Machine learning-based prediction model for postoperative delirium in non-cardiac surgery.

BACKGROUND: Postoperative delirium is a common complication that is distressing. This study aimed to demonstrate a prediction model for delirium. METHODS: Among 203,374undergoing non-cardiac surgery between January 2011 and June 2019 at Samsung Medical Center, 2,865 (1.4%) were diagnosed with postoperative delirium. After comparing performances of machine learning algorithms, we chose variables for a prediction model based on an extreme gradient boosting algorithm. Using the top five variables, we generated a prediction model for delirium and conducted an external validation. The Kaplan-Meier and Cox survival analyses were used to analyse the difference of delirium occurrence in patients classified as a prediction model. RESULTS: The top five variables selected for the postoperative delirium prediction model were age, operation duration, physical status classification, male sex, and surgical risk. An optimal probability threshold in this model was estimated to be 0.02. The area under the receiver operating characteristic (AUROC) curve was 0.870 with a 95% confidence interval of 0.855-0.885, and the sensitivity and specificity of the model were 0.76 and 0.84, respectively. In an external validation, the AUROC was 0.867 (0.845-0.877). In the survival analysis, delirium occurred more frequently in the group of patients predicted as delirium using an internal validation dataset (p < 0.001). CONCLUSION: Based on machine learning techniques, we analyzed a prediction model of delirium in patients who underwent non-cardiac surgery. Screening for delirium based on the prediction model could improve postoperative care. The working model is provided online and is available for further verification among other populations. TRIAL REGISTRATION: KCT 0006363.

Accuracy of Cloud-Based Speech Recognition Open Application Programming Interface for Medical Terms of Korean.

BACKGROUND: There are limited data on the accuracy of cloud-based speech recognition (SR) open application programming interfaces (APIs) for medical terminology. This study aimed to evaluate the medical term recognition accuracy of current available cloud-based SR open APIs in Korean. METHODS: We analyzed the SR accuracy of currently available cloud-based SR open APIs using real doctor-patient conversation recordings collected from an outpatient clinic at a large tertiary medical center in Korea. For each original and SR transcription, we analyzed the accuracy rate of each cloud-based SR open API (i.e., the number of medical terms in the SR transcription per number of medical terms in the original transcription). RESULTS: A total of 112 doctor-patient conversation recordings were converted with three cloud-based SR open APIs (Naver Clova SR from Naver Corporation; Google Speech-to-Text from Alphabet Inc.; and Amazon Transcribe from Amazon), and each transcription was compared. Naver Clova SR (75.1%) showed the highest accuracy with the recognition of medical terms compared to the other open APIs (Google Speech-to-Text, 50.9%, P < 0.001; Amazon Transcribe, 57.9%, P < 0.001), and Amazon Transcribe demonstrated higher recognition accuracy compared to Google Speech-to-Text (P < 0.001). In the sub-analysis, Naver Clova SR showed the highest accuracy in all areas according to word classes, but the accuracy of words longer than five characters showed no statistical differences (Naver Clova SR, 52.6%; Google Speech-to-Text, 56.3%; Amazon Transcribe, 36.6%). CONCLUSION: Among three current cloud-based SR open APIs, Naver Clova SR which manufactured by Korean company showed highest accuracy of medical terms in Korean, compared to Google Speech-to-Text and Amazon Transcribe. Although limitations are existing in the recognition of medical terminology, there is a lot of rooms for improvement of this promising technology by combining strengths of each SR engines.

Prognosis of Myocardial Injury After Non-Cardiac Surgery in Adults Aged Younger Than 45 Years.

