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Abstract Background Assessment of measurable residual disease (MRD) is an essential prognostic tool for B-lymphoblastic leukaemia (B-ALL). In this study, we evaluated the utility of next-generation sequencing (NGS)–based MRD assessment in real-world clinical practice. Method The study included 93 paediatric patients with B-ALL treated at our institution between January 2017 and June 2022. Clonality for IGH or IGK rearrangements was identified in most bone marrow samples (91/93, 97.8%) obtained at diagnosis. Results In 421 monitoring samples, concordance was 74.8% between NGS and multiparameter flow cytometry and 70.7% between NGS and reverse transcription-PCR. Elevated quantities of clones of IGH alone (P

AbstractRecently, Generation Z, born from 1995 to 2010, started entering the labor market and is becoming an important human resource. They will account for 27% of the workforce by 2025, therefore, studying this cohort and how they perceive careers is critically significant. However, literature on Generation Z’s self-perceived careers lacks literature summaries that can shed light on the current landscape of the research field. This study employs bibliometric methodologies to identify current research trends, assess state-of-the-art, and indicate future research direction. Results show 108 papers published between 2016 and 2022. Growth trends, geographical locations, leading sources, and authors are identified. Top documents are indicated, with main and trending topics, which provide suggestions for researchers who conduct research in this area.

Abstract 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.

Optical coherence tomography (OCT) is a noninvasive, high-resolution imaging technique widely used in clinical practice to depict the structure of the retina. Over the past few decades, ophthalmologists have used OCT to diagnose, monitor, and treat retinal diseases. However, manual analysis of the complicated retinal layers using two colors, black and white, is time consuming. Although ophthalmologists have more experience, their results may be prone to erroneous diagnoses. Therefore, in this study, we propose an automatic method for diagnosing five retinal diseases based on the use of hybrid and ensemble deep learning (DL) methods. DL extracts a thousand constitutional features from images as features for training classifiers. The machine learning method classifies the extracted features and fuses the outputs of the two classifiers to improve classification performance. The distribution probabilities of two classifiers of the same class are aggregated; then, class prediction is made using the class with the highest probability. The limited dataset is resolved by the fine-tuning of classification knowledge and generating augmented images using transfer learning and data augmentation. Multiple DL models and machine learning classifiers are used to access a suitable model and classifier for the OCT images. The proposed method is trained and evaluated using OCT images collected from a hospital and exhibits a classification accuracy of 97.68% (InceptionResNetV2, ensemble: Extreme gradient boosting (XG-Boost) and k-nearest neighbor (k-NN). The experimental results show that our proposed method can improve the OCT classification performance; moreover, in the case of a limited dataset, the proposed method is critical to develop accurate classifications.

Background : : Acute complications within 100 days after allogeneic hematopoietic stem cell transplantation (HSCT) can increase immediate mortality as well as the risk of chronic complications and morbidity. A comprehensive review collecting systemic complications following transplantation would be important in pediatric patients. Methods : : We report a retrospective study of pediatric patients who underwent allogeneic HSCT during the 11 years (2009-2020), and their acute complications after transplantation within 100 days. A total 227 pediatric patients' (90 females, 137 males) data were collected. Results : : Among the patients, 62.6% (N=142) suffered from acute graft-versus-host disease, and 118 (52.0%) patients had an acute infection. Pulmonary complications occurred in 52 (22.9%) patients followed by hepatic sinusoidal obstruction syndrome in 30 (18.1%) patients. In the study, 19 died within the first 100 days after HSCT (8.4%), and the 5-year overall survival rate of the patients was 65.4%. Conclusion : : This study widens the understanding of acute toxicities of pediatric HSCT. A significant number of children still have experienced a variety of acute infectious or non-infectious complications after allogeneic HSCT that contribute to morbidity and mortality. Therefore, continuous efforts are needed to reduce them.

