Fracture Risk Among Stroke Survivors According to Poststroke Disability Status and Stroke Type.

BACKGROUND: Stroke survivors face physical and cognitive challenges, leading to an increased dependency and a higher fall risk. We aimed to investigate the impact of poststroke disability and stroke type on fracture risk at various sites compared with matched controls. METHODS: This retrospective cohort study used data from the Korean National Health Insurance System database (2010-2018), including patients with stroke and 1:1 matched controls. Stroke survivors were grouped based on the presence and severity of their poststroke disability and stroke type. The primary outcome was a newly diagnosed fracture, analyzed by Cox proportional hazard regression analyses adjusting for potential confounders. RESULTS: Among 223 358 stroke survivors (mean age, 64.8±10.9 years; 61.2% men), 16 344 fractures occurred during a mean follow-up of 3.7±2.5 years. In matched controls (n=322 161; mean age, 65.4±11.2 years; 61.3% men), 20 398 fractures were identified. Stroke survivors had increased overall fracture risk compared with matched controls (adjusted hazard ratio [aHR], 1.40 [95% CI, 1.37-1.43]). Specifically, hip fracture risk was even greater in stroke survivors (incidence rate per 1000 person-years, 4.7 [95% CI, 4.5-4.8]; aHR, 2.42 [95% CI, 2.30-2.55]) than controls (incidence rate, 2.2 [95% CI, 2.1-2.3]). The risk of vertebral fractures (aHR, 1.29 [95% CI, 1.25-1.34]) and other fractures (aHR, 1.19 [95% CI, 1.15-1.23]) was also higher than that of the control group. Hip fracture risk was the highest among stroke survivors with severe poststroke disability (aHR, 4.82 [95% CI, 4.28-5.42]), although vertebral or other fracture risk was the highest among those with mild poststroke disability. No significant difference in fracture risk was found between hemorrhagic and ischemic stroke survivors when stratified by disability status. CONCLUSIONS: Our findings showed increased subsequent fracture risk among stroke survivors, particularly those with poststroke disability and for hip fracture. Bone health assessment and treatment should be emphasized as an essential part of stroke management.

Tubulointerstitial nephritis antigen-like 1 from cancer-associated fibroblasts contribute to the progression of diffuse-type gastric cancers through the interaction with integrin ß1.

BACKGROUND: Tumor cells of diffuse-type gastric cancer (DGC) are discohesive and infiltrate into the stroma as single cells or small subgroups, so the stroma significantly impacts DGC progression. Cancer-associated fibroblasts (CAFs) are major components of the tumor stroma. Here, we identified CAF-specific secreted molecules and investigated the mechanism underlying CAF-induced DGC progression. METHODS: We conducted transcriptome analysis for paired normal fibroblast (NF)-CAF isolated from DGC patient tissues and proteomics for conditioned media (CM) of fibroblasts. The effects of fibroblasts on cancer cells were examined by transwell migration and soft agar assays, western blotting, and in vivo. We confirmed the effect of blocking tubulointerstitial nephritis antigen-like 1 (TINAGL1) in CAFs using siRNA or shRNA. We evaluated the expression of TINAGL1 protein in frozen tissues of DGC and paired normal stomach and mRNA in formalin-fixed, paraffin-embedded (FFPE) tissue using RNA in-situ hybridization (RNA-ISH). RESULTS: CAFs more highly expressed TINAGL1 than NFs. The co-culture of CAFs increased migration and tumorigenesis of DGC. Moreover, CAFs enhanced the phosphorylation of focal adhesion kinase (FAK) and mesenchymal marker expression in DGC cells. In an animal study, DGC tumors co-injected with CAFs showed aggressive phenotypes, including lymph node metastasis. However, increased phosphorylation of FAK and migration were reduced by blocking TINAGL1 in CAFs. In the tissues of DGC patients, TINAGL1 was higher in cancer than paired normal tissues and detected with collagen type I alpha 1 chain (COL1A1) in the same spot. Furthermore, high TINAGL1 expression was significantly correlated with poor prognosis in several public databases and our patient cohort diagnosed with DGC. CONCLUSIONS: These results indicate that TINAGL1 secreted by CAFs induces phosphorylation of FAK in DGC cells and promotes tumor progression. Thus, targeting TINAGL1 in CAFs can be a novel therapeutic strategy for DGC.

