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Wild-type transthyretin cardiac amyloidosis (ATTRwt) has been recognized as an important cause of heart failure with preserved ejection fraction; thus, its accurate diagnosis is crucial. Herein, we describe the case of a 76-year-old man who presented with dyspnea and palpitation. On observing the laboratory evaluations and clinical course, we suspected cardiac amyloidosis. However, optical microscopic analysis by Congo-red and direct fast scarlet staining revealed no amyloid deposits in the biopsy samples. Therefore, a more thorough investigation was pursued by examining the myocardial tissue under electron microscopy. We could recognize amyloid deposits between the myocardial fibers using electron microscopy. We submitted all the pathological specimens to a specialized facility for genetic testing to ensure the accurate diagnosis of the amyloidosis disease type. As a result, a biopsy sample from the minor salivary gland was stained with the Congo red stain. Anti-transthyretin antibody detected using immunohistochemical analysis of amyloidosis supported the presence of transthyretin form of amyloid proteins. Genetic testing revealed the absence of TTR gene mutations. The final diagnosis was ATTRwt. We believe that this case suggests the usefulness of electron microscopy in the diagnosis of ATTRwt and other related disorders. Further study is warranted to validate our findings.

Type 2 diabetes mellitus represents an international health concern with its growing number of patients worldwide. At the same time, excessive salt consumption is also seen as a major cause of diseases such as hypertension and may expedite renal complications in diabetic patients. In this study, we investigated the effects of excessive sodium chloride supplementation on the kidney of the Spontaneously Diabetic Torii-Leprfa (SDT fatty) rat, an obese type 2 diabetes model. Male and female SDT fatty rats and normal Sprague-Dawley (SD) rats at 5 weeks of age were loaded with 0.3% sodium chloride (NaCl) in drinking water for 13 weeks. Blood serum and urinary parameters were observed throughout the experiment and kidney samples were examined in histopathological and genetical analyses. Significant changes on the body weight, blood pressure, urine volume, creatinine clearance, blood urea nitrogen (BUN), relative gene expressions of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), monocyte chemotactic protein-1 (MCP-1) and transforming growth factor-β (TGF-β) were observed in the salt-loaded male SDT fatty rats. Urinary L-type fatty acid-binding protein (L-FABP) and albumin levels were higher observed in the salt-loaded male SDT fatty rats throughout the period, but urinary albumin levels in the female SDT fatty rats remain unchanged. In the kidney, slight Armani-Ebstein changes, tubular degeneration, hyaline cast, and inflammatory cell infiltration were observed in female SDT fatty rats while the levels of some changes were higher in the salt-loaded group. The kidney of the salt-loaded male SDT fatty rats demonstrated a higher degree of lesions compared to the female group and the male unloaded group. Histopathological changes in salt-loaded SDT fatty rats show that excessive salt consumption may act as a diabetic pathology exacerbation factor, but the pathology may be influenced by gender difference. Urinary L-FABP levels may act as a useful biomarker to detect slight tubular damages in the kidney. Excessive salt loading was shown to exacerbate the renal injury in SDT fatty rats.

Aims/introduction To establish novel therapies to combat diabetic kidney disease, a human disease-relevant animal model is essential. However, a type 2 diabetic mouse model presenting progressive kidney fibrosis has not yet been established. Kidneys of streptozotocin-induced diabetic CD-1 mice showed severe fibrosis compared with other backgrounds of mice associated with the suppression of antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline. The BKS background (BKSdb / db ) is often utilized for diabetic kidney disease research; the kidney fibrosis in the BKSdb / db phenotype is minimal. Materials and methods We generated CD-1db / db mice by backcrossing the db gene into the CD-1 background, and analyzed phenotypic differences compared with BKSdb / db and CD-1db / m mice. Results Male CD-1db / db mice appeared to have elevated blood glucose levels compared with those of BKSdb / db mice. Fasting insulin levels declined in CD-1db / db mice. Plasma cystatin C levels tended to be elevated in CD-1db / db mice from 16 to 24 weeks-of-age. Male CD-1db / db mice showed significantly progressive kidney and heart fibrosis from 16 to 24 weeks-of-age when compared with that of age-matched BKSdb / db mice. The gene expression profile showed fibrogenic program-associated genes in male CD-1db / db mice. Male CD-1db / db mice displayed significantly lower urine antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline when compared to that of BKSdb / db at 24 weeks-of-age. The gene expression of prolyl oligopeptidase, the enzyme essential for antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline production from thymosin β4, was significantly lower in the CD-1 mice. Thymosin β4 levels were also lower in CD-1 mice. Conclusions These results suggest that CD-1db / db mice are a novel type 2 diabetic mouse model with progressive kidney and heart fibrosis.

