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Background: The exosome-mediated extracellular secretion of miRNAs occurs in many cancers, and RAB27A is a potent regulator of exosome secretion. For metastatic renal cell carcinoma (RCC), this study examines the mechanisms of cancer metastasis via the RAB27A-regulated secretion of specific miRNAs. Methods: RAB27A knockdown (KD) and overexpressing (OE) RCC cells were used to examine cell migration and adhesion. The particle counts and sizes of exosomes in RAB27A OE cells were analyzed using Exoview, and those of intraluminal vesicles (ILV) and multivesicular bodies (MVB) were measured using an electron microscope. Analysis of RNA sequences, protein–protein interaction networks, and the competing endogenous RNA (ceRNA) network were used to identify representative downregulated miRNAs that are likely to undergo cargo-sorting into exosomes and subsequent secretion. A molecular beacon of miR-137-3p, one of the most representatively downregulated genes with a fold change of 339, was produced, and its secretion was analyzed using Exoview. RAB27A OE and control cells were incubated in an exosome-containing media to determine the uptake of tumor suppressor miRNAs that affect cancer cell metastasis. Results: Migration and cell adhesion were higher in RAB27A OE cells than in RAB27A KD cells. Electron microscopy revealed that the numbers of multivesicular bodies and intraluminal vesicles per cell were higher in RAB27A OE cells than in control cells, suggesting their secretion. The finding revealed that miR-127-3p was sorted into exosomes and disposed of extracellularly. Protein–protein interaction analysis revealed MYCN to be the most significant hub for RAB27A-OE RCC cells. ceRNA network analysis revealed that MAPK4 interacted strongly with miR-127-3p. Conclusion: The disposal of miR-127-3p through exosome secretion in RAB27A overexpressing cells may not inhibit the MAPK pathway to gain metastatic potential by activating MYCN. The exosomes containing miRNAs are valuable therapeutic targets for cancer treatment. [ABSTRACT FROM AUTHOR]

Perilipin (PLIN) is a major structural protein located on the surface of lipid droplets. PLIN plays an important role in human metabolism and is associated with metabolic diseases, such as obesity, diabetes, hypertension, and endocrine disorders. The dysregulation of lipid metabolism is one of the most prominent metabolic changes observed in cancers. Therefore, the PLIN protein family has recently attracted attention owing to its role in lipid metabolism and cancer. To date, no studies have addressed the association between the prognosis of lung cancer and PLIN1 expression. For the first time, we found that high PLIN1 expression was significantly correlated with worse disease-free survival (DFS) in lung squamous cell carcinoma (SCC). We examined PLIN1 expression by the immunohistochemical analysis of surgical lung SCC specimens obtained from 94 patients. We analyzed the correlation between PLIN1 expression, clinicopathological data, and patient survival, using a chi-squared test, Kaplan–Meier analysis with log-rank tests, and the multivariate Cox proportional hazards regression test. High PLIN1 expression was significantly correlated with lower DFS in the Kaplan–Meier analysis and the multivariate Cox proportional hazards regression model. High PLIN1 expression was significantly correlated with worse prognosis in lung SCC. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Histiocytic necrotizing lymphadenitis (HNL) is a self-limiting disease characterized by cervical lymphadenopathy and fever. Epstein–Barr virus (EBV) has been implicated as a cause of HNL in some reports but not in others. The aim of this study was to compare the clinical features and laboratory findings in children and adults with HNL and to evaluate the relationship between EBV infection and HNL. Methods: The records of patients diagnosed with biopsy-confirmed HNL at Gyeongsang National University Hospital from May 2009 to December 2012 were retrospectively reviewed. Clinical features, laboratory data (blood count, biochemistry, and serology), and computed tomography findings were collected. Immunohistochemistry for CD4, CD8, CD68, and myeloperoxidase (MPO), and in situ hybridization for EBV RNA were performed on archived lymph node biopsies from pediatric and adult patients. Results: A total of 16 children and 31 adults were diagnosed with HNL. Fever was present in 87.5% of children and 25.8% of adults (P <0.0001). Fever duration was longer for children (mean, 5.06 days) than for adults (mean, 0.63 days; P =0.008). Necrosis of the involved lymph nodes was observed in eight (50%) children and six (19.4%) adults (P =0.045). HNL recurred in five (31.35%) children and one (3.2%) adult (P =0.015). All had detectable CD4, CD8, CD68, and MPO immunoreactivity. EBV reactivity was higher in children (26.7%) than in adults (6.7%) without statistical support. Conclusions: There is more variability in the clinical presentation and laboratory findings in children with HNL than in adults. In particular, the degree and duration of fever was more severe in children than in adults, and necrosis of lymph nodes was more frequent in children than in adults. There was no definitive correlation between EBV reactivity and NHL. Further study of the relationship between EBV and HNL is needed with a larger number of patients. [Copyright &y& Elsevier]

