Synthetic Data Improve Survival Status Prediction Models in Early-Onset Colorectal Cancer.

PURPOSE: In artificial intelligence-based modeling, working with a limited number of patient groups is challenging. This retrospective study aimed to evaluate whether applying synthetic data generation methods to the clinical data of small patient groups can enhance the performance of prediction models. MATERIALS AND METHODS: A data set collected by the Cancer Registry Library Project from the Yonsei Cancer Center (YCC), Severance Hospital, between January 2008 and October 2020 was reviewed. Patients with colorectal cancer younger than 50 years who started their initial treatment at YCC were included. A Bayesian network-based synthesizing model was used to generate a synthetic data set, combined with the differential privacy (DP) method. RESULTS: A synthetic population of 5,005 was generated from a data set of 1,253 patients with 93 clinical features. The Hellinger distance and correlation difference metric were below 0.3 and 0.5, respectively, indicating no statistical difference. The overall survival by disease stage did not differ between the synthetic and original populations. Training with the synthetic data and validating with the original data showed the highest performances of 0.850, 0.836, and 0.790 for the Decision Tree, Random Forest, and XGBoost models, respectively. Comparison of synthetic data sets with different epsilon parameters from the original data sets showed improved performance >0.1%. For extremely small data sets, models using synthetic data outperformed those using only original data sets. The reidentification risk measures demonstrated that the epsilons between 0.1 and 100 fell below the baseline, indicating a preserved privacy state. CONCLUSION: The synthetic data generation approach enhances predictive modeling performance by maintaining statistical and clinical integrity, and simultaneously reduces privacy risks through the application of DP techniques.

Generative Adversarial Network-Based Fault Detection in Semiconductor Equipment with Class-Imbalanced Data.

This research proposes an application of generative adversarial networks (GANs) to solve the class imbalance problem in the fault detection and classification study of a plasma etching process. Small changes in the equipment part condition of the plasma equipment may cause an equipment fault, resulting in a process anomaly. Thus, fault detection in the semiconductor process is essential for success in advanced process control. Two datasets that assume faults of the mass flow controller (MFC) in equipment components were acquired using optical emission spectroscopy (OES) in the plasma etching process of a silicon trench: The abnormal process changed by the MFC is assumed to be faults, and the minority class of Case 1 is the normal class, and that of Case 2 is the abnormal class. In each case, additional minority class data were generated using GANs to compensate for the degradation of model training due to class-imbalanced data. Comparisons of five existing fault detection algorithms with the augmented datasets showed improved modeling performances. Generating a dataset for the minority group using GANs is beneficial for class imbalance problems of OES datasets in fault detection for the semiconductor plasma equipment.

Preparation of particle-attached microneedles using a dry coating process.

The standard process for manufacturing microneedles containing API requires a way to process the API, including dissolving the API in a co-solvent and a drying process. In this study, the authors introduce a novel microneedle system that involves physically attaching API particles to the biocompatible adhesive surface of the microneedles. To manufacture particle-attached microneedles, an adhesive surface was prepared by coating polydimethylsiloxane (PDMS) mixed with an elastomer base and a curing agent at a ratio of 40:1 (PDMS40) onto polylactic acid microneedles (PLA), and then attaching ovalbumin (OVA) particles with a mean diameter of 10 µm to the PDMS adhesive layer. The OVA particles were delivered for 5 min into porcine skin with a delivery efficiency of 93% ex vivo and into mouse skin with a delivery efficiency of over 90% in vivo. Finally, mouse experiments with OVA particle-attached microneedles showed a value of OVA antibody titer similar to that produced by intramuscular administration. Particle-attached microneedles are a novel microneedle system with a dry coating process and rapid API delivery into the skin. Particle-attached microneedles can provide a wide range of applications for administering drugs and vaccines.

Association of neutrophil-to-lymphocyte ratio, radiotherapy fractionation/technique, and risk of development of distant metastasis among patients with locally advanced rectal cancer.

