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Sarcoidosis is a systemic granulomatous disease. In pulmonary sarcoidosis, granulomatous vascular involvement is a common feature that occurs in all types of vessels, including large elastic arteries to venules, but sarcoidosis complicated with pulmonary infarction has not been reported. We report a case of a 60 years old female, who was operated on a clinical diagnosis of lung cancer, and histological examination revealed a pulmonary infarction and sarcoidosis. In the pulmonary elastic arteries, granulomas infiltrated the adventitia and media, and caused elastic fiber collapse and destruction. Arterial occlusion by granulomas was observed in the edge of the infarcted area. It was considered that the arterial sarcoidosis granuloma involvement was the cause of pulmonary infarction. Sarcoidosis is a significant risk factor for cardiovascular events. However, pulmonary infarction is an extremely rare complication of sarcoidosis. Our case suggests that sarcoidosis may cause vascular events in the lungs.

BACKGROUND Carcinoma of the ampulla of Vater is an uncommon ampullo-pancreatobiliary neoplasm, and the most common histological type is adenocarcinoma with a tubular growth pattern. Invasive micropapillary carcinoma (IMPC) is an aggressive variant of adenocarcinoma in several organs that is associated with lymph node metastasis and poor prognosis. IMPC was first described as a histological subtype of breast cancer; however, IMPC of the ampulla of Vater is extremely rare, with only three articles reported in the English literature. CASE SUMMARY We have reported a case of IMPC of the ampulla of Vater in an 80-year-old man. Microscopically, the surface area of the carcinoma was composed of tubulopapillary structures mimicking intra-ampullary papillary-tubular neoplasm, and the deep invasive front area exhibited a pattern of IMPC. The carcinoma showed lymphatic invasion and extensive lymph node metastasis. The immunohistochemical study revealed mixed intestinal and gastric/pan-creatobiliary phenotypes. CONCLUSION This rare subtype tumor in the ampulla of Vater showed a histologically mixed phenotype and exhibited aggressive behavior.

BACKGROUND Cancer genome profiling of cytology specimens using next-generation sequencing (NGS) requires adequate and good-quality DNA. Genomic examination of cytology samples was conventionally performed on cell block (CB) or smear specimens than on residual liquid-based cytology (LBC) specimens, which are high-quality DNA sources even after long-term storage. METHODS We estimated tumor fractions of 37 residual LBC specimens, including 30 fine needle aspiration (FNA) samples from the thyroid (12 papillary thyroid carcinomas and two malignant lymphomas), lymph node (13 metastatic carcinomas and one malignant lymphoma), and breast cancer (one phyllodes tumor and one invasive ductal carcinoma), two pancreatic carcinoma samples, and five liquid (ascites, pleural effusion, and cerebrospinal fluid) samples. The DNA was extracted from all samples and subjected to NGS using a customized cancer gene panel comprising 28 cancer-related genes. RESULTS NGS analysis revealed somatic mutations corresponding to pathological diagnosis with adequate variant allele frequency (VAF) in 24 LBC specimens, which had significantly higher tumor fraction (72.5% ± 4.9%). Ten cases, including the five fluid samples, had very small tumor fractions (7.5% ± 2.3%) to obtain sufficient VAF. Other two samples had high tumor fractions but showed very low VAF, indicating the presence of fusion genes. The remaining one sample yielded no DNA recovery. CONCLUSION The residual LBC specimens collected by FNA from the thyroid gland and lymph node were verified to carry high tumor fraction and could serve as an alternate source for molecular testing to screen and diagnose cancers without the use of CB or smears.

Wnt signaling is relevant for a wide range of biological processes, including reproductive function. The function of Wnt10a in female fertility, however, remains obscure. In the present study, we explored the structure and function of the female reproductive organs in Wnt10a knockout (KO) mice. The expression of β-catenin signaling was significantly lower in the ovaries of the Wnt10a KO mice compared with wild-type (WT) mice. In addition, the estrous cycles were disrupted, ovarian follicles were diminished, and endometria were thinner, accompanied by lower serum estrogen levels, and higher testosterone and progesterone levels in Wnt10a KO mice. The expression of the ovarian cytochrome P450 family 19 subfamily A member 1 (Cyp19a1) was significantly lower in Wnt10a KO mice. We detected no significant changes in the levels of the gonadotropins between WT and KO mice. Together, our findings indicate that deficiency of Wnt10a causes female infertility through β-catenin and Cyp19a1signaling pathways in mice.

Verruciform xanthoma is a rare benign verrucopapillary lesion that develops in the oral mucosa and genital skin. Its development in the esophagus is extremely rare, with only 5 reported cases. We present 2 cases of verruciform xanthoma of the esophagus. Case 1 involved a 91-year-old woman, who had hypertension and chronic gastritis with Helicobacter pylori infection, with a 12-year history of a 10-mm white-yellow elevated lesion on the esophagus, 35 cm from the incisor teeth. Case 2 involved a 70-year-old man with fundic gland polyp, hyperlipidemia, and lung cancer, who had a 10-mm whitish granular/verrucoid lesion on the esophagus, 28 cm from the incisor teeth. Microscopically, these lesions show verrucous and papillomatous epithelial hyperplasia with neutrophilic intraepithelial exocytosis. The histological hallmark is the presence of numerous foamy histiocytes infiltrating the elongated squamous epithelial papillae. Although its etiology is unknown, irritation or trauma caused by radiotherapy has been suggested.

