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이 연구에서는 규범 문법에서 서술격조사로 분류하고 있는 ‘이다’에 대해 한국어교육 문법에서는 이를 어떻게 범주화하고 제시하고 있는지를 살펴보고, 외국어로서의 한국어 문법 교육의 수월성과 효율성의 관점에서 검토하고자 한다. ‘이다’에 대해서는 이론 문법 안에서도 많은 논의가 존재한다. 외국인을 위한 한국어교육 문법에서도 ‘이다’를 서술격조사로 범주화하는 것이 ‘이다’의 교육하는 데에 효율적일지에 대한 의문이 제기될 수 있다. 이에 본고에서는 ‘이다’의 범주에 대한 국어학적인 논의와 함께 한국어교육 문법에서의 논의를 살펴보았다. 또한 한국어교육을 위한 참조용 문법을 보여주는 한국어 교육용 문법서들과 교수-학습 문법을 보여주는 한국어 교재에서 ‘이다’를 어떻게 다루고 있는지를 살펴보았다. 이를 통해 참조용 문법에서는 주로 ‘이다’를 서술격조사나 용언 중 하나로 범주화하고 있는 반면, 한국어 교재에서 ‘이다’를 다루는 방식은 그것을 접사로서 바라보는 관점에 가까운 모습을 보이고 있다는 것을 알 수 있었다. 본고에서는 ‘이다’에 대한 세 가지의 관점, 즉 서술격조사로 보는 관점과 용언으로 보는 관점, 접사로 보는 관점을 검토하고 ‘이다’가 보이는 형태적인 복잡성을 고려해 보았을 때, 한국어교육에서는 이를 접사로서 범주화하는 것이 적절함을 주장하였다.

Malignant cells can increase in number using immune escape mechanisms such as immune checkpoints. In this study, we evaluated the expression of an immune checkpoint programmed death 1 (PD-1) on T-cell subsets in chronic myeloid leukemia (CML). We obtained bone marrow aspirate samples from CML patients and from individuals without evidence of hematologic malignancies (controls). PD-1 expression on T-cell subsets was measured using flow cytometric analysis. PD-1 expression levels on CD8+ T-cells were significantly lower in complete hematologic response (CHR) than in controls, chronic phase, and blast phase (BP). In CML patients receiving imatinib and dasatinib, PD-1 expression levels on CD8+ T-cells were lower than that at diagnosis. PD-1 expression levels on CD8+ T-cells were positively correlated with quantitative levels of the BCR/ABL fusion gene. PD-1 expression levels on CD4+ T-cells were higher in BP than in CHR. PD-1 expression levels on CD4+ T-cells did not differ significantly according to different medications or quantitative BCR/ABL1 fusion gene levels. Low PD-1 expression on CD8+ T-cells might play a role in maintaining CHR in CML patients. Immune monitoring of PD-1 expression on CD8+ T-cells may predict the disease course. In cases of refractory disease or resistance to imatinib or dasatinib, the use of PD-1 inhibitors would be helpful.

Parainfluenza virus (PIV) infection is a significant cause of morbidity and mortality, especially in hematologic malignancy patients including hematopoietic stem cell transplantation (HCT) recipients. However, limited information is available for risk stratification in PIV-infected patients with hematologic malignancy with or without HCT. Patients with hematologic malignancy diagnosed with PIV from January 2009 to December 2018 were retrospectively included in a tertiary care hospital in Seoul, South Korea. Upper respiratory tract infection (URTI) was defined as the detection of PIV in a nasopharyngeal sample with URTI symptoms without new pulmonary infiltrates. Lower respiratory tract infection (LRTI) was defined as detection of PIV in either upper or lower respiratory tract samples with new pulmonary infiltrates, with or without hypoxia. PIV-associated mortality was defined as death with respiratory failure and persistent LRTI within 90 days after diagnosis. The study included 143 adult patients. Of these, 55 (38%) progressed to or initially presented with LRTI. Among these, 22 (40%) died from PIV-associated mortality. An immunodeficiency risk score was developed from associated risk factors using a multivariable Cox regression model. Patients were stratified into low (0–2), moderate (3–5), and high risk (6–8) groups with PIV-associated mortalities of 0%, 9%, and 67%, respectively (p

Background There are various reports on the effects of the anesthetic method on neurologic complications. A population-based study was conducted to estimate the effect of anesthetic method on the incidence of postoperative delirium in patients that underwent total hip replacement arthroplasty in South Korea. Methods The Korean National Health Insurance claims database was used to retrospectively identify and analyze 24,379 cases of total hip replacement arthroplasty, defined as patients having a claim record with the operation code 'N0711,' from January 2008 to December 2017. Patients were divided into two groups, a general anesthesia group (n = 9,921) and a regional anesthesia group (n = 14,458). The incidence of delirium was assessed in cases when patients used medications for delirium, such as haloperidol, chlorpromazine, olanzapine, and risperidone. Results Of the 9,921 patients receiving general anesthesia and 14,458 receiving regional anesthesia, 142 (1.43%) and 209 (0.86%) experienced postoperative delirium after total hip replacement arthroplasty, respectively. There was no significant difference between the groups (P = 0.92). In logistic regression analysis, sex (P = 0.038) and patients with acquired immune deficiency syndrome (P = 0.008) were predictors of postoperative delirium. Conclusions Our results revealed that the anesthetic method was not associated with the incidence of postoperative delirium. In addition, the results suggest that male patients and patients with acquired immune deficiency syndrome undergoing total hip replacement arthroplasty carefully managed for postoperative delirium after surgery.

Background Intravenous dexmedetomidine has been reported to potentiate the anesthetic effect of local anesthetics and improve the quality of postoperative analgesia when used as an adjuvant in neuraxial block. We compared the effects of intravenous dexmedetomidine and midazolam for sedation on combined spinal-epidural (CSE) anesthesia. Methods This study included 50 patients undergoing total knee arthroplasty. CSE anesthesia was given using 10 mg bupivacaine for all patients. After checking the maximum sensory and motor levels, the patients were randomly allocated into two groups of 25 each to receive intravenous continuous infusion of dexmedetomidine (Group D) or midazolam (Group M) for sedation during surgery. Regression block level, hemodynamic changes, and sedation score were compared between the groups when the patients entered the postanesthetic care unit (PACU). For patient-controlled epidural analgesia, 0.2% levobupivacaine with 650 µg of fentanyl (150 ml in total) was infused at a rate of 1 ml/h, in addition to a 3-ml bolus dose with a 30-min lockout time. The visual analogue scale scores, additional analgesic demand, patient satisfaction, and adverse events between the two groups were also compared postoperatively. Results A significant difference was observed in relation to the sensory block level in the PACU (Group D: 6.3 ± 2.1; Group M: 3.2 ± 1.9) (P = 0.002). The motor block level and other outcomes showed no significant intergroup differences. Conclusions Intravenous injection of dexmedetomidine, rather than midazolam, for procedural sedation is associated with prolonged sensory block, with comparable incidences of adverse events during CSE anesthesia.

