Comparison of treatment outcomes of pelvis external radiotherapy with and without vaginal brachytherapy for cervical cancer patients with positive or close vaginal resected margins.

BACKGROUND: We evaluated whether there is a difference in the local recurrence and survival after pelvic external radiotherapy (ERT) with and without boost vaginal brachytherapy (VB) in cervical cancer patients with positive or close vaginal resected margins (RM). METHODS: We retrospectively reviewed FIGO stage IA-IIB cervical cancer patients treated with postoperative ERT between 1997 and 2018. The sixty patients showing close (safety margin < 5 mm) or positive vaginal RM were included. ERT was delivered with median 50.4 Gy in 28 fractions to the pelvis and VB with median 30 Gy in 6 fractions. RESULTS: The median follow-up duration was 46 months. Five out of 30 patients treated with ERT alone experienced vaginal recurrence within 2 years after surgery. The 5-year local control (LC) was 100% in patients receiving ERT + VB compared with 81.3% in patients receiving ERT alone (log rank p = 0.022). The 5-year pelvic control (PC) was 95.8% for patients receiving ERT + VB and 76.8% for ERT alone (p = 0.041). The 5-year overall survival and recurrence-free survival (RFS) were not significantly different between treatment groups. In multivariate analysis, perineural invasion was a significant risk factor for PC (p = 0.024). Parametrial involvement (p = 0.044) and vascular invasion (p = 0.032) were unfavorable prognostic factors for RFS. Late toxicity occurrences were not significant in both groups. CONCLUSION: VB after ERT improved LC and PC in cervical cancer patients with close or positive RM after hysterectomy. The toxicities were not increased after VB was added to ERT.

15-Keto prostaglandin E2 induces heme oxygenase-1 expression through activation of Nrf2 in human colon epithelial CCD 841 CoN cells.

Prostaglandin E2 (PGE2) plays a key role in inflammation-associated carcinogenesis. NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the oxidation of the 15(S)-hydroxyl group of PGE2 to generate 15-keto PGE2. 15-PGDH has been known as a tumor suppressor in various malignancies including colon cancer. However, the molecular mechanisms underlying the tumor-suppressive function of 15-PGDH remain largely unresolved. In this study, we found that 15-keto PGE2 upregulated the expression of heme oxygenase-1 (HO-1), a representative antioxidative and anti-inflammatory enzyme, at both transcriptional and translational levels, in human colon epithelial CCD 841 CoN cells. A redox-sensitive transcription factor, NF-E2-related factor (Nrf2) plays a critical role in the regulation of HO-1 and other cytoprotective proteins. 15-Keto PGE2 induced translocation of Nrf2 into the nucleus and antioxidant response element-driven luciferase activity. Furthermore, the silencing of the Nrf2 gene abolished 15-keto PGE2-induced HO-1 expression in CCD 841 CoN cells. 15-Keto PGE2 activated AKT signaling, and the pharmacological AKT inhibitor, LY294002 suppressed the 15-keto PGE2-induced HO-1 expression. 15-Keto PGE2 generates the reactive oxygen species which is suppressed by the general antioxidant N-acetyl-l-cysteine. N-acetyl-l-cysteine treatment attenuated the 15-keto PGE2-induced phosphorylation of GSK3ß, transcriptional activity of Nrf2, and subsequently HO-1 expression. However, 13,14-dihydro-15-keto PGE2 lacking the α,ß-unsaturated carbonyl moiety failed to induce intracellular production of reactive oxygen species, HO-1 expression and nuclear translocation of Nrf2. In conclusion, 15-keto PGE2 induces HO-1 expression through Nrf2 activation in human colon epithelial cells.

Near-Infrared Transmittance Spectral Imaging for Nondestructive Measurement of Internal Disorder in Korean Ginseng.