BACKGROUND: We investigated the prognostic impact of the neutrophil-to-lymphocyte ratio (NLR) in patients with locally advanced rectal cancer (LARC) and whether modifiable factors in radiotherapy (RT) influenced the NLR. METHODS: Data of 1386 patients who were treated with neoadjuvant RT and concurrent or sequential chemotherapy for LARC between 2006 and 2019 were evaluated. Most patients (97.8%) were treated with long-course RT (LCRT; 50-50.4 Gy in 25-28 fractions) using three-dimensional conformal radiotherapy (3D-CRT) (n = 851) or helical tomotherapy (n = 504), and 30 patients underwent short-course RT (SCRT; 25 Gy in 5 fractions, followed by XELOX administration for 6 weeks). Absolute neutrophil and lymphocyte counts were obtained at initial diagnosis, before and during the preoperative RT course, and after preoperative concurrent chemoradiotherapy. The primary endpoint was distant metastasis-free survival (DMFS). RESULTS: The median follow-up time was 61.3 (4.1-173.7) months; the 5-year DMFS was 80.1% and was significantly associated with the NLR after RT but not before. A post-RT NLR ≥ 4 independently correlated with worse DMFS (hazard ratio, 1.42; 95% confidence interval, 1.12-1.80), along with higher ypT and ypN stages. Post-RT NLR (≥ 4) more frequently increased following LCRT (vs. SCRT, odds ratio [OR] 2.77, p = 0.012) or helical tomotherapy (vs. 3D-CRT, OR 1.29, p < 0.001). CONCLUSIONS: Increased NLR after neoadjuvant RT is associated with increased distant metastasis risk and poor survival outcome in patients with LARC. Moreover, high NLR following RT is directly related to RT fractionation, delivery modality, and tumor characteristics. These results are hypothesis-generating only, and confirmatory studies are required.

N-3 PUFA ameliorated bone loss induced by postmenopausal depression following exposure to chronic mild stress and maternal separation by regulating neuronal processes.

Depression induced by chronic mild stress (CMS) reduced bone mass in ovariectomized (OVX) rats, and maternal separation (MS) during early life aggravated depression-induced bone mass destruction. N-3 polyunsaturated fatty acids (PUFA) have been shown to improve bone mass and depression, but the bone-protecting effects of n-3 PUFA were unclear in CMS+MS-induced depression models. The purpose of this study was to determine whether n-3 PUFA improved CMS+MS-induced postmenopausal bone loss via its antidepressant-like action. Rats were fed diets containing 0% of total energy intake (en %) of n-3 PUFA during lifetime or 1 en % n-3 PUFA during pre-weaning or post-weaning periods, or their entire lifetimes and were allocated to CMS or CMS+MS groups after OVX. Lifetime supply of n-3 PUFA enhanced bone mass and microarchitecture, and expression of runt-related transcription factor 2, while decreasing blood levels of amino-terminal cross-linked telopeptide of type 1 collagen and the expression of receptor activator of nuclear factor kappa Β ligand/osteoprotegerin, activating transcription factor 4, and adrenergic receptor ß2. Lifetime supply of n-3 PUFA decreased levels of adrenocorticotropic hormone and corticosterone and the expression of corticotropin-releasing factor in the brain but increased expression of the glucocorticoid receptor, serotonin-2C receptor, cAMP response element-binding protein (CREB), and calmodulin kinase IV and serotonin levels. Supply of n-3 PUFA during the pre-and post-weaning periods had beneficial effects on the brain but not on the bones. Lifetime supply of n-3 PUFA ameliorated bone loss induced by chronic stress by regulating hypothalamic-pituitary-adrenal axis activity and serotonin-CREB signaling.

Deep-Learning-Based Natural Language Processing of Serial Free-Text Radiological Reports for Predicting Rectal Cancer Patient Survival.

