Outside-in signaling by femoral cuff injury induces a distinct vascular lesion in adipose triglyceride lipase knockout mice.

Genetic deficiency of adipose triglyceride lipase (ATGL), a rate-limiting enzyme for intracellular triglyceride (TG) hydrolysis, causes TG-deposit cardiomyovasculopathy (TGCV), a recently identified rare cardiovascular disorder (ORPHA code: 565612) in humans. One of the major characteristics of TGCV is a novel type of diffuse and concentric coronary atherosclerosis with ATGL-deficient smooth muscle cells (SMCs). Patients with TGCV have intractable coronary artery disease. Therefore, it is crucial to investigate the mechanisms underlying vascular lesions in ATGL deficiency using animal models. Cuff injury is an experimental procedure to induce vascular remodeling with neointimal formation with SMCs after placing a cuff around the adventitial side of the artery without direct influence on endothelium. We report the effect of cuff injury on femoral arteries of ATGL-knockout (ATGL⁻/⁻) mice. Cuff-induced concentric neointimal formation with migrating SMCs was exacerbated in ATGL⁻/⁻ mice, mimicking atherosclerotic lesions in patients with TGCV. In the media, cell death of SMCs and loss of elastic fibers increased. Perivascular infiltrating cells expressing tumor necrosis factor-α (TNF-α) were more prominent in ATGL⁻/⁻ mice than in wild-type (WT) mice. In Boyden chamber experiments, a greater number of ATGL⁻/⁻ SMCs migrated in response to TNF-α compared to WT SMCs. These data, for the first time, demonstrated that outside-in signaling by cuff-induced neointimal formation where paracrine stimuli from adventitial infiltrating cells may lead to neointimal formation and mediolysis in ATGL-deficient conditions. Cuff injury might be a valuable model for understanding the mechanisms underlying the development of atherosclerotic lesions in patients with TGCV.

Macrophage CCL22 expression in the tumor microenvironment and implications for survival in patients with squamous cell carcinoma of the tongue.

BACKGROUND: CCL22, mainly synthesized by monocyte-derived alternative (M2) macrophages, belongs to the CC family of chemokines. CCR4, the receptor for CCL22, is expressed in regulatory T cells (Tregs) and Th2 cells. The Yamamoto-Kohama (YK) mode of invasion has been associated with tumor prognosis. Herein, we investigated the role of CCL22 in the tumor microenvironment and its effect on the overall survival rate in patients with tongue squamous cell carcinoma (SCC). METHODS: Tumor sections obtained from 92 patients with tongue SCC were graded based on the mode of invasion according to the YK classification. The expressions of several markers (CCL22, CD8, and Ki-67 by immunohistochemistry; CCR4 and FoxP3 by immunofluorescent staining) were evaluated. Student's t test and chi-square tests were used to compare differences between numerical variables and groups, respectively. Survival curves were plotted according to the Kaplan-Meier method and compared using a log-rank test. Hazard ratios and 95% confidence intervals were estimated using univariate or multivariate Cox proportional hazard models. RESULTS: The expression of CCL22 was significantly correlated with YK classification, overall survival rate (P < 0.001), a decrease in the number of CD8-positive cells, and an increase in the tumor Ki-67 index. In addition, CCR4-positive cells were observed around CCL22-positive macrophages. CONCLUSION: These findings indicate that the expression of CCL22 in the tumor microenvironment led to a deterioration in the prognosis of patients with tongue SCC by influencing the balance of M1- and M2-like macrophages.

Depletion of WNT10A Prevents Tumor Growth by Suppressing Microvessels and Collagen Expression.

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.

A Surgical Case of Inflammatory Myofibroblastic Tumor of the Liver: Potentially Characteristic Gross Features.

We herein reported a very rare surgical case of inflammatory myofibroblastic tumor (IMT) of the liver, showing potentially unique and specific gross findings on its cut surface: our IMT demonstrated a relatively well-demarcated and partly infiltrative and likely extrahepatic (ie serosal) but not intrahepatic mass, appearing firm and hemorrhagic, and yellow-whitish in color. The patient, who was a woman in her early 70s with 2-year follow-up for lung cryptococcosis and traffic accident, incidentally presented with unenhanced and low-density, heterogeneous mass on abdominal dynamic CT in the peripheral right lobe of the liver. We could conclusively diagnose the current lesion as the hepatic IMT after thorough analyses including a wide panel of immunohistochemical antibodies. Despite that, all clinicians and pathologists should be aware that the potentially characteristic, extrahepatic gross feature of IMT of the liver might also be one of the powerful supplementary tools for reaching its correct diagnosis. One of our aims in the presented case report is to emphasize that the hepatic IMT should be considered clinicopathologically in the differential diagnosis of mass lesions on the liver.

