MicroRNA-150 regulates the cytotoxicity of natural killers by targeting perforin-1

Background: Perforin-1 (Prf1) is the predominant cytolytic protein secreted by natural killer (NK) cells. For a rapid immune response, resting NK cells contain high Prf1 mRNA concentrations while exhibiting minimal cytotoxicity caused by a blockage of Prf1 protein synthesis, implying that an unknown posttranscriptional regulatory mechanism exists. Objective: We sought to determine whether microRNA-150 (miR-150) posttranscriptionally regulates Prf1 translation in both mouse and human NK cells at rest and at various time points after activation. Methods: Mouse NK cells with a targeted deletion of miR-150 (miR-150(-/-) NK cells), primary human NK cells, and NK92 MI cells were used to investigate the role of miR-150 in NK cells. NK cell cytotoxicity assays and Western blotting proved that activated miR-150(-/-) NK cells expressed upregulated Prf1, augmenting NK cell cytotoxicity. When immunodeficient mice were injected with miR-150(-/-) NK cells, there was a significant reduction in tumor growth and metastasis of B16F10 melanoma. Results: We report that miR-150 binds to 39 untranslated regions of mouse and human Prf1, posttranscriptionally downregulating its expression. Mouse wild-type NK cells displayed downregulated miR-150 expression in response to IL-15, which led to corresponding repression and induction of Prf1 during rest and after IL-15 activation, respectively. Conclusion: Our results indicate that miR-150 is a common posttranscriptional regulator for Prf1 in mouse and human NK cells that represses NK cell lytic activity. Thus the therapeutic control of miR-150 in NK cells could enhance NK cell-based immunotherapy against cancer, providing a better clinical outcome.X112523Ysciescopu

Use of the Clock Drawing Test and the Rey–Osterrieth Complex Figure Test-copy with convolutional neural networks to predict cognitive impairment

Background The Clock Drawing Test (CDT) and Rey–Osterrieth Complex Figure Test (RCFT) are widely used as a part of neuropsychological test batteries to assess cognitive function. Our objective was to confirm the prediction accuracies of the RCFT-copy and CDT for cognitive impairment (CI) using convolutional neural network algorithms as a screening tool. Methods The CDT and RCFT-copy data were obtained from patients aged 60–80 years who had more than 6 years of education. In total, 747 CDT and 980 RCFT-copy figures were utilized. Convolutional neural network algorithms using TensorFlow (ver. 2.3.0) on the Colab cloud platform ( www.colab.research.google.com ) were used for preprocessing and modeling. We measured the prediction accuracy of each drawing test 10 times using this dataset with the following classes: normal cognition (NC) vs. mildly impaired cognition (MI), NC vs. severely impaired cognition (SI), and NC vs. CI (MI + SI). Results The accuracy of the CDT was better for differentiating MI (CDT, 78.04 ± 2.75; RCFT-copy, not being trained) and SI from NC (CDT, 91.45 ± 0.83; RCFT-copy, 90.27 ± 1.52); however, the RCFT-copy was better at predicting CI (CDT, 77.37 ± 1.77; RCFT, 83.52 ± 1.41). The accuracy for a 3-way classification (NC vs. MI vs. SI) was approximately 71% for both tests; no significant difference was found between them. Conclusions The two drawing tests showed good performance for predicting severe impairment of cognition; however, a drawing test alone is not enough to predict overall CI. There are some limitations to our study: the sample size was small, all the participants did not perform both the CDT and RCFT-copy, and only the copy condition of the RCFT was used. Algorithms involving memory performance and longitudinal changes are worth future exploration. These results may contribute to improved home-based healthcare delivery.The costs for manuscript publication, design of the study, data management, and writing of the manuscript were supported by the Ministry of Education of the Republic of Korea and the National Research Foundation of Korea (NRF-2017S1A6A3A01078538)

