Change in Severity and Clinical Manifestation of MIS-C Over SARS-CoV-2 Variant Outbreaks in Korea.

BACKGROUND: There is difference in the incidence of multi-system inflammatory syndrome in children (MIS-C) in patients with different variants of severe acute respiratory syndrome coronavirus 2, however, little is known about the epidemiology in Asian countries. We investigated and compared the epidemiology of the MIS-C during omicron-dominant period with that of previous periods in South Korea. METHODS: We obtained clinical, epidemiological and laboratory data on MIS-C cases from national MIS-C surveillance in South Korea. We defined pre-delta period as January 2020-May 2021; delta period as June 2021-December 2021; and omicron period as January 2022-April 2022. We describe the clinical characteristics and outcomes of MIS-C patients by period. RESULTS: A total of 91 cases were assessed to be MIS-C cases. Number of MIS-C cases have increased from six cases during pre-delta period to 66 cases during omicron period, while the incidence rate (the number of MIS-C cases per 100,000 cases of reported coronavirus disease 2019) has decreased from 38.5 cases per 100,000 (95% confidence interval [CI], 14.1-83.9) during pre-delta period to 1.6 cases per 100,000 (95% CI, 1.2-2.0) during omicron periods. During pre-delta period, 66.7% and 100% had hypotension and gastrointestinal involvement, respectively; while during omicron period, 12.1% and 6.1% had such clinical manifestations. Fifty percent of pre-delta MIS-C patients were taken intensive care unit (ICU) cares, while 10.6% of patients during omicron periods were in ICUs. CONCLUSION: Omicron period were associated with less severe clinical manifestation compared to pre-delta and delta periods. Although incidence rate of MIS-C was lower for the omicron period than pre-delta and delta periods, number of patients reported with MIS-C may pose a substantial clinical burden.

Capture of influenza by medullary dendritic cells via SIGN-R1 is essential for humoral immunity in draining lymph nodes.

A major pathway for B cell acquisition of lymph-borne particulate antigens relies on antigen capture by subcapsular sinus macrophages of the lymph node. Here we tested whether this mechanism is also important for humoral immunity to inactivated influenza virus. By multiple approaches, including multiphoton intravital imaging, we found that antigen capture by sinus-lining macrophages was important for limiting the systemic spread of virus but not for the generation of influenza-specific humoral immunity. Instead, we found that dendritic cells residing in the lymph node medulla use the lectin receptor SIGN-R1 to capture lymph-borne influenza virus and promote humoral immunity. Thus, our results have important implications for the generation of durable humoral immunity to viral pathogens through vaccination.

Endocytosis and recycling of immune complexes by follicular dendritic cells enhances B cell antigen binding and activation.

Stromal-derived follicular dendritic cells (FDCs) are a major reservoir for antigen that are essential for formation of germinal centers, the site where memory and effector B cells differentiate. A long-standing question is how FDCs retain antigen in its native form for extended periods and how they display it to specific B cells. Here we found that FDCs acquired complement-coated immune complexes (ICs) from noncognate B cells via complement receptors 1 and 2 (CD35 and CD21, respectively) and rapidly internalized them by an actin-dependent pathway. ICs were retained intact within a nondegradative cycling compartment and were displayed periodically on the cell surface where they were accessible to antigen-specific B cells. This would explain how antigens are protected from damage and retained over long periods of time, while remaining accessible for B cells.

Cochlin produced by follicular dendritic cells promotes antibacterial innate immunity.

Cochlin, an extracellular matrix protein, shares homologies with the Factor C, a serine protease found in horseshoe crabs, which is critical for antibacterial responses. Mutations in the COCH gene are responsible for human DFNA9 syndrome, a disorder characterized by neurodegeneration of the inner ear that leads to hearing loss and vestibular impairments. The physiological function of cochlin, however, is unknown. Here, we report that cochlin is specifically expressed by follicular dendritic cells and selectively localized in the fine extracellular network of conduits in the spleen and lymph nodes. During inflammation, cochlin was cleaved by aggrecanases and secreted into blood circulation. In models of lung infection with Pseudomonas aeruginosa and Staphylococcus aureus, Coch(-/-) mice show reduced survival linked to defects in local cytokine production, recruitment of immune effector cells, and bacterial clearance. By producing cochlin, FDCs thus contribute to the innate immune response in defense against bacteria.