Most electronic medical records, such as free-text radiological reports, are unstructured; however, the methodological approaches to analyzing these accumulating unstructured records are limited. This article proposes a deep-transfer-learning-based natural language processing model that analyzes serial magnetic resonance imaging reports of rectal cancer patients and predicts their overall survival. To evaluate the model, a retrospective cohort study of 4,338 rectal cancer patients was conducted. The experimental results revealed that the proposed model utilizing pre-trained clinical linguistic knowledge could predict the overall survival of patients without any structured information and was superior to the carcinoembryonic antigen in predicting survival. The deep-transfer-learning model using free-text radiological reports can predict the survival of patients with rectal cancer, thereby increasing the utility of unstructured medical big data.

N-3 PUFA improved post-menopausal depression induced by maternal separation and chronic mild stress through serotonergic pathway in rats-effect associated with lipid mediators.

Early life maternal separation (MS) increases the vulnerability to depression in rats with chronic mild stress (CMS). N-3 polyunsaturated fatty acids (PUFA) improved depressive behaviors in rats with acute stress; however, their effects on rats with MS+CMS were not apparent. The purpose of the present study was to investigate the hypothesis that lifetime n-3 PUFA supplementation improves post-menopausal depression through the serotonergic and glutamatergic pathways while modulating n-3 PUFA-derived metabolites. Female rats were fed diets of either 0% n-3 PUFA during lifetime or 1% energy n-3 PUFA during pre-weaning, post-weaning, or lifetime periods. Rats were allocated to non-MS or MS groups and underwent CMS after ovariectomy. N-3 PUFA increased brain n-3 PUFA-derived endocannabinoid/oxylipin levels, and reversed depressive behaviors. N-3 PUFA decreased blood levels of adrenocorticotropic hormone and corticosterone, and brain expressions of corticotropin-releasing factor and miRNA-218, which increased the expression of the glucocorticoid receptor. N-3 PUFA decreased the expression of tumor necrosis factor-α, interleukin (IL)-6, IL-1ß, and prostaglandin E2, while increased the expression of miRNA-155. N-3 PUFA also increased brainstem serotonin levels and hippocampal expression of the serotonin-1A receptor, cAMP response element-binding protein (CREB), phospho-CREB, and brain-derived neurotrophic factor. However, n-3 PUFA did not affect brain expression of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor subtype 1, N-methyl-D-aspartate receptor subtype 2B, or miRNA-132. Moreover, n-3 PUFA exposure during lifetime caused greater effects than pre- and post-weaning periods. The present study suggested that n-3 PUFA improved depressive behaviors through serotonergic pathway while modulating the metabolites of n-3 PUFA in post-menopausal depressed rats with chronic stress.

N-3 PUFA Have Antidepressant-like Effects Via Improvement of the HPA-Axis and Neurotransmission in Rats Exposed to Combined Stress.

Early life and adulthood stress increase vulnerability for mental illness, and eventually trigger depression. N-3 polyunsaturated fatty acids (PUFA) have antidepressant effects, but their effect on rats exposed to combined stress has been not investigated. This study aimed to investigate whether n-3 PUFA supplementation had antidepressant-like effects in rat models of depression induced by a combination of chronic mild stress (CMS) and maternal separation (MS) through the modulation of the hypothalamic-pituitary-adrenal (HPA) axis and neurotransmission. Rats were fed the n-3 PUFA diet during the pre-weaning or post-weaning period or for lifetime, and allocated to different groups based on the type of induced stress: non-stress (NS), CMS + MS, or CMS alone. N-3 PUFA improved the depressive behaviors of the CMS alone and CMS + MS groups and modulated the HPA-axis by reducing the circulating adrenocorticotropic hormone, corticosterone, and corticotropin-releasing factor expression, and increasing glucocorticoid receptor expression. N-3 PUFA also modulated brain phospholipid fatty acid concentration, thus reducing inflammatory cytokines; improved the serotonergic pathway, thus increasing the expression of the brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), serotonin-1A receptor, and serum levels of serotonin; but did not affect glutamatergic neurotransmission. Furthermore, n-3 PUFA decreased the hippocampal expression of microRNA-218 and -132, increased that of microRNA-155, and its lifetime supplementation was more beneficial than pre- or post-weaning supplementation. This study suggests that n-3 PUFA has an antidepressant effect in rats exposed to combined stress, through the improvement of the HPA-axis abnormalities, the BDNF-serotonergic pathway, and the modulation of microRNAs.