Localized malignant pleural mesothelioma arising in the interlobar fissure: a unique surgical case masquerading clinicopathologically as primary lung adenocarcinoma.

An 80-year-old male with previous workplace exposure to asbestos presented with a history of an increase in the pulmonary-to-hilar mass, measuring more than 50 mm in diameter, likely in the right lower lobe. We first interpreted it as suspicious of primary lung adenocarcinoma with direct invasion to the right hilar lymph node. A right middle and lower lobectomy with partial resection of upper lobe was performed, and gross examination showed a hilar tumor lesion, involving the middle/lower lobe to hilar lymph node and looking whitish to yellow-grayish, partly adjacent to the right pulmonary artery. On microscopic examination, the tumor was located on the extrapulmonary, interlobar pleural fissure, predominantly composed of a proliferation of atypical epithelioid cells, often arranged in an irregular and fused tubular growth pattern with an involvement of pulmonary artery. Immunohistochemically, these atypical cells are positive for several mesothelial markers, including calretinin, cytokeratin 5/6, and WT-1, whereas negative for thyroid transcription factor 1. Furthermore, p16 deletions were specifically detected by fluorescence in situ hybridization, and electron microscopy showed numerous, significantly elongated microvilli. Taken together, we finally made a diagnosis of localized malignant pleural mesothelioma, epithelioid-type, arising in the right interlobar fissure between lower and middle lobes. We should be aware that, owing to its characteristic features, clinicians and pathologists might be able to raise interlobar fissure localized malignant pleural mesothelioma as one of the differential diagnoses, based on careful clinicopathological examinations.

Findings as a starting point to unravel the underlying mechanisms of in vivo interactions involving Wnt10a in bone, fat and muscle.

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.

Two Surgical Cases of Combined Hepatocellular-Cholangiocarcinoma, Intermediate-Cell Subtype: Potentially Characteristic Gross Features.

We herein reported two rare surgical cases of primary combined hepatocellular-cholangiocellular carcinoma, intermediate-cell subtype (CHC-INT), showing potentially characteristic and specific gross findings on their cut surface: both CHC-INTs demonstrated poorly demarcated and expansive and/or infiltrative hepatic nodules in lobulated margins, appearing clearly whitish in color. We were finally able to accurately diagnose the current lesions after thorough analyses including an appropriate and wide panel of immunohistochemical antibodies. Despite that, all pathologists should be aware that the potentially characteristic gross features of primary CHC-INT might also be one of the powerful supplementary tools for reaching its correct, conclusive diagnosis.

Myoepithelial carcinoma of the parotid gland: A case of adequate fine-needle aspiration cytology specimens rendering a conclusive diagnosis possible.

An 80-year-old male presented with a history of a hard right parotid mass that had gradually increased in size, with subsequent facial paralysis. A fine-needle aspiration biopsy was performed. The cytologic specimens contained a substantial number of sheet-like clusters or small groups of a mixture of plasmacytoid, oval to spindled, or large epithelioid cells having hyperchromatic pleomorphic nuclei, abundant cytoplasm with occasional inclusion body-like materials, and prominent nucleoli, in a relatively clear background. We first interpreted it as a carcinoma, suggestive of myoepithelial differentiation. Radical parotidectomy was performed, and a gross examination of the neoplasm revealed a non-capsulated and ill-defined tumor lesion, with a grayish or yellowish cut surface, associated with fat invasion. On a microscopic examination, the tumor was predominantly composed of the solid proliferation of atypical cells including a mixture of oval to spindled, plasmacytoid, or epithelioid cells, often arranged in a trabecular and reticular growth pattern with patchy eosinophilic hyalinized stroma. Immunohistochemistry showed that the carcinoma cells were specifically positive for p63, cytokeratins, and vimentin. Finally, electron microscopy demonstrated that their phenotype was consistent with a myoepithelial origin containing many bundles of variably thin actin filaments. Therefore, we finally made a diagnosis of myoepithelial carcinoma, defined as the malignant counterpart of benign myoepithelioma. We should be aware that owing to its characteristic cytological features, cytopathologists may be able to make a correct diagnosis of myoepithelial carcinoma, based on multiple and adequate samplings.

