Feasibility of extracting cancer stage and metastasis codes from health insurance claims of outpatients and expressibility in ICD-11: a cross-sectional study using national health insurance data from South Korea.

OBJECTIVES: This study aimed to evaluate the incidence of health insurance claims recording the cancer stage and TNM codes representing tumor extension size (T), lymph node metastasis (N), and distant metastasis (M) for patients diagnosed with cancer and to determine whether this extracted data could be applied to the new ICD-11 codes. DESIGN: A cross-sectional study design was used, with the units of analysis as individual outpatients. Two dependent variables were extraction feasibility of cancer stage and TNM metastasis information from each claim. Expressibility of the two variables in ICD-11 was descriptively analysed. SETTING AND PARTICIPANTS: The study was conducted in South Korea and study participants were outpatients: lung cancer (LC) (46616), stomach cancer (SC) (50103) and colorectal cancer (CC) (54707). The data set consisted of the first health insurance claim of each patient visiting a hospital from 1 July to 31 December 2021. RESULTS: The absolute extraction success rates for cancer stage based on claims with cancer stage was 33.3%. The rates for stage for LC, SC and CC were 30.1%, 35.5% and 34.0%, respectively. The rate for TNM was 11.0%. The relative extraction success rates for stage compared with that for CC (the reference group) were lower for patients with LC (adjusted OR (aOR), 0.803; 95% CI 0.782 to 0.825; p<0.0001) but higher for SC (aOR 1.073; 95% CI 1.046 to 1.101; p<0.0001). The rates of TNM compared that for CC were 40.7% lower for LC (aOR, 0.593; 95% CI 0.569 to 0.617; p<0.0001) and 43.0% lower for SC (aOR 0.570; 95% CI 0.548 to 0.593; p<0.0001). There were limits to expressibility in ICD-11 regarding the detailed cancer stage and TNM metastasis codes. CONCLUSION: Extracting cancer stage and TNM codes from health insurance claims were feasible, but expressibility in ICD-11 codes was limited. WHO may need to create specific cancer stage and TNM extension codes for ICD-11 due to the absence of current rules in ICD-11.

Isoflavone-enriched soybean leaves (Glycine max) restore loss of dermal collagen fibers induced by ovariectomy in the Sprague Dawley rats.

Phytoestrogens, such as isoflavones, are known for their capacity to simulate various physiological impacts of estrogen in the human body. Our research evaluated the effects of isoflavone-enriched soybean leaves (IESL) on collagen fiber loss prompted by ovariectomy in Sprague Dawley (SD) rats, thereby simulating menopausal changes in women. IESL, bolstered with an increased concentration of isoflavones through a metabolite farming process, contained a significantly higher amount of isoflavones than regular soybean leaves. Our results indicate that the administration of IESL can counteract the decrease in relative optical density and dermal thickness of collagen fibers caused by ovariectomy in SD rats, with more pronounced effects observed at higher isoflavone dosages. These outcomes suggest that soybean leaves rich in isoflavones may hold potential benefits in combating collagen degradation and skin aging symptoms related to menopause. Further research is needed to fully understand the exact molecular pathways at play and the potential clinical relevance of these findings.

COX-2 Acts as a Key Mediator of Trifluoperazine-induced Cell Death in U87MG Glioma Cells.

BACKGROUND/AIM: Glioblastoma multiforme (GBM) is one of the most common brain tumors with a poor prognosis. Previously, we reported that trifluoperazine (TFP), a well-known antipsychotic, has anti-glioma activity through the modulation of intracellular calcium levels. The present study aimed to investigate the anti-cancer mechanism of action of TFP on glioma cells. MATERIALS AND METHODS: The effect of TFP on U87MG cells was examined using a viability assay, flow cytometry, enzyme-linked immunosorbent assay, quantitative real-time PCR, western blot analysis, colony formation, and immunocytochemistry. RESULTS: TFP treatment decreased cell viability. To test the possible involvement of COX-2 in the anticancer activity of TFP on U87MG cells, a COX-2 inhibitor was applied. COX-2 inhibitor pretreatment restored TFP-induced reduction in viability to the control level. Additionally, TFP-induced changes in the apoptotic cell population, production of prostaglandins (PGE2, PGD2, 15d-PGJ2), and nuclear translocation of peroxisome proliferator-activated receptor γ (PPARγ) were ameliorated by COX-2 inhibitor pretreatment. CONCLUSION: TFP suppressed the proliferation of U87MG glioma cell in a COX-2/PPARγ-dependent manner.

