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Overlap myositis (OM) associated with Sjögren’s syndrome (SS) is a relatively uncommon disorder. It is more difficult to detect OM when a patient had not been previously diagnosed with SS. We report a case of OM associated SS that initially presented with dysphagia followed by proximal weakness. If proximal muscle weakness is preceded by dysphagia, the possibility of OM associated with connective-tissue disease should be considered.

Objective Studies on gait and autonomic dysfunction have been insufficient so far, particularly de novo Parkinson’s disease (PD). The aim of this study was to identify the association between gait dynamics and autonomic dysfunction in patients with de novo PD.Methods A total 38 patients with de novo PD were retrospectively included in this study. Details of patients’ dysautonomia were assessed using the Scales for Outcomes in Parkinson’s Disease-Autonomic Dysfunction (SCOPA-AUT). For assessment of gait, a computerized gait analysis was performed using the GAITRite system for forward gait and backward gait. High SCOPA-AUT score (PD-HSAS) group and low SCOPA-AUT score (PD-LSAS) group were identified according to their SCOPA-AUT scores.Results Nineteen (50%) patients with high SCOPA-AUT scores above median value (12.5) were assigned into the PD-HSAS group and others were assigned to the PD-LSAS group. Compared with the PD-LSAS group, the PD-HSAS group exhibited slower gait, shorter stride, decreased cadence, increased double support phase, decreased swing phase, and increased variability in swing time. Total SCOPA-AUT score showed significantly positive correlations with gait variability and instability but a negative correlation with gait hypokinesia. In subdomain analysis, urinary dysautonomia was highly associated with impairment of gait dynamics. All significant results were found to be more remarkable in backward gait than in forward gait.Conclusion Our findings suggest that alteration in gait dynamics, especially backward gait, is highly associated with autonomic dysfunction in patients with de novo PD.

Myotonic dystrophy type 1 (DM1) is a rare autosomal dominant disorder with various phenotypes involving multiple systems. Stroke co-occurrence in DM1 is rare, but can cause severe dysfunction in a patient’s quality of life. However, the mechanism of stroke in patients with DM1 is poorly understood. In this case report, we present a patient who was diagnosed with DM1 while suffering from a brain embolic infarction due to antiphospholipid syndrome (APS). This is the first known case of DM1 with APS. The coexistence of these two multisystem diseases may make the diagnosis difficult, and there is the possibility of symptoms involving multiple organs. We should pay attention to the possibility of the coexistence of autoimmune disease and stroke in DM1 patients based on this rare case of a DM1 patient with stroke and an autoimmune disease.

In this study, the materialistic characteristics were reviewed based on the conservation treatment and scientific analysis results obtained for the abdominal bones excavated during the 8th excavation survey of the remains of Bokam-ri, Naju. In divination, the animal’s scapula is typically dotted, and the tool used is called the oracle bone. The oracle bone excavated from the no. 6 spherical historical site was artificially damaged during the divination process. Exfoliation and degradation also occurred on the burial environments due to various factors such as earth pressure, freezing, and thawing. In the process of cleaning, an X-ray three-dimensional tomography analysis was performed to estimate the internal shape of the abdominal bone collected from the soil, and mesh-type data were extracted and applied to the preservation process. The data obtained through the 3D scanning process was prepared with a precise measurement drawing. The restored product of the oracle bone and the pedestal were 3D printed based on the modeling data so that they could be used for further research and exhibition. X-ray irradiation and X-ray digital imaging showed that the marks and cracks that were difficult to observe were accurately recorded. To identify the species of scapula used as a material for the oracle bone, the estimated group of mammals was compressed and a sample was produced. Then its morphological comparison was conducted, and it was estimated that the left scapula of a male wild boar was used as a fortune-telling tool.

Tissue regeneration is the ultimate treatment for many degenerative diseases, however, repair and regeneration of damaged organs or tissues remains a challenge. Previously, we showed that B1 Ab and H3 Ab induce stem cells to differentiate into microglia and brown adipocyte-like cells, while trafficking to the brain and heart, respectively. Here, we present data showing that another selected agonist antibody, P1 antibody, induces the migration of cells to the pancreatic islets and differentiates human stem cells into beta-like cells. Interestingly, our results suggest the purified P1 Ab induces beta-like cells from fresh, human CD34