The grading of ginseng (Panax ginseng) including the evaluation of internal quality attributes is essential in the ginseng industry for quality control. Assessment for inner whitening, a major internal disorder, must be conducted when identifying high quality ginseng. Conventional methods for detecting inner whitening in ginseng root samples use manual inspection, which is time-consuming and inaccurate. This study develops an internal quality measurement technique using near-infrared transmittance spectral imaging to evaluate inner whitening in ginseng samples. Principle component analysis (PCA) was used on ginseng hypercube data to evaluate the developed technique. The transmittance spectra and spectral images of ginseng samples exhibiting inner whitening showed weak intensity characteristics compared to normal ginseng in the region of 900-1050 nm and 1150-1400 nm respectively, owing to the presence of whitish internal tissues that have higher optical density. On the basis of the multivariate analysis method, even a simple waveband ratio image has the great potential to quickly detect inner whitening in ginseng samples, since these ratio images show a significant difference between whitened and non-whitened regions. Therefore, it is possible to develop an efficient and rapid spectral imaging system for the real-time detection of inner whitening in ginseng using minimal spectral wavebands. This novel strategy for the rapid, cost-effective, non-destructive detection of ginseng's inner quality can be a key component for the automation of ginseng grading.

Multispectral Fluorescence Imaging Technique for On-Line Inspection of Fecal Residues on Poultry Carcasses.

Rapid and reliable inspection of food is essential to ensure food safety, particularly in mass production and processing environments. Many studies have focused on spectral imaging for poultry inspection; however, no research has explored the use of multispectral fluorescence imaging (MFI) for on-line poultry inspection. In this study, the feasibility of MFI for on-line detection of fecal matter from the ceca, colon, duodenum, and small intestine of poultry carcasses was investigated for the first time. A multispectral line-scan fluorescence imaging system was integrated with a commercial poultry conveying system, and the images of chicken carcasses with fecal contaminants were scanned at processing line speeds of one, three, and five birds per second. To develop an optimal detection and classification algorithm to distinguish upper and lower feces-contaminated parts from skin, the principal component analysis (PCA) and partial least square discriminant analysis (PLS-DA) were first performed using the spectral data of the selected regions, and then applied in spatial domain to visualize the feces-contaminated area based on binary images. Our results demonstrated that for the spectral data analysis, both the PCA and PLS-DA can distinguish the high and low feces-contaminated area from normal skin; however, the PCA analysis based on selected band ratio images (F630 nm/F600 nm) exhibited better visualization and discrimination of feces-contaminated area, compared with the PLS-DA-based developed chemical images. A color image analysis using histogram equalization, sharpening, median filter, and threshold value (1) demonstrated 78% accuracy. Thus, the MFI system can be developed utilizing the two band ratios for on-line implementation for the effective detection of fecal contamination on chicken carcasses.

Magnetic resonance imaging during definitive chemoradiotherapy can predict tumor recurrence and patient survival in locally advanced cervical cancer: A multi-institutional retrospective analysis of KROG 16-01.

OBJECTIVE: Definitive chemoradiotherapy (CRT) followed by brachytherapy is a standard treatment for locally advanced cervical cancer. During CRT, marked reduction of cervical tumor is often observed in magnetic resonance imaging (MRI). The primary aim of this study was to assess the association between tumor response in MRI using FIGO classification and clinical outcomes. METHODS: Multi-institutional data were retrospectively reviewed to identify the significance of MR tumor response on tumor recurrence and patient survival. 225 patients with histologically confirmed squamous cell carcinoma of the cervix, staged as FIGO Ib2-IVa on initial pelvic MRI, were included. Post-CRT MRI was performed median 35days after the beginning of CRT and before brachytherapy. A median 54Gy of external radiation was given with weekly cisplatin during CRT. RESULTS: 112 (49.7%) of the 225 patients showed a positive response in post-CRT MRI and were named the responsive arm. After a median follow-up time of 36.2months, the responsive arm had significantly lower para-aortic recurrence (7.5% vs. 12.4%; p=0.04) and distant metastasis (13.2% vs. 27.6%; p=0.03) rates than did the non-responsive arm. The responsive arm had significantly higher 3-year cause-specific survival rate (94.6% vs. 81.1%, p<0.01) than did the non-responsive arm. In the multivariate analysis, tumor size (hazard ratio, 1.91 and 95% confidence interval, 1.07-3.43; p=0.028) and positive MR response (hazard ratio, 1.75 and 95% confidence interval, 1.06-2.27; p=0.045) were significant factors for recurrence-free survival CONCLUSION: Early tumor response evaluation with MRI using FIGO classification effectively predicted distant tumor metastasis and disease-specific survival in locally advanced cervical cancer.

Effect of Coenzyme Q10 on Radiation Nephropathy in Rats.

The kidney is one of the most radiosensitive organs in the abdominal cavity and is the dose-limiting structure in cancer patients receiving abdominal or total body irradiation. In the present study, the effect of coenzyme Q10 (CoQ10) on radiation nephropathy was evaluated in rats. A total of 72 rats were equally randomized into 4 groups: Control, CoQ10, irradiation with 10 Gy (RT) + placebo, or RT + CoQ10. The 2 RT groups received single 10 Gy of abdominal irradiation. The 2 CoQ10 groups were supplemented daily with 1 mL of soybean oil containing 10 mg/kg of CoQ10. The RT + placebo and control groups received same dose of soybean oil. After 24 weeks, laboratory and histopathologic findings were compared. The 2 RT groups showed significant increases in blood urea nitrogen (BUN) and creatinine levels and significant pathologic changes such as glomerulosclerosis and tubulointerstitial fibrosis. CoQ10 supplementation resulted in significant reductions of BUN and creatinine levels compared with the RT + placebo group (P < 0.001 and P = 0.038, respectively). CoQ10 treatment significantly attenuated glomerular and tubular changes of irradiated kidney in semiquantitative analysis (P < 0.001 for both). Administration of CoQ10 can alleviate the radiation-induced nephropathy.

Activity of ERK regulates mucin 3 expression and is involved in undifferentiated Caco-2 cell death induced by 3-oxo-C12-homoserine lactone.

The signal molecule, 3-oxo-C12-homoserine lactone (3-oxo-C12-HSL), is similar to a mammalian hormone in bacteria. Although most studies have examined the effects of high 3-oxo-C12-HSL concentrations (>200 µM) on mammalian cellular functions because ~600 µM 3-oxo-C12-HSL can be secreted in biofilms of Pseudomonas aeruginosa grown in vitro, we previously showed that a low 3-oxo-C12-HSL concentration (30 µM) induces the apoptosis of undifferentiated Caco-2 cells through suppressing Akt activity. Here, we found that a low concentration of 3-oxo-C12-HSL-activated ERK1/2 in undifferentiated Caco-2 cells. Incubating cells with the ERK pathway inhibitor U0126 for 30 min alleviated the mucin 3 (MUC3) expression suppressed by 3-oxo-C12-HSL, and the upregulation of MUC3 expression induced by a 48-h incubation with U0126-reduced cell death. Thus, altered MUC3 expression caused by long-term attenuated ERK1/2 activity might correlate with the death of undifferentiated Caco-2 cells induced by 3-oxo-C12-HSL.

Sinus irrigation as an adjunctive therapy for odontogenic maxillary sinusitis - an in-depth analysis.

BACKGROUND: Odontogenic maxillary sinusitis (OMS) is widely acknowledged in both the dentistry and otolaryngology fields. Recently, iatrogenic odontogenic maxillary sinusitis cases can be encountered frequently. The purpose of this study was to evaluate the effect of intraoral sinus irrigation using the small lateral window approach in patients with odontogenic maxillary sinusitis by comparing pre- and postoperative volumetric measurement of CBCT and symptoms. We surveyed 21 patients who visited the Oral and Maxillofacial Surgery Department at PNUDH from 2016 to 2022. All the patients' information was extracted from an electronic database. The patients with a follow-up period of 2 months or more were included. The three-dimensional volumetric measurement was performed using the ImageJ program (National Institute of Health, University of Wisconsin). RESULTS: Among 21 patients, 16 (76.1%) were male, and 5 (23%) were female. The most common type of surgery was general anesthesia (16 cases) in which oroantral fistula was present in 7 cases. In the causes of maxillary sinusitis, there were seven implant-related patients, five patients of tooth extraction, seven patients of bone grafting, and two patients in other groups. Radiographic opacity decreased by 40.15% after sinus irrigation especially in bone graft and tooth extraction cases. Clinically, symptoms improved in 17 patients (80.9%). CONCLUSION: By this study, it can be concluded that maxillary sinus irrigation using the small lateral window approach is a clinically and radiologically effective treatment method for odontogenic maxillary sinusitis.

Contribution of the 7ß-hydroxysteroid dehydrogenase from Ruminococcus gnavus N53 to ursodeoxycholic acid formation in the human colon.

Bile acid composition in the colon is determined by bile acid flow in the intestines, the population of bile acid-converting bacteria, and the properties of the responsible bacterial enzymes. Ursodeoxycholic acid (UDCA) is regarded as a chemopreventive beneficial bile acid due to its low hydrophobicity. However, it is a minor constituent of human bile acids. Here, we characterized an UDCA-producing bacterium, N53, isolated from human feces. 16S rDNA sequence analysis identified this isolate as Ruminococcus gnavus, a novel UDCA-producer. The forward reaction that produces UDCA from 7-oxo-lithocholic acid was observed to have a growth-dependent conversion rate of 90-100% after culture in GAM broth containing 1 mM 7-oxo-lithocholic acid, while the reverse reaction was undetectable. The gene encoding 7ß-hydroxysteroid dehydrogenase (7ß-HSDH), which facilitates the UDCA-producing reaction, was cloned and overexpressed in Escherichia coli. Characterization of the purified 7ß-HSDH revealed that the kcat/Km value was about 55-fold higher for the forward reaction than for the reverse reaction, indicating that the enzyme favors the UDCA-producing reaction. As R. gnavus is a common, core bacterium of the human gut microbiota, these results suggest that this bacterium plays a pivotal role in UDCA formation in the colon.

Retrospective analysis of treatment outcomes for extranodal NK/T-cell lymphoma (ENKL), nasal type, stage I-IIE: single institute experience of combined modality treatment for early localized nasal extranodal NK/T-cell lymphoma (ENKL).

Extranodal natural killer/T-cell lymphoma (ENKL) is a very aggressive disease frequently involving the nasal cavity and upper aerodigestive tract. We retrospectively reviewed the treatment outcomes and treatment-associated complications of the patients with stage I-II early localized ENKL. A total of 24 patients were included. All patients were treated with combined chemoradiotherapy. Three, sixteen, and five patients were initially treated with radiation therapy, chemotherapy, and surgical procedures, respectively. Nine patients underwent hematopoietic stem cell transplantation (HSCT), and four patients administered immunotherapy with pegylated-interferon alpha. The mean observation time was 71.6 months (range, 29.7-183.6 months). Twenty patients achieved complete remission; thus, the overall response rate was 83.3 %. The 5-year overall survival (OS) and relapse-free survival (RFS) rates were 70.3 % and 62.2 %, respectively. In univariate analysis, HSCT was a significant prognostic indicator for OS and RFS. By combining HSCT, the 5-year OS and RFS rates were 100.0 % vs. 52.5 % (p = 0.018) and 88.9 % vs. 45.7 % (p = 0.045), respectively. Also, absence of B symptoms was a good prognostic factor for RFS, the 5-year RFS rate, 75.0 % vs. 25.0 % (p = 0.010), and B symptoms were significant for RFS in multivariate analysis (odds ratio = 7.4, confidence interval = 1.6~34.1, p = 0.011). However, a total of four cases of grade 3 toxicities were reported. Radiation dose range (≤4,500 vs. >4,500 cGy) was significantly correlated with late complications, as more severe complications occurred more frequently with a radiation dose >4,500 cGy (p = 0.026, in multivariate analysis). For more efficient treatment of ENKL, chemotherapy, HSCT, and/or immunotherapy can be combined with radiation therapy to prolong long-term survival and achieve good local control. Also, lower radiation dose could be administered to avoid severe late complications.

Retrospective review of angiography before cannulation of newly created vascular accesses in hemodialysis patients.

PURPOSE: To investigate vascular access status before first cannulation and the clinical implications of angiography performed before cannulation. MATERIALS AND METHODS: A retrospective review of 300 consecutive patients who underwent angiography after vascular access surgery and before cannulation between August 2004 and April 2010 was performed. Angiography was performed 4-6 weeks after the surgery but before the first cannulation. RESULTS: Angiography revealed 94 (31.3%) cases of severe stenosis (≥ 50% luminal narrowing) that required percutaneous transluminal angioplasty (PTA) or a second operation. No stenosis was observed in 122 (40.7%) cases, and mild stenosis (< 50% luminal narrowing) was observed in 84 (28%) cases. For the 94 cases with severe stenosis, PTA was performed in 66, and a second operation was performed in 16. In the other cases (n = 12), HD was maintained by a permanent catheter, or the patients were transferred to another institution. PTA was an immediate success in all patients who underwent the procedure except two. Of 84 patients with mild stenosis, 70 were followed for 1 year; vascular access dysfunction occurred in 15, and 11 of these underwent successful PTA. Of the 122 patients with normal angiographic findings, 102 were followed for 1 year, and vascular access dysfunction did not occur in any of these patients. CONCLUSIONS: Early postoperative angiography before the first hemodialysis is helpful for the early detection and treatment of vascular access dysfunction.

Optimal timing for local ablative treatment of bone oligometastases in non-small cell lung cancer.

Oligometastases is a term commonly used to describe a disease state characterized by a limited number of distant metastases, and represents a transient phase between localized and widespread systemic diseases. This subgroup of stage IV cancer has increased in clinical importance due to the possibility of curative rather than palliative treatment. Among advanced lung cancer patients, 30-40% show bone metastases, and can show complications such as pathological fractures. Many prospective studies have shown efficacy of localized treatment in oligometastatic non-small cell lung cancer (NSCLC) in improving progression-free survival and overall survival. Compared to metastases in other organs, bone metastases are unique in terms of tumor microenvironment and clinical outcomes. Radiotherapy is the most frequently used treatment modality for local ablative treatment for both primary and metastatic lesions. Stereotactic body radiation therapy demonstrated more rapid and effective pain control compared to conventional 3D conformal radiotherapy. Radiotherapy improved outcomes in terms of time-to-skeletal related events skeletal-related events (SRE), hospitalization for SRE, pain relief, and overall survival in patients with bone metastases. Decision on timing of local ablative treatment depends on patient's overall clinical status, treatment goals, potential side effects of each approach, and expected initial responses to systemic anti-cancer treatment.

Parent involvement in school: English speaking versus Spanish speaking families.

The purpose of the present study was to explore the relationships between three predictor variables (attitude toward school, parent-child communication, and school commitment action) and the criterion variable (parent involvement) in a representative sample and to examine if these relationships were consistent across three groups (English speaking Caucasian family, English speaking Latino family, and Spanish speaking Latino families). Using a national database (N = 9.841), multi-group SEM analyses were conducted to investigate the relationship between three predictor variables and the criterion variable in three family groups. While all three predictor variables significantly predicted parent involvement in English speaking Caucasian and Latino families, only two variables (parent-child communication and school commitment actions), significantly predicted parent involvement in Spanish speaking Latino families. The results of this study suggest that when administrators, teachers and counselors in school strive to share specific school-related information with Latino families, Spanish speaking families are more likely to become involved with schools.

Effects of Lymphovenous Anastomosis Surgery Using Ultrasonography in Lymphedema From a Pressure Perspective.

OBJECTIVE: To analyze the effects of lymphovenous anastomosis (LVA) surgery after 1 year using the elastic index (EI) and volume. METHODS: This study was a retrospective study of 41 patients, with lymphedema, who underwent LVA surgery between July 2018 and June 2020. Limb circumference, used to determine the volume of the limb with lymphedema, and EI, which reflects tissue stiffness and measured using ultrasonography were measured for each patient before and 1 year after LVA surgery. To examine the effect of LVA, differences in the preoperative and 1-year postoperative volumes and EIs were analyzed using the Wilcoxon signed-rank test. RESULTS: The mean volume and EI of the dominant site in upper-extremity lymphedema were 2,309.4 cm3 and 1.4, respectively, preoperatively and 2,237.1 cm3 and 0.9, respectively, at 1 year postoperatively. The mean volume and EI difference of the dominant site 1 year after surgery was -16.6 cm3 (p=0.22) and -0.5 (p<0.001). The mean volume and EI of dominant site in lower-extremity lymphedema were 6,137.0 cm3 and 1.2, respectively, preoperatively, and 5,832.6 cm3 and 1.1, respectively, at 1 year postoperatively. The mean volume and EI difference of the dominant site 1 year postoperatively were -320.9 cm3 (p=0.04) and -0.2 (p=0.09), respectively. CONCLUSION: LVA surgery is more effective in reducing pressure than in reducing volume, which may be helpful in preventing the progression of lymphedema.

Development of Prediction Models for Acute Myocardial Infarction at Prehospital Stage with Machine Learning Based on a Nationwide Database.

Models for predicting acute myocardial infarction (AMI) at the prehospital stage were developed and their efficacy compared, based on variables identified from a nationwide systematic emergency medical service (EMS) registry using conventional statistical methods and machine learning algorithms. Patients in the EMS cardiovascular registry aged >15 years who were transferred from the public EMS to emergency departments in Korea from January 2016 to December 2018 were enrolled. Two datasets were constructed according to the hierarchical structure of the registry. A total of 184,577 patients (Dataset 1) were included in the final analysis. Among them, 72,439 patients (Dataset 2) were suspected to have AMI at prehospital stage. Between the models derived using the conventional logistic regression method, the B-type model incorporated AMI-specific variables from the A-type model and exhibited a superior discriminative ability (p = 0.02). The models that used extreme gradient boosting and a multilayer perceptron yielded a higher predictive performance than the conventional logistic regression-based models for analyses that used both datasets. Each machine learning algorithm yielded different classification lists of the 10 most important features. Therefore, prediction models that use nationwide prehospital data and are developed with appropriate structures can improve the identification of patients who require timely AMI management.

Hyperglycemic hyperosmolar syndrome caused by steroid therapy in a patient with lupus nephritis.

A 51-yr-old female was referred to our outpatient clinic for the evaluation of generalized edema. She had been diagnosed with idiopathic thrombocytopenic purpura (ITP). She had taken no medicine. Except for the ITP, she had no history of systemic disease. She was diagnosed with systemic lupus erythematosus. Immunosuppressions consisting of high-dose steroid were started. When preparing the patient for discharge, a generalized myoclonic seizure occurred at the 47th day of admission. At that time, the laboratory and neurology studies showed hyperglycemic hyperosmolar syndrome. Brain MRI and EEG showed brain atrophy without other lesion. The seizure stopped after the blood sugar and serum osmolarity declined below the upper normal limit. The patient became asymptomatic and she was discharged 10 weeks after admission under maintenance therapy with prednisolone, insulin glargine and nateglinide. The patient remained asymptomatic under maintenance therapy with deflazacort and without insulin or medication for blood sugar control.

Economic Analysis of the Use of VCS2000 for Pork Carcass Meat Yield Grading in Korea.

Currently, the pork industry is incorporating in-line automation with the aim of increasing the slaughtered pork carcass throughput while monitoring quality and safety. In Korea, 21 parameters (such as back-fat thickness and carcass weight) are used for quality grading of pork carcasses. Recently, the VCS2000 system-an automatic meat yield grading machine system-was introduced to enhance grading efficiency and therefore increase pork carcass production. The VCS2000 system is able to predict pork carcass yield based on image analysis. This study also conducted an economic analysis of the system using a cost-benefit analysis. The subsection items of the cost-benefit analysis considered were net present value (NPV), internal rate of return (IRR), and benefit/cost ratio (BC ratio), and each method was verified through sensitivity analysis. For our analysis, the benefits were grouped into three categories: the benefits of reducing labor costs, the benefits of improving meat yield production, and the benefits of reducing pig feed consumption through optimization. The cost-benefit analysis of the system resulted in an NPV of approximately 615.6 million Korean won, an IRR of 13.52%, and a B/C ratio of 1.65.

Event Prediction Model Considering Time and Input Error Using Electronic Medical Records in the Intensive Care Unit: Retrospective Study.

BACKGROUND: In the era of artificial intelligence, event prediction models are abundant. However, considering the limitation of the electronic medical record-based model, including the temporally skewed prediction and the record itself, these models could be delayed or could yield errors. OBJECTIVE: In this study, we aim to develop multiple event prediction models in intensive care units to overcome their temporal skewness and evaluate their robustness against delayed and erroneous input. METHODS: A total of 21,738 patients were included in the development cohort. Three events-death, sepsis, and acute kidney injury-were predicted. To overcome the temporal skewness, we developed three models for each event, which predicted the events in advance of three prespecified timepoints. Additionally, to evaluate the robustness against input error and delays, we added simulated errors and delayed input and calculated changes in the area under the receiver operating characteristic curve (AUROC) values. RESULTS: Most of the AUROC and area under the precision-recall curve values of each model were higher than those of the conventional scores, as well as other machine learning models previously used. In the error input experiment, except for our proposed model, an increase in the noise added to the model lowered the resulting AUROC value. However, the delayed input did not show the performance decreased in this experiment. CONCLUSIONS: For a prediction model that was applicable in the real world, we considered not only performance but also temporal skewness, delayed input, and input error.

12α-Hydroxylated bile acid induces hepatic steatosis with dysbiosis in rats.

There is an increasing need to explore the mechanism of the progression of non-alcoholic fatty liver disease. Steroid metabolism is closely linked to hepatic steatosis and steroids are excreted as bile acids (BAs). Here, we demonstrated that feeding WKAH/HkmSlc inbred rats a diet supplemented with cholic acid (CA) at 0.5 g/kg for 13 weeks induced simple steatosis without obesity. Liver triglyceride and cholesterol levels were increased accompanied by mild elevation of aminotransferase activities. There were no signs of inflammation, insulin resistance, oxidative stress, or fibrosis. CA supplementation increased levels of CA and taurocholic acid (TCA) in enterohepatic circulation and deoxycholic acid (DCA) levels in cecum with an increased ratio of 12α-hydroxylated BAs to non-12α-hydroxylated BAs. Analyses of hepatic gene expression revealed no apparent feedback control of BA and cholesterol biosynthesis. CA feeding induced dysbiosis in cecal microbiota with enrichment of DCA producers, which underlines the increased cecal DCA levels. The mechanism of steatosis was increased expression of Srebp1 (positive regulator of liver lipogenesis) through activation of the liver X receptor by increased oxysterols in the CA-fed rats, especially 4ß-hydroxycholesterol (4ßOH) formed by upregulated expression of hepatic Cyp3a2, responsible for 4ßOH formation. Multiple regression analyses identified portal TCA and cecal DCA as positive predictors for liver 4ßOH levels. The possible mechanisms linking these predictors and upregulated expression of Cyp3a2 are discussed. Overall, our observations highlight the role of 12α-hydroxylated BAs in triggering liver lipogenesis and allow us to explore the mechanisms of hepatic steatosis onset, focusing on cholesterol and BA metabolism.

15-Deoxy-Δ12,14-prostaglandin J2 up-regulates the expression of 15-hydroxyprostaglandin dehydrogenase through DNA methyltransferase 1 inactivation.

15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is the key enzyme that catalyses the conversion of prostaglandin E2 to a keto metabolite. The expression of 15-PGDH is ubiquitously repressed in various human malignancies. However, the molecular mechanisms underlying down-regulation of 15-PGDH expression remain largely unknown. 15-Deoxy-△12,14-prostaglandin J2 (15d-PGJ2), an endogenous ligand of peroxisome proliferator-activated receptor γ, has been reported to have anti-inflammatory and anticarcinogenic activities. In the present study, we have found that 15d-PGJ2 induces expression and catalytic activity of 15-PGDH in human breast cancer (MDA-MB-231) cells. 15d-PGJ2 decreased the level of CpG methylation in the 15-PGDH promoter in MDA-MB-231 cells as determined by the bisulphite genome sequencing and methyl-specific PCR. 15d-PGJ2 inhibited the catalytic activity of methyltransferase 1 (DNMT1) but did not influence its expression. Biotinylated 15d-PGJ2 directly interacted with DNMT1 and reduced its catalytic activity. Chromatin-immunoprecipitation analysis revealed that 15d-PGJ2 significantly attenuated DNMT1 binding to the activator protein-1 transcription factor present in the 15-PGDH promoter region. A nonelectrophilic analogue 9,10-dihydro-15d-PGJ2 failed to suppress the methylation of CpG islands present in 15-PGDH promoter and did not affect both DNMT1 activity and 15-PGDH expression. These findings suggest that the α,ß-unsaturated carbonyl group present in 15d-PGJ2 is essential for its inactivation on DNMT1 and expression of 15-PGDH. In conclusion, 15d-PGJ2 plays as a hypomethylating agent through direct interaction with DNMT1 and consequently suppresses DNMT1-mediated hypermethylation of 15-PGDH promoter, leading to up-regulation of 15-PGDH expression.