Patients with peripheral arterial disease (PAD) are at a higher risk of developing postoperative complications. Arachidonate 5-lipoxygenase-activating protein (ALOX5AP) plays an important role in atherosclerosis pathogenesis. In this study, the relationship between PAD and several single nucleotide polymorphisms (SNPs) of ALOX5AP (rs17216473, rs10507391, rs4769874, rs9551963, rs17222814, and rs7222842) was investigated in elderly patients undergoing general surgery. The medical records of 129 patients aged > 55 years who underwent elective general surgery between May 2018 and August 2019 were retrospectively reviewed. The A/A in rs17216473, A/A in rs10507391, G/G in rs4769874, and A/A in rs9551963 were calculated as 0 points and the rest as 1 point to define the genetic risk score. The prevalence of PAD tended to increase with higher genetic risk scores (patients had less ALOX5AP gene polymorphism of A/A in rs17216473, A/A in rs10507391, G/G in rs4769874, or A/A in rs9551963) (p = 0.005). Multivariate logistic regression analysis revealed that the genetic risk score (p = 0.009) and age (p = 0.007) were positively correlated with the prevalence of PAD. Genetic polymorphisms of ALOX5AP and age were associated with the prevalence of PAD in this study.

Microsatellite instability-high (MSI-H) colorectal cancer (CRC) is different from microsatellite stable (MSS) CRC concerning biological, and clinical features. In MSI-H CRCs, defects of mismatch repair genes produce increased mutation accumulation in repetitive DNA sequences. To see whether candidate tumor suppressor genes (TSGs) are altered in MSI-H CRC, we studied frameshift mutation and protein expression of candidate TSGs of RGS2, HNF1A, HNF1B, CAPN12, RCBTB2, ATE1, PKNOX1, and USP19. We found frameshift mutations of RGS2 in 5 (5%), HNF1A in 6 (6%), HNF1B in 2 (2%), CAPN12 in 3 (3%), RCBTB2 in 4 (4%), ATE1 in 2 (2%), PKNOX1 in 2 (2%), and USP19 in 2 (2%) MSI-H CRCs. However, we found no such mutations in MSS CRCs. RCBTB2, CAPN12, HNF1A, and HNF1B frameshift mutations revealed the regional difference in the same tumors. In addition, we identified loss of RGS2, HNF1A, and CAPN12 protein expression irrespective of MSI phenotype in 13-29% of CRCs. The results indicate that many TSGs harbor concurrent inactivating mutations and protein loss in MSI-H CRCs with intratumoral mutational heterogeneity, and that MSS CRCs are altered by protein losses. These alterations could contribute to CRC development and underlying mechanisms and consequences of the TSG alterations remain to be clarified.

Background Preterm labor and miscarriage may occur in stressful situations, such as a surgical operation or infection during pregnancy. Pharyngeal and buccal abscess and facial bone fractures are inevitable dental surgeries in pregnant patients. Remifentanil is an opioid analgesic that is commonly used for general anesthesia and sedation. Nonetheless, no study has investigated the effects of remifentanil on amniotic epithelial cells. This study evaluated the effects of remifentanil on the factors related to uterine contraction and its mechanism of action on amniotic epithelial cells. Methods Amniotic epithelial cells were preconditioned at various concentrations of remifentanil for 1 h, followed by 24-h lipopolysaccharide (LPS) exposure. MTT assays were performed to assess the cell viability in each group. The effects of remifentanil on factors related to uterine contractions in amniotic epithelial cells were assessed using a nitric oxide (NO) assay, western blot examinations of the expression of nuclear factor-kappa B (NF-κB), cyclooxygenase 2 (COX2), and prostaglandin E2 (PGE2), and RT-PCR examinations of the expression of the proinflammatory cytokines interleukin (IL)-1β and tumor necrosis factor-alpha (TNF-α). Results Remifentanil did not affect viability and nitric oxide production of amniotic epithelial cells. Western blot analysis revealed that remifentanil preconditioning resulted in decreased expressions of NF-κB and PGE2 in the cells in LPS-induced inflammation, and a tendency of decreased COX2 expression. The results were statistically significant only at high concentration. RT-PCR revealed reduced expressions of IL-1β and TNF-α. Conclusions Preconditioning with remifentanil does not affect the viability of amniotic epithelial cells but reduces the expression of factors related to uterine contractions in situations where cell inflammation is induced by LPS, which is an important inducer of preterm labor. These findings provide evidence that remifentanil may inhibit preterm labor in clinical settings.

This study aims to analyze the modality development of beginners of Korean and discuss the development order of the modality. The modality is a grammatical category that indicates speaker’s subjective judgment and attitude toward the proposition that has highly semantic and pragmatic usefulness in communication. In this study free conversational speech of 8 beginners of Korean were collected regularly for 5 months and examined the frequency of use and the number of speakers of modal grammar. As a results, among the various grammatical items, ‘-고 싶다’, ‘-(으)ㄹ 것이다’(의향), ‘-(으)ㄹ 수 있다/없다’, ‘-아/어 보다’, ‘-아야/어야 되다/하다’ were uttered relatively frequently, in the early periods in about 3months after the beginning of Korean learning, and about six months after the beginning of the Korean learning, -는/(으)ㄴ/(으)ㄹ 것 같다’, ‘-(으)ㄹ 것이다’(추측), ‘-아/어 주다’ were uttered by almost all learners. This modality development was not completely consistent with the order of learning. This study is meaningful in that it provides important information needed to determine the order of modality. (Wonkwang Digital University)