Characterization of gastric cancer-stimulated signaling pathways and function of CTGF in cancer-associated fibroblasts.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME) that play an important role in cancer progression. Although the mechanism by which CAFs promote tumorigenesis has been well investigated, the underlying mechanism of CAFs activation by neighboring cancer cells remains elusive. In this study, we aim to investigate the signaling pathways involved in CAFs activation by gastric cancer cells (GC) and to provide insights into the therapeutic targeting of CAFs for overcoming GC. METHODS: Alteration of receptor tyrosine kinase (RTK) activity in CAFs was analyzed using phospho-RTK array. The expression of CAFs effector genes was determined by RT-qPCR or ELISA. The migration and invasion of GC cells co-cultured with CAFs were examined by transwell migration/invasion assay. RESULTS: We found that conditioned media (CM) from GC cells could activate multiple receptor tyrosine kinase signaling pathways, including ERK, AKT, and STAT3. Phospho-RTK array analysis showed that CM from GC cells activated PDGFR tyrosine phosphorylation, but only AKT activation was PDGFR-dependent. Furthermore, we found that connective tissue growth factor (CTGF), a member of the CCN family, was the most pronouncedly induced CAFs effector gene by GC cells. Knockdown of CTGF impaired the ability of CAFs to promote GC cell migration and invasion. Although the PDGFR-AKT pathway was pronouncedly activated in CAFs stimulated by GC cells, its pharmacological inhibition affected neither CTGF induction nor CAFs-induced GC cell migration. Unexpectedly, the knockdown of SRC and SRC-family kinase inhibitors, dasatinib and saracatinib, significantly impaired CTGF induction in activated CAFs and the migration of GC cells co-cultured with CAFs. SRC inhibitors restored the reduced expression of epithelial markers, E-cadherin and Zonula Occludens-1 (ZO-1), in GC cells co-cultured with CAFs, as well as CAFs-induced aggregate formation in a 3D tumor spheroid model. CONCLUSIONS: This study provides a characterization of the signaling pathways and effector genes involved in CAFs activation, and strategies that could effectively inhibit it in the context of GC. Video Abstract.

Current practices and perceived effectiveness of polynucleotides for treatment of facial erythema by cosmetic physicians.

BACKGROUND: Polynucleotides (PN) are increasingly used for the treatment of facial erythema in the Republic of Korea. However, there are limited pre-clinical and clinical data on the efficacy of polynucleotides for facial erythema. In this study, we investigated the current practice and perceived effectiveness of polynucleotide treatment for facial erythema among cosmetic physicians. METHODS: By conducting a survey among clinicians who use PN in clinical practice, we explored the current practices and assessed the perceived effectiveness of polynucleotides in treating facial erythema. RESULTS: A total of 557 physicians who used polynucleotides for facial erythema participated in the survey. Polynucleotides were used by 84.4%, 66.4%, and 47.4% of physicians for facial erythema caused by inflammatory facial dermatosis, repeated laser/microneedle radiofrequency, and steroid overuse, respectively. Among those users, 88.1%, 90%, and 83.7% respectively in those same categories answered that polynucleotides were "highly effective" or "effective." Furthermore, they agreed that polynucleotides have the following properties: wound healing/regeneration (95.8%), protection of skin barrier (92.2%), hydration (90.5%), vascular stabilization (81.0%), and anti-inflammation (79.5%). CONCLUSION: Our findings showed that cosmetic physicians in the Republic of Korea have used PN as a part of combination treatment for facial erythema resulting from inflammatory facial dermatosis and repeated laser/ microneedle radiofrequency, rather than from steroid overuse. Also, most clinicians agreed that PN was effective for treatment of facial erythema. Given the lack of pre-clinical and clinical trial evidence, the empirical responses of practicing physicians provide useful information to guide clinical practice and further research.

Inhibiting the GAS6/AXL axis suppresses tumor progression by blocking the interaction between cancer-associated fibroblasts and cancer cells in gastric carcinoma.