BACKGROUND: Renal proximal tubulopathy plays a crucial role in kidney disease, but its molecular mechanism is incompletely understood. Because proximal tubular cells consume a lot of energy during reabsorption, the relationship between fatty acids (FAs) and proximal tubulopathy has been attracting attention. The purpose of this study is to investigate the association between change in renal FA composition and tubulopathy. METHODS: Mice with cisplatin-induced nephrotoxicity were used as a model of AKI and 5/6-nephrectomized mice were used as a model of CKD. Renal FA composition in mice was measured by GC-MS. Human tubular epithelial cells (HK-2 cells) were used for in vitro studies. RESULTS: In kidneys of AKI mice, increased stearic acid (C18:0) and decreased palmitic acid (C16:0) were observed, accompanied by increased expression of the long-chain FA elongase Elovl6. Similar results were also obtained in CKD mice. We show that C18:0 has higher tubular toxicity than C16:0 via induction of ER stress. Using adenovirus-expressing Elovl6 or siRNA for Elovl6 in HK-2 cells, we demonstrated that increased Elovl6 expression contributes to tubulopathy via increasing C18:0. Elovl6 knockout suppressed the increased serum creatinine levels, renal ER stress, and inflammation that would usually result after 5/6 nephrectomy. Advanced oxidation protein products (AOPPs), specifically an oxidized albumin, was found to induce Elovl6 via the mTORC1/SREBP1 pathway. CONCLUSIONS: AOPPs may contribute to renal tubulopathy via perturbation of renal FAs through induction of Elovl6. The perturbation of renal FAs induced by the AOPPs-Elovl6 system could be a potential target for the treatment of tubulopathy.

A cavotricuspid isthmus pouch can be a breakout site for gap conduction of cavotricuspid isthmus block line. If the previous block line is electrically silent, high‐density 3‐D mapping and pouchgraphy are useful to find the pouch and ablate within it.

Introduction The majority of pulmonary carcinoid (PC) tumors can be cured by surgical resection alone, but a significant proportion of patients experience recurrence. As PC is insensitive to conventional chemotherapy, further clarification of the molecular mechanisms of metastasis is needed in order to develop targeted therapeutics. Methods We performed comprehensive whole-exome sequencing (WES) of primary tumors and corresponding normal lung tissues from 14 PC patients (including 4 patients who developed postsurgical distant metastasis) and RNA sequencing of primary tumors from 6 PC patients (including 4 patients who developed postsurgical distant metastasis). Exon array-based gene expression analysis was performed in 25 cases of PC. Results We identified a total of 139 alterations in 136 genes. MUC6 and SPTA1 were recurrently mutated at a frequency of 21% (3/14) and 14% (2/14), respectively. Mucin protein family genes including MUC2, MUC4 and MUC6 were mutated in a mutually exclusive manner in 36% (5/14). Pathway analysis of the mutated genes revealed enrichment of genes involved in mitogen-activated protein kinase (MAPK) signaling, regulation of the actin cytoskeleton and focal adhesion, and transforming growth factor (TGF)-β signaling. RNA sequencing revealed a total of 8 novel fusion transcripts including one derived from a chromosomal translocation between the TRIB2 and PRKCE genes. All of the 8 fusion genes were detected in primary PCs that had developed metastasis after surgical resection. We identified 14 genes (DENND1B, GRID1, CLMN, DENND1B, NRP1, SEL1L3, C5orf13, TNFRSF21, TES, STK39, MTHFD2, OPN3, MET, and HIST1H3C) up-regulated in 5 PCs that had relapsed after surgical resection. Conclusions In this study we identified novel somatic mutations and chromosomal rearrangements in PC by examining clinically aggressive cases that had developed postsurgical metastasis. It will be essential to validate the clinical significance of these genetic changes in a larger independent patient cohort.