Background: The first treatment option for major depressive disorder (MDD) is antidepressants, however, there is substantial demand for alternative therapies due to its low compliance and remission rates. This study was aimed to explore the effectiveness, safety, and feasibility of electroacupuncture plus moxibustion therapy for MDD. Methods: Thirty adults with MDD were randomly assigned to the treatment group (TG) or control group (CG). The TG was treated with electroacupuncture plus moxibustion, and the CG received sham interventions at non-acupoints for 8 weeks. The primary outcome measure was the intergroup difference of the mean change of total score of the Hamilton rating scale for depression (HRSD) between baseline and week 9. Secondary outcome measures were Beck's depression inventory, insomnia severity index, the state-trait anxiety inventory, the EuroQol-5 dimension index, the measure yourself medical outcome profile version 2, and frontal alpha asymmetry measured by electroencephalography. Adverse events (AEs) were monitored for safety assessment. Results: The primary outcome measure was not significantly different between the two groups (p=0.2641), although the scores of HRSD in both groups improved significantly after treatment. No significant difference was identified between groups in secondary outcome measures. The incidence of AE was not significantly different between the two groups (p=0.1067). Conclusion: A clinical trial using electroacupuncture plus moxibustion for MDD seems feasible. However, further studies with the larger size, adopting ideal controls are warranted to provide a confirmative conclusion to the efficacy and safety of electroacupuncture plus moxibustion for MDD. Trial registration: The protocol was registered at Korean Clinical Trial Registry (CRIS-KCT0001810)

This study aims to investigate fermentative metabolites in probiotic vegetable juice from four crop varieties (Brassica oleracea var. capitata, B. oleracea var. italica, Daucus carota L., and Beta vulgaris) and their antioxidant properties. Vegetable juice was inoculated with two lactic acid bacteria (LAB) (Companilactobacillus allii WiKim39 and Lactococcus lactis WiKim0124) isolated from kimchi and their properties were evaluated using untargeted UPLC-QTOF-MS/MS and GC-MS. The samples were also evaluated for radical (DPPH• and OH•) scavenging activities, lipid peroxidation, and ferric-reducing antioxidant power. The fermented vegetable juices exhibited high antioxidant activities and increased amounts of total phenolic compounds. Fifteen compounds and thirty-two volatiles were identified using UPLC-QTOF-MS/MS and GC-MS, respectively. LAB fermentation significantly increased the contents of d-leucic acid, indole-3-lactic acid, 3-phenyllactic acid, pyroglutamic acid, γ-aminobutyric acid, and gluconic acid. These six metabolites showed a positive correlation with antioxidant properties. Thus, vegetable juices fermented with WiKim39 and WiKim0124 can be considered as novel bioactive health-promoting sources.

Thermal interface materials (also known as thermal pads) are widely used as a crucial part to dissipate heat generated in miniaturized and integrated electronic components. Here, we systematically investigated the effects of small ceramic and metallic powders in rubbery thermal composite pads with a high content of aluminum oxide filler on the thermal conductivity of the composite pads. We optimized the compositions of aluminum oxide fillers with two different sizes in a polydimethylsiloxane (PDMS) matrix for rubbery composite pads with a high thermal conductivity. Based on the optimized compositions, zinc oxide powder or copper powder with an average size of 1 μm was used to replace 5 μm-sized aluminum oxide filler to examine the effects of the small ceramic and metallic powders, respectively, on the thermal conductivity of the composite pads. When zinc oxide powder was used as the replacement, the thermal conductivity of the rubbery composite pads decreased because more air bubbles were generated during the processing of the mixed paste with increased viscosity. On the other hand, when the copper powder was used as a replacement, a thermal conductivity of up to 2.466 W/m·K was achieved for the rubbery composite pads by optimizing the mixing composition. SEM images and EDS mapping confirmed that all fillers were evenly distributed in the rubbery composite pads.

Background Scoring systems developed for predicting survival after allogeneic hematopoietic cell transplantation (HCT) show suboptimal prediction power, and various factors affect posttransplantation outcomes. Objective A prediction model using a machine learning–based algorithm can be an alternative for concurrently applying multiple variables and can reduce potential biases. In this regard, the aim of this study is to establish and validate a machine learning–based predictive model for survival after allogeneic HCT in patients with hematologic malignancies. Methods Data from 1470 patients with hematologic malignancies who underwent allogeneic HCT between December 1993 and June 2020 at Asan Medical Center, Seoul, South Korea, were retrospectively analyzed. Using the gradient boosting machine algorithm, we evaluated a model predicting the 5-year posttransplantation survival through 10-fold cross-validation. Results The prediction model showed good performance with a mean area under the receiver operating characteristic curve of 0.788 (SD 0.03). Furthermore, we developed a risk score predicting probabilities of posttransplantation survival in 294 randomly selected patients, and an agreement between the estimated predicted and observed risks of overall death, nonrelapse mortality, and relapse incidence was observed according to the risk score. Additionally, the calculated score demonstrated the possibility of predicting survival according to the different transplantation-related factors, with the visualization of the importance of each variable. Conclusions We developed a machine learning–based model for predicting long-term survival after allogeneic HCT in patients with hematologic malignancies. Our model provides a method for making decisions regarding patient and donor candidates or selecting transplantation-related resources, such as conditioning regimens.

BACKGROUND Scoring systems developed for predicting survival after allogeneic hematopoietic cell transplantation (HCT) show suboptimal prediction power, and various factors affect posttransplantation outcomes. OBJECTIVE A prediction model using a machine learning–based algorithm can be an alternative for concurrently applying multiple variables and can reduce potential biases. In this regard, the aim of this study is to establish and validate a machine learning–based predictive model for survival after allogeneic HCT in patients with hematologic malignancies. METHODS Data from 1470 patients with hematologic malignancies who underwent allogeneic HCT between December 1993 and June 2020 at Asan Medical Center, Seoul, South Korea, were retrospectively analyzed. Using the gradient boosting machine algorithm, we evaluated a model predicting the 5-year posttransplantation survival through 10-fold cross-validation. RESULTS The prediction model showed good performance with a mean area under the receiver operating characteristic curve of 0.788 (SD 0.03). Furthermore, we developed a risk score predicting probabilities of posttransplantation survival in 294 randomly selected patients, and an agreement between the estimated predicted and observed risks of overall death, nonrelapse mortality, and relapse incidence was observed according to the risk score. Additionally, the calculated score demonstrated the possibility of predicting survival according to the different transplantation-related factors, with the visualization of the importance of each variable. CONCLUSIONS We developed a machine learning–based model for predicting long-term survival after allogeneic HCT in patients with hematologic malignancies. Our model provides a method for making decisions regarding patient and donor candidates or selecting transplantation-related resources, such as conditioning regimens.