Relationship between CCL22 Expression by Vascular Smooth Muscle Cells and Macrophage Histamine Receptors in Atherosclerosis.

AIM: CCL22, mainly synthesized by monocyte-derived alternative (M2) macrophages, belongs to the CC family of chemokines and is involved in monocyte migration and recruitment. We have previously investigated CCL22 and histamine in atherosclerosis. Here, we investigated the hypothesis that CCL22 is involved in atherosclerosis, which is influenced by the differentiation of macrophage phenotypes via histamine. METHODS: CCL22 expression was investigated in human carotid arteries and coronary arteries with bare metal stents. Ligated carotid arteries of wild-type (C57BL/6J) and apolipoprotein E-deficient mice were also used as atherosclerotic models. The localization and expression of CCL22 and classical (M1)-like and M2-like macrophages in various human and mouse atherosclerotic lesions were investigated by immunohistochemical examination and quantitative real-time polymerase chain reaction. Histamine is expressed in atherosclerosis, and it induces inflammation and immunity. Human- and mice-derived monocytes and macrophages were used to examine the role of histamine in macrophage differentiation and CCL22-expression. Macrophages derived from histamine receptor 1 (H1R)- and 2 (H2R)-knockout (KO) mice were also examined. RESULTS: Atherosclerotic lesions showed a distribution of heterogeneous macrophage phenotypes with M1-like and M2-like macrophage dominant sites. CCL22 was distributed in sparse areas of vascular smooth muscle cells (VSMCs) and associated with M2-like macrophages. Moreover, H2R stimulation was associated with CCL22 expression via M2-like macrophage dominant differentiation. CONCLUSION: The expression of M1- or M2-like macrophages in atherosclerosis were observed to be dependent on the distribution of VSMCs owing to differences in causal stimuli and the switching of histamine receptors via Th1 or Th2 cytokines. These results suggest that CCL22 may control atherosclerosis.

Critical in vivo roles of WNT10A in wound healing by regulating collagen expression/synthesis in WNT10A-deficient mice.

BACKGROUND: We have reported that WNT10A plays a critical role in the growth of fibroblasts/myofibroblasts and microvascular endothelial cells, i.e.; wound healing/scarring. To ascertain the in vivo regulatory, central functions of WNT10A, we examined the net effects of WNT10A depletion using WNT10A-deficient mice (WNT10A-/-). METHODS AND RESULTS: We generated WNT10A-/-mice, displaying a range of unique phenotypes of morpho/organogenetic failure, such as growth retardation, alopecia, kyphosis and infertility, and then focused on the functions of WNT10A in wound healing. We subjected C57BL/6J wild-type (WT) or WNT10A-/-mice to skin ulcer formation. The WNT10A-/-mice had significantly larger injured areas and delayed wound healing, which were associated with (a) a smaller number of fibroblasts/myofibroblasts and microvessels; and (b) more reduced expression and synthesis of collagen, compared with WT mice with intact WNT10A expression, especially in those with activated myofibroblasts. CONCLUSIONS: These observations indicate that WNT10A signaling can play a pivotal in vivo role in wound healing by regulating the expression and synthesis of collagen, as one of fibrogenic factors, at least in part, and critical in vivo roles of WNT10A-mediated effective wound healing are extremely closely associated with collagen expression.

Critical in vivo roles of histamine and histamine receptor signaling in animal models of metabolic syndrome.

Histamine, a classic low-molecular-weight amine, is synthesized from L-histidine by histidine decarboxylase (HDC), and histamine-specific receptors (HRs) are essential for its actions. Our serial in vivo studies have uniquely reported that expression of histamine/HRs is variably identified in atherosclerotic lesions, and that HDC-gene knockout mice without histamine/HRs signaling show a marked reduction of atherosclerotic progression. These data have convinced us that histamine plays a pivotal role in the pathogenesis of atherosclerosis. Among four subclasses of HRs, the expression profile of the main receptors (H1/2R) has been shown to be switched from H2R to H1R during monocyte to macrophage differentiation, and H1R is also predominant in smooth muscle and endothelial cells of atheromatous plaque. Using various animal models of H1/2R-gene knockout mice, H1R and H2R were found to reciprocally but critically regulate not only hypercholesterolemia-induced atherosclerosis and injury-induced arteriosclerosis, but also hyperlipidemia-induced nonalcoholic fatty liver disease (NAFLD). Metabolic syndrome manifests obesity, dyslipidemia, insulin resistance, atherosclerosis, and/or NAFLD, i.e. the dysregulation of lipid/bile acid/glucose metabolism. Therefore, although its etiology is complicated and multifactorial, histamine/HRs signaling has a close relationship with the development of metabolic syndrome. We herein review diverse, key in vivo roles of histamine/HR signaling in the pathogenesis of metabolic syndrome.

