TGF-ß and RAS jointly unmask primed enhancers to drive metastasis.

Epithelial-to-mesenchymal transitions (EMTs) and extracellular matrix (ECM) remodeling are distinct yet important processes during carcinoma invasion and metastasis. Transforming growth factor ß (TGF-ß) and RAS, signaling through SMAD and RAS-responsive element-binding protein 1 (RREB1), jointly trigger expression of EMT and fibrogenic factors as two discrete arms of a common transcriptional response in carcinoma cells. Here, we demonstrate that both arms come together to form a program for lung adenocarcinoma metastasis and identify chromatin determinants tying the expression of the constituent genes to TGF-ß and RAS inputs. RREB1 localizes to H4K16acK20ac marks in histone H2A.Z-loaded nucleosomes at enhancers in the fibrogenic genes interleukin-11 (IL11), platelet-derived growth factor-B (PDGFB), and hyaluronan synthase 2 (HAS2), as well as the EMT transcription factor SNAI1, priming these enhancers for activation by a SMAD4-INO80 nucleosome remodeling complex in response to TGF-ß. These regulatory properties segregate the fibrogenic EMT program from RAS-independent TGF-ß gene responses and illuminate the operation and vulnerabilities of a bifunctional program that promotes metastatic outgrowth.

A monoclonal antibody that targets a NaV1.7 channel voltage sensor for pain and itch relief.

Voltage-gated sodium (NaV) channels control the upstroke of the action potentials in excitable cells. Multiple studies have shown distinct roles of NaV channel subtypes in human physiology and diseases, but subtype-specific therapeutics are lacking and the current efforts have been limited to small molecules. Here, we present a monoclonal antibody that targets the voltage-sensor paddle of NaV1.7, the subtype critical for pain sensation. This antibody not only inhibits NaV1.7 with high selectivity, but also effectively suppresses inflammatory and neuropathic pain in mice. Interestingly, the antibody inhibits acute and chronic itch despite well-documented differences in pain and itch modulation. Using this antibody, we discovered that NaV1.7 plays a key role in spinal cord nociceptive and pruriceptive synaptic transmission. Our studies reveal that NaV1.7 is a target for itch management, and the antibody has therapeutic potential for suppressing pain and itch. Our antibody strategy may have broad applications for voltage-gated cation channels.

Risk Factors for Abdominal Aortic Aneurysm in Patients With Diabetes.

OBJECTIVE: Although diabetes has been shown to be negatively associated with development of abdominal aortic aneurysm (AAA), patients with diabetes may still develop aneurysms. In this study we examined risk factors for development of AAA in patients with diabetes. METHODS: Adults over 50 years with diabetes who underwent health screening between 2009 and 2012 were followed for incident AAA until December 31, 2019. Cox proportional hazard regression models were used to calculate multivariate hazard ratios (HR) and 95% confidence intervals (CI) for risk factors associated with AAA. RESULTS: Among 1,913,066 participants (55.3% men), 6,996 AAA cases were identified during a mean follow-up of 7.7 years. Increased AAA risk was observed for age ≥ 65 years (HR 2.69, 95% CI 2.55-2.83), men (HR 1.81, 95% CI 1.69-1.94), smoking (ex-smoker ≥ 20 pack-years, HR 1.75, 95% CI 1.61-1.89; current smoker < 20 pack-years, HR 1.76, 95% CI 1.59-1.94; current smoker ≥ 20 pack-years, HR 2.40, 95% CI 2.23-2.59), abdominal obesity (HR 1.30, 95% CI 1.23-1.38), and comorbidities: hypertension (HR 1.63, 95% CI 1.53-1.73), dyslipidemia (HR 1.35, 95% CI 1.29-1.42), chronic kidney disease (HR 1.52, 95% CI 1.44-1.61), cardiovascular disease (HR 1.71, 95% CI 1.58-1.86). Heavy (HR 0.67, 95% CI 0.61-0.74) and mild alcohol consumption (HR 0.78, 95% CI 0.74-0.83), overweight (HR 0.87, 95% CI 0.81-0.93) and obesity (HR 0.81, 95% CI 0.75-0.87), longer diabetes duration (≥ 5 years: HR 0.74, 95% CI 0.70-0.78), and using ≥ 3 oral hypoglycemic agents (HR 0.84, 95% CI 0.79-0.90) were associated with decreased AAA risk, while insulin use was associated with a marginally increased risk (HR 1.09, 95% CI 1.00-1.18). Among the oral hypoglycemic agents, metformin (HR 0.95, 95% CI 0.90-1.00), thiazolidinedione (HR 0.87, 95% CI 0.79-0.97), and sulfonylurea (HR 0.88, 95% CI 0.83-0.93) were associated with decreased risk of AAA. CONCLUSIONS: Although diabetes is associated with decreased AAA risk, those with comorbid cardiometabolic diseases, abdominal obesity, and smoking history should be aware of increased AAA risk. Further studies are warranted to verify the potential use of oral hypoglycemic agents for reducing AAA risk.