In hematopoietic stem cell transplant recipients, the incidence of tuberculosis in positive interferon-γ release assay (IGRA) without isoniazid prophylaxis (3.58/100 person-years) was higher than in negative or indeterminate IGRA (1.15/100 person-years; P = .01) and in positive IGRA with isoniazid prophylaxis (0/100 person-years; P = .09). The number needed to treat was 22 (95% confidence interval, 12–99) with positive IGRA results.

Oxalosis is a metabolic disorder characterized by the accumulation of calcium oxalate deposits in various organ systems. Bone oxalosis is a systemic manifestation of oxalosis, in which calcium oxalate deposits accumulate in the skeletal system. This report describes a 69-year-old female patient who presented with right hip pain and was later found to have an osseous mass-like lesion in the right proximal femur, with radiographic findings resembling those of a benign bone tumor. CT-guided biopsy and surgical biopsy showed that the mass had pathologic findings typical of bone oxalosis. Because the patient had no predisposing factors for systemic oxalosis and had no hyperoxalemia or hyperoxaluria, she could be diagnosed with localized bone oxalate deposition disease or bone oxaloma rather than bone oxalosis. This is the first report of this clinical entity to present as a benign-appearing bone mass and without any predisposing systemic causes.

Our previous research indicated that a reduced-intensity conditioning regimen (fludarabine and melphalan at 100 mg/m2) was useful in allogeneic hematopoietic cell transplantation (HCT) for patients with lymphoma. This retrospective study evaluated the reduced-intensity conditioning regimen in allogeneic HCT for adult patients with hemophagocytic lymphohistiocytosis (HLH). Sixteen patients with HLH were evaluated, including 6 patients who were enrolled in a prospective clinical trial (NCT00772811) and 10 patients who received the same conditioning regimen (fludarabine at 30 mg/m2/day on days –6 to –2 and melphalan at 100 mg/m2 on day –2). The median age was 42 years (range, 18 to 64), and 12 patients had Epstein-Barr virus (EBV)-associated HLH. Donors were an HLA matched sibling for 10 patients, an unrelated matched volunteer for 4 patients, and a mismatched family member for 2 patients. After excluding 3 patients who died soon after HCT, 12 patients achieved an engraftment (neutrophil median, day 12; platelet median, day 16). Five patients experienced acute graft-versus-host disease (GVHD), including 1 case of grade II and 4 cases of grades III to IV. Chronic GVHD occurred in 3 patients (moderate, 1 case; severe, 2 cases). After a median follow-up of 33.8 months 1 patient progressed, 3 patients relapsed, and 9 patients died. Five deaths were unrelated to relapse or progression and were caused by infection (n = 3), bleeding (n = 1), and GVHD (n = 1). No deaths or relapses were observed at >124 days post-transplant. The overall survival rate was 48.6%, and significant differences were observed according to pretransplant ferritin level (P = .007) and cytopenia lineage (P = .021). Before allogeneic HCT 10 of 12 patients still tested positive for EBV DNA: 6 patients tested negative for EBV DNA after HCT, 2 patients had persistent EBV DNA, and 2 patients were unassessable because of early death. Conditioning therapy using a lower dose of melphalan combined with fludarabine appears to be promising in allogeneic HCT for adults with HLH. However, strategies are needed to reduce the risk of early death.

BACKGROUND: Preterm labor is a leading risk factor for neonatal death and long-term impairment and linked closely with inflammation. Non-obstetric surgery is occasionally needed during pregnancy and the anesthetic drugs or surgery itself can give rise to inflammation. Here, we examined the influence of propofol pretreatment on the expression of cyclooxygenase-2 (COX-2) and prostaglandin E(2) (PGE(2)) after lipopolysaccharide (LPS) stimulation. In addition, we evaluated the expression of pro-inflammatory cytokines and nuclear factor kappa B (NF-κB). METHODS: Human amnion-derived WISH cells were used to investigate the effect of propofol on the LPS-induced expression of inflammatory substances involved in preterm labor. For the experiment, WISH cells were pretreated with various concentrations propofol (0.01–10 μg/ml) for 1 h and then treated with LPS (1 μg/ml) for 24 h. Cytotoxicity was evaluated using MTT assay. PGE(2) concentration was assessed by ELISA. Protein expressions of COX-2, PGE(2) and NF-κB were analyzed by western blotting analysis. RT-PCR was used for analysis of mRNA expression of COX-2, PGE(2), interlukin (IL)-1β and tumor necrosis factor (TNF)-α. RESULTS: Propofol showed no cytotoxicity on the WISH cells. LPS-induced PGE(2) production and COX-2 and PGE(2) expression were decreased after propofol pretreatment. Propofol also attenuated the LPS-induced mRNA expression of IL-1β and TNF-α. Moreover, the activation of NF-κB was inhibited by propofol pretreatment on LPS-stimulated WISH cells. CONCLUSION: We demonstrated that propofol suppresses the expression of inflammatory substances enhanced by LPS stimulation. Furthermore, this inhibitory effect of propofol on the inflammatory substance expression is mediated by suppression of NF-κB activation.

Delivery of synovium-resident mesenchymal stem cells (synMSCs) to cartilage defect site might provide a novel therapeutic modality for treatment of articular cartilage diseases. However, low isolation efficiency of synMSCs limits their therapeutic application. Niche-preserving non-enzymatic isolation of synMSCs was firstly attempted by employing micro-organ culture system based on recapitulating tissue-specific homeostasis ex vivo. The isolated synMSCs retained superior long-term growth competency, proliferation and chondrogenic potential to bone marrow-derived MSCs (BMSCs). It was noted that synMSCs demonstrated 9-fold increase in cartilaginous micro-tissue formation and 13-fold increase in sulfated proteoglycans deposition compared to BMSCs. For delivery of synMSCs, fibrous PLGA scaffolds were specifically designed for full-thickness osteochondral defects in rabbits. The scaffolds provided effective micro-environment for growth and host-integration of synMSCs. Combined delivery of synMSCs with bone morphogenetic proteins-7 (BMP-7) was designed to achieve synergistic therapeutic efficacy. BMP-7-loaded PLGA nanoparticles electrosprayed onto the scaffolds released BMP-7 over 2 weeks to conform with its aimed role in stimulating early stage endochondral ossification. Scaffold-supported combined administration of synMSCs with BMP-7 resulted in high proteoglycan and collagen type II induction and thick hyaline cartilage formation. Intra-articular co-delivery of synMSCs with BMP-7 via fibrous PLGA scaffolds may be a promising therapeutic modality for articular cartilage repair.