Background : : Hemophilia requires a lifetime care for bleeding control and complications. Although patients diagnosed with hemophilia receive factor replacement, they also experience a variety of medical problems as they age. Elective surgery can be performed through appropriate factor replacement during and after surgery. However, for patients with inhibitors, this remains a problem to be overcome. Methods : : Patients treated for congenital bleeding disorders between 2008 and 2021 were enrolled in this study. The patients were classified according to the type, severity, and presence of inhibitors. The patients underwent planned coagulation factor replacement depending on the type of surgery. Results : : A total of 232 patients treated for congenital bleeding disorders were enrolled. Among them hemophilia A was most prevalent, followed by hemophilia B. In total, 78 of the patients underwent surgery, including 31 major and 55 minor surgeries. Orthopedic surgery was the most common surgery, and patients with inhibitors had significantly more postoperative hospitalization days. Nine patients were incidentally diagnosed. Twelve patients with hemophilia with inhibitors underwent surgery, and 6 of them experienced post-operative complications. Conclusion : : Proper surgical planning and monitoring with a multidisciplinary team will be required for appropriate perioperative management of patients with hemophilia, especially in patients with inhibitor and elderly hemophilia patients.

Purpose – The article is to review recent literature studies of employee turnover to identify antecedents of employee turnover in the hospitality sector to reduce the literature gaps and present a wider scope of turnover factor and understanding of employee motivational factors in their job decision. Design/methodology/approach – The recent literature studies published over the last two decades were reviewed and structured into the three levels of employee turnover factors, including individual, team and organizational level. Findings – The antecedents on organizational levels were frequently studied and suggested as strong predictors to employee turnover in the hospitality sectors. The team and organizational factors also influence employee turnover, yet the factors on the team level may not have a significant direct impact but rather an indirect impact through the organizational or individual level. The factors of the individual level may not explain the fundamental reasons behind the turnover. Yet, it might be a more reliable predictor of employee turnover as factors on the other levels are often mediated by individual factors. Originality/value – The article contributes to the knowledge base by articulating a wide range of updated employee turnover factors in the hospitality that brings an updated insight into employee motivational factors in the hospitality sector.

Abstract Retinal organoids derived from human-induced pluripotent stem cells (hiPSC) are powerful tools for studying retinal development as they model spatial and temporal differentiation of retinal cell types. Vertebrate retinal development involves a delicate and coordinated process of retinal progenitor cell (RPC) differentiation, and the mammalian target of rapamycin complex 1 (mTORC1) has been reported to play a significant role in this complex process. Herein, using hiPSC-derived retinal organoids, we identify the time-dependent role of mTORC1 in retinal development, specifically in retinal ganglion cell (RGC) differentiation and the retinal lamination process, during the early stages of retinal organoid (RO) development. mTORC1 activity in ROs was the highest at 40 days of differentiation. MHY1485-induced hyperactivation of mTORC1 during this period resulted in a significant increase in the overall size of ROs compared to the untreated controls and rapamycin-treated Ros; there was also a marked increase in proliferative activity within the inner and outer layers of ROs. Moreover, the MHY1485-treated ROs showed a significant increase in the number of ectopic RGCs in the outer layers (indicating disruption of retinal laminar structure), with robust expression of HuC/D-binding proteins in the inner layers. These results demonstrate that mTORC1 plays a critical role in the development of hiPSC-derived ROs, especially during the early stages of differentiation.

Optical coherence tomography (OCT) is widely used to detect and classify retinal diseases. However, OCT-image-based manual detection by ophthalmologists is prone to errors and subjectivity. Thus, various automation methods have been proposed; however, improvements in detection accuracy are required. Particularly, automated techniques using deep learning on OCT images are being developed to detect various retinal disorders at an early stage. Here, we propose a deep learning-based automatic method for detecting and classifying retinal diseases using OCT images. The diseases include age-related macular degeneration, branch retinal vein occlusion, central retinal vein occlusion, central serous chorioretinopathy, and diabetic macular edema. The proposed method comprises four main steps: three pretrained models, DenseNet-201, InceptionV3, and ResNet-50, are first modified according to the nature of the dataset, after which the features are extracted via transfer learning. The extracted features are improved, and the best features are selected using ant colony optimization. Finally, the best features are passed to the k-nearest neighbors and support vector machine algorithms for final classification. The proposed method, evaluated using OCT retinal images collected from Soonchunhyang University Bucheon Hospital, demonstrates an accuracy of 99.1% with the incorporation of ACO. Without ACO, the accuracy achieved is 97.4%. Furthermore, the proposed method exhibits state-of-the-art performance and outperforms existing techniques in terms of accuracy.