Wip1 controls the translocation of the chromosomal passenger complex to the central spindle for faithful mitotic exit.

Dramatic cellular reorganization in mitosis critically depends on the timely and temporal phosphorylation of a broad range of proteins, which is mediated by the activation of the mitotic kinases and repression of counteracting phosphatases. The mitosis-to-interphase transition, which is termed mitotic exit, involves the removal of mitotic phosphorylation by protein phosphatases. Although protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) drive this reversal in animal cells, the phosphatase network associated with ordered bulk dephosphorylation in mitotic exit is not fully understood. Here, we describe a new mitotic phosphatase relay in which Wip1/PPM1D phosphatase activity is essential for chromosomal passenger complex (CPC) translocation to the anaphase central spindle after release from the chromosome via PP1-mediated dephosphorylation of histone H3T3. Depletion of endogenous Wip1 and overexpression of the phosphatase-dead mutant disturbed CPC translocation to the central spindle, leading to failure of cytokinesis. While Wip1 was degraded in early mitosis, its levels recovered in anaphase and the protein functioned as a Cdk1-counteracting phosphatase at the anaphase central spindle and midbody. Mechanistically, Wip1 dephosphorylated Thr-59 in inner centromere protein (INCENP), which, subsequently bound to MKLP2 and recruited other components to the central spindle. Furthermore, Wip1 overexpression is associated with the overall survival rate of patients with breast cancer, suggesting that Wip1 not only functions as a weak oncogene in the DNA damage network but also as a tumor suppressor in mitotic exit. Altogether, our findings reveal that sequential dephosphorylation of mitotic phosphatases provides spatiotemporal regulation of mitotic exit to prevent tumor initiation and progression.

Predictors of Acceptance of Cosmetic Surgery in South Korean Women.

BACKGROUND: Examining the characteristics of the growing cosmetic surgery (CS) consumer population could help promote safer cosmetic procedure practices. We identified the predictors of acceptance of cosmetic surgery (ACS) among South Korean women aged 20-69 years. METHODS: An online survey was administered to 291 randomly sampled participants during August 30-September 6, 2021. An equal number of participants from each age group was selected. They completed a questionnaire concerning the general and CS-related characteristics, acceptance of cosmetic surgery scale, appearance satisfaction, self-esteem, and depression. The mean participants' age and body mass index were 44.12 (± 13.79) years and 22.15 (± 3.39) kg/m2, respectively. RESULTS: Approximately 90.0% of the participants had been exposed to a CS advertisement, with 96.2% having acquired information regarding the CS side effects and 52.6% considering CS in future. Eighty-eight (30.2%) participants had undergone CS. The most common surgical and non-surgical categories were eyelid surgery and botulinum toxin injection, respectively. The ACS increased with decreasing age (ß = - 0.12, p < .05), exposure to a CS advertisement (ß = 0.10, p < .05), consideration of undergoing CS in future (ß = 0.59, p < .001), and increasing depression scores (ß = 0.29, p < .001); collectively, these factors explained 43.0% of the variance (F = 25.21, p < .001). CONCLUSIONS: "Consideration of undergoing CS" was the strongest ACS predictor in the multiple regression analysis for the entire study population and according to CS history. Future studies should conduct an in-depth analysis based on the current CS trends, intention to undergo CS in future, and past CS experiences of South Korean women aged 20-69 years. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Surveillance of COVID-19-Associated Multisystem Inflammatory Syndrome in Children, South Korea.

A concerning development during the coronavirus disease pandemic has been multisystem inflammatory syndrome in children. Reports of this condition in East Asia have been limited. In South Korea, 3 cases were reported to the national surveillance system for multisystem inflammatory syndrome in children. All case-patients were hospitalized and survived with no major disease sequelae.