BACKGROUND: This study compared myocardial injury after non-cardiac surgery (MINS) and mortalities between patients under and over the age of 45 years.Methods and Results:From January 2010 and June 2019, patients with cardiac troponin measurement within 30 days after non-cardiac surgery were enrolled and divided into groups according to age: >45 (≥45 years) and <45 (<45 years). Further analyses were conducted only in patients who were diagnosed with MINS. The outcomes were MINS and 30-day mortality. Of the 35,223 patients, 31,161 (88.5%) patients were in the >45-year group and 4,062 (11.5%) were in the <45-year group. After adjustment with inverse probability of weighting, the <45-years group showed a lower incidence of MINS and cardiovascular mortality (16.6% vs. 11.7%; odds ratio, 0.77; 95% confidence interval [CI], 0.69-0.84; P<0.001 and 0.4% vs. 0.2%; hazard ratio [HR], 0.41; 95% CI, 0.19-0.88; P=0.02, respectively). In a comparison of only the <45-years group, MINS was associated with increased 30-day mortality (0.7% vs. 10.3%; HR, 10.48; 95% CI, 6.18-17.78; P<0.001), but the mortalities of patients with MINS did not differ according to age. CONCLUSIONS: MINS has a comparable prognostic impact in patients aged under and over 45 years; therefore, future studies need to also consider patients aged <45 years regarding risk factors of MINS and screening of perioperative troponin elevation.

Association Between High Body Mass Index and Mortality Following Myocardial Injury After Noncardiac Surgery.

BACKGROUND: Despite an association between obesity and increased risks for various diseases, obesity has been paradoxically reported to correlate with improved mortality in patients with established cardiovascular disease. However, its effect has not been evaluated to date in patients with myocardial injury after noncardiac surgery (MINS). METHODS: From January 2010 to June 2019, of a total of 35,269 adult patients with postoperative cardiac troponin level data, 5633 (16.0%) patients had MINS as diagnosed by postoperative cardiac troponin I above the 99th-percentile upper reference of 40 ng·L-1 using the TnI-Ultra immunoassay. Patients with MINS were divided into 3 groups according to body mass index (BMI), with 3246 (57.6%) were in the normal (18.5-25 kg·m-2), 425 (7.5%) in the low BMI (<18.5 kg·m-2), and 1962 (34.8%) in the high BMI (≥25 kg·m-2) groups, respectively. The primary outcome was mortality during the first year after surgery, and the mortality during 30 days was also compared. RESULTS: Following adjustment for confounding with inverse probability of treatment weighting, mortality within the first year appeared to be significantly lower in the high BMI group compared with the normal (14.8% vs 20.9%; hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.66-0.85; P < .001) and the low BMI (14.8% vs 25.6%; HR: 0.56; 95% CI, 0.48-0.66; P < .001) groups. CONCLUSIONS: High BMI may be associated with decreased mortality following MINS. Further investigations are needed to support this finding.

Elevated high-sensitivity C-reactive protein concentrations may be associated with increased postdischarge mortality in patients with myocardial injury after noncardiac surgery: A retrospective observational study.

BACKGROUND: Myocardial injury after noncardiac surgery (MINS) is one of the most common cardiovascular complications associated with mortality and morbidity during the first 2 years after surgery. However, the relevant variables associated with mortality after discharge in patients with MINS have not been fully investigated. OBJECTIVES: This study aimed to evaluate the association between persistent inflammation detected by high-sensitivity C-reactive protein (hsCRP) at discharge and postdischarge mortality after MINS. DESIGN: Retrospective observational analysis of acquired data from Samsung Medical Center Troponin in Noncardiac Operation (SMC-TINCO) registry. SETTING: A tertiary hospital from January 2010 to June 2019. PATIENTS: Patients who were discharged alive after a diagnosis of MINS. MAIN OUTCOME MEASURES: The primary endpoint was postdischarge 1-year mortality, and 30-day mortality and the mortality from 30 days to 1 year was also compared. RESULTS: Data from a total of 4545 adult patients were divided into two groups according to hsCRP concentration at discharge. There were 757 (16.7%) patients in the normal hsCRP group and 3788 (83.3%) patients in the elevated hsCRP group. After inverse probability weighting, 1-year mortality was significantly higher in the elevated group than the normal group (hazard ratio 1.93, 95% CI 1.45 to 2.57, P  < 0.001). Thirty-day mortality and the mortality from 30 days to 1 year were also increased in the elevated group. CONCLUSION: In patients with MINS, an elevated hsCRP concentration at discharge appeared to be associated with increased mortality. Further research is needed to determine whether controlling inflammation can be helpful in reducing mortality.