Abstract Background Pazopanib, a multitargeted tyrosine kinase inhibitor, is recommended as the standard treatment for refractory soft tissue sarcoma (STS). However, there are comparatively few molecular determinants for predicting pazopanib efficacy. Based on correlative studies regarding the predictive impact of PD-L1, we investigated the clinical relevance of PD-L1 expression and evaluated its value for predicting pazopanib efficacy. Methods Tumour tissues from patients with advanced STS who went on to receive pazopanib were assessed for PD-L1 expression. Immunohistochemistry was performed using an anti-PD-L1 antibody, and the PD-L1 tumour proportion score (TPS) was calculated as the percentage of at least 100 viable cells with positive expression, defined as TPS ≥ 1%. Results Among the 67 patients, 8 (11.9%) achieved partial response and a median progression-free survival (PFS) of 4.8 months (95% CI 3.8–5.7). PD-L1 expression in tumour cells was detected in 13 (19.4%) cases and the TPS scores ranged from 1 to 100%, as follows: 0 (n = 54, 80.6%), 1–9% (n = 3, 4.5%), 10–49% (n = 9, 13.4%), and ≥ 50% (n = 1, 1.5%). PD-L1 positive tumours exhibited a poorer response to pazopanib treatment than the PD-L1 negative tumours (0% vs 14.8%, P = 0.07). PD-L1-positive tumours had significantly shorter PFS than the PD-L1-negative tumours (median PFS 2.8 vs 5.1 months, P = 0.003), and PD-L1 positivity was an independent predictor of poor response to pazopanib treatment (HR 2.77, 95% CI; 1.45–5.56, P = 0.006). Conclusion We identified that PD-L1 expression can help predict the clinical outcome of patients with advanced STS treated with pazopanib. Based on our study, stratification should be actively considered in order to identify patients who will benefit from pazopanib or further therapeutic strategies for future clinical trials.

Abstract Background Neurodegeneration, an early event in the pathogenesis of diabetic retinopathy (DR), precedes clinically detectable microvascular damage. Autophagy dysregulation is considered a potential cause of neuronal cell loss, however underlying mechanisms remain unclear. The mechanistic target of rapamycin (mTOR) integrates diverse environmental signals to coordinate biological processes, including autophagy. Here, we investigated the role of mTOR signaling in neuronal cell death in DR. Methods Diabetes was induced by a single intraperitoneal injection of streptozotocin and tissue samples were harvested at 1, 2, 3, 4, and 6 months of diabetes. Early-stage of DR was investigated in 1-month-diabetic mice treated with phlorizin (two daily subcutaneous injections at a dose of 200 mg/kg of body weight during the last 7 full days of the experiment and the morning of the 8th day, 3 h before sacrifice) or rapamycin (daily intraperitoneal injections, at a dose of 3 mg/kg for the same period as for phlorizin treatment). The effect of autophagy modulation on retinal ganglion cells was investigated in 3-months-diabetic mice treated with phlorizin (two daily subcutaneous injections during the last 10 full days of the experiment and the morning of the 11th day, 3 h before sacrifice) or MHY1485 (daily i.p. injections, at a dose of 10 mg/kg for the same period as for phlorizin treatment). Tissue samples obtained from treated/untreated diabetic mice and age-matched controls were used for Western blot and histologic analysis. Results mTOR-related proteins and glucose transporter 1 (GLUT1) was upregulated at 1 month and downregulated in the following period up to 6 months. Diabetes-induced neurodegeneration was characterized by an increase of apoptotic marker—cleaved caspase 3, a decrease of the total number of cells, and NeuN immunoreactivity in the ganglion cell layer, as well as an increase of autophagic protein. Insulin-independent glycemic control restored the mTOR pathway activity and GLUT1 expression, along with a decrease of autophagic and apoptotic proteins in 3-months-diabetic mice neuroretina. However, blockade of autophagy using MHY1485 resulted in a more protective effect on ganglion cells compared with phlorizin treatment. Conclusion Collectively, our study describes the mechanisms of neurodegeneration through the hyperglycemia/ mTOR/ autophagy/ apoptosis pathway. Video Abstract

