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Background: Congenital dermoid sinus of the anterior chest region (CDACR) is a rare developmental anomaly. Therefore, the aim of our study was to draw attention to this underrecognized lesion. Methods: From 2011 to 2019, our study group included 11 patients who presented to our hospital with pits and masses of their anterior chest walls. All lesions were surgically excised with histologic confirmation of the diagnosis of CDACR. The medical records of these patients were reviewed for the following data: patient age, gender, clinical characteristics of the lesion and site of involvement, department first visited, diagnostic evaluation, management, postoperative complications, and histopathological findings. Results: There was a clear left‐sided predominance, with 10/11 cases occurring on the left and a female predominance of eight cases out of 11. Although the pits were present at birth, the mean age at presentation was 19.7 months. All patients showed clinical signs of infection at the time of presentation and were treated with antibiotics. Seven patients had a history of abscess formation treated with incision and drainage. Ultrasound was performed in eight patients. In all cases, the lesions, including pit and sinus, were completely excised. Conclusions: Congenital dermoid sinus of the anterior chest region is likely underrecognized. We encountered a high frequency of complications such as infections or abscesses prior to surgical excision. Complete excision of CDACR is not technically difficult. Therefore, surgical removal should be considered, even for asymptomatic lesions, to avoid future complications and for cosmesis. [ABSTRACT FROM AUTHOR]

Plexiform fibromyxoma is a very rare and recently described benign mesenchymal tumor that occurs specifically in the stomach. It is characterized by a multinodular plexiform involvement of gastric wall of bland spindle cells in myxoid and/or fibromyxoid stroma. Here we present the cytological features of gastric plexiform fibromyxoma and discuss the differential diagnoses of this tumor. [ABSTRACT FROM AUTHOR]

Bovine mastitis caused by Prototheca has been reported globally, and its incidence is increasing in dairy herds. The present study aimed to investigate the occurrence of Prototheca and persistence of Prototheca zopfii strains in Korean dairy herds. A total of 187 (7.5%) P. zopfii strains were isolated from 2,508 quarter milk samples collected from 50 dairy farms throughout Korea from 2015 to 2017. Prototheca zopfii was isolated from one farm among the 50 farms over the 3-yr period. The P. zopfii isolates belonged to genotype 2. Overall, Prototheca-positive quarter milk samples showed high somatic cell counts with an average value of log 6.48 ± 6.54 cells/mL. Prototheca zopfii was found to be persistent in an infected farm over a 2-yr period. To the best of our knowledge, this is the first report on the presence and persistence of protothecal mastitis caused by P. zopfii genotype 2 in a Korean dairy herd. This disease leads to a significant increase in somatic cell counts in milk, which persists for more than 1 yr in the affected cow udder. These results suggest that P. zopfii could pose a serious risk to dairy herds. Thus, strict surveillance for protothecal mastitis is urgently needed and sanitary conditions regarding the environment and milk collection are essential because of the lack of effective treatment options. [ABSTRACT FROM AUTHOR]

Background: Oxidative stress induces various intracellular damage, which might be correlated with tumorigenesis. Accumulated oxidative stresses might inactivate protein tyrosine phosphatase (PTP) by oxidizing it, and inducing the phosphorylation of H2AX (γH2AX) in response to DNA damage.Methods: We evaluated the clinical significance of the expression of oxidized-PTP and γH2AX in 169 gastric carcinomas.Results: Immunohistochemical expression of nuclear oxidized-PTP, cytoplasmic oxidized-PTP, and γH2AX expression were significantly associated with each other, and their expressions predicted shorter survival of gastric carcinoma patients. In multivariate analysis, nuclear oxidized-PTP (overall survival; p <  0.001, relapse-free survival; P <  0.001) was an independent indicator of poor prognosis of gastric carcinoma patients. In addition, co-expression patterns of nuclear oxidized-PTP and γH2AX were independent indicators of poor prognosis of gastric carcinoma patients (overall survival; P <  0.001, relapse-free survival; P <  0.001).Conclusions: This study suggests that oxidative stress-mediated oxidation of PTP might be involved in the progression of gastric carcinomas. In addition, this study suggests that individual and co-expression pattern of nuclear oxidized-PTP and γH2AX might be used as a prognostic marker of gastric carcinomas. [ABSTRACT FROM AUTHOR]

Abstract: Spontaneous regression of hepatocellular carcinoma (HCC) is extremely rare. Among the numerous proposed mechanisms of spontaneous regression for HCC, immunological factors, which have yet to be fully understood, may have the most important roles in this rare phenomenon. A regressing HCC with lymphoid stroma is reported. A hepatic mass was detected in a 57-year-old man by abdominal computed tomography during a follow-up health check. The resected tumor was 2.7×2.4cm2 in size, and was composed of two distinct nodules with a complete rim of fibrous tissue separating the tumor from the adjacent liver parenchyma. Microscopically, one nodule was replaced by a remarkable infiltration of inflammatory cells with insignificant amounts of vital tumor cells. The other nodule demonstrated a small portion of well- to moderately-differentiated hepatocellular carcinoma cells forming 2–3 thick trabeculae with massive inflammatory infiltrates. Infiltrating inflammatory cells were composed of T cells (CD4+>CD8+), macrophages, B cells, and other cells in order of prevalence. Epstein-Barr virus was not detected. After 60 months of follow-up, the patient is in good health without evidence of tumor recurrence. [Copyright &y& Elsevier]

Abstract: We introduce a new architecture of information granulation-based and genetically optimized Hybrid Self-Organizing Fuzzy Polynomial Neural Networks (HSOFPNN). Such networks are based on genetically optimized multi-layer perceptrons. We develop their comprehensive design methodology involving mechanisms of genetic optimization and information granulation. The architecture of the resulting HSOFPNN combines fuzzy polynomial neurons (FPNs) that are located at the first layer of the network with polynomial neurons (PNs) forming the remaining layers of the network. The augmented version of the HSOFPNN, “IG_gHSOFPNN”, for brief, embraces the concept of information granulation and subsequently exhibits higher level of flexibility and leads to simpler architectures and rapid convergence speed to optimal structure in comparison with the HSOFPNNs and SOFPNNs. The GA-based design procedure being applied at each layer of HSOFPNN leads to the selection of preferred nodes of the network (FPNs or PNs) whose local characteristics (such as the number of input variables, the order of the polynomial, a collection of the specific subset of input variables, the number of membership functions for each input variable, and the type of membership function) can be easily adjusted. In the sequel, two general optimization mechanisms are explored. The structural optimization is realized via GAs whereas the ensuing detailed parametric optimization is afterwards carried out in the setting of a standard least square method-based learning. The obtained results demonstrate a superiority of the proposed networks over the existing fuzzy and neural models. [Copyright &y& Elsevier]

Adenomyoma of the small intestine is a rare tumor-like lesion composed of exocrine-type ducts and hypertrophic smooth muscle. We describe two cases of adenomyoma of the small intestine. One was an ileal adenomyoma that presented with intussusception occurring in a 7-month-old boy. The other was a jejunal adenomyoma found incidentally in a 63-year-old man with colon cancer. Histologically, the lesions composed of benign ducts and bundles of smooth muscle. The second case was detected on contrast-enhanced computed tomography scan as a small enhancing polypoid mass. We review the previous literature of adenomyoma of the small intestine. [ABSTRACT FROM AUTHOR]