Purpose: MET amplification is a frequent mechanism of resistance to EGFR tyrosine kinase inhibitors (TKI) in patients with EGFR-mutated non–small cell lung cancer (NSCLC), and combined treatment with EGFR TKIs and MET TKIs has been explored as a strategy to overcome resistance. However, durable response is invariably limited by the emergence of acquired resistance. Here, we investigated the preclinical activity of REGN5093-M114, a novel antibody–drug conjugate targeting MET in MET-driven patient-derived models. Experimental Design: Patient-derived organoids, patient-derived cells, or ATCC cell lines were used to investigate the in vitro/in vivo activity of REGN5093-M114. Results: REGN5093-M114 exhibited significant antitumor efficacy compared with MET TKI or unconjugated METxMET biparatopic antibody (REGN5093). Regardless of MET gene copy number, MET-overexpressed TKI-naïve EGFR-mutant NSCLC cells responded to REGN5093-M114 treatment. Cell surface MET expression had the most predictive power in determining the efficacy of REGN5093-M114. REGN5093-M114 potently reduced tumor growth of EGFR-mutant NSCLC with PTEN loss or MET Y1230C mutation after progression on prior osimertinib and savolitinib treatment. Conclusions: Altogether, REGN5093-M114 is a promising candidate to overcome the challenges facing functional MET pathway blockade.

Malakoplakia is a rare pseudotumor that arises in the context of recurrent infections, particularly in immunocompromised states. We report a case of renal allograft parenchymal malakoplakia.A 59-year-old woman successfully received a cadaveric renal transplant in June 2018. Two months after transplantation, she was treated for a urinary tract infection (UTI). In March 2019, she underwent allograft biopsy for increasing creatinine. The biopsy identified T cell mediated rejection and steroid pulse therapy was performed. In December 2019, she was hospitalized for right flank pain and pyuria, and her creatinine level was 1.9 mg/dL. Radiographic findings were suggestive of a hematoma or abscess in the perirenal area, and septated fluid collection was suspected. Biopsy results suggested malakoplakia, and von Kossa stain was positive for Michaelis- Gutmann bodies. Tissue culture demonstrated Escherichia coli, and this was treated with antibiotics. The dose of tacrolimus was reduced. The patient was discharged after 1 month of hospitalization and was maintained on oral antibiotics. Follow-up imaging revealed an increase in the extent of lesion into the adjacent abdominal wall. Assuming the case to be refractory, we performed surgical resection and abscess drainage. Although the renal parenchymal involvement persisted, the size showed a decreasing trend over 2 months of serial observation with ultrasonography.Malakoplakia should be considered as a differential diagnosis for recurrent UTI with graft dysfunction. Malakoplakia can be successfully treated with reduction in immunosuppression and medical therapy using long-term antibiotic treatment in most cases. However, early surgical treatment must be considered for refractory cases.

Mitochondria are intracellular organelles that regulate cell survival and death, and hyperglycemia modulates mitochondrial function in endothelial cells. In the current study, we have discovered that high glucose (HG) treatment reduces FUNDC1 (FUN14 domain containing 1) expression in endothelial cells. FUNDC1 expression in mitochondria inhibits proteasomal degradation of COX-IV, and regulates mitochondrial complexes I and IV activity and ATP synthesis. FUNDC1 depletion in HG affects mitochondrial complexes I and IV activity and ATP synthesis and promotes mitochondrial damage through loss of mitochondrial membrane potential and ROS (Reactive Oxygen Species) production. BAM15, a mitochondrial uncoupler, improves mitochondrial function and endothelial survival more effectively. Co-treatment of HG with BAM15 increased FUNDC1 protein expression, mitochondrial translocation of FUNDC1 in HG-treated cells. BAM15-induced up regulation of FUNDC1 expressions improve mitochondrial expression of COX-IV, and complex I and IV activity and ATP synthesis. Our findings propose that FUNDC1 expression in endothelial cells under hyperglycemic stress play a significant role in limiting vascular damage and apoptotic cell death.

This study’s aim was to investigate the association between optic disc morphology and the occurrence of paracentral scotoma in eyes with open-angle glaucoma (OAG) and myopia. Two-hundred and eleven myopic eyes with OAG were classified into three groups according to the location of visual field (VF) defect (99 paracentral scotoma, 65 peripheral scotoma, and 47 no VF defect). Optic disc morphology was assessed based on the tilt ratio and eccentricity of the central retinal vessel trunk (CRVT). Clinical characteristics of the three groups were compared, and factors affecting the occurrence of paracentral scotoma were determined. Eyes with paracentral scotoma had a higher tilt ratio than the other groups (ps ≤ 0.04). Multiple linear regression showed that a nasal location of CRVT (p < 0.001), longer axial length (p = 0.001), and lower VF mean deviation (p = 0.021) were significantly associated with higher tilt ratio. In logistic regression analysis, tilt ratio was the only factor that was significantly associated with the occurrence of paracentral scotoma (odds ratio = 7.12, p = 0.032). In conclusion, the optic disc tilt ratio increased with nasal shift of CRVT, longer axial length, and lower VF mean deviation. Higher optic disc tilt was significantly associated with the occurrence of paracentral scotoma in eyes with OAG and myopia.