Pre-operative anaemia and myocardial injury after noncardiac surgery: A retrospective study.

BACKGROUND: Pre-operative anaemia is associated with adverse outcomes of noncardiac surgery, but its association with myocardial injury after noncardiac surgery (MINS) has not been fully investigated. OBJECTIVE: The association between pre-operative anaemia and MINS. DESIGN: A single-centre retrospective cohort study. SETTING: Tertiary care referral centre. PATIENTS: Patients with measured cardiac troponin (cTn) I levels after noncardiac surgery. INTERVENTIONS: Patients were separated according to pre-operative anaemia (haemoglobin <13 g dl-1 in men and <12 g dl-1 in women). Anaemia was further stratified into mild and moderate-to-severe at a haemoglobin level threshold of 11 g dl-1. MAIN OUTCOME MEASURES: The primary outcome was MINS, defined as a peak cTn I level more than 99th percentile of the upper reference limit within 30 postoperative days. RESULTS: Data from a total of 35 170 patients were collected, including 22 062 (62.7%) patients in the normal group and 13 108 (37.3%) in the anaemia group. After propensity score matching, 11919 sets of patients were generated, and the incidence of MINS was significantly associated with anaemia [14.5 vs. 21.0%, odds ratio (OR) 1.57, 95% confidence interval (CI) 1.47 to 1.68, P < 0.001]. For the entire population, multivariable analysis showed a graded association between anaemia severity and MINS (OR 1.32, 95% CI 1.22 to 1.43, P < 0.001 for mild anaemia and OR 1.80, 95% CI 1.66 to 1.94, P < 0.001 for moderate-to-severe anaemia compared with the normal group) and a significantly higher incidence of MINS for moderate-to-severe anaemia than mild anaemia (18.6 vs. 28.6%, OR 1.37, 95% CI 1.25 to 1.50, P < 0.001). The estimated threshold for pre-operative haemoglobin associated with MINS was 12.2 g dl-1, with an area under the curve of 0.622. CONCLUSIONS: Pre-operative anaemia was independently associated with MINS, suggesting that MINS may be related to the association between anaemia and postoperative mortality. TRIAL REGISTRATION: SMC 2019-08-048.

COX-2- and endoplasmic reticulum stress-independent induction of ULBP-1 and enhancement of sensitivity to NK cell-mediated cytotoxicity by celecoxib in colon cancer cells.

In the present study, we investigated whether celecoxib could induce the expression of NKG2D ligands in clonogenic colon cancer cells, and increase their susceptibility to NK cell-mediated cell death. Celecoxib and its non-coxib analog, 2,5-dimethyl celecoxib, induced ULBP-1 and DR5 in both COX-2 negative HCT-15 cells and COX-2 positive HT-29 cells. Celecoxib increased their susceptibility to NK92 cells in both DELFIA assay and soft agar colony forming assay. The inducibility of ULBP-1 and DR5 by celecoxib was not different between CD44- and CD44+ HCT-15 cells, and CD133- and CD133+ HT-29 cells. Celecoxib increased the susceptibility of highly clonogenic CD44+ HCT-15 and CD133+ HT-29 cells to NK92 cells, at least comparable to less clonogenic CD44- HCT-15 and CD133- HT-29 cells, respectively. In addition, celecoxib induced CHOP, and thapsigargin, an inducer of ER (endoplasmic reticulum) stress, induced DR5 but not ULBP1 in HCT-15. Taken together, these findings suggest that celecoxib induces the expression of ULBP-1 as well as DR5 in clonogenic colon cancer cells via COX-2 and ER stress-independent pathways, and increases their susceptibility to NK cells.