Simple Summary: In our previous study, purinergic P2Y2 receptor (P2Y2R) activation by ATP was found to play an important role in tumor progression and metastasis by regulating various responses in cancer cells and modulating crosstalk between cancer cells and endothelial cells (ECs). Therefore, we expected that P2Y2R would play a critical role in radioresistance and enhanced tumor progression in radioresistant triple-negative breast cancer (RT-R-TNBC). However, interestingly, P2Y2R expression was slightly decreased in RT-R-TNBC cells, while the expression of A2AR was significantly increased both in RT-R-TNBC cells and in tumor tissues, especially triple negative breast cancer (TNBC) tissues of breast cancer (BC) patients. Thus, we aimed to investigate the role of adenosine A2A receptor (A2AR) and its signaling pathway in the progression of RT-R-TNBC. The results reveal for the first time the role of A2AR in the progression and metastasis of RT-R-BC cells and suggest that the adenosine (ADO)-activated intracellular A2AR signaling pathway is linked to the AKT-β-catenin pathway to regulate RT-R-BC cell invasiveness and metastasis. Recently, we found that the expressions of adenosine (ADO) receptors A2AR and A2BR and the ectonucleotidase CD73 which is needed for the conversion of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) and the extracellular ADO level are increased in TNBC MDA-MB-231 cells and RT-R-MDA-MB-231 cells compared to normal cells or non-TNBC cells. The expression of A2AR, but not A2BR, is significantly upregulated in breast cancer tissues, especially TNBC tissues, compared to normal epithelial tissues. Therefore, we further investigated the role of ADO-activated A2AR and its signaling pathway in the progression of RT-R-TNBC. ADO treatment induced MDA-MB-231 cell proliferation, colony formation, and invasion, which were enhanced in RT-R-MDA-MB-231 cells in an A2AR-dependent manner. A2AR activation by ADO induced AKT phosphorylation and then β-catenin, Snail, and vimentin expression, and these effects were abolished by A2AR-siRNA transfection. In an in vivo animal study, compared to 4T1-injected mice, RT-R-4T1-injected mice exhibited significantly increased tumor growth and lung metastasis, which were decreased by A2AR-knockdown. The upregulation of phospho-AKT, β-catenin, Snail, and vimentin expression in mice injected with RT-R-4T1 cells was also attenuated in mice injected with RT-R-4T1-A2AR-shRNA cells. These results suggest that A2AR is significantly upregulated in BC tissues, especially TNBC tissues, and ADO-mediated A2AR activation is involved in RT-R-TNBC invasion and metastasis through the AKT-β-catenin pathway. [ABSTRACT FROM AUTHOR]