Complete microbial synthesis of crocetin and crocins from glycerol in Escherichia coli.

BACKGROUND: Crocin, a glycosylated apocarotenoid pigment predominantly found in saffron, has garnered significant interest in the field of biotechnology for its bioactive properties. Traditional production of crocins and their aglycone, crocetin, typically involves extraction from crocin-producing plants. This study aimed to develop an alternative biosynthetic method for these compounds by engineering the metabolic pathways of zeaxanthin, crocetin, and crocin in Escherichia coli strains. RESULTS: Employing a series of genetic modifications and the strategic overexpression of key enzymes, we successfully established a complete microbial pathway for synthesizing crocetin and four glycosylated derivatives of crocetin, utilizing glycerol as the primary carbon source. The overexpression of zeaxanthin cleavage dioxygenase and a novel variant of crocetin dialdehyde dehydrogenase resulted in a notable yield of crocetin (34.77 ± 1.03 mg/L). Further optimization involved the overexpression of new types of crocetin and crocin-2 glycosyltransferases, facilitating the production of crocin-1 (6.29 ± 0.19 mg/L), crocin-2 (5.29 ± 0.24 mg/L), crocin-3 (1.48 ± 0.10 mg/L), and crocin-4 (2.72 ± 0.13 mg/L). CONCLUSIONS: This investigation introduces a pioneering and integrated microbial synthesis method for generating crocin and its derivatives, employing glycerol as a sustainable carbon feedstock. The substantial yields achieved highlight the commercial potential of microbial-derived crocins as an eco-friendly alternative to plant extraction methods. The development of these microbial processes not only broadens the scope for crocin production but also suggests significant implications for the exploitation of bioengineered compounds in pharmaceutical and food industries.

Emergence and genomic chion of Proteus mirabilis harboring blaNDM-1 in Korean companion dogs.

Proteus mirabilis is a commensal bacterium dwelling in the gastrointestinal (GI) tract of humans and animals. Although New Delhi metallo-ß-lactamase 1 (NDM-1) producing P. mirabilis is emerging as a threat, its epidemiology in our society remains largely unknown. LHPm1, the first P. mirabilis isolate harboring NDM-1, was detected from a companion dog that resides with a human owner. The whole-genome study revealed 20 different antimicrobial resistance (AMR) genes against various classes of antimicrobial agents, which corresponded to the MIC results. Genomic regions, including MDR genes, were identified with multiple variations and visualized in a comparative manner. In the whole-genome epidemiological analysis, multiple phylogroups were identified, revealing the genetic relationship of LHPm1 with other P. mirabilis strains carrying various AMR genes. These genetic findings offer comprehensive insights into NDM-1-producing P. mirabilis, underscoring the need for urgent control measures and surveillance programs using a "one health approach".

Editor's Choice - Glycaemic Status and Risk of Abdominal Aortic Aneurysm: A Nationwide Cohort Study of Four Million Adults using Korean National Health Screening Data.