Identification of radiation-induced aberrant hypomethylation in colon cancer.

BACKGROUND: Exposure to ionizing radiation (IR) results in the simultaneous activation or downregulation of multiple signaling pathways that play critical roles in cell type-specific control of survival or death. IR is a well-known genotoxic agent and human carcinogen that induces cellular damage through direct and indirect mechanisms. However, its impact on epigenetic mechanisms has not been elucidated, and more specifically, little information is available regarding genome-wide DNA methylation changes in cancer cells after IR exposure. Recently, genome-wide DNA methylation profiling technology using the Illumina HumanMethylation450K platform has emerged that allows us to query >450,000 loci within the genome. This improved technology is capable of identifying genome-wide DNA methylation changes in CpG islands and other CpG island-associated regions. RESULTS: In this study, we employed this technology to test the hypothesis that exposure to IR not only induces differential DNA methylation patterns at a genome-wide level, but also results in locus- and gene-specific DNA methylation changes. We screened for differential DNA methylation changes in colorectal cancer cells after IR exposure with 2 and 5 Gy. Twenty-nine genes showed radiation-induced hypomethylation in colon cancer cells, and of those, seven genes showed a corresponding increase in gene expression by reverse transcriptase polymerase chain reaction (RT-PCR). In addition, we performed chromatin immunoprecipitation (ChIP) to confirm that the DNA-methyltransferase 1 (DNMT1) level associated with the promoter regions of these genes correlated with their methylation level and gene expression changes. Finally, we used a gene ontology (GO) database to show that a handful of hypomethylated genes induced by IR are associated with a variety of biological pathways related to cancer. CONCLUSION: We identified alterations in global DNA methylation patterns and hypomethylation at specific cancer-related genes following IR exposure, which suggests that radiation exposure plays a critical role in conferring epigenetic alterations in cancer.

The ameliorative effect of silibinin against radiation-induced lung injury: protection of normal tissue without decreasing therapeutic efficacy in lung cancer.

BACKGROUND: Silibinin has been known for its role in anti-cancer and radio-protective effect. Radiation therapy for treating lung cancer might lead to late-phase pulmonary inflammation and fibrosis. Thus, this study aimed to investigate the effects of silibinin in radiation-induced lung injury with a mouse model. METHODS: In this study, we examined the ability of silibinin to mitigate lung injury in, and improve survival of, C57BL/6 mice given 13 Gy thoracic irradiation and silibinin treatments orally at 100 mg/kg/day for seven days after irradiation. In addition, Lewis lung cancer (LLC) cells were injected intravenously in C57BL/6 mice to generate lung tumor nodules. Lung tumor-bearing mice were treated with lung radiation therapy at 13 Gy and with silibinin at a dose of 100 mg/day for seven days after irradiation. RESULTS: Silibinin was shown to increase mouse survival, to ameliorate radiation-induced hemorrhage, inflammation and fibrosis in lung tissue, to reduce the number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) and to reduce inflammatory cell infiltration in the respiratory tract. In LLC tumor injected mice, lung tissue from mice treated with both radiation and silibinin showed no differences compared to lung tissue from mice treated with radiation alone. CONCLUSIONS: Silibinin treatment mitigated the radiation-induced lung injury possibly by reducing inflammation and fibrosis, which might be related with the improved survival rate. Silibinin might be a useful agent for lung cancer patients as a non-toxic complementary approach to alleviate the side effects by thorax irradiation.

Antitumor effect of dendritic cell loaded ex vivo and in vivo with tumor-associated antigens in lung cancer model.