We identified 199 Staphylococcus aureus isolates from quarter milk samples of 1,289 dairy cattle between 2014 and 2018. About 66% of the isolates were resistant to at least 1 antimicrobial agent; the highest rate of resistance was to penicillin, followed by resistance to ampicillin, erythromycin, and sulfadimethoxine. We obtained 30 methicillin-resistant S. aureus (MRSA) strains from 6 farms in 3 provinces. The MRSA strains exhibited a significantly higher resistance rate to most of the tested antimicrobials than the oxacillin-susceptible strains. The MRSA strains represented 5 genotypes: ST72-t324- SCCmec IV (n = 14), ST30 - t1752- SCCmec IV (n = 8), ST188-t189- SCCmec NT (n = 6), ST188-t2284- SCCmec NT (n = 1), and NT - NT- SCCmec IV (n = 1). One of the ST188 MRSA strains represented a novel staphylococcal protein A (spa) type (t2284). In addition, 7 of the 8 ST30 MRSA strains were Panton-Valentine leukocidin (PVL)–positive and carried various staphylococcal enterotoxin encoding genes. This is the first report of PVL-positive ST30 MRSA - t1752- SCCmec IV from bovine mastitis in Korea. All of ST72-t324- SCCmec IV MRSA strains carried staphylococcal enterotoxin and leukotoxin encoding genes. They were also sensitive to most of the tested non-β-lactam antimicrobials. In contrast, ST188-t189 MRSA strains were resistant to multiple antimicrobials and predominantly carried the leukotoxin encoding gene. Taken together, these findings may indicate that dairy cows could be a major source for spreading MRSA strains, and contaminated milk could be a vehicle for transmission. Suitable hygienic measures should be established in dairy farms and processing plants to limit the likelihood of introducing MRSA into the food chain. [ABSTRACT FROM AUTHOR]

Background: FAM83H has been implicated in cancer progression, and PD1 is an important target for anti-cancer immune checkpoint therapy. Recent studies suggest an association between FAM83H expression and immune infiltration. However, studies on the roles of FAM83H and its relationship with PD1 in breast carcinomas have been limited. Methods: Immunohistochemical expression of FAM83H and PD1 and their prognostic significance were evaluated in 198 breast carcinomas. Results: The expression of FAM83H in cancer cells was significantly associated with the presence of PD1-positive lymphoid cells within breast carcinoma tissue. Individual and co-expression patterns of nuclear FAM83H and PD1 were significantly associated with shorter survival of breast carcinomas in univariate analysis. In multivariate analysis, the expression of nuclear FAM83H (overall survival, p < 0.001; relapse-free survival, p = 0.003), PD1 (overall survival, p < 0.001; relapse-free survival, p = 0.003), and co-expression patterns of nuclear FAM83H and PD1 (overall survival, p < 0.001; relapse-free survival, p < 0.001) were the independent indicators of overall survival and relapse-free survival of breast carcinoma patients. Conclusions: This study suggests a close association between FAM83H expression and the infiltration of PD1-positive lymphoid cells in breast carcinomas and their expression as the prognostic indicators for breast carcinoma patients, and further studies are needed to clarify this relationship. [ABSTRACT FROM AUTHOR]

Liver injury can be acute or chronic, resulting from a variety of factors, including viral hepatitis, drug overdose, idiosyncratic drug reaction, or toxins, while the progression of pathogenesis in the liver rises due to the involvement of numerous cytokines and growth factor mediators. Thus, the identification of more effective biomarker-based active phytochemicals isolated from medicinal plants is a promising strategy to protect against CCl4-induced liver injury. Vitis vinifera L. (VE) and Centella asiatica (CE) are well-known medicinal plants that possess anti-inflammatory and antioxidant properties. However, synergism between the two has not previously been studied. Here, we investigated the synergistic effects of a V. vinifera L. (VE) leaf, C. asiatica (CE) extract combination (VCEC) against CCl4-induced liver injury. Acute liver injury was induced by a single intraperitoneal administration of CCl4 (1 mL/kg). VCEC was administered orally for three consecutive days at various concentrations (100 and 200 mg/kg) prior to CCl4 injection. The extent of liver injury and the protective effects of VCEC were evaluated by biochemical analysis and histopathological studies. Oxidative stress was evaluated by measuring malondialdehyde (MDA) and glutathione (GSH) levels and Western blotting. VCEC treatment significantly reduced serum transaminase levels (AST and ALT), tumor necrosis factor-α (TNF-α), and reactive oxygen species (ROS). CCl4- induced apoptosis was inhibited by VCEC treatment by reducing cleaved caspase-3 and Bcl2-associated X protein (Bax). VCEC-treated mice significantly restored cytochrome P450 2E1, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) expression in CCl4-treated mice. In addition, VCEC downregulated overexpression of proinflammatory cytokines and hepatic nuclear factor kappa B (NF-κB) and inhibited CCl4-mediated apoptosis. Collectively, VCEC exhibited synergistic protective effects against liver injury through its antioxidant, anti-inflammatory, and antiapoptotic ability against oxidative stress, inflammation, and apoptosis. Therefore, VCEC appears promising as a potential therapeutic agent for CCl4-induced acute liver injury in mice. [ABSTRACT FROM AUTHOR]

Protein disulfide isomerase (PDI) is one of the most abundant proteins in the endoplasmic reticulum (ER) and is known as a primary ER resident target of cigarette smoke-induced oxidation. PDI dysfunction triggers unfolded protein response and ER stress. Endoplasmic reticulum oxidoreductin 1-α (ERO1A) is a major regulator of PDI, and recent evidence implicates PDI and ERO1A as tumor prognostic factors. However, the associated role of PDI and ERO1A and their prognostic impact in non-small cell lung cancers (NSCLCs) remains unknown. The present study investigated the expression of PDI and ERO1A using immunohistochemistry and examined its association with smoking status and their prognostic impact in 198 NSCLCs. PDI and ERO1A expression were observed in 71.2 and 69.2% of NSCLCs, respectively, and their expressions were significantly associated with each other (P<0.001). Individual PDI (P=0.001) and ERO1A (P=0.005) expression were significantly associated with shorter overall survival (OS) in univariate analysis. PDI expression was significantly associated with never smoking (P=0.003). PDI expression (P<0.001) and the co-expression of PDI and ERO1A (P<0.001) were independent poor prognostic factors for OS in patients with NSCLC in multivariate analysis. Individual expression and co-expression of PDI and ERO1A may be used as novel prognostic indicators of NSCLC outcome. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses the case study of a 67-year-old man with ileocecal lymphoma, who was diagnosed with incidental esophageal xanthoma.

Background: PAK4 and PHF8 are involved in cancer progression and are under evaluation as targets for cancer therapy. However, despite extensive studies in human cancers, there are limited reports on the roles of PAK4 and PHF8 in gallbladder cancers. Methods: Immunohistochemical expression of PAK4 and PHF8 and their prognostic significance were evaluated in 148 human gallbladder carcinomas. Results: PAK4 expression was significantly associated with PHF8 expression in gallbladder carcinomas. Positive expression of nuclear PAK4, cytoplasmic PAK4, nuclear PHF8, and cytoplasmic PHF8 were significantly associated with shorter overall survival and relapse-free survival in univariate analysis. Multivariate analysis showed that nuclear PAK4 expression and nuclear PHF8 expression were independent predictors of overall survival and relapse-free survival in gallbladder carcinomas. Furthermore, coexpression of nuclear PAK4 and nuclear PHF8 predicted shorter overall survival (p < 0.001) and relapse-free survival (p < 0.001) of gallbladder carcinoma in multivariate analysis. Conclusions: This study suggests that the individual and coexpression patterns of PAK4 and PHF8 as the prognostic indicators for gallbladder carcinoma patients. [ABSTRACT FROM AUTHOR]

