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Background/aim: To investigate whether high-dose-rate (HDR) intracavitary brachytherapy (IBT) dose ratios can predict treatment outcomes in patients with stage IIB cervical cancer., Patients and Methods: Ninety-three patients treated with weekly cisplatin-based concurrent chemoradiotherapy and HDR IBT were analyzed. Potential prognostic factors and treatment outcomes were compared between low-HDR-IBT-ratio (≤0.43) and high-HDR-IBT-ratio (>0.43) groups, and univariate and multivariate analyses were performed., Results: Five-year disease-specific survival (DSS) and progression-free survival (PFS) rates were significantly shorter in the low-compared to the high-HDR-IBT-ratio group. A high HDR IBT ratio was confirmed as an independent prognostic factor for DSS and PFS., Conclusion: A high HDR IBT dose ratio improves DSS and PFS in patients with stage IIB cervical cancer. Therefore, active administration of HDR IBT beyond previously accepted levels may be necessary for the treatment of locally advanced cervical cancer., (Copyright© 2017 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Compared to other foods, the use of common bio-elements to identify the geographical origin of potato remains limited. Thus, this study aimed to verify whether the cultivation regions of raw potato tubers could be determined by the stable isotope composition analysis of bio-elements. δ(13)CVPDB and δ(15)NAIR in potato were influenced by region and cultivar, whereas δ(18)OVSMOW and δ(34)SVCDT were only influenced by region (p<0.0001). A two-dimensional plot of δ(18)OVSMOW and δ(34)SVCDT effectively distinguished between high and low altitude regions, and also reliably discriminated Wanju, Haenam, and Boseong cultivars in low altitude regions. δ(34)SVCDT was the main component that was responsible for the separation of samples in the principal component analysis (eigenvector of -0.6209) and orthogonal projection to latent structure-discriminant analysis (VIP value of 1.0566). In conclusion, this study improves our understanding of how the isotope composition of potato tubers varies with respect to cultivation regions and cultivars., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Oxidative stress in primary aldosteronism (PA) is thought to worsen aldosterone-induced damage by activating proinflammatory processes. Therefore, we investigated whether inflammatory markers associated with oxidative stress is increased with negative impacts on heart function as evaluated by echocardiography in patients with PA., Methods: Thirty-two subjects (mean age, 50.3±11.0 years; 14 males, 18 females) whose aldosterone-renin ratio was more than 30 among patients who visited Severance Hospital since 2010 were enrolled. Interleukin-1β (IL-1β), IL-6, IL-8, monocyte chemoattractant protein 1, tumor necrosis factor α (TNF-α), and matrix metalloproteinase 2 (MMP-2), and MMP-9 were measured. All patients underwent adrenal venous sampling with complete access to both adrenal veins., Results: Only MMP-2 level was significantly higher in the aldosterone-producing adenoma (APA) group than in the bilateral adrenal hyperplasia (BAH). Patients with APA had significantly higher left ventricular (LV) mass and A velocity, compared to those with BAH. IL-1β was positively correlated with left atrial volume index. Both TNF-α and MMP-2 also had positive linear correlation with A velocity. Furthermore, MMP-9 showed a positive correlation with LV mass, whereas it was negatively correlated with LV end-systolic diameter., Conclusion: These results suggest the possibility that some of inflammatory markers related to oxidative stress may be involved in developing diastolic dysfunction accompanied by LV hypertrophy in PA. Further investigations are needed to clarify the role of oxidative stress in the course of cardiac remodeling., Competing Interests: No potential conflict of interest relevant to this article was reported.

Purpose: The objective of this prospective study was to evaluate the relationship between the circulating lymphocyte subpopulation counts during preoperative chemoradiotherapy (CRT) and tumor response in locally advanced rectal cancer., Materials and Methods: From August 2015 to June 2016, 10 patients treated with preoperative CRT followed by surgery were enrolled. Patients received conventional fractionated radiotherapy (50.4 Gy) with fluorouracil-based chemotherapy. Surgical resection was performed at 4 to 8 weeks after the completion of preoperative CRT. The absolute blood lymphocyte subpopulation was obtained prior to and after 4 weeks of CRT. We analyzed the association between a tumor response and change in the lymphocyte subpopulation during CRT., Results: Among 10 patients, 2 (20%) had evidence of pathologic complete response. In 8 patients with clinically node positive, 4 (50%) had nodal tumor response. All lymphocyte subpopulation counts at 4 weeks after CRT were significantly lower than those observed during pretreatment (p < 0.01). A high decrease in natural killer (NK) cell, count during CRT (baseline cell count - cell count at 4 weeks) was associated with node down staging (p = 0.034)., Conclusion: Our results suggest that the change of lymphocyte subset to preoperative CRT may be a predictive factor for tumor response in rectal cancer., Competing Interests: No potential conflict of interest relevant to this article was reported.

Previous rodent studies showed that when injected into the brain, free fatty acids (FFAs) reduced food intake in an oleate-specific manner. The present study was performed to test whether food intake is regulated by circulating FFAs in an oleate-specific manner. Male Wistar rats received an intravenous infusion of olive, safflower, or coconut oil (100mg/h), together with heparin, to raise circulating oleate, linoleate, or palmitate, respectively, and their effects on overnight food intake were evaluated. Compared to other oils, olive oil infusion showed a significantly greater effect to reduce food intake (P<0.01). Total caloric intake, the sum of the calories from the diet and infused oil, was significantly reduced with olive oil (P<0.01) but not with coconut or safflower oil infusion, suggesting an oleate-specific effect on caloric intake. To further test this idea, different groups of rats received an intravenous infusion of oleate, linoleate, or octanoate (0.5mg/h). Oleate infusion decreased overnight food intake by 26% (P<0.001), but no significant effect was seen with linoleate, octanoate, or vehicle infusion (P>0.05). The effects of olive oil or oleate infusion could not be explained by changes in plasma glucose, insulin, leptin, or total FFA levels. The olive oil effect on food intake was not reduced in vagotomized rats, suggesting that oleate sensing may not involve peripheral sensors. In contrast, olive oil's effect was attenuated in high-fat-fed rats, suggesting that this effect is regulated (or impaired) under physiological (or pathological) conditions. Taken together, the present study provides evidence that circulating oleate is sensed by the brain differentially from other FFAs to control feeding in rats., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Vibrio cholerae , a Gram-negative bacterium, is the causative agent of pandemic cholera. Previous studies have shown that the survival of the seventh pandemic El Tor biotype V. cholerae strain N16961 requires production of acetoin in a glucose-rich environment. The production of acetoin, a neutral fermentation end-product, allows V. cholerae to metabolize glucose without a pH drop, which is mediated by the production of organic acid. This finding suggests that inhibition of acetoin fermentation can result in V. cholerae elimination by causing a pH imbalance under glucose-rich conditions. Here, we developed a simple high-throughput screening method and identified an inducer of medium acidification (iMAC). Of 8364 compounds screened, we identified one chemical, 5-(4-chloro-2-nitrobenzoyl)-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)-dione, that successfully killed glucose-metabolizing N16961 by inducing acidic stress. When N16961 was grown with abundant glucose in the presence of iMAC, acetoin production was completely suppressed and concomitant accumulation of lactate and acetate was observed. Using a beta-galactosidase activity assay with a single-copy p alsD::lacZ reporter fusion, we show that that iMAC likely inhibits acetoin production at the transcriptional level. Thin-layer chromatography revealed that iMAC causes a significantly reduced accumulation of intracellular (p)ppGpp, a bacterial stringent response alarmone known to positively regulate acetoin production. In vivo bacterial colonization and fluid accumulation were also markedly decreased after iMAC treatment. Finally, we demonstrate iMAC-induced bacterial killing for 22 different V. cholerae strains belonging to diverse serotypes. Together, our results suggest that iMAC, acting as a metabolic modulator, has strong potential as a novel antibacterial agent for treatment against cholera.

Death receptor 4 (DR4) is a cell surface receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and triggers apoptosis upon ligation with TRAIL or aggregation. MEK/ERK signaling is a well known and the best-studied effector pathway downstream of Ras and Raf. This study focuses on determining the impact of pharmacological MEK inhibition on DR4 expression and elucidating the underlying mechanism. We found that several MEK inhibitors including MEK162, AZD6244, and PD0325901 effectively decreased DR4 protein levels including cell surface DR4 in different cancer cell lines. Accordingly, pre-treatment of TRAIL-sensitive cancer cell lines with a MEK inhibitor desensitized them to TRAIL-induced apoptosis. These results indicate that MEK inhibition negatively regulates DR4 expression and cell response to TRAIL-induced apoptosis. MEK inhibitors did not alter DR4 protein stability, rather decreased its mRNA levels, suggesting a transcriptional regulation. In contrast, enforced activation of MEK/ERK signaling by expressing ectopic B-Raf (V600E) or constitutively activated MEK1 (MEK1-CA) or MEK2 (MEK2-CA) activated ERK and increased DR4 expression; these effects were inhibited when a MEK inhibitor was present. Promoter analysis through deletion and mutation identified the AP-1 binding site as an essential response element for enhancing DR4 transactivation by MEK1-CA. Furthermore, inhibition of AP-1 by c-Jun knockdown abrogated the ability of MEK1-CA to increase DR4 promoter activity and DR4 expression. These results suggest an essential role of AP-1 in mediating MEK/ERK activation-induced DR4 expression. Our findings together highlight a previously undiscovered mechanism that positively regulates DR4 expression through activation of the MEK/ERK/AP-1 signaling pathway., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Aims: This study aimed to evaluate the effects of esmolol treatment for patients with refractory ventricular fibrillation (RVF) in out-of-hospital cardiac arrest (OHCA)., Methods: This single-centre retrospective pre-post study evaluated patients who were treated between January 2012 and December 2015. Some patients had received esmolol (loading dose: 500μg/kg, infusion: 0-100μg/kg/min) for RVF (≥3 defibrillation attempts), after obtaining consent from the patient's guardian., Results: Twenty-five patients did not receive esmolol (the control group), and 16 patients received esmolol. Sustained return of spontaneous circulation (ROSC) was significantly more common in the esmolol group, compared to the control group (56% vs. 16%, p=0.007). Survival and good neurological outcomes at 30 days, 3 months and at 6 months were >2-fold better in the esmolol group, compared to the control group, although these increases were not statistically significant., Conclusions: The findings of our study suggest that administration of esmolol may increase the rate of sustained ROSC and ICU survival among patients with RVF in OHCA. Further larger-scale, prospective studies are necessary to determine the effect of esmolol for RVF in OHCA., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The 3rd generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs; e.g., AZD9291), which selectively and irreversibly inhibit EGFR activating and T790M mutants, represent very promising therapeutic options for patients with non-small cell lung cancer (NSCLC) that has become resistant to 1st generation EGFR-TKIs due to T790M mutation. However, eventual resistance to the 3rd generation EGFR-TKIs has already been described in the clinic, resulting in disease progression. Therefore, there is a great challenge and urgent need to understand how this resistance occurs and to develop effective strategies to delay or overcome the resistance. The current study has demonstrated that Met amplification and hyperactivation is a resistance mechanism to both 1st and 3rd generation EGFR-TKIs since both erlotinib- and AZD9291-resistant HCC827 cell lines possessed amplified Met gene and hyperactivated Met, and were cross-resistant to AZD9291 or erlotinib. Met inhibition overcame the resistance of these cell lines to AZD9291 both in vitro and in vivo, including enhancement of apoptosis or G1 cell cycle arrest. Hence, we suggest that Met inhibition is also an effective strategy to overcome resistance of certain EGFR-mutated NSCLCs with Met amplification to AZD9291, warranting the further clinical validation of our findings., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Our institution has implemented two different adjuvant protocols in treating patients with non-small cell lung cancer (NSCLC): chemotherapy followed by concurrent chemoradiotherapy (CT-CCRT) and sequential postoperative radiotherapy (PORT) followed by postoperative chemotherapy (POCT). We aimed to compare the clinical outcomes between the two adjuvant protocols., Materials and Methods: From March 1997 to October 2012, 68 patients were treated with CT-CCRT (n = 25) and sequential PORT followed by POCT (RT-CT; n = 43). The CT-CCRT protocol consisted of 2 cycles of cisplatin-based POCT followed by PORT concurrently with 2 cycles of POCT. The RT-CT protocol consisted of PORT followed by 4 cycles of cisplatin-based POCT. PORT was administered using conventional fractionation with a dose of 50.4-60 Gy. We compared the outcomes between the two adjuvant protocols and analyzed the clinical factors affecting survivals., Results: Median follow-up time was 43.9 months (range, 3.2 to 74.0 months), and the 5-year overall survival (OS), locoregional recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were 53.9%, 68.2%, and 51.0%, respectively. There were no significant differences in OS (p = 0.074), LRFS (p = 0.094), and DMFS (p = 0.490) between the two protocols. In multivariable analyses, adjuvant protocol remained as a significant prognostic factor for LRFS, favouring CT-CCRT (hazard ratio [HR] = 3.506, p = 0.046) over RT-CT, not for OS (HR = 0.647, p = 0.229)., Conclusion: CT-CCRT protocol increased LRFS more than RT-CT protocol in patients with completely resected NSCLC, but not in OS. Further studies are warranted to evaluate the benefit of CCRT strategy compared with sequential strategy., Competing Interests: No potential conflict of interest relevant to this article was reported.

Objectives: To determine whether the Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) helps predict biochemical recurrence (BCR) after radical prostatectomy for prostate cancer (PCa)., Methods: We included 158 patients with PCa who underwent magnetic resonance imaging (MRI) and radical prostatectomy (RP). Clinical (prostate-specific antigen, greatest percentage of core, and percentage of positive core number), PI-RADSv2 score on MRI, and surgical parameters (Gleason score, extracapsular extension, seminal vesicle invasion, and tumour volume) were investigated. Univariate and multivariate analyses using Cox's proportional hazards model were performed to assess parameters predictive of BCR (two consecutive prostate specific antigens ≥0.2 ng/ml). Kaplan-Meier survival curves were analyzed., Results: The rate of BCR was 13.3 % (21/158) after surgery (median follow-up, 25 months; range, 12-36). No subject with a PI-RADS score <4 had BCR. In univariate analysis, all parameters were significant for BCR (p < 0.05), except seminal vesicle invasion (p = 0.254). Meanwhile, PI-RADS score was the only independent parameter for BCR in multivariate analysis (p < 0.05). Two-year, BCR-free survival post-RP was significantly lower for PI-RADS ≥4 (84.7-85.5 %) than for PI-RADS <4 (100 %; p < 0.05)., Conclusion: As a preoperative imaging tool, PI-RADSv2 may be useful to predict BCR after radical prostatectomy for PCa., Key Points: • No subject with PI-RADS <4 had BCR after RP • PI-RADSv2 was the only predictor of BCR in multivariate analysis • Two-year, BCR-free survival following RP was lower for PI-RADS≥4 than for PI-RADS<4 • Inter-rater agreement was good for PI-RADS ≥4 or not.

Purpose To retrospectively analyze whether Prostate Imaging Reporting and Data System (PI-RADS) version 2 is helpful for the detection of clinically significant prostate cancer. Materials and Methods Institutional review board approved this retrospective study. A total of 425 patients with prostate cancer who had undergone magnetic resonance (MR) imaging and radical prostatectomy were included. Preoperative parameters such as prostate-specific antigen, biopsy Gleason score, greatest percentage of the core, percentage of the positive core number, and score at PI-RADS version 2 with MR imaging were investigated. Two independent readers performed PI-RADS scoring. Clinically significant prostate cancer was defined as follows: (a) Gleason score of 7 or greater, (b) tumor volume of 0.5 cm(3) or greater, or a (c) positive extracapsular extension or seminal vesicle invasion. The reference standard was based on review of surgical specimen. Logistic regression was conducted to determine which parameters are associated with the presence of clinically significant cancer. Interreader agreement (ie, score ≥4 or not) was investigated by using κ statistics. Results At univariate analysis, all of the preoperative parameters were significant for clinically significant prostate cancer (P < .05). However, multivariate analysis revealed that PI-RADS score was the only significant parameter for both readers (reader 1: odds ratio = 28.170, P = .002; reader 2: odds ratio = 5.474, P = .007). The interreader agreement was excellent for PI-RADS score of 4 or greater (weighted κ = 0.801; 95% confidence interval: 0.737, 0.865). Conclusion The use of PI-RADS version 2 may help preoperatively diagnose clinically significant prostate cancer. (©) RSNA, 2016.

Aim: To investigate whether common terminology criteria for adverse events (CTCAE) grade 4 lymphopenia (<200 cells/μl) during concurrent chemoradiotherapy (CCRT) is relevant to poor survival., Patients and Methods: We analyzed 124 patients with newly diagnosed Federation of Gynecology and Obstetrics (FIGO) stage I-III cervical cancer who received weekly cisplatin-based CCRT and brachytherapy using Kaplan-Meier curves and the Cox proportional hazard models., Results: Grade 4 lymphopenia significantly predicted disease-specific survival (DSS) and progression-free survival (PFS) (adjusted hazard ratio (95% confidence interval (CI))=3.6 (1.37-9.44), p=0.009 and 3.28 (1.27-8.48), p=0.014, respectively). The 5-year DSS and 3-year PFS were significantly higher among patients with grade 2-3 lymphopenia (≥200 cells/μl) than among those with grade 4 lymphopenia (84.8% vs. 50.4%, p<0.001, and 80.7% vs. 50%, p=0.002, respectively)., Conclusion: Severe lymphopenia during CCRT could predict poor survival., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

The aim of this study was to compare the accuracy of and the time required for image fusion between real-time ultrasonography (US) and pre-procedural magnetic resonance (MR) images using automatic registration by a liver surface only method and automatic registration by a liver surface and vessel method. This study consisted of 20 patients referred for planning US to assess the feasibility of percutaneous radiofrequency ablation or biopsy for focal hepatic lesions. The first 10 consecutive patients were evaluated by an experienced radiologist using the automatic registration by liver surface and vessel method, whereas the remaining 10 patients were evaluated using the automatic registration by liver surface only method. For all 20 patients, image fusion was automatically executed after following the protocols and fused real-time US and MR images moved synchronously. The accuracy of each method was evaluated by measuring the registration error, and the time required for image fusion was assessed by evaluating the recorded data using in-house software. The results obtained using the two automatic registration methods were compared using the Mann-Whitney U-test. Image fusion was successful in all 20 patients, and the time required for image fusion was significantly shorter with the automatic registration by liver surface only method than with the automatic registration by liver surface and vessel method (median: 43.0 s, range: 29-74 s vs. median: 83.0 s, range: 46-101 s; p = 0.002). The registration error did not significantly differ between the two methods (median: 4.0 mm, range: 2.1-9.9 mm vs. median: 3.7 mm, range: 1.8-5.2 mm; p = 0.496). The automatic registration by liver surface only method offers faster image fusion between real-time US and pre-procedural MR images than does the automatic registration by liver surface and vessel method. However, the degree of accuracy was similar for the two methods., (Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Purpose: We compared the treatment results and toxicity in nasopharyngeal carcinoma (NPC) patients treated with concurrent chemotherapy (CCRT) alone (the CRT arm) or neoadjuvant chemotherapy followed by CCRT (the NCT arm)., Materials and Methods: A multi-institutional retrospective study was conducted to review NPC patterns of care and treatment outcome. Data of 568 NPC patients treated by CCRT alone or by neoadjuvant chemotherapy followed by CCRT were collected from 15 institutions. Patients in both treatment arms were matched using the propensity score matching method, and the clinical outcomes were analyzed., Results: After matching, 300 patients (150 patients in each group) were selected for analysis. Higher 5-year locoregional failure-free survival was observed in the CRT arm (85% vs. 72%, p=0.014). No significant differences in distant failure-free survival (DFFS), disease-free survival (DFS), and overall survival were observed between groups. In subgroup analysis, the NCT arm showed superior DFFS and DFS in stage IV patients younger than 60 years. No significant difference in compliance and toxicity was observed between groups, except the radiation therapy duration was slightly shorter in the CRT arm (50.0 days vs. 53.9 days, p=0.018)., Conclusion: This study did not show the superiority of NCT followed by CCRT over CCRT alone. Because NCT could increase the risk of locoregional recurrences, it can only be considered in selected young patients with advanced stage IV disease. The role of NCT remains to be defined and should not be viewed as the standard of care.

B-Raf inhibitors have been used for the treatment of some B-Raf-mutated cancers. They effectively inhibit B-Raf/MEK/ERK signaling in cancers harboring mutant B-Raf, but paradoxically activates MEK/ERK in Ras-mutated cancers. Death receptor 5 (DR5), a cell surface pro-apoptotic protein, triggers apoptosis upon ligation with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or aggregation. This study focused on determining the effects of B-Raf inhibition on DR5 expression and DR5 activation-induced apoptosis in Ras-mutant cancer cells. Using chemical and genetic approaches, we have demonstrated that the B-Raf inhibitor PLX4032 induces DR5 upregulation exclusively in Ras-mutant cancer cells; this effect is dependent on Ras/c-Raf/MEK/ERK signaling activation. PLX4032 induces DR5 expression at transcriptional levels, largely due to enhancing CHOP/Elk1-mediated DR5 transcription. Pre-exposure of Ras-mutated cancer cells to PLX4032 sensitizes them to TRAIL-induced apoptosis; this is also a c-Raf/MEK/ERK-dependent event. Collectively, our findings highlight a previously undiscovered effect of B-Raf inhibition on the induction of DR5 expression and the enhancement of DR5 activation-induced apoptosis in Ras-mutant cancer cells and hence may suggest a novel therapeutic strategy against Ras-mutated cancer cells by driving their death due to DR5-dependent apoptosis through B-Raf inhibition.

Indigenous microbes inside the host intestine maintain a complex self-regulating community. The mechanisms by which gut microbes interact with intestinal pathogens remain largely unknown. Here we identify a commensal Escherichia coli strain whose expansion predisposes mice to infection by Vibrio cholerae, a human pathogen. We refer to this strain as 'atypical' E. coli (atEc) because of its inability to ferment lactose. The atEc strain is resistant to reactive oxygen species (ROS) and proliferates extensively in antibiotic-treated adult mice. V. cholerae infection is more severe in neonatal mice transplanted with atEc compared with those transplanted with a typical E. coli strain. Intestinal ROS levels are decreased in atEc-transplanted mice, favouring proliferation of ROS-sensitive V. cholerae. An atEc mutant defective in ROS degradation fails to facilitate V. cholerae infection when transplanted, suggesting that host infection susceptibility can be regulated by a single gene product of one particular commensal species.

Background: There is overlap in imaging features between borderline and benign ovarian tumors., Purpose: To analyze diagnostic performance of magnetic resonance imaging (MRI) combined with tumor markers for differentiating borderline from benign ovarian tumor., Material and Methods: Ninety-nine patient with MRI and surgically confirmed ovarian tumors 5 cm or larger (borderline, n = 37; benign, n = 62) were included. On MRI, tumor size, septal number (0; 1-4; 5 or more), and presence of solid portion such as papillary projection or septal thickening 0.5 cm or larger were investigated. Serum tumor markers (carbohydrate antigen 125 [CA 125] and CA 19-9) were recorded. Multivariate analysis was conducted for assessing whether combined MRI with tumor markers could differentiate borderline from benign tumor. The diagnostic performance was also analyzed., Results: Incidence of solid portion was 67.6% (25/37) in borderline and 3.2% (2/62) in benign tumors (P < 0.05). In all patients, without combined analysis of MRI with tumor markers, multivariate analysis revealed solid portion (P < 0.001) and CA 125 (P = 0.039) were significant for predicting borderline tumors. When combined analysis of MRI with CA 125 ((i) the presence of solid portion or (ii) CA 125 > 44.1 U/mL with septal number ≥5 for borderline tumor) is incorporated to multivariate analysis, it was only significant (P = 0.001). The sensitivity, specificity, PPV, NPV, and accuracy of combined analysis of MRI with CA 125 were 89.1%, 91.9%, 86.8%, 93.4, and 90.9%, respectively., Conclusion: Combined analysis of MRI with CA 125 may allow better differentiation between borderline and benign ovarian tumor compared with MRI alone., (© The Foundation Acta Radiologica 2015.)

Background: The purpose of this study was to investigate whether the minimum absolute lymphocyte count (ALC) during radiotherapy (RT) could predict clinical outcome in patients with nasopharyngeal cancer (NPC)., Methods: We analyzed 70 patients with NPC including 63 patients treated with chemoradiotherapy and used multivariate analysis to determine whether minimum ALC affected clinical outcome., Results: Patients were grouped by minimum ALC, with a cutoff of 245 cells/μL. Five-year disease-specific survival (DSS) and progression-free survival (PFS) for patients with minimum ALC ≥245 versus minimum ALC <245 were 88.1% versus 60.8% (p = .004) and 71.2% versus 35.2% (p = .004). All 10 patients with minimum ALC <120 experienced disease progression. Four of 6 patients (67%) with ALC <120 who died experienced disease progression within 6 months., Conclusion: Minimum ALC may predict poor 5-year DSS and should be evaluated by prospective studies. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1061-E1067, 2016., (© 2015 Wiley Periodicals, Inc.)

Objective: This study assesses the association between abdominal aortic calcification (AAC) and renal function of living kidney donors and evaluate AAC as a surrogate marker for nephrosclerosis., Methods: Between January 2010 and March 2013, 287 donors who underwent living donor nephrectomy were enrolled. We analyzed computed tomography angiographies and quantified AAC scores by calculating the Agatston score for the abdominal aorta. The donors were stratified into the non-AAC group (AAC score = 0; n = 238) and the AAC group (AAC score >0; n = 49). The relationship between AAC and perioperative estimated glomerular filtration rate was analyzed. For the 180 donors consenting to implantation biopsy, the nephrosclerosis score was defined as the sum of abnormalities, including glomerulosclerosis, tubular atrophy, interstitial fibrosis, and arteriosclerosis., Results: The mean AAC score was 185.5 ± 263.3 in the AAC group. The AAC group was older than the non-AAC group (51.1 ± 6.1 vs 37.9 ± 11 years; P < .001). Perioperative renal function was not different between the 2 groups. However, among the AAC group, donors with an AAC score of >100 were associated with delayed renal function recovery (P = .035). Donors with AAC were more likely to have glomerulosclerosis (50.0% vs 29.1%; P = .022), tubular atrophy (62.5% vs 33.1%; P = .002), and a higher nephrosclerosis score (P = .002)., Conclusions: Living donors with an AAC score of >100 require close observation because they have a higher probability of delayed renal function recovery after donation. AAC is associated with nephrosclerosis in healthy adults., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims: To determine whether the level of plasma neutrophil gelatinase-associated lipocalin (NGAL) can predict acute kidney injury (AKI) and clinical outcomes after recovery of spontaneous circulation (ROSC) in patients with out-of-hospital cardiac arrest (OHCA)., Methods: We conducted a prospective observational study of consecutive admitted patients with ROSC after OHCA between January 2013 and March 2015. Plasma was collected within 4h of ROSC to determine the level of NGAL. Outcome variables were AKI, 30-day survival, and good neurological outcome (GNO). We evaluated the association between NGAL and outcomes., Results: Fifty-four patients were included. AKI occurred in 26 (48.0%); 15 (27.7%) survived over 30 days and 8 had GNO (14.8%). NGAL was significantly lower in the group with non-AKI, 30-day survival, and GNO. To predict AKI, 30-day survival, and GNO, the area under the receiver operating characteristic curve for NGAL was 0.810, 0.728, and 0.875, respectively. In a logistic regression model, NGAL >189 ngml(-1) was strongly associated with AKI (odds ratio [OR] 7.01, 95% confidence interval [CI]: 1.89-26.01) in a multivariate model. A lower level of NGAL was strongly associated with 30-day survival (OR 6.12, 95% CI: 1.64-23.42 at NGAL <153.5 ngml(-1)) and GNO (OR 19.83, 95% CI: 2.21-178.32 at NGAL <129.5 ngml(-1)) in a univariate model, but was not significantly associated with outcomes in a multivariate model., Conclusions: Plasma NGAL is a strong predictor of AKI in patients exhibiting OHCA at ICU admission. Lower levels of NGAL are associated with greater chance of 30-day survival and GNO., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

The typical presentation of intussusception includes intermittent severe abdominal pain, vomiting, rectal bleeding, and the presence of an abdominal mass. We present a case of intussusception after abdominal blunt trauma along with a literature review. A 4-year-old girl was admitted to the emergency department after a bicycle accident. She complained of progressively worsening abdominal pain, but there was no vomiting, fever, bloody stool, or abdominal mass. She was finally diagnosed with traumatic intussusception by ultrasonography and treated with air reduction. Because the typical symptoms are unusual in traumatic intussusception, close attention must be paid to avoid a delayed diagnosis., Competing Interests: No potential conflict of interest relevant to this article was reported.

The causative agent of pandemic cholera, Vibrio cholerae, infects the anaerobic environment of the human intestine. Production of cholera toxin (CT), a major virulence factor of V. cholerae, is highly induced during anaerobic respiration with trimethylamine N-oxide (TMAO) as an alternative electron acceptor. However, the molecular mechanism of TMAO-stimulated CT production is not fully understood. Herein, we reveal that CT production during anaerobic TMAO respiration is affected by glucose fermentation. When the seventh pandemic V. cholerae O1 strain N16961 was grown with TMAO and additional glucose, CT production was markedly reduced. Furthermore, an N16961 Δcrp mutant, devoid of cyclic AMP receptor protein (CRP), was defective in CT production during growth by anaerobic TMAO respiration, further suggesting a role of glucose metabolism in regulating TMAO-mediated CT production. TMAO reductase activity was noticeably decreased when grown together with glucose or by mutation of the crp gene. A CRP binding region was identified in the promoter region of the torD gene, which encodes a structural subunit of the TMAO reductase. Gel shift assays further confirmed the binding of purified CRP to the torD promoter sequence. Together, our results suggest that the bacterial ability to respire using TMAO is controlled by CRP, whose activity is dependent on glucose availability. Our results reveal a novel mechanism for the regulation of major virulence factor production by V. cholerae under anaerobic growth conditions.

Purpose: Postoperative radiation therapy (PORT) and postoperative chemotherapy (POCT) can be administered as adjuvant therapies in patients with non-small cell lung cancer (NSCLC). The aim of this study was to present the clinical outcomes in patients treated with PORT-first with or without subsequent POCT in stage IIIA-N2 NSCLC., Methods and Materials: From January 2002 to November 2014, the conditions of 105 patients with stage IIIA-N2 NSCLC who received PORT-first with or without subsequent POCT were analyzed. PORT was initiated within 4 to 6 weeks after surgical resection. Platinum-based POCT was administered 3 to 4 weeks after the completion of PORT. We analyzed the outcomes and the clinical factors affecting survival., Results: Of 105 patients, 43 (41.0%) received POCT with a median of 4 cycles (range, 2-6 cycles). The follow-up times ranged from 3 to 123 months (median, 30 months), and the 5-year overall survival (OS) was 40.2%. The 5-year OS of patients treated with PORT and POCT was significantly higher than that of patients with PORT (61.3% vs 29.2%, P<.001). The significant prognostic factors affecting OS were the use of POCT (hazard ratio [HR] = 0.453, P=.036) and type of surgery (pneumonectomy/lobectomy; HR = 2.845, P<.001)., Conclusions: PORT-first strategy after surgery appeared not to compromise the clinical outcomes in the treatment of stage IIIA-N2 NSCLC. The benefit of POCT on OS was preserved even in the PORT-first setting. Further studies are warranted to compare the sequencing of PORT and POCT, guaranteeing the proper use of POCT., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Cancer cells feature increased de novo lipogenesis. Sterol regulatory element-binding protein 1 (SREBP1), when presented in its mature form (mSREBP1), enhances lipogenesis by increasing transcription of several of its target genes. Mammalian target of rapamycin (mTOR) complexes, mTORC1 and mTORC2, are master regulators of cellular survival, growth and metabolism. A role for mTORC1 in the regulation of SREBP1 activity has been suggested; however, the connection between mTORC2 and SREBP1 has not been clearly established and hence is the focus of this study. mTOR kinase inhibitors (for example, INK128), which inhibit both mTORC1 and mTORC2, decreased mSREBP1 levels in various cancer cell lines. Knockdown of rictor, but not raptor, also decreased mSREBP1. Consistently, reduced mSREBP1 levels were detected in cells deficient in rictor or Sin1 compared with parent or rictor-deficient cells with re-expression of ectopic rictor. Hence it is mTORC2 inhibition that causes mSREBP1 reduction. As a result, expression of the mSREBP1 target genes acetyl-CoA carboxylase and fatty-acid synthase was suppressed, along with suppressed lipogenesis in cells exposed to INK128. Moreover, mSREBP1 stability was reduced in cells treated with INK128 or rictor knockdown. Inhibition of proteasome, GSK3 or the E3 ubiquitin ligase, FBXW7, prevented mSREBP1 reduction induced by mTORC2 inhibition. Thus mTORC2 inhibition clearly facilitates GSK3-dependent, FBXW7-mediated mSREBP1 degradation, leading to mSREBP1 reduction. Accordingly, we conclude that mTORC2 positively regulates mSREBP1 stability and lipogenesis. Our findings reveal a novel biological function of mTORC2 in the regulation of lipogenesis and warrant further study in this direction.

Aim: The grey-to-white matter ratio (GWR) is a reliable predictor of the neurological outcome of out-of-hospital cardiac arrest (OHCA). However, the reliability in patients receiving extracorporeal membrane oxygenation-assisted cardiopulmonary resuscitation (ECPR) remains unknown. We evaluated the utility of the GWR in predicting neurological outcomes in ECPR-treated patients., Methods: This single-centre retrospective study was conducted from July 2009 to January 2014. Patients who received ECPR for OHCA were classified into two groups: Cerebral performance category(CPC) 1-2 was defined as good, CPC 3-5 as poor outcome. Four GWR (GWR-AV[average], GWR-CO[cortex], GWR-BG[basal ganglia], and GWR-SI [simplified])were evaluated and compared between the groups., Results: Of 38 patients who received ECPR for OHCA, 30 patients were enrolled. Five (16.7%) had a good outcome and 25(83.3%) a poor outcome. All GWR were significantly higher in the good outcome group than in the poor outcome group. ROC curve analysis produced the following areas under the curve: GWR-AV=0.920 (95% CI 0.761 to 0.987), GWR-BG=0.872 (95%CI 0.699 to 0.965), GWR-CO=0.952 (95% CI 0.806 to 0.997), and GWR-SI=0.848(95% CI 0.670 to 0.962). The cut-off value with 100% specificity for the prediction of the poor outcome was 1.23 for GWR-AV (sensitivity: 76%), 1.24 for GWR-BG (sensitivity: 88.0%), 1.22 for GWR-CO (sensitivity: 64%), and 1.21 for GWR-SI (sensitivity: 76%)., Conclusions: In ECPR, GWR of patients with poor outcome was significantly lower than that of patients with good outcome., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

We evaluated the prognostic value of F-fluorodeoxyglucose positron emission tomography (FDG PET) parameters for limited-stage small-cell lung cancer (LS-SCLC).We retrospectively enrolled 59 LS-SCLC patients who underwent pretreatment FDG PET/CT. Various PET parameters were measured in all malignant lesions, and we recorded the highest maximum standardized uptake value (SUVmax), and sum of metabolic tumor volume (MTVsum) and total lesion glycolysis (TLGsum). The relationship between the highest SUVmax and volumetric PET parameters was evaluated. The prognostic significances of PET parameters and clinical variables were assessed using Cox's proportional hazard regression analysis. Overall survival (OS) and progression-free survival (PFS) were assessed by the Kaplan-Meier method.The SUVmax of the highest metabolic lesion had a significant positive correlation with MTVsum and TLGsum (P < 0.001). Upon multivariate analysis, the highest SUVmax was an independent predictor of OS (1 unit increase, hazard ratio [HR]: 1.133, P = 0.003) and MTVsum was a significant prognostic factor of PFS (10-cm increase, HR: 1.027, P = 0.034) after adjusting for age, sex, performance status, tumor stage, and treatment modality. The highest SUVmax was a prognostic factor for PFS with marginal significance (1 unit increase, HR: 1.078, P = 0.053). Patients with higher SUVmax (≥11) were also characterized by a significantly shorter median OS (P < 0.001) and PFS (P = 0.002) compared with patients with lower SUVmax.The highest SUVmax is an independent prognostic factor for survival in LS-SCLC patients. Therefore, the highest SUVmax might be a possible imaging biomarker for risk stratification in LS-SCLC. A further study in a large cohort is needed to validate the prognostic significance of the parameter.

Inhibition of B-Raf/MEK/ERK signaling is an effective therapeutic strategy against certain types of cancers such as melanoma and thyroid cancer. While demonstrated to be effective anticancer agents, B-Raf or MEK inhibitors have also been associated with early tumor progression and development of secondary neoplasms. The ligation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with its receptor, death receptor 5 (DR5), leading to induction of apoptosis, offers a promising anticancer strategy. Importantly, this is also a natural immunosurveillance mechanism against cancer development. We previously demonstrated that activated B-Raf/MEK/ERK signaling positively regulates DR5 expression. Hence, our current work sought to address whether B-Raf/MEK/ERK inhibition and the consequent suppression of DR5 expression impede cancer cell response to DR5 activation-induced apoptosis and activated immune cell-induced killing. We found that both B-Raf (for example, PLX4032) and MEK inhibitors (for example, AZD6244 and PD0325901) effectively inhibited ERK1/2 phosphorylation and reduced DR5 levels in both human thyroid cancer and melanoma cells. Similar to the observed effect of genetic knockdown of the B-Raf gene, pre-treatment of cancer cell lines with either B-Raf or MEK inhibitors attenuated or abolished cellular apoptotic response induced by TRAIL or the DR5 agonistic antibody AMG655 or cell killing by activated T cells. Our findings clearly show that inhibition of B-Raf/MEK/ERK signaling suppresses DR5 expression and impairs DR5 activation-induced apoptosis and T cell-mediated killing of cancer cells. These findings suggest a potential negative impact of B-Raf or MEK inhibition on TRAIL- or DR5-mediated anticancer therapy and on TRAIL/DR5-mediated immune-clearance of cancer cells.

The purpose of this study was to investigate whether the minimum absolute lymphocyte count during radiotherapy (min ALC) and the absolute lymphocyte count 1 month after radiotherapy (post ALC) could predict clinical outcome in limited-stage small cell lung cancer (LS-SCLC) patients. We analyzed 73 LS-SCLC patients treated with chemotherapy and radiotherapy; we collected data on the min ALC from 62 patients and on the post ALC from 60 patients. Both min ALC and post ALC were statistically significant predictors of overall survival in multivariate analysis (hazard ratio [95 % confidence interval] 2.67 [1.06-6.75], P = 0.038 and 2.62 [1.19-5.74], P = 0.016, respectively). The median overall survival of the patients with min ALC ≤297 and >297 cells/μL was 12.2 and 35.3 months, respectively (P < 0.001). Patients with post ALC ≤698 and >698 cells/μL had an overall survival of 19.3 and 46.9 months, respectively (P = 0.001). The median overall survival of the lymphopenia (min ALC ≤ 297 cells/μL or post ALC ≤ 698 cells/μL) and the non-lymphopenia group (min ALC > 297 cells/μL and post ALC > 698 cells/μL) was 19.0 and 131.7 months, respectively, while the median progression survival was 8.1 and 16.6 months, respectively (P < 0.001 and P = 0.001). Radiation-related lymphopenia could predict poor survival in LS-SCLC. Its prognostic role should be evaluated in further prospective studies.

Background: Clinical benefits from standard therapies against glioblastoma (GBM) are limited in part due to intrinsic radio- and chemoresistance of GBM and inefficient targeting of GBM stem-like cells (GSCs). Novel therapeutic approaches that overcome treatment resistance and diminish stem-like properties of GBM are needed., Methods: We determined the expression levels of ubiquitination-specific proteases (USPs) by transcriptome analysis and found that USP1 is highly expressed in GBM. Using the patient GBM-derived primary tumor cells, we inhibited USP1 by shRNA-mediated knockdown or its specific inhibitor pimozide and evaluated the effects on stem cell marker expression, proliferation, and clonogenic growth of tumor cells., Results: USP1 was highly expressed in gliomas relative to normal brain tissues and more preferentially in GSC enrichment marker (CD133 or CD15) positive cells. USP1 positively regulated the protein stability of the ID1 and CHEK1, critical regulators of DNA damage response and stem cell maintenance. Targeting USP1 by RNA interference or treatment with a chemical USP1 inhibitor attenuated clonogenic growth and survival of GSCs and enhanced radiosensitivity of GBM cells. Finally, USP1 inhibition alone or in combination with radiation significantly prolonged the survival of tumor-bearing mice., Conclusion: USP1-mediated protein stabilization promotes GSC maintenance and treatment resistance, thereby providing a rationale for USP1 inhibition as a potential therapeutic approach against GBM., (© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: The objective of this study was to explore the relationship between the circulating lymphocyte level during preoperative chemoradiotherapy (CRT) and pathologic complete response (pCR) in locally advanced rectal cancer., Materials and Methods: From May 2010 to May 2013, 52 patients treated with preoperative CRT followed by surgery, were analysed. Patients received conventional fractionated radiotherapy (50-54 Gy) with fluorouracil-based chemotherapy. Surgical resection was performed at 4 to 8 weeks after the completion of preoperative CRT. Absolute blood lymphocyte counts and their relative percentage in total white blood cell counts were obtained from complete blood count tests performed prior to and after 4, 8, and 12 weeks of CRT. We analysed the association between achieving pCR and change in blood lymphocyte level during CRT, as well as clinical parameters., Results: Among 52 patients, 14 (26.9%) had evidence of pCR. Sustaining the blood lymphocyte count during CRT (lymphocyte count at 4 weeks/baseline lymphocyte count > 0.35; odds ratio, 8.33; p=0.02) and initial carcinoembryonic antigen < 4.4 ng/mL (odds ratio, 6.71; p=0.03) were significantly associated with pCR in multivariate analyses., Conclusion: Sustaining blood lymphocyte count during preoperative CRT was predictive for pCR in rectal cancer. Further studies are warranted to investigate the association between pathologic responses and circulating lymphocyte count with its subpopulation during preoperative CRT.

Insulin is one of the main factors affecting bone and energy metabolism, however, the direct effect of insulin on osteoclast differentiation remains unclear. Thus, in order to help elucidate that puzzle, the authors investigated the roles and regulatory mechanisms of insulin on osteoclasts differentiation. Co-stimulation with insulin and RANKL significantly enhanced the number of larger (>100 μm) osteoclastic cells and of TRAP-positive multinucleated cells compared with treatment by RANKL alone. Conversely, the insulin receptor shRNA markedly decreased osteoclast differentiation induced by insulin and RANKL. Insulin treatment significantly activated ERK1/2 MAP kinase as well as markedly induced the expression of NFATc1, an osteoclast marker gene, and Atp6v0d2, an osteoclast fusion-related gene. The pretreatment of PD98059, an ERK1/2 inhibitor, or insulin receptor shRNA effectively suppressed osteoclast differentiation and, in addition, blocked the expression of NFATc1 and Atp6vod2 induced by insulin stimulation. These data reveal insights into the regulation of osteoclast differentiation and fusion through ERK1/2 activation and the induction of NFATc1 and Atp6v0d2 by insulin., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The role of death receptor 5 (DR5), a well-known cell surface pro-apoptotic protein, in the negative regulation of invasion and metastasis of human cancer cells and the underlying mechanisms are largely unknown and were hence the focus of this study. In this report, we have demonstrated that DR5 functions to suppress invasion and metastasis of human cancer cells, as evidenced by enhanced cancer cell invasion and metastasis upon genetic suppression of DR5 either by gene knockdown or knockout. When DR5 is suppressed, FADD and caspase-8 may recruit and stabilize TRAF2 to form a metastasis and invasion signaling complex, resulting in activation of ERK and JNK/AP-1 signaling that mediate the elevation and activation of matrix metalloproteinase-1 (MMP1) and eventual promotion of cancer invasion and metastasis. Our findings thus highlight a novel non-apoptotic function of DR5 as a suppressor of human cancer cell invasion and metastasis and suggest a basic working model elucidating the underlying biology.

Purpose: Past studies have reported that S-allylcysteine (SAC) inhibits the migration and invasion of cancer cells through the restoration of E-cadherin, the reduction of matrix metalloproteinase (MMP) and Slug protein expression, and inhibition of the production of reactive oxygen species (ROS). Furthermore, evidence is emerging that shows that ROS induced by radiation could increase Met activation. Following on these reports of SAC and Met, we investigated whether SAC could suppress Met activation., Materials and Methods: Wound healing, invasion, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium (MTT), soft agar colony forming, western blotting, and gelatin zymography assays were performed in the human nasopharyngeal cancer cell lines HNE1 and HONE1 treated with SAC (0, 10, 20, or 40 mM) and hepatocyte growth factor (HGF)., Results: This study showed that SAC could suppress the migration and invasion of HNE1 and HONE1 cell lines by inhibiting p-Met. An increase of migration and invasion induced by HGF and its decrease in a dose dependent manner by SAC in wound healing and invasion assays was observed. The reduction of p-Met by SAC was positively correlated with p-focal adhesion kinase (p-FAK) and p-extracellular related kinase (p-ERK in both cell lines). SAC reduced Slug, MMP2, and MMP9 involved in migration and invasion with the inhibition of Met-FAK signaling., Conclusion: These results suggest that SAC inhibited not only Met activation but also the downstream FAK, Slug, and MMP expression. Finally, SAC may be a potent anticancer compound for nasopharyngeal cancer treated with radiotherapy.

Our aim was to improve the detection of prostate cancer by evaluating whether contrast-enhanced ultrasound (CEUS) or sonoelastography (SE) is more helpful in guiding targeted biopsy (TB) performed before systematic biopsy (SB). A total of 52 patients suspected of having prostate cancer were prospectively included and randomly assigned to either the CEUS or SE group. Different, independent radiologists performed TB and twelve-core SB. Within each group, cancer detection rates based on core number were compared between SB and TB. We evaluated the effect of TB on core-based cancer detection rates between the CEUS and SE groups. Cancer detection was higher in overall TB cores 16.4% (28/171) than SB cores 11.4% (71/624) in both groups. In the SE group, TB cores revealed higher cancer detection than did SB cores from 4.49% (14/312) to 12.86% (9/70) (p = 0.01). Compared with CEUS, SE may improve detection rates when considering additional TB guidance methods., (Copyright © 2015 World Federation for Ultrasound in Medicine & Biology. All rights reserved.)

Purpose: To define the role of neoadjuvant and concurrent chemotherapy in stage II nasopharyngeal carcinoma, we compared the treatment outcomes of patients treated with curative radiotherapy with or without chemotherapy., Materials and Methods: From 2004 to 2011, 138 patients with American Joint Committee on Cancer (AJCC) 2002 stage II nasopharyngeal carcinoma were treated with curative radiotherapy in 12 hospitals in South Korea. Treatment methods included radiotherapy alone in 34 patients, neoadjuvant chemotherapy followed by radiotherapy alone in seven, concurrent chemoradiotherapy in 80, and neoadjuvant chemotherapy followed by concurrent chemoradiotherapy in 17. Adjuvant chemotherapy was used in 42 patients. Total radiation dose ranged from 64 Gy to 74.2 Gy (median, 70 Gy)., Results: Median follow-up was 48 months (range, 7 to 97 months) for all patients. At the last follow-up, 13 patients had died and 32 had experienced treatment failure; locoregional failure occurred in 14, distant failure in 16, and both in two. Five-year locoregional relapse-free survival, distant metastasis-free survival, progression-free survival, and overall survival were 86.2%, 85.5%, 74.4%, and 88.2%, respectively. Multivariate analyses showed that the significant prognostic factors were concurrent chemotherapy and N stage for locoregional relapse-free survival, concurrent chemotherapy for progression-free survival, and age and N stage for overall survival. Neither neoadjuvant nor concurrent chemotherapy improved distant metastasis-free survival., Conclusion: Concurrent chemotherapy significantly improved 5-year locoregional relapse-free survival and progression-free survival in stage II nasopharyngeal carcinoma. However, neoadjuvant chemotherapy failed to improve either.

A 64-year-old female with primary adrenal insufficiency presented with a right adrenal mass showing quantitative nonadenoma features on dedicated adrenal computed tomography (CT). CT showed direct invasion of the mass to the adjacent hepatic parenchyma, and high uptake was noted on 18F-fluorodeoxyglucose positron emission tomography/CT. Laparoscopy revealed gross invasion of the adrenal lesion into the liver, which led to the en bloc resection including the involved liver. Polymerase chain reaction analysis of the surgical specimen revealed adrenal tuberculosis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Interstitial fibrosis and tubular atrophy (IF/TA) is a common cause of kidney allograft loss. Several noninvasive techniques developed to assess tissue fibrosis are widely used to examine the liver. However, relatively few studies have investigated the use of elastographic methods to assess transplanted kidneys. The aim of this study was to explore the clinical implications of the acoustic radiation force impulse (ARFI) technique in renal transplant patients. A total of 91 patients who underwent living donor renal transplantation between September 2010 and January 2013 were included in this prospective study. Shear wave velocity (SWV) was measured by ARFI at baseline and predetermined time points (1 week and 6 and 12 months after transplantation). Protocol biopsies were performed at 12 months. Instead of reflecting IF/TA, SWVs were found to be related to time elapsed after transplantation. Mean SWV increased continuously during the first postoperative year (P < 0.001). In addition, mixed model analysis showed no correlation existed between SWV and serum creatinine (r = -0.2426, P = 0.0771). There was also no evidence of a relationship between IF/TA and serum creatinine (odds ratio [OR] = 1.220, P = 0.7648). Furthermore, SWV temporal patterns were dependent on the kidney weight to body weight ratio (KW/BW). In patients with a KW/BW < 3.5 g/kg, mean SWV continuously increased for 12 months, whereas it decreased after 6 months in those with a KW/BW ≥ 3.5 g/kg.No significant correlation was observed between SWV and IF/TA or renal dysfunction. However, SWV was found to be related to the time after transplantation. Renal hemodynamics influenced by KW/BW might impact SWV values.

Purpose: To analyze computed tomography (CT) characteristics of adrenal adenomas with hypercortisolism on adrenal CT compared to adenomas with hyperaldosteronism., Materials and Methods: Thirty-two adrenal adenomas, consisting of group A (hypercortisolism, n = 16) and group B (hyperaldosteronism, n = 16), were evaluated with adrenal CT. Thirty-four patients without adrenal nodule on CT and hormonal abnormality (group C) were selected for comparison. In adenomas, lesion size, attenuation value, and absolute and relative washout were compared between groups A and B. The mean adrenal thickness was compared quantitatively and qualitatively between groups., Results: All of adenomas satisfied absolute (≥60%) or relative (≥40%) washout criteria of adrenal CT. The mean adrenal thickness was 1.6 ± 0.3 mm in group A, 2.9 ± 0.5 mm in group B, and 3.0 ± 0.4 mm in group C (group A versus B or C, P < 0.001; group B versus C, P = 0.775). For differentiating group A from B, the area under the curve of quantitative and qualitative analyses for contralateral adrenal thickness was 0.982 and 0.934, respectively. Both sensitivity and specificity with cutoff of 2.0 mm or less in thickness and probably thin or more in visual score were 93.7% and 93.7%, and 87.5% and 93.7%, respectively, for predicting group A., Conclusions: Contralateral adrenal thinning on CT helps predict adrenal adenomas with hypercortisolism.

Objective: The purpose of this study was to retrospectively investigate whether preoperative MRI plays a key role in clinical prediction of micrometastasis (< 1 cm) to pelvic lymph nodes in prostate cancer., Materials and Methods: One hundred one patients with prostate cancer who underwent preoperative MRI and radical prostatectomy with pelvic lymph node dissection were included. None of the patients had a pelvic lymph node with a short-axis diameter of 1 cm or larger on MRI. Both clinical (prostate-specific antigen, biopsy Gleason score, greatest percentage of biopsy core, and percentage of positive cores) and MRI parameters (tumor apparent diffusion coefficient and tumor staging) were assessed. The univariate, multivariate, and ROC curve analyses were conducted., Results: Of 101 patients, nine (8.9%) had pelvic lymph node metastases. In univariate analysis, all of the clinical and MRI parameters were related to micrometastasis to pelvic lymph nodes (p < 0.05). However, multivariate analysis revealed that only preoperative MRI stage was significant (p = 0.044). AUC of preoperative MRI stage was 0.954 (odds ratio, 21.7). Respective sensitivity and specificity of preoperative tumor staging by MRI were 100% and 65.2% with cutoff of T3a or more, and 88.9% and 94.6% with cutoff of T3b for predicting micrometastasis to pelvic lymph nodes., Conclusion: Preoperative MRI staging may play a role in prediction of micrometastasis (< 1 cm) to pelvic lymph nodes in prostate cancer.

Purpose: To investigate the patterns of care for patients with nasopharyngeal carcinoma (NPC) in South Korea., Materials and Methods: A multi-institutional retrospective study was performed (Korean Radiation Oncology Group [KROG] 11-06) on a total of 1,445 patients from 15 institutions., Results: Of the 1,445 patients, more than half were stages III (39.9%) and IV (35.8%). In addition to patterns of care, we also investigated trends over time with the periods 1988-1993, 1994-2002, and 2003-2011. The frequencies of magnetic resonance imaging and positron emission tomography-computed tomography were markedly increased in the third period compared to previous 2 periods. Concurrent chemoradiation (CCRT) was performed on 894 patients (61.9%), neoadjuvant chemotherapy on 468 patients (32.4%), and adjuvant chemotherapy on 366 patients (25.3%). Of stage II-IV patients, CCRT performed on 78.8% in 2003-2011 compared to 15.0% in 1988-1993. For patients treated with CCRT, cisplatin was the most commonly used agent in 81.3% of patients. Over the periods of time, commonly used radiotherapy (RT) techniques were changed from 2-dimensional RT (1988-1993, 92.5%) to 3-dimensional RT (2003-2011, 35.5%) or intensity-modulated RT (IMRT; 2003-2011, 56.5%). Median RT doses given to primary tumors, high-risk lymphatics, and low-risk lymphatics were 70.0 Gy, 58.1 Gy, and 48.0 Gy, respectively. Adoption of IMRT increased the dose per fraction and escalated total radiation dose., Conclusion: Assessment of the patterns of care for NPC patients in South Korea demonstrated that management for NPC including diagnostic imaging, treatment regimen, RT techniques and dose schedule, advanced in accordance with the international guidelines.

Inflammation is implicated in metabolic abnormalities in obesity and type 2 diabetes. Because θ-defensins have anti-inflammatory activities, we tested whether RTD-1, a θ-defensin, improves metabolic conditions in diet-induced obesity (DIO). DIO was induced by high-fat feeding in obese-prone CD rats from 4 wk of age. Starting at age 10 wk, the DIO rats were treated with saline or RTD-1 for 4 or 8 wk. DIO rats gained more weight than low-fat-fed controls. RTD-1 treatment did not alter body weight or calorie intake in DIO rats. Plasma glucose, FFA, triglyceride (TG), and insulin levels increased in DIO rats; RTD-1 normalized plasma glucose and FFA levels and showed tendencies to lower plasma insulin and TG levels. Hepatic and skeletal muscle TG contents increased in DIO rats; RTD-1 decreased muscle, but not hepatic, TG content. Insulin sensitivity, estimated using homeostasis model assessment of insulin resistance and the glucose clamp technique, decreased in DIO rats, but this change was markedly reversed by RTD-1. RTD-1 had no significant effects on plasma cytokine/chemokine levels or IL-1β and TNF-α expression in liver or adipose tissues. RTD-1 treatment decreased hepatic expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, suggesting that the effect of RTD-1 on plasma glucose (or insulin action) might be mediated by its effect to decrease hepatic gluconeogenesis. Thus, RTD-1 ameliorated insulin resistance and normalized plasma glucose and FFA levels in DIO rats, supporting the potential of RTD-1 as a novel therapeutic agent for insulin resistance, metabolic syndrome, or type 2 diabetes., (Copyright © 2015 the American Physiological Society.)

Carfilzomib (CFZ) is a second generation proteasome inhibitor approved for the treatment of patients with multiple myeloma. It induces apoptosis in human cancer cells; but the underlying mechanisms remain undefined. In the present study, we show that CFZ decreases the survival of several human cancer cell lines and induces apoptosis. Induction of apoptosis by CFZ occurs, at least in part, due to activation of the extrinsic apoptotic pathway, since FADD deficiency protected cancer cells from undergoing apoptosis. CFZ increased total and cell surface levels of DR5 in different cancer cell lines; accordingly it enhanced TRAIL-induced apoptosis. DR5 deficiency protected cancer cells from induction of apoptosis by CFZ either alone or in combination with TRAIL. These data together convincingly demonstrate that DR5 upregulation is a critical mechanism accounting for CFZ-induced apoptosis and enhancement of TRAIL-induced apoptosis. CFZ inhibited the degradation of DR5, suggesting that DR5 stabilization contributes to CFZ-induced DR5 upregulation. In summary, the present study highlights the important role of DR5 upregulation in CFZ-induced apoptosis and enhancement of TRAIL-induced apoptosis in human cancer cells.

Objectives: To prospectively determine whether multi-parametric MRI (mpMRI) - contrast-enhanced ultrasound (CEUS) correlated, imaging-guided target biopsy (TB) method could improve the detection of prostate cancer in re-biopsy setting of patients with prior negative biopsy., Methods: From 2012 to 2014, a total of 42 Korean men with a negative result from previous systematic biopsy (SB) and elevated prostate-specific antigen underwent 3T mpMRI and real-time CEUS guided TB. Target lesions were determined by fusion of mpMRI and CEUS. Subsequently, 12-core SB was performed by a different radiologist. We compared core-based cancer detection rates (CaDR) using the generalized linear mixed model (GLIMMIX) for each biopsy method., Results: Core-based CaDR was higher in TB (17.92%, 38 of 212 cores) than in SB (6.15%, 31 of 504 cores) (p < 0.0001; GLIMMIX). In the cancer-positive TB cores, CaDR with suspicious lesions by mpMRI was higher than that by CEUS (86.8% vs. 60.5%, p= 0.02; paired t-test) and concordant rate between mpMRI and CEUS was significantly different with discordant rate (48% vs. 52%, p=0.04; McNemar's test)., Conclusion: The mpMRI-CEUS correlated TB technique for the repeat prostate biopsy of patients with prior negative biopsy can improve CaDR based on the number of cores taken.

When V. cholerae encounters nutritional stress, it activates (p)ppGpp-mediated stringent response. The genes relA and relV are involved in the production of (p)ppGpp, whereas the spoT gene encodes an enzyme that hydrolyzes it. Herein, we show that the bacterial capability to produce (p)ppGpp plays an essential role in glucose metabolism. The V. cholerae mutants defective in (p)ppGpp production (i.e. ΔrelAΔrelV and ΔrelAΔrelVΔspoT mutants) lost their viability because of uncontrolled production of organic acids, when grown with extra glucose. In contrast, the ΔrelAΔspoT mutant, a (p)ppGpp overproducer strain, exhibited better growth in the presence of the same glucose concentration. An RNA sequencing analysis demonstrated that transcriptions of genes consisting of an operon for acetoin biosynthesis were markedly elevated in N16961, a seventh pandemic O1 strain, but not in its (p)ppGpp(0) mutant during glucose-stimulated growth. Transposon insertion in acetoin biosynthesis gene cluster resulted in glucose-induced loss of viability of the ΔrelAΔspoT mutant, further suggesting the crucial role of acetoin production in balanced growth under glucose-rich environments. Additional deletion of the aphA gene, encoding a negative regulator for acetoin production, failed to rescue the (p)ppGpp(0) mutant from the defective glucose-mediated growth, suggesting that (p)ppGpp-mediated acetoin production occurs independent of the presence of AphA. Overall, our results reveal that (p)ppGpp, in addition to its well known role as a stringent response mediator, positively regulates acetoin production that contributes to the successful glucose metabolism and consequently the proliferation of V. cholerae cells under a glucose-rich environment, a condition that may mimic the human intestine., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Glioblastoma multiforme (GBM) is the most malignant World Health Organization grade IV brain tumor. GBM patients have a poor prognosis because of its resistance to standard therapies, such as chemotherapy and radiation. Since stem-like cells have been associated with the treatment resistance of GBM, novel therapies targeting the cancer stem cell (CSC) population is critically required. However, GBM CSCs share molecular and functional characteristics with normal neural stem cells (NSCs). To elucidate differential therapeutic targets of GBM CSCs, we compared surface markers of GBM CSCs with adult human NSCs and found that GD2 and CD90 were specifically overexpressed in GBM CSCs. We further tested whether the GBM CSC specific markers are associated with the cancer stemness using primarily cultured patient-derived GBM cells. However, results consistently indicated that GBM cells with or without GD2 and CD90 had similar in vitro sphere formation capacity, a functional characteristics of CSCs. Therefore, GD2 and CD90, GBM specific surface markers, might not be used as specific therapeutic targets for GBM CSCs, although they could have other clinical utilities.

Objective: Among infants and preschool children with complaint of upper extremity immobility, pulled elbow, also known as nursemaid's elbow or radial head subluxation is the most common cause presenting to pediatric emergency departments. However, proper tools to diagnose pulled elbow remain limited. We conducted a study to determine the feasibility of ultrasonography in diagnosing pulled elbow., Methods: Infants and preschool children presenting to an urban emergency department with the complaint of upper extremity immobility between April and July 2013 were enrolled. The following ultrasonographic information was recorded: (1) whether there was a change in the shape of the supinator muscle, (2) whether there was an annular ligament in place, and (3) whether there was an enlargement of the synovial fringe. We used the affected arms' ultrasonographic images as the study group and opposite arms' ultrasonographic images as the control group., Results: When we diagnosed pulled elbow using ultrasonographic findings (i.e., the annular ligament was not in place), we found the following results: sensitivity, 64.9% (95% CI, 47.5% to 79.8%); specificity, 100.0% (95% CI, 90.5% to 100.0%); positive predictive value, 100.0% (95% CI, 85.8% to 100.0%); and negative predictive, 74.0% (95% CI, 59.7% to 85.4%)., Conclusion: A pulled elbow can easily be confirmed by ultrasonography when the annular ligament is displaced., Competing Interests: No potential conflict of interest relevant to this article was reported.

Purpose: The purpose of this study was to investigate the prognostic effect of pulmonary function at the beginning of postoperative radiotherapy (PORT) in non-small cell lung cancer (NSCLC)., Materials and Methods: From January 2002 to December 2012, 115 patients with NSCLC who underwent PORT and took the forced expiratory volume in 1 second (FEV1) at the beginning of PORT were analysed. PORT began within 4-6weeks following surgery, and the 3-dimensional conformal technique was used with conventional fractionation. The high and low FEV1 groups were divided by the median absolute value of FEV1 at the beginning of PORT, and we compared the clinical factors and survival between two groups., Results: The median absolute value of FEV1 at the beginning of PORT was 1.68L (range, 0.83-3.89), and patients were divided into low and high FEV1 groups (<1.68L versus ⩾1.68L). Patients in the low FEV1 group showed a lower preoperative FEV1 (mean, 1.94L versus 2.73L, p<0.001) and received more pneumonectomy (36.8% versus 8.6%, p<0.001) compared to the high FEV1 group. The overall median follow-up time was 31months (range, 3-110), and 5-year locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS) and overall survival (OS) were 52.4%, 48.9%, and 45.9%, respectively. Five-year OS of the low FEV1 group was significantly lower than that of the high FEV1 group (35.4% versus 56.9%, p=0.002), and no significant differences were found in LRRFS and DMFS. In a multivariate analysis, the difference of OS between the low and high FEV1 groups remained significant (Hazard Ratio=2.04, CI, 1.18-3.55, p=0.011)., Conclusions: The FEV1 at the beginning of PORT was an independent significant prognostic factor in patients with NSCLC who received PORT. Considering this analysis was limited to only patients receiving PORT, further studies are warranted to compare the survival effect of postoperative pulmonary function between groups with/without PORT., (Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Alginate-overproducing mucoid Pseudomonas aeruginosa, responsible for chronic airway infections in cystic fibrosis (CF) patients, is resistant to antibiotic treatments and host immune clearance. In this study, we performed a phenotype microarray screen and identified sulfate ion as a molecule that can suppress alginate production. When a mucoid P. aeruginosa strain CM21 and additional mucoid isolates were grown with 5% sodium sulfate, significantly decreased levels of alginate were produced. Suppression of alginate production was also induced by other sulfate salts. Expression of a reporter gene fused to the algD promoter was considerably decreased when grown with sulfate. Furthermore, bacterial cell shape was abnormally altered in CM21, but not in PAO1, a prototype nonmucoid strain, suggesting that sulfate-stimulated cell shape change is associated with transcriptional suppression of the alginate operon. Finally, a CM21 lpxC mutant defective in lipid A biosynthesis continued to produce alginate and maintained the correct cell shape when grown with sulfate. These results suggest a potential involvement of lipoploysaccharide biosynthesis in the sulfate-induced reversion to nonmucoid phenotype. This study proposes a novel strategy that can be potentially applied to treat persistent infection by recalcitrant mucoid P. aeruginosa., (© 2014 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.)