FOXO3a Expression Regulated by ERK Signaling is Inversely Correlated With Y-Box Binding Protein-1 Expression in Prostate Cancer.

BACKGROUND: FOXO3a is a member of the forkhead O transcription factors. FOXO3a induces the factors that contribute to cell cycle arrest and is considered a tumor suppressor in several malignant tumors. Y-box binding protein-1 (YB-1) is a multifunctional protein whose high expression is correlated with poor prognoses in various malignant tumors. In the current study, we investigated the relationship between FOXO3a and YB-1 to validate their functional roles in prostate cancer. METHODS: Western blotting and cytotoxicity assays were conducted in prostate cancer cells, LNCaP, and 22Rv1 cells. We also evaluated the protein expressions of FOXO3a and YB-1 in human prostate cancer tissues, using radical prostatectomy specimens. Then, we investigated the correlations between protein expressions and clinicopathologic parameters. RESULTS: We found that both FOXO3a and YB-1 proteins were phosphorylated by ERK signaling, resulting in FOXO3a inactivation and YB-1 activation in LNCaP and 22Rv1 cells. Inversely, inhibition of MEK or treatment with metformin activated FOXO3a through inactivation of ERK signaling and suppressed the viability of LNCaP and 22Rv1 cells in a dose-dependent manner. In immunohistochemical analysis, FOXO3a nuclear expression was inversely correlated with YB-1 nuclear expression (P < 0.0001). Furthermore, high FOXO3a nuclear expression was inversely correlated with a higher Gleason grade (P < 0.0001) and higher preoperative PSA (P = 0.0437). CONCLUSIONS: These results showed that in prostate cancer, FOXO3a, and YB-1 play inverse reciprocal roles as a tumor-suppressor gene and oncogene, respectively, through their master regulator ERK. Prostate 77:145-153, 2017. © 2016 Wiley Periodicals, Inc.

The Differential Impact of Body Mass Index and the Feature of Metabolic Syndrome on Oncological Outcomes Following Different Surgical Procedures in Japanese Men with Prostate Cancer.

PURPOSE: This study aimed to examine the differential impact of body mass index and the feature of metabolic syndrome (MetS; obesity, hypertension, diabetes mellitus, and dyslipidemia) on biochemical recurrence (BCR) following radical prostatectomy (RP) treatment for prostate cancer using different surgical procedures. METHODS: This study included 283 Japanese patients with clinically localized prostate cancer who were treated with RP between 2008 and 2012. The prognostic significance of overweight and the feature of MetS were analyzed according to surgical procedures. RESULTS: BCR occurred in 68/283 (24.0%) men. Overweight and the feature of MetS were predictors of BCR in patients who had undergone open RP (ORP), but not in those treated with laparoscopic surgery. Multivariate analyses incorporating preoperative and postoperative risk factors revealed that overweight and the feature of MetS were independent BCR risk factors when treated with ORP. CONCLUSIONS: In Japanese men, overweight and the feature of MetS were associated with worse outcomes following RP, particularly ORP, compared with those following laparoscopic surgery. These results suggest that laparoscopic surgery can overcome the surgical challenges associated with abdominal obesity.

PD-L1 expression in papillary renal cell carcinoma.

BACKGROUND: The immune escape or tolerance of cancer cells is considered to be closely involved in cancer progression. Programmed death-1 (PD-1) is an inhibitory receptor expressed on activating T cells, and several types of cancer cells were found to express PD-1 ligand 1 (PD-L1) and ligand 2 (PD-L2). METHODS: In the present study, we investigated PD-L1/2 expression in papillary renal cell carcinoma (pRCC). RESULT: We found PD-L1 expression in 29 of 102 cases, but no PD-L2 expression was seen. PD-L1 expression was not significantly correlated with any clinicopathological factor, including progression-free survival and overall survival. The frequency of PD-L1-positive cases was higher in type 2 (36%) than in type 1 (22%) pRCC; however, there was no significant difference in the percentages of score 0 cases (p value = 0.084 in Chi-square test). The frequency of high PD-L1 expression cases was higher in type 2 (23%) than in type 1 (11%), and the frequency of high PD-L1 expression cases was higher in grade 3/4 (21%) than in grade 1/2 (13%). However, no significant association was found between PD-L1 expression and all clinicopathological factors in pRCC. CONCLUSION: High expression of PD-L1 in cancer cells was potentially associated to highly histological grade of malignancy in pRCC. The evaluation of the PD-L1 protein might still be useful for predicting the efficacy of anti-cancer immunotherapy using immuno-checkpoint inhibitors, however, not be useful for predicting the clinical prognosis.