Novel function of histamine signaling via histamine receptors in cholesterol and bile acid metabolism: Histamine H2 receptor protects against nonalcoholic fatty liver disease.

We have reported that the function of histamine and its receptors (HRs) has a close relationship with the development of nonalcoholic fatty liver disease (NAFLD). However, much less is known regarding its pathogenic and molecular mechanism(s), including the early stage of hepatic and intestinal function for lipid and bile acid (BA) metabolism. We used H1R and H2R knockout mice (H1/2R-KO) to clarify those pivotal roles in cholesterol/BA metabolism, in which H1/2R-KO mice were separately fed a short-term 1% cholesterol or cholic acid (CA) diet. [(3) H]Cholesterol absorption study revealed that significantly enhanced accumulation occurred in the jejunum, blood and liver, but not in the feces, of H2R-KO mice, compared to wild-type and H1R-KO mice. Furthermore, four weeks after the high-cholesterol diet, the H2R-KO jejunum but not liver exhibited increased expressions of cholesterol transporters, consistent with higher plasma lipoprotein levels. Five days after CA diet, the H2R-KO mice showed significantly higher expressions of ileal BA-reabsorption and hepatic BA-efflux factors, corresponding to higher serum but lower fecal BA levels. The following long-term CA diets resulted in severe injury to the H2R-KO liver. Histamine/H2R signaling might have a protective role in the initial phase during NAFLD progression, correlated with cholesterol and BA metabolism in the liver/intestine.

Polypeptide N-acetylgalactosaminyltransferase-6 expression independently predicts poor overall survival in patients with lung adenocarcinoma after curative resection.

BACKGROUND: Polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts) are important glycosyltransferases in cancer, but the clinical role of its individual isoforms is unclear. We investigated the clinical significance and survival relevance of one isoform, GalNAc-T6 in lung adenocarcinoma after curative resection. RESULTS: GalNAc-T6 was identified in 27.8% (55/198) of patients, and statistically indicated advanced TNM stage (P = 0.069). Multivariate analysis showed GalNAc-T6 to be an independent predictor for reduced overall survival of patients (P = 0.027), and the result was confirmed with bootstraping techniques, and on line "Kaplan-Meier Plotter" and "SurvExpress" database analysis, respectively. Moreover, ROC curve demonstrated that GalNAc-T6 expression significantly improved the accuracy of survival prediction. METHODS: With 198 paraffin-embedded tumor samples from lung adenocarcinoma patients, GalNAc-T6 expression was immunohistochemically assessed for the association with clinicopathological parameters. The prognostic significance was evaluated by Cox proportional hazards regression analysis with 1000 bootstraping. "Kaplan-Meier Plotter", "SurvExpress" database analysis, and receiver-operating characteristic (ROC) curve were performed to provide further validation. CONCLUSIONS: GalNAc-T6 expression correlated significantly with advanced TNM stage, and independently predicted worse OS for lung adenocarcinoma.

Overexpression of Peroxiredoxin 4 Affects Intestinal Function in a Dietary Mouse Model of Nonalcoholic Fatty Liver Disease.

BACKGROUND: Accumulating evidence has shown that methionine- and choline-deficient high fat (MCD+HF) diet induces the development of nonalcoholic fatty liver disease (NAFLD), in which elevated reactive oxygen species play a crucial role. We have reported that peroxiredoxin 4 (PRDX4), a unique secretory member of the PRDX antioxidant family, protects against NAFLD progression. However, the detailed mechanism and potential effects on the intestinal function still remain unclear. METHODS & RESULTS: Two weeks after feeding mice a MCD+HF diet, the livers of human PRDX4 transgenic (Tg) mice exhibited significant suppression in the development of NAFLD compared with wild-type (WT) mice. The serum thiobarbituric acid reactive substances levels were significantly lower in Tg mice. In contrast, the Tg small intestine with PRDX4 overexpression showed more suppressed shortening of total length and villi height, and more accumulation of lipid in the jejunum, along with lower levels of dihydroethidium binding. The enterocytes exhibited fewer apoptotic but more proliferating cells, and inflammation was reduced in the mucosa. Furthermore, the small intestine of Tg mice had significantly higher expression of cholesterol absorption-regulatory factors, including liver X receptor-α, but lower expression of microsomal triglyceride-transfer protein. CONCLUSION: Our present data provide the first evidence of the beneficial effects of PRDX4 on intestinal function in the reduction of the severity of NAFLD, by ameliorating oxidative stress-induced local and systemic injury. We can suggest that both liver and intestine are spared, to some degree, by the antioxidant properties of PRDX4.

Strong expression of polypeptide N-acetylgalactosaminyltransferase 3 independently predicts shortened disease-free survival in patients with early stage oral squamous cell carcinoma.

The polypeptide N-acetylgalactosaminyltransferase (GalNAc-Ts) family of enzymes regulates the critical initial steps of mucin-type O-glycosylation. Among GalNAc-Ts that may significantly influence cancer biology, thus affecting cell differentiation, adhesion, invasion, and/or metastasis, GalNAc-T3 exhibits a high expression in several human cancers, closely associated with tumor progression and a poor prognosis. However, the expression pattern of GalNAc-T3 in oral squamous cell carcinoma (OSCC) remains obscure. Since postoperative recurrence of even early stage OSCC (ESOSCC) occurs at an early phase, significantly affecting their clinical course and worse outcome, the identification of clinically significant accurate biomarkers is needed. Therefore, we investigated the correlation between the immunohistochemical GalNAc-T3 expression and various clinicopathological characteristics and recurrence using 110 paraffin-embedded tumor samples obtained from patients with surgically resected ESOSCC (T1-2N0). Recurrence was recognized in 37 of 110 (33.6 %) patients. The GalNAc-T3 expression was considered to be strongly positive when 20 % or more of the cancer cells showed positive cytoplasmic staining. Consequently, a strong expression of GalNAc-T3 was observed in 40 patients (36.4 %), showing a close relationship to poor differentiation, the presence of lymphatic and vascular invasion, and recurrence. Univariate and multivariate analyses further demonstrated that the patients with a strong GalNAc-T3+ status had markedly lower disease-free survival (DFS) rates, especially within the first 2 years postoperatively. Therefore, GalNAc-T3 might play a role in the pathogenesis of ESOSCC recurrence, and its immunohistochemical detection potentially predicts a shorter DFS and may be a useful parameter for providing clinical management against ESOSCC in the early postoperative phase.

An autopsy case of myocardial infarction due to idiopathic thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder characterized by systemic platelet-von Willebrand factor aggregation, organ ischemia and profound thrombocytopenia. In this report, we describe an autopsy case of a 77-year-old Japanese man diagnosed with idiopathic TTP. He had no history of cardiovascular disease symptoms, such as chest pain, ST segment elevation, and elevation of cardiac enzyme levels, except arrhythmia. The patient suddenly died despite receiving many treatments. On autopsy, macroscopically and microscopically, acute and chronic myocardial infarction manifested as petechiae and fibrotic foci and covered a wide area in the myocardium, including the area near the atrioventricular node. The microthrombi in the small arterioles and capillaries were platelet thrombi, which showed positive results for periodic acid-Schiff stain and factor VIII on immunohistochemical staining. The cause of the sudden death was suspected to be myocardial infarction, including a cardiac conduction system disorder due to multiple platelet microthrombi. Asymptomatic myocardial infarction is an important cause of death in TTP. Therefore, the heart tissue, including the sinus-atrial node and the atrioventricular node, should be microscopically examined more closely in autopsy cases of patients with TTP who experienced sudden death of TTP. This report is a critical teaching case considering that its cause of sudden death may be arrhythmia due to a myocardial infarction including cardiac conduction system disorder by platelet microthrombi. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2113354005156739.

Novel function of histamine signaling in hyperlipidemia-induced atherosclerosis: Histamine H1 receptors protect and H2 receptors accelerate atherosclerosis.

Histamine is not only essential for acute inflammatory reactions, but it also participates in a chronic inflammatory disorder. We generated apolipoprotein E (apoE) and histamine receptors (HHRs), including the major H1 and H2 receptors (HH1R, HH2R) double knockout mice (DKO) to clarify the role of HHRs in hyperlipidemia-induced atherosclerosis, in which apoE-KO and DKO mice were fed a high cholesterol diet. We found that pronounced hyperlipidemia-induced atherosclerotic progression occurred in HH1R/apoE-DKO mice, but in HH2R/apoE-DKO mice less atherosclerosis, despite pro-atherogenic serum cholesterol levels compared with apoE-KO mice. Furthermore, the increased expressions of scavenger receptors (SRs), such as SR-A, CD36 and lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), nuclear factor-kappa B (NFκB), monocyte chemoattractant protein (MCP-1), matrix metalloproteinases (MMPs) or liver X receptor (LXR)-related inflammatory signaling factors, were consistent with the pro-atherogenic phenotype of HH2R/apoE-DKO mice. We hypothesize that histamine/HH1R and HH2R signaling has conflicting innate functions, inflammatory/atherogenic and anti-inflammatory/anti-atherogenic actions, and that there are innate links between histamine signaling and hyperlipidemia-induced atherosclerosis, independently of serum cholesterol metabolism. Specific histamine signaling blockers, in particular, HH2R blockers, are a possible novel therapeutic target for hyperlipidemia-induced atherosclerosis.

The combination of strong immunohistochemical mtTFA expression and a high survivin index predicts a shorter disease-specific survival in pancreatic ductal adenocarcinoma.

Mitochondrial transcription factor A (mtTFA) plays a crucial role in both the transcription and maintenance of mitochondrial DNA. A high expression of mtTFA has been demonstrated in several solid tumors, and is closely associated with cancer cell survival/apoptosis and growth. However, its expression pattern in pancreatic ductal adenocarcinoma (PAC) remains to be elucidated. Additionally, our groups have recently revealed that a subset of apoptosis-related genes is strongly regulated by mtTFA, and that two putative mtTFA binding sites are present in the promoter region of the survivin gene, which is a member of the inhibitor-of-apoptosis protein family. We therefore investigated the correlation of the immunohistochemical mtTFA expression and the survivin index with various clinicopathological variables and the prognosis, using 70 paraffin-embedded tumor samples from patients with surgically-resected PAC. The mtTFA expression or survivin index was considered to be strong or high when ≥30% or 10% of the PAC cells showed positive staining, respectively. Strong mtTFA expression and/or a high survivin index was revealed to have a significant relationship to a pathologically high tumor grading and advanced tumor stage. Moreover, mtTFA showed significantly high co-expression with survivin. Univariate and multivariate analyses demonstrated that both the strong mtTFA expression and high survivin index groups had significantly shorter survival rates, especially within the first two years postoperatively. The combination of strong mtTFA expression and a high survivin index may predict a poor prognosis in patients with PAC, and these new biomarkers might offer useful information for the early clinical management.

CCL22/Macrophage-derived Chemokine Expression in Apolipoprotein E-deficient Mice and Effects of Histamine in the Setting of Atherosclerosis.

AIM: Macrophage-derived chemokine (CCL22) is a member of the CC-family of chemokines synthesized by monocyte-derived macrophages. Previous studies have reported a relationship between CCL22 and atherosclerosis and the role of histamine in this pathway. Histamine ncreases the CCL22 expression in human monocytes via the H2 receptor. In this study, we investigated the effects of CCL22 and the role of histamine in mouse monocytes with respect to atherosclerosis. METHODS AND RESULTS: The expression of CCL22 was investigated in apolipoprotein E (apoE)-deficient mice. The mice had high serum concentrations of CCL22 and their atherosclerotic lesions contained abundant levels of CCL22. In addition, when the mouse monocyte cell line (J774A.1 cells) differentiated into macrophage-like cells, the cells showed a similar expression of CCL22 and reduced expression of H2 receptors. Histamine is synthesized from l-histidine by histidine decarboxylase (HDC) in a single enzymatic step. HDC knockout mice were compared with apoE/HDC double knockout mice. The findings indicated that the expression of CCL22 in atherosclerosis models is under the influence of histamine. In addition, in vitro studies using J774A.1 cells and an in vivo study using histamine receptor knockout mice showed that histamine stimulates the CCL22 expression via the histamine H2 receptor. CONCLUSIONS: The current results support our previous CCL22 studies in the setting of human atherosclerosis and suggest that this molecule is involved in the atherogenic processes in a mouse model of atherosclerosis.