Improving the microbiological quality of salted Chinese cabbage, used in kimchi, an important part of the Asian culinary scene, is critical for minimising exposure to foodborne pathogens. This study evaluated the effects of a sequential combination of washing treatments using plasma-activated water (PAW), tap water, and sodium hypochlorite (NaOCl) and mild heating (MH) at 60 °C on the inactivation of background microbiota and inoculated foodborne pathogens and the quality of shredded salted Chinese cabbages. Treatment with 120-PAW alone resulted in 2.0, 2.2, 1.8, and 0.9 log CFU/g reduction in mesophilic aerobic bacteria, lactic acid bacteria, yeast and moulds, and coliforms, respectively, while subsequent MH treatment reduced the counts of lactic acid bacteria, yeast and moulds, and coliforms to below detection limits. Sequential combination of washing with 120-PAW followed by MH caused 3.4 and 3.7 log CFU/g reductions in Listeria monocytogenes and Staphylococcus aureus inoculated into salted Chinese cabbages. The combined treatment caused negligible changes in moisture content, reducing sugar content, instrumental hardness, and CIE colour values. The salinity and peroxidase activity were significantly (P

Background and purpose A cognitive intervention (CI) is thought to improve cognition and delay cognitive decline via neuronal plasticity and cognitive resilience. Subjective cognitive decline (SCD) might be the first symptomatic stage of Alzheimer's disease, but few studies have examined the beneficial effect of CIs in SCD. We aimed to determine the efficacy of a 12-week, small-group-based, multidomain CI in elderly patients with SCD. Methods Participants diagnosed with SCD (aged 55-75 years) were consecutively allocated to three groups: group 1, which received group-based CI implementation with lifestyle modifications; group 2, which received home-based lifestyle modifications without CI; and group 3, in which no action was taken. The primary outcome variables were the scores on computerized tests of the Cambridge Neuropsychological Test Automated Battery (CANTAB). The secondary outcomes included scores on tests evaluating general cognition, memory, visuospatial, and executive functions, as well as scores for the quality of life (QoL), anxiety, depression, and degree of subjective complaints. Changes in scores during the study period were compared between groups. Results The study was completed by 56 SCD participants. The baseline characteristics did not differ among the groups. The primary outcomes (CANTAB scores) did not differ among the groups. However, the outcomes for phonemic word fluency, verbal memory, QoL, and mood were better for group 1 than for the other two groups. Improvements in verbal memory function and executive function were related to the baseline cognitive scores and group differences. Conclusions CI in SCD seems to be partially beneficial for executive function, memory, QoL, and mood, suggesting that CI is a useful nonpharmacological treatment option in this population.

This study investigated the effect of radio frequency (RF) heating at 27.12 MHz on the inactivation of pre-existing microorganisms and salting characteristics of shredded kimchi cabbages. Samples of shredded kimchi cabbages were subjected to 27.12 MHz RF heating at different power levels (1,000 and 1,500 W) or to hot water (HW) at 60 and 70℃. RF heating at 1,500 W for 3 min reduced the populations of aerobic bacteria, yeast and molds, coliforms, and lactic acid bacteria in the shredded kimchi cabbage samples by 2.56, 1.26, 4.36, and 4.31 log CFU/g, respectively; moreover, survival plots fitted using the Weibull model for 1,500 W RF heating yielded Dr values of 1.92, 2.66, 1.81, and 0.75 min, respectively. The salinity of shredded kimchi cabbages treated with RF and HW heating increased more rapidly than that of the control during salting. With respect to the moisture content and hardness in the shredded kimchi cabbages, no significant differences were observed among the treatments, after salting for 4 h. In addition, the surface temperature distributions of the RF-heated samples were relatively uniform compared to those of the HW-heated samples. These results clearly indicated that the RF heating technology has the potential to decontaminate kimchi cabbages of pre-existing microorganisms, before the salting process.

This study aims to develop a control algorithm that can operate an intermittently working variable refrigerant flow (VRF) heating system in a cost-effective manner. An artificial neural network (ANN) model, which is designed to predict the heating energy cost during the next control cycle, is embedded in the control algorithm. By comparing the predicted energy costs for the different setpoint combinations for the system parameters, such as the air handling unit (AHU) supply air temperature, condensing warm fluid temperature, condensing warm fluid amount, and refrigerant condensing temperature, the control algorithm can determine the most cost-effective setpoints to optimally operate the heating system. Two major processes are conducted—development of the predictive control algorithm in which the ANN model is embedded, and performance tests in terms of prediction accuracy and cost efficiency using computer simulation. Results analysis reveals that the ANN model accurately predicts the energy cost, presenting a low coefficient of variation of the root mean square error value (7.42%) between the simulated and predicted results. In addition, the predictive control algorithm significantly saves on the heating energy cost by as much as 7.93% compared with the conventional heuristic control method. From the results analysis, the ANN model and the control algorithm show the potential for prediction accuracy and cost-effectiveness of the intermittently working VRF heating system.

β2-microglobulin (B2M), a component of major histocompatibility complex class I, plays an important role in host immune reaction to tumor, and inactivation of B2M is known to contribute to resistance to immune checkpoint blockade (ICB) treatment. To further characterize the B2M alterations in tumors, we analyzed B2M hotspot mutations in 2765 benign and malignant tumor tissues by Sanger sequencing and found B2M mutations in 9 (7.5%) microsatellite-unstable (MSU) colorectal cancers (CRCs) and 3 leukemias (0.6–1.3%), but not in other tumors. Targeted sequencing panel analysis for MSU CRCs showed that B2M-mutated MSU CRCs harbored more driver mutations including TP53 than B2M-wild-type MSU CRCs. Of note, bi-allelic B2M alterations, which had been known to be accumulated during ICB treatment, were frequently found (3/9) in ICB treatment-naive CRCs. Clinicopathologic parameters including CD8 + T cell numbers, cancer stages and patients’ survival, however, were not significantly different between B2M-mutated and B2M-wild-type MSU CRCs. Our results indicate that B2M mutation abundance is tissue type-specific (e.g., MSU CRCs) and that genetic makeup of B2M mutation might possibly shape the MSU CRC genomes even before the ICB therapies. Our results show that B2M mutation is common in MSU CRCs, which is one of the main targets for ICB treatment, suggesting that frequent B2M mutation status should be reminded for MSU CRCs in patient selection of ICB.