Epithelial to Mesenchymal Transition in Clear Cell Renal Cell Carcinoma with Rhabdoid Features.

AIMS: The aims of this study were to investigate the association of renal cell carcinoma (RCC) displaying rhabdoid features and morphologically mesenchymal characteristics with epithelial to mesenchymal transition (EMT), and to clarify the expression of EMT markers. METHODS: We investigated the expression of EMT markers (E-cadherin, vimentin, Snail, Slug, ZEB1, ZEB2 and Twist1) using immunohistochemistry, Western blotting and real-time polymerase chain reaction in 18 cases of clear cell RCC (ccRCC) with rhabdoid features and 74 ccRCC cases with Fuhrman grade 1-3 (G1 to G3). RESULTS: In ccRCCs with rhabdoid features, low E-cadherin and high vimentin expression were found. In G1 to G3 ccRCCs, low E-cadherin expression and high expression of vimentin, ZEB1 and ZEB2 were found. There was no significant difference in the immunoexpression of E-cadherin and vimentin between the two ccRCC groups. CONCLUSIONS: The rhabdoid features may histologically and biologically be associated with EMT in ccRCC. There is a possibility that in G1 to G3 ccRCCs showing epithelial structures, other cell-cell adhesion mechanisms apart from E-cadherin adhesion may continue to work, and that ccRCC with rhabdoid features may be caused by an inactivation or loss of these mechanisms.

Amide proton transfer (APT) magnetic resonance imaging of prostate cancer: comparison with Gleason scores.

OBJECTIVE: To evaluate the utility of amide proton transfer (APT) imaging in estimating the Gleason score (GS) of prostate cancer (Pca). MATERIALS AND METHODS: Sixty-six biopsy-proven cancers were categorized into four groups according to the GS: GS-6 (3 + 3); GS-7 (3 + 4/4 + 3); GS-8 (4 + 4) and GS-9 (4 + 5/5 + 4). APT signal intensities (APT SIs) and apparent diffusion coefficient (ADC) values of each GS group were compared by one-way analysis of variance with Tukey's HSD post hoc test. RESULTS: The mean and standard deviation of the APT SIs (%) and ADC values (×10(-3) mm(2)/s) were as follows: GS-6, 2.48 ± 0.59 and 1.16 ± 0.26; GS-7, 5.17 ± 0.66 and 0.92 ± 0.18; GS-8, 2.56 ± 0.85 and 0.86 ± 0.17; GS-9, 1.96 ± 0.75 and 0.85 ± 0.18, respectively. The APT SI of the GS-7 group was highest, and there were significant differences between the GS-6 and GS-7 groups and the GS-7 and GS-9 groups (p < 0.05). The ADC value of the GS-6 group was significantly higher than each value of the GS-7, GS-8, and GS-9 groups (p < 0.05), but no significant differences were obtained among the GS-7, GS-8, and GS-9 groups. CONCLUSION: The mean APT SI in Pca with a GS of 7 was higher than that for the other GS groups.

Microfluidic Preparation of Nanoparticles Using Poly(ethylene Glycol)-distearoylphosphatidylethanolamine for Solubilizing Poorly Soluble Drugs.