Comparative analysis of the tumor immune-microenvironment of primary and brain metastases of non-small-cell lung cancer reveals organ-specific and EGFR mutation-dependent unique immune landscape.

BACKGROUND: To evaluate the characteristics of the tumor immune-microenvironment in brain metastases of non-small-cell lung cancer (NSCLC), we investigated the immunophenotype of primary NSCLC and its brain metastasis. METHODS: Expression profiling of 770 immune-related genes in 28 tissues from primary and brain metastases of NSCLC was performed using the NanoString nCounter PanCancer Immune Profiling Panel. The immune cell profiles were validated by immunohistochemistry of 42 matched samples. RESULTS: Based on unsupervised clustering and principal component analysis of the immune-related gene expression profile, tumors were primarily clustered according to the involved organ and further grouped according to the EGFR mutation status. Fifty-four genes were significantly differentially expressed between primary and brain metastatic tumors. Clustering using these genes showed that tumors harboring mutated EGFR tended to be grouped together in the brain. Pathway analysis revealed that various immune-related functions involving immune regulation, T cell activity, and chemokines were enriched in primary tumors compared to brain metastases. Diverse immune-related pathways were upregulated in brain metastases of EGFR-mutated compared to EGFR-wild-type adenocarcinoma, but not in primary tumors. The interferon-γ-related gene signature was significantly decreased in brain metastases. The anti-inflammatory markers TOLLIP and HLA-G were upregulated in brain metastases. The proportions of most immune cell subsets were decreased in brain metastases, but those of macrophages and CD56dim-NK-cells were increased, as was the ratios of CD163+M2- to iNOS+M1-macrophages and NCR1+NK-cells to CD3+T cells. CONCLUSIONS: Our findings illustrate the immune landscape of brain metastases from NSCLC and reveal potential therapeutic strategies targeting cellular and non-cellular components of the tumor immune-microenvironment.

Podoplanin-rich stromal networks induce dendritic cell motility via activation of the C-type lectin receptor CLEC-2.

To initiate adaptive immunity, dendritic cells (DCs) move from parenchymal tissues to lymphoid organs by migrating along stromal scaffolds that display the glycoprotein podoplanin (PDPN). PDPN is expressed by lymphatic endothelial and fibroblastic reticular cells and promotes blood-lymph separation during development by activating the C-type lectin receptor, CLEC-2, on platelets. Here, we describe a role for CLEC-2 in the morphodynamic behavior and motility of DCs. CLEC-2 deficiency in DCs impaired their entry into lymphatics and trafficking to and within lymph nodes, thereby reducing T cell priming. CLEC-2 engagement of PDPN was necessary for DCs to spread and migrate along stromal surfaces and sufficient to induce membrane protrusions. CLEC-2 activation triggered cell spreading via downregulation of RhoA activity and myosin light-chain phosphorylation and triggered F-actin-rich protrusions via Vav signaling and Rac1 activation. Thus, activation of CLEC-2 by PDPN rearranges the actin cytoskeleton in DCs to promote efficient motility along stromal surfaces.

Controlling an Outbreak of Multidrug-resistant Acinetobacter baumannii in a Pediatric Intensive Care Unit: a Retrospective Analysis.