Hepatic fibrosis is a form of irregular wound-healing response with acute and chronic injury triggered by the deposition of excessive extracellular matrix. Epithelial–mesenchymal transition (EMT) is a dynamic process that plays a crucial role in the fibrogenic response and pathogenesis of liver fibrosis. In the present study, we postulated a protective role of 3,3′-diindolylmethane (DIM) against TGF-β1 mediated epithelial–mesenchymal transition (EMT) in vitro and carbon tetrachloride (CCl4)-induced liver fibrosis in mice. TGF-β1-induced AML-12 hepatocyte injury was evaluated by monitoring cell morphology, measuring reactive oxygen species (ROS) and mitochondrial membrane potential, and quantifying apoptosis, inflammatory, and EMT-related proteins. Furthermore, CCl4-induced liver fibrosis in mice was evaluated by performing liver function tests, including serum ALT and AST, total bilirubin, and albumin to assess liver injury and by performing H&E and Sirius red staining to determine the degree of liver fibrosis. Immunoblotting was performed to determine the expression levels of inflammation, apoptosis, and Nrf2/HO-1 signaling-related proteins. DIM treatment significantly restored TGF-β1-induced morphological changes, inhibited the expression of mesenchymal markers by activating E-cadherin, decreased mitochondrial membrane potential, reduced ROS intensity, and upregulated levels of Nrf2-responsive antioxidant genes. In the mouse model of CCl4-induced liver fibrosis, DIM remarkably attenuated liver injury and liver fibrosis, as reflected by the reduced ALT and AST parameters with increased serum Alb activity and fewer lesions in H&E staining. It also mitigated the fibrosis area in Sirius red and Masson staining. Taken together, our results suggest a possible molecular mechanism of DIM by suppressing TGF-β1-induced EMT in mouse hepatocytes and CCl4-induced liver fibrosis in mice. [ABSTRACT FROM AUTHOR]

In human colorectal cancer (CRC), TP53 is one of the most important driver genes. Immunohistochemistry (IHC) has been used most often to assess the variational status of TP53. Recently, next-generation sequencing (NGS) of the TP53 gene has increased. However, to our knowledge, a comparison between TP53 status evaluated by IHC and NGS has not been studied. Therefore, the primary aim of this study was to compare the clinical effect of TP53 status evaluated by IHC and NGS in patients with CRC. The secondary aim was to investigate the correlation between expression of p53 by IHC and variational status of TP53 by NGS. We performed immunohistochemical staining of p53 and sequencing of TP53 by NGS in 204 human samples of CRC. We then analyzed the correlation between variational status of TP53 and p53 expression, along with their prognostic impact in CRC patients. There was significant correlation between p53 expression and TP53 variation, TP53 variation and higher N stage, and positive p53 expression and higher N stage. Positive IHC expression of p53 was significantly associated with overall survival (OS) of CRC patients by univariate analysis and was revealed as an independent prognostic factor by multivariate analysis. Additionally, the nonsense/frameshift p53 expression pattern showed a significantly better prognosis than the wild type and missense p53 expression patterns. However, the variational status of TP53 was not significant in OS of CRC patients. These results suggest that IHC expression of p53 protein correlates with variation status of TP53 and expression of p53 protein rather than variation status of TP53 has more significant impact on the OS of CRC patients. [ABSTRACT FROM AUTHOR]

Abstract: Cortactin is an F-actin binding protein involved in cell migration and tumor metastasis. Recent reports suggest that silent mating-type information regulation 2 homologue 1 (sirtuin1; SIRT1) enhances the function of cortactin and promotes cell migration. We investigated SIRT1 and cortactin expression in 144 invasive non-small cell lung cancers (NSCLC) and 19 adenocarcinomas in situ (AIS) by immunohistochemistry and evaluated their clinicopathological significance in NSCLC. Positive SIRT1 and cortactin expression was observed in 67% (96 of 144) and 58% (84 of 144) of patients with invasive NSCLC, respectively. SIRT1 and cortactin expression was significantly associated with unfavorable clinicopathological factors, including high pathological T stage, lymph node metastasis, and advanced tumor invasion (AIS vs. invasive adenocarcinoma). Cortactin was significantly associated with high pathological T stage and lymph node metastasis in SIRT1-positive tumors. Cytoplasmic SIRT1 was significantly associated with high pathological T stage and large tumor size compared to that of nuclear SIRT1. Large tumor size, high pathological T stage, lymph node metastasis, and cytoplasmic SIRT1 expression were significantly associated with shorter overall survival in a univariate analysis. Our findings suggest that SIRT1 and cortactin may play a role in the progression of NSCLC and may cooperate during tumor progression in NSCLC. [Copyright &y& Elsevier]

Abstract: We introduce a new architecture of hybrid fuzzy polynomial neural networks (HFPNN) that is based on a genetically optimized multi-layer perceptron and develop their comprehensive design methodology involving mechanisms of genetic optimization. The construction of HFPNN exploits fundamental technologies of computational intelligence (CI), namely fuzzy sets, neural networks, and genetic algorithms (GAs). The architecture of the resulting genetically optimized HFPNN (namely gHFPNN) results from a synergistic usage of the hybrid system generated by combining fuzzy polynomial neurons (FPNs)-based fuzzy neural networks (FNN) with polynomial neurons (PNs)-based polynomial neural networks (PNN). The design of the conventional HFPNN exploits the extended group method of data handling (GMDH) with some essential parameters of the network being provided by the designer and kept fixed throughout the overall development process. This restriction may hamper a possibility of producing an optimal architecture of the model. The augmented gHFPNN results in a structurally optimized structure and comes with a higher level of flexibility in comparison to the one we encounter in the conventional HFPNN. The GA-based design procedure being applied at each layer of HFPNN leads to the selection of preferred nodes (FPNs or PNs) available within the HFPNN. In the sequel, two general optimization mechanisms are explored. First, the structural optimization is realized via GAs whereas the ensuing detailed parametric optimization is carried out in the setting of a standard least square method-based learning. The performance of the gHFPNN is quantified through experimentation where we exploit data coming from processes of pH neutralization and NOx emission. These datasets have already been used quite intensively in fuzzy and neurofuzzy modeling. The obtained results demonstrate superiority of the proposed networks over the existing fuzzy and neural models. [Copyright &y& Elsevier]

In this paper, we introduce a category of Multi-Fuzzy-Neural Networks (Multi-FNNs) models, analyze the underlying architectures and propose a comprehensive identification framework. The proposed Multi-FNNs are based on a concept of fuzzy rule-based FNNs that use H ard C-M eans (HCM) clustering and evolutionary fuzzy granulation and exploit linear inference being treated as a generic inference mechanism of approximate reasoning. By this nature, this FNN model is geared toward capturing relationships between information granules–fuzzy sets. The form of the information granules themselves (in particular their distribution and a type of membership functions) becomes an important design feature of the FNN model that contributes to its structural and parametric optimization. The genetically guided global optimization is then augmented by more refined gradient-based learning mechanisms such as a standard back-propagation. The HCM algorithm, whose role is to carry out preprocessing of the experimental data, is utilized to determine the structure of Multi-FNNs. The detailed parameters of the Multi-FNN (such as apexes of membership functions, learning rates, and momentum coefficients) are adjusted using genetic algorithms. The proposed aggregate performance index helps achieve a sound balance between approximation and generalization (predictive) abilities of the model. To evaluate an effectiveness of the introduced model, several numeric data sets are experimented with. Those include a time-series data of gas furnace, NOx emission process of gas turbine power plant and some synthetic data. [Copyright &y& Elsevier]

In this paper, we introduce a general category of multi-fuzzy-neural networks (FNNs), analyze their underlying architecture and propose a comprehensive identification framework. The proposed multi-FNNs dwells on a concept of linear fuzzy inference-based FNNs. The design of the model uses a standard HCM (Hard C-Means) clustering algorithm and carries out an evolutionary fuzzy granulation of experimental data. The performance of the model is quantified through a series of experimental studies involving synthetic and real-world data. [Copyright &y& Elsevier]