Microfluidic systems have shown promise for the production of nanoparticles from mixtures of aqueous and organic solutions, including liposomes, oil-in-water nanoemulsions, and lipid nanoparticles. They offer important practical advantages, including low reagent consumption, parallelization, and automation, and are ideally suited to high-throughput optimization and scale-up. In this study, we developed a new method for the formulation of nanoparticles of poorly soluble drug compounds. The nanoparticles, prepared by microfluidic mixing using only poly(ethylene glycol)-distearoylphosphatidylethanolamine (PEG-DSPE), were highly stable and uniform in size. By mixing an organic solution of poorly soluble cyclosporine A and PEG-DSPE with water in the microfluidic device, amorphous cyclosporine A nanoparticles (CsA-NPs), with an encapsulation efficiency of approximately 90% and a particle size of 100-200 nm, were obtained. Analysis of the microfluidic process parameters revealed that particle size distribution was significantly controlled by the flow rate ratio. The obtained CsA-NPs were stable for up to 150 days at room temperature, and the pharmacokinetic profile was similar to that of the commercial formulation containing Cremophor EL, which has been reported to induce serious adverse effects after intravenous administration. These findings provide a useful technical platform for the safe solubilization of poorly soluble compounds and their subsequent pharmaceutical development.

Ureterosciatic hernia successfully treated by ureteral stent placement.

A 76-year-old woman with history of cholecystectomy, hysterectomy, and vesicourethral suspension presented with acute lumbar backache and discomfort in the lower abdomen and severe nausea, with frequent vomiting, but without any associated fever. Physical examination revealed knocking tenderness at the left costal-vertebral angle. The patient's serum white blood cell count was 14,900/mm(3) and the results of other laboratory tests, including urinalysis, were normal. Non-enhanced computed tomography revealed left hydroureteronephrosis and obstruction of the distal left ureter with herniation into the sciatic foramen. A left ureteral stent was inserted with a double-J stent. The stent was removed after 2 months and thereafter the patient did not experience any recurrence.

The SWI/SNF chromatin-remodeling complex status in renal cell carcinomas with sarcomatoid or rhabdoid features.

The presence of sarcomatoid or rhabdoid features (which are associated with advanced disease and poor prognosis) is rarely observed in the subtypes of renal cell carcinoma (RCC). The SWI/SNF chromatin-remodeling complex, which is composed of evolutionarily conserved core subunits including SMARCB1/INI1 (SMARCB1), SMARCA4/BRG1 (SMARCA4), SMARCC1/BAF155 (SMARCC1), and SMARCC2/BAF170 (SMARCC2), can be regarded as the prototype of an epigenetic regulator of gene expression that is involved in tumor suppression. We analyzed the histological, immunohistochemical, and clinicopathological status in 72 cases of RCC with sarcomatoid or rhabdoid features, focusing on the expression status of the subunits of SWI/SNF chromatin-remodeling complex proteins. Cases with lost or reduced expression were defined as showing aberrant expression. The frequency of aberrant SMARCA4 immunoexpression of a sarcomatoid or rhabdoid component in clear cell RCC (ccRCC) (47/50, 94%) was significantly higher than that in non-ccRCC (4/9, 44%) (p < 0.001). In ccRCC without sarcomatoid or rhabdoid features, aberrant SMARCA4 immunoexpression was observed in 33 of 48 (67%) cases. Immunoreactivities for SMARCB1, SMARCA2, and SMARCC2 were retained in almost all subtypes of RCC. The patients with aberrant SMARCA4 expression in RCC with sarcomatoid or rhabdoid features achieved shorter progression-free survival compared with the patients with retained SMARCA4 expression (all subtypes of RCC, p = 0.0212; ccRCC, p = 0.0265). These results suggest that in ccRCC, aberrant SMARCA4 expression is one of the adverse prognostic factors or a high-grade malignant transforming factor. The evaluation of SMARCA4 immunoexpression may be a useful diagnostic tool to help distinguish ccRCC from non-ccRCC.

Relationship Among Tumor Attenuation Value of Pre-contrast Computed Tomography (CT), Washout Rate and Constituent Cells in Adrenal Adenoma: Proposition of a New Approach for Diagnosing Adrenal Adenoma on Dynamic CT.