Various ex vivo or in vivo loading protocols have been developed or evaluated for the delivery of tumor antigens to dendritic cells (DCs). We compared the antitumor effect of mature DCs electroporation-pulsed (EP/mDC) ex vivo with tumor cell lysate and immature DCs (iDCs) injected into the tumor apoptosed by ionizing radiation (IR/iDC) in lung cancer model. DCs were generated from bone marrow of C57BL/6 mice. Ionizing radiation (IR) was applied at a dose of 10 Gy to the tumor on the right thigh. iDCs were intratumorally injected into the irradiated tumor and EP/mDC was injected subcutaneously in the right flank. DC injection induced strong tumor-specific immunity against Lewis lung carcinoma, as compared with the tumor-bearing control and IR only treated mice. The growth of a distant tumor on the right and left flank was inhibited by IR/iDC and EP/mDC. Particularly, IR/iDC resulted in a more significant inhibition of tumor growth and prolonged survival time. It was related to increase of tumor-specific interferon-gamma, cytotoxicity, and decrease of regulatory T-cells. The results indicate that DCs electroporation-pulsed with tumor cell lysate induce a potent antitumor effect, but that iDCs intratumoral injected into the irradiated tumor induce a more potent antitumor effect.

Association of preoperative blood glucose level with delirium after non-cardiac surgery in diabetic patients.

BACKGROUND: Hyperglycemia has shown a negative association with cognitive dysfunction. We analyzed patients with high preoperative blood glucose level and hemoglobin A1c (HbA1c) level to determine the prevalence of postoperative delirium. METHODS: We reviewed a database of 23,532 patients with diabetes who underwent non-cardiac surgery. Acute hyperglycemia was defined as fasting blood glucose > 140 mg/dl or random glucose > 180 mg/dl within 24 h before surgery. Chronic hyperglycemia was defined as HbA1c level above 6.5% within three months before surgery. The incidence of delirium was compared according to the presence of acute and chronic hyperglycemia. RESULTS: Of the 23,532 diabetic patients, 21,585 had available preoperative blood glucose level within 24 h before surgery, and 18,452 patients reported levels indicating acute hyperglycemia. Of the 8,927 patients with available HbA1c level within three months before surgery, 5,522 had levels indicating chronic hyperglycemia. After adjustment with inverse probability weighting, acute hyperglycemia was related to higher incidence of delirium (hazard ratio: 1.33, 95% CI [1.10,1.62], P = 0.004 for delirium) compared with controls without acute hyperglycemia. On the other hand, chronic hyperglycemia did not correlate with postoperative delirium. CONCLUSIONS: Preoperative acute hyperglycemia was associated with postoperative delirium, whereas chronic hyperglycemia was not significantly associated with postoperative delirium. Irrespective of chronic hyperglycemia, acute glycemic control in surgical patients could be crucial for preventing postoperative delirium.

Association between Preoperative Glucose Dysregulation and Delirium after Non-Cardiac Surgery.

This study aimed to investigate the association between glucose dysregulation and delirium after non-cardiac surgery. Among a total of 203,787 patients who underwent non-cardiac surgery between January 2011 and June 2019 at our institution, we selected 61,805 with available preoperative blood glucose levels within 24 h before surgery. Patients experiencing glucose dysregulation were divided into three groups: hyperglycemia, hypoglycemia, and both. We compared the incidence of postoperative delirium within 30 days after surgery between exposed and unexposed patients according to the type of glucose dysregulation. The overall incidence of hyperglycemia, hypoglycemia, and both was 5851 (9.5%), 1452 (2.3%), and 145 (0.2%), respectively. The rate of delirium per 100 person-months of the exposed group was higher than that of the unexposed group in all types of glucose dysregulation. After adjustment, the hazard ratios of glucose dysregulation in the development of delirium were 1.35 (95% CI, 1.18-1.56) in hyperglycemia, 1.36 (95% CI, 1.06-1.75) in hypoglycemia, and 3.14 (95% CI, 1.27-7.77) in both. The subgroup analysis showed that exposure to hypoglycemia or both to hypo- and hyperglycemia was not associated with delirium in diabetic patients, but hyperglycemia was consistently associated with postoperative delirium regardless of the presence of diabetes. Preoperative glucose dysregulation was associated with increased risk of delirium after non-cardiac surgery. Our findings may be helpful for preventing postoperative delirium, and further investigations are required to verify the association and mechanisms for the effect we observed.