[Purpose] Immunosuppressive tumor microenvironment (TME) is the major hurdle to cancer immunotherapy. Advanced hepatocellular carcinoma (aHCC) is one of the representative cold tumors with immunosuppressive TME and presents obvious correlation between immune check point expression, such as programmed cell death ligand 1 (PD-L1), and poorer prognosis. In aHCC patients, cancer cells and stellate cells in TME appeared to express high level of PD-L1, which should suppress activities of antitumor immune cells. In this context, the combination of PD-1/PD-L1 inhibitors and other therapeutic modalities are tried to treat aHCC. The chimeric antigen receptor (CAR) T cell therapy is a potent way of eradicating cells expressing targetable antigens. Removal of PD-L1 expressing cells in the aHCC TME will improve the clinical outcomes of current therapies against aHCC. In the present study, we developed an autologous anti-PD-L1 CAR T strategy and show high efficacy of tumor suppression using an HCC xenograft model. [Result] We constructed second generation CAR lentiviral vector expressing an unique anti-PD-L1 scFv manifesting moderated affinity. The scFv was specifically generated by phage display technique using human B cell-derived naïve cDNA library, which targets PD-L1 with intermediate affinity in solid tumor TME. As the secondary signaling motif, CD28 was chosen and tested along with CD3 zeta chain. The effector CAR T, named VPC1, cells specifically recognized PD-L1 expressing HCC cells and exhibited rapid and robust cytotoxic activity in 2D and 3D culture experiments. In an HCC xenograft NSG mouse model, VPC1 CAR T cells significantly suppressed the tumor growth. More importantly, VPC-1-treated animals have well tolerated the CAR T therapy with no significant adverse manifestations during one month observation period and exhibited gradual weight gains since 3 days after CAR T cell injection. [Conclusion] We hereby report that a new autologous PD-L1 CAR-T therapeutic is capable of eradicating solid tumors expressing PD-L1, which would significantly potentiate efficacies of current conventional and immunotherapeutic strategies. Citation Format: Kyung-Sik Lee, Hye-Seong Park, Guk-Yeol Park, Gi-Chan Lee, Eun-Ji Choi, Jae-in Yu, Seung-Joo Yang, Mihwa Kim, Yoonjoo Choi, Je-Jung Lee, Joon Haeng Rhee, Bum Chan Park, Jae Eun Park. Development of an anti hepatocellular carcinoma CAR T strategy targeting PDL1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6189.

The importance of evergreen oak species is increasing due to changes in the ecosystem caused by climate change and environmental changes such as fine dust and carbon dioxide. The Quercus myrsinifolia Blume seeds showed a recalcitrant seed property, where the germination rate decreased when the moisture content was decreased. For seedling propagation of evergreen oak, the effect of oak seed coat (pericarp and testa) removal on germination and seedling growth as well as the effect of potting soil and irrigation cycle on seedling quality were investigated. The germination rate and germination characteristics of Q. myrsinifolia evergreen oak seeds showed significant differences depending on the storage period and the presence or absence of seed coat. Seed coat removal significantly increased germination rate compared to intact seeds, accelerated mean germination time, and increased germination rate and germination value. There was no significant difference in germination rate according to the storage period. The growth of Q. myrsinifolia seedlings was much better in the seeds with the seed coat removed than the intact seeds. The root collar diameter of seedlings germinated from intact seeds was 2.44 mm, and the root collar diameter of seedlings from which the seed coat was removed was 3.38 mm. As a result of the growth characteristics according to the potting soil, 1- and 3-year-old Q. myrsinifolia seedlings showed excellent root growth in commercial potting soil and sand mixed potting soil. Consequently, seedling quality index was 0.124–0.257 according to irrigation and 0.149–0.262 according to potting soil. From observing the root growth of the seedlings according to the irrigation treatment, in the case of 3-year-old seedlings, the total root length was 432 cm when irrigated every 3 days, and the growth was the best. The above results are expected to contribute significantly to the mass propagation of Q. myrsinifolia, which is important for warming and urban greening.

Background This study presents outcomes of management in graft failure (GF) after allogeneic hematopoietic stem cell transplantation (HCT) and provides prognostic information including rare cases of autologous reconstitution (AR). Methods We analyzed risk factors and outcomes of primary and secondary GF, and occurrence of AR in 1,630 HCT recipients transplanted over period of 18 years (January 2000–September 2017) at our center. Results Primary and secondary GF occurred in 13 (0.80%), and 69 patients (10-year cumulative incidence, 4.5%) respectively. No peri-transplant variables predicted primary GF, whereas reduced intensity conditioning (RIC) regimen (relative risk [RR], 0.97–28.0, P < 0.001) and lower CD34+ cell dose (RR, 2.44–2.84, P = 0.002) were associated with higher risk of secondary GF in multivariate analysis. Primary GF demonstrated 100% mortality, in the secondary GF group, the 5-year Kaplan-Meier survival rate was 28.8%, relapse ensued in 18.8%, and AR was observed in 11.6% (n = 8). In survival analysis, diagnosis of aplastic anemia (AA), chronic myeloid leukemia and use of RIC had a positive impact. There were 8 patients who experienced AR, which was rarely reported after transplantation for acute leukemia. Patient shared common characteristics such as young age (median 25 years), use of RIC regimen, absence of profound neutropenia, and had advantageous survival rate of 100% during follow period without relapse. Conclusion Primary GF exhibited high mortality rate. Secondary GF had 4.5% 10-year cumulative incidence, median onset of 3 months after HCT, and showed 5-year Kaplan-Meier survival of 28.8%. Diagnosis of severe AA and use of RIC was both associated with higher incidence and better survival rate in secondary GF group. AR occurred in 11.6% in secondary GF, exhibited excellent prognosis., Graphical Abstract