Objectives Because lactate is believed to support tumor growth, monocarboxylate transporters (MCTs), which transport lactate, have been investigated in multiple tumors. However, the significance of MCTs in pancreatic cancer is unclear. Methods A retrospective survey was conducted on 240 patients who underwent surgical resection for pancreatic ductal adenocarcinoma without preoperative treatment. The expression of MCT1, MCT2, MCT3, MCT4, and the glucose transporter 1 (GLUT1) was assessed in tumor cells and cancer-associated fibroblasts (CAFs) by tissue microarrays and immunohistochemistry. The impact of their expression on patient outcome and clinicopathological characteristics was also analyzed. Results In tumor cells, MCT1, MCT2, MCT3, MCT4, and GLUT1 were detected in 52 (22%), 31 (13%), 149 (62%), 204 (85%), and 235 (98%) cases, respectively. In CAFs, MCT2, MCT4, and GLUT1 were detected in 9 (3.8%), 178 (74%), and 36 (15%) cases, respectively. In tumor cells, MCT1 expression was associated with extended overall and progression-free survival and decreased nodal metastasis. Conversely, MCT4 expression in CAFs was associated with shortened survival. Conclusions In tumor cells, MCT1 expression is associated with better prognosis and reduced nodal metastasis in pancreatic cancer, contrary to findings of past in vitro studies. Conversely, MCT4 expression in CAFs is indicative of worse prognosis.

Objectives To study the promotive effect of salt-induced hypertension on crystal deposition and urolithiasis using a salt-sensitive rat hypertension model. Methods Hyperoxaluria and hypercalciuria were induced in male Dahl salt-sensitive rats with administration of ethylene glycol and alfacalcidol. Hypertension was induced by a high-salt diet. Eplerenone, a selective mineralocorticoid receptor antagonist, was given. Blood and urine were collected to evaluate renal function, electrolytes and the blood renin-angiotensin-aldosterone system. Renal calcium content was also evaluated. Histological examination, transcriptome analysis with DNA microarray and semiquantitative reverse transcriptase polymerase chain reaction were carried out. Results A high-salt diet increased crystal deposition in Dahl salt-sensitive rats with hypertension, and eplerenone administration significantly suppressed it. The mRNA expression profile was associated with crystal formation, growth, adhesion and cellular injury, and it was regulated in the group exposed to a high-salt diet and ethylene glycol. Conclusions A high-salt diet has a promotive effect on salt-sensitive hypertension and urolithiasis. This promotive effect can be prevented by eplerenone administration. Hence, salt-sensitive hypertension has promotive effects on crystal deposition in Dahl salt-sensitive rats.

Peroxiredoxin 4 (PRDX4), initially reported as an antioxidant, is overexpressed in lung cancer and participates in its progression. However, its role in the urethane-induced lung tumor model is undetermined. The aim of this study was to investigate the effect of PRDX4 overexpression on carcinogen-induced lung tumor development. Human PRDX4 overexpression transgenic (Tg) mice (hPRDX4+/+) and non-Tg mice were intraperitoneally injected with urethane to induce lung tumor. After 6 months, tumor formation was compared between groups and possible mechanisms for the difference in tumor development were investigated. The serum and lung PRDX4 expressions were enhanced after urethane stimulation in Tg mice. Both the average number of tumors (≥0.5 mm) and tumor diameter per mouse in the Tg group were significantly larger than in non-Tg controls, while body weight was lower in the Tg group. Compared with non-Tg controls, tumor cell proliferation was enhanced, while tumor cell apoptosis was suppressed in Tg mice. Systemic oxidative stress and oxidative stress in lung tumors were inhibited by PRDX4 overexpression. The balance of prooxidant enzymes and antioxidant enzymes was also shifted to a decreased level in Tg tumor. In lung tumor tissue, the density of microvessel penetrated into tumor was higher in the Tg group; macrophage infiltration was enhanced in Tg tumors, while there was no difference in T lymphocyte infiltration; the expressions of cytokines, including interleukin-1 beta (IL-1β) and matrix metallopeptidase 9 (MMP9), were elevated in Tg tumors, which resulted from enhanced phosphorylation of nuclear factor-κB p65 (NF-κB p65) and c-Jun, respectively. In conclusion, PRDX4 overexpression modulated tumor microenvironment and promoted tumor development in the mouse urethane-induced lung cancer model.

