Matrisomics: Beyond the extracellular matrix for unveiling tumor microenvironment.

The matrisome, a group of proteins constituting or interacting with the extracellular matrix (ECM), has garnered attention as a potent regulator of cancer progression. An increasing number of studies have focused on cancer matrisome utilizing diverse -omics approaches. Here, we present diverse patterns of matrisomal populations within cancer tissues, exploring recent -omics studies spanning different '-omics' levels (epigenomics, genomics, transcriptomics, and proteomics), as well as newly developed sequencing techniques such as single-cell RNA sequencing and spatial transcriptomics. Some matrisome genes showed uniform patterns of upregulated or downregulated expression across various cancers, while others displayed different expression patterns according to the cancer types. This matrisomal dysregulation in cancer was further examined according to their originating cell type and spatial location in the tumor tissue. Experimental studies were also collected to demonstrate the identified roles of matrisome genes during cancer progression. Interestingly, many studies on cancer matrisome have suggested matrisome genes as effective biomarkers in cancer research. Although the specific mechanisms and clinical applications of cancer matrisome have not yet been fully elucidated, recent techniques and analyses on cancer matrisomics have emphasized their biological importance in cancer progression and their clinical implications in deciding the efficacy of cancer treatment.

Streamlining pediatric vital sign assessment: innovations and insights.

Accurate assessment of pediatric vital signs is critical for detecting abnormalities and guiding medical interventions, but interpretation is challenging due to age-dependent physiological variations. Therefore, this study aimed to develop age-specific centile curves for blood pressure, heart rate, and respiratory rate in pediatric patients and create a user-friendly web-based application for easy access to these data. We conducted a retrospective cross-sectional observational study analyzing 3,779,482 records from the National Emergency Department Information System of Korea, focusing on patients under 15 years old admitted between January 2016 and December 2017. After applying exclusion criteria to minimize the impact of patients' symptoms on vital signs, 1,369,608 records were used for final analysis. The box-cox power exponential distribution and Lambda-Mu-Sigma (LMS) method were used to generate blood pressure centile charts, while heart rate and respiratory rate values were drawn from previously collected LMS values. We developed comprehensive age-specific centile curves for systolic, diastolic, and mean blood pressure, heart rate, and respiratory rate. These were integrated into a web-based application ( http://centile.research.or.kr ), allowing users to input patient data and promptly obtain centile and z-score information for vital signs. Our study provides an accessible system for pediatric vital sign evaluation, addressing previous limitations and offering a practical solution for clinical assessment. Future research should validate these centile curves in diverse populations.

COVID-19 and Neurodevelopmental Delays in Early Childhood: A Longitudinal Analysis of Developmental Outcomes in Korean Children.

This study employed a longitudinal analysis to evaluate the association between the coronavirus disease 2019 pandemic and neurodevelopment by analyzing over 1.8 million children from the Korean Developmental Screening Test for Infants and Children included in South Korea's National Health Screening Program. We compared the developmental outcomes in five age groups-9-17 months, 18-29 months, 30-41 months, 42-53 months, and 54-65 months-between the pre-pandemic (2018-2019) and pandemic (2020-2021) periods. Significant increases in potential developmental delays were observed during the pandemic in communication, cognitive, social interaction, self-care, and fine motor skills across most age groups. All five age groups experienced notable disruptions in communication and fine motor skills. Children from socioeconomically disadvantaged backgrounds faced higher risks across all domains. These findings highlight the need for targeted interventions and continuous monitoring to support the developmental needs of children affected by pandemic-related disruptions.

Cellular Plasticity in Gut and Liver Regeneration.

The intestine and liver share a unique regenerative property that sets them apart from other mammalian visceral organs. The intestinal epithelium exhibits rapid renewal, making it one of the fastest renewing tissues in humans. Under physiological conditions, intestinal stem cells within each intestinal crypt continuously differentiate into the different types of intestinal epithelial cells to maintain intestinal homeostasis. However, when exposed to tissue damage or stressful conditions such as inflammation, intestinal epithelial cells in the gastrointestinal tract exhibit plasticity, allowing fully differentiated cells to regain their stem cell properties. Likewise, hepatic epithelial cells possess a remarkable regenerative capacity to restore lost liver mass through proliferation-mediated liver regeneration. When the proliferation-mediated regenerative capacity is impaired, hepatocytes and biliary epithelial cells (BECs) can undergo plasticity-mediated regeneration and replenish each other. The transition of mammalian liver progenitor cells to hepatocytes/BECs can be observed under tightly controlled experimental conditions such as severe hepatocyte injury accompanied by the loss of regenerative capacity. In this review, we will discuss the mechanism by which cellular plasticity contributes to the regeneration process and the potential therapeutic implications of understanding and harnessing cellular plasticity in the gut and liver.