Trifluoperazine and Its Analog Suppressed the Tumorigenicity of Non-Small Cell Lung Cancer Cell; Applicability of Antipsychotic Drugs to Lung Cancer Treatment.

Despite significant advances in diagnostic and therapeutic technologies, lung cancer remains the leading cause of cancer-related mortality worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases. Recently, some antipsychotics have been shown to possess anticancer activity. However, the effects of antipsychotics on NSCLC need to be further explored. We examined the effects of trifluoperazine (TFP), a commonly used antipsychotic drug, and its synthetic analogs on A549 human lung cancer cells. In addition, cell proliferation analysis, colony formation assay, flow cytometry, western blot analysis, and in vivo xenograft experiments were performed. Key genes and mechanisms possibly affected by TFP are significantly related to better survival outcomes in lung cancer patients. Treatment with TFP and a selected TFP analog 3dc significantly inhibited the proliferation, anchorage-dependent/independent colony formation, and migration of A549 cells. Treatment with 3dc affected the expression of genes related to the apoptosis and survival of A549 cells. Treatment with 3dc promoted apoptosis and DNA fragmentation. In all experiments, including in vivo studies of metastatic lung cancer development, 3dc had more substantial anticancer effects than TFP. According to our analysis of publicly available clinical data and in vitro and in vivo experiments, we suggest that some kinds of antipsychotics prevent the progression of NSCLC. Furthermore, this study indicates a synthetic TFP analog that could be a potential therapeutic for lung cancer.

Resveratrol prevents hypoxia-induced retinal ganglion cell death related with ErbB2.

AIM: To confirm the changes in proteins related with hypoxia-induced retinal cell death and to assess the effects of resveratrol (Res). METHODS: The therapeutic effect of Res was verified using an ischemic/reperfusion (I/R) model in vivo and a hypoxia modelin retinal ganglion cells (RGCs) in vitro. Death of RGCs were confirmed by TUNEL assay. Protein expression was confirmed by Western blotting and immunohistochemistry. In addition, flow cytometric analysis was used to confirm the response in the cell unit to obtain more accurate data. RESULTS: ErbB2 expression and apoptosis in the ganglion cell layer (GCL) increased after I/R injury. Treatment of Res rescued I/R-induced ganglion cell death, downregulated apoptosis and ErbB2 protein expression in the retina. In subsequent in vitro models, Res affects apoptosis by regulating the phosphorylation and expression of mouse double minute 2 homolog (MDM2), along with those of ErbB2. These results suggest that Res reverses GCL-specific apoptosis via downregulation of ErbB2 in ischemic injury. CONCLUSION: In light of Res favorable properties, it should be evaluated in the treatment of RGC death and related retinal disease characterized by ErbB2 and MDM2 expression. Therefore, Res is appropriate therapeutic agent for treating ischemic injury-related eye diseases by targeting the expression of ErbB2 and MDM2.

CHI3L1 (YKL-40) is expressed in human gliomas and regulates the invasion, growth and survival of glioma cells.

Chitinase 3-like 1 (CHI3L1) is a secreted glycoprotein that has pleiotropic activity in aggressive cancers. In our study, we examined the expression and function of CHI3L1 in glioma cells. CHI3L1 was highly expressed in human glioma tissue, whereas its expression in normal brain tissue was very low. CHI3L1 suppression by shRNA reduced glioma cell invasion, anchorage-independent growth and increased cell death triggered by several anticancer drugs, including cisplatin, etoposide and doxorubicin, whereas CHI3L1 overexpression had the opposite effect in glioma cells. Because the invasive nature of glioma cells plays a critical role in the high morbidity of glioma, we have further defined the role of CHI3L1 in the process of glioma invasion. Downregulation of CHI3L1 results in decreased cell-matrix adhesion and causes a marked increase in stress fiber formation and cell size with fewer cellular processes. Furthermore, the expression and activity of matrix metalloproteinase-2 was also decreased in glioma cells in which CHI3L1 was knocked down. Taken together, these results suggest that CHI3L1 plays an important role in the regulation of malignant transformation and local invasiveness in gliomas. Thus, targeting the CHI3L1 molecule may be a potential therapeutic molecular target for gliomas.