AIM: To elucidate the relationship among tumor attenuation of pre-contrast-enhanced (TApre) computed tomography (CT), washout rate and clear cell ratio (CCR) in adrenal adenoma (AA) and propose a new approach for diagnosing AA on dynamic CT. MATERIALS AND METHODS: The training set consisted of 43 AAs and 15 non-AAs, while the validation set comprised 44 AAs and 11 non-AAs. Using the training set, the pairwise correlation between CCR, TApre and washout rate in AA was evaluated by linear regression analysis. A predictive formula for diagnosing AA was established by multiple logistic regression analysis using washout rate and TApre. Using the validation set, the diagnostic performance of this formula was investigated by comparing with the conventional diagnostic criteria: TApre ≤10 HU or washout rate ≥an optimal threshold calculated in the training set. RESULTS: Washout rate increased as CCR decreased, and as TApre increased. The formula predicting the probability of AA was: p(AA)=1/{1+exp(-1.5257+0.4923× TApre-0.3264×washout rate)}. Diagnostic performance of this formula was sensitivity of 93.2% and accuracy of 89.1%, while for the conventional diagnostic criteria, sensitivity was 81.8-86.4% and accuracy 81.8-83.6%. CONCLUSION: The diagnostic potential of dynamic CT for diagnosing AA may be improved by changing the threshold of washout rate based on substituting TApre for CCR.

Impact of body mass index on CT attenuation of adrenal adenoma.

OBJECTIVE: To investigate whether lipid metabolism-related factors regulate unenhanced CT attenuation in adrenal adenoma (AA). MATERIALS AND METHODS: Thirty-six patients with surgically proven AAs were enrolled in this study. The patients' underlying diseases were the following: primary aldosteronism (n = 24), Cushing's syndrome (n = 8), subclinical Cushing's syndrome (n = 3) and non-functioning AA (n = 1). Unenhanced CT attenuation of AAs and liver was measured. Pathologically, clear cell ratio (CCR) constituting each AA was qualitatively assessed. Clinical data including tumor diameter, body mass index (BMI), hemoglobin A1c, triglyceride, total cholesterol, blood cortisol and plasma aldosterone levels were also obtained. Simple and multiple linear regression analyses were performed to evaluate the radiological and clinicopathological factors associated with CT attenuation of AAs for all patients and separately for 25 patients with primary aldosteronism or non-functioning AA. RESULTS: For all patients, there was a significant correlation between CT attenuation and each of CCR, BMI and blood cortisol levels (p < 0.05). For patients with primary aldosteronism or non-functioning AA, there was also a significant correlation between CT attenuation and CCR or BMI (p < 0.05). CONCLUSION: In addition to pathological factors, lipid-metabolism-related factors including BMI and blood cortisol levels can affect unenhanced CT attenuation of AA.

Tumor Enhancement on Dynamic CT: A Predictive Factor for Recurrence After Nephrectomy in Localized T1 Clear Cell Renal Cell Carcinoma.

AIM: To investigate whether radiological parameters obtained on dynamic computed tomography (CT), especially those related to tumor enhancement, are predictive factors for recurrence after nephrectomy in localized stage T1 clear cell renal cell carcinoma (ccRCC). MATERIALS AND METHODS: We retrospectively studied 88 patients with localized stage T1 ccRCC who underwent dynamic CT preoperatively. Seven patients had recurrent disease after surgery. Tumor attenuations were measured by placing a region of interest in the solid region. TApre and TAneph were defined as the tumor attenuation values of the pre-contrast and nephrographic phase, respectively. The correlations between disease-free survival and clinicopathological factors, including the radiological parameter TAneph - TApre (ΔTAneph), were analyzed by Cox proportional hazards model or Kaplan-Meier method with the log-rank test. RESULTS: Only ΔTAneph was significantly and positively correlated with disease-free survival (p<0.05). Tumor size also tended to be negatively correlated with disease-free survival (p<0.1). The 5- and 10-year disease-free survival rates of the group with high ΔTAneph (≥86 HU) were 97.4% and 97.4%, while those of the group with low ΔTAneph (<86 HU) were 89.6% and 71.6%, respectively. CONCLUSION: Tumor enhancement in the nephrographic phase of CT was a predictive factor for recurrence after nephrectomy in patients with localized stage T1 ccRCC.