TRAF2 and TRAF3 genes of tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) family are involved in diverse cell signaling, and function as both tumor suppressor gene and oncogene. Alterations of TRAF2 and TRAF3 in colon cancer (CC) along with their regional difference and microsatellite instability (MSI) are largely unknown. In the present study, we analyzed TRAF2 and TRAF3 frameshift mutations in 168 sporadic CCs (100 high MSI (MSI-H) and 68 microsatellite-stable (MSS) CCs). We identified TRAF2 and TRAF3 frameshift mutations in 4 (4%) and 3 CCs (3%) with MSI-H, respectively, but none in 68 cases of MSS CCs. Of the 168 CCs, we analyzed the mutations in multi-regions for 39 CCs (16 MSI-H and 23 MSS CCs), and discovered that 12.5% (2/16) and 6.3% (1/16) of MSI-H CCs exhibited regional difference in TRAF2 and TRAF3 mutations, respectively. In the multi-region samples of 23 MSS CCs, neither TRAF2 nor TRAF3 frameshift mutation was found. In 40% of CCs, both TRAF2 and TRAF3 expressions were increased compared to normal colon cells. Our data indicate that TRAF2 and TRAF3 frameshift mutations and their regional difference as well as altered expressions are present in MSI-H CCs, which could contribute to MSI-H cancer development.

Background and objectives There are limited data in real clinical practice on the diagnostic value of a bronchoalveolar lavage (BAL) fluid galactomannan (GM) assay in patients with suspected invasive pulmonary aspergillosis (IPA) who had negative serum GM results. Thus, we investigated the diagnostic performance of a BAL GM assay in patients with negative serum GM assay results who were suspected to have IPA. Methods This retrospective study was performed between May 2008 and April 2019 at a tertiary care hospital in Seoul, South Korea. All patients with suspected IPA whose serum GM assays revealed negative results who sequentially underwent BAL were enrolled in this study. Results A total of 341 patients with suspected IPA including 4 cases of proven IPA, 38 case of probable IPA, 107 cases of possible IPA, and 192 patients without IPA were enrolled. Of these 341 patients, 107 (31%) with possible IPA were excluded from the final analysis. Of 42 patients with proven and probable IPA who had initial negative serum GM results, 24 (57%) had positive BAL GM results (n = 24) or BAL fungal culture results (n = 8). In addition, BAL revealed evidence of other opportunistic infections including Pneumocystis jirovecii pneumonia (14% [26/190]), cytomegalovirus (CMV) pneumonia (5% [9/188]), and respiratory viral pneumonia (6% [12/193]). Conclusion Sequential BAL in patients with suspected IPA who had initial negative serum GM results provided additional diagnostic yield in approximately half of patients with evidence of another co-infection.

This study aimed to distinguish between Korean and Chinese red pepper powder (RPP) using inorganic elemental analysis data combined with orthogonal partial least squares-discriminant analysis (OPLS-DA). Elemental concentrations were obtained for 31 Korean and 31 Chinese RPP samples that were collected in Korea. Energy dispersive X-ray fluorescence spectroscopy detected 11 elements in these samples. Rb and Cl concentrations were selected as the variables which best allowed distinguishing between Korean and Chinese RPP using an S-plot from OPLS-DA. Rb and Cl concentrations in the Korean RPP samples were ≤ 1.6 mg/100 g (measured by inductively coupled plasma-optical emission spectroscopy) and ≤ 215 mg/100 g, respectively. A blind trial demonstrated that Korean RPP containing ≥ 50 g/100 g of Chinese RPP could be identified by applying predetermined ranges of Rb and Cl concentrations, suggesting that analysis of these two elements is a possible approach to distinguish between Korean and Chinese RPP.

Core-binding factor (CBF)-acute myeloid leukemia (AML) generally have a favorable prognosis. However, approximately 50% of patients experience disease relapse during or after post-remission therapy. Retrospective studies on autologous hematopoietic cell transplantation (AHCT) have shown improved survival with decreased relapse rate in CBF-AML. In this prospective study, we evaluate the outcomes of AHCT following high-dose cytarabine (HiDAC) consolidation in patients with CBF-AML in first complete remission (CR). Adult patients with CBF-AML achieving first CR after induction chemotherapy were eligible for the study. High-dose chemotherapy before AHCT included intravenous busulfan (3.2 mg/kg/day, days − 7 to − 5) and etoposide (400 mg/m2/day, days − 3 to − 2). Twenty-nine patients, 17 with t(8;21) and 12 with inv(16), underwent AHCT following 2 or 3 courses of HiDAC consolidation. The estimated 5-year overall and disease-free survival rates were between 89.0% and 82.5%, respectively. The cumulative incidences of relapse and non-relapse mortality were between 17.5% and 0%, respectively. Presence of measurable residual disease (MRD) before AHCT and KIT mutation were significantly associated with relapse after transplantation. In conclusion, the post-remission strategy of AHCT following HiDAC consolidation in CBF-AML was feasible and efficacious. Assays for MRD and KIT mutation may guide selection of patients who will benefit from AHCT in CBF-AML in first CR.

Eun-Ji Choi,1,2 Soon Ji Park,1 Yeong-Min Yoo,1 Ji-Uk Yoon,1,2 Sang-Wook Shin,1,2 Gyeong-Jo Byeon1,2 1Department of Anesthesia and Pain Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Republic of Korea; 2Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Republic of KoreaCorrespondence: Gyeong-Jo ByeonDepartment of Anesthesia and Pain Medicine, Pusan National University Yangsan Hospital, Geumoro 20, Yangsan, Gyeongnam, 50612, Republic of KoreaTel +82-55-360-2129Fax +82-55-360-2149Email byeongj@pusan.ac.krBackground: Transforaminal epidural steroid injections (TF-ESIs) effectively deliver small amounts of drugs to inflamed sites via the ventral epidural space. However, there is a high risk of nerve damage as the needle narrowly approaches the spinal nerve. Therefore, we devised an oblique interlaminar (OIL) approach as an alternative method. We compared the efficacy of fluoroscopic-guided OIL-ESIs with that of TF-ESIs in the management of lower back and unilateral lumbosacral radicular pain.Materials and Methods: Sixty-six patients were randomized to receive a fluoroscopic-guided ESI either through the OIL (n = 33, group OIL) or TF (n = 33, group TF) approach. They were evaluated for effective pain relief using the visual analogue scale (VAS) and for functional improvement using the Oswestry Disability Index (ODI) and Roland Morris Disability Questionnaire (RMDQ). Other outcome measures were the presence of ventral and contralateral spread of contrast, patients’ satisfaction, and adverse events.Results: There were no significant differences between the groups in the VAS, ODI, and RMDQ scores during the 12-week period. The differences in the ODI and RMDQ scores before and after the treatment were higher in group TF than in group OIL. The contralateral spread of contrast was higher in group OIL than in group TF. There were no significant differences in the other outcomes between the groups.Conclusion: ESIs delivered through the OIL approach are equally effective in pain relief and functional improvement as those delivered via the TF approach in the management of low back and unilateral lumbosacral radicular pain.Keywords: epidural analgesia, fluoroscopy, low back pain, radicular pain, steroid injection