This paper introduces an identification method for nonlinear models in the form of Fuzzy-Neural Networks (FNN). In this model, we use two forms of the fuzzy inference methods—a simplified and linear fuzzy inference, and exploit a standard Error Back Propagation learning algorithm. The FNN modeling and identification environment realizes parameter identification through a synergistic usage of clustering techniques, genetic optimization and a complex search method. We use a Hard C-Means (HCM) clustering algorithm to determine initial apexes of the membership functions of the information granules used in this fuzzy model. The parameters such as apexes of membership functions, learning rates, and momentum coefficients are then adjusted using hybrid algorithm. The proposed hybrid identification algorithm is carried out by combining both genetic optimization (genetic algorithm, GA) and the improved complex method. An aggregate objective function (performance index) with a weighting factor is introduced to achieve a sound balance between approximation and generalization of the model. According to the selection and adjustment of the weighting factor of this objective function, we reveal how to design a model with sound approximation and generalization abilities. The proposed model is experimented with using several time series data (gas furnace, sewage treatment process and NOx emission process data of gas turbine power plant). [Copyright &y& Elsevier]

This paper proposes an identification method for nonlinear models realized in the form of implicit rule-based fuzzy-neural networks (FNN). The design of the model dwells on the technologies of computational intelligence (CI), namely fuzzy sets, neural networks, and genetic algorithm. The FNN modeling and identification environment realizes parameter estimation through a synergistic usage of clustering techniques, genetic optimization and a complex search method. An HCM (Hard C-Means) clustering algorithm helps determine an initial location (parameters) of the membership functions of the information granules to be used in this fuzzy model. The parameters such as apexes of membership functions, learning rates, and momentum coefficients are then adjusted using the optimization algorithm of a GA hybrid scheme. The proposed GA hybrid scheme combines GA with the improved complex method to guarantee both global optimization and local convergence. An aggregate objective function (performance index) is used in the model design in order to achieve a sound balance between its approximation and generalization abilities. The proposed type of the model is experimented with several time series data (gas furnace, sewage treatment process, and NOx emission process data of gas turbine power plant). [Copyright &y& Elsevier]

Background: IL4Rα and IL13Rα1 are constituents of the type II IL4 receptor. Recently, IL4Rα and IL13Rα1 were reported to have roles in cancer progression and suggested as potential prognostic markers. However, studies on IL4Rα and IL13Rα1 in soft-tissue sarcomas have been limited. Methods: This study investigated the immunohistochemical expression of IL4Rα and IL13Rα1 in 89 soft-tissue sarcomas of the extremities, superficial trunk, and retroperitoneum. Immunohistochemical staining for IL4Rα and IL13Rα1 were scored according to a combination of staining intensity and staining area in tissue microarray samples. Positivity for the immunohistochemical expression of IL4Rα and IL13Rα1 were determined using receiver operating curve analysis. Statistical analysis was performed using regression analysis and a chi-square test. Results: In human soft-tissue sarcomas, immunohistochemical expression of IL4Rα was significantly associated with IL13Rα1 expression. Nuclear and cytoplasmic expression of IL4Rα and IL13Rα1 were significantly associated with shorter survival of soft-tissue sarcoma patients in univariate analysis. Multivariate analysis indicated that nuclear expression of IL4Rα and IL13Rα1 were independent indicators of shorter overall survival (IL4Rα; p = 0.002, IL13Rα1; p = 0.016) and relapse-free survival (IL4Rα; p = 0.022, IL13Rα1; p < 0.001) of soft-tissue sarcoma patients. Moreover, the co-expression pattern of nuclear IL4Rα and IL13Rα1 was an independent indicator of shorter survival of soft-tissue sarcoma patients (overall survival; overall p < 0.001, relapse-free survival; overall p < 0.001). Conclusions: This study suggests IL4Rα and IL13Rα1 are associated with the progression of soft-tissue sarcoma, and the expression of IL4Rα and IL13Rα1 might be novel prognostic indicators of soft-tissue sarcoma patients. [ABSTRACT FROM AUTHOR]

Background: Recently, FAM83H was reported to have roles in cancer progression in conjunction with oncogenic molecules such as MYC and b-catenin. Moreover, the data from the public database indicates a molecular relationship between FAM83H and zinc finger proteins, especially between FAM83H and ZNF16. However, studies on FAM83H and ZNF16 in gallbladder cancer have been limited. Methods: This study investigated the expression of FAM83H and ZNF16 in 105 gallbladder carcinomas. Results: In human gallbladder carcinomas, immunohistochemical expression of FAM83H was significantly associated with ZNF16 expression. In univariate analysis, nuclear and cytoplasmic expression of FAM83H or ZNF16 were significantly associated with shorter survival of gallbladder carcinoma patients. Multivariate analysis revealed the nuclear expression of FAM83H as an independent indicator of poor prognosis of overall survival (p = 0.005) and relapse-free survival (p = 0.005) of gallbladder carcinoma patients. Moreover, co-expression patterns of nuclear FAM83H and ZNF16 were also independent indicators of shorter survival of gallbladder carcinoma patients (overall survival; p < 0.001, relapse-free survival; p < 0.001). Conclusions: This study suggests FAM83H and ZNF16 are associated with the progression of gallbladder carcinoma, and the expressions of FAM83H and ZNF16 might be novel prognostic indicators of gallbladder carcinoma patients. [ABSTRACT FROM AUTHOR]

Introduction The purpose of the study was to examine potential of 131 I-labeled chitosan hydrogels (Chi) for treatment of liver cancer. Methods Orthotopic hepatoma was induced by McA-RH7777-fLuc cells (1 × 10 7 ) that were injected into the left hepatic lobe of rats. Ten days later, tumor-bearing rats evidenced by bioluminescence received 125 I-labeled Chi with left hepatic artery access. Pharmacokinetics and excretion (n = 8) and biodistribution (n = 6/time point) were studied after injection. To examine therapeutic potential, animals (n = 8/group) were also treated with Chi labeled with or without 131 I. Changes in tumor volume by magnetic resonance (MR) imaging were studied. Results The rate of tumor induction assessed by bioluminescence imaging was 72% (68/95). Gamma counter and scintigraphy imaging analyses showed accumulation of 125 I-labeled Chi dominantly in the liver. A small fraction of 125 I-labeled Chi was detected in the stomach (2.02 ± 3.07%ID) and muscle (1.37 ± 1.48%ID) at 2 d post-treatment. Blood sample analysis showed the maximum blood concentration of 0.09 ± 0.03%ID/mL, which peaked at 0.60 ± 0.45 d. Over a 4-week period, 31.22 ± 8.16%ID were excreted in the urine and 3.5 ± 1.3% in the feces. Treatment of Chi (median, 876 mm 3 ; IQR, 496 mm 3 –1413 mm 3 ) markedly reduced the extent of tumor growth, compared to controls (median, 12,085 mm 3 ; IQR, 7786 mm 3 –25,832 mm 3 ; P < 0.05 vs control). 131 I Chi (median, 80 mm 3 ; IQR, 35 mm 3 –172 mm 3 ; P < 0.05 vs control) induced a greater tumor-suppressing effect, compared to Chi alone. Conclusions In this study, we have characterized a new radioembolization device, 131 I Chi, in vivo and provided evidence for its therapeutic potential. Advances in knowledge Transarterial embolization is a conceivable treatment option for patients with inoperable liver cancer to mitigate the disease progression. Recently, we have developed chitosan-based hydrogel microparticles. In the present study, the hydrogel microparticles were radiolabeled with 131 I for treatment of liver cancer. Our results demonstrated that a hepatic arterial injection of 125 I-labeled Chi resulted in substantial liver accumulation, which was accompanied by virtually no extrahepatic deposition. The results of the present study also showed that administration of 131 I Chi markedly suppressed tumor growth, compared to controls and to animals receiving unlabeled Chi. 131 I-labeled chitosan hydrogel microparticles represent a new therapeutic approach for treatment of liver cancer. [ABSTRACT FROM AUTHOR]