The intravitreal (IVT) injection method is a choice when targeting the inner retina for gene therapy. However, the transduction efficiency of adeno-associated virus (AAV) vectors administered by the IVT route is usually low and may be affected by several factors. To improve the transduction efficiency, we developed a novel illuminated long-needle attached injection system and injected AAV2-CMV (cytomegalovirus)-EGFP in front of the retina in rabbit eyes. Ophthalmological examinations were performed and the levels of pro-inflammatory cytokines in the aqueous humor were assessed at the baseline and 1 month, and the results were compared with those of the conventional injection method. Retinal tissues were used for immunohistochemistry. In the ophthalmological examinations, no significant inflammatory signs were detected in both groups, except for transient, mild hyperemia. In the tissues of the rabbits in the peripapillary injection group, significantly increased GFP expression was detected at the ganglion cell and the inner nuclear layers (p < 0.01). There were no differences between groups in glial activation and expressions of interleukin (IL)-6 and IL-8. These results suggest that peripapillary IVT injection in front of the retina would be safe and efficiently transduce viral vectors into the retina of large animals and is considered as a potential method for use in clinical trials.

Background : : Approximately 8% of male patients presenting with primary mediastinal germ cell tumors (GCTs) have Klinefelter syndrome (KS), while patients diagnosed with retroperitoneal GCTs also exhibit a range of chromosomal abnormalities. The exact mechanism underlying the development of GCTs in Klinefelter syndrome is unknown, but KS frequently goes underdiagnosed as a result of its varied symptoms and a low general awareness of this condition. Thus, the Children’s Oncology Group recommends screening of Klinefelter syndrome in pediatric and adolescent male subjects who present with GCTs. Methods : : We retrospectively reviewed the medical records of extragonadal germ cell tumor patients treated at Severance hospital, department of pediatrics or division of pediatric hematology-oncology over the last ten years. Results : : A total of 95 patients with extragonadal germ cell tumors were included in this study. Karyotyping was done in eight patients out of 95 patients, three patients with KS and one patient with Down syndrome. Twelve of extragonadal GCT patients presented at mediastinum, with most common histology of mature teratoma, and three patients presented with chromosomal abnormalities, two with KS and one with Down syndrome. A total of nine patients were diagnosed with retroperitoneal GCTs and only one had KS. Conclusion : : We described the characteristics of 95 cases of extragonadal GCTs. Although the mechanism of extragonadal GCTs in KS is not clear, karyotyping in pediatric and adolescent extragonadal GCT patients could be helpful in figuring out chromosomal abnormalities including KS and their roles in GCT pathophysiology, which can contribute to improve one’s health.

Choroidal neovascularization (CNV) is a defining characteristic feature of neovascular age-related macular degeneration (nAMD) that frequently results in irreversible vision loss. The current strategies for the treatment of nAMD are mainly based on neutralizing vascular endothelial growth factor (VEGF). However, anti-VEGF therapies are often associated with subretinal fibrosis that eventually leads to damages in macula. In this study, we tested whether an anti-fibrotic and anti-angiogenic protein CCN5 can potentially be an effective and safe therapeutic modality in a mouse model of CNV. Laser photocoagulation was utilized to induce CNV, which was followed by intravitreal injection of recombinant adeno-associated virus serotype 2 encoding CCN5 (rAAV2-CCN5). Our data demonstrated that rAAV2-CCN5, but not a control viral vector, rAAV2-VLP, prominently attenuated both CNV lesions and angiogenesis. Aflibercept, which was utilized as a positive control, exhibited similar effects on CNV lesions and angiogenesis in our experimental settings. Upon laser photocoagulation, retinal pigmented epithelium (RPE) cells underwent significant morphological changes including cellular enlargement and loss of hexagonality. rAAV2-CCN5 significantly normalized these morphological defects. Laser photocoagulation also led to fibrotic deformation in RPE cells through inducing epithelial-mesenchymal transition (EMT), which was completely blocked by rAAV2-CCN5. In a striking contrast, aflibercept as well as rAAV2-VLP failed to exhibit any effects on EMT. Collectively, this study suggest that CCN5 might provide a potential novel strategy for the treatment of nAMD with a capability to inhibit CNV and fibrosis simaultaneously.