The Draft Genome of an Octocoral, Dendronephthya gigantea

Coral reefs composed of stony corals are threatened by global marine environmental changes. However, soft coral communities of octocorallian species, appear more resilient. The genomes of several cnidarians species have been published, including from stony corals, sea anemones, and hydra. To fill the phylogenetic gap for octocoral species of cnidarians, we sequenced the octocoral, Dendronephthya gigantea, a nonsymbiotic soft coral, commonly known as the carnation coral. The D. gigantea genome size is similar to 276 Mb. A high-quality genome assembly was constructed from PacBio long reads (29.85 Gb with 108x coverage) and Illumina short paired-end reads (35.54 Gb with 128x coverage) resulting in the highest N50 value (1.4 Mb) reported thus far among cnidarian genomes. About 12% of the genome is repetitive elements and contained 28,879 predicted protein-coding genes. This gene set is composed of 94% complete BUSCO ortholog benchmark genes, which is the second highest value among the cnidarians, indicating high quality. Based on molecular phylogenetic analysis, octocoral and hexacoral divergence times were estimated at 544 MYA. There is a clear difference in Hox gene composition between these species: unlike hexacorals, the Antp superclass Evx gene was absent in D. gigantea. Here, we present the first genome assembly of a nonsymbiotic octocoral, D. gigantea to aid in the comparative genomic analysis of cnidarians, including stony and soft corals, both symbiotic and nonsymbiotic. The D. gigantea genome may also provide clues to mechanisms of differential coping between the soft and stony corals in response to scenarios of global warming

Prevalence and detection of low-allele-fraction variants in clinical cancer samples

Accurate detection of genomic alterations using high-throughput sequencing is an essential component of precision cancer medicine. We characterize the variant allele fractions (VAFs) of somatic single nucleotide variants and indels across 5095 clinical samples profiled using a custom panel, CancerSCAN. Our results demonstrate that a significant fraction of clinically actionable variants have low VAFs, often due to low tumor purity and treatment-induced mutations. The percentages of mutations under 5% VAF across hotspots in EGFR, KRAS, PIK3CA, and BRAF are 16%, 11%, 12%, and 10%, respectively, with 24% for EGFR T790M and 17% for PIK3CA E545. For clinical relevance, we describe two patients for whom targeted therapy achieved remission despite low VAF mutations. We also characterize the read depths necessary to achieve sensitivity and specificity comparable to current laboratory assays. These results show that capturing low VAF mutations at hotspots by sufficient sequencing coverage and carefully tuned algorithms is imperative for a clinical assay

Comparison of CpG island hypermethylation and repetitive DNA hypomethylation in premalignant stages of gastric cancer, stratified for Helicobacter pylori infection