N-3 PUFA improved pup separation-induced postpartum depression via serotonergic pathway regulated by miRNA.

Stress and ovarian hormone fluctuation are risk factors for postpartum depression (PPD). Previous studies suggested antidepressant-like effects of n-3 polyunsaturated fatty acids (PUFA), but their effect on dam animal with additional stress were not clear. The purpose of the present study was to investigate the hypothesis that n-3 PUFA improved PPD through the serotonergic and glutamatergic pathways by modulating miRNA. Rats were fed n-3 PUFA or control diet from gestation, with pup separation (PS) on postpartum days 2-14 and non-PS controls. N-3 PUFA reversed PS-induced depressive behaviors, including increased immobility, latencies to contact first pup and retrieve all pups, and decreased sucrose preference. N-3 PUFA also modulated the hypothalamic-pituitary-adrenal (HPA) axis by decreasing circulating levels of adrenocorticotropic hormone and corticosterone and expression of hypothalamic corticotrophin releasing factor and hippocampal miRNA-218 but increasing the hippocampal expression of glucocorticoid receptor. N-3 PUFA inhibited neuroinflammation by decreasing circulating levels of prostaglandin E2 and hippocampal expression of tumor necrosis factor-α, interleukin-6, and miRNA-155. In addition, n-3 PUFA up-regulated the serotonergic pathway by increasing circulating levels of serotonin and hippocampal expression of serotonin-1A receptor, cAMP response element binding protein (CREB), pCREB, brain-derived neurotrophic factor, and miRNA-182 but did not affect the glutamatergic pathway according to the hippocampal expression of N-methyl-D-aspartate receptor-2B. The present study suggested that n-3 PUFA improved PPD through the serotonergic pathway by modifying the HPA axis, neuroinflammation, and related miRNAs.

Eicosapentaenoic acid and docosahexaenoic acid, but not α-linolenic acid, decreased low-density lipoprotein cholesterol synergistically with estrogen via regulation of cholesterol synthesis and clearance in ovariectomized rats.

Our previous study showed that n-3 polyunsaturated fatty acid (PUFA) and estrogen (E) had synergistic hypocholesterolemic effects by inhibiting cholesterol synthesis and enhancing bile acid synthesis. The purpose of the present study was to investigate the hypothesis that α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) decrease low-density lipoprotein cholesterol (LDL-C), synergistically with E, via hepatic cholesterol synthesis and clearance. Rats were fed a diet with either 0% n-3 PUFA or 1% ALA, EPA, or DHA, relative to total energy consumption, for the entire 12-week study. After ovariectomy, rats were injected with either corn oil or E every 4 days for the last 3 weeks of the study. In combination with E, dietary supplementation with EPA or DHA increased the phosphorylated adenosine monophosphate-activated protein kinase/adenosine monophosphate-activated protein kinase ratio and LDL receptor expression, and it decreased the expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase, sterol regulatory element-binding protein-2, and proprotein convertase subtilisin/kexin type 9 in the liver. In addition, dietary supplementation with EPA or DHA increased hepatic expression of cholesterol 7α-hydroxylase, sterol 12α-hydroxylase, and sterol 27-hydroxylase. However, E decreased the expression of cholesterol 7α-hydroxylase and sterol 12α-hydroxylase and increased the expression of estrogen receptor α and ß in the liver. ALA had no significant effects on cholesterol metabolism. In conclusion, the present study suggests that dietary supplementation with EPA and DHA decreased LDL-C synthesis and increased bile acid synthesis and LDL-C clearance by LDL receptor, synergistically with E.

Low-linoleic acid diet and oestrogen enhance the conversion of α-linolenic acid into DHA through modification of conversion enzymes and transcription factors.