The type of occupant activities is a significantly important factor to determine indoor thermal comfort; thus, an accurate method to estimate occupant activity needs to be developed. The purpose of this study was to develop a deep neural network (DNN) model for estimating the joint location of diverse human activities, which will be used to provide a comfortable thermal environment. The DNN model was trained with images to estimate 14 joints of a person performing 10 common indoor activities. The DNN contained numerous shortcut connections for efficient training and had two stages of sequential and parallel layers for accurate joint localization. Estimation accuracy was quantified using the mean squared error (MSE) for the estimated joints and the percentage of correct parts (PCP) for the body parts. The results show that the joint MSEs for the head and neck were lowest, and the PCP was highest for the torso. The PCP for individual activities ranged from 0.71 to 0.92, while typing and standing in a relaxed manner were the activities with the highest PCP. Estimation accuracy was higher for relatively still activities and lower for activities involving wide-ranging arm or leg motion. This study thus highlights the potential for the accurate estimation of occupant indoor activities by proposing a novel DNN model. This approach holds significant promise for finding the actual type of occupant activities and for use in target indoor applications related to thermal comfort in buildings.

Luteolin (3′,4′,5,7-tetrahydroxyflavone), a type of flavonoid found in medicinal herbs and vegetables, has been of great interest due to its antioxidative, anti-inflammatory, and anticarcinogenic effects. Despite these beneficial biological properties, the ease with which luteolin forms molecular crystals in conventional aqueous formulations has hampered much wider applications. In this study, we introduce an oil-in-water (O/W) nanoemulsion vehicle system for enhanced follicular delivery of luteolin. The luteolin-loaded nanoemulsion, which had an average hydrodynamic size of approximately 290 nm, was produced by the assembly of poly(ethylene oxide)-block-poly(e-caprolactone) and lecithin at the O/W interface. The luteolin-loaded nanoemulsion showed outstanding stability against drop coalescence and aggregation. This was confirmed from the slight drop size increase after repeated freeze–thaw cycling and long-term storage. Moreover, in vivo hair growth evaluation demonstrated that the luteolin-loaded nanoem...

BACKGROUND Liver transplantation (LT) has the incidence of 30-day mortality about 5-10%, Jo et al. reported that 30-day mortality and 1-year mortality for DDLT were 30%, and 39% respectively. It is not easy to create a model for predicting post-transplantation outcomes based on pretransplant variables. MELD does not take into account individual complications such as hepatic encephalopathy (HE), and research has shown that the greater the severity of pretransplant HE, the lower the survival rate after LT; the importance of monitoring for HE is therefore emphasized. METHODS The medical records of adult patients who underwent deceased donor LT (DDLT) were retrospectively reviewed for analysis of the effect of HE on the long-term survival rate of post-transplant for more than 1 year. RESULTS Presence of HE is not statistically associated to patient survival (P=0.062), but the hazard ratio is 1.954 (95% CI, 0.968, 3.943). In addition, the severe HE group significantly decreased survival compared to the non-HE group, and the cumulative 1- and 3-year overall survival rates were 80.9% and 78.7%, respectively, in non HE group, and 65.7% and 56.1%, respectively, in severe HE group (P=0.031). CONCLUSIONS Severe HE is a factor influencing the long-term survival over 3 years in the patients who underwent DDLT. Although prospective validation should be conducted to determine the prognostic value of HE severity, efforts could be made to reduce the severity of HE before DDLT, and consider severity of HE rather than MELD score in DDLT allocation.

Immune thrombocytopenia (ITP) is an autoimmune condition characterized by platelet destruction through antibody-mediated mechanism. ITP is one of the manifestations of a coronavirus disease, as well as an adverse event occurring after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several cases of ITP have been described after vaccination with two mRNA-based vaccines—BTN162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)—against SARS-CoV-2. Herein, we report a case of ITP occurring after vaccination with ChAdOx1 adenovirus vector nCoV-19 (AstraZeneca) vaccine in Korea. A 66-year-old woman presented with multiple ecchymoses on both upper and lower extremities and gingival bleeding, appearing 3 days after receiving the first dose of ChAdOx1 nCoV-19. Her laboratory results showed isolated severe thrombocytopenia without evidence of combined coagulopathy. She was diagnosed with ITP and successfully treated with high-dose dexamethasone and intravenous immunoglobulin. Clinical suspicion to identify vaccine-related ITP is important to promptly initiate appropriate treatment., Graphical Abstract

Epigenetic dysregulation is a hallmark of cancers, and examples of its cancer-associated expression and mutation alterations are rapidly growing. Histone methylation, a process by which methyl groups are transferred to amino acids of histone proteins, is crucial for the epigenetic gene regulation. NSD2 (nuclear receptor-binding SET domain protein 2) and SETMAR are epigenetic regulators for histone methylation. KDM2B, also known as FBXL10, is a histone demethylase that targets histone methylation processes. They are known to be altered in many cancers, but somatic frameshift mutation and expression of these genes remain undetermined in many other subsets of cancers, including high microsatellite instability (MSI-H) colon cancer (CC). In this study, we analyzed mononucleotide repeats in coding sequences of NSD2, KDM2B and SETMAR genes, and found frameshift mutations in 10 %, 2 % and 1 % of CCs with MSI-H, respectively. Of note, there was no frameshift mutation of these genes in microsatellite stable (MSS) CCs. In addition, we discovered that 2 and 2 of 16 CRCs (12.5 % and 12.5 %) harbored intratumoral heterogeneity (ITH) of the NSD2 and KDM2B frameshift mutations, respectively. In the immunohistochemistry for NSD2, intensity of NSD2 immunostaining in MSI-H CC is decreased compared to that in MSS. These results suggest that NSD2 might be altered at multiple levels (frameshift mutation, mutational ITH and expression) in MSI-H CCs, and could be related to MSI-H cancer pathogenesis.