Association between the COVID-19 pandemic and childhood development aged 30 to 36 months in South Korea, based on the National health screening program for infants and children database.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has had a significant impact on the neurodevelopment of children. However, the precise effects of the virus and the social consequences of the pandemic on pediatric neurodevelopment are not yet fully understood. We aimed to compare the neurodevelopment of children between before and during the COVID-19 pandemic, as well as examine the impact of socioeconomic status (SES) and regional differences on the development. METHODS: The study used the Korean Developmental Screening Test to compare the difference in the risk of neurodevelopmental delay between before and during the COVID-19 pandemic. Multivariable logistic regression analysis was conducted to identify the relationship between experiencing the COVID-19 pandemic and the risk of neurodevelopmental delay. Stratified analyses were performed to determine whether the developmental delays caused by the pandemic's impact varied depending on SES or regional inequality. RESULTS: This study found an association between the experience of COVID-19 and a higher risk of neurodevelopmental delay in communication (adjusted OR [aOR]: 1.21, 95% confidence interval [CI]: 1.19, 1.22; P-value: < 0.0001) and social interaction (aOR: 1.15, 95% CI: 1.13, 1.17; P-value: < 0.0001) domains among children of 30-36 months' ages. Notably, the observed association in the Medicaid group of children indicates a higher risk of neurodevelopmental delay compared to those in the non-Medicaid group. CONCLUSIONS: These findings highlight the need to be concerned about the neurodevelopment of children who experienced the COVID-19 pandemic. The study also calls for increased training and support for Medicaid children, parents, teachers, and healthcare practitioners. Additionally, policy programs focused on groups vulnerable to developmental delays are required.

Healthcare service use and medical outcomes of tracheostomy-dependent children: a nationwide study.

BACKGROUND: Despite the rising trend of tracheostomies in children, there is a lack of comprehensive resources for families to navigate the challenges of living with a tracheostomy, emphasising the need for evidence-based support in understanding postoperative care and long-term adjustments. This study aimed to examine the pattern of using healthcare services and nationwide medical outcomes in children who underwent a tracheotomy before the age of 2 years. METHODS: This retrospective study used the National Health Insurance System database from 2008 to 2016 and included all children codified with tracheotomy procedure codes before their second birthday. Healthcare utilisation, such as medical costs, number of hospital visits, home healthcare nursing and medical diagnoses on readmission, in the first 2 years after tracheotomy was evaluated. Multivariable logistic regression analysis was used to determine the factors affecting mortality. RESULTS: In total, 813 patients were included in this study. Their use of healthcare services and the accompanying expenses were higher than the national medians for similar age groups; however, both metrics decreased in the second year. The major causes of admission within 2 years of surgery were respiratory and neurological diseases. The mortality rate within 2 years was 37.8%. Higher risks of mortality were associated with having two or more complex chronic conditions. Use of home healthcare nursing services was associated with a lower mortality risk. CONCLUSION: Paediatric patients with more complex chronic conditions tended to have higher mortality rates within 2 years after surgery. However, receiving home healthcare nursing was significantly associated with a reduced risk of death. Many causes of hospitalisation may be preventable with education and supportive care. Therefore, further research for establishing an integrated care system for these patients and their caregivers is required.

SIRT1 ISGylation accelerates tumor progression by unleashing SIRT1 from the inactive state to promote its deacetylase activity.