DNA damage response (DDR) molecules are protective against genotoxic stresses. DDR molecules are also involved in the survival of cancer cells in patients undergoing anti-cancer therapies. Therefore, DDR molecules are potential markers of cancer progression in addition to being potential therapeutic targets. In this study, we evaluated the immunohistochemical expression of PARP1, γH2AX, BRCA1, and BRCA2 and their prognostic significance in 112 cases of soft tissue sarcoma (STS). The expression of PARP1, γH2AX, BRCA1, and BRCA2 were significantly associated with each other and were associated with higher tumor stage and presence of distant metastasis. The expression of PARP1, γH2AX, and BRCA2 were significantly associated with shorter disease-specific survival (DSS) and event-free survival (EFS) by univariate analysis. BRCA1 expression was associated with shorter DSS. Multivariate analysis revealed the expression of PARP1 and γH2AX to be independent indicators of poor prognosis of DSS and EFS. BRCA2 expression was an independent indicator of poor prognosis of DSS. In addition, the combined expressional patterns of PARP1, γH2AX, BRCA1, and BRCA2 (CSddrm) were independent prognostic predictors of DSS (P < 0.001) and EFS (P = 0.016). The ten-year DSS rate of the CSddrm-low, CSddrm-intermediate, and CSddrm-high subgroups were 81%, 26%, and 0%, respectively. In conclusion, this study demonstrates that the individual and combined expression patterns of the DDR molecules PARP1, γH2AX, BRCA1, and BRCA2 could be predictive of the prognosis of STS patients and suggests that controlling the activity of these DDR molecules could be employed in new therapeutic stratagems for the treatment of STS. [ABSTRACT FROM AUTHOR]

Objective: To differentiate smoking-related interstitial fibrosis (SRIF) from usual interstitial pneumonia (UIP) with emphysema on CT in combined pulmonary fibrosis and emphysema (CPFE) patients. Materials and Methods: This study was approved by the institutional review board and informed consent was waived. We included 65 patients who underwent lung biopsy under the suspicion of UIP pattern on HRCT, and after radiologic-pathologic correlation, they were divided into three groups: UIP without emphysema (n = 30), UIP with emphysema (n = 26), and SRIF (n = 9). The quantitative extent of emphysema in the entire lung was visually assessed and fibrotic patterns were qualitatively analyzed based on six characteristics (asymmetry, juxta-subpleural sparing, emphysema beside the honeycombing area, absence of ground grass attenuation/reticulation in honeycombing area, inhomogeneous honeycombing, and absence of honeycombing in the upper lobes). Kaplan-Meier analysis was used for survival analysis, and logistic regression with a receiver operating characteristic curve was used to predict the possibility of SRIF. Results: In qualitative analysis of fibrotic patterns, SRIF tended to exhibit more than three of six fibrotic features, whereas UIP with emphysema demonstrated about two of these characteristics (p = 0.035). In addition, SRIF had a higher extent of emphysema than UIP with emphysema when they have same amount of fibrosis (p = 0.014). In patients with SRIF, 5-year survival rate was 85.7%, while it was 40.7% in UIP with emphysema patients (p = 0.035). Conclusion: Fibrotic CT patterns and survival rate differed between SRIF and UIP with emphysema among CPFE patients, which explains the variable prognosis of CPFE. [ABSTRACT FROM AUTHOR]

Background: Gallbladder cancer is commonly associated with inflammation, which indicates that inflammation-related cytokines and cytokine receptors are related to the progression of gallbladder cancers. Interleukin 4 (IL4) is a well-known cytokine that promotes the differentiation of naive helper T cells (Th0) to T helper type 2 cells (Th2). IL13 is a cytokine that is secreted by Th2 cells. IL4 and IL13 are closely related in immune responses. However, the role of IL4Rα and IL13Rα1 signaling pathway has not been fully understood in the development of gallbladder cancer. Methods: In human gallbladder carcinomas, the expression of IL4Rα and IL13Rα1 were evaluated with immunohistochemical staining in tissue microarray tissue sections. After knockdown of IL4Rα or IL13Rα1, cell assays to measure the proliferation and apoptosis and Western blotting analysis were conducted in SNU308 human gallbladder cancer cells. Since Janus kinases2 (JAK2) was considered as one of the down-stream kinases under IL4Rα and IL13Rα1 complex, the same kinds of experiments were performed in SNU308 cells treated with AZD1480, Janus-associated kinases2 (JAK2) inhibitor, to demonstrate the cytotoxic effect of AZD1480 in SNU308 cells. Results: Immunohistochemical expression of IL4Rα was significantly associated with the expression of IL13Rα1 in human carcinoma tissue. In univariate analysis, nuclear expression of IL4Rα, cytoplasmic expression of IL4Rα, nuclear expression of IL13Rα1, and cytoplasmic expression of IL13Rα1 were significantly associated with shorter overall survival and shorter relapse-free survival. Multivariate analysis revealed nuclear expression of IL4Rα as an independent poor prognostic indicator of overall survival and relapse-free survival. Then, we found that knockdown of IL4Rα or IL13Rα1 decreased viability and induced apoptosis in SNU308 cells via activation of FOXO3 and similarly, AZD1480 decreased viability and induced apoptosis in SNU308 cells with dose dependent manner. Conclusions: Taken together, our results suggest that IL4Rα and IL13Rα1 might be involved in the development of human gallbladder cancer cells and IL4Rα and IL13Rα1 complex/JAK2 signaling pathway could be efficient therapeutic targets for gallbladder cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Nerve growth factor (NGF) is a neurotrophin and has been suggested to induce heme oxygenase-1 (HO1) expression. Although the role of HO1 in tumorigenesis remains controversial, recent evidence suggests NGF and HO1 as tumor-progressing factors. However, the correlative role of NGF and HO1 and their prognostic impact in breast carcinoma is unknown.Methods: We investigated the expression and prognostic significance of the expression of NGF and HO1 in 145 cases of breast carcinoma.Results: Immunohistochemical expression of NGF and HO1 was observed in 31% and 49% of breast carcinoma, respectively. The expression of NGF and HO1 significantly associated with each other, and both have a significant association with histologic grade, HER2 expression, and latent distant metastasis. The expression of NGF and HO1 predicted shorter overall survival of breast carcinoma by univariate and multivariate analysis. NGF expression was an independent prognostic indicator for relapse-free survival by multivariate analysis. The combined expression pattern of NGF and HO1 was also an independent prognostic indicator of overall survival and relapse-free survival. The patients with tumors expressing NGF had the shortest survival and the patients with tumor, which did not express NGF or HO1 showed the longest survival time.Conclusions: This study has demonstrated that individual expression of NGF or HO1, and the combined NGF/HO1 expression pattern could be prognostic indicators for breast carcinoma patients. [ABSTRACT FROM AUTHOR]

Recently, the roles of SIRT1 and deleted in breast cancer 1 (DBC1) in human cancer have been extensively studied and it has been demonstrated that they are involved in many human carcinomas. However, their clinical significance for soft-tissue sarcomas has not been examined. In this study, we evaluated the expression and prognostic significance of the expression of SIRT1, DBC1, P53, β-catenin, cyclin D1, and KI67 in 104 cases of soft-tissue sarcomas. RESULTS: Immunohistochemical expression of SIRT1, DBC1, P53, β-catenin, and cyclin D1 were seen in 71%, 74%, 53%, 48%, and 73% of sarcomas, respectively. The expression of SIRT1, DBC1, P53, β-catenin, and cyclin D1 were significantly correlated with advanced clinicopathological parameters such as higher clinical stage, higher histological grade, increased mitotic counts, and distant metastasis. The expression of SIRT1, DBC1, P53, β-catenin, cyclin D1, and KI67 were significantly correlated with each other and positive expression of all of these predicted shorter overall survival and event-free survival by univariate analysis. Multivariate analysis revealed the expression of SIRT1 as an independent prognostic indicator for overall survival and event-free survival of sarcoma patients. In conclusion, this study demonstrates that SIRT1- and DBC1-related pathways may be involved in the progression of soft-tissue sarcomas and can be used as clinically significant prognostic indicators for sarcoma patients. Moreover, the SIRT1- and DBC1-related pathways could be new therapeutic targets for the treatment of sarcomas. [ABSTRACT FROM AUTHOR]