Development of manufacturing method for rapidly disintegrating oral tablets using the crystalline transition of amorphous sucrose.

The industrial manufacturing of rapidly disintegrating oral tablets with a sufficient tensile strength was investigated. The manufacturing method of the tablets involved the crystalline transition of amorphous sucrose that was produced in the process of fluidized bed granulation of mannitol using sucrose solution as a binder. The aim of this article was to clarify the usefulness of amorphous sucrose formed during the granulation for the rapidly disintegrating oral tablets manufacturing, and to investigate the effects of crystalline transition of the amorphous sucrose in granules on the characteristics of the resultant tablets prepared by this crystalline transition (CT) method. The X-ray diffraction measurement and thermal analysis showed that amorphous sucrose was effectively formed in granules consisting of 95% mannitol and 5% sucrose when the granulation was performed on the condition of water content of 4%. The tensile strength of tablets comprised of the granules, which were compressed before the crystallization of amorphous sucrose, increased remarkably after storage, because new internal solid bridges were formed in the tablets as a result of the crystallization. We conclude that rapidly disintegrating oral tablets can effectively be manufactured by the CT method using the granules obtained by the fluidized bed granulation method.

Renal cell carcinoma with rhabdoid-like features lack intracytoplasmic inclusion bodies and show aggressive behavior.

In renal cell carcinoma (RCC), tumor cells with rhabdoid features are characterized by eccentric nuclei, prominent nucleoli, and eosinophilic cytoplasm with intracytoplasmic inclusion bodies. In RCC, tumor cells have also been observed resembling rhabdomyoblasts or rhabdoid but without intracytoplasmic inclusion bodies, and here, we defined these rhabdoid-like features of these cells. To this end, we studied a series of clear cell RCC (ccRCC) with rhabdoid features and compared them with a series of ccRCC with rhabdoid-like features to clarify the differences in the immunohistochemical profile and biological behavior. From 695 cases of ccRCC (80.8 % of all RCCs), 18 cases with rhabdoid features (2.1 % of all RCCs) and 25 cases with rhabdoid-like features (2.9 % of all RCCs) were investigated. The 5-year survival rate for ccRCC with rhabdoid features was 44.7 % and for ccRCC with rhabdoid-like features 30.3 %. Although ccRCC with rhabdoid features showed immunohistochemical co-expression of epithelial markers and vimentin as seen in malignant rhabdoid tumors, ccRCC with rhabdoid-like features showed no such co-expression. Multivariate analyses of cancer-specific survival revealed that perinephric tissues invasion was an independent prognostic factor in ccRCC with rhabdoid features (p = 0.0253) but not in ccRCC with rhabdoid-like features. In summary, although their prognosis is similar, the marker profile and pattern of extension of ccRCC with rhabdoid-like is different from that of ccRCC with rhabdoid features. Therefore, ccRCC with rhabdoid-like features should be distinguished from ccRCC with rhabdoid features.

A Retroperitoneal Isolated Enteric Duplication Cyst Mimicking a Teratoma: A Case Report and Literature Review.

Enteric duplication cysts lacking anatomic association with the gastrointestinal tract are called isolated enteric duplication cysts (IEDCs). We present an atypical case of a retroperitoneal IEDC with a tortuous tubular complex shape that enfolded the surrounding retroperitoneal fat and mimicked a retroperitoneal teratoma. Multiplanar reconstruction images should be used to evaluate such a lesion correctly. A tortuous tubular complex shape could be a key finding to differentiate from other retroperitoneal cysts.

A case report of primary malignant melanoma of male urethra with distinct appearance in multiple regions.