4'-Acetoamido-4-hydroxychalcone, a chalcone derivative, inhibits glioma growth and invasion through regulation of the tropomyosin 1 gene.

Chalcones are precursors of flavonoids and have been shown to have anti-cancer activity. Here, we identify the synthetic chalcone derivative 4'-acetoamido-4-hydroxychalcone (AHC) as a potential therapeutic agent for the treatment of glioma. Treatment with AHC reduced glioma cell invasion, migration, and colony formation in a concentration-dependent manner. In addition, AHC inhibited vascular endothelial growth factor-induced migration, invasion, and tube formation in HUVECs. To determine the mechanism underlying the inhibitory effect of AHC on glioma cell invasion and migration, we investigated the effect of AHC on the gene expression change and found that AHC affects actin dynamics in U87MG glioma cells. In actin cytoskeleton regulating system, AHC increased tropomyosin expression and stress fiber formation, probably through activation of PKA. Suppression of tropomyosin expression by siRNA or treatment with the PKA inhibitor H89 reduced the inhibitory effects of AHC on glioma cell invasion and migration. In vivo experiments also showed that AHC inhibited tumor growth in a xenograft mouse tumor model. Together, these data suggest that the synthetic chalcone derivative AHC has potent anti-cancer activity through inhibition of glioma proliferation, invasion, and angiogenesis and is therefore a potential chemotherapeutic candidate for the treatment of glioma.

Phosphorylation of STAT3 and ERBB2 mediates hypoxia­induced VEGF release in ARPE­19 cells.

Neovascularization in the retina can cause loss of vision. Vascular endothelial growth factor (VEGF) serves an important role in the pathogenesis of retinal vascular diseases. Hypoxia is a notable cause of VEGF release and both STAT3 and ERBB2 are known to be associated with VEGF. In addition, STAT3 and ERBB2 interact with each other. In the present study, it was hypothesized that signal transducer and activator of transcription 3 (STAT3) and erbB­2 receptor tyrosine kinase 2 (ERBB2) may be involved in the regulation of hypoxia­induced VEGF in the retina. Cells of the retinal pigment epithelium (RPE) are an important source of VEGF. Therefore, the RPE­derived human cell line ARPE­19 was exposed to hypoxia. Hypoxia­induced phosphorylation of STAT3 and ERBB2 in ARPE­19 cells was decreased by AG490, an inhibitor of Janus kinase 2, as were hypoxia­induced VEGF release and tube formation in human umbilical vein endothelial cells. Thus, phosphorylation of ERBB2 and STAT3 regulates hypoxia­induced VEGF release in ARPE­19 cells. The results of the present study suggested that inhibition of ERBB2 and STAT3­mediated pathways under hypoxia may represent a new strategy for treating retinal vascular disease.

Resveratrol epigenetically regulates the expression of zinc finger protein 36 in non­small cell lung cancer cell lines.

Zinc finger protein 36 (ZFP36) is an AU­rich element protein that binds to 3'­untranslated regions and promotes the decay of target mRNAs. Downregulation of ZFP36 expression in turn results in stabilization of target mRNAs. A recent study indicated that downregulation of ZFP36 expression in human liver cancer is caused by epigenetic mechanisms. The purpose of the present study was to investigate the potential of resveratrol (Res) to induce ZFP36 expression. Promoter methylation was analyzed using methylation­sensitive restriction analysis. It was determined that Res treatment increased ZFP36 expression and decreased the mRNA levels of ZFP36 target genes in A549 lung cancer cells. Additionally, Res suppressed the expression of DNA (cytosine­5)­methyltransferase 1 and induced demethylation of the ZFP36 promoter. Collectively, the present results demonstrated that Res has anticancer activity through its epigenetic regulation of ZFP36 in non­small cell lung cancer.

Size distribution of serum extracellular vesicles in mice with atherosclerosis.