Highlights: [•] The effect of glutamine administration on GVHD was evaluated in a mouse model. [•] Glutamine therapy improved the microscopic findings of GVHD of target organs. [•] Glutamine therapy improved the survival of GVHD mice. [•] Glutamine therapy decreased the serum levels of TNF-α in GVHD mice. [•] Glutamine therapy increased the fractions of blood CD4+/CD25+ cells in GVHD mice. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Autologous adipose-derived stromal cells (ASCs) are an obvious source of osteogenic cells and can be easily isolated from adipose tissue. We evaluated the potential of ASCs seeded onto a scaffold to heal tibial defects. Methods: Autologous ASCs were obtained from adipose tissue by collagenase digestion. The cells were seeded in three-dimensional poly(lactic)-glycolic acid (PLGA) scaffolds and cultured in osteogenic medium for four weeks. Evidence of osteogenesis was assessed by von Kossa staining in three-dimensional cultures following osteogenic induction. The critical size tibial defects (10mm) were created using a rat model. Defects were either left empty (sham group), treated with a PLGA scaffold alone (PLGA group), or a PLGA/ASC composite (PLGA/ASC group). Using radiologic and histologic analyses, we assessed total bone volume and vascular density. Total RNA was prepared from regenerated bone and analyzed for osteogenic marker gene expression. Results: In three-dimensional cultures, the PLGA/ASC composite showed multiple calcified extracellular matrix nodules on von Kossa staining after four weeks of differentiation. Near complete healing was observed between the PLGA/ASC engrafted tibial defects on plain radiographs and micro-CT findings. Total bone volume and mechanical strength were significantly higher in the PLGA/ASC group compared to the sham and PLGA groups. Histologic analysis revealed increased new bone formation along capillaries in the PLGA/ASC group. Real-time RT-PCR analysis revealed a significant increase in the expression of osteogenic genes in the PLGA/ASC group. Conclusions: The results showed that the repair of tibial defects was accelerated by implantation of autologous ASCs seeded onto a PLGA scaffold. Therefore, PLGA/ASC is a promising new cell-based therapy for healing critical size tibial defects. [Copyright &y& Elsevier]

Abstract: Introduction: Allografting has become widely available for the elimination of morbidity due to autogenous bone grafting procedures for spinal fusion. Enhancement of stable bone formation could facilitate this procedure. COMP-Ang1 is a recombinant chimeric protein of angiopoietin-1 that induces angiogenesis and vascular enlargement. We investigated the osteogenic potential of COMP-Ang1 for spinal fusion with allograft based on the enhancement of angiogenesis. Methods: Sixty Sprague–Dawley rats underwent bilateral posterior and posterolateral arthrodesis with allograft at L3–4 and L4–5. The animals were divided into three groups (n=20 each): 1) no treatment (sham group); 2) the bovine serum albumin-impregnated collagen sponge group (BSA group); 3) the COMP-Ang1-impregnated collagen sponge group (COMP-Ang1 group). Animals were sacrificed at six weeks for evaluation of spinal fusion using manual palpation, radiographs, and biomechanical and histomorphometric assessments. Total RNA was prepared from the fusion site and analyzed for osteogenic marker protein expression using RT-PCR analysis. Results: The fusion rates determined by manual palpation were 38.9% in the sham group, 42.1% in the BSA group, and 89.5% in the COMP-Ang1 group. Optical density of fusion masses in the COMP-Ang1 group was significantly higher than those in the sham and BSA groups (p<0.001). Total bone volume was significantly higher in the COMP-Ang1 group than in the sham and BSA groups (p<0.001). The mechanical strength was significantly greater in the COMP-Ang1 group than in the sham and BSA groups (p<0.01). Histologically, the fusion site of the COMP-Ang1 group showed a larger number of reactive bones compared with those in the BSA and sham groups. Immunostaining of endothelial cells for factor VIII revealed that COMP-Ang1 group showed higher levels of vascularity in the fusion site. Runt-related transcription factor 2 and its target genes were significantly up-regulated in the COMP-Ang1 group. Conclusions: COMP-Ang1 induced radiologically and histologically demonstrable active osteogenesis by promoting angiogenesis in spinal fusions. It was concluded that COMP-Ang1 enhances spinal fusion and hence the strength of the fusion. [Copyright &y& Elsevier]

Abstract: Large cell neuroendocrine carcinomas (LCNECs) of the stomach are rare and represent only a small percentage of all gastric endocrine tumors. Here we report a case of a rare combination of gastric LCNEC concurrent with gastric adenocarcinoma. A 50-year-old man presented with heartburn sensation for 2 weeks. An endoscopic evaluation revealed a relatively well-demarcated ulcerative elevated lesion at the lower body of the stomach. Grossly, the gastric mass was a 5×4.5cm-sized ulcerative fungating lesion. Microscopically, two separated lesions were recognized. The main lesion showed neuroendocrine morphology, such as nests and trabeculae. Most of the tumor cells had large, vesicular nuclei with prominent eosinophilic nucleoli, variable amounts of eosinophilic cytoplasm, and immunoreactivity for synaptophysin and chromogranin A. The other lesion was a well-differentiated adenocarcinoma of early gastric cancer type IIa located adjacent mucosa of the main lesion. We diagnosed this lesion as gastric LCNEC concurrent with focal adenocarcinoma, collision type. [Copyright &y& Elsevier]

Abstract: Introduction: During distraction osteogenesis, new and highly vascularized bone is formed, with angiogenesis preceding osteogenesis. We investigated the possibility that COMP–Ang1, an angiogenic factor, may facilitate bone formation. Methods: Rats were divided into three groups. Control rats underwent tibial distraction without treatment. In the two remaining groups, BSA (100μg) or COMP–Ang1 (100μg) were injected transcutaneously into the center of the distraction zone. Using radiographic and histologic analyses, we assessed total bone volume, vascular density, and bone mineral density. Total RNA was prepared from regenerated bone and analyzed for osteogenic marker protein expression using real-time RT–PCR analysis. Results: Bone formation in the distraction gap progressed more quickly in the COMP–Ang1-treated group than in the BSA-treated group. Histological findings and immunostaining of endothelial cells for factor VIII revealed that Comp–Ang1 group animals exhibited higher levels of vascularity. NanoCT and dual-energy X-ray absorptiometry analyses revealed increased new bone formation along capillaries in the COMP–Ang1 group compared with the BSA group. Runt-related transcription factor 2 and its target genes, including bone sialoprotein, type 1 collagen, osteopontin, and osterix, were significantly upregulated in the COMP–Ang1 group. Conclusions: Our results are consistent with previous descriptions of the positive relationship between angiogenesis and osteogenesis. In addition, our results suggest the potential use of COMP–Ang1 as a therapeutic agent for treatment of distracted limbs by enhancing angiogenesis. [Copyright &y& Elsevier]