BACKGROUND: Multidrug-resistant Acinetobacter baumannii (MDRAB) is widespread among intensive care units worldwide, posing a threat to patients and the health system. We describe the successful management of a MDRAB outbreak by implementing an infection-control strategy in a pediatric intensive care unit (PICU). METHODS: This retrospective study investigated the patients admitted to the PICU in periods 1 (8 months) and 2 (7 months), from the index MDRAB case to intervention implementation, and from intervention implementation to cessation of MDRAB spread. An infection-control strategy was designed following six concepts: 1) cohort isolation of colonized patients, 2) enforcement of hand hygiene, 3) universal contact precautions, 4) environmental management, 5) periodic surveillance culture study, and 6) monitoring and feedback. RESULTS: Of the 427 patients, 29 were confirmed to have MDRAB colonization, of which 18 had MDRAB infections. Overall incidence per 1,000 patient days decreased from 7.8 (period 1) to 5.8 (period 2). The MDRAB outbreak was declared terminated after the 6-month follow-up following period 2. MDRAB was detected on the computer keyboard and in condensed water inside the ventilator circuits. The rate of hand hygiene performance was the lowest in the three months before and after index case admission and increased from 84% (period 1) to 95% (period 2). Patients with higher severity, indicated by a higher Pediatric Risk of Mortality III score, were more likely to develop colonization (P = 0.030), because they had invasive devices and required more contact with healthcare workers. MDRAB colonization contributed to an increase in the duration of mechanical ventilation and PICU stay (P < 0.001), but did not affect mortality (P = 0.273). CONCLUSION: The MDRAB outbreak was successfully terminated by the implementation of a comprehensive infection-control strategy focused on the promotion of hand hygiene, universal contact precautions, and environmental management through multidisciplinary teamwork.

The generalizability of empirically derived syndromes of collateral-reported elder psychopathology across 11 societies.

The purpose of this study was to test whether a syndrome model of elder psychopathology derived from collateral ratings, such as from spouses and adult children, in the United States would be generalizable in 11 other societies. Societies represented South America, Asia, and Europe. The Older Adult Behavior Checklist (OABCL) was completed by collateral informants for 6141 60- to 102-year-olds. The tested model comprised syndromes designated as Anxious/Depressed, Worries, Somatic Complaints, Functional Impairment, Memory/Cognition Problems, Thought Problems, and Irritable/Disinhibited. The model was tested using confirmatory factor analyses in each society separately. The primary model fit index showed a good fit for all societies, while the secondary model fit indices showed acceptable to a good fit for all societies. The items loaded strongly on their respective factors, with a median item loading of 0.69 across the 11 societies. By syndrome, the overall median item loadings ranged from 0.47 for Worries to 0.77 for Functional Impairment. The OABCL syndrome structure was thus generalizable across the tested societies. The OABCL can be used for broad assessment of psychopathology for elders of diverse backgrounds in nursing services and research.

Comprehensive Gene Expression Analyses of Immunohistochemically Defined Subgroups of Muscle-Invasive Urinary Bladder Urothelial Carcinoma.

A number of urinary bladder urothelial carcinoma (UB UC) mRNA-based classification systems have been reported. It also has been observed that treatment response and prognosis are different for each molecular subtype. In this study, cytokeratin (CK)5/6 and CK20 immunohistochemistry (IHC) were performed, and IHC-based subgroup classification was applied. UB UC was classified into CK5/6 single-positive (SP), CK20 SP, double-positive (DP) and double-negative (DN) subgroups, and transcriptional analysis was performed. The results of gene ontology (GO) terms and functional analysis using differentially expressed genes indicate that, CK5/6 SP and DP subgroups were enriched in cell migration, immune activation, interleukin 6-Janus kinase-signal transducer and activator of transcription 3 (IL6-JAK-STAT3) signaling pathway and tumor necrosis factor-α signaling via the nuclear factor-κB (NF-κB) signaling pathway signature gene. In addition, compared with the other subgroups, the DN subgroup showed inhibited cell movement, cell migration, and cell activation. Furthermore, in survival analysis, the CK5/6 SP subgroup was significantly associated with poor progression-free survival (p = 0.008). The results of our study indicate that the CK5/6 positive subgroup exhibited high gene expression signature related to aggressive behavior and exhibited worse clinical outcome.

Risk factors affecting the treatment outcome of pediatric foreign body aspiration: significance of time factors.