ISG15 is an interferon-stimulated ubiquitin-like protein (UBL) with multifaceted roles as a posttranslational modifier in ISG15 conjugation (ISGylation). However, the mechanistic consequences of ISGylation in cancer have not been fully elucidated, largely due to a lack of knowledge on the ISG15 target repertoire. Here, we identified SIRT1, a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase, as a new target for ISGylation. SIRT1 ISGylation impairs the association of SIRT1 with its negative regulator, deleted in breast cancer 1 (DBC1), which unleashes SIRT1 from its inactive state and leads to an increase in its deacetylase activity. Importantly, SIRT1 ISGylation promoted lung cancer progression and limited lung cancer cell sensitivity to DNA damage-based therapeutics in vivo and in vitro models. The levels of ISG15 mRNA and protein were significantly higher in lung cancer tissues than in adjacent normal tissues. Accordingly, elevated expression of SIRT1 and ISG15 was associated with poor prognosis in lung cancer patients, a finding that could be translated for lung cancer patient stratification and disease outcome evaluation. Taken together, our findings provide a mechanistic understanding of the regulatory effect of SIRT1 ISGylation on tumor progression and therapeutic efficacy in lung cancer.

NAMPT-Driven M2 Polarization of Tumor-Associated Macrophages Leads to an Immunosuppressive Microenvironment in Colorectal Cancer.

Nicotinamide phosphoribosyltransferase (NAMPT) is a metabolic enzyme with key roles in inflammation. Previous studies have examined the consequences of its upregulated expression in cancer cells themselves, but studies are limited with respect to its role in the other cells within the tumor microenvironment (TME) during colorectal cancer (CRC) progression. Using single-cell RNA sequencing (scRNA-seq) data, it is founded that NAMPT is highly expressed in SPP1+ tumor-associated macrophages (TAMs), a unique subset of TAMs associated with immunosuppressive activity. A NAMPThigh gene signature in SPP1+ TAMs correlated with worse prognostic outcomes in CRC patients. The effect of Nampt deletion in the myeloid compartment of mice during CRC development is explored. NAMPT deficiency in macrophages resulted in HIF-1α destabilization, leading to reduction in M2-like TAM polarization. NAMPT deficiency caused significant decreases in the efferocytosis activity of macrophages, which enhanced STING signaling and the induction of type I IFN-response genes. Expression of these genes contributed to anti-tumoral immunity via potentiation of cytotoxic T cell activity in the TME. Overall, these findings suggest that NAMPT-initiated TAM-specific genes can be useful in predicting poor CRC patient outcomes; strategies aimed at targeting NAMPT may provide a promising therapeutic approach for building an immunostimulatory TME in CRC progression.

Development of a deep learning model that predicts critical events of pediatric patients admitted to general wards.

Early detection of deteriorating patients is important to prevent life-threatening events and improve clinical outcomes. Efforts have been made to detect or prevent major events such as cardiopulmonary resuscitation, but previously developed tools are often complicated and time-consuming, rendering them impractical. To overcome this problem, we designed this study to create a deep learning prediction model that predicts critical events with simplified variables. This retrospective observational study included patients under the age of 18 who were admitted to the general ward of a tertiary children's hospital between 2020 and 2022. A critical event was defined as cardiopulmonary resuscitation, unplanned transfer to the intensive care unit, or mortality. The vital signs measured during hospitalization, their measurement intervals, sex, and age were used to train a critical event prediction model. Age-specific z-scores were used to normalize the variability of the normal range by age. The entire dataset was classified into a training dataset and a test dataset at an 8:2 ratio, and model learning and testing were performed on each dataset. The predictive performance of the developed model showed excellent results, with an area under the receiver operating characteristics curve of 0.986 and an area under the precision-recall curve of 0.896. We developed a deep learning model with outstanding predictive power using simplified variables to effectively predict critical events while reducing the workload of medical staff. Nevertheless, because this was a single-center trial, no external validation was carried out, prompting further investigation.

Eleven years of experience in operating a pediatric rapid response system at a children's hospital in South Korea.

BACKGROUND: Various rapid response systems have been developed to detect clinical deterioration in patients. Few studies have evaluated single-parameter systems in children compared to scoring systems. Therefore, in this study we evaluated a single-parameter system called the acute response system (ARS). METHODS: This retrospective study was performed at a tertiary children's hospital. Patients under 18 years old admitted from January 2012 to August 2023 were enrolled. ARS parameters such as systolic blood pressure, heart rate, respiratory rate, oxygen saturation, and whether the ARS was activated were collected. We divided patients into two groups according to activation status and then compared the occurrence of critical events (cardiopulmonary resuscitation or unexpected intensive care unit admission). We evaluated the ability of ARS to predict critical events and calculated compliance. We also analyzed the correlation between each parameter that activates ARS and critical events. RESULTS: The critical events prediction performance of ARS has a specificity of 98.5%, a sensitivity of 24.0%, a negative predictive value of 99.6%, and a positive predictive value of 8.1%. The compliance rate was 15.6%. Statistically significant increases in the risk of critical events were observed for all abnormal criteria except low heart rate. There was no significant difference in the incidence of critical events. CONCLUSIONS: ARS, a single parameter system, had good specificity and negative predictive value for predicting critical events; however, sensitivity and positive predictive value were not good, and medical staff compliance was poor.