Our previous study found that highly metastatic breast cancer cells, such as MDA-MB-231 cells, release higher levels of ATP and exhibit greater P2Y2 receptor (P2Y2R) activity than lowly metastatic breast cancer cells, and that P2Y2R activation mediated by ATP plays a significant role in tumor progression and metastasis. In addition, we reported that radiotherapy-resistant (RT-R) breast cancer cells promote invasion and tumor growth through the activation of P2Y2R by ATP released from RT-R-breast cancer cells than breast cancer cells. Moreover, increased numbers of cancer stem cells (CSCs) were observed among the RT-R-breast cancer cell population. Therefore, in this study, we investigated the expression level of five CSC markers (CD24, CD44, Oct3/4, Notch-4 and ALDH1A1) as well as P2Y2R in the tumor tissues of patients with breast cancer and determined which CSC marker correlates with P2Y2R in breast cancer. According to the immunohistochemical analysis, CD44, Oct3/4 and Notch-4 but not ALDH1A1 were significantly expressed in the tumor tissues (n=180) compared with the normal epithelial tissues (n=20) of patients with breast cancer. It was demonstrated that P2Y2R expression was increased in tumor tissues of patients with breast cancer compared with normal epithelial tissue. Notably, it was identified that P2Y2R expression has a significant correlation with only the CSC marker Notch-4 in patients with breast cancer. The results of this study suggested for the first time to the best of our knowledge that Notch-4 has a notable correlation with P2Y2R, which has important roles in tumor progression and metastasis. [ABSTRACT FROM AUTHOR]

Background: The prognostic impact of the expression of CD8 and programmed death-ligand 1 (PD-L1) has not been established in patients with resectable non-small cell lung cancer (NSCLC).Methods: Surgical tissue specimens were obtained from 136 patients with NSCLC who underwent surgical resection. The expression levels of CD8 and PD-L1 were assessed using tissue microarrays and immunohistochemistry.Results: The CD8-positive group showed significant increases in overall survival (OS) (median, not reached [NR] vs. 28.452 months) and relapse-free survival (RFS) (median, NR vs. 14.916 months) compared with the CD8-negative group. In contrast to CD8, the PD-L1-negative group demonstrated significant increases in OS (median, NR vs. 29.405 months) and RFS (median, 63.573 vs. 17.577 months) compared with the PD-L1-positive group. Two prognostic groups were stratified according to CD8/PD-L1 expression: group 1 (CD8-positive/PD-L1-negative) vs. group 2 (CD8/PD-L1: positive/positive, negative/negative, negative/positive). Group 1 had better OS (median, NR vs. 29.405 months) and RFS (median, NR vs. 17.577 months) than group 2. Multivariate analysis indicated that group 1 constituted an independent favourable prognostic factor for OS (hazard ratio [HR], 0.329, p = 0.001) and RFS (HR, 0.293; p < 0.001).Conclusions: Positive CD8 and negative PD-L1 expression together may be favourable prognostic markers in resectable NSCLC. [ABSTRACT FROM AUTHOR]

Objectives: Sirtuins (1-7) are evolutionarily conserved NAD-dependent deacetylases that play an important role in carcinogenesis. However, their role in renal cell carcinoma (RCC) remains unclear. The objective of the present study was to examine the role of SIRTs in RCC carcinogenesis and prognosis.Materials and Methods: Paraffin-embedded specimens from 102 patients who underwent extirpative renal surgeries for renal masses between January 2004 and December 2010 were examined. SIRT expression was compared between RCC and adjacent normal kidney tissues by immunohistochemical staining. Survival differences and cancer-specific survival were analyzed with the Kaplan-Meier log-rank test and univariate and multivariate Cox regression analyses, respectively.Results: SIRT1, SIRT3, and SIRT6 expression was significantly lower in RCC than in normal tissues (P = 0.001, P = 0.006, and P = 0.033, respectively), whereas the expression of other SIRT proteins did not differ significantly between the 2 tissues. SIRT3 expression was significantly associated with longer cancer-specific survival (HR = 0.133, P = 0.047), after adjusting for age, T stage, Fuhrman grade, Karnofsky performance status, and distant metastases. Kaplan-Meier analysis showed that patients with high-SIRT3 expression had relatively better survival than those with low-SIRT3 expression (P = 0.046, log-rank test).Conclusions: Our results provide preliminary evidence suggesting that SIRT1, SIRT3, and SIRT6 function as tumor suppressors in RCC. In particular, SIRT3 seems to have a favorable influence on the survival of patients with clear cell RCC. [ABSTRACT FROM AUTHOR]