(A-B) The surface expression levels of EGFR, MET, REGN5093 and IgG4 control of each cell were measured by flow cytometry. MFI stands for mean fluorescence intensity.

Whole Exom Sequencing_Somatic Mutation

Information of ATCC cell lines

Cells were seeded on a 96-well plate and incubated with the REGN5093-M114, Control Ab-M114, and EGFR TKIs (osimertinib, lazertinib). Cell viability was measured after 5 days of REGN5093-M114 treatment and 3 days of capmatinib treatment via CellTiter-Glo. The curved graphs show the cell viability results for a single drug, and the bar-graphs show the cell viability for the combination of two drugs.

Proposed treatment strategy for MET-driven acquired resistance to EGFR TKI in EGFR-mutant NSCLC patients.

(A-C) The treatment history of each preclinical model patient was expressed in a bar model. Immunohistochemical evaluation of YHIM1035, YHIM1042 and YHIM1061 tumor sections using p-MET (3077), MET (8198), Ki67 (9027) antibody. and tumor volumes were measured once every 3 days.

(A-B) Cells were incubated with the REGN5093-M114, IgG4 control-M114, osimertinib for 5 days, capmatinib for 3 days. Cell viability was analyzed via CellTiter-Glo. The curved graphs show the cell viability results for a single drug, and the bar-graphs show the cell viability for the combination of two drugs.

Purpose:MET amplification is a frequent mechanism of resistance to EGFR tyrosine kinase inhibitors (TKI) in patients with EGFR-mutated non–small cell lung cancer (NSCLC), and combined treatment with EGFR TKIs and MET TKIs has been explored as a strategy to overcome resistance. However, durable response is invariably limited by the emergence of acquired resistance. Here, we investigated the preclinical activity of REGN5093-M114, a novel antibody–drug conjugate targeting MET in MET-driven patient-derived models.Experimental Design:Patient-derived organoids, patient-derived cells, or ATCC cell lines were used to investigate the in vitro/in vivo activity of REGN5093-M114.Results:REGN5093-M114 exhibited significant antitumor efficacy compared with MET TKI or unconjugated METxMET biparatopic antibody (REGN5093). Regardless of MET gene copy number, MET-overexpressed TKI-naïve EGFR-mutant NSCLC cells responded to REGN5093-M114 treatment. Cell surface MET expression had the most predictive power in determining the efficacy of REGN5093-M114. REGN5093-M114 potently reduced tumor growth of EGFR-mutant NSCLC with PTEN loss or MET Y1230C mutation after progression on prior osimertinib and savolitinib treatment.Conclusions:Altogether, REGN5093-M114 is a promising candidate to overcome the challenges facing functional MET pathway blockade.

(A-B) Each cell viability was measured after treatment with REGN 5093-M114 for 5 days, capmatinib and tepotinib for 3 days. REGN 5093-M114 was treated with concentration of 0 µg/ml, 0.03 µg/ml, 0.1 µg/ml, 0.3 µg/ml, 1 µg/ml, 3 µg/ml. MET TKIs, capmatinib and tepotinib were treated with serial concentrations from 0nM to 100nM.

The REGN5093-M114, Control Ab-M114 or osimertinib were treated with serial concentration. Cells were seeded on a 96-well plate and incubated, Cell viability was analyzed via CellTiter-Glo. The curve graph represents the viability for a single drug, and the bar graph shows the viability for two drugs.

(A-B) Apoptosis level was measured after incubated with drugs for 48 hours. YU1089 and HCC827 AR cells were treated with osimertinib, capmatinib or tepotinib at a concentration of 100nM, Control Ab-M114 at 1 µg/ml or REGN5093-M114 at 1 µg/ml.

(A-D) YUO-006 and YUO-010 (Patient-derived organoids), YU-1089 and YU-1095 (Patient-derived cells) or HCC827-AR and H820 (ATCC cell lines) were seeded on a 96-well plate and incubated with the MET TKIs (tepotinib) and EGFR TKIs (osimertinib or gefitinib) for 3 days. EGFR TKIs was treated with concentration of 0nM, 30nM, 100nM. MET TKIs, tepotinib were treated with serial concentrations from 0nM to 100nM. The bar-graphs show the cell viability for the combination of two drugs, and the curved graphs show the cell viability results for a single drug.