Aim: There are limited data on the feasibility of programmed death ligand-1 (PD-L1) expression as a prognostic biomarker in metastatic angiosarcoma. Patients & methods: We retrospectively collected and analyzed the data on PD-L1 expression in 70 angiosarcoma patients who were diagnosed at our center between 2005 and 2019. Results: Thirteen (19%) patients had PD-L1 expression. Metastatic angiosarcoma patients who were PD-L1-negative (n = 24) showed longer median progression-free survival (4.9 vs 1.6 months; p = 0.04) and median overall survival (OS; 10.9 vs 5.4 months; p = 0.01) than those who were PD-L1-positive (n = 4). PD-L1 status proved to be a significant factor for OS. Conclusion: Metastatic angiosarcoma patients with PD-L1 expression showed shorter survival. PD-L1 status is an independent prognostic factor for OS in metastatic angiosarcoma patients.

BackgroundGenetic variations in calpain-10 and adiponectin gene are known to influence insulin secretion and resistance in type 2 diabetes mellitus. Recently, several single nucleotide polymorphisms (SNPs) in calpain-10 and adiponectin gene have been reported to be associated with type 2 diabetes and various metabolic derangements. We investigated the associations between specific calpain-10 and adiponectin gene polymorphisms and Korean type 2 diabetes patients.MethodsOverall, 249 type 2 diabetes patients and 131 non-diabetic control subjects were enrolled in this study. All the subjects were genotyped for SNP-43 and -63 of calpain-10 gene and G276T and T45G frequencies of the adiponectin gene. The clinical characteristics and measure of glucose metabolism were compared within these genotypes.ResultsAmong calpain-10 polymorphisms, SNP-63 T/T were more frequent in diabetes patients, and single SNP-63 increases the susceptibility to type 2 diabetes. However, SNP-43 in calpain-10 and T45G and intron G276T in adiponectin gene were not significantly associated with diabetes, insulin resistance, nor insulin secretion.ConclusionVariations in calpain-10, SNP-63 seems to increase the susceptibility to type 2 diabetes in Koreans while SNP-43 and adiponectin SNP-45, -276 are not associated with impaired glucose metabolism.

Abstract Background Polycomb repressive complex 2 (PRC2; formed by EZH2, SUZ12, and EED protein subunits) and PRC1 (BMI1 protein) induce gene silencing through histone modification by H3K27me3. In the present study, we characterized the PRC expression pattern and its clinical implication in sarcoma. Methods Using immunohistochemistry, we analyzed PRC expression in 105 sarcoma patients with 5 subtypes: synovial sarcoma (n = 18), rhabdomyosarcoma (n = 28), Ewing sarcoma (n = 15), osteosarcoma (n = 30), and others (n = 14). Results The median age at diagnosis in the patient cohort was 26.8 years (range: 1–78 years) and the male-to-female ratio was 1:4. Initial disease presentation was locoregional disease in 83% of patients and initial metastatic disease in the remaining 17%. PRC expression was not significantly different according to histologic subtype (P = 0.400). Overall survival (OS) was significantly poor for SUZ12 high (P = 0.001), EED1 high (P = 0.279), and H3K27me3 high (P = 0.009). Ultimately, patients with PRC2high had significantly inferior OS than the no expression group (P = 0.009). In the Cox proportional hazard model adjusted for stage, histologic grade, surgery, margin and initial metastasis, SUZ12 expression (P = 0.020, HR 29.069, 95% CI 1.690–500.007), H3K27me3 (P = 0.010, HR 3.743, 95% CI 1.370–10.228) expression was significantly associated with shorter OS. Conclusion We detected PRC expression in various sarcomas and demonstrated its independent negative prognostic role, suggesting the PRC axis as promising therapeutic target for treating sarcoma.

Abstract 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.

Intracranial germinoma sometimes present as bifocal germinoma, and whether bifocal germinoma should be treated as a synchronous or disseminated disease remains unclear. This study aimed to determine the optimal treatment modality for bifocal germinoma. Patients with bifocal germinoma who received radiotherapy (RT) from March 1990 to August 2017 were included for analysis. A total of 21 patients were included. The median follow-up period was 76.2 months (range, 6.2-305.4 months). There were 17 patients who received cranio-spinal irradiation (CSI) with local RT; 3, whole ventricular RT (WVRT) with local RT; and 1, local RT only. Three recurrences occurred (1 patient each among those who underwent CSI, WVRT, and local RT). Recurrence in the patient who received CSI and who received WVRT occurred in the right thalamus and right frontal convexity, respectively. Meanwhile, the patient who received local RT showed not only a recurred lesion in the hypothalamus, but also cerebrospinal fluid seeding. For this patient, salvage CSI was performed and complete response was achieved after treatment. However, after 9 years and 6 months, he was diagnosed with glioblastoma and expired. As for toxicity, although 17 patients showed decrease in complete blood count levels during treatment, all patients recovered soon after treatment completion. Our findings suggest that bifocal germinoma may be considered as a disseminated disease when considering the patterns of failure according to RT fields. In addition, patients who received CSI showed low acute toxicity rates. However, further studies are necessary to confirm these findings.