BACKGROUND: The effects of cancer-associated fibroblasts (CAF) on the progression of gastric carcinoma (GC) has recently been demonstrated. However, agents targeting the interaction between CAF and GC cells have not been applied in a clinical setting. Here, we examined if inhibition for Axl receptor tyrosine kinase (AXL) can suppress CAF-induced aggressive phenotype in GC. METHODS: We investigated the function of CAF-derived growth arrest-specific 6 (GAS6), a major ligand of AXL, on the migration and proliferation of GC cells. The effect of the AXL inhibitor, BGB324, on the CAF-induced aggressive phenotype of GC cells was also investigated. In addition, we performed immunohistochemistry to examine the expression of phosphorylated AXL protein in 175 GC tissues and evaluated its correlation with the prognosis. RESULTS: The qPCR and western blot analysis showed that GAS6 expression was higher in CAF relative to other cells. We found that co-culture with CAF increased the phosphorylation of AXL (P-AXL), differentiation into a mesenchymal-like phenotype, and cell survival in GC cell lines. When the expression of AXL was genetically inhibited in GC cells, the effect of CAF was reduced. BGB324, a small molecule inhibitor of AXL, suppressed the effects of CAF on GC cell lines. In GC tissues, high levels of P-AXL were significantly associated with poor overall survival (P = 0.022). CONCLUSIONS: We concluded that CAF are a major source of GAS6 and that GAS6 promotes an aggressiveness through AXL activation in GC. We suggested that an AXL inhibitor may be a novel agent for GC treatment.

Association of Body Image Distortion with Smartphone Dependency and Usage Time in Adolescents: A Cross-Sectional Korean Youth Study.

Background: Adolescent dependency on smartphones is the highest among all age groups. Adolescents can be influenced to evaluate their body image by popular ideals about beautiful bodies via smartphone content, which can cause body image distortion. This study aimed to examine the association between body image distortion and smartphone dependency and the duration of smartphone usage among Korean adolescents. Methods: This study used data from the 16th Korean Youth Risk Behavior Web-Based Survey (2020), and included 42,981 participants, who were grouped according to self-reported duration of smartphone usage and smartphone dependency, as measured by a questionnaire. Body image distortion is defined as an exaggerated subjective body image compared to the actual body image. Multivariable-adjusted logistic regression was used to determine the odds ratios (ORs) with 95% confidence intervals (CIs) of body image distortion on smartphone dependency and usage time after adjusting for various factors related to body image distortion. Results: Among the 42,981 participants, both moderate and high levels of smartphone dependency were associated with body image distortion in boys (moderate: adjusted OR [aOR], 1.11; 95% CI, 1.01-1.22; high: aOR, 1.18; 95% CI, 1.05-1.32) and girls (moderate: aOR, 1.14; 95% CI, 1.05-1.23; high: aOR, 1.30; 95% CI, 1.18-1.42) compared to the low-level dependency group. However, no significant association was found between smartphone usage duration and body image distortion. Conclusion: Our study demonstrated that moderate to high levels of smartphone dependency are associated with body image distortion in adolescents. Therefore, it is necessary to establish strategies for checking and managing adolescents' smartphone dependence.

Changes in the Prevalence of Metabolic Syndrome before and after the COVID-19 Pandemic According to Household Income Levels.

Background: Since the World Health Organization's pandemic declaration in March 2020, Korea has witnessed shifts in lifestyle behaviors, impacting habits tied to socioeconomic status and contributing to metabolic syndrome (MetS). To investigate this issue, the current study aimed to investigate changes in MetS prevalence, particularly based on income levels before and after the coronavirus disease 2019 (COVID-19) pandemic. Methods: This study used data from the 8th Korea National Health and Nutrition Examination Survey (2019-2020). A total of 6,840 individuals aged 30-65 years were included in this study. Household income was divided into high (≥75th percentile), middle (25-75th percentile), and low (≤25th percentile). A multivariable logistic regression analysis was performed to explore the interaction between this association before and after the COVID-19 pandemic. Results: A statistically significant difference was found in the prevalence of MetS before and after the COVID-19 pandemic (26.7% to 30.2%, P=0.001). These changes differed based on income levels. The increase in the prevalence of MetS was statistically significant in the low- and high-income groups but not in the middle-income group (low: 8.0%p increase [P=0.039], middle: 1.0%p increase [P=0.522], high: 6.4%p increase [P<0.001]). The interaction between household income and the COVID-19 pandemic on MetS was statistically significant (P for interaction= 0.032). Conclusion: This study revealed that P for interaction between household income, MetS, and the period before and after the COVID-19 pandemic was significant. Changes in physical activity and eating habits during the COVID- 19 pandemic may have contributed to these differences.