Quorum sensing of Acinetobacter nosocomialis for cell-to-cell communication produces N-3-hydroxy dodecanoyl-DL-homoserine lactone (OH-dDHL) by an AnoR/I two-component system. However, OH-dDHL-driven apoptotic mechanisms in hosts have not been clearly defined. Here, we investigated the induction of apoptosis signaling pathways in bone marrow-derived macrophages treated with synthetic OH-dDHL. Moreover, the quorum-sensing system for virulence regulation was evaluated in vivo using wild-type and anoI-deletion mutant strains. OH-dDHL decreased the viability of macrophage and epithelial cells in dose- and time-dependent manners. OH-dDHL induced Ca2+ efflux and caspase-12 activation by ER stress transmembrane protein (IRE1 and ATF6a p50) aggregation and induced mitochondrial dysfunction through reactive oxygen species (ROS) production, which caused cytochrome c to leak. Pretreatment with a pan-caspase inhibitor reduced caspase-3, -8, and -9, which were activated by OH-dDHL. Pro-inflammatory cytokine and paraoxonase-2 (PON2) gene expression were increased by OH-dDHL. We showed that the anoI-deletion mutant strains have less intracellular invasion compared to the wild-type strain, and their virulence, such as colonization and dissemination, was decreased in vivo. Consequently, these findings revealed that OH-dDHL, as a virulence factor, contributes to bacterial infection and survival as well as the modification of host responses in the early stages of infection. [ABSTRACT FROM AUTHOR]

CK2α/CSNK2A1 is involved in cancer progression by phosphorylating various signaling molecules. Considering the role of CSNK2A1 in cancer progression and the phosphorylation of SIRT6 and the role of SIRT6 in chemoresistance through the DNA damage repair pathway, CSNK2A1 and SIRT6 might be involved in resistance to conventional anti-cancer therapies. We evaluated the expression of CSNK2A1 and phosphorylated SIRT6 in the 37 osteosarcoma patients and investigated the effects of CSNK2A1 and the phosphorylation of SIRT6 on Ser338 on resistance to the anti-cancer effects of doxorubicin. Higher expression of CSNK2A1 and phosphorylated SIRT6 was associated with shorter survival in osteosarcoma patients. U2OS and KHOS/NP osteosarcoma cells with induced overexpression of CSNK2A1 were resistant to the cytotoxic effects of doxorubicin, and the knock-down of CSNK2A1 potentiated the cytotoxic effects of doxorubicin. CSNK2A1 overexpression-mediated resistance to doxorubicin was associated with SIRT6 phosphorylation and the induction of the DNA damage repair pathway molecules. CSNK2A1- and SIRT6-mediated resistance to doxorubicin in vivo was attenuated via mutation of SIRT6 at the Ser338 phosphorylation site. Emodin, a CSNK2A1 inhibitor, potentiated the cytotoxic effects of doxorubicin in osteosarcoma cells. This study suggests that blocking the CSNK2A1-SIRT6-DNA damage repair pathway might be a new therapeutic stratagem for osteosarcomas. [ABSTRACT FROM AUTHOR]

Previously, we reported a close relationship between type II IL4Rα and IL13Rα1 complex and poor outcomes in renal cell carcinoma (RCC). In this study, we investigated the clinicopathologically significant oncogenic role of IL13Rα2, a kind of the independent receptor for IL13, in 229 RCC patients. The high expression of IL13Rα2 was closely related to relapse-free survival in specific cancers in univariate and multivariate analysis. Then, the oncogenic role of IL13Rα2 was evaluated by performing in vitro assays for cell proliferation, cell cycle arrest, and apoptosis in A498, ACHN, Caki1, and Caki2, four kinds of RCC cells after transfection of siRNA against IL13Rα2. Cell proliferation was suppressed, and apoptosis was induced in A498, ACHN, Caki1, and Caki2 cells by knockdown of IL13Rα2. Interestingly, the knockdown of IL13Rα2 decreased the phosphorylation of JAK2 and increased the expression of FOXO3. Furthermore, the knockdown of IL13Rα2 reduced the protein interaction among IL13Rα2, phosphorylated JAK2, and FOXO3. Since phosphorylation of JAK2 was regulated by IL13Rα2, we tried to screen a novel JAK2 inhibitor from the FDA-approved drug library and selected telmisartan, a clinically used medicine against hypertension, as one of the strongest candidates. Telmisartan treatment decreased the cell proliferation rate and increased apoptosis in A498, ACHN, Caki1, and Caki2 cells. Mechanistically, telmisartan treatment decreased the phosphorylation of JAK2 and increased the expression of FOXO3. Taken together, these results suggest that IL13Rα2 regulates the progression of RCC via the JAK2/FOXO3-signaling path pathway, which might be targeted as the novel therapeutic option for RCC patients. [ABSTRACT FROM AUTHOR]

SCRIB is a polarity protein important in maintaining cell junctions. However, recent reports have raised the possibility that SCRIB might have a role in human cancers. Thus, this study evaluated the roles of SCRIB in ovarian cancers. In 102 human ovarian carcinomas, nuclear expression of SCRIB predicted shorter survival of ovarian carcinoma patients, especially in the patients who received post-operative chemotherapy. In SKOV3 and SNU119 ovarian cancer cells, overexpression of SCRIB stimulated the proliferation and invasion of cells. Knockout of SCRIB inhibited in vivo tumor growth of SKOV3 cells and overexpression of SCRIB promoted tumor growth. Overexpression of SCRIB stimulated epithelial-to-mesenchymal transition by increasing the expression of N-cadherin, snail, TGF-β1, and smad2/3, and decreasing the expression of E-cadherin; the converse was observed with inhibition of SCRIB. In conclusion, this study presents the nuclear expression of SCRIB as a prognostic marker of ovarian carcinomas and suggests that SCRIB is involved in the progression of ovarian carcinomas by stimulating proliferation and epithelial-to-mesenchymal transition-related invasiveness. [ABSTRACT FROM AUTHOR]

Background: SIRT6 has diverse roles in cells, and the role of SIRT6 in tumorigenesis is controversial. Considering the role of SIRT6 as an inducer of DNA damage repair, it might be involved in resistance to anti-cancer therapy. Methods: We evaluated the prognostic significance of SIRT6 in 37 osteosarcomas and investigated the therapeutic efficacy of SIRT6 on the anticancer effects of doxorubicin, olaparib, and ATM inhibitor. Results: Immunohistochemical expression of SIRT6 was significantly associated with shorter overall survival and relapse-free survival of osteosarcoma patients, especially in patients who received adjuvant chemotherapy. In U2OS and KHOS/NP osteosarcoma cells, knock-down of SIRT6 significantly potentiated apoptotic effects of doxorubicin and SIRT6 overexpression induced resistance to doxorubicin. Moreover, SIRT6 induced the DNA damage repair pathway and SIRT6-mediated resistance to doxorubicin was attenuated by blocking the DNA damage repair pathway with olaparib and ATM inhibitor. Conclusions: This study suggests that suppression of SIRT6 in combination with doxorubicin might be an effective modality in the treatment of osteosarcoma patients, especially for osteosarcomas with shorter survival with high expression of SIRT6. [ABSTRACT FROM AUTHOR]

Background: Although the adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs) on the upper gastrointestinal tract have been well characterized, those specific to the lower gastrointestinal tract are less clear, as only a limited number of articles and case reports exist in the literature. Case presentation: We describe a case of a 69-year-old woman who presented to the emergency department due to sudden onset abdominal distension and pain. Notably, she reported using intramuscular diclofenac sodium twice daily for 14 days after knee joint replacement surgery. The patient denied any other coexisting diseases. As a subsequent X-ray and computed tomography (CT) scan showed free air in the abdomen, an exploratory laparotomy was performed, revealing four free perforations in the terminal ileum. Findings on microscopic analysis were non-specific. Conclusion: We report a unique case of multiple ileal perforations due to regular diclofenac sodium injections and contend that ileal perforation can be considered as a source for pneumoperitoneum with concomitant peritonitis in patients with a history of NSAID use if other possibilities are excluded. [ABSTRACT FROM AUTHOR]