Five-Day Spacing of Two Fractionated Ablative Radiotherapies Enhances Antitumor Immunity.

PURPOSE: This study aimed to enhance tumor control and abscopal effects by applying diverse stereotactic ablative radiation therapy (SABR) schedules. METHODS AND MATERIALS: FSaII, CT-26, and 4T1 cells were used for tumor growth delay and lung metastases analysis after 1- or 5-day intervals radiation therapy (RT) with 40, 20, and 20 Gy, respectively. Immunodeficient BALB/c-nude, immunocompetent C3H, and BALB/c mouse models were used. For immune monitoring, FSaII tumors were analyzed using flow cytometry, immunofluorescence staining, and real-time quantitative reverse transcription polymerase chain reaction. The spleens were used for the ELISpot assay and flow cytometry to determine effector CD8 T cells. For abscopal effect analysis in CT-26 tumors, the volume of the nonirradiated secondary tumors was measured after primary tumors were irradiated with 1-day or 5-day intervals. RESULTS: Contrary to the high-dose 1-day interval RT, the 5-day interval RT significantly delayed tumor growth in immunocompetent mice, which was not observed in immunodeficient mice. In addition, the 5-day interval RT significantly reduced the number of lung metastases in FSaII and CT-26 tumors. Five-day spacing was more effective than 1-day interval in enhancing the antitumor immunity via increasing the secretion of tumor-specific IFN-γ, activating the CD8 T cells, and suppressing the monocytic myeloid-derived suppressor cells. The 5-day spacing inhibited nonirradiated secondary tumor growth more effectively than did the 1-day interval. CONCLUSIONS: Compared with the 1-day interval RT, the 5-day interval RT scheme demonstrated enhanced antitumor immunity of CD8 T cells associated with inhibition of myeloid-derived suppressor cells. Enhancing antitumor immunity leads to significant improvements in both primary tumor control and the abscopal effect.

Evaluation of the quality and quantity of artificial intelligence-generated responses about anesthesia and surgery: using ChatGPT 3.5 and 4.0.

Introduction: The large-scale artificial intelligence (AI) language model chatbot, Chat Generative Pre-Trained Transformer (ChatGPT), is renowned for its ability to provide data quickly and efficiently. This study aimed to assess the medical responses of ChatGPT regarding anesthetic procedures. Methods: Two anesthesiologist authors selected 30 questions representing inquiries patients might have about surgery and anesthesia. These questions were inputted into two versions of ChatGPT in English. A total of 31 anesthesiologists then evaluated each response for quality, quantity, and overall assessment, using 5-point Likert scales. Descriptive statistics summarized the scores, and a paired sample t-test compared ChatGPT 3.5 and 4.0. Results: Regarding quality, "appropriate" was the most common rating for both ChatGPT 3.5 and 4.0 (40 and 48%, respectively). For quantity, responses were deemed "insufficient" in 59% of cases for 3.5, and "adequate" in 69% for 4.0. In overall assessment, 3 points were most common for 3.5 (36%), while 4 points were predominant for 4.0 (42%). Mean quality scores were 3.40 and 3.73, and mean quantity scores were - 0.31 (between insufficient and adequate) and 0.03 (between adequate and excessive), respectively. The mean overall score was 3.21 for 3.5 and 3.67 for 4.0. Responses from 4.0 showed statistically significant improvement in three areas. Conclusion: ChatGPT generated responses mostly ranging from appropriate to slightly insufficient, providing an overall average amount of information. Version 4.0 outperformed 3.5, and further research is warranted to investigate the potential utility of AI chatbots in assisting patients with medical information.

Current Health Data Standardization Project and Future Directions to Ensure Interoperability in Korea.