BACKGROUND AND AIMS: Atherosclerosis is a prominent vascular lesion, and potentially causing ischemic alterations in the brain and heart. Recent studies have reported that physiological and pathological alterations in atherosclerosis and extracellular vesicles (EV) are related. This study aimed to investigate the association between the extent of atherosclerotic lesions and the number of serum EVs in a mouse model of atherosclerosis (wild-type). METHODS: Eighteen 3-week-old C57BL/6 N male mice(wild-type) were purchased. Twelve mice were fed a 45% high-fat diet (HFD) for six months. Six mice were provided standard laboratory chow for six months. The entire aorta, from the aortic sinus to the division of the iliac artery, was dissected out from each mouse. Furthermore, the degree of atherosclerosis was microscopically determined. Serum EVs were quantified by size via nanoparticle tracking analysis. RESULTS: The number of EVs in the high-atherosclerotic score group (1.43 × 109) was higher than that in the low- atherosclerotic score group (0.7 × 109) in the range of 211.5-222.5 nm (p = 0.033). CONCLUSIONS: Enumeration of EVs is a potential method of detecting atherosclerosis.

Ethanol-induced oxidative stress is mediated by p38 MAPK pathway in mouse hippocampal cells.

It has been known that ethanol causes neuronal cell death through oxidative stress. Ethanol itself and reactive oxygen species (ROS) produced by ethanol modulate intracellular signaling pathways including mitogen-activated protein kinase (MAPK) cascades. This study was conducted to examine the impact of ethanol on MAPK signaling in HT22 cells. Ethanol (100 and 400mM) caused activation of ERK, p38 MAPK, and JNK. ERK activation occurred in early time and p38 MAPK activation was evident when ERK activation was diminished. Specific inhibitor of p38 MAPK (SB203580) protected HT22 cells against ethanol, which was accompanied by an inhibition of ROS accumulation. However, inhibitors of ERK (U0126) and JNK (SP600125) had no effects on ethanol-induced neuronal cell death when they are treated with ethanol for 24h. These results suggest that p38 MAPK may have important roles in ROS accumulation during ethanol-induced oxidative stress in HT22 cells.

Anti-diabetic Effects of Ethanol Extract from Bitter Melon in Mice Fed a High-fat Diet.

Present study aimed to determine the effect of 'bitter melon', a popularly used fruit in Bangladesh and several other Asian countries, on high-fat-diet-induced type 2 diabetes. To investigate the effect, ethanol extract from bitter melon (BME) as a dietary supplement with mouse chow was used. BME was found to significantly attenuate the high-fat diet (HFD) -induced body weight and total fat mass. BME also effectively reduced the insulin resistance induced by the HFD. Furthermore, dietary supplementation of BME was highly effective in increasing insulin sensitivity and reducing hepatic fat and obesity. These results indicate that BME could be effective in attenuating type 2 diabetes and could therefore be a preventive measure against type 2 diabetes.

Suppression of survival kinases and activation of JNK mediate ethanol-induced cell death in the developing rat brain.

Administration of ethanol to immature rat pups during the period in which synaptogenesis occurs triggers extensive apoptotic cell death in the brain. This ethanol-induced cell death is known to be mediated by Bax activation, which is caused by mitochondrial dysfunction. However, little data is available regarding the regulation of survival signaling pathways and their downstream events that lead to Bax activation. Thus, in the present study, we aimed to investigate the effect of ethanol on survival signaling pathways and their downstream events that lead to cell death in the rat brain during the brain developmental period. Ethanol (3 g/kg, 20% in saline) was administered subcutaneously to post-natal 7-day-old rat pups twice at 2-h intervals and the pups were sacrificed at 4 h following the first ethanol injection. Ethanol treatment suppressed the activation of survival kinases, particularly Akt, Erk1/2 and PKAalpha, whereas it increased the activation of JNK. Moreover, dissociation of dephosphorylated Bad from 14-3-3 and the interaction of activated JNK with Bcl-2 were elevated by ethanol treatment. The present study demonstrated that ethanol treatment during the brain developmental period induced mitochondrial dysfunction, which led to cell death by the suppression of survival kinases, Bad release from 14-3-3 and inactivation of Bcl-2 by activated JNK.

Effects of postnatal alcohol exposure on hippocampal gene expression and learning in adult mice.