A 61-year-old man received an esophagogastroduodenoscopy for further investigation of mesenteric lymphadenopathy. Esophagogastroduodenoscopy revealed swollen gastric folds and cobble stone mucosa in the gastric body. Magnifying endoscopy with narrow-band imaging showed branched abnormal vessels and the absence or destruction of gastric pits. Endoscopic ultrasonography (EUS) depicted homogeneously hypoechoic thickening of the submucosal layer where the mucosal changes were observed. The patient was diagnosed with follicular lymphoma by biopsy of these lesions. We should recognize that these endoscopic features are consistent with follicular lymphoma involving the stomach and that concurrent EUS is useful for diagnosis and identification of adequate biopsy sites.

Background: We recently reported that WNT10A plays a pivotal role in wound healing by regulating collagen expression/synthesis, as the depletion of WNT10A dramatically delays skin ulcer formation. WNT signaling also has a close correlation with the cancer microenvironment and proliferation, since tumors are actually considered to be 'unhealing' or 'overhealing' wounds. To ascertain the in vivo regulatory functions of WNT10A in tumor growth, we examined the net effects of WNT10A depletion using Wnt10a-deficient mice (Wnt10a -/-). Methods and Results: We subjected C57BL/6J wild-type (WT) or Wnt10a -/- mice to murine melanoma B16-F10 cell transplantation. Wnt10a -/- mice showed a significantly smaller volume of transplanted melanoma as well as fewer microvessels and less collagen expression and more necrosis than WT mice. Conclusions: Taken together, our observations suggest that critical in vivo roles of Wnt10a-depleted anti-stromagenesis prevent tumor growth, in contrast with true wound healing/scarring.

Plexiform fibromyxoma (PFM) is a rare gastrointestinal tract tumor that develops in the stomach in most cases. Here, we report an extremely rare case of esophageal PFM. A female in her mid-30 s presented with difficulty in swallowing and breathing. Endoscopic examination revealed a submucosal tumor measuring approximately 45 × 50 mm in the upper thoracic esophagus. The biopsied specimen did not show definite histological evidence of gastrointestinal stromal tumors (GISTs). Since imatinib administration based on a clinical diagnosis of GIST did not show a therapeutic effect for tumor reduction, tumor resection was performed. The resected tumor exhibited proliferation of spindle tumor cells with abundant myxoid and vascular stroma separated by a muscular layer, indicating a plexiform arrangement. Immunohistochemical analysis demonstrated that the tumor cells diffusely expressed vimentin and alpha-smooth muscle actin, but not desmin, c-kit, DOG1, and CD34. MALAT1-GLI1 fusion was detected in formalin-fixed paraffin-embedded tissue using RT-PCR and Sanger sequencing. The results suggested that a fibromyxoid tumor can develop in the esophagus, showing an identical histology and MALAT1-GLI1 fusion to gastric PFM.

Ancillary immunohistochemical tools can facilitate an integrated diagnosis of endometrial pathology. According to The Cancer Genome Atlas classification, endometrial cancers are of four molecular subtypes: mismatch repair (MMR)-deficient (MMR-d), p53 mutation (p53mut), DNA polymerase epsilon (POLE) mutation (POLEmut), and no specific molecular profile (NSMP). As the specific histological and immunohistochemical features of POLEmut and NSMP subtypes are unknown, these cancers are categorized based on molecular analysis. In this study, we analyzed POLEmut-subtype endometrioid carcinoma (EC) using a custom-made cancer gene panel and the Catalog of Somatic Mutations in Cancer (COSMIC) database, extracted a characteristic genome profile, and identified an immunohistochemical marker that could be used as a diagnostic tool. The results indicated that the POLEmut-subtype EC exhibited nonsense mutations in the ataxia telangiectasia mutated (ATM) gene and a subsequent loss of ATM expression, which was monitored through immunohistochemical analysis. Moreover, analyses using the COSMIC database indicated that POLEmut-subtype EC cases often harbored similar ATM nonsense mutations. These results suggest that ATM expression is a potential immunohistochemical marker for the differential diagnosis of POLEmut- and NSMP-subtype EC. DATA AVAILABILITY: The data supporting the findings of this study are available upon request from the corresponding author. The data are not publicly available because of privacy or ethical restrictions.

Aim We have recently established a novel swine model for studies of atherosclerosis using MicrominipigsTM (µMPs) fed a high-fat/high-cholesterol diet (HcD). Using this swine model, we re-evaluated the effects of dietary cholic acid (CA) on serum lipid profile, atherosclerosis and hepatic injuries. Methods The µMPs were fed HcD supplemented with 0.7% CA (HcD＋CA) for eight weeks, and the effect of CA on serum lipoprotein levels, expression of oxidative stress markers, adiposity and lesion formation in the aorta, liver, and other organs was investigated. Results The HcD＋CA-fed group exhibited more visceral adiposity, progression of atherosclerosis and higher serum levels of oxidative stress markers than the HcD-fed group, even though they showed similar serum lipid levels. The liver demonstrated increased lipid accumulation, higher expression of oxidative stress markers, accelerated activation of foamy Kupffer cells and stellate cells, and increased hepatocyte apoptosis, indicating non-alcoholic fatty liver disease (NAFLD). Intriguingly, foamy macrophage mobilization was observed in various organs, including the reticuloendothelial system, pulmonary capillary vessels and skin very often in HcD＋CA-fed µMPs. Conclusion To our knowledge, this is the first large animal model, in which visceral obesity, NAFLD and atherosclerosis are concomitantly induced by dietary manipulation. These data suggest the detrimental effects of CA, potentially through local and systemic activation of oxidative stress-induced signaling to macrophage mobilization, on the acceleration of visceral adiposity, atherosclerosis and NAFLD.