Conversion of α-linolenic acid (ALA) into the longer chain n-3 PUFA has been suggested to be affected by the dietary intake of linoleic acid (LA), but the mechanism is not well known. Therefore, the purpose of this study was to evaluate the effect of a low-LA diet with and without oestrogen on the fatty acid conversion enzymes and transcription factors. Rats were fed a modified American Institute of Nutrition-93G diet with 0% n-3 PUFA or ALA, containing low or high amounts of LA for 12 weeks. At 8 weeks, the rats were injected with maize oil with or without 17ß-oestradiol-3-benzoate (E) at constant intervals for the remaining 3 weeks. Both the low-LA diet and E significantly increased the hepatic expressions of PPAR-α, fatty acid desaturase (FADS) 2, elongase of very long chain fatty acids 2 (ELOVL2) and ELOVL5 but decreased sterol regulatory element binding protein 1. The low-LA diet, but not E, increased the hepatic expression of FADS1, and E increased the hepatic expression of oestrogen receptor-α and ß. The low-LA diet and E had synergic effects on serum and liver levels of DHA and on the hepatic expression of PPAR-α. In conclusion, the low-LA diet and oestrogen increased the conversion of ALA into DHA by upregulating the elongases and desaturases of fatty acids through regulating the expression of transcription factors. The low-LA diet and E had a synergic effect on serum and liver levels of DHA through increasing the expression of PPAR-α.

Protein supplementation improves muscle mass and physical performance in undernourished prefrail and frail elderly subjects: a randomized, double-blind, placebo-controlled trial.

Background: Age-related loss of muscle mass and function is a major component of frailty. Nutrition supplementation with exercise is an effective strategy to decrease frailty by preventing sarcopenia, but the effect of protein alone is controversial. Objective: The present study was performed to investigate a dose-dependent effect of protein supplementation on muscle mass and frailty in prefrail or frail malnourished elderly people. Design: A 12-wk double-blind randomized controlled trial was conducted in elderly subjects aged 70-85 y with ≥1 of the Cardiovascular Health Study frailty criteria and a Mini Nutritional Assessment score ≤23.5 (n = 120). Participants were randomly assigned to 1 of 3 groups: 0.8, 1.2, or 1.5 g protein · kg-1 · d-1, with concealed allocation and intention-to-treat analysis. Primary outcomes were appendicular skeletal muscle mass (ASM) and skeletal muscle mass index (SMI) measured by dual-energy X-ray absorptiometry. Results: After the 12-wk intervention, the 1.5-g protein · kg-1 · d-1 group had higher ASM (mean ± SD: 0.52 ± 0.64 compared with 0.08 ± 0.68 kg, P = 0.036) and SMI (ASM/weight: 0.87% ± 0.69% compared with 0.15% ± 0.89%, P = 0.039; ASM/BMI: 0.02 ± 0.03 compared with 0.00 ± 0.04, P = 0.033; ASM:fat ratio: 0.04 ± 0.11 compared with -0.02 ± 0.10, P = 0.025) than the 0.8-g protein · kg-1 · d-1 group. In addition, gait speed was improved in the 1.5-g protein · kg-1 · d-1 group compared with the 0.8-g protein · kg-1 · d-1 group (0.09 ± 0.07 compared with 0.04 ± 0.07 m/s, P = 0.039). There were no significant differences between the 1.2- and 0.8-g protein · kg-1 · d-1 groups in muscle mass and physical performance. No harmful adverse effects were observed. Conclusions: The present study indicates that protein intake of 1.5 g · kg-1 · d-1 has the most beneficial effects in regard to preventing sarcopenia and frailty compared with protein intakes of 0.8 and 1.2 g · kg-1 · d-1 in prefrail or frail elderly subjects at risk of malnutrition. This trial was registered at cris.nih.go.kr as KCT0001923.

CXCR3-deficient natural killer cells fail to migrate to B16F10 melanoma cells.