Fetal alcohol syndrome (FAS) is a condition resulting from excessive drinking by pregnant women. Symptoms of FAS include abnormal facial features, stunted growth, intellectual deficits and attentional dysfunction. Many studies have investigated FAS, but its underlying mechanisms remain unknown. This study evaluated the relationship between alcohol exposure during the synaptogenesis period in postnatal mice and subsequent cognitive function in adult mice. We delivered two injections, separated by 2 h, of ethanol (3 g/kg, ethanol/saline, 20% v/v) to ICR mice on postnatal day 7. After 10 weeks, we conducted a behavioral test, sacrificed the animals, harvested brain tissue and analyzed hippocampal gene expression using a microarray. In ethanol-treated mice, there was a reduction in brain size and decreased neuronal cell number in the cortex, and also cognitive impairment. cDNA microarray results indicated that 1,548 genes showed a > 2-fold decrease in expression relative to control, whereas 974 genes showed a > 2-fold increase in expression relative to control. Many of these genes were related to signal transduction, synaptogenesis and cell membrane formation, which are highlighted in our findings.

Resveratrol suppresses vascular endothelial growth factor secretion via inhibition of CXC-chemokine receptor 4 expression in ARPE-19 cells.

The present study characterizes the effects of resveratrol (Res) on vascular endothelial growth factor (VEGF) secretion in retinal pigment epithelial (RPE) cells. ARPE-19 cells were treated with CoCl2, a hypoxia mimetic agent. CoCl2 treatment increased protein levels of hypoxia inducible factor-1α (HIF-1α) and CXC-chemokine receptor 4 (CXCR4), and secretion of VEGF. To confirm the effects of Res on VEGF secretion, the human umbilical vein endothelial cell tube formation assay was performed with conditioned medium from Res-treated ARPE-19 cells. The well-known antioxidant Res effectively blocked these effects and reduced phosphorylation of nuclear factor (NF)-κB, an upstream activator of CXCR4. Furthermore, Res also suppressed VEGF secretion induced by SDF-1, a ligand of CXCR4. Conditioned medium from Res-treated ARPE-19 cells clearly suppressed tube formation compared with hypoxia-treated conditioned medium. The results demonstrated that Res inhibited the hypoxia mimetic CoCl2-induced expression of VEGF in ARPE-19 cells. Res suppressed CXCR4 expression through decreased phosphorylation of NF-κB, resulting in downregulation of VEGF secretion.

Resveratrol Induces Glioma Cell Apoptosis through Activation of Tristetraprolin.

Tristetraprolin (TTP) is an AU-rich elements (AREs)-binding protein, which regulates the decay of AREs-containing mRNAs such as proto-oncogenes, anti-apoptotic genes and immune regulatory genes. Despite the low expression of TTP in various human cancers, the mechanism involving suppressed expression of TTP is not fully understood. Here, we demonstrate that Resveratrol (3,5,4'-trihydroxystilbene, Res), a naturally occurring compound, induces glioma cell apoptosis through activation of tristetraprolin (TTP). Res increased TTP expression in U87MG human glioma cells. Res-induced TTP destabilized the urokinase plasminogen activator and urokinase plasminogen activator receptor mRNAs by binding to the ARE regions containing the 3' untranslated regions of their mRNAs. Furthermore, TTP induced by Res suppressed cell growth and induced apoptosis in the human glioma cells. Because of its regulation of TTP expression, these findings suggest that the bioactive dietary compound Res can be used as a novel anti-cancer agent for the treatment of human malignant gliomas.

Tristetraprolin inhibits the growth of human glioma cells through downregulation of urokinase plasminogen activator/urokinase plasminogen activator receptor mRNAs.

Urokinase plasminogen activator (uPA) and urokinase plasminogen activator receptor (uPAR) play a major role in the infiltrative growth of glioblastoma. Downregulatoion of the uPA and uPAR has been reported to inhibit the growth glioblastoma. Here, we demonstrate that tristetraprolin (TTP) inhibits the growth of U87MG human glioma cells through downregulation of uPA and uPAR. Our results show that expression level of TTP is inversely correlated with those of uPA and uPAR in human glioma cells and tissues. TTP binds to the AU-rich elements within the 3' untranslated regions of uPA and uPAR and overexpression of TTP decreased the expression of uPA and uPAR through enhancing the degradation of their mRNAs. In addition, overexpression of TTP inhibited the growth and invasion of U87MG cells. Our findings implicate that TTP can be used as a promising therapeutic target to treat human glioma.