Heterotopic gastric mucosa in the duodenal bulb is a rare congenital disorder with varied clinical presentations. The mechanism of formation of a duodenal ulcer is failure of balance of the attack factor and the defense factor, which is the same as the mechanism of formation of a gastric ulcer. However, the true etiology of the duodenal ulcer remains unknown. Gastric mucosa can secrete gastric juice which injures itself, but the duodenal mucosa does not contain cells secreting a digestive enzyme. We assume that duodenal ulcers are caused by the presence of heterotopic gastric mucosa that can secrete gastric acid. This study was designed to assess the prevalence and associations of heterotopic gastric mucosa in duodenal ulcers. The present study included 137 patients who underwent biopsy or resection of duodenal ulcer. We detected gastric foveolar metaplasia due to inflammation from a heterotopic gastric mucosa using immunohistochemical staining. Heterotopic gastric mucosa consists of foveolar epithelium (MUC5AC-positive) and fundic gland (H⁺K⁺ ATPase-positive parietal cells, pepsinogen I-positive chief cells and MUC6-positive mucous neck cells), whereas gastric metaplasia is composed of foveolar epithelium without fundic glands. These specimens were stained with toluidine blue for detection of Helicobacter pylori infection. Among the 137 patients with duodenal ulcer, 76 cases (55%) had heterotopic gastric mucosa in the obtained specimens, and Helicobacter pylori was found in 45 cases (59%,45/76) among those with heterotopic gastric mucosa. Our results suggest that heterotopic gastric mucosa was strongly associated with concurrent duodenal ulcer.

Lymphoepithelioma-like carcinoma (LELC) of the liver is extremely rare, and lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) is an uncommon variant form of HCC, exhibiting relatively good prognosis compared to conventional HCC. LELC is defined as a tumour composed of undifferentiated epithelial cells with densely infiltrating lymphoid stroma. LEL-HCC represents a unique immune response against tumour cells, which may contribute to the superior clinical outcomes. However, the exact aetiology remains unknown. We report a case of a 76-year-old man with a prior hepatitis B virus infection. A 20 mm tumour was detected in the liver. Microscopically, the tumour displayed characteristics of poorly differentiated HCC with a dense lymphocytic and plasma cell infiltration and was diagnosed as LEL-HCC. We describe a unique pathological finding with immunohistochemical data demonstrating T-cell dominant lymphocytic and polyclonal plasma cell infiltration, along with programmed death ligand 1 expression in the tumour cells and lymphocytes.

Wnt10a is a member of the WNT family. Although deficiency of this gene causes symptoms related to teeth, hair, nails, and skin, we recently demonstrated a new phenotype of Wnt10a knockout (KO) mice involving bone and fat. The in vivo effect of the Wnt10a gene on bone and fat is unclear, and the relationship between bone/fat and muscle in Wnt10a signaling is also interesting. We aimed to evaluate the tissue changes in Wnt10a KO mice compared to wild-type mice and show the findings as a starting point to unravel the underlying mechanisms of in vivo interactions involving Wnt10a in bone, fat and muscle. Trabecular bone loss in the lower limbs of Wnt10a mice and decreased bone mineralization were observed. The adipose tissue in bone marrow was also decreased, and adipocyte differentiation was reduced. The body fat mass in Wnt10a KO mice was decreased, and white adipocytes in subcutaneous fat were converted to beige adipocytes. The muscle weight of the lower limbs was not decreased despite trabecular bone loss, but Gdf8/myostatin expression was reduced in the subcutaneous fat and gastrocnemius muscles of Wnt10a KO mice. Thus, in vivo deletion of Wnt10a inhibited osteogenic activity, promoted beige adipogenesis of white adipocytes and maintained muscle mass. These results suggest that regulation of Gdf8 by Wnt10a may help maintain the muscle mass of Wnt10a KO mice. This study was the first to histologically evaluate the bone, fat and muscle phenotypes of Wnt10a KO mice. The results of this study, which were obtained by investigating the three tissues together, could influence the understanding of in vivo interactions involving the Wnt10a gene.

Fibromuscular dysplasia (FMD) is an idiopathic, segmental, nonatherosclerotic, non-inflammatory vascular disease, which is often complicated by the occurrence of dissection. Although it is known to occur in all arteries, aortic involvement is relatively rare. To date, 33 cases of aortic FMD have been reported in available English literature, among which only three cases have been complicated by the occurrence of dissection. We describe the case of a 40-year-old woman diagnosed with aortic FMD complicated by the occurrence of a type A aortic dissection. Non-invasive imaging revealed an ascending to descending thoracic aneurysm measuring 8 cm in diameter associated with dissection. Histopathologically, a segment of the wall of the aneurysm showed architectural disorganization of the aortic wall with loss of elastic fibers, collagen deposition, and irregular proliferation of smooth muscle cells in the intima and media-features suggesting FMD. No atheromatous plaque or medial cystic degeneration was observed in the aorta. Although aortic FMD is sometimes fatal, it is often very difficult to diagnose using imaging techniques. Therefore, performing a histopathological diagnosis is very important and should be emphasized.

// Taiji Hamada 1 , Masakazu Souda 1 , Takuya Yoshimura 2 , Shoko Sasaguri 1 , Kazuhito Hatanaka 1 , Takashi Tasaki 1 , Takako Yoshioka 1 , Yasuyo Ohi 3 , Sohsuke Yamada 4 , Masato Tsutsui 5 , Yoshihisa Umekita 6 and Akihide Tanimoto 1 1 Department of Molecular and Cellular Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. 2 Department of Oral and Maxillofacial Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. 3 Department of Pathology, Sagara Hospital, Social Medical Corporation Hakuaikai, Kagoshima, Japan. 4 Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. 5 Department of Pharmacology, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan. 6 Division of Organ Pathology, Faculty of Medicine, Tottori University, Yonago, Japan. Correspondence to: Akihide Tanimoto, e-mail: akit09@m3.kufm.kagoshima-u.ac.jp Key words: PCP4/PEP19, breast cancer, apoptosis, CaMKK, Akt Received: April 23, 2014 Accepted: June 23, 2014 Published: July 08, 2014 ABSTRACT The PCP4/PEP19 is a calmodulin-binding anti-apoptotic peptide in neural cells but its potential role in human cancer has largely been unknown. We investigated the expression of PCP4/PEP19 in human breast cancer cell lines MCF-7, SK-BR-3, and MDA-MB-231 cells, and found that estrogen receptor (ER)-positive MCF-7 and ER-negative SK-BR-3 cells expressed PCP4/PEP19. In the MCF-7 cells, cell proliferation was estrogen-dependent, and PCP4/PEP19 expression was induced by estrogen. In both cell lines, PCP4/PEP19 knockdown induced apoptosis and slightly decreased Akt phosphorylation. Knockdown of calcium/calmodulin-dependent protein kinase kinase 1 (CaMKK1), resulting in decreased phospho-Akt Thr308 , enhanced apoptosis in SK-BR-3 but not in MCF-7 cells. CaMKK2 knockdown moderately decreased phospho-Akt Thr308 and increased apoptosis in MCF-7 cells but not in SK-BR-3 cells. These data indicated that PCP4/PEP19 regulates apoptosis but exact mechanism is still unknown. PCP4/PEP19 can therefore potentially serve as independent oncotarget for therapy of PCP4/PEP19-positive breast cancers irrespective of ER expression.

Pseudo-Meigs' syndrome accompanied by massive ascites in uterine leiomyoma is rare. We encountered a rare case of a 37-year-old, nulliparous woman with a lower abdominal tumor and severe abdominal distention due to massive ascites. Serum cancer antigen 125 and vascular endothelial growth factor levels were elevated to 1007.9 U/mL and 103 pg/mL, respectively. She was tentatively diagnosed with ovarian cancer. Emergency concentrated ascites re-infusion therapy was performed to improve dyspnea, abdominal pain, and her preoperative respiratory condition. Concentrated ascites re-infusion therapy eliminated dyspnea and abdominal discomfort without decreasing serum albumin levels. The patient underwent laparotomy, which revealed a fist-sized pedunculated uterine leiomyoma arising from the right uterine fundus. Myomectomy was performed. Pseudo-Meigs' syndrome mimics advanced ovarian cancer due to massive ascites and markedly elevated serum cancer antigen 125 and vascular endothelial growth factor levels. Concentrated ascites re-infusion therapy was effective in improving the subjective symptoms of pseudo-Meigs' syndrome and the patient's preoperative condition.

Aims: Consumption of a high-fructose diet (HFrD) can induce the development of a metabolic syndrome, manifesting as nonalcoholic steatohepatitis (NASH) and/or type 2 diabetes mellitus (T2DM), via a process in which oxidative stress plays a critical role. Peroxiredoxin 4 (PRDX4) is a unique and only known secretory member of the PRDX antioxidant family. However, its putative roles in the development of NASH and/or T2DM have not been investigated. Results: To elucidate the functions of PRDX4 in a metabolic syndrome, we established a nongenetic mouse model of T2DM by feeding mice a HFrD after injecting a relatively low dose of streptozotocin. Compared with wild-type (WT), human PRDX4 transgenic (Tg) mice exhibited significant improvements in insulin resistance, characterized by a lower glucose and insulin concentration and faster responses in glucose tolerance tests. The liver of Tg also showed less severe vesicular steatosis, inflammation, and fibrosis, along with lower lipid concentrations, lower levels of oxidative stress markers, more decreased expression of hepatic aminotransferase, and more reduced stellate cell activation than those in the WT liver, reminiscent of human early NASH. Hepatocyte apoptosis was also significantly repressed in Tg mice. By contrast, serum adiponectin levels and hepatic adiponectin receptor expression were significantly lower in WT mice, consistent with greater insulin resistance in the peripheral liver tissue compared with Tg mice. Innovation and Conclusion: Our data for the first time show that PRDX4 may protect against NASH, T2DM, and the metabolic syndrome by ameliorating oxidative stress-induced injury. Antioxid. Redox Signal. 19, 1983–1998.

Background: The polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts) family of enzymes regulates the initial steps of mucin-type O-glycosylation. N-acetylgalactosaminyltransferases might show novel patterns of GalNAc-T glycosylation on tumour-derived proteins, which could influence cancer biology, but its mechanisms are unclear. We investigated the association of GalNAc-T3 and -T6 expressions with clinicopathological features and prognoses of patients with renal cell carcinomas (RCCs). Methods: Expressions of GalNAc-T3/6 and cell-adhesion molecules were analysed immunohistochemically in 254 paraffin-embedded tumour samples of patients with RCC. Results: Of 138 GalNAc-T3+ cases, 46 revealed significant co-expression with GalNAc-T6. N-acetylgalactosaminyltransferases-3+ expression showed a close relationship to poor clinical performance and large tumour size, or pathologically high Fuhrman's grading, and presence of vascular invasion and necrosis. The GalNAc-T3-positivity potentially suppressed adhesive effects with a significantly low β-catenin expression. Univariate and multivariate analyses showed the GalNAc-T3+ group, but not the GalNAc-T6+ group, to have significantly worse survival rates. Conclusion: N-acetylgalactosaminyltransferases-3 expression independently predicts high-grade tumour and poor prognosis in patients with RCC, and may offer a therapeutic target against RCC.

Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays a crucial role in stress-induced apoptosis. Recently, we have reported that suppressed macrophage apoptosis in ASK1 and apolipoprotein E double-knockout mice accelerates atheromatous plaques in the hyperlipidemia-induced atherosclerotic model. However, the pathogenic role of smooth muscle cell (SMC) apoptosis in atherosclerosis still remains unclear. We investigated neointimal remodeling in ligated carotid arteries of ASK1-deficient mice (ASK1(-/-)) for 3 weeks. ASK1(-/-) mice had significantly more suppressed intimal formation, inversely manifesting as potential anti-atherogenic aspects of ASK1 deficiency, characterized by fewer SMCs and less collagen synthesis; and fewer apoptotic SMCs, infiltrating T lymphocytes, and microvessels, associated with decreased apoptosis of luminal endothelial cells, compared with those of wild-type mice. Injured arteries of ASK1(-/-) mice also showed significantly down-regulated expression of pro-apoptotic markers, adhesion molecules, and pro-inflammatory signaling factors. Moreover, tumor necrosis factor-α-induced apoptosis was markedly suppressed in cultured aortic SMCs from ASK1(-/-) mice. These findings suggest that ASK1 accelerates mechanical injury-induced vascular remodeling with activated SMC migration via increased neovascularization and/or enhanced SMC and endothelial cell apoptosis. ASK1 expression, especially in the SMCs, might be crucial, and reciprocally responsible for various pro-atherogenic functions, and SMC apoptosis seems to be detrimental in this model.

Pancreatic cancer is still a disease of high mortality despite availability of diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic neoplasms. MUC1 and MUC4 are high molecular weight transmembrane mucins. These are overexpressed in many carcinomas, and high expression of these molecules is a risk factor associated with poor prognosis. We evaluated the methylation status of MUC1 and MUC4 promoter regions in pancreatic tissue samples from 169 patients with various pancreatic lesions by the methylation specific electrophoresis (MSE) method. These results were compared with expression of MUC1 and MUC4, several DNA methylation/demethylation factors (e.g. ten-eleven translocation or TET, and activation-induced cytidine deaminase or AID) and CAIX (carbonic anhydrase IX, as a hypoxia biomarker). These results were also analyzed with clinicopathological features including time of overall survival of PDAC patients. We show that the DNA methylation status of the promoters of MUC1 and MUC4 in pancreatic tissue correlates with the expression of MUC1 and MUC4 mRNA. In addition, the expression of several DNA methylation/demethylation factors show a significant correlation with MUC1 and MUC4 methylation status. Furthermore, CAIX expression significantly correlates with the expression of MUC1 and MUC4. Interestingly, our results indicate that low methylation of MUC1 and/or MUC4 promoters correlates with decreased overall survival. This is the first report to show a relationship between MUC1 and/or MUC4 methylation status and prognosis. Analysis of epigenetic changes in mucin genes may be of diagnostic utility and one of the prognostic predictors for patients with PDAC.

Aim: A growing body of evidence has shown that increased formation of oxidized molecules and reactive oxygen species within the vasculature (i.e., the extracellular space) plays a crucial role in the initiation and progression of atherosclerosis and in the formation of unstable plaques. Peroxiredoxin 4 (PRDX4) is the only known secretory member of the antioxidant PRDX family. However, the relationship between PRDX4 and susceptibility to atherosclerosis has remained unclear. Results: To define the role of PRDX4 in hyperlipidemia-induced atherosclerosis, we generated hPRDX4 transgenic (Tg) and apolipoprotein E (apoE) knockout mice (hPRDX4+/+/apoE−/−). After feeding the mice a high-cholesterol diet, they showed fewer atheromatous plaques, less T-lymphocyte infiltration, lower levels of oxidative stress markers, less necrosis, a larger number of smooth muscle cells, and a larger amount of collagen, resulting in thickened fibrous cap formation and possible stable plaque phenotype as compared with apoE−/− mice. We also detected greater suppression of apoptosis and decreased Bax expression in hPRDX4+/+/apoE−/− mice than in apoE−/− mice. Bone marrow transplantation from hPRDX4+/+ donors to apoE−/− mice confirmed the antiatherogenic aspects of PRDX4, revealing significantly suppressed atherosclerotic progression. Innovation: In this study, we demonstrated for the first time that PRDX4 suppressed the development of atherosclerosis in apoE−/− mice fed a high-cholesterol diet. Conclusion: These data indicate that PRDX4 is an antiatherogenic factor and, by suppressing oxidative damage and apoptosis, that it may protect against the formation of vulnerable (unstable) plaques. Antioxid. Redox Signal. 17, 1362–1375.

Macrophage-derived chemokine (CCL22) is a member of the CC-family of chemokines and is synthesized by monocyte-derived macrophages and dendritic cells (DCs). In this study, we investigate the relationship between monocytes/macrophages and histamine in atherosclerosis and discover that histamine levels regulate various immunologically important molecules and influences atherosclerotic progression. Immunohistochemical analysis of human atherosclerotic lesions revealed that macrophages and DCs express CCL22. The human acute monocytic leukemia cell line (THP-1) adhered to culture plates and morphologically changed to macrophage-like cells when treated with tetradecanoylphorbol-13-acetate (TPA). Macrophage-like cells derived from THP-1 cells and cultivated peripheral blood mononuclear cells (PBMCs) show similar expression of CCL22. Gene expression of CCL22 was also detected in THP-1 cells treated with histamine and the expression of the protein produced by the CCL22 gene is similar in PBMCs and THP-1 cells. In addition, the histamine H2 receptor mediated these reactions. Our results suggest that CCL22 expression in monocytes is regulated by histamine, and that CCL22 is involved centrally in the development of human atherosclerotic lesions. In conclusion, CCL22 is a marker that is a characteristic of the monocytes/ macrophages migrating into atherosclerotic lesions and histamine plays a role in regulating its expression.

A male infant born prematurely at 31 weeks of gestation weighed 789 g and had mildly brown-colored oral/tracheal aspirates at delivery. The amniotic fluid was also discolored, and its index was below 5. The patient died of hypoxemic respiratory and cardiac failure 2 hours after birth. The maternal profiles showed placenta previa and intrauterine growth restriction (IUGR) at 22 weeks of gestation, and revealed recurrent episodes of antenatal and substantial vaginal bleeding and oligohydramnios, indicating chronic abruption-oligohydramnios sequence. The thickened placenta, weighing 275 g, grossly displayed unevenness and diffuse opacity with green to brown discoloration in the chorioamniotic surface, and revealed chronic massive subchorial hematomas (Breus' mole) with old peripheral blood clot, circumvallation, and infarction. Microscopically, diffuse Berlin-blue staining-positive hemosiderin deposits were readily encountered in the chorioamniotic layers of the chorionic plate, consistent with diffuse chorioamniotic hemosiderosis (DCH) due to Breus' mole, accompanied by diffuse amniotic necrosis. At autopsy, an external examination showed several surface anomalies and marked pulmonary hypoplasia, 0.006 (less 0.012) of lung:body weight ratio. Since Breus' mole has a close relationship with intrauterine hemorrhage, resulting in DCH, IUGR, and/or pulmonary hypoplasia of the newborn, the present features might be typical.

This is a case report of a 65-year-old female with malakoplakia in the urinary bladder. An ultrasound scan showed many tumor-like polyp lesions, where a transurethral resection was performed. Since the lesions revealed gross papillary neoplasms, malignancy was suspected. However, histpathological examination showed an aggregation of many infiltrating histiocytes containing characteristic Michaelis-Gutmann bodies positively reactive with von Kossa staining, indicating a typical case of malakoplakia of the urinary bladder. Immunohistochemical study demonstrated that the cytoplasms of the histiocytes were focally positive for an anti-Escherichia coli antibody. One of the etiologies of malakoplakia is infection by Escherichia coli, which is supported by our data.

Objective— The pathogenic role of macrophage apoptosis in atherosclerosis is still debatable, but it is considered to be a suppressor of plaque progression in early stages but a promoter of plaque necrosis in advanced stages. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays a pivotal role in stress-induced apoptosis. In the current study, we investigated the functions of ASK1 in hyperlipidemia-induced atherosclerosis. Methods and Results— We generated ASK1 and apolipoprotein E (apoE) double-knockout mice (ASK1 −/− /apoE −/− ) and analyzed atherosclerosis in ASK1 −/− /apoE −/− mice fed a high-cholesterol diet for 12 weeks. ASK1 −/− /apoE −/− mice had accelerated hyperlipidemia-induced atherosclerosis, which was characterized by less apoptosis of macrophages and fewer necrotic areas, and more macrophages and elastolysis compared with apoE −/− mice. Bone marrow transplantation from ASK1 −/− or wild-type to apoE −/− mice confirmed the above observation that the recipient mice of ASK1 −/− donors had more pronounced hyperlipidemia-induced atherosclerosis than recipient mice of wild-type donors. Conclusion— These findings suggest that ASK1 suppresses hyperlipidemia-induced atherosclerosis via increased macrophage apoptosis and that ASK1 may cause pronounced plaque vulnerability via necrotic core development.

Proliferation of non-neoplastic striated muscle cells in the lung is rare and has been frequently observed in cases of cardiovascular and pulmonary congenital malformations. We present an extremely rare case of pulmonary rhabdomyomatous dysplasia (RD) in neurofibromatosis type 1 (NF-1). A male neonate was born at 35 weeks’ gestation after normal pregnancy. Postnatally, besides patent ductus arteriosus and posterior mediastinal mass, abnormal cystic lesions in the left upper and lower lung were detected. No bronchial atresia and stenosis were identified. Partial lobectomy specimens showed hypoplastic lung parenchyma with cystic lesions resembling terminal bronchioles and distinctive proliferation of non-neoplastic striated muscle fibers in the interstitium. The posterior mediastinal mass consisted of neurofibroma. Considering that cafe au lait spots and freckling occurred at 2 months of age, a diagnosis of NF-1 was made. The patient died of aspiration pneumonia at the age of 30 months. To the best of our knowledge, this is the first case of pulmonary RD in NF-1.

Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disease characterized by alveolar accumulation of surfactant lipids and proteins. It is usually autoimmune and secondary to hematologic malignancy or infection. To date, only 5 case reports of PAP associated with lung cancers, including 2 cases of squamous cell carcinoma and 3 cases of adenocarcinoma, have been published. To the best of our knowledge, no case of PAP with small cell lung carcinoma has been reported thus far. We herein report the first case of PAP associated with small cell lung carcinoma.

Multistructure assemblies consisting of porphyrin and gold nanoparticles have been fabricated on an indium-tin-oxide electrode by using alternate gold–sulfur self-assembling. Structural and morphological characterizations of the assemblies have been carried out by absorption spectra and scanning electron micrographs. The results verified that the degree of each self-assembling was considerably lower than monolayer level. The assemblies exhibit clear photocurrent responses ascribing to photoexcitation of porphyrin in the presence of oxygen as a sacrificial electron acceptor. The photocurrent was larger for higher number of assembling cycles.

Acridinylresorcinol host 3 (9-(3,5-dihydroxy-1-phenyl)acridine) forms such adducts as 3.(benzene), 3.(chloroform), 3.0.5(toluene), and 3.(isobutyl benzoate). Modified acridinol host 4 (9-(3,5-dihydroxy-1-phenyl)-4-hydroxyacridine) having an additional OH group on the acridine ring affords such adducts as 4.(benzene), 4.(chloroform), 4.0.5(toluene).0.5(water), 4.(methanol).(water), and 4.(ethyl acetate). In the crystals, hosts 3 and 4 form hydrogen-bonded (O-H...O-H) poly(resorcinol) chains which are linked together via interchain O-H...N hydrogen bonds to give a coordinatively saturated (O-H...O-H...N) 2D net composed of doubly hydrogen-bonded and antiparallel-stacked, self-complementary cyclic dimer 3(2) or 4(2) as a rigidified building block, the otherwise flexible O-H...O-H hydrogen bonds being thereby taken in a cyclophane-like structure. This network turns out to be remarkably well preserved among the above adducts. Guest molecules, which are disordered in many cases, are incorporated in the cavities left. The binding of small polar guests to host 4 is primarily due to hydrogen bonding to the OH group on the acridine ring. The latter therefore acts only as a polarity modifier of preserved cavities. Adduct 3.(benzene), that is, 3(2).2(benzene) readily loses one of two guest molecules bound in each cavity to give a microporous half-filled adduct 3(2).(benzene) which adsorbs 1 mol of benzene to regenerate the starting full adduct without involving a phase change, as confirmed by X-ray powder diffractions and reversible Langmuir-type adsorption/desorption isotherms. The self-complementarity strategy for designing rigid crystal structures is discussed with a particular reference to the possibility of systematic perturbation/variation approaches in crystal engineering.

High-mobility group box (HMGB) proteins are ubiquitous, abundant nuclear non-histone chromosomal proteins that play a critical role in binding to distorted DNA structures and subsequently regulating DNA transcription, replication, repair, and recombination. Both HMGB1 and HMGB2 exhibit a high expression in several human cancers and are closely associated with tumor progression and a poor prognosis. However, the expression patterns of these molecules in pancreatic ductal adenocarcinoma (PDAC) remain to be elucidated. As most cases of postoperative relapse of PDAC occur within the first 2 years, the clinical significance of accurate biomarkers is needed. Therefore, we investigated the correlation between the immunohistochemical HMGB1 and HMGB2 expression and the clinicopathological characteristics and prognosis using 62 paraffin-embedded tumor samples obtained from patients with surgically resected PDAC. The HMGB1/2 expression was considered to be positive when 10 % or more of the cancer cells showed positive nuclear, not merely cytoplasmic, staining. Consequently, the expression of HMGB1/2 was observed in 54 (87.1 %) and 31 (50.0 %) patients, respectively. Unexpectedly, a positive HMGB1 expression was found to have a significantly close relationship with a negative HMGB2 expression. The univariate and multivariate analyses demonstrated that the patients with a HMGB1+ and HMGB2− status had markedly lower disease-specific survival rates, especially within the first 2 years postoperatively, whereas those with a HMGB1+ status alone did not. Therefore, the combination of a HMGB1+ and HMGB2− expression potentially predicts a poor prognosis in patients with PDAC, and these new biomarkers may be useful parameters for clinical management in the early postoperative phase.

Castleman’s disease in the pelvic cavity is rare. We present a 72-year-old woman with hyaline vascular type of Castleman’s disease of the right ovary. Right ovarian enlargement was detected in the medical examination. Computed tomography revealed a solid mass, measured 2.5 cm in size, in the right ovary. A bilateral salpingo-oophorectomy was performed. Morphologically, lymphoid follicles with regressed germinal centers (GCs) were surrounded by a broad mantle zone composed of concentric rings of small lymphocytes, and the hyalinized blood vessels with plump endothelial cells penetrated radially into GCs. Proliferation of follicular dendritic cells, which were positive for CD21 and epidermal growth factor receptor, were detected in GCs and mantle zone. No other lesions were found. To the best of our knowledge, this is the first case of hyaline vascular type of Castleman’s disease of ovarian primary.

24Na in the human body, activated by neutrons emitted at the JCO criticality accident, was observed for 62 subjects, where 148 subjects were measured by the whole body counter of JNC Tokai Works. The 148 subjects, including JCO employees and the contractors, residents neighboring the site and emergency service officers, were measured by the whole-body counter. The neutron-energy spectrum around the facility was calculated using neutron transport codes (ANISN and MCNP), and the relation between an amount of activated sodium in human body and neutron dose was evaluated from the calculated neutron energy spectrum and theoretical neutron capture probability by the human body. The maximum 24Na activity in the body was 7.7 kBq (83 Bq(24Na)/g(23Na)) and the relevant effective dose equivalent was 47 mSv.