A 66-year-old man presented with macrohematuria. Cystoscope examination found a 5 mm nodular tumor at external urethral orifice and multiple papillary tumors at fossa navicularis of urethra; those are non-black colored. Transurethral resection of the urethra tumor was performed, and pathologically diagnosed as malignant melanoma. Image examinations showed no lymphadenopathy and metastasis. Accordingly, total penectomy was conducted to remove the remaining tumors, resulting in surgically curative resection. After the operation, monthly interferon-ß injection into inguinal region has been administered as adjuvant therapy, resulting in no recurrence at 6 months after penectomy.

Factors affecting the characteristics of rapidly disintegrating tablets in the mouth prepared by the crystalline transition of amorphous sucrose.

The aim of this study is to investigate the factors affecting the characteristics of rapidly disintegrating tablets containing an amorphous ingredient prepared by crystalline transition method (CTM) under various storage conditions. Effect of storage conditions and formulating ratio of amorphous sucrose on the characteristic changes (tensile strength, porosity, and disintegration time) of the rapidly disintegrating tablets was studied. The storage conditions of different temperature and humidity affected the rate of crystalline transition and the increase in the tablet tensile strength. The faster crystalline transition resulted in a faster rate of increase in the tablet tensile strength. Regarding the effect of the formulating ratio of amorphous sucrose, in the case of 20-100%, the tensile strength after storage as a function of the porosity could be plotted on the same curve. For tablets containing 100% amorphous sucrose, the tablets with different porosity changed to almost the same structure due to the crystalline transition. Hence, the higher formulating ratio of amorphous sucrose provided the longer disintegration time in the mouth. Therefore, we concluded that the formulating ratio of 10-20% of the amorphous sucrose in the tablet is suitable for the rapidly disintegrating tablet in the mouth when prepared by CTM.

Low Serum Testosterone But Not Obesity Predicts High Gleason Score at Biopsy Diagnosed as Prostate Cancer in Patients with Serum PSA Lower than 20 ng/ml.

BACKGROUND/AIM: The impact of testosterone or obesity on the pathological grade of prostate cancer remains controversial. Therefore, in this study, we investigated the relationship of serum testosterone and body mass index (BMI) to Gleason score at biopsy. PATIENTS AND METHODS: This study included 128 Japanese patients diagnosed with prostate cancer from 2000 through 2012 whose serum testosterone level and BMI were measured before treatment. Associations between clinical parameters, including pre-treatment serum testosterone level and BMI, and Gleason score at biopsy were examined. RESULTS: The median serum testosterone and BMI were 434 ng/dl (interquartile range=362-542 ng/dl) and 23.5 kg/m(2) (interquartile range=21.7-25.4 kg/m(2)), respectively. Gleason score at biopsy was <7, 7 and >7 for 58 patients (45.3%), 52 patients (40.6%) and 18 patients (14.1%), respectively. On univariate analysis, positive finding at digital rectal examination (DRE), high prostate-specific antigen level at diagnosis and low serum testosterone level, but not BMI, were correlated with high Gleason score at biopsy. Multivariate analysis identified positive finding at DRE and low serum testosterone level as significant predictors of a high Gleason score at prostate biopsy. By combining these parameters, the predictive ability of a high Gleason score was improved. CONCLUSION: This study showed that positive finding at DRE and a low pre-treatment serum testosterone level, but not obesity, may be factors predictive of aggressive prostate cancer, indicating the diagnostic value of serum testosterone, as well as DRE findings, in risk assessment.

Prognostic Impact of Serum Testosterone and Body Mass Index Before Androgen-deprivation Therapy in Metastatic Prostate Cancer.