OBJECTIVE: This retrospective cohort study aimed to confirm the previously reported inverse association between diabetes mellitus (DM) and abdominal aortic aneurysm (AAA) using large population based data. It also investigated the associations between AAA and impaired fasting glucose (IFG) and new onset DM (not yet treated). METHODS: A representative dataset was obtained from the Korean National Health Insurance Service. Participants who were aged ≥ 50 years and received a national health examination in 2009 were included and followed until 31 December 2019. Glycaemic status was defined based on fasting plasma glucose level and the relevant diagnostic codes. AAA was ascertained using medical facility use records with relevant diagnostic codes or aneurysm repair surgery. A Cox proportional hazards model was used to examine the association between glycaemic status and AAA, with adjustment for confounders. Additionally, the interactions between glycaemic status and subgroups based on baseline characteristics were examined. RESULTS: The study population comprised 4 162 640 participants. Participants with IFG or DM were significantly more likely to be male, older, and have comorbidities compared with normoglycaemic participants at baseline. The incidence of AAA was lower in participants with IFG or DM compared with normoglycaemic participants. The AAA risk was lower in patients with DM than in patients with IFG, and decreased linearly according to glycaemic status: the adjusted hazard ratio was 0.88 (95% confidence interval [CI] 0.85 - 0.91) for IFG, 0.72 (95% CI 0.67 - 0.78) for newly diagnosed DM, 0.65 (95% CI 0.61 - 0.69) for DM duration < 5 years, and 0.47 (95% CI 0.44 - 0.51) for DM duration ≥ 5 years compared with the normoglycaemia group. Both IFG and DM were related to reduced AAA risk in all subgroups, suggesting an independent association. CONCLUSION: Both IFG and DM, even when not treated with antihyperglycaemic medication, were associated with a lower incidence of AAA. The AAA risk decreased linearly according to DM duration.

Identification of maximal tumor size associated with negligible lymph node metastasis for endoscopic submucosal dissection of undifferentiated-type early gastric cancer.

BACKGROUND AND AIMS: When treating undifferentiated-type early gastric cancer (UD-EGC) that is limited to the mucosa (clinically T1a), endoscopic submucosal dissection (ESD) can be considered if the tumor is 2 cm or less and is not ulcerated. However, there is insufficient evidence to determine the relationships between tumor size and oncological safety of ESD in UD-EGC. METHODS: The pathology reports of Korean patients who were diagnosed with UD-EGC (n = 5286) were retrospectively reviewed. The cumulative incidence of lymph node metastasis (LNM) according to tumor size was evaluated in subgroups. The tumor-size cut-off was identified as the upper limit of the 95% confidence interval (CI) of cumulative LNM incidence that did not exceed 1.0%. RESULTS: We identified 1516 patients with non-ulcerated T1a tumors ≤2 cm in size. Among patients without lymphatic invasion, 1.5% (95% CI 0.91-2.16%) had LNM. In patients with poorly differentiated tubular adenocarcinoma (PD), LNM increased from 0 to 0.74% based on a tumor size of 1.0 cm. Regardless of tumor size, smaller percentages of undifferentiated-type (UD) and poorly cohesive carcinoma (PCC) patients experienced LNM than did those with PD. In non-ulcerated mucosal cancer without lymphatic invasion and tumor size ≤0.9 cm, no LNM was observed in patients with UD (95% CI 0-0.53%), PCC (95% CI 0-0.59%), or PD (95% CI 0-0.86%) histologic type. CONCLUSION: In patients diagnosed with non-ulcerated T1a UD-EGC, ESD can be performed if the tumor size is 0.9 cm or less, regardless of histologic type.

A novel treatment strategy targeting cellular pathways with natural products to alleviate sarcopenia.

Sarcopenia is a condition marked by a significant reduction in muscle mass and strength, primarily due to the aging process, which critically impacts muscle protein dynamics, metabolic functions, and overall physical functionality. This condition leads to increased body fat and reduced daily activity, contributing to severe health issues and a lower quality of life among the elderly. Recognized in the ICD-10-CM only in 2016, sarcopenia lacks definitive treatment options despite its growing prevalence and substantial social and economic implications. Given the aging global population, addressing sarcopenia has become increasingly relevant and necessary. The primary causes include aging, cachexia, diabetes, and nutritional deficiencies, leading to imbalances in protein synthesis and degradation, mitochondrial dysfunction, and hormonal changes. Exercise remains the most effective intervention, but it is often impractical for individuals with limited mobility, and pharmacological options such as anabolic steroids and myostatin inhibitors are not FDA-approved and are still under investigation. This review is crucial as it examines the potential of natural products as a novel treatment strategy for sarcopenia, targeting multiple mechanisms involved in its pathogenesis. By exploring natural products' multi-targeted effects, this study aims to provide innovative and practical solutions for sarcopenia management. Therefore, this review indicates significant improvements in muscle mass and function with the use of specific natural compounds, suggesting promising alternatives for those unable to engage in regular physical activity.