Pseudo-Meigs' syndrome accompanied by massive ascites in uterine leiomyoma is rare. We encountered a rare case of a 37-year-old, nulliparous woman with a lower abdominal tumor and severe abdominal distention due to massive ascites. Serum cancer antigen 125 and vascular endothelial growth factor levels were elevated to 1007.9 U/mL and 103 pg/mL, respectively. She was tentatively diagnosed with ovarian cancer. Emergency concentrated ascites re-infusion therapy was performed to improve dyspnea, abdominal pain, and her preoperative respiratory condition. Concentrated ascites re-infusion therapy eliminated dyspnea and abdominal discomfort without decreasing serum albumin levels. The patient underwent laparotomy, which revealed a fist-sized pedunculated uterine leiomyoma arising from the right uterine fundus. Myomectomy was performed. Pseudo-Meigs' syndrome mimics advanced ovarian cancer due to massive ascites and markedly elevated serum cancer antigen 125 and vascular endothelial growth factor levels. Concentrated ascites re-infusion therapy was effective in improving the subjective symptoms of pseudo-Meigs' syndrome and the patient's preoperative condition.

Some of the superannuated equipment were replaced in the nuclear fuel reprocessing plant at the Tokai-works of the Power Reactor and Nuclear Fuel Development Corporation (PNC). The authors have been investigating the airborne particle sizes of radiological materials in the decommissioning process using Andersen samplers. This paper describes information on the particle sizes during the cutting processes. The activity median aerodynamic diameters (AMAD) of the aerosols ranged from 2 to 4μm, and their geometric standard deviations were in the range of approximately 2-3.

Abstract Paratesticular liposarcoma is a rare neoplasm, described in single case studies or components of larger studies, as histologically well-differentiated liposarcoma (WDL) and dedifferentiated liposarcoma (DL). However, leiomyosarcomatous differentiation is an extremely rare occurrence in WDL and DL. We report a case of leiomyosarcomatous differentiation in a 77-year-old man. The patient presented with a painless right scrotal mass. Magnetic resonance imaging showed a large mass along the right spermatic cord. The resected mass, measuring 17.5 × 12 × 5 cm, was composed of a high-grade pleomorphic undifferentiated sarcomatous component with necrosis. Atypical smooth muscle differentiation was also detected. Additional tumor sampling revealed the presence of a WDL component. Immunohistochemical analysis of the pleomorphic sarcomatous component showed positive staining for MDM2 and CDK4, and negative staining for alpha smooth muscle actin (αSMA) and desmin. The smooth muscle component was positive for αSMA and desmin, and negative for MDM2 and CDK4. Extension from primary retroperitoneal sarcoma was not proved. We diagnosed of DL with leiomyosarcomatous differentiation. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1484291498104021.

Pancreatic hamartoma is a rare tumor, and its characteristic histopathologic features have not yet been fully evaluated. In this study, we collected 9 cases of pancreatic hamartoma to elucidate distinctive histopathologic features that can serve to establish this tumor as a clear disease entity and thus formulate useful histopathologic criteria for this tumor. The cases comprised 4 men and 5 women with a mean age of 62.7 years. The average tumor diameter was 3.3 cm. All patients underwent surgical treatment, and none showed any recurrence postoperatively. Macroscopically, pancreatic hamartomas were well-demarcated tumors with a solid or solid and cystic appearance. Microscopically, these tumors comprised mature acini and small-sized to medium-sized ducts showing a distorted architecture with various amounts of fibrous stroma. Strikingly, the tumors consistently lacked concentric elastic fibers in their duct walls, peripheral nerves, and well-formed islets of Langerhans, all of which exist in both the normal and atrophic pancreas. Immunohistochemically, scattered chromogranin A-positive neuroendocrine cells were observed in the acinar and ductal components. Ductal components were positive for S-100 protein. Spindle-shaped stromal cells expressed CD34 and/or c-kit. These histopathologic features were distinct from those of 5 cases of pancreatic ductal adenocarcinoma, 3 cases of type 1 autoimmune pancreatitis (lymphoplasmacytic sclerosing pancreatitis), 3 cases of alcoholic chronic pancreatitis, and 5 cases of normal pancreas. In conclusion, pancreatic hamartomas share some distinctive histopathologic features and clinical outcomes (neither recurrence nor metastasis) that allow them to be interpreted as malformative lesions. The term "hamartoma" is appropriate for these unique lesions.

The patient presented here, a 74-year-old female, had a 3-year history of a gradually enlarging painless nodule in the right submental lateral region of the neck. A neck CT scan showed a well-demarcated cystic lesion, measuring 25 mm in diameter, but without any definite evidence of neoplastic foci in the lymph nodes, thyroid gland, or lung. Clinicians first interpreted it as branchial cleft cyst, and a cystectomy was performed. Gross examination revealed a unilocular cystic lesion filled with yellowish clear fluids, containing a markedly thinned fibrous wall with smooth inner surface, partly coexisting with tiny solid and papillary-like components. On microscopic examination, the cystic tumor was lined by mono-layered ciliated columnar or metaplastic stratified squamous epithelium with underlying ectopic thyroid follicles or lymphocytic infiltrate, reminiscent of thyroglossal duct cyst (TDC), partly adjacent to the compressed lymph node tissue. Its solid parts were composed of a proliferation of atypical cuboidal to columnar epithelial cells with occasional nuclear grooves or intranuclear inclusions, arranged in a papillary growth pattern with supporting delicate fibrovascular cores. Immunohistochemically, these atypical cells were positive for thyroid transcription factor 1, thyroglobulin, and cytokeratin 19. Therefore, we finally made a diagnosis of papillary carcinoma (PC) arising in TDC in the lateral neck. Although metastatic thyroid PC of cervical lymph node was an important differential diagnosis owing to various overlapping clinicopathological features, coexistent benign lining epithelium or thyroid follicles, a histological hallmark of TDC, were present in the current case.