AIM: Although the impact of testosterone or obesity on the efficacy of androgen-deprivation therapy (ADT) has been reported, there exist few comprehensive analyses on the impact of these factors on ADT outcome. Therefore, in the present study, we investigated the relationship between serum testosterone or body mass index (BMI) and prognosis among men treated with primary ADT for metastatic prostate cancer. PATIENTS AND METHODS: The study included fifty-six Japanese patients with prostate cancer treated at our Institution from 2000 through 2012. The relationship between serum testosterone or BMI and progression-free survival, cancer-specific survival, and overall survival among men with metastatic prostate cancer treated with primary ADT was examined. RESULTS: The median of serum testosterone and BMI were 397 ng/dl (interquartile range (IQR), 278-464 ng/dl) and 21.9 kg/m(2) (IQR, 19.2-23.6 kg/m(2)), respectively. Median progression-free survival, cancer-specific survival, and overall survival were 23.2 months, 68.9 months, and 68.1 months, respectively. Among clinicopathological parameters, the lowest-quartile group of serum testosterone level was a significant predictor of poor cancer-specific survival and overall survival as well as survival from castration resistance. However, BMI was not associated with prognosis. CONCLUSION: Serum testosterone level, but not obesity, is a prognostic factor for outcome including survival after getting castration-resistant prostate cancer in men with metastatic prostate cancer having undergone primary ADT.

Numerical evaluation of the capping tendency of microcrystalline cellulose tablets during a diametrical compression test.

Capping is one of the major problems that occur during the tabletting process in the pharmaceutical industry. This study provided an effective method for evaluating the capping tendency during diametrical compression test using the finite element method (FEM). In experiments, tablets of microcrystalline cellulose (MCC) were compacted with a single tabletting machine, and the capping tendency was determined by visual inspection of the tablet after a diametrical compression test. By comparing the effects of double-radius and single-radius concave punch shapes on the capping tendency, it was observed that the capping tendency of double-radius tablets occurred at a lower compaction force compared with single-radius tablets. Using FEM, we investigated the variation in plastic strain within tablets during the diametrical compression test and visualised it using the output variable actively yielding (AC YIELD) of ABAQUS. For both single-radius and double-radius tablets, a capping tendency is indicated if the variation in plastic strain was initiated from the centre of tablets, while capping does not occur if the variation began from the periphery of tablets. The compaction force estimated by the FEM analysis at which the capping tendency was observed was in reasonable agreement with the experimental results.

Mutual regulation between Raf/MEK/ERK signaling and Y-box-binding protein-1 promotes prostate cancer progression.

PURPOSE: Y-box-binding protein-1 (YB-1) is known to conduct various functions related to cell proliferation, anti-apoptosis, epithelial-mesenchymal transition, and castration resistance in prostate cancer. However, it is still unknown how YB-1 affects cancer biology, especially its correlations with the mitogen-activated protein kinase (MAPK) signaling pathway. Therefore, we aimed to examine the interaction between YB-1 and the MAPK pathway in prostate cancer. EXPERIMENTAL DESIGN: Quantitative real-time PCR, Western blotting, and co-immunoprecipitation assay were conducted in prostate cancer cells. YB-1, phosphorylated YB-1 (p-YB-1), and ERK2 protein expressions in 165 clinical specimens of prostate cancer were investigated by immunohistochemistry. YB-1, p-YB-1, and ERK2 nuclear expressions were compared with clinicopathologic characteristics and patient prognoses. RESULTS: EGF upregulated p-YB-1, whereas MEK inhibitor (U0126, PD98059) decreased p-YB-1. Inversely, silencing of YB-1 using siRNA decreased the expression of ERK2 and phosphorylated MEK, ERK1/2, and RSK. Furthermore, YB-1 interacted with ERK2 and Raf-1 and regulated their expressions, through the proteasomal pathway. Immunohistochemical staining showed a significant correlation among the nuclear expressions of YB-1, p-YB-1, and ERK2. The Cox proportional hazards model revealed that high ERK2 expression was an independent prognostic factor [HR, 7.947; 95% confidence interval (CI), 3.527-20.508; P<0.0001]. CONCLUSION: We revealed the functional relationship between YB-1 and MAPK signaling and its biochemical relevance to the progression of prostate cancer. In addition, ERK2 expression was an independent prognostic factor. These findings suggest that both the ERK pathway and YB-1 may be promising molecular targets for prostate cancer diagnosis and therapeutics.