Aims The aim of this study was to investigate the expression of Hsp90β and GRP94, and elucidate the clinical significance of their expression, in patients with resectable non-small-cell lung cancer ( NSCLC). Methods and results Surgical tissue specimens were obtained from 208 patients with NSCLC who underwent surgical resection. The expression levels of Hsp90β and GRP94 were assessed with tissue microarrays and immunohistochemistry. No correlations were observed between Hsp90β or GRP94 expression and several clinicopathological factors. The high-Hsp90β group [median overall survival ( OS) 20.4 months; 95% confidence interval ( CI) 0.000-40.864] showed a significant decrease in OS as compared with the low-Hsp90β group (median OS not reached; P = 0.003). In contrast to the Hsp90β analysis, the GRP94 analysis did not show a difference in OS. Moreover, in subgroup analyses of patients with squamous cell carcinoma histology, OS ( P = 0.012) and relapse-free survival ( P = 0.044) were significantly worse in the high-Hsp90β group than in the low-Hsp90β group. Multivariate analysis suggested that old age [hazard ratio ( HR) 1.568; 95% CI 1.019-2.412; P = 0.041], advanced disease ( HR 2.066; 95% CI 1.218-3.502; P = 0.007) and high Hsp90β expression ( HR 1.802; 95% CI 1.061-3.060; P = 0.029) were independent poor prognostic factors for OS. Conclusions Hsp90β expression might be a useful marker of poor OS, although further large prospective studies are warranted to validate our findings. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma ( MCL), owing to its insensitivity to chemotherapy, has a poor prognosis, with a median survival of 3 years to 4 years. MCL frequently infiltrates other organs. However, reports involving kidney in living patients are rare. Here, we report a case of MCL with renal involvement leading to end stage renal disease that required renal replacement therapy. A 69-year-old man diagnosed with MCL 3 years earlier was admitted to our emergency room due to uremic symptoms. After eight cycles of chemotherapy, he had displayed complete remission, but experienced a recurrence 1.5 years later; after refusing chemotherapy, the patient was lost on follow-up in the final 10 months. On presentation at the emergency room, the patient's serum blood urea nitrogen was 109.5 mg/dL, and creatinine was 11.1 mg/dL. All serological markers for secondary glomerulonephritis were negative. Renal biopsy revealed 50% sclerosis of the glomerulus and small dense lymphocyte infiltration of the tubulo-interstitium. Similar cells were found on the gastric mucosa. Despite our recommendation for chemotherapy, he refused all treatments except for hemodialysis, which was maintained for 12 months until his death. This patient represents the first case report of the renal involvement of MCL leading to end stage renal disease. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The preferred treatment of pediatric intraoral ranulas remains controversial. We present our experience with ranulas at the Gyeongsang National University Hospital and review the literature. Methods: The study involved 17 children under 15 years of age who visited our hospital from 2001 to 2008 and were diagnosed with a ranula exceeding 2cm in diameter. The age and gender of the patients, the surgical procedures, presurgical observation period, postsurgical follow-up period, and complications of each case were determined. The unruptured specimens were all subjected to detailed pathological analysis. Results: The patients were on average 9.3 years and there were 10 girls and 7 boys. Spontaneous resolution was not detected in any of the cases during the presurgical observation period. Indeed, in two cases, the ranula had increased in size. The ranula and sublingual gland (SG) were resected in all cases. The average operation time was 1h. Recurrence and complications were not detected in any of the cases. Pathological analyses revealed that there was no communication of the ranula with the SG in any of the cases. Conclusions: Our experiences suggest that the presurgical observation period need not be longer than 3 months and that the resection of ranulas along with the ipsilateral SG is a safe and effective primary treatment for symptomatic pediatric intraoral ranulas that exceed 2cm in diameter. [Copyright &y& Elsevier]