CpG island hypermethylation and genomic DNA hypomethylation are found not only in gastric cancers but also in associated premalignant lesions. Helicobacter pylori infection induces aberrant CpG island hypermethylation in gastric mucosae. However, little is known about the relationship between H. pylori infection and aberrant methylation in premalignant lesions. The present study characterized methylation changes in a subset of genes and repetitive DNA elements (ALU, LINE-1, SAT2) and examined their relationship with H. pylori infection in premalignant lesions of gastric cancers. We performed MethyLight analysis of 25 genes and SAT2 and COBRA analysis of ALU and LINE-1 in 212 gastric tissue samples. H. pylori infection was closely associated with enhanced hypermethylation of CpG island loci in chronic gastritis samples, but this association was not found among intestinal metaplasias, gastric adenomas and gastric cancers. The number of methylated genes was greater in intestinal metaplasia and gastric adenoma samples than in chronic gastritis samples, regardless of H. pylori infection. Methylation of repetitive DNA elements in gastric lesions generally decreased with progression of the gastric lesion along the multistep carcinogenesis. No difference was noted in the number of methylated genes in chronic gastritis or intestinal metaplasia between gastric cancer patients and non-cancer subjects. In conclusion, we found that there was no enhanced CpG island hypermethylation in gastric cancer and premalignant lesions in association with H. pylori infection and our findings suggest that CpG island hypermethylation and repetitive DNA hypomethylation are enhanced with progression of the gastric lesion through the multistep carcinogenesis, regardless of the status of H. pylori infection. Copyright (C) 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.Qian XM, 2008, CANCER LETT, V263, P107, DOI 10.1016/j.canlet.2007.12.023Yoo EJ, 2008, VIRCHOWS ARCH, V452, P515, DOI 10.1007/s00428-008-0596-7Leung WK, 2008, LANCET ONCOL, V9, P279, DOI 10.1016/S1470-2045(08)70072-XKang GH, 2008, LAB INVEST, V88, P161, DOI 10.1038/labinvest.3700707Kaise M, 2008, HELICOBACTER, V13, P35Lauwers GY, 2007, GASTROENTEROL CLIN N, V36, P813, DOI 10.1016/j.gtc.2007.08.008Ushijima T, 2007, J BIOCHEM MOL BIOL, V40, P142Cho NY, 2007, J PATHOL, V211, P269, DOI 10.1002/path.2106LAUWERS GY, 2007, GASTROENTEROL CLIN N, V36, pR6Nakajima T, 2006, CANCER EPIDEM BIOMAR, V15, P2317, DOI 10.1158/1055-9965.EPI-06-0436Ogino S, 2006, J MOL DIAGN, V8, P209, DOI 10.2353/jmoldx.2006.050135Ehrlich M, 2006, ONCOGENE, V25, P2636, DOI 10.1038/sj.onc.1209145Maekita T, 2006, CLIN CANCER RES, V12, P989, DOI 10.1158/1078-0432.CCR-05-2096Sato F, 2006, CANCER, V106, P483, DOI 10.1002/cncr.21657Vauhkonen M, 2006, BEST PRACT RES CL GA, V20, P651, DOI 10.1016/j.bpg.2006.03.016Karpf AR, 2005, CANCER RES, V65, P8635, DOI 10.1158/0008-5472Weisenberger DJ, 2005, NUCLEIC ACIDS RES, V33, P6823, DOI 10.1093/nar/gki987Jemal A, 2004, CA-CANCER J CLIN, V54, P8Yamanaka M, 2003, INT J CANCER, V106, P382, DOI 10.1002/ijc.11227Kang GH, 2003, LAB INVEST, V83, P635, DOI 10.1097/01.LAB.0000067481.08984.3FBariol C, 2003, AM J PATHOL, V162, P1361Ehrlich M, 2002, ONCOGENE, V21, P5400, DOI 10.1038/sj.onc.1205651Waki T, 2002, AM J PATHOL, V161, P399Terry MB, 2002, SEMIN RADIAT ONCOL, V12, P111, DOI 10.1053/srao.30814Asaka M, 2001, HELICOBACTER, V6, P294Rashid A, 2001, AM J PATHOL, V159, P1129Leung WK, 2001, CANCER, V91, P2294Kang GH, 2001, CANCER RES, V61, P2847Shimoyama T, 2000, VIRCHOWS ARCH, V436, P585Asaka M, 1997, GASTROENTEROLOGY, V113, pS56Cravo M, 1996, GUT, V39, P434FORMAN D, 1995, ALIMENT PHARM THERAP, V9, P71SATO F, 1995, AM J SURG PATHOL S1, V19, pS37STEMMERMANN GN, 1994, CANCER, V74, P5561

Biopsychological and pathophysiological features of Cold-Heat subgroup of Sasang typology with Sasang Digestive Function Inventory, Sasang Personality Questionnaire and Body Mass Index

Background: The Sasang typology is a traditional Korean personalized medicine and its Cold-Heat subgroup identification is essential for effective use of medical herbs and acupuncture. The purpose of this study was to discover differences between Cold-Heat subgroups with objective clinical measures and to examine its clinical usefulness. Methods: The pathophysiological symptoms of the digestive system, temperament and body shape of 241 patients were measured using the Sasang Digestive Function Inventory (SDFI), Sasang Personality Questionnaire (SPQ) and Body Mass Index (BMI). The differences between Cold and Heat subgroups of each Sasang types were tested by Analysis of Covariance considering age and sex, while the associations of SDFI, SPQ and BMI with Cold-Heat subgroup were examined by logistic regression analysis. Results: There were significant differences between Cold and Heat subgroups in SDFI, SPQ and BMI for the So-Yang, SDFI and BMI for the Tae-Eum type and SDFI-Digestion subscale for the So-Eum type. Moreover, the SDFI-Digestion was a substantial predictor for Cold-Heat subgroup identification in three Sasang types. The logistic regression model with SDFI, SPQ and BMI correctly predicted 81.9%, 77% and 75.5% of the Cold-Heat subgroups in So-Yang, Tae-Eum and So-Eum types, respectively. Conclusion: The results of the present study showed that the objective and validated clinical measures of SDFI, SPQ and BMI would be useful for differentiating Cold-Heat subgroups of Sasang typology. Further clinical studies on pathophysiological mechanisms in Cold-Heat subgroup are required to generalize these results. Keywords: Sasang typology, Cold-Heat subgroup, Sasang Digestive Function Inventory (SDFI), Sasang Personality Questionnaire (SPQ), Body Mass Index (BMI

Helicobacter pylori-infection-associated CpG island hypermethylation in the stomach and its possible association with polycomb repressive marks