Clinical importance of weight gain and associated factors in patients with moderate to severe ulcerative colitis: results from the MOSAIK cohort in Korea.

BACKGROUND: Many patients with ulcerative colitis (UC) gain weight after treatment. However, the clinical significance of weight gain in these patients remains unclear. This study aimed to evaluate body weight changes after treatment in patients newly diagnosed with moderate-to-severe UC and their effects on patients' prognosis. METHODS: The change in weight between diagnosis and 1 year after treatment in 212 patients enrolled in the MOSAIK cohort (mean age, 40 years; males, 60%) was analyzed. Significant weight gain was defined as a weight increase of ≥ 5% from the baseline at 1 year. Factors associated with significant weight gain and the effect of significant weight gain on the risk of major adverse outcomes (clinical relapse, hospitalization, and new use of steroids or biologics) during a follow-up period of 20 months were evaluated. RESULTS: Mean weight gain at 1 year was 1.7 ± 4.2 kg. The proportion of overweight/obese patients increased by 9.0% from 37.9% to 46.9%. Thirty-two percent had significant weight gain; extensive colitis at diagnosis was the only factor associated with significant weight gain (odds ratio 6.5, 95% confidence interval 1.4-31.0, p = 0.006). In multivariable analysis, significant weight gain was not associated with the risk of major adverse outcomes. Weight loss symptoms at diagnosis were associated with an increased risk for new steroid use after 1 year. CONCLUSIONS: Approximately one-third of patients with moderate-to-severe UC had significant weight gain after 1 year of treatment. However, significant weight gain was not associated with the patient's prognosis.

Primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD): a condition exemplifying the crosstalk of the gut-liver axis.

The close relationship between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) provides a good opportunity to comprehend the gut-liver axis. The gut and the liver have reciprocal interactions, including how gut inflammation influences the liver through immune cells and the microbiota and how the microbiota in the gut modifies bile acids, which are produced and secreted from the liver. PSC-IBD shows distinct clinical findings from classical IBD. In addition, a distinct genetic predisposition and unique microbiota composition suggest that PSC-IBD is an independent disease entity. Understanding the pathogenesis of PSC-IBD helps to develop novel and effective therapeutic agents. Given the high risk of malignancies associated with PSC-IBD, it is critical to identify patients at high risk and implement appropriate surveillance and monitoring strategies. In this review, we provide an overview of PSC-IBD, which exemplifies the gut-liver axis.

Treatment of primary sclerosing cholangitis combined with inflammatory bowel disease.

Primary sclerosing cholangitis (PSC) is a progressive cholestatic, inflammatory, and fibrotic disease that is strongly associated with inflammatory bowel disease (IBD). PSC-IBD represents a unique disease entity and patients with this disease have an increased risk of malignancy development, such as colorectal cancer and cholangiocarcinoma. The pathogenesis of PSC-IBD involves genetic and environmental factors such as gut dysbiosis and bile acids alteration. However, despite the advancement of disease characteristics, no effective medical therapy has proven to have a significant impact on the prognosis of PSC. The treatment options for patients with PSC-IBD do not differ from those for patients with PSC alone. Potential candidate drugs have been developed based on the pathogenesis of PSC-IBD, such as those that target modulation of bile acids, inflammation, fibrosis, and gut dysbiosis. In this review, we summarize the current medical treatments for PSC-IBD and the status of new emerging therapeutic agents.

Multivalent Carbohydrate Nanocomposites for Tumor Microenvironment Remodeling to Enhance Antitumor Immunity.