Background: FAM83H was initially identified as a protein essential for dental enamel formation. Recent reports have shown that FAM83H is also involved in the progression of human cancers in conjunction with tumor-associated molecules, such as MYC and β-catenin. However, the role of FAM83H in sarcoma has not yet been investigated. Methods: The expression and roles of FAM83H and β-catenin were evaluated in human osteosarcomas from 34 patients and osteosarcoma cells. Results: The expression of nuclear FAM83H, cytoplasmic FAM83H, and β-catenin were significantly associated with each other and significantly associated with shorter survival of osteosarcoma patients by univariate analysis. In multivariate analysis, cytoplasmic expression of FAM83H was an independent indicator of shorter survival of osteosarcoma patients (overall survival; P < 0.001, relapse-free survival; P < 0.001). In U2OS, MG63, and KHOS/NP osteosarcoma cells, the knock-down of FAM83H decreased proliferation and invasion activity and overexpression of FAM83H increased proliferation and invasion activity. In KHOS/NP cells, knock-down of FAM83H significantly inhibited, and overexpression of FAM83H significantly increased in vivo growth of cells. In addition, the knock-down of FAM83H decreased protein expression of β-catenin, active β-catenin, cyclin D1, vimentin, and snail. Overexpression of FAM83H increased protein expression of β-catenin, active β-catenin, cyclin D1, vimentin, and snail. However, the expression of β-catenin mRNA was not significantly altered with knock-down or overexpression of FAM83H. In addition, FAM83H and β-catenin shown to directly interact via immunoprecipitation and nuclear and cytoplasmic localization of β-catenin was decreased with knock-down of FAM83H. Moreover, the ubiquitination and proteasomal degradation of β-catenin was increased with knock-down of FAM83H. Conclusions: This study suggests that FAM83H is involved in the progression of osteosarcomas via a mechanism involving the stabilization of β-catenin and the promotion of proliferation and invasiveness of osteosarcomas. [ABSTRACT FROM AUTHOR]

Background: PARP1 facilitates the recovery of DNA-damaged cells by recruiting DNA damage response molecules such as γH2AX and BRCA1/2, and plays a role in resistance to antitumor therapies. Therefore, PARP inhibition being evaluated as an anti-cancer therapy. However, there are limited studies regrading PARP inhibition in osteosarcoma. Methods: We evaluated the expression of DNA damage response molecules in 35 human osteosarcomas and investigated the effects of co-treatment of the PARP inhibitor, olaparib, and doxorubicin in osteosarcoma cells. Results: The expression patterns of PARP1, γH2AX, BRCA1, and BRCA2 were significantly associated with shorter survival of osteosarcoma patients. In osteosarcoma cells, knock-down of PARP1 and treatment of olaparib significantly inhibited proliferation of cells and induced apoptosis. Moreover, the anti-tumor effect was more significant with co-treatment of olaparib and doxorubicin in vitro and in vivo. Conclusions: This study suggests that combined use of a PARP inhibitor with doxorubicin, a DNA damaging agent, might be effective in the treatment of osteosarcoma patients, especially in the poor-prognostic subgroups of osteosarcoma expressing PARP1, γH2AX, or BRCA1/2. [ABSTRACT FROM AUTHOR]

Deleted in breast cancer 1 (DBC1/CCAR2) is a protein of interest because of its diverse roles in tumorigenesis and its possible role as an androgen receptor (AR) co-activator. However, there are limited studies on the role of DBC1 in osteosarcoma. Therefore, we investigated the role of DBC1 and AR and their relationship in osteosarcoma. Immunohistochemical expression of DBC1 and AR was significantly associated with higher clinical stage and higher histologic grade, and predicted shorter survival. Especially, DBC1 expression was an independent prognostic indicator of overall survival (p = 0.005) and relapse-free survival (p = 0.004) by multivariate analysis. In osteosarcoma cell lines, U2OS and SaOS2, the knock down of DBC1 and AR with siRNA significantly reduced cellular proliferation and inhibited proliferation-related signaling. In addition, the knock down of DBC1 and AR decreased the invasion activity and inhibited invasion-related signaling of osteosarcoma cells. Interestingly, DBC1 affects the stabilization of AR protein via a mechanism involving the ubiquitination of AR. Proteosome-mediated degradation and poly-ubiquitination of AR were increased with the knock-down of DBC1. In conclusion, this study has shown that DBC1 is involved in the stabilization of AR protein and DBC1-AR pathways might be involved in the progression of osteosarcoma. [ABSTRACT FROM AUTHOR]

Recently, the possibility of PD1 pathway-targeted therapy has been extensively studied in various human malignant tumors. However, no previous study has investigated their potential application for soft-tissue sarcomas (STS). In this study, we evaluated the clinical impact of intra-tumoral infiltration of PD1-positive lymphocytes and PD-L1 expression in tumor cells in 105 cases of STS. Intra-tumoral infiltration of PD1-positive lymphocytes and PD-L1 expression were seen in 65% and 58% of STS, respectively. Both PD1-positivity and PD-L1 expression were significantly associated with advanced clinicopathological parameters such as higher clinical stage, presence of distant metastasis, higher histological grade, poor differentiation of tumor, and tumor necrosis. Moreover, both PD1-positivity and PD-L1 positivity were independent prognostic indicators of overall survival (OS) and event-free survival (EFS) of STS by multivariate analysis. In addition, the combined pattern of PD1- and PD-L1-positivity was also an independent prognostic indicator for OS and EFS by multivariate analysis. The patents with a PD1+/PD-L1+ pattern had the shortest survival time. In conclusion, this study is the first to demonstrate that the infiltration of PD1 positive lymphocytes and PD-L1 expression in STS cells could be used as novel prognostic indicators for STS. Moreover, the evaluation of PD1- and PD-L1-positivity in STS is also available as possible criteria for selection of patients suitable for PD1-based immunotherapy. [ABSTRACT FROM AUTHOR]

STUDY DESIGN: In vitro and in vivo study. OBJECTIVE: To evaluate the role of recombinant human bone morphogenetic protein-2 (rhBMP2) on breast cancer cell (MDA-MB-231 cells) growth. SUMMARY OF BACKGROUND DATA: Bone morphogenetic proteins (BMPs) are expressed in a variety of human carcinoma cell lines and are known to promote tumor invasion and metastasis. However, their roles in tumor progression have not been fully clarified. In addition, there is no in vivo study regarding the inhibitory effect of BMP2 on breast cancer cell proliferation. METHOD: Cell proliferation was determined by BrdU incorporation assay and flow cytometry. BMP2 signal transduction pathways were estimated on Western blot. Fifteen animals were divided into 2 groups; 1 (control = 5) was breast cancer cells alone, while the other (experiment = 5) was rhBMP2 + breast cancer cells. Cancer cells were injected into 2 sites (subcutaneous and femur) of nude mice with or without BMP2. Tumor size was determined by direct measurements for subcutaneous tumor formation and by femur radiographs. Histological and immunohistochemical analyses were performed. RESULTS: RhBMP2 inhibited the proliferation of MDA-MB-231 cells in vitro. Inhibition was associated with changes in both the Smad and Wnt signaling pathways and was ultimately mediated through effects on various cell cycle proteins. Furthermore, rhBMP2 inhibited the growth of MDA-MB-231 cells injected both subcutaneously and intrafemorally. CONCLUSION: In this model using human breast adenocarcinoma cell line, rhBMP2 has no stimulatory effect of tumor growth. Therefore, we can provide the basic science data to support the utilization in the management of patients with spine tumor in the future. [ABSTRACT FROM AUTHOR]