Exploring age-standardized cancer incidence rates and regional disparities: A retrospective cohort study of 8 major cancers in South Korea.

BACKGROUND: We analyzed trends in cancer incidence and regional disparities of eight major types of cancer in Korea. METHODS: This retrospective cohort study used the data of 17 cities/provinces from the Korea Central Cancer Registry (1999-2020) in South Korea. Age-standardized incidence rates (per 100,000 person-years), between-group variance (per 100,000 person-years)2, and annual percentage changes ( %) were calculated for the eight most common malignancies. Joinpoint regression was utilized to identify the points at which significant changes occur in cancer incidence or regional disparity trends over time to characterize these trends. RESULTS: The incidence of stomach cancer decreased as regional disparity decreased and that of colorectal cancer initially increased but recently declined, showing fluctuations in regional disparity. The incidence and regional disparity in liver cancer decreased. The incidence of lung cancer remained stable, with reduced regional disparities. The incidence of breast cancer rose with increasing regional disparity, whereas the incidence of cervical cancer decreased, accompanied by decreased regional disparity. A significant increase in prostate cancer was found, with initially reduced regional disparities but later showed a resurgence. The incidence of thyroid cancer fluctuated alongside variations in regional disparities. CONCLUSION: This study revealed cancer incidence and regional variations in each cancer type in Korea. More studies are needed to understand the underlying factors and potential interventions for reducing cancer incidence and addressing regional disparity.

Association of Coffee or Green Tea with Ferritin or Hemoglobin in Premenopausal Women.

BACKGROUND: This study aimed to examine the association between coffee or green tea consumption and ferritin or hemoglobin levels in premenopausal women. METHODS: We used the fifth Korea National Health and Nutrition Examination Survey (2010-2012), and a total of 4,322 individuals were surveyed. In women of reproductive age, average ferritin and hemoglobin levels were calculated according to coffee or green tea consumption. Covariates included in the analysis were demographic variables, such as age, body mass index, education, drinking, smoking, history of hypertension, history of diabetes diagnosis, physical activity, total energy intake, and daily iron intake. RESULTS: In 4,322 participants, the average hemoglobin level was 12.90±0.02 g/dL, and the average level of ferritin was 31.95±0.67 ng/mL. As a result of testing, correlation between ferritin and coffee intake and difference in ferritin levels according to coffee consumption was significant (P<0.05). In this study, a post hoc test indicated that ferritin level significantly differed between one and two cups, two and three cups, and three and one cup groups (overall P<0.001). Additionally, there was a negative correlation between ferritin level and coffee intake; ferritin level decreased by 2.09 ng/mL with a one-cup increase in daily coffee consumption. CONCLUSION: In premenopausal women, coffee intake is associated with low serum ferritin levels. Our results indicate that drinking >2 cups of coffee significantly affect ferritin levels in Korean premenopausal women.

Molecular and Immune Profiling of Syngeneic Mouse Models Predict Response to Immune Checkpoint Inhibitors in Gastric Cancer.