The prognostic significance of O6-methylguanine DNA methyltransferase (MGMT) inactivation was evaluated in patients with diffuse large B-cell lymphoma (DLBCL) who received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in addition to rituximab. In this retrospective study, we used the methylation-specific polymerase chain reaction to investigate MGMT promoter methylation status and immunohistochemistry to evaluate MGMT expression in patients with DLBCL who received rituximab plus CHOP (R-CHOP) chemotherapy. No difference in patient characteristics, disease characteristics, response, or survival in patients with DLBCL who received front-line R-CHOP chemotherapy was observed according to MGMT methylation status and MGMT expression. On multivariate analysis, Grade 3–4 mucositis in the MGMT methylated group was significantly higher than that in the MGMT unmethylated group (hazard ratio (HR) 2.40, 95% CIs: 1.26–7.26, p = 0.014). This study demonstrated that inactivation of MGMT does not appear to play an important role in patients with DLBCL who received R-CHOP chemotherapy either with regard to the response rate or overall survival. Additionally, Grade 3–4 mucositis was found to be significantly related with inactivation of MGMT by a multivariate analysis. [ABSTRACT FROM AUTHOR]

Abstract: Background: To investigate the feasibility of combining several serum markers into a valid serum screening tool for gastric cancer, we performed a study evaluating the association between gastric cancer and precancerous conditions and a blood test for gastric acidity (the blood quininium resin test [QRT]) combined with serum pepsinogen levels. Methods: We performed immunoradiometric assays of serum pepsinogen I (PG I), II (PG II) levels, and QRT''s in 10 endoscopically normal subjects, in 20 patients with chronic atrophic gastritis, and in 13 patients with biopsy-confirmed gastric adenocarcinoma. Results: Serum PG I, II levels, I/II ratio were significantly different among normal, gastritis, and cancer patients. Serum PG I/II ratios were much lower in cancer patients. Serum quinine levels by QRT were correlated with PG I/II ratio (r s =0.39, p <0.01). Age was negatively correlated both with PG I/II ratio (r s =−0.58, p <0.01) and serum quinine level (r s =−0.45, p <0.01). The screening using serum PG levels was more valid (sensitivity of 69%, specificity of 77%) than that using QRT alone. The combination of serum PG levels and QRT increased specificity for detecting gastric cancer to 87% without altering sensitivity. Conclusion: Although blood QRT is a useful addition to other serum screening tests for gastric cancer, these tests alone are not sufficiently accurate as screening tools for gastric cancer. [Copyright &y& Elsevier]

Recently, ramucirumab, a drug that targets vascular endothelial growth factor receptor (VEGFR), was clinically approved; therefore, we evaluated VEGFR2 expression and its predictive roles in tumor progression in clear cell renal cell carcinoma (CCRCC). Since we do not have many options for treating aggressive renal cell carcinoma patients, the application of anti-VEGFR2 therapy might be useful. Myoferlin (MYOF) is a 230 kDa transmembrane multi-C2-domain protein that contributes to plasma membrane repair, fusion, and endocytosis and is overexpressed in several invasive cancer cell lines, including breast, pancreas, and malignant melanoma. It forms a complex with VEGFR2 to inhibit VEGFR2 degradation. In this study, a total of 152 patients who had undergone nephrectomy for CCRCC were enrolled. Based on tissue microarray (TMA) blocks, the positive intensity and high proportion of MYOF showed a statistically significant correlation with the negative intensity (p < 0.001) and low proportion (p < 0.001) of VEGFR2, respectively. In addition, Fuhrman's nuclear grade ≥3 showed a significant correlation with VEGFR2 expression. In multivariate analysis, CCRCC patients with positive MYOF and negative VEGFR2 expression demonstrated poor clinical outcomes. We confirmed that positive MYOF expression and negative VEGFR2 expression were positively correlated in this CCRCC population. Knocking down MYOF in Caki-1 cells resulted in the downregulation of VEGFR2 at both mRNA and protein levels. Wound healing assays revealed that the loss of MYOF in Caki-1 cells decreased cell confluence compared to that in control cells. We demonstrated that MYOF influences cellular proliferation of the metastatic CCRCC cell line by regulating VEGFR2 degradation. Combined therapies targeting the MYOF and VEGFR2 pathways might be effective against metastatic CCRCC to increase patient survival. [ABSTRACT FROM AUTHOR]