Supplementary Data from Aberrant Transcript Usage Is Associated with Homologous Recombination Deficiency and Predicts Therapeutic Response

Purpose:Gastric cancer remains the leading cause of cancer-related deaths in Northeast Asia. Population-based endoscopic screenings in the region have yielded successful results in early detection of gastric tumors. Endoscopic screening rates are continuously increasing, and there is a need for an automatic computerized diagnostic system to reduce the diagnostic burden. In this study, we developed an algorithm to classify gastric epithelial tumors automatically and assessed its performance in a large series of gastric biopsies and its benefits as an assistance tool.Experimental Design:Using 2,434 whole-slide images, we developed an algorithm based on convolutional neural networks to classify a gastric biopsy image into one of three categories: negative for dysplasia (NFD), tubular adenoma, or carcinoma. The performance of the algorithm was evaluated by using 7,440 biopsy specimens collected prospectively. The impact of algorithm-assisted diagnosis was assessed by six pathologists using 150 gastric biopsy cases.Results:Diagnostic performance evaluated by the AUROC curve in the prospective study was 0.9790 for two-tier classification: negative (NFD) versus positive (all cases except NFD). When limited to epithelial tumors, the sensitivity and specificity were 1.000 and 0.9749. Algorithm-assisted digital image viewer (DV) resulted in 47% reduction in review time per image compared with DV only and 58% decrease to microscopy.Conclusions:Our algorithm has demonstrated high accuracy in classifying epithelial tumors and its benefits as an assistance tool, which can serve as a potential screening aid system in diagnosing gastric biopsy specimens.

BRCA1/2 mutations account for only a small fraction of homologous recombination (HR) deficiency (HRD) cases. Recently developed genomic HRD (gHRD) tests suffer confounding factors that cause low precision in predicting samples that will respond to PARP inhibitors and DNA damaging agents. Here we present molecular and clinical evidence of transcriptional HRD (tHRD) that is based on aberrant transcript usage (aTU) of minor isoforms. Specifically, increased TU of nonfunctional isoforms of DNA repair genes was prevalent in breast and ovarian cancer with gHRD. Functional assays validated the association of aTU with impaired HR activity. Machine learning–based tHRD detection by the transcript usage (TU) pattern of key genes was superior to directly screening for gHRD or BRCA1/2 mutations in accurately predicting responses of cell lines and patients with cancer to PARP inhibitors and genotoxic drugs. This approach demonstrated the capability of tHRD status to reflect functional HR status, including in a cohort of olaparib-treated ovarian cancer with acquired platinum resistance. Diagnostic tests based on tHRD are expected to broaden the clinical utility of PARP inhibitors.Significance:A novel but widespread transcriptional mechanism by which homologous recombination deficiency arises independently of BRCA1/2 mutations can be utilized as a companion diagnostic for PARP inhibitors.

Abnormal fat accumulation with gut microbiota dysbiosis results in hepatic inflammation by upregulating the release of lipopolysaccharide (LPS) and inflammatory cytokine. Gochujang, a traditional fermented condiment, has beneficial effects, such as anti-colonic inflammatory effects. However, Gochujang has been controversial because of its high salt content (the Korean Paradox). Thus, the present study aimed to investigate the preventative effects of Gochujang on hepatic inflammation and related gut microbiota through discussing the Korean Paradox. The mice were divided into groups including a normal diet (ND), high-fat diet (HD), HD with salt (SALT), HD with a high percentage of beneficial microbiota Gochujang (HBM), and HD with diverse beneficial microbiota Gochujang (DBM). Gochujang markedly reduced lipid accumulation, hepatic injury, and inflammation response. Furthermore, Gochujang attenuated protein expression involved in the JNK/IκB/NF-κB pathway. Additionally, Gochujang regulated the gut microbiota-derived LPS production and Firmicutes/Bacteroidetes ratio. Gochujang regulated the levels of gut microbiota such as Bacteroides, Muribaculum, Lactobacillus, and Enterorhabdus, which were correlated with hepatic inflammation. Salt did not have foregoing effects, meaning that the salt content in Gochujang did not affect its anti-inflammatory effect. In conclusion, Gochujang showed anti-hepatic inflammation effects via reduced lipid accumulation, hepatic injury, and inflammatory response together with reorganization of gut microbiota dysbiosis regardless of salt content and the difference of micro bacteria composition.

Supplementary Figure from Aberrant Transcript Usage Is Associated with Homologous Recombination Deficiency and Predicts Therapeutic Response

Supplementary Figure S1-8, Supplementary Table S1-9

Supplementary Figure 3. The relationship between Notch1 and miR-34 family members.

Supplementary Figure 4. Overexpression of miR-34a by lentiviral system in primary cells.

Supplementary Methods, Figure Legends

Supplementary Figure 1. Expression levels of cancer stem cell markers in tumorsphere cells.