PURPOSE: Appropriate preclinical mouse models are needed to evaluate the response to immunotherapeutic agents. Immunocompetent mouse models have rarely been reported for gastric cancer. Thus, we investigated immunophenotypes and responses to immune checkpoint inhibitor (ICI) in immunocompetent mouse models using various murine gastric cancer cell lines. MATERIALS AND METHODS: We constructed subcutaneous syngeneic tumors with murine gastric cancer cell lines, YTN3 and YTN16, in C57BL/6J mice. Mice were intraperitoneally treated with IgG isotype control or an anti-programmed death-ligand 1 (PD-L1) neutralizing antibody. We used immunohistochemistry to evaluate the tumor-infiltrating immune cells of formalin-fixed paraffin-embedded mouse tumor tissues. We compared the protein and RNA expression between YTN3 and YTN16 cell lines using a mouse cytokine array and RNA sequencing. RESULTS: The mouse tumors revealed distinct histological and molecular characteristics. YTN16 cells showed upregulation of genes and proteins related to immunosuppression, such as Ccl2 (CCL2) and Csf1 (M-CSF). Macrophages and exhausted T cells were more enriched in YTN16 tumors than in YTN3 tumors. Several YTN3 tumors were completely regressed by the PD-L1 inhibitor, whereas YTN16 tumors were unaffected. Although treatment with a PD-L1 inhibitor increased infiltration of T cells in both the tumors, the proportion of exhausted immune cells did not decrease in the non-responder group. CONCLUSION: We confirmed the histological and molecular features of cancer cells with various responses to ICI. Our models can be used in preclinical research on ICI resistance mechanisms to enhance clinical efficacy.

Targeting GAS6/AXL signaling improves the response to immunotherapy by restoring the anti-immunogenic tumor microenvironment in gastric cancer.

AIMS: Immunotherapy has shown remarkable effects on several malignancies; however, its impact on gastric cancers has been limited. Therefore, a novel strategy to overcome resistance to immunotherapy is required. In this study, we compared the gene expression profiles of two murine GC cell lines that exhibited different effects on tumor immunity. The functions of specific genes related to negative tumor immunity and the impact of a specific inhibitor were evaluated in syngeneic GC mouse models. MATERIALS AND METHODS: RT-PCR and Western blotting validated Gas6 and AXL expression in murine cell lines. RT-PCR compared YTN16 and YTN3 GC cell's impact on T cell activation. AXL, the receptor for GAS6 in YTN16, was validated by western blotting. Gas6 was inhibited in YTN16 cells using shRNA, and then the gene expression pattern, effects to T cell activation, and tumor growth were assessed. YTN16 cells were injected into mice and treated with CCB-3233, anti-PD-1 antibody, or both. Immunohistochemistry and flow cytometry evaluated tumor-infiltrating immune cells. KEY FINDINGS: YTN16 cells expressed more Gas6 and had reduced T cell activation compared to YTN3 cells. AXL activation was higher in YTN16. CCB-3233 reduced AXL phosphorylation. Knocking down Gas6 in YTN16 reduced immunosuppression-related genes and increased tumor-infiltrating T cells. Combined CCB-3233 and anti-PD-1 treatment reduced tumor growth and increased T-cell infiltration. Human GC data revealed a negative correlation between GAS6 and immune activation-related genes. SIGNIFICANCE: The GAS6/AXL pathway contributes to immunotherapy resistance in GC. Targeting this pathway may be a novel therapeutic strategy.

Curcumin inhibits the cancer­associated fibroblast­derived chemoresistance of gastric cancer through the suppression of the JAK/STAT3 signaling pathway.

The present study aimed to investigate whether the Janus­activated kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway is a critical mechanism underlying the cancer­associated fibroblast (CAF)­induced chemoresistance of gastric cancer (GC). In addition, the present study tried to suggest a natural product to compromise the effects of CAF on the chemoresistance of GC. The results of cell proliferation assay revealed that the conditioned medium (CM) collected from CAFs further increased resistance to 5­fluorouracil (5­FU) in GC cell lines. Secretome analysis revealed that the levels of several secreted proteins, including C­C motif chemokine ligand 2, C­X­C motif chemokine ligand 1, interleukin (IL)­6 and IL­8, were increased in the CM from CAFs co­cultured with cancer cells compared to CM from cancer cells. Western blot analysis revealed that CAFs activated the JAK/STAT3 signaling pathway in cancer cells. The experimental models revealed that curcumin abrogated the CAF­mediated activation of the JAK/STAT3 signaling pathway in GC cells. In vivo data revealed the synergistic effects of curcumin with 5­FU treatment in xenograft GC tumors. These data strongly suggest that the suppression of the JAK/STAT3 signaling pathway counteracts the CAF­induced chemoresistance of GC cells. It is suggested that curcumin may be a suitable natural product which may be used to overcome chemoresistance by inhibiting the CAF­induced activation of the JAK/STAT3 signaling pathway in GC.

