Immunohistoochemical evaluation of GATA-3, pAKT and Ki-67 in triple negative breast carcinoma

Background: Triple-negative breast cancers lack expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor -2. These tumors have been known to be clinically aggressive. We evaluate GATA-3, pAKT and Ki-67 expression in 35 triple negative breast carcinomas.Materials and Methods: A total of 35 triple negative breast carcinomas were included in this study. The histological subtyping was done according to Japanese guidelines for breast cancer.Results: GATA-3 was positive in 60% (21/35) of tumors. High GATA-3 expression was observed in ductal carcinoma in situ.  pAKT expression was demonstrated in 85.7 % (30/35) of TNBCs. The levels of expression of GATA-3 and pAKT showed no significant association with nuclear grading. (P=0.761 and P=0.487, respectively). Ki-67 labeling index was positively correlated with nuclear grading (p&lt;0.001).Conclusion: GATA-3 expression has no relation with ER and PR expression and pAKT and GATA-3 are strongly expressed in TNBCs. </p

Animal models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver of a patient without a history of alcohol abuse. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can progress to liver cirrhosis and hepatocellular carcinoma. NAFLD is regarded as a hepatic manifestation of metabolic syndrome and incidence has been increasing worldwide in line with the increased prevalence of obesity, type 2 diabetes, and hyperlipemia. Animal models of NAFLD/NASH give crucial information, not only in elucidating pathogenesis of NAFLD/NASH but also in examining therapeutic effects of various agents. An ideal model of NAFLD/NASH should correctly reflect both hepatic histopathology and pathophysiology of human NAFLD/NASH. Animal models of NAFLD/NASH are divided into genetic, dietary, and combination models. In this paper, we review commonly used animal models of NAFLD/NASH referring to their advantages and disadvantages

β4 and β6 Integrin Expression Is Associated with the Subclassification and Clinicopathological Features of Intrahepatic Cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is a heterogeneous group of cancers of the intrahepatic biliary tract. However, few studies have evaluated integrin expression according to an ICC subgroup. We immunohistochemically investigated α6β4 (β4) and αvβ6 (β6) integrin expressions in 48 ICCs, and evaluated their relationship with clinical and pathological parameters and ligand expression, as well as transforming growth factor (TGF)-β1. β4 and β6 expressions were detected in 46 (96%) and 35 (73%) ICC cases, respectively. We classified ICC into negative, low (β4, 29 cases; β6, 36 cases), or high (β4, 19 cases; β6, 12 cases) integrin expression groups. β4 and β6 integrin levels were higher in the non-peripheral central localization type ICC than in the peripheral localization type; they were also higher in the periductal-infiltrating or intraductal-growth types than in the mass-forming type ICC; lastly, they were higher in the well-differentiated type than in the poorly-differentiated type ICC. High expression was related to bile duct invasion. In addition, β4 and β6 expressions were associated with mucin production and the expression of cytoplasmic epithelial membrane antigen, laminin-5, and tenascin-C. TGF-β1 was correlated with β6 expression and poor overall survival. These results suggest that integrin expression is associated with subclassification and clinicopathological features of ICC through the coincident expression of their ligands and TGF-β1

Gross Cystic Disease Fluid Protein-15 (GCDFP-15) Expression Characterizes Breast Mucinous Carcinomas in Older Women

The predominant histological subtype of breast mucinous carcinoma in older women is type B (hypercellular type), and, in younger women, it is type A (hypocellular type). The characteristics of mucinous carcinomas of the same histological subtype may differ between older and younger women. This study aims to systematically clarify the pathological/immunohistochemical features of mucinous carcinomas. A total of 21 surgical cases of mucinous carcinoma (type A/B: 9/12 cases) in the older group (&ge;65 years) and 16 cases (type A/B: 14/2 cases) in the younger group (&le;55 years) (n = 37) were included. Gross cystic disease fluid protein-15 (GCDFP-15) and eight other markers were used for immunostaining. The GCDFP-15-positive rate in the older group was high regardless of the histological subtype (type A, 77.8%; type B, 91.7%). The GCDFP-15 positivity in the older group was significantly higher than that in the younger group (p &lt; 0.001 for Allred score). Among type A, GCDFP-15 positivity was significantly higher in the older group than in the younger group (p = 0.042 for the Allred score and p = 0.007 for the positivity rate). The present results suggest that GCDFP-15 expression characterizes mucinous carcinomas in older women

A missense mutation in the RSRSP stretch of Rbm20 causes dilated cardiomyopathy and atrial fibrillation in mice

Dilated cardiomyopathy (DCM) is a fatal heart disease characterized by left ventricular dilatation and cardiac dysfunction. Recent genetic studies on DCM have identified causative mutations in over 60 genes, including RBM20, which encodes a regulator of heart-specific splicing. DCM patients with RBM20 mutations have been reported to present with more severe cardiac phenotypes, including impaired cardiac function, atrial fibrillation (AF), and ventricular arrhythmias leading to sudden cardiac death, compared to those with mutations in the other genes. An RSRSP stretch of RBM20, a hotspot of missense mutations found in patients with idiopathic DCM, functions as a crucial part of its nuclear localization signals. However, the relationship between mutations in the RSRSP stretch and cardiac phenotypes has never been assessed in an animal model. Here, we show that Rbm20 mutant mice harboring a missense mutation S637A in the RSRSP stretch, mimicking that in a DCM patient, demonstrated severe cardiac dysfunction and spontaneous AF and ventricular arrhythmias mimicking the clinical state in patients. In contrast, Rbm20 mutant mice with frame-shifting deletion demonstrated less severe phenotypes, although loss of RBM20-dependent alternative splicing was indistinguishable. RBM20^ protein cannot be localized to the nuclear speckles, but accumulated in cytoplasmic, perinuclear granule-like structures in cardiomyocytes, which might contribute to the more severe cardiac phenotypes

Solute carrier transporters, reduced folate carrier 1 and equilibrative nucleoside transporter 1, as immunohistochemical markers for high-grade malignancy in bladder cancer

Clinicopathological parameters derived from initial transurethral resection of bladder tumor (TUR-Bt) have limitations in predicting tumor progression in bladder cancer. Reduced folate carrier 1 (RFC1) and equilibrative nucleoside transporter 1 (ENT1) are solute carrier (SLC) transporters supporting cellular uptake of endogenous bioactive substances and anti-cancer drugs. The aim of this study was to elucidate the role of SLC transporters in bladder cancer and investigate the potential of RFC1 and ENT1 expression as immunohistochemical markers for high-grade malignancy. We compared T-stage with the immunohistochemical expression of RFC1 and ENT1 and other clinicopathological parameters; moreover, we also used multiple logistic regression model to assess relative contributions for T-stage in bladder cancer (n=130). Concurrently, 57 TUR-Bt-derived imprint cytological samples were stained to evaluate the implication of cytological analysis. Elevated expression levels of RFC1 and ENT1 were significantly correlated with higher T-stage (p < .0001) and efficiently predicted tumor progression, compared with other clinicopathological parameters (RFC1, p = .0325; ENT1, p = .0171). Independent variables of optimal model for predicting T-stage were gender, age, histological grade, expression levels of RFC1 and ENT1. Cytological analysis was consistent with immunostained-tissue data. We reveal RFC1 and ENT1 as potential immunohistocytochemical markers for high-grade malignancy in bladder cancer

Inhibitory Effects of Japanese Herbal Medicines Sho-saiko-to and Juzen-taiho-to on Nonalcoholic Steatohepatitis in Mice

<div><p>Although Japanese herbal medicines (JHMs) are widely used in Japan, only a few studies have investigated their effects on nonalcoholic steatohepatitis (NASH). In the present study, we examined the effect of 4 kinds of JHMs [sho-saiko-to (TJ-9), inchin-ko-to (TJ-135), juzen-taiho-to (TJ-48), and keishi-bukuryo-gan (TJ-25)] on a mouse model of NASH. Db/db mice were divided into 6 groups: control diet (control), methionine- and choline-deficient diet (MCD), and MCD diet supplemented with TJ-9, TJ-135, TJ-48, and TJ-25 (TJ-9, TJ-135, TJ-48, and TJ-25, respectively). All mice were sacrificed after 4 weeks of treatment, and biochemical, pathological, and molecular analyses were performed. Serum alanine aminotransferase levels and liver histology, including necroinflammation and fibrosis, were significantly alleviated in the TJ-9 and TJ-48 groups compared with the MCD group. The expression level of transforming growth factor (TGF)-β1 mRNA in the liver was significantly suppressed by TJ-48. Although the differences were not statistically significant, the expression levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 were lower, and those of peroxisome proliferators-activated receptor (PPAR)γ were higher in the TJ-9 and/or TJ-48 groups than in the MCD group. Similarly, even though the results were not statistically significant, malondialdehyde levels in liver tissues were lower in the TJ-9 and TJ-48 groups than in the MCD group. We showed that JHMs, especially TJ-9 and TJ-48, inhibited the necroinflammation and fibrosis in the liver of a mouse model of NASH, even though the mechanisms were not fully elucidated. Further studies are needed in the future to investigate the possibility of clinical application of these medicines in the treatment for NASH.</p></div

Photomicrographs of the liver.

<p>Mice of the MCD group show marked hepatic steatosis (A), but steatosis is suppressed in mice of the TJ-48 group (B). Necroinflammatory foci (arrows) are scattered in the liver of mice of the MCD group (C), but lobular inflammation is suppressed in mice of the TJ-9 group (D). (Hematoxylin and eosin stain; A and B: ×100; C and D: ×200).</p