Natural killer (NK) cells eliminate cancer cells in a contact-dependent manner. However, how NK cells find cancer cells remain unclear. Here, using time-lapse imaging, we investigated how individual NK cells migrate toward cancer cells. Although naïve B16F10 cancer cells produce low levels of chemokines, IFN-γ-treated B16F10 cells secreted high levels of CXCL10, low levels of CCL5, but did not secrete CCL2, CCL7, or CXCL12. Wild-type NK cells migrated well toward cancer cells and killed them, whereas NK cells deficient in CXCR3 did not. CXCR3-deficient NK cells also showed slower migration speed than did wild-type NK cells. Taken together, our data show that NK cells find cancer cells, at least in part, by sensing CXCL10 produced by cancer cells and suggest that a strategy to increase CXCL10 secretion by cancer cells may improve the efficacy of NK cell-based immunotherapy.

Quinazoline-Based Hydroxamic Acids: Design, Synthesis, and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity.

In our search for novel histone deacetylases inhibitors, we have designed and synthesized a series of novel hydroxamic acids and N-hydroxybenzamides incorporating quinazoline heterocycles (4a - 4i, 6a - 6i). Bioevaluation showed that these quinazoline-based hydroxamic acids and N-hydroxybenzamides were potently cytotoxic against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung). In term of cytotoxicity, several compounds, e.g., 4g, 4c, 4g - 4i, 6c, and 6h, displayed from 5- up to 10-fold higher potency than SAHA (suberoylanilidehydroxamic acid, vorinostat). The compounds were also generally comparable to SAHA in inhibiting HDACs with IC50 values in sub-micromolar range. Some compounds, e.g., 4g, 6c, 6e, and 6h, were even more potent HDAC inhibitors compared to SAHA in HeLa extract assay. Docking studies demonstrated that the compounds tightly bound to HDAC2 at the active binding site with binding affinities higher than that of SAHA. Detailed investigation on the estimation of absorption, distribution, metabolism, excretion, and toxicity (ADMET) suggested that compounds 4g, 6c, and 6g, while showing potent HDAC2 inhibitory activity and cytotoxicity, also potentially displayed ADMET characteristics desirable to be expected as promising anticancer drug candidates.

Cd226-/- natural killer cells fail to establish stable contacts with cancer cells and show impaired control of tumor metastasis in vivo.

CD226 is an activating receptor expressed on natural killer (NK) cells, CD8+ T cells, and other immune cells. Upon binding to its ligands expressed on target cells, CD226 activates intracellular signaling that triggers cytokine production and degranulation in NK cells. However, the role of CD226 in contact dynamics between NK and cancer cells has remained unclear. Our time-lapse images showed that individual wild-type CD226+ NK cells contacted B16F10 melanoma cells for 23.7 min, but Cd226-/- NK cells only for 12.8 min, although both NK cell subsets showed equal contact frequency over 4 h. On the surface of B16F10 cells, CD226+ cells stayed at the same site with oscillating movement (named stable contact), while Cd226-/- NK cells moved around at a velocity of 4 µm/min (named unstable contact). Consequently, Cd226-/- NK cells did not kill B16F10 cells in vitro and did not inhibit their metastasis into the lung in vivo. Taken together, our data demonstrate that CD226 enables prolonged stable interaction between NK and cancer cells, which is needed for efficient killing of cancer cells.

EPA and DHA, but not ALA, have antidepressant effects with 17ß-estradiol injection via regulation of a neurobiological system in ovariectomized rats.