The EEF1AKMT3/MAP2K7/TP53 axis suppresses tumor invasiveness and metastasis in gastric cancer.

The importance of methylation in the tumorigenic responses of nonhistone proteins, such as TP53, PTEN, RB1, AKT, and STAT3, has been emphasized in numerous studies. In parallel, the corresponding nonhistone protein methyltransferases have been acknowledged in the pathophysiology of cancer. Thus, this study aimed to explore the pathological role of a nonhistone methyltransferase in gastric cancer (GC), identify nonhistone substrate protein, and understand the underlying mechanism. Interestingly, among the 24 methyltransferases and methyltransferase family 16 (MTF16) proteins, EEF1AKMT3 (METTL21B) expression was prominently lower in GC tissues than in normal adjacent tissues and was associated with a worse prognosis. In addition, EEF1AKMT3-knockdown induced gastric tumor invasiveness and migration. Through gain and loss-of-function studies, mass spectrometry analysis, RNA-seq, and phospho-antibody array, we identified EEF1AKMT3 as a novel tumor-suppressive methyltransferase that catalyzes the monomethylation of MAP2K7 (MKK7) at K296, thereby decreasing the phosphorylation, ubiquitination, and degradation of TP53. Furthermore, EEF1AKMT3, p-MAP2K7, and TP53 protein levels were positively correlated in GC tissues. Collectively, our results delineate the tumor-suppressive function of the EEF1AKMT3/MAP2K7/TP53 signaling axis and suggest the dysregulation of the signaling axis as potential targeted therapy in GC.

Cancer-Associated Fibroblast-Induced Resistance to Chemotherapy and Radiotherapy in Gastrointestinal Cancers.

In the past few decades, the role of cancer-associated fibroblasts (CAFs) in resistance to therapies for gastrointestinal (GI) cancers has emerged. Clinical studies focusing on GI cancers have revealed that the high expression of CAF-related molecules within tumors is significantly correlated with unfavorable therapeutic outcomes; however, the exact mechanisms whereby CAFs enhance resistance to chemotherapy and radiotherapy in GI cancers remain unclear. The cells of origin of CAFs in GI cancers include normal resident fibroblasts, mesenchymal stem cells, endothelial cells, pericytes, and even epithelial cells. CAFs accumulated within GI cancers produce cytokines, chemokines, and growth factors involved in resistance to therapies. CAF-derived exosomes can be engaged in stroma-related resistance to treatments, and several non-coding RNAs, such as miR-92a, miR-106b, CCAL, and H19, are present in CAF-derived exosomes and transferred to GI cancer cells. The CAF-induced desmoplastic reaction interferes with drug delivery to GI cancer cells, evoking resistance to chemotherapy. However, due to the heterogeneity of CAFs in GI cancers, identifying the exact mechanism underlying CAF-induced resistance may be difficult. Recent advancements in single-cell "omics" technologies could offer clues for revealing the specific subtypes and biomarkers related to resistance.

Role of Cancer-Associated Fibroblast in Gastric Cancer Progression and Resistance to Treatments.

Although the survival of gastric cancer (GC) patients has gradually improved, the outcomes of advanced GC patients remain unsatisfactory despite standard treatment with conventional chemotherapy or targeted agents. Several studies have shown that cancer-associated fibroblasts (CAFs), a major component of tumor stroma in GC, may have significant roles in GC progression and resistance to treatments. CAFs are a major source of various secreted molecules in the tumor microenvironment, which stimulate cancer cells and other noncancerous components of GC. Surprisingly, these factors could be involved in gastric carcinogenesis. Cytokines, including interleukin-6 and interleukin-11, or growth factors, such as fibroblast growth factor produced from CAFs, can directly activate GC cells and consequently lead to the development of an aggressive phenotype. Galectin-1 or hepatocyte growth factor can be involved in CAF-derived neovascularization in GC. In addition, recent studies showed that CAFs can affect tumor immunity through M2 polarization of tumor-associated macrophages. Finally, the current study aimed to introduce several inhibitory agents and evaluate their suppressive effects on CAFs in patients with GC progression. However, further studies are required to evaluate their safety and select appropriate patients for application in clinical settings.