Introduction: Although the syndrome of inappropriate antidiuretic hormone has connection with various malignant tumors, there are few reports associated with advanced gastric cancer.Case Presentation: We describe the case of a 63-year-old Korean male with inappropriate antidiuretic hormone syndrome due to an ectopic antidiuretic hormone-producing advanced gastric adenocarcinoma manifested with overt serum hypo-osmolar hyponatremia and high urinary sodium concentrations. His adrenal, thyroidal, and renal functioning were normal, and the hyponatremia improved following removal of the tumor. The cancer cells were immunostained and found to be positive for the antidiuretic hormone. To our knowledge, this is the first report of an antidiuretic hormone-secreting advanced gastric adenocarcinoma associated with the syndrome of inappropriate antidiuretic hormone, showing cancer cells immunostained for the antidiuretic hormone.Conclusions: Although a strong relationship between gastric cancer and the syndrome of inappropriate antidiuretic hormone remains to be established, we suggest that gastric cancer could be included as a differential diagnosis of cancer that is associated with the syndrome of antidiuretic hormone. [ABSTRACT FROM AUTHOR]

Introduction: The development of various benign oral mucosal lesions associated with dental implants, such as pyogenic granuloma or peripheral giant cell granuloma, has been rarely reported. However, the occurrence of vascular diseases, such as hemangioma, related to dental implants has not been explored in the literature. In this study, we report a case of co-development of pyogenic granuloma and capillary hemangioma on the alveolar ridge associated with a dental implant in a patient undergoing antithrombotic therapy. To the best of our knowledge, this is first case of hemangioma formation associated with a dental implant.Case Presentation: A 68-year-old Korean man was referred for intermittent bleeding and a dome-shaped overgrowing mass on his upper alveolar ridge. He underwent dental implantation 5 years ago, and was started on warfarin for cerebral infarction a year ago. He had experienced gum bleeding and gingival mass formation 6 months after warfarinization; then, his implant fixture was removed. However, his gingival mass has been gradually increasing. The gingival mass was surgically excised, and revealed the coexistence of pyogenic granuloma and capillary hemangioma in histological analysis of the specimen. The lesion has showed no recurrence for more than a year.Conclusions: Regarding immunostaining features, the endothelial cell markers, CD34 and CD31, and the mesenchymal cell marker, vimentin, were strongly detected, but cell proliferation marker, Ki-67, was negatively expressed in the endothelial cells of the hemangioma portion. However, in the pyogenic granuloma portion, CD34 was almost negatively detected, whereas vimentin and Ki-67 were highly detected in the fibroblast-like tumor cells. According to these heterogeneous characteristics of the lesion, the patient was diagnosed with coexistence of pyogenic granuloma and capillary hemangioma associated with the dental implant on the attached gingiva. We recommend that patients with dental implants who have chronic peri-implantitis under antithrombotic therapy should be closely followed to ensure early detection of oral mucosal abnormalities. [ABSTRACT FROM AUTHOR]