Our previous studies found that n-3 polyunsaturated fatty acids (PUFAs) and estrogen had synergistic antidepressant-like effects. The purpose of the present study was to investigate the hypothesis that three major n-3 PUFAs, α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), individually had antidepressant effects combined with 17ß-estradiol-3-benzoate (E) through a neurobiological pathway in ovariectomized rats. Rats were fed a modified American Institute of Nutrition-93G diet with 0% n-3 PUFAs and 1% ALA, EPA and DHA relative to total energy intake for 12 weeks and were injected with corn oil or E every 4 days during the last 3 weeks. Supplementation of EPA, DHA and E increased serum concentrations of serotonin and climbing behavior, and decreased immobility during a forced swimming test. Supplementation with EPA, DHA and E also decreased hippocampal expressions of interleukin-6 and tumor necrosis factor-α, and increased cAMP response element binding protein, brain-derived neurotrophic factor (BDNF) and estrogen receptor-α. Immunofluorescence staining consistently showed elevated expressions of BDNF. Magnetic resonance spectroscopy showed that E increased glucose and decreased glutamate, glutamine and myo-inositol concentrations regardless of n-3 PUFA supplementation. In addition, supplementation with EPA, DHA and E decreased levels of nitrite and nitrate. However, ALA had no antidepressant effect. The present study suggested that the antidepressant-like effects of EPA and DHA supplementation and E injection could be due to the regulation of serotonergic neurotransmission and inflammatory cytokines rather than due to the antioxidative system. Supplementation with n-3 PUFA and E had the additional function of modulating neurometabolites in the hippocampus.

Cholesterol induces autophagic and apoptotic death in gastric carcinoma cells.

Despite conflicting results, there is evidence to suggest an inverse link between total body cholesterol levels and the risk of certain malignancies. Based on previous reports, this phenomenon appears to vary with cancer site, and, in particular, more consistent data on inverse relations was reported in the risk of gastric cancer. In the current study, the effect of cholesterol on gastric cancer cell viability was examined using an in vitro cell culture system. Addition of cholesterol in culture medium resulted in reduced viability and clonogenicity of SNU601, SNU638 and SNU216 gastric cancer cells by induction of both autophagic and apoptotic death. Transient inactivation of ERK1/2 was linked to reduction of cholesterol-mediated cell viability, and tumor necrosis factor­related apoptosis-inducing ligand receptor 2 (TRAIL­R2/DR5) was also involved in cell death signaling. In conclusion, these results imply that cholesterol can act as a signal regulator to modulate cell viability and that proper cellular cholesterol levels may be advantageous to suppress growth of gastric carcinomas.

Blood stream infections in patients in the burn intensive care unit.

BACKGROUND: The study on bacteremia helps empirically select the proper antibiotics before the results of culture test about causative pathogen. The purpose of this study is to investigate causative pathogen in bloodstream infection, changing aspects based on elapsed time after burn, relationship with other sites and resistance of important causative pathogen against antibiotics through analysis on bacteria isolated from blood culture of patients hospitalized in burn intensive care unit (BICU). MATERIALS AND METHODS: A retrospective study was conducted targeting patients hospitalized in BICU from January 2007 to June 2011. Changes of causative pathogen in bloodstream infection based on elapsed time after injury were analyzed. We would like to examine the relationship between bloodstream infection and infection on other body parts by comparing results of cultures in burn wound site, sputum, urine and catheter tip. Antibiotics resistance patterns of Pseudomonas aeruginosa, Acinetobacter baumannii, Staphylococcus aureus, Enterococcus species, and Klebsiella pneumoniae were studied. RESULTS: A total of 2,337 burn patients were hospitalized in BICU for 54 months. Causative pathogen was cultured in blood cultures from 397 patients (17.0%). P. aeruginosa (169, 30.1%) was the most cultured and A. baumannii (107, 19.0%) and S. aureus (81, 14.4%) were followed. It was confirmed that the relative frequency of A. baumannii tended to get lower as the period got longer after injury, but the relative frequency of K. pneumoniae got higher as the period got longer after injury. With comparison without bacteremia, P. aeruginosa bacteremia showed high probability in which the same bacteria were cultured in wound site, sputum and cathether tip, and A. baumannii bacteremia and candida bacteremia had high probability in sputum, and urine and catheter tip, respectively. 95.9% of P. aeruginosa and 95.3% of A. baumannii showed the resistance against carbapenem. 96.3% of S. aureus was methicillin resistant and 36.2% of Enterococcus species were vancomycin resistant. 75.0% of K. pneumonia were extended-spectrum beta-lactamase (ESBL)-producing bacteria. CONCLUSIONS: Since the highly antibiotic resistant microorganisms were isolated from the patients hospitalized in BICU during early phase, the empirical selection of antibiotics targeting these pathogens should be considered before the results of microbiologic culture test. In addition, use of empirical antifungal agent after 1 week of injury can be considered for patients who have risk factor of fungal infection.

Lipid raft-dependent death receptor 5 (DR5) expression and activation are critical for ursodeoxycholic acid-induced apoptosis in gastric cancer cells.

Ursodeoxycholic acid (UDCA) is known as a suppressor of cholestatic liver diseases and colorectal cancer development. Here, we demonstrate that UDCA induces apoptosis without necrotic features in SNU601, SNU638, SNU1 and SNU216 human gastric cancer cells, implying its possible use as an effective chemotherapeutic agent in treatment of gastric cancer. UDCA-induced apoptosis was dominantly mediated by an extrinsic pathway dependent on caspase-8, -6 and -3. UDCA increased expression of death receptor 5 [(DR5), also known as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 2], and this DR appeared to be responsible for UDCA-induced apoptosis, as evidenced by DR5 knockdown. UDCA triggered formation of lipid rafts that played crucial roles in UDCA-induced apoptotic actions. Lipid rafts were required not only for provision of a proper site for DR5 action but also for mediation of DR5 expression. In addition, reactive oxygen species (ROS) and protein kinase C (PKC) δ appeared to be implicated in UDCA-induced raft-dependent DR5 expression. Our results indicate that UDCA-induced apoptosis is mediated by DR5 expression, which is regulated by the raft formation/ROS production/PKCδ activation pathway and DR5 localization into lipid rafts in gastric cancer cells. Tumor-suppressive activity of UDCA was confirmed in an in vivo system: UDCA (120 mg/kg/day) significantly decreased tumor growth in gastric cancer xenograft mice. Taken together, our results demonstrate that UDCA can be used as a potent chemotherapeutic agent for treatment of gastric cancer.

Implication of PI3K-dependent HSP27 and p53 expression in mild heat shock-triggered switch of metabolic stress-induced necrosis to apoptosis in A549 cells.

Previously, we showed that mild heat shock modulates patterns of cell death in response to glucose deprivation (GD), a common characteristic of the tumor microenvironment, by switching necrosis to apoptosis through ERK-dependent suppression of reactive oxygen species production in A549 cells. In the present study, we further examined the molecular mechanism underlying mild heat shock-induced necrosis-to-apoptosis switch. We examined the possible implication of p53 and heat shock proteins (HSPs) in the mechanism. Inhibition of p53 by pifithrin-alpha or p53 siRNA markedly suppressed apoptosis induced by heat shock/GD. On the other hand, silencing of HSP27, but not of HSP70, reversed heat shock/GD-induced apoptosis to necrosis, and HSP27 overexpression suppressed GD-induced necrosis. We further demonstrate that mild heat shock activated AKT and ERK1/2 through phosphorylation. Prevention of PI3K by LY294002 blocked heat shock/GD-induced apoptosis without reversing the cell death mode to necrosis, while inhibition of MEK1/2 by U0126 reversed heat shock/GD-induced apoptosis to necrosis, indicating a different role(s) of PI3K and ERK1/2 in heat shock/GD-induced cell death mode determination. We also found that mild heat shock increased HSP27 and p53 protein levels dependent on PI3K and suppressed the GD-induced increase in RIPA-insoluble HSP27 and p53 protein levels dependent on PI3K and ERK1/2. In conclusion, these results indicate that PI3K-dependent HSP27 and p53 induction and PI3K- and ERK1/2-dependent inhibition of the GD-induced increase in RIPA-insoluble HSP27 and p53 protein levels by heat play a key role(s) in heat shock-mediated switch of GD-induced necrosis to apoptosis.