Axon regeneration is limited in the central nervous system, which hinders the reconstruction of functional circuits following spinal cord injury (SCI). Although various extrinsic molecules to repel axons following SCI have been identified, the role of semaphorins, a major class of axon guidance molecules, has not been thoroughly explored. Here we show that expression of semaphorins, including Sema5a and Sema6d, is elevated after SCI, and genetic deletion of either molecule or their receptors (neuropilin1 and plexinA1, respectively) suppresses axon retraction or dieback in injured corticospinal neurons. We further show that Olig2+ cells are essential for SCI-induced semaphorin expression, and that Olig2 binds to putative enhancer regions of the semaphorin genes. Finally, conditional deletion of Olig2 in the spinal cord reduces the expression of semaphorins, alleviating the axon retraction. These results demonstrate that semaphorins function as axon repellents following SCI, and reveal a novel transcriptional mechanism for controlling semaphorin levels around injured neurons to create zones hostile to axon regrowth.

The biological influence of antidiabetic drugs on cancer cells and diabetic cancer patients has not yet been completely elucidated. We reported that a dipeptidyl peptidase (DPP)-4 inhibitor accelerates mammary cancer metastasis by inducing epithelial–mesenchymal transition (EMT) through the CXCL12/CXCR4/mTOR axis. Metformin has been shown to inhibit the mTOR signaling pathway. In this study, we investigated whether metformin mitigates breast cancer metastasis induced by a DPP-4 inhibitor via suppression of mTOR signaling. In cultured mouse mammary and human breast cancer cells, metformin suppressed DPP-4 inhibitor KR62436 (KR)-induced EMT and cell migration via suppression of the mTOR pathway associated with AMPK activation. For the in vivo study, metformin intervention was performed in an allograft 4T1 breast cancer model mouse with or without KR. We also analyzed mice transplanted with shRNA-mediated DPP-4 knockdown 4T1 cells. Treatment with metformin inhibited the lung metastasis of DPP-4–deficient 4T1 mammary tumor cells generated by either KR administration or DPP-4 knockdown. Immunostaining of primary tumors indicated that DPP-4 suppression promoted the expression of EMT-inducing transcription factor Snail through activation of the CXCR4-mediated mTOR/p70S6K pathway in an allograft breast cancer model; metformin abolished this alteration. Metformin treatment did not alter DPP-4–deficiency-induced expression of CXCL12 in either plasma or primary tumors. Our findings suggest that metformin may serve as an antimetastatic agent by mitigating the undesirable effects of DPP-4 inhibitors in patients with certain cancers. Implications: Metformin could combat the detrimental effects of DPP-4 inhibitor on breast cancer metastasis via mTOR suppression, suggesting the potential clinical relevance. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/19/1/61/F1.large.jpg.

Anticoagulation therapy is essential for preventing thrombus formation in the left atrial appendage (LAA) and subsequent ischemic strokes in patients with atrial fibrillation (AF). The complete disappearance of any existing LAA thrombi is crucial before AF ablation. Currently, warfarin and direct oral anticoagulants are widely used for this purpose. However, treatment strategies for anticoagulation-resistant LAA thrombi are not well established. Here, we present a case of an 85-year-old male who was scheduled to undergo AF ablation. He developed an LAA thrombus that was resistant to 300 mg/day of dabigatran. Low-dose pimobendan was prescribed in addition to dabigatran; three months later, the thrombus was dissolