Staging accuracy of MRI of the prostate with special reference to the influence of the time of last ejaculation on the detection of seminal vesicle invasion.

AIM: To evaluate the Prostate Imaging Reporting and Data System, version 2.1 (PIRADS V2.1) criteria for seminal vesicle invasion (SVI) and examine whether the timing of last ejaculation influences the detection of SVI. MATERIALS AND METHODS: The study population consisted of 68 patients (34 with SVI, 34 without SVI, matching groups by age and prostate volume) who underwent PIRADS V2.1-compliant multiparametric magnetic resonance imaging (MRI; 34 at 1.5 T, 34 at 3 T). Before the examination, the time of last ejaculation (38/68 ≤ 5 days, 30/68 > 5 days) was collected via a questionnaire. The five PIRADS V2.1 criteria for SVI with subsequent overall assessment were evaluated retrospectively by two independent examiners (examiner 1 with >10 years of experience, examiner 2 with 6 months of experience) in a single-blinded fashion for all patients using a questionnaire and a six-point scale (0 = no, 1 = very likely not, 2 = probably not, 3 = possible, 4 = probable, 5 = certain). RESULTS: E1 achieved high specificity (100%) and positive predictive value (PPV; 100%) in the overall assessment, independent of the time of last ejaculation (sensitivity = 76.5%, negative predictive value [NPV] = 81%). The area under the curve (AUC) value was 0.882; for E2, it was 0.765. At ≤5 days, the AUC values of E1 and E2 differed significantly (0.867 versus 0.681, p=0.016), as did the diffusion restriction criterion (0.833 versus 0.681, p=0.028). E1 showed high AUC values independent of time. E2 had better values for all criteria at >5 days than at ≤5 days. There were no significant differences between the examiners in all observations at >5 days. CONCLUSION: The PIRADS V2.1 criteria are well suited for an experienced examiner to detect SVI independent of time point. An inexperienced examiner will benefit from patients being abstinent >5 days prior to MRI.

Efficacy, Immunogenicity, and Safety of a 9-Valent Human Papillomavirus Vaccine: Subgroup Analysis of Participants From Asian Countries.

Background: A 9-valent human papillomavirus-6/11/16/18/31/33/45/52/58 (9vHPV) vaccine extends coverage to 5 next most common oncogenic types (31/33/45/52/58) in cervical cancer versus quadrivalent HPV (qHPV) vaccine. We describe efficacy, immunogenicity, and safety in Asian participants (India, Hong Kong, South Korea, Japan, Taiwan, and Thailand) from 2 international studies: a randomized, double-blinded, qHPV vaccine-controlled efficacy study (young women aged 16-26 years; NCT00543543; Study 001); and an immunogenicity study (girls and boys aged 9-15 years; NCT00943722; Study 002). Methods: Participants (N = 2519) were vaccinated at day 1 and months 2 and 6. Gynecological samples (Study 001 only) and serum were collected for HPV DNA and antibody assessments, respectively. Injection-site and systemic adverse events (AEs) were monitored. Data were analyzed by country and vaccination group. Results: 9vHPV vaccine prevented HPV-31/33/45/52/58-related persistent infection with 90.4%-100% efficacy across included countries. At month 7, ≥97.9% of participants seroconverted for each HPV type. Injection-site AEs occurred in 77.7%-83.1% and 81.9%-87.5% of qHPV and 9vHPV vaccine recipients in Study 001, respectively, and 62.4%-85.7% of girls/boys in Study 002; most were mild to moderate. Conclusions: The 9vHPV vaccine is efficacious, immunogenic, and well tolerated in Asian participants. Data support 9vHPV vaccination programs in Asia. Clinical Trials Registration: NCT00543543; NCT00943722.

STAT3 activation in endothelial cells is important for tumor metastasis via increased cell adhesion molecule expression.

Metastasis is a life-threatening feature of cancer and is primarily responsible for cancer patient mortality. Cross talk between tumor cells and endothelium is important for tumor progression and metastasis. However, very little is known about the mechanisms by which endothelial cells (ECs) that are close to tumor cells, respond to the tumor cells during tumor progression and metastasis. In this study, we exploited the use of EC-specific signal transducer activator of transcription 3 (STAT3) knockout mice to investigate the role of STAT3 in ECs in tumor progression and metastasis. We found that the loss of STAT3 in ECs did not affect primary Lewis lung carcinoma (LLC) tumor growth, but it reduced in vivo LLC metastasis in experimental and spontaneous metastasis models. Mechanistically, STAT3 activation upregulated cell adhesion molecule expression, including E-selectin and P-selectin, in murine endothelial MS-1 cells treated with tumor cell-conditioned media in vitro and in pre-metastatic lungs of tumor-bearing mice in vivo. We also found that both E-selectin and P-selectin were, at least in part, responsible for STAT3-induced adhesion and invasion of LLC cells through an EC monolayer. However, tumor cell-conditioned media from B16F10 melanoma cells did not activate STAT3 in MS-1 cells. As a result, EC STAT3 knockout did not affect B16F10 melanoma cell metastasis. In addition, various human cancer cells activated STAT3 in human ECs (HUVECs), resulting in increased cell adhesion molecule expression. Collectively, our findings demonstrate that STAT3 activation in ECs promotes tumor metastasis through the induction of cell adhesion molecules, demonstrating a role for ECs in response to tumor cells during tumor metastasis.

Adenosine A2A receptor and ERK-driven impulsivity potentiates hippocampal neuroblast proliferation.

Dampened adenosine A2A receptor (A2AR) function has been implicated in addiction through enhancement of goal-directed behaviors. However, the contribution of the A2AR to the control of impulsive reward seeking remains unknown. Using mice that were exposed to differential reward of low rate (DRL) schedules during Pavlovian-conditioning, second-order schedule discrimination, and the 5-choice serial reaction time task (5-CSRTT), we demonstrate that deficits of A2AR function promote impulsive responses. Antagonism of the A2AR lowered ERK1 and ERK2 phosphorylation in the dorsal hippocampus (dHip) and potentiated impulsivity during Pavlovian-conditioning and the 5-CSRTT. Remarkably, inhibition of ERK1 and ERK2 phosphorylation by U0126 in the dHip prior to Pavlovian-conditioning exacerbated impulsive reward seeking. Moreover, we found decreased A2AR expression, and reduced ERK1 and ERK2 phosphorylation in the dHip of equilibrative nucleoside transporter type 1 (ENT1-/-) null mice, which displayed exacerbated impulsivity. To determine whether impulsive response behavior is associated with hippocampal neuroblast development, we investigated expression of BrdU+ and doublecortin (DCX+) following 5-CSRTT testing. These studies revealed that impulsive behavior driven by inhibition of the A2AR is accompanied by increased neuroblast proliferation in the hippocampus.

The Co-regulatory Role of 5-Lipoxygenase and Cyclooxygenase-2 in the Carcinogenesis and their Promotion by Cigarette Smoking in Colons.

The arachidonic acid metabolizing enzymes, cyclooxygenase-2 (COX-2) and 5- lipoxygenase (5-LOX), are both highly expressed during the carcinogenesis in colons. Cigarette smoking promotes these carcinogenic processes at the early stage during adenoma formation. In this article, the involvement of COX-2 and 5-LOX, alongside with the dual COX/5-LOX inhibitors in colorectal cancer development is introduced. The co-regulation of 5-LOX and COX-2 in colon cancer growth and its relationship with cigarette smoke and hyaluronic acid-CD44v6 is also described. It is envisaged that dual inhibition of 5-LOX/COX could be the most promising therapeutic option for the treatment of colorectal cancer in humans.

Angiopoietin 2 induces astrocyte apoptosis via αvß5-integrin signaling in diabetic retinopathy.

The vascular leakage in diabetic retinopathy leads to macular edema and vision loss. Although astrocyte play an important role in regulating blood-brain barrier integrity in the brain, the precise role of astrocyte in blood-retinal barrier was yet to be elucidated. This study aimed to investigate the role of angiopoietin 2 (Ang2) in astrocyte loss and vascular leakage in the early streptozotocin-induced diabetic retinopathy. We demonstrated that vascular leakage occurred with astrocyte loss in early diabetic mice retina as Ang2 increased. The astrocyte loss and vascular leakage were inhibited by intravitreal injection of Ang2-neutralizing antibody. In vitro, Ang2 aggravated high glucose-induced astrocyte apoptosis via GSK-3ß activation. Ang2 directly bound to αvß5 integrin, which was abundant in astrocyte, and the blockade of αvß5 integrin, in vitro, effectively attenuated Ang2-induced astrocyte apoptosis. In vivo, intravitreal injection of anti-αvß5-integrin antibody inhibited astrocyte loss in early diabetic retinopathy. Taken together, Ang2 induced astrocyte apoptosis under high glucose via αvß5-integrin/GSK-3ß/ß-catenin pathway. Therefore, we suggest that Ang2/integrin signaling could be a potential therapeutic target to prevent the vascular leakage by astrocyte loss in early diabetic retinopathy.

Up-regulation of acid-sensing ion channels in the capsule of the joint in frozen shoulder.

The purpose of this study was to evaluate the expression of acid-sensing ion channels (ASICs) in the capsule and synovial fluid of patients with frozen shoulder. Capsular tissue and synovial fluid were obtained from 18 patients with idiopathic frozen shoulder (FS group) and 18 patients with instability of the shoulder (control group). The expressions of ASIC1, ASIC2, and ASIC3 in the capsule were determined using the reverse transcriptase-polymerase chain reaction, immunoblot analysis, and immunohistochemistry (IHC). The concentrations in synovial fluid were evaluated using an enzyme-linked immunosorbent assay. The mRNA expression of ASIC1, ASIC2 and ASIC3 in the capsule were significantly increased in the FS group compared with the control group. The protein levels of these three ASICs were also increased. The increased expressions were confirmed by IHC. Of the ASICs, ASIC3 showed the greatest increase in both mRNA and levels of expression compared with the control group. The levels of ASIC1 and ASIC3 in synovial fluid were significantly increased in the FS group. This study suggests that ASICs may play a role as mediators of inflammatory pain and be involved in the pathogenesis of frozen shoulder.

Abatement of fluorinated compounds using a 2.45GHz microwave plasma torch with a reverse vortex plasma reactor.

Abatement of fluorinated compounds (FCs) used in semiconductor and display industries has received an attention due to the increasingly stricter regulation on their emission. We have developed a 2.45GHz microwave plasma torch with reverse vortex reactor (RVR). In order to design a reverse vortex plasma reactor, we calculated a volume fraction and temperature distribution of discharge gas and waste gas in RVR by ANSYS CFX of computational fluid dynamics (CFD) simulation code. Abatement experiments have been performed with respect to SF6, NF3 by varying plasma power and N2 flow rates, and FCs concentration. Detailed experiments were conducted on the abatement of NF3 and SF6 in terms of destruction and removal efficiency (DRE) using Fourier transform infrared (FTIR). The DRE of 99.9% for NF3 was achieved without an additive gas at the N2 flow rate of 150 liter per minute (L/min) by applying a microwave power of 6kW with RVR. Also, a DRE of SF6 was 99.99% at the N2 flow rate of 60 L/min using an applied microwave power of 6kW. The performance of reverse vortex reactor increased about 43% of NF3 and 29% of SF6 abatements results definition by decomposition energy per liter more than conventional vortex reactor.

Validation of multisociety combined task force definitions of abnormal disk morphology.

BACKGROUND AND PURPOSE: The multisociety task force descriptively defined abnormal lumbar disk morphology. We aimed to use their definitions to provide a higher level of evidence for the validation of MR imaging in the evaluation of this pathology in patients who have undergone diskectomy by retrospectively classifying their preoperative MRI. MATERIALS AND METHODS: This retrospective, institutional review board-approved study included 54 of 86 consecutive patients (47 men; average age, 44 years) enrolled in an ongoing prospective trial of surgically treated lumbar disk herniation who had preoperative MRI and documented intraoperative classification of the abnormal disk as protrusion, extrusion, or sequestration by the treating surgeon. Preoperative MRI was classified by 2 blinded radiologists; discrepancies were resolved by a third reader. Statistical analysis of interobserver agreement and imaging compared with surgical findings was performed. RESULTS: The readers disagreed on only 1 of the 54 cases. The third reader resolved the disagreement. Eight protrusions and 46 extrusions were found on imaging, with no sequestrations. At surgery, there were 13 protrusions and 40 extrusions, with 2 of the extrusions also containing sequestrations; the remaining case had only sequestration. There were 16 discrepancies between imaging and surgery, resulting in 70% agreement. CONCLUSIONS: This study, which was intended to validate the multisociety combined task force definitions of abnormal disk morphology by using MR imaging with a surgical criterion standard, found 70% agreement between imaging diagnosis and surgical findings. Although reasonable, this finding highlights differences that often exist between intraoperative and preoperative imaging findings of lumbar disk herniation.

Antioxidative effects of ethyl 2-(3-(benzo[d]thiazol-2-yl)ureido)acetate against amyloid ß-induced oxidative cell death via NF-κB, GSK-3ß and ß-catenin signaling pathways in cultured cortical neurons.

We have previously shown that 2-(3-(benzo[d]thiazol-2-yl)ureido)acetate (KHG21834) attenuates amyloid beta(Aß)25-35-induced apoptotic death and shows anti-inflammatory activity against Aß25-35-induced microglial activation. However, antioxidative effects of KHG21834 against Aß-induced oxidative stress have not yet been reported. In the present study, we investigated the antioxidative function of KHG21834 in primary cultured cortical neurons, to expand the potential therapeutic efficacy of KHG21834. Pretreatment with KHG21834 protected against Aß-induced neuronal cell death and mitochondrial damage, and significantly restored GSH levels and the activities of catalase, superoxide dismutase, and glutathione peroxidase, and also suppressed the production of reactive oxygen species and protein oxidation. These results imply that KHG21834 may play a role in cellular defense mechanisms against Aß-induced oxidative stress in cultured cortical neurons. Furthermore, KHG21834 significantly attenuated the effects of Aß treatment on levels of NF-κB, ß-catenin, and GSK-3ß proteins in cortical neurons. Taken together, our results suggest that the antioxidant effects of KHG21834 may result at least in part from its ability to regulate the NF-κB, ß-catenin, and GSK-3ß signaling pathways. To our knowledge, this is the first report showing that KHG21834 significantly attenuates Aß25-35-induced oxidative stress in primary cortical neurons, and provides novel insights into KHG21834 as a possible therapeutic agent for the treatment of Aß-mediated neurotoxicity involving oxidative stress.

PHF2 histone demethylase acts as a tumor suppressor in association with p53 in cancer.

Plant homeodomain finger 2 (PHF2) has a role in epigenetic regulation of gene expression by demethylating H3K9-Me2. Several genome-wide studies have demonstrated that the chromosomal region including the PHF2 gene is often deleted in some cancers including colorectal cancer, and this finding encouraged us to investigate the tumor suppressive role of PHF2. As p53 is a critical tumor suppressor in colon cancer, we tested the possibility that PHF2 is an epigenetic regulator of p53. PHF2 was associated with p53, and thereby, promoted p53-driven gene expression in cancer cells under genotoxic stress. PHF2 converted the chromatin that is favorable for transcription by demethylating the repressive H3K9-Me2 mark. In an HCT116 xenograft model, PHF2 was found to be required for the anticancer effects of oxaliplatin and doxorubicin. In PHF2-deficient xenografts, p53 expression was profoundly induced by both drugs, but its downstream product p21 was not, suggesting that p53 cannot be activated in the absence of PHF2. To find clinical evidence about the role of PHF2, we analyzed the expressions of PHF2, p53 and p21 in human colon cancer tissues and adjacent normal tissues from patients. PHF2 was downregulated in cancer tissues and PHF2 correlated with p21 in cancers expressing functional p53. Colon and stomach cancer tissue arrays showed a positive correlation between PHF2 and p21 expressions. Informatics analyses using the Oncomine database also supported our notion that PHF2 is downregulated in colon and stomach cancers. On the basis of these findings, we propose that PHF2 acts as a tumor suppressor in association with p53 in cancer development and ensures p53-mediated cell death in response to chemotherapy.

Animal models of gastrointestinal inflammation and cancer.

Inflammation and cancer are the two major disorders in the gastrointestinal tract. They are causally related in their pathogenesis. It is important to study animal models' causal relationship and, in particular, to discover new therapeutic agents for such diseases. There are several criteria for these models in order to make them useful in better understanding the etiology and treatment of the said diseases in humans. In this regard, animal models should be similar as possible to human diseases and also be easy to produce and reproducible and also economic to allow a continuous replication in different laboratories. In this review, we summarize the various animal models for inflammatory and cancerous disorders in the upper and lower gastrointestinal tract. Experimental approaches are as simple as by giving a single oral dose of alcohol or other noxious agents or by injections of multiple dosages of ulcer inducing agents or by parenteral administration or in drinking water of carcinogens or by modifying the genetic makeups of animals to produce relatively long-term pathological changes in particular organs. With these methods they could induce consistent inflammatory responses or tumorigenesis in the gastrointestinal mucosa. These animal models are widely used in laboratories in understanding the pathogenesis as well as the mechanisms of action for therapeutic agents in the treatment of gastrointestinal inflammation and cancer.

Cigarette smoking and gastrointestinal diseases: the causal relationship and underlying molecular mechanisms (review).

Cigarette smoking is an important risk factor for gastrointestinal (GI) disorders, including peptic ulcers, inflammatory bowel diseases, such as Crohn's disease and cancer. In this review, the relationship between smoking and GI disorders and the underlying mechanisms are discussed. It has been demonstrated that cigarette smoking is positively associated with the pathogenesis of peptic ulcers and the delay of ulcer healing. Mechanistic studies have shown that cigarette smoke and its active ingredients can cause mucosal cell death, inhibit cell renewal, decrease blood flow in the GI mucosa and interfere with the mucosal immune system. Cigarette smoking is also an independent risk factor for various types of cancer of the GI tract. In this review, we also summarize the mechanisms through which cigarette smoking induces tumorigenesis and promotes the development of cancer in various sections of the GI tract. These mechanisms include the activation of nicotinic acetylcholine receptors, the formation of DNA adducts, the stimulation of tumor angiogenesis and the modulation of immune responses in the GI mucosa. A full understanding of these pathogenic mechanisms may help us to develop more effective therapies for GI disorders in the future.

The Janus face of cathelicidin in tumorigenesis.

Cathelicidin is a host defense peptide with multiple innate immunity-related functions. Recent findings indicate that cathelicidin is frequently dysregulated in human cancers where it plays a paradoxical yet dominant role in the regulation of tumor malignancy. In this review, the regulation of malignant phenotypes by cathelicidin in relation to the activation of its receptors and intracellular signaling is discussed.

Rapid genotyping of Plasmodium vivax Pvs25 and Pv38 genes by using mismatch specific endonuclease.

Mismatch specific endonuclease (MSE) method was used to detect natural polymorphisms in Pvs25 and Pv38 genes of Plasmodium vivax. Eighty seven patients with P. vivax were recruited in the Republic of Korea (ROK). Pvs25 and Pv38 genes were amplified by polymerase chain reaction (PCR), and the PCR amplicons were mixed with reference DNA sequences. Following the denaturation and gradual annealing, the product mixtures were cleaved by the MSE. Heteroduplex types were readily detected by gel electrophoresis, where extra bands with shorter sizes would appear from the cleavage. After MSE cleavage of 657- bp product from Pvs25 mixtures, three genotypes were detected, while Pv38 mixtures with 1220-bp products presented two genotypes in ROK isolates. After the MSE cleavage, the mismatched samples of Pvs25 and Pv38 were completely sequenced, and the results were in complete agreement with the MSE analyses. In conclusion, genotyping of Pvs25 and Pv38 with MSE cleavage could be a potential method for the high-throughput screening of the large field samples.

Intermediate-risk grouping of cervical cancer patients treated with radical hysterectomy: a Korean Gynecologic Oncology Group study.

BACKGROUND: In this study, we sought to identify a criterion for the intermediate-risk grouping of patients with cervical cancer who exhibit any intermediate-risk factor after radical hysterectomy. METHODS: In total, 2158 patients with pathologically proven stage IB-IIA cervical cancer with any intermediate-risk factor after radical hysterectomy were randomly assigned to two groups, a development group and a validation group, at a ratio of 3 : 1 (1620 patients:538 patients). To predict recurrence, multivariate models were developed using the development group. The ability of the models to discriminate between groups was validated using the log-rank test and receiver operating characteristic (ROC) analysis. RESULTS: Four factors (histology, tumour size, deep stromal invasion (DSI), and lymphovascular space involvement (LVSI)) were significantly associated with disease recurrence and included in the models. Among the nine possible combinations of the four variables, models consisting of any two of the four intermediate-risk factors (tumour size ≥3 cm, DSI of the outer third of the cervix, LVSI, and adenocarcinoma or adenosquamous carcinoma histology) demonstrated the best performance for predicting recurrence. CONCLUSION: This study identified a 'four-factor model' in which the presence of any two factors may be useful for predicting recurrence in patients with cervical cancer treated with radical hysterectomy.