STIM1 is the only currently known intracellular calcium sensor that functions as the calcium influx regulator controlling immune cell activation. STIM1 function in immune cell calcium signalling has been studied extensively; however, its role in microglia, innate immune cells in brain, has not been fully understood. Here, we report that STIM1−/− murine microglia lost store-operated calcium influx and displayed aberrant immunological functions. Microglial functions regulated by chronic and global Ca2+i changes were reduced significantly, including cytokine releases and opsonin-dependent phagocytosis. More dramatically, cellular functions governed by Ca2+ regulation in local microdomains at the cell periphery, such as UDP-induced phagocytosis and ATP-stimulated chemotactic migration, were severely reduced in STIM1−/− microglia. Interestingly, UDP-induced Orai1 mobilization to the peripheral region was greatly attenuated in STIM1−/− microglia. Their chemotactic migration defect was reproduced in vivo in embryonic brain; the aggregated number of STIM1−/− microglia in LPS- (lipopolysaccharide-) injected lesions was much smaller than that in wild-type microglia. Furthermore, the neuron phagoptosis activities of activated microglia were significantly diminished in the STIM1−/− microglia. These in vitro and in vivo results suggest that STIM1-mediated store-operated calcium entry is important for the regulation of global Ca2+i changes which differentiates into active immune state of microglia, but it is more crucial for the regulation of local [Ca2+] microdomains which mediates the acute motility of murine microglia.

Wernicke's encephalopathy is an acute neurological disorder characterized by mental confusion, oculomotor dysfunction, and ataxia. It has been reported in individuals with alcohol dependence, hyperemesis gravidarum, and prolonged parenteral nutrition without vitamin supplementation. Here we present the case of a 13-year-old male patient with neuroblastoma and a history of poor oral intake and nausea for 3 months. After admission, he showed gait disturbances, nystagmus, and excessive dizziness; his mental state, however, indicated he was alert, which did not fit the classical triad of Wernicke's encephalopathy. A diagnosis of Wernicke's encephalopathy was made only after brain magnetic resonance imaging and serum thiamine level analyses were performed. The patient's symptoms remained after 5 days of treatment with 100-mg thiamine once daily; thus, we increased the dosage to 500 mg 3 times daily, 1,500 mg per day. His symptoms then improved after 20 days of replacement therapy. This case report describes a pediatric patient who was promptly diagnosed with Wernicke's encephalopathy, despite only 2 suspicious symptoms, and who completely recovered after high doses of thiamine were given intravenously.

PurposeRetinoblastoma (RB) is the most common primary malignant intraocular tumor in children. Although systemic chemotherapy has been the primary treatment, intra-arterial chemotherapy (IAC) represents a new treatment option. Here, we performed alternate systemic chemotherapy and IAC and retrospectively reviewed the efficacy and safety of this approach.MethodsPatients diagnosed with intraocular RB between January 2000 and December 2011 at Severance Children's Hospital, Yonsei University, were reviewed. Before February 2010, the primary treatment for RB was chemotherapy (non-IAC/CTX). Since February 2010, the primary treatment for RB has been IAC (IAC/CTX). External beam radiotherapy or high-dose chemotherapy were used as "last resort" treatments just prior to enucleation at the time of progression or recurrence during primary treatment. Enucleation-free survival (EFS) and progression-free survival were assessed.ResultsWe examined 19 patients (median age, 11.9 months; range, 1.4 to 75.6 months) with a sum of 25 eyes, of which, 60.0% were at advanced Reese Ellsworth (RE) stages. The enucleation rate was 33.3% at early RE stages and 81.8% at advanced RE stages (P=0.028). At 36 months, EFS was significantly higher in the IAC/CTX group than in the non-IAC/CTX group (100% vs. 40.0%, P=0.016). All 5 patients treated with IAC achieved eye preservation, although most patients were at advanced RE stages (IV-V).ConclusionDespite the limitation of a small sample size, our work shows that an alternative combined approach using IAC and CTX may be safe and effective for eye preservation in advanced RB.