Helicobacter pylori infection can induce CpG island (CGI) hypermethylation in gastric mucosa. Recently, genes occupied by Polycomb proteins in embryonic stem cells were shown to be vulnerable to aberrant DNA hypermethylation in cancers. To explore the relationship between H. pylori infection and DNA methylation changes in neoplastic and non-neoplastic stomach, we analyzed 25 CGIs and repetitive DNA elements from 82 chronic gastritis and 69 gastric carcinomas. Twenty-three CGIs showed significantly higher methylation levels in H. pylori-negative gastric carcinoma (n = 28) than in H. pylori-negative chronic gastritis (n = 39; P < 0.05), indicating cancer-associated methylation. Eight CGIs exhibited significantly higher methylation levels in H. pylori-positive chronic gastritis (n = 43) than in H. pylori-negative chronic gastritis (n = 39; P < 0.05). Six CGIs showed both cancer-associated and H. pylori-associated hypermethylation. Six (75%) of the eight H. pylori-associated hypermethylated genes contained at least one of three repressive marks (Suzl2 occupancy, Eed occupancy, histone H3 K27 trimethylation), whereas 31% of the remaining cancer-associated hypermethylated genes had at least one mark. The findings suggest that H. pylori infection strongly induces CGI hypermethylation in gastric epithelial cells and that susceptibility to H. pylori-induced DNA hypermethylation may be determined by Polycomb repressive marks in stem or progenitor cells

Influence of IL1B polymorphism on CpG island hypermethylation in Helicobacter pylori-infected gastric cancer

Helicobacter pylori infection can induce aberrant CpG island hypermethylation in gastric mucosal epithelial cells. Single nucleotide polymorphisms of proinflammatory cytokine genes encoding for interleukin 1B (IL1B), IL6, and IL8 have been demonstrated to be associated with an increased risk of gastric cancer. To identify the influence of host genetic factors in CpG island hypermethylation induced by H. pylori infection, we analyzed H. pylori-infected chronic gastritis (n = 111) and gastric cancer samples (n = 78) for the methylation status of eight genes previously shown to be hypermethylated in chronic gastritis and single nucleotide polymorphisms of IL1B, IL6, and IL8. The methylation levels were then compared between different genotypes. Gastric cancers from patients with the IL1B-511T/T allele showed significantly higher methylation levels in five genes as compared with gastric cancers from IL1B-511 C carriers (P < 0.05). An increased level of hypermethylation in association with the IL1B-511T/T allele was observed in chronic gastritis samples, but the association was not statistically significant. These findings suggest that the IL1B-511T/T allele is associated with enhanced hypermethylation of multiple CpG island loci, which might contribute to an increase in the risk for gastric cancer in individuals with H. pylori infection and IL1B-511T/T allele.Yoo EJ, 2008, VIRCHOWS ARCH, V452, P515, DOI 10.1007/s00428-008-0596-7Kang GH, 2008, LAB INVEST, V88, P161, DOI 10.1038/labinvest.3700707Perri F, 2007, AM J GASTROENTEROL, V102, P1361, DOI 10.1111/j.1572-0241.2007.01284.xChan AOO, 2007, GUT, V56, P595, DOI 10.1136/gut.2006.113258Widschwendter M, 2007, NAT GENET, V39, P157Schlesinger Y, 2007, NAT GENET, V39, P232, DOI 10.1038/ng1950Ohm JE, 2007, NAT GENET, V39, P237, DOI 10.1038/ng1972Li C, 2007, J GASTROEN HEPATOL, V22, P234, DOI 10.1111/j.1440-1746.2006.04379.xWehbe H, 2006, CANCER RES, V66, P10517, DOI 10.1158/0008-5472.CAN-06-2130Mihara M, 2006, AM J PATHOL, V169, P1643, DOI 10.2353/ajpath.2006.060552Leung WK, 2006, CLIN CANCER RES, V12, P3216, DOI 10.1158/1078-0432.CCR-05-2442Ushijima T, 2006, J GASTROENTEROL, V41, P401, DOI 10.1007/s00535-006-1846-6Ogino S, 2006, J MOL DIAGN, V8, P209, DOI 10.2353/jmoldx.2006.050135Lee TI, 2006, CELL, V125, P301Chan AOO, 2006, GUT, V55, P463, DOI 10.1136/gut.2005.077776Maekita T, 2006, CLIN CANCER RES, V12, P989, DOI 10.1158/1078-0432.CCR-05-2096Taguchi A, 2005, CANCER EPIDEM BIOMAR, V14, P2487, DOI 10.1158/1055-9965.EPI-05-0326Hodge DR, 2005, CANCER RES, V65, P4673Chang YW, 2005, INT J CANCER, V114, P465, DOI 10.1002/ijc.20724Chan AOO, 2003, GUT, V52, P502Hwang IR, 2002, GASTROENTEROLOGY, V123, P1793, DOI 10.1053/gast.2002.37043Trinh BN, 2001, METHODS, V25, P456, DOI 10.1006/meth.2001.1268Hodge DR, 2001, J BIOL CHEM, V276, P39508Terry CF, 2000, J BIOL CHEM, V275, P18138El-Omar EM, 2000, NATURE, V404, P398EADS CA, 2000, NUCLEIC ACIDS RES, V28, P32, DOI DOI 10.1093/NAR/28.8.E32Hmadcha A, 1999, J EXP MED, V190, P1595Wang MC, 1999, J GASTROENTEROL, V34, P10Jones PA, 1999, NAT GENET, V21, P163Fishman D, 1998, J CLIN INVEST, V102, P1369Olomolaiye O, 1998, EUR J IMMUNOGENET, V25, P267*IARC WORK GROUP E, 1994, IARC MON EV CARC RIS, V61, P1WALLACE JL, 1991, AM J PHYSIOL, V261, P559