Long-term follow-up results of facial nerve schwannoma with good facial nerve function: a multicenter study.

PURPOSE: Facial nerve schwannomas (FNSs) are rare intracranial tumors, and the optimal management of these tumors remains unclear. We investigated the long-term follow-up results of FNS with good facial nerve function. METHODS: At nine medical centers in the Korean Facial Nerve Study Group, 43 patients undergoing observation periods longer than 12 months for FNS with good facial nerve function (House-Brackmann grade ≤ II) were enrolled, and clinical and radiographic data were obtained for these cases. RESULTS: The mean follow-up period was 63 months. In the majority of cases, tumors involved multiple segments (81.4%) and only eight cases were confined to a single site. There were no cases where the tumor was confined to the extratemporal region. Tumor size increased slightly, with an average estimated change of 0.48 mm/year. Twenty (46.5%) of 43 patients showed no change in tumor size. Seven patients (16.3%) showed worsening House-Brackmann (H-B) grade, of which two patients deteriorated from H-B grade I to II, four worsened to grade III, and one deteriorated to grade IV. The remaining 36 patients (83.7%) showed no change in facial nerve function. There was no difference in H-B grade according to tumor size at the time of diagnosis or change in tumor size. CONCLUSION: We conducted a large-scale observational study of FNS with good facial nerve function. Our study showed that many patients maintained facial nerve function during long-term follow-up. Conservative management with regular examination and imaging can be an appropriate option for managing FNS with good facial nerve function.

Strategies for Overcoming Immune Evasion in Bladder Cancer.

Tumors intricately shape a highly immunosuppressive microenvironment, hampering effective antitumor immune responses through diverse mechanisms. Consequently, achieving optimal efficacy in cancer immunotherapy necessitates the reorganization of the tumor microenvironment and restoration of immune responses. Bladder cancer, ranking as the second most prevalent malignant tumor of the urinary tract, presents a formidable challenge. Immunotherapeutic interventions including intravesical BCG and immune checkpoint inhibitors such as atezolizumab, avelumab, and pembrolizumab have been implemented. However, a substantial unmet need persists as a majority of bladder cancer patients across all stages do not respond adequately to immunotherapy. Bladder cancer establishes a microenvironment that can actively hinder an efficient anti-tumor immune response. A deeper understanding of immune evasion mechanisms in bladder cancer will aid in suppressing recurrence and identifying viable therapeutic targets. This review seeks to elucidate mechanisms of immune evasion specific to bladder cancer and explore novel pathways and molecular targets that might circumvent resistance to immunotherapy.

The Potentiality of Natural Products and Herbal Medicine as Novel Medications for Parkinson's Disease: A Promising Therapeutic Approach.

As the global population ages, the prevalence of Parkinson's disease (PD) is steadily on the rise. PD demonstrates chronic and progressive characteristics, and many cases can transition into dementia. This increases societal and economic burdens, emphasizing the need to find effective treatments. Among the widely recognized causes of PD is the abnormal accumulation of proteins, and autophagy dysfunction accelerates this accumulation. The resultant Lewy bodies are also commonly found in Alzheimer's disease patients, suggesting an increased potential for the onset of dementia. Additionally, the production of free radicals due to mitochondrial dysfunction contributes to neuronal damage and degeneration. The activation of astrocytes and the M1 phenotype of microglia promote damage to dopamine neurons. The drugs currently used for PD only delay the clinical progression and exacerbation of the disease without targeting its root cause, and come with various side effects. Thus, there is a demand for treatments with fewer side effects, with much potential offered by natural products. In this study, we reviewed a total of 14 articles related to herbal medicines and natural products and investigated their relevance to possible PD treatment. The results showed that the reviewed herbal medicines and natural products are effective against lysosomal disorder, mitochondrial dysfunction, and inflammation, key mechanisms underlying PD. Therefore, natural products and herbal medicines can reduce neurotoxicity and might improve both motor and non-motor symptoms associated with PD. Furthermore, these products, with their multi-target effects, enhance bioavailability, inhibit antibiotic resistance, and might additionally eliminate side effects, making them good alternative therapies for PD treatment.