To identify prognostic factors and define the optimal management of patients with supratentorial primitive neuroectodermal tumors (sPNETs), we investigated treatment outcomes and explored the prognostic value of specific molecular markers.A total of 47 consecutive patients with pathologically confirmed sPNETs between May 1985 and June 2012 were included. Immunohistochemical analysis of LIN28, OLIG2, and Rad51 expression was performed and correlated with clinical outcome.With a median follow-up of 70 months, 5-year overall survival (OS) and progression-free survival (PFS) was 55.5% and 40%, respectively, for all patients. Age, surgical extent, and radiotherapy were significant prognostic factors for OS and PFS. Patients who received initially planned multimodal treatment without interruption (i.e., radiotherapy and surgery (≥subtotal resection), with or without chemotherapy) showed significantly higher 5-year OS (71.2%) and PFS (63.1%). In 29 patients with available tumor specimens, tumors with high expression of either LIN28 or OLIG2 or elevated level of Rad51 were significantly associated with poorer prognosis.We found that multimodal treatment improved outcomes for sPNET patients, especially when radiotherapy and ≥subtotal resection were part of the treatment regimen. Furthermore, we confirmed the prognostic significance of LIN28 and OLIG2 and revealed the potential role of Rad51 in sPNETs.

Age-related macular degeneration (AMD) is the leading cause of vision loss and blindness among people over the age of 60. Vascular endothelial growth factor (VEGF) plays a major role in pathological angiogenesis in AMD. Herein, we present the development of an anti- human VEGF repebody, which is a small-sized protein binder consisting of leucine-rich repeat (LRR) modules. The anti-VEGF repebody selected through a phage-display was shown to have a high affinity and specificity for human VEGF. We demonstrate that this repebody effectively inhibits in vitro angiogenic cellular processes, such as proliferation and migration, by blocking the VEGF-mediated signaling pathway. The repebody was also shown to have a strong suppression effect on choroidal neovascularization (CNV) and vascular leakage in vivo. Our results indicate that the anti-VEGF repebody has a therapeutic potential for treating neovascular AMD as well as other VEGF-involved diseases including diabetic retinopathy and metastatic cancers.

Canine distemper virus (CDV), a close relative of measles virus (MV), is widespread and well known for its broad host range. When the goal of measles eradication may be achieved, and when measles vaccination will be stopped, CDV might eventually cross the species barrier to humans and emerge as a new human pathogen. In order to get an impression how fast such alterations may occur, we characterized required adaptive mutations to the human entry receptors CD150 (SLAM) and nectin-4 as first step to infect human target cells. Recombinant wild-type CDV-A75/17(red) adapted quickly to growth in human H358 epithelial cells expressing human nectin-4. Sequencing of the viral attachment proteins (hemagglutinin, H, and fusion protein, F) genes revealed that no adaptive alteration was required to utilize human nectin-4. In contrast, the virus replicated only to low titres (10(2) pfu/ml) in Vero cells expressing human CD150 (Vero-hSLAM). After three passages using these cells virus was adapted to human CD150 and replicated to high titres (10(5) pfu/ml). Sequence analyses revealed that only one amino acid exchange in the H-protein at position 540 Asp→Gly (D540G) was required for functional adaptation to human CD150. Structural modelling suggests that the adaptive mutation D540G in H reflects the sequence alteration from canine to human CD150 at position 70 and 71 from Pro to Leu (P70L) and Gly to Glu (G71E), and compensates for the gain of a negative charge in the human CD150 molecule. Using this model system our data indicate that only a minimal alteration, in this case one adaptive mutation, is required for adaptation of CDV to the human entry receptors, and help to understand the molecular basis why this adaptive mutation occurs.