PURPOSE: The aim of this study was to identify the factors affecting the prognosis of children with foreign body aspiration (FBA) after undergoing rigid bronchoscopy. METHODS: This was a case series with a chart review of 49 children under 3 years of age who underwent rigid bronchoscopy for suspected FBA at a single tertiary institution. RESULTS: The time from symptom onset to hospitalization positively correlated with the total hospitalization time (p < 0.001), postoperative hospitalization time (p = 0.006), and operation time (p = 0.013). The time from symptom onset to operation positively correlated with the total hospitalization time (p < 0.001) and operation time (p = 0.046). The time from hospitalization to operation and the operation time positively correlated with the total hospitalization time (p = 0.026, 0.044) and postoperative hospitalization time (p = 0.049, 0.003). The time from symptom onset to hospitalization positively correlated with the incidence of pneumonia (p = 0.028). CONCLUSION: Rapid hospitalization after symptom onset, rapid surgery after symptom onset, and rapid surgery after hospitalization improve the prognosis of patients with FBA. Further, a short operation time also plays a role in improving patient prognosis.

Cosmetic Surgery and Self-esteem in South Korea: A Systematic Review and Meta-analysis.

PURPOSE: Advances in medical technology coupled with rapid growth of web-based mass media and social networking services have considerably increased public access to cosmetic surgery. In South Korea, in particular, the number of people undergoing cosmetic surgery has been rapidly increasing, and studies related to cosmetic surgery have markedly increased. We report an integrative review of studies examining the relationship between cosmetic surgery and self-esteem in Korea. We aimed to identify relevant variables and determine their overall effect sizes. METHODS: This study was designed based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Two researchers separately performed the literature search, selected 16 papers based on the inclusion and exclusion criteria, and analyzed them. RESULTS: Of the 16 papers on cosmetic surgery and self-esteem, 5 (33.3%) involved both men and women, and the remaining 11 (66.7%) involved only women. The respondents included teenagers and adults. The total number of respondents was 6296, with an average of 393.5 per paper. Most studies (n = 13, 81.3%) used the Rosenberg Self-Esteem Scale. Self-esteem was correlated with variables grouped into the following six categories: appearance management intention, cosmetic surgery intention, sociocultural attitude, body satisfaction, BMI, and stress. The effect sizes from the meta-analysis with correlation coefficients were 0.157, - 0.118, 0.023, 0.175, - 0.045, and - 0.085. CONCLUSIONS: Among the relevant variables categorized in this study, sociocultural attitude, BMI, and stress showed weak effect sizes, and the appearance management intention, cosmetic surgery intention, and body satisfaction categories showed intermediate effect sizes. The results of this study are expected to serve as a concrete basis for the development of strategies to minimize the adverse effects of the ever-growing cosmetic surgery industry. This information can help elucidate the psychologic characteristics of individuals seeking cosmetic surgery and contribute to optimal medical outcomes. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Factors Affecting Acceptance of Cosmetic Surgery in Adults in Their 20s-30s.

BACKGROUND: This descriptive study investigates cosmetic surgery experience, awareness of side effects, self-esteem, and acceptance of cosmetic surgery (ACS) and aims to identify factors that affect ACS. METHODS: Data on 398 randomly selected participants from a panel of sex-stratified adults in their 20s and 30s registered online with a Korean survey company were collected in September 2019. The data were analyzed using descriptive statistics, crosstabs, Chi-square test, ANOVA, Pearson's correlation, and multiple linear regression. RESULTS: Among the subjects, 47.2% were male and 52.8% were female. The average age of the subjects was 29.98 years. While 91.7% of the subjects previously acquired information on side effects related to cosmetic surgery, the most frequent source was from "bus stops and subway stops," reported by 83.6% of them. Blepharoplasty was the most frequently performed procedure reported by 50 of the 89 subjects (22.4%) who underwent 1 or more cosmetic surgery procedures. Among 187 subjects (47.0%) considering cosmetic surgery in the future, "botulinum toxin" was the most frequently considered procedure. ACS of the subjects was higher with employment (ß = .15, p < .001), previous experience with cosmetic surgery (ß = .22, p < .001), consideration for future cosmetic surgery (ß = .49, p < .001), and lower appearance satisfaction (AS) (ß = -.10, p = .008), and the explanatory power of these variables was 41.7% (F = 72.08, p < .001). CONCLUSIONS: Most of the subjects in this study were aware of the side effects of cosmetic surgery, and about half were considering cosmetic surgery in the future. Employment status, previous experience with cosmetic surgery, consideration for future cosmetic surgery, and AS were found to be factors affecting ACS. Correlations between age, BMI, ACS, AS, depression, and self-esteem were identified. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the table of contents or the online instructions to authors www.springer.com/00266 .

