real‐world practice. [ABSTRACT FROM AUTHOR]

Keywords: acute promyelocytic leukaemia; drug resistance; MAPK expression; metabolic reprogramming EN acute promyelocytic leukaemia drug resistance MAPK expression metabolic reprogramming 1 5 5 08/03/22 20220701 NES 220701 Acute promyelocytic leukaemia (APL) is a rare blood cancer, classified as a subtype of acute myeloid leukaemia, and is treated with targeted therapy.1 Cancer metabolism has been studied extensively in solid cancers; however, metabolic reprogramming in blood cancer has not yet been studied extensively. According to the Gene Ontology analysis, genes related to RA signalling were enriched in the thyroid hormone-signalling pathway and lipid cellular response (Figure 3E). [Extracted from the article]

• A CytoScan XON assay was developed to assess exon-level CNVs. • The assay detected 15 out of 23 small exon-level CNVs identified by NGS. • Three of the undetected exon level CNVs were false positives in the NGS results. • The assay could not detect the three exon-level CNVs in PKD1 and TSC2. • The assay is a promising complementary tool for the detection of exon-level CNVs. Next-generation sequencing (NGS)-based copy number variants (CNVs) have high false-positive rates. The fewer the exons involved, the higher the false-positive rate. A CytoScan XON assay was developed to assess exon-level CNVs. Twenty-three clinically relevant exon-level CNVs in 20 patient blood samples found in previous NGS studies were compared with the results from the CytoScan XON and multiplex ligation-dependent probe amplification (MLPA). Fifteen of the 23 exon-level CNVs were consistent with the NGS results. Among these, eight were confirmed using MLPA. In six out of eight discrepancies between the CytoScan Xon and NGS, MLPA was performed, and three were negative, indicating that the CNVs in NGS were false positives. The CytoScan XON exhibits a sensitivity of 72.7% for small exon-level CNVs, along with a specificity of 100%. The assay could not detect the three exon-level CNVs in PKD1 and TSC2 that were detected using both NGS and MLPA. This could be due to the distribution of the probes in some areas, and the CNV-calling regions containing multiple exons. The CytoScan XON assay is a promising complementary tool for the detection of exon-level CNVs, provided that the users carefully examine the distribution of probes and calling regions. [ABSTRACT FROM AUTHOR]

Simple Summary: Acute myeloid leukemia (AML) is a complicated disease with well-studied genetic mutations that have been used in both risk stratification as well as targets for treatment. In this study, we examined the varying prognostic significance of different lengths of the special mutation, named internal tandem duplication or ITD, of a commonly mutated gene in AML named FLT3. We found that the longer the size of the ITD mutation, the better the clinical outcomes. The prognostic significance of the length of internal tandem duplication (ITD) insertions in mutant FLT3 genes in acute myeloid leukemia (AML) is controversial. We conducted a retrospective study to evaluate the correlation between the ITD base-pair (bp) insertion length and clinical outcomes. The mutational status of the FLT3 gene was evaluated in 402 of 467 consecutive AML patients treated at the University of Maryland Greenebaum Comprehensive Cancer Center between 2013 and 2020; 77 had FLT3-ITD mutations. Patients were divided into three cohorts based on bp insertion length (<30 (0–33rd percentile), 30–53 (34th–66th percentile),and >53 (>66th percentile)). The median overall survival (OS) of patients was 16.5 months (confidence interval (CI) 7.3-NA), 18.5 months (CI 7.3-NA), and 21.9 months (CI 19.1-NA) (p = 0.03) for the <30, 30–53, and >53 bp insertion length cohorts, respectively. The adjusted median event-free survival (EFS) for the ITD insertion lengths >30, 30–53, and >53 bp was 11.1 months (CI 2.8–16.5), 5.2 months (CI 2.9–12.6), and 9.1 months (CI 5.4-NA) (p = 0.5), respectively. Complete remission (CR) rates were 64% (<30 inserted bp), 55% (30–53 inserted bp), and 79% (>53 inserted bp) (p = 0.23). For patients treated with gilteritinib and midostaurin, the unadjusted median OS was not statistically significantly different between cohorts. [ABSTRACT FROM AUTHOR]

Accurate detection of cytogenetic abnormalities has become more important for improving risk-adapted treatment strategies in multiple myeloma (MM). However, precise cytogenetic testing by fluorescence in situ hybridization (FISH) is challenged by the dilution effect of bone marrow specimens and poor growth of plasma cells ex vivo. It has been suggested that FISH should be performed in combination with plasma cell enrichment strategies. We examined cytogenetic abnormalities in newly diagnosed MM and compared the efficacy of three different enrichment modalities for FISH: direct FISH (n = 137), fluorescence immunophenotyping and interphase cytogenetics as a tool for the investigation of neoplasms (FICTION) technique (n = 224), and a plasma cell sorting FISH with fluorescence-activated cell sorter (FACS) (n = 132). FISH disclosed cytogenetic abnormalities in 38.0% of samples by direct FISH, 56.3% by FICTION, and 95.5% by FACS-FISH, and the percentage of cells with abnormal signals detected by FISH was significantly higher by FACS-FISH than direct FISH or FICTION. Our results suggest that the efficacy of FISH is dependent on the plasma cell enrichment modalities and reveal that plasma cell sorting FISH with FACS enables better detection of cytogenetic abnormalities in diagnostic MM samples. [ABSTRACT FROM AUTHOR]