Point cloud data sets are frequently used in machines to sense the real world because sensors such as LIDAR are readily available to be used in many applications including autonomous cars and drones. PointNet and PointNet++ are widely used point-wise embedding methods for interpreting Point clouds. However, even for recent models based on PointNet, real-time inference is still challenging. The solution to a faster inference is sampling, where, sampling is a method to reduce the number of points that is computed in the next module. Furthest Point Sampling (FPS) is widely used, but disadvantage is that it is slow and it is difficult to select critical points. In this paper, we introduce Feature-Based Sampling (FBS), a novel sampling method that applies the attention technique. The results show a significant speedup of the training time and inference time while the accuracy is similar to previous methods. Further experiments demonstrate that the proposed method is better suited to preserve critical points or discard unimportant points.

Background We investigated the potential association between pathogenic BRCA1/2 variants and retinoblastoma pathogenicity. Methods In this single-centre, retrospective case series, we performed hereditary cancer panel tests using blood samples for patients with retinoblastoma diagnosed between March 2017 and October 2021. Bioinformatics prediction tools were then used to conduct in silico pathogenicity assessments for patients with BRCA1/2 family variants, in addition to the American College of Medical Genetics and Genomics (ACMG) variant classification. One patient with a germline BRCA1 variant was analysed with whole-genome sequencing (WGS), mutational signature analysis and methylation analysis for RB1 and BRCA using the patient's tumour and blood samples. Results Of 30 retinoblastoma patients who underwent panel sequencing, six (20%) were found to carry germline variants in the BRCA1/2 or BRIP1 genes. Among these six patients, two had pathogenic or likely pathogenic variants as per the ACMG variant classification. Additionally, three patients showed potential pathogenic BRCA1/2 family variants through further analysis with alternative bioinformatics prediction tools. In the WGS analysis of a tumour from a patient with a germline likely pathogenic BRCA1 variant in one allele, we observed the loss of one RB1 allele due to a large deletion. No somatic non-synonymous mutations or frameshift indels were detected in the RB1 locus of the remaining allele. This sample also showed BRCA1 gene promoter hypermethylation in the tumour, indicating additional epigenetic silencing. Conclusion This study demonstrated that some retinoblastoma patients harboured germline BRCA1/2 family variants, which may be associated with the development of retinoblastoma along with RB1 mutations. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to predict high-risk neuroblastoma among neuroblastic tumors using radiomics features extracted from MRI. Materials and Methods: Pediatric patients (age≤18 years) diagnosed with neuroblastic tumors who had pre-treatment MR images available were enrolled from institution A from January 2010 to November 2019 (training set) and institution B from January 2016 to January 2022 (test set). Segmentation was performed with regions of interest manually drawn along tumor margins on the slice with the widest tumor area by two radiologists. First-order and texture features were extracted and intraclass correlation coefficients (ICCs) were calculated. Multivariate logistic regression (MLR) and random forest (RF) models from 10-fold cross-validation were built using these features. The trained MLR and RF models were tested in an external test set. Results: Thirty-two patients (M:F=23:9, 26.0±26.7 months) were in the training set and 14 patients (M:F=10:4, 33.4±20.4 months) were in the test set with radiomics features (n=930) being extracted. For 10 of the most relevant features selected, intra- and interobserver variability was moderate to excellent (ICCs 0.633–0.911, 0.695–0.985, respectively). The area under the receiver operating characteristic curve (AUC) was 0.94 (sensitivity 67%, specificity 91%, and accuracy 84%) for the MLR model and the average AUC was 0.83 (sensitivity 44%, specificity 87%, and accuracy 75%) for the RF model from 10-fold cross-validation. In the test set, AUCs of the MLR and RF models were 0.94 and 0.91, respectively. Conclusion: An MRI-based radiomics model can help predict high-risk neuroblastoma among neuroblastic tumors. [ABSTRACT FROM AUTHOR]

This article provides information on the diagnosis of a rare hemoglobinopathy called Hemoglobin Boras in a Korean patient. Hemoglobinopathies are genetic disorders that affect hemoglobin, resulting in various symptoms. The patient in this case presented with anemia, jaundice, and an enlarged spleen. Laboratory tests, including hemoglobin electrophoresis and genetic testing, confirmed the diagnosis. The article highlights the importance of considering Hemoglobin Boras as a potential cause when observing unique hemoglobin electrophoresis patterns. Additionally, the document references several scientific articles related to the analysis and evaluation of different types of hemoglobin disorders, providing valuable information for researchers and healthcare professionals studying and treating these conditions. [Extracted from the article]