Metabolomic study of polyamines in rat urine following intraperitoneal injection of γ-hydroxybutyric acid.

INTRODUCTION: Recently, illegal abuse of γ-hydroxybutyric acid (GHB) has increased in drug-facilitated crimes, but the determination of GHB exposure and intoxication is difficult due to rapid metabolism of GHB. Its biochemical mechanism has not been completely investigated. And a metabolomic study by polyamine profile and pattern analyses was not performed in rat urine following intraperitoneal injection with GHB. OBJECTIVES: Urinary polyamine (PA) profiling by gas chromatography-tandem mass spectrometry was performed to monitor an altered PA according to GHB administration. METHODS: Polyamine profiling analysis by gas chromatography-mass spectrometry combined with star pattern recognition analysis was performed in this study. The multivariate statistical analysis was used to evaluate discrimination among control and GHB administration groups. RESULTS: Six polyamines were determined in control, single and multiple GHB administration groups. Star pattern showed distorted hexagonal shapes with characteristic and readily distinguishable patterns for each group. N1-Acetylspermine (p < 0.001), putrescine (p < 0.006), N1-acetylspermidine (p < 0.009), and spermine (p < 0.027) were significantly increased in single administration group but were significantly lower in the multiple administration group than in the control group. N1-Acetylspermine was the main polyamine for discrimination among control, single and multiple administration groups. Spermine showed similar levels in single and multiple administration groups. CONCLUSIONS: The polyamine metabolic pattern was monitored in GHB administration groups. N1-Acetylspermine and spermine were evaluated as potential biomarkers of GHB exposure and addiction.

Diagnostic Odyssey and Application of Targeted Exome Sequencing in the Investigation of Recurrent Infant Deaths in a Syrian Consanguineous Family: a Case of Spinal Muscular Atrophy with Respiratory Distress Type 1.

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive disorder caused by a defect in the immunoglobulin mu binding protein 2 (IGHMBP2) gene, leading to motor neuron degeneration. We identified an infant with SMARD1 by targeted exome sequencing from a consanguineous Syrian family having a history of recurrent infant deaths. The patient initially presented intrauterine growth retardation, poor sucking, failure to thrive, and respiratory failure at the age of two months, and an inborn error of metabolism was suspected at first. Over a period of one month, the infant showed rapid progression of distal muscular weakness with hand and foot contractures, which were suggestive of neuromuscular disease. Using targeted exome sequencing, the mutation in IGHMBP2 was confirmed, although the first report was normal. Targeted exome sequencing enabled identification of the genetic cause of recurrent mysterious deaths in the consanguineous family. Additionally, it is suggested that a detailed phenotypic description and communication between bioinformaticians and clinicians is important to reduce false negative results in exome sequencing.

Experience and Acceptance of Cosmetic Procedures Among South Korean Women in Their 20s.

PURPOSE: This study aimed to investigate the relationship between acceptance of cosmetic surgery (ACS) and cosmetic procedure experience in women in their 20s. METHODS: We collected 330 randomly sampled women in their 20s in November 2017. The collected data were analyzed by descriptive statistics, t test, crosstabs, Chi-square test, ANOVA, Pearson's correlation, and binary logistic regression. RESULTS: Almost all (97.9%) of the subjects had heard about the side effects of cosmetic surgery, and "Internet" was the most common source of information (57.3%). The number of subjects who had already undergone more than 1 cosmetic procedure was 124 women (37.6%), and the first age of cosmetic procedure was 21.81 (± 2.83) years old. ACS had a negative correlation with appearance satisfaction (r = - 0.18, p = 0.001). There was positive correlation between appearance satisfaction and self-esteem (r = 0.62, p < 0.001) and negative correlation between appearance satisfaction and body mass index (BMI) (r = - 0.28, p < 0.001). The higher the age of 1 year, the greater the probability of experience of cosmetic procedure (1.17 times) (OR 1.17, p = 0.002), and the higher the ACS score, the greater the probability of cosmetic procedure being 1.06 times (OR 1.06, p < 0.001). The higher the BMI score, the lower the probability of experiencing cosmetic procedure by 0.84 times (OR 0.84, p < 0.001). CONCLUSION: Age, ACS and BMI were the factors influencing the cosmetic procedure experience, and the cosmetic procedure experience led to more cosmetic procedures. LEVEL OF EVIDENCE V: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

MET Receptor Tyrosine Kinase Regulates the Expression of Co-Stimulatory and Co-Inhibitory Molecules in Tumor Cells and Contributes to PD-L1-Mediated Suppression of Immune Cell Function.

The MET tyrosine receptor kinase is essential for embryonic development and tissue regeneration by promoting cell survival, proliferation, migration, and angiogenesis. It also contributes to tumor development and progression through diverse mechanisms. Using human cancer cell lines, including Hs746T (MET-mutated/amplified), H596 (MET-mutated), and H1993 (MET-amplified) cells, as well as BEAS-2B bronchial epithelial cells, we investigated whether MET is involved in the regulation of immune checkpoint pathways. In a microarray analysis, MET suppression using a MET inhibitor or siRNAs up-regulated co-stimulatory molecules, including 4-1BBL, OX40L, and CD70, and down-regulated co-inhibitory molecules, especially PD-L1, as validated by measuring total/surface protein levels in Hs746T and H1993 cells. MET activation by HGF consistently increased PD-L1 expression in H596 and BEAS-2B cells. Co-culture of human peripheral blood mononuclear cells with Hs746T cells suppressed interferon-γ production by the immune cells, which was restored by MET inhibition or PD-L1 blockade. A significant positive correlation between MET and PD-L1 expression in lung cancer was determined in an analysis based on The Cancer Genome Atlas (TCGA) and in an immunohistochemistry study. The former also showed an association of MET overexpression in a PD-L1high tumor with the decreased expressions of T-cell effector molecules. In summary, our results point to a role for MET overexpression/activation in the immune escape of tumors by PD-L1 up-regulation. MET-targeted-therapy combined with immunotherapy may therefore be an effective treatment strategy in patients with MET-dependent cancer.

Tamoxifen therapy improves overall survival in luminal A subtype of ductal carcinoma in situ: a study based on nationwide Korean Breast Cancer Registry database.

PURPOSE: To determine the prognostic role of tamoxifen therapy for patients with ductal carcinoma in situ (DCIS) according to molecular subtypes. METHODS: Data of 14,944 patients with DCIS were analyzed. Molecular subtypes were classified into four categories based on expression of estrogen receptor (ER)/progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Kaplan-Meier estimator was used for overall survival analysis while Cox proportional hazards model was used for univariate and multivariate analyses. RESULTS: Luminal A subtype (ER/PR+, HER2-) showed higher (P = .009) survival rate than triple-negative (TN) subtype. Tamoxifen therapy group showed superior (P < .001) survival than no-tamoxifen therapy group. It had survival benefit only for luminal A subtype (P = .001). Tamoxifen therapy resulted in higher survival rate in subgroups with positive ER (P = .006), positive PR (P = .009), and negative HER2 (P < .001). In luminal A subtype, tamoxifen therapy showed lower hazard ratio (HR) compared to no-tamoxifen therapy (HR, 0.420; 95% CI 0.250-0.705; P = .001). Tamoxifen therapy was a significant independent factor by multivariate analysis (HR, 0.538; 95% CI 0.306-0.946; P = .031) as well as univariate analysis. CONCLUSION: Tamoxifen therapy group showed superior prognosis than the no-tamoxifen therapy group. Its prognostic influence was only effective for luminal A subtype. Patients with luminal A subtype showed higher survival rate than those with TN subtype. Active tamoxifen therapy is recommended for DCIS patients with luminal A subtype, and routine tests for ER, PR, and HER2 should be considered for DCIS.