TGF-ß in developmental and fibrogenic EMTs.

TGF-ß plays a prominent role as an inducer of epithelial-mesenchymal transitions (EMTs) during development and wound healing and in disease conditions such as fibrosis and cancer. During these processes EMT occurs together with changes in cell proliferation, differentiation, communication, and extracellular matrix remodeling that are orchestrated by multiple signaling inputs besides TGF-ß. Chief among these inputs is RAS-MAPK signaling, which is frequently required for EMT induction by TGF-ß. Recent work elucidated the molecular basis for the cooperation between the TGF-ß-SMAD and RAS-MAPK pathways in the induction of EMT in embryonic, adult and carcinoma epithelial cells. These studies also provided direct mechanistic links between EMT and progenitor cell differentiation during gastrulation or intra-tumoral fibrosis during cancer metastasis. These insights illuminate the nature of TGF-ß driven EMTs as part of broader processes during development, fibrogenesis and metastasis.

Neuregulin-1 reverses anxiety-like behavior and social behavior deficits induced by unilateral micro-injection of CoCl2 into the ventral hippocampus (vHPC).

Neuregulin-1 (NRG1) is an epidermal growth factor family member with essential roles in the developing and adult nervous systems. In recent years, establishing evidence has collectively suggested that NRG1 is a new modulator of central nervous system (CNS) injury and disease, with multifaceted roles in neuroprotection, remyelination, neuroinflammation, and other repair mechanisms. NRG1 signaling exerts its effects via the tyrosine kinase receptors ErbB2-ErbB4. The NRG1/ErbB network in CNS pathology and repair has evolved, primarily in recent years. In the present study, we demonstrated that a unilateral microinjection of CoCl2 into the ventral hippocampus (vHPC) induced hypoxic insult and led to anxiety-related behaviors and deficit sociability in mice. NRG1 treatment significantly alleviated the CoCl2-induced increase of hypoxic-related molecules and behavioral abnormalities. Furthermore, NRG1 reduced the CoCl2-induced neuroinflammation and neuronal deficits in the vHPC or primary hippocampal neurons in mice. Collectively, these results suggest that NRG1 ameliorates hypoxia by alleviating synaptic deficits and behavioral abnormalities of the CoCl2-induced vHPC hypoxic model.

Whole genome structure and resistance genes in carbapenemase-producing multidrug resistant ST378 Klebsiella pneumoniae.

BACKGROUND: Carbapenemase-producing Klebsiella pneumoniae (CPKP) is one of the most dangerous multidrug-resistant (MDR) pathogens in human health due to its widespread circulation in the nosocomial environment. CPKP carried by companion dogs, which are close to human beings, should be considered a common threat to public health. However, CPKP dissemination through companion animals is still under consideration of major diagnosis and surveillance systems. METHODS: Two CPKP isolates which were genotyped to harbor bla NDM-5-encoding IncX3 plasmids, were subjected to the whole-genome study. Whole bacterial DNA was isolated, sequenced, and assembled with Oxford Nanopore long reads and corrected with short reads from the Illumina NovaSeq 6000 platform. The whole-genome structure and positions of antimicrobial resistance (AMR) genes were identified and visualized using CGView. Worldwide datasets were downloaded from the NCBI GenBank database for whole-genome comparative analysis. The whole-genome phylogenetic analysis was constructed using the identified whole-chromosome SNP sites from K. pneumoniae HS11286. RESULTS: As a result of the whole-genome identification, 4 heterogenous plasmids and a single chromosome were identified, each carrying various AMR genes. Multiple novel structures were identified from the AMR genes, coupled with mobile gene elements (MGE). The comparative whole-genome epidemiology revealed that ST378 K. pneumoniae is a novel type of CPKP, carrying a higher prevalence of AMR genes. CONCLUSIONS: The characterized whole-genome analysis of this study shows the emergence of a novel type of CPKP strain carrying various AMR genes with variated genomic structures. The presented data in this study show the necessity to develop additional surveillance programs and control measures for a novel type of CPKP strain.

Risk of overactive bladder after hysterectomy for uterine fibroids.