Ski-slope hearing loss (HL), which refers to increased auditory threshold at high frequencies, is common in adults. However, genetic contributions to this post-lingual HL remain largely unknown. Here, we prospectively investigated deafness-associated and novel candidate genes causing ski-slope HL. We analyzed 192 families with post-lingual HL via gene panel and/or exome sequencing. With an overall molecular diagnostic rate of 35.4% (68/192) in post-lingual HL, ski-slope HL showed a lower diagnostic rate (30.7%) compared with other conditions (40.7%). In patients who showed HL onset before the age of 40, genetic diagnostic probability was significantly lower for ski-slope HL than for other conditions. Further analysis of 51 genetically undiagnosed patients in the ski-slope HL group identified three variants in delta-like ligand 1 (DLL1), a Notch ligand, which presented in vitro gain-of-function effects on Notch downstream signaling. In conclusion, genetic diagnostic rates in post-lingual HL varied according to audiogram patterns with age-of-onset as a confounding factor. DLL1 was identified as a candidate gene causing ski-slope HL. [ABSTRACT FROM AUTHOR]

This paper proposes a diagnosis technique algorithm for a brushless dc motors under a stator inter-turn fault (ITF) condition using input impedance. The algorithm has early detection and various speed-range detection advantages. To early and accurately detect the ITF, the rotating speed, input current, voltage, resistance, and inductance must be analyzed. Therefore, we choose the input impedance as the detection factor because it includes all these factors. In this paper, the fault-detection system works without requiring a fast Fourier transform and the calculation of the negative-sequence impedance from the comparison of the measured impedance with the database impedance. The proposed technique was verified by the simulation and experiment. [ABSTRACT FROM AUTHOR]

Exposure of human Jurkat T cells to JNK inhibitor IX (JNKi), targeting JNK2 and JNK3, caused apoptotic DNA fragmentation along with G 2 /M arrest, phosphorylation of Bcl-2, Mcl-1, and Bim, Δψm loss, and activation of Bak and caspase cascade. These JNKi-induced apoptotic events were abrogated by Bcl-2 overexpression, whereas G 2 /M arrest, cyclin B1 up-regulation, Cdk1 activation, and phosphorylation of Bcl-2 family proteins were sustained. In the concomitant presence of the G 1 /S blocking agent aphidicolin and JNKi, the cells underwent G 1 /S arrest and failed to induce all apoptotic events. The JNKi-induced phosphorylation of Bcl-2 family proteins and mitochondrial apoptotic events were suppressed by the Cdk1 inhibitor. Immunofluorescence microscopic analysis revealed that mitotic spindle defect and prometaphase arrest were the underlying factors for the G 2 /M arrest. These results demonstrate that JNKi-induced mitochondrial apoptosis was caused by microtubule damage-mediated prometaphase arrest, prolonged Cdk1 activation, and phosphorylation of Bcl-2 family proteins in Jurkat T cells. [ABSTRACT FROM AUTHOR]

This study explored the effect of thalidomide and cyclophosphamide on stem cell collection, in addition to assessing their efficacy as induction therapy for myeloma patients destined for autologous stem cell transplantation (ASCT). We analyzed newly diagnosed myeloma patients who received TCD (thalidomide 100 mg/day for 28 days, oral cyclophosphamide 150 mg/m2/day and dexamethasone 40 mg/day on days 1-4) as induction therapy prior to ASCT. Peripheral stem cells were mobilized with granulocyte colony-stimulating factor and cyclophosphamide. Thirty-six patients (median age 54 years) received TCD chemotherapy (median 4 cycles). The overall response rate to TCD was 77.8% (28/36). The median number of CD34+ cells was 6.5 × 106/kg, and 2 patients failed to achieve the optimal number of CD34+ cells, i.e. 4.0 × 106/kg, although they were able to attain >2.0 × 106/kg. The overall response rate increased up to 94.4% (34/36) after ASCT; this included 9 patients with a stringent complete response without transplantation-related mortality. Four patients died due to disease progression and 17 were found to have progressed after ASCT (the median progression-free survival after ASCT was 19.6 months). TCD chemotherapy can be an effective and feasible induction regimen prior to ASCT for myeloma patients. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]