Urinary Function of the Sasang Type and Cold-Heat Subgroup Using the Sasang Urination Inventory in Korean Hospital Patients

Introduction. The Sasang type-specific pathophysiological symptom is pivotal for the Sasang type classification and pattern identification. The Sasang Urination and Defecation Inventory (SUDI) for urinary function analysis was developed; however, the clinical usefulness of urination-related subscales of SUDI in the Sasang type and Cold-Heat subgroup was not reported with acceptable validation analysis. Methods. The clinical diagnosis of the Sasang type and Cold-Heat subgroup, responses to SUDI items, and weight and height of the 350 hospital patients were acquired retrospectively. The Sasang Urination Inventory (SUI) with SUI-CHR (problematic physical characteristics of urine), SUI-HSS (hypersensitivity of urinary urgency and high frequency), and SUI-DIS (urinary discomfort of hesitancy and residual urine sense) subscales using 12 items of SUDI were improvised. The item and construct validity of the SUI were examined using item response theory and confirmatory factor analysis, and the clinical usefulness of the SUI in Sasang type and Cold-Heat subgroup differentiation was attested. Results. The SUI and its subscales showed acceptable structural validity and have clinical usefulness in the Tae-Eum type. The Tae-Eum type has a significantly higher SUI-CHR score than did the So-Yang type, and the Heat subgroup has a significantly higher SUI-HSS score than did the Cold subgroup in the Tae-Eum type. Discussion. The distinctive Sasang type- and Cold-Heat subscale-specific pathological symptoms in urinary function were revealed using the SUI. The SUI combined with objective Sasang typology measures might be useful for integrative precision medicine combining Eastern and Western practice and for evidence-based clinical education for medical professions

The Application of Knowledge-Based Clinical Decision Support Systems to Detect Antibiotic Allergy

Prevention of drug allergies is important for patient safety. The objective of this study was to evaluate the outcomes of antibiotic allergy-checking clinical decision support system (CDSS), K-CDSTM. A retrospective chart review study was performed in 29 hospitals and antibiotic allergy alerts data were collected from May to August 2022. A total of 15,535 allergy alert cases from 1586 patients were reviewed. The most frequently prescribed antibiotics were cephalosporins (48.5%), and there were more alerts of potential cross-reactivity between beta-lactam antibiotics than between antibiotics with the same ingredients or of the same class. Regarding allergy symptoms, dermatological disorders were the most common (38.8%), followed by gastrointestinal disorders (28.4%). The 714 cases (4.5%) of immune system disorders included 222 cases of anaphylaxis and 61 cases of severe cutaneous adverse reactions. Alerts for severe symptoms were reported in 6.4% of all cases. This study confirmed that K-CDS can effectively detect antibiotic allergies and prevent the prescription of potentially allergy-causing antibiotics among patients with a history of antibiotic allergies. If K-CDS is expanded to medical institutions nationwide in the future, it can prevent an increase in allergy recurrence related to drug prescriptions through cloud-based allergy detection CDSSs