INTRODUCTION AND HYPOTHESIS: We evaluated the association between previous hysterectomy for uterine fibroids and the risk of developing overactive bladder (OAB). METHODS: We used national health insurance data. The hysterectomy group (aged 40 to 59) comprised patients who underwent hysterectomy for uterine leiomyoma or adenomyosis between 1 January 2011 and 31 December 2014, and the control group (aged 40 to 59) comprised patients who visited a medical facility for a checkup during the same time period. Propensity score matching (PSM, 1:1) was performed to balance confounders. OAB events were defined by drug prescriptions (beta 3 agonist or anticholinergics) for more than 1 month based on previous studies. RESULTS: After matching, 58,195 cases (hysterectomy group) and 58,195 controls (nonhysterectomy group) were enrolled. The mean follow-up period was 7.9 years in the nonhysterectomy group and 8.0 years in the hysterectomy group. There was no significant difference in the rate of OAB development between the groups (0.3% vs 0.3%; p=0.061). Additionally, compared with the nonhysterectomy group (hazard ratio: 1 (reference)), hysterectomy without adnexal surgery (hazard ratio: 1.169 [0.915-1.493]) and hysterectomy with adnexal surgery (hazard ratio: 1.342 [0.83-2.171]) did not significantly increase the risk of OAB after adjusting for confounders; this relationship remained nonsignificant after stratifying patients according to age group. CONCLUSIONS: Previous hysterectomy with or without adnexal surgery for the treatment of uterine fibroids did not increase the risk of developing OAB, defined as drug therapy lasting more than 1 month.

TonEBP recognizes R-loops and initiates m6A RNA methylation for R-loop resolution.

R-loops are three-stranded, RNA-DNA hybrid, nucleic acid structures produced due to inappropriate processing of newly transcribed RNA or transcription-replication collision (TRC). Although R-loops are important for many cellular processes, their accumulation causes genomic instability and malignant diseases, so these structures are tightly regulated. It was recently reported that R-loop accumulation is resolved by methyltransferase-like 3 (METTL3)-mediated m6A RNA methylation under physiological conditions. However, it remains unclear how R-loops in the genome are recognized and induce resolution signals. Here, we demonstrate that tonicity-responsive enhancer binding protein (TonEBP) recognizes R-loops generated by DNA damaging agents such as ultraviolet (UV) or camptothecin (CPT). Single-molecule imaging and biochemical assays reveal that TonEBP preferentially binds a R-loop via both 3D collision and 1D diffusion along DNA in vitro. In addition, we find that TonEBP recruits METTL3 to R-loops through the Rel homology domain (RHD) for m6A RNA methylation. We also show that TonEBP recruits RNaseH1 to R-loops through a METTL3 interaction. Consistent with this, TonEBP or METTL3 depletion increases R-loops and reduces cell survival in the presence of UV or CPT. Collectively, our results reveal an R-loop resolution pathway by TonEBP and m6A RNA methylation by METTL3 and provide new insights into R-loop resolution processes.

Status of the Newborn Hearing Screening in the 4-Months Age National Infant Health Checkup in Korea: A Nationwide Population-Based Study.

BACKGROUND: The aims of this study are to review data on 4-months age National Health Screening Program for Infants and Children (NHSPIC) using a National Health Insurance Service (NHIS) database, and to analyze the newborn hearing screening (NHS) results and related characteristics of the 4-months NHSPIC for 7 years in South Korea. METHODS: We analyzed a NHIS database of infants who had participated in the 4-month age NHSPIC from 2010 to 2016. According to the results of hearing questionnaires and physical examination, we analyzed the outcomes of NHS and related infantile and socioeconomic factors. RESULTS: Among 3,128,924 of total eligible infants in Korea between the year 2010 and 2016, 69.2% (2,164,621 infants) conducted 4-months age NHSPIC, and 94.4% (2,042,577 infants) of which performed hearing questionnaires regarding NHS. Among the total hearing examinees, premature infants accounted for 3.6%, infants who were hospitalized in the neonatal intensive care unit (NICU) for more than 5 days accounted for 5.6%, and infants with head and neck abnormalities were 0.6%. The NHS performing rate was 79.1% for total hearing examinees in 2010, but gradually increased to 88.9% in 2016. The NHS performing rate in 2016 was 93.4% for premature infants, 91.7% for NICU hospitalized babies. The mean referral rate was 0.6% for total hearing examinees, 1.4% for premature infants, and 2.3% for NICU hospitalized babies. When we analyzed the NHS performing rate and the referral rate according to the household income level, the NHS performing rate of infants in Medical Aid programs was the lowest as 65.6%, and the NHS performing rates in other five levels of NHIS was higher ranging between 85.1% to 86.0%. The referral rate of infants in the Medical Aid program (3.8%) was significantly higher than those of infants in other classes (1.10-1.25%). CONCLUSION: The estimated overall NHS performing rate in Korea gradually increased and was 88.9% in 2016. The overall referral rate was low as 0.6%, and it was significantly different depending on the infant's health condition and household income levels. We assume that our finding would help to establish policies managing hearing impaired children, and to develop the customized hearing care service programs considering the household economic levels.