OBJECTIVES: The need for interoperability at the national level was highlighted in Korea, leading to a consensus on the importance of establishing national standards that align with international technological standards and reflect contemporary needs. This article aims to share insights into the background of the recent national health data standardization policy, the activities of the Health Data Standardization Taskforce, and the future direction of health data standardization in Korea. METHODS: To ensure health data interoperability, the Health Data Standardization Taskforce was jointly organized by the public and private sectors in December 2022. The taskforce operated three working groups. It reviewed international trends in interoperability standardization, assessed the current status of health data standardization, discussed its vision, mission, and strategies, engaged in short-term standardization activities, and established a governance system for standardization. RESULTS: On September 15, 2023, the notice of "Health Data Terminology and Transmission Standards" in Korea was thoroughly revised to improve the exchange of health information between information systems and ensure interoperability. This notice includes the Korea Core Data for Interoperability (KR CDI) and the Korea Core Data Transmission Standard (HL7 FHIR KR Core), which are outcomes of the taskforce's efforts. Additionally, to reinforce the standardized governance system, the Health-Data Standardization Promotion Committee was established. CONCLUSIONS: Active interest and support from medical informatics experts are needed for the development and widespread adoption of health data standards in Korea.

Perioperative adverse cardiac events and mortality after non-cardiac surgery: a multicenter study.

BACKGROUND: Perioperative adverse cardiac events (PACE), a composite of myocardial infarction, coronary revascularization, congestive heart failure, arrhythmic attack, acute pulmonary embolism, cardiac arrest, and stroke during 30-day postoperative period, is associated with long-term mortality, but with limited clinical evidence. We compared long-term mortality with PACE using data from nationwide multicenter electronic health records. METHODS: Data from 7 hospitals, converted to Observational Medical Outcomes Partnership Common Data Model, were used. We extracted records of 277,787 adult patients over 18 years old undergoing non-cardiac surgery for the first time at the hospital and had medical records for more than 180 days before surgery. We performed propensity score matching and then an aggregated meta­analysis. RESULTS: After 1:4 propensity score matching, 7,970 patients with PACE and 28,807 patients without PACE were matched. The meta­analysis showed that PACE was associated with higher one-year mortality risk (hazard ratio [HR]: 1.33, 95% CI [1.10, 1.60], P = 0.005) and higher three-year mortality (HR: 1.18, 95% CI [1.01, 1.38], P = 0.038). In subgroup analysis, the risk of one-year mortality by PACE became greater with higher-risk surgical procedures (HR: 1.20, 95% CI [1.04, 1.39], P = 0.020 for low-risk surgery; HR: 1.69, 95% CI [1.45, 1.96], P < 0.001 for intermediate-risk; and HR: 2.38, 95% CI [1.47, 3.86], P = 0.034 for high-risk). CONCLUSIONS: A nationwide multicenter study showed that PACE was significantly associated with increased one-year mortality. This association was stronger in high-risk surgery, older, male, and chronic kidney disease subgroups. Further studies to improve mortality associated with PACE are needed.

Histone demethylase JMJD2B-mediated cell proliferation regulated by hypoxia and radiation in gastric cancer cell.

Histone modifying factors are functional components of chromatin and play a role in gene regulation. The expression level of JMJD2B, a histone demethylase, is notably up-regulated in cancer tissues. Upregulation of JMJD2B promotes cancer cell proliferation under hypoxic conditions through target gene expression. Here, we describe the patterns of histone methylation and JMJD2B expression under various stressed conditions, such as hypoxia and radiation, in a gastric cancer cell line. JMJD2B expression in AGS cells was actively regulated by hypoxia and radiation. Chromatin immunoprecipitation experiments demonstrated that binding of JMJD2B on the cyclin A1 (CCNA1) promoter resulted in CCNA1 upregulation under hypoxic conditions. Furthermore, we confirmed that AGS cell proliferation was directly affected by JMJD2B and CCNA1 expression by performing experiments with JMJD2B depleted cells. Interestingly, the effects of JMJD2B on cell growth under hypoxia were remarkably repressed after gamma-ray irradiation. These results suggest that JMJD2B may play a central role in gastric cancer cell growth and might constitute a novel therapeutic target to overcome hypoxia-induced radio-resistance, thereby improving the efficiency of radiation therapy.