Current cancer immunotherapeutic strategies mainly focus on remodeling the tumor microenvironment (TME) to make it favorable for antitumor immunity. Increasing attention has been paid to developing innovative immunomodulatory adjuvants that can restore weakened antitumor immunity by conferring immunogenicity to inflamed tumor tissues. Here, a galactan-enriched nanocomposite (Gal-NC) is developed from native carbohydrate structures through an optimized enzymatic transformation for effective, stable, and biosafe innate immunomodulation. Gal-NC is characterized as a carbohydrate nanoadjuvant with a macrophage-targeting feature. It is composed of repeating galactan glycopatterns derived from heteropolysaccharide structures of plant origin. The galactan repeats of Gal-NC function as multivalent pattern-recognition sites for Toll-like receptor 4 (TLR4). Functionally, Gal-NC-mediated TLR activation induces the repolarization of tumor-associated macrophages (TAMs) toward immunostimulatory/tumoricidal M1-like phenotypes. Gal-NC increases the intratumoral population of cytotoxic T cells, the main effector cells of antitumor immunity, via re-educated TAMs. These TME alterations synergistically enhance the T-cell-mediated antitumor response induced by αPD-1 administration, suggesting that Gal-NC has potential value as an adjuvant for immune checkpoint blockade combination therapies. Thus, the Gal-NC model established herein suggests a glycoengineering strategy to design a carbohydrate-based nanocomposite for advanced cancer immunotherapies.

Mechanisms of interactions in pattern-recognition of common glycostructures across pectin-derived heteropolysaccharides by Toll-like receptor 4.

Complex pectin, originating from terrestrial plant cell walls has been attracting research attention as a promising source of a new innate immune modulator. Numerous bioactive polysaccharides associated with pectin are newly reported every year, but the general mechanism of their immunological action remains unclear owing to the complexity and heterogeneity of pectin. Herein, we systematically investigated the interactions in pattern-recognition for common glycostructures of pectic heteropolysaccharides (HPSs) by Toll-like receptors (TLRs). The compositional similarity of glycosyl residues derived from pectic HPS was confirmed by conducting systematic reviews, leading to molecular modeling of representative pectic segments. Via structural investigation, the inner concavity of leucine-rich repeats of TLR4 was predicted to act as a binding motif for carbohydrate recognition, and subsequent simulations predicted the binding modes and conformations. We experimentally demonstrated that pectic HPS exhibits the non-canonical and multivalent binding aspects for TLR4 resulting in receptor activation. Furthermore, we showed that pectic HPSs were selectively clustered with TLR4 during endocytosis, inducing downstream signals to cause phenotypic activation of macrophages. Overall, we have presented a better explanation for the pattern recognition of pectic HPS and further proposed an approach to understand the interaction between complex carbohydrates and proteins.

Changes in fecal metabolic and lipidomic features by anti-TNF treatment and prediction of clinical remission in patients with ulcerative colitis.

Background: Therapeutic targets for ulcerative colitis (UC) and prediction models of antitumor necrosis factor (TNF) therapy outcomes have not been fully reported. Objective: Investigate the characteristic metabolite and lipid profiles of fecal samples of UC patients before and after adalimumab treatment and develop a prediction model of clinical remission following adalimumab treatment. Design: Prospective, observational, multicenter study was conducted on moderate-to-severe UC patients (n = 116). Methods: Fecal samples were collected from UC patients at 8 and 56 weeks of adalimumab treatment and from healthy controls (HC, n = 37). Clinical remission was assessed using the Mayo score. Metabolomic and lipidomic analyses were performed using gas chromatography mass spectrometry and nano electrospray ionization mass spectrometry, respectively. Orthogonal partial least squares discriminant analysis was performed to establish a remission prediction model. Results: Fecal metabolites in UC patients markedly differed from those in HC at baseline and were changed similarly to those in HC during treatment; however, lipid profiles did not show these patterns. After treatment, the fecal characteristics of remitters (RM) were closer to those of HC than to those of non-remitters (NRM). At 8 and 56 weeks, amino acid levels in RM were lower than those in NRM and similar to those in HC. After 56 weeks, levels of 3-hydroxybutyrate, lysine, and phenethylamine decreased, and dodecanoate level increased in RM similarly to those in HC. The prediction model of long-term remission in male patients based on lipid biomarkers showed a higher performance than clinical markers. Conclusion: Fecal metabolites in UC patients markedly differ from those in HC, and the levels in RM are changed similarly to those in HC after anti-TNF therapy. Moreover, 3-hydroxybutyrate, lysine, phenethylamine, and dodecanoate are suggested as potential therapeutic targets for UC. A prediction model of long-term remission based on lipid biomarkers may help implement personalized treatment.