Altered secretome by diesel exhaust particles and lipopolysaccharide in primary human nasal epithelium.

BACKGROUND: Airway epithelial cells can actively participate in the defense against environmental pathogens to elicit local or systemic inflammation. Diesel exhaust particles (DEP), a main component of urban air pollution with particulate matter, are associated with the occurrence of acute and chronic upper airway inflammatory diseases. OBJECTIVES: We sought to investigate the effect of DEP alone or in combination with lipopolysaccharide on the secretome in the primary human nasal epithelium (PHNE) and to find potential biomarkers to relate DEP exposure to upper airway inflammatory diseases. METHODS: PHNE was cultured at an air-liquid interface to create a differentiated in vivo-like model. Secreted proteins (secretome) on the bottom media of the PHNE were analyzed by mass spectrometry-based label-free quantitative proteomics and ELISA. RESULTS: Considerably more differentially expressed secreted proteins were identified in response to DEP plus lipopolysaccharide than to DEP alone. Some canonical pathways related to inflammation and cancer such as the p53, ß-catenin, and extracellular signal-regulated kinase 1/2 pathways were involved. Among differentially expressed secreted proteins, leukemia inhibitory factor was also detected at a high level in the middle ear effusions of otitis media patients, and the leukemia inhibitory factor level was significantly correlated with daily mean mass concentrations of atmospheric particulate matter averaged over 8 days before sample collection. CONCLUSIONS: Apical stimulation with DEP and lipopolysaccharide can significantly alter the basal secretome in PHNE, and this alteration can be reflected by surrounding inflammation with effusion of fluids in vivo such as middle ear effusions in otitis media patients.

The Anti-Inflammatory Effects of Adipose Tissue Mesenchymal Stem Cell Exosomes in a Mouse Model of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a group of chronic, relapsing inflammatory disorders that affect the gastrointestinal tract, with the primary subtypes being ulcerative colitis (UC) and Crohn's disease (CD). We aimed to evaluate the therapeutic potential of extracellular vesicles released by adipose-tissue-derived mesenchymal stem cells, which we, in this manuscript, call "exosomes" (ASC-EXOs), in a mouse model of IBD. We specifically aimed to determine the effectiveness of different treatment protocols and compare the effects with that of anti-IL-12 p40 monoclonal antibody. The addition of dextran sulfate sodium (DSS) to drinking water induced multiple signs of IBD, including weight loss, soft stool, and bloody feces. ASC-EXOs given by either intraperitoneal (IP) or intravenous (IV) routes resulted in moderate improvement in these signs of IBD. IV ASC-EXOs resulted in significantly reduced body weight loss, improved histopathological scoring, and suppressed the disease activity index (DAI) compared to the IBD control group. Also, a reduction in PCR for pro-inflammatory cytokines was observed. IV ASC treatment resulted in dose-related reduction in IBD signs, including weight loss. An increasing number of injections with ASC-EXOs reduced histopathological scores as well as DAI. Co-administration of ASC-EXOs with anti-IL-12 p40 significantly decreased DAI scores in the ASC-EXO + anti-IL-12 p40 group. In conclusion, ASC-EXOs have potential as a therapeutic agent for IBD, but the route of administration, number of injections, and dosage need to be considered to optimize the effects of ASC-EXO treatment. This study also highlights the potential benefits of combination therapies of ASC-EXOs and anti-IL-12. Our findings pave the way for further studies to unravel the underlying therapeutic mechanisms of ASC-EXOs in IBD treatment.