Vertical distance between umbilicus to aortic bifurcation on coronal view in Korean women.

OBJECTIVE: To evaluate the vertical distance between umbilicus to aortic bifurcation on coronal view in Korean women and their relation with body mass index (BMI) and woman's age. METHODS: This retrospective study included 257 women who visited emergency center at university-based hospital from January to December 2011. All women underwent abdomino-pelvic computerized tomography (CT) due to various symptoms in a supine position. By using the electronic coronal CT images, the vertical distance between umbilicus and aortic bifurcation was measured. If aortic bifurcation was located below umbilicus, the distance was expressed as minus value (i.e., caudal to umbilicus). Age of woman, body weight, height and calculated BMI (kg/m(2)) were also recorded. RESULTS: Aortic bifurcation was located caudal to umbilicus in 52.9% and cephalad to umbilicus in 37.4%. The vertical distance had a negative relationship with BMI (r=.0.180, P=0.004), as well as woman's age (r=-0.382, P<0.001). However, a multivariate analysis revealed that the vertical distance had a significant negative relationship with woman's age (P<0.001) but not with BMI (P=0.510). An equation could be drawn to estimate the vertical distance by using woman's age and BMI: vertical distance (mm)=12.6-0.3×(age)-0.2×(BMI). CONCLUSION: The vertical distance from umbilicus to aortic bifurcation on coronal view showed a significant inverse correlation with woman's age, however, the distances varied widely. Most older or obese Korean women had aortic bifurcation caudal to umbilicus.

Effects of chronic restraint stress on body weight, food intake, and hypothalamic gene expressions in mice.

BACKGROUND: Stress affects body weight and food intake, but the underlying mechanisms are not well understood. METHODS: We evaluated the changes in body weight and food intake of ICR male mice subjected to daily 2 hours restraint stress for 15 days. Hypothalamic gene expression profiling was analyzed by cDNA microarray. RESULTS: Daily body weight and food intake measurements revealed that both parameters decreased rapidly after initiating daily restraint stress. Body weights of stressed mice then remained significantly lower than the control body weights, even though food intake slowly recovered to 90% of the control intake at the end of the experiment. cDNA microarray analysis revealed that chronic restraint stress affects the expression of hypothalamic genes possibly related to body weight control. Since decreases of daily food intake and body weight were remarkable in days 1 to 4 of restraint, we examined the expression of food intake-related genes in the hypothalamus. During these periods, the expressions of ghrelin and pro-opiomelanocortin mRNA were significantly changed in mice undergoing restraint stress. Moreover, daily serum corticosterone levels gradually increased, while leptin levels significantly decreased. CONCLUSION: The present study demonstrates that restraint stress affects body weight and food intake by initially modifying canonical food intake-related genes and then later modifying other genes involved in energy metabolism. These genetic changes appear to be mediated, at least in part, by corticosterone.

PKCη Regulates the TGFß3-induced Chondevrepogenic Differentiation of Human Mesenchymal Stem Cell.

Transforming growth factor (TGF) family is well known to induce the chondevrepogenic differentiation of mesenchymal stem cells (MSC). However, the precise signal transduction pathways and underlying factors are not well known. Thus the present study aims to evaluate the possible role of C2 domain in the chondevrepogenic differentiation of human mesenchymal stem cells. To this end, 145 C2 domains in the adenovirus were individually transfected to hMSC, and morphological changes were examined. Among 145 C2 domains, C2 domain of protein kinase C eta (PKCη) was selected as a possible chondevrepogenic differentiation factor for hMSC. To confirm this possibility, we treated TGFß3, a well known chondevrepogenic differentiation factor of hMSC, and examined the increased-expression of glycosaminoglycan (GAG), collagen type II (COL II) as well as PKCη using PT-PCR, immunocytochemistry and Western blot analysis. To further evaluation of C2 domain of PKCη, we examined morphological changes, expressions of GAG and COL II after transfection of PKCη -C2 domain in hMSC. Overexpression of PKCη-C2 domain induced morphological change and increased GAG and COL II expressions. The present results demonstrate that PKCη involves in the TGF-ß3-induced chondevrepogenic differentiation of hMSC, and C2 domain of PKCη has important role in this process.