The histone demethylase JMJD1A regulates adrenomedullin-mediated cell proliferation in hepatocellular carcinoma under hypoxia.

We studied the roles of JMJD1A and its target gene ADM in the growth of hepatocellular carcinomas (HCCs) and breast cancer cells under hypoxic conditions. Hypoxia stimulated HepG2 and Hep3B cell proliferation but had no effect on MDA-MB-231 cell proliferation. Interestingly, the JMJD1A and ADM expressions were enhanced by hypoxia only in HepG2 and Hep3B cells. Our ChIP results showed that hypoxia-induced HepG2 and Hep3B cell proliferation is mediated by JMJD1A upregulation and subsequent decrease in methylation in the ADM promoter region. Furthermore, JMJD1A gene silencing abrogated the hypoxia-induced ADM expression and inhibited HepG2 and Hep3B cell growth. These data suggest that JMJD1A might function as a proliferation regulator in some cancer cell types.

A possible usage of a CDK4 inhibitor for breast cancer stem cell-targeted therapy.

Cancer stem cells (CSCs) are one of the main reasons behind cancer recurrence due to their resistance to conventional anti-cancer therapies. Thus, many efforts are being devoted to developing CSC-targeted therapies to overcome the resistance of CSCs to conventional anti-cancer therapies and decrease cancer recurrence. Differentiation therapy is one potential approach to achieve CSC-targeted therapies. This method involves inducing immature cancer cells with stem cell characteristics into more mature or differentiated cancer cells. In this study, we found that a CDK4 inhibitor sensitized MDA-MB-231 cells but not MCF7 cells to irradiation. This difference appeared to be associated with the relative percentage of CSC-population between the two breast cancer cells. The CDK4 inhibitor induced differentiation and reduced the cancer stem cell activity of MDA-MB-231 cells, which are shown by multiple marker or phenotypes of CSCs. Thus, these results suggest that radiosensitization effects may be caused by reducing the CSC-population of MDA-MB-231 through the use of the CDK4 inhibitor. Thus, further investigations into the possible application of the CDK4 inhibitor for CSC-targeted therapy should be performed to enhance the efficacy of radiotherapy for breast cancer.

Enhanced maturation and function of dendritic cells using hydrogel coated plate and antigen electroporation.

Dendritic cells (DCs) are potent antigen-presenting cells that can be matured in vitro from immature dendritic cells (iDCs) in the presence of several biological agents such as cytokine cocktail, CD40L, TNF-a and antigen loading, which are necessary and achieved using various protocols, such as lipofection, passive pulse or electroporation. However, these DCs maturation protocols may cause with a significant loss of cells because of cellular attachment and spreading during culturing. Some biomaterials that influence adhesion and development of cells have been used in cell culture techniques, and it was thought that they might be applied on the culture of DCs. In this study, we used polyHEMA, which is a hydrogel coating biomaterial that prevents DCs from adherence, and investigated whether hydrogel coating affects the maturation of iDCs. The efficiency in the generation of mDCs was improved through hydrogel coating procedure and a dendritic cell maturation marker, CD83, was significantly increased in hydrogel-coated culture condition. The antigen-loaded mDCs from electroporation were further expressed the CD83. The mDCs generated in the hydrogel-coated culture condition showed more, longer and thicker dendrites, and produced more amounts of cytokines such as IL-12 and IFN-γ. Therefore, it was suggested that the hydrogel-coated culture condition could improve function of mDCs. Cheol-Hun Son and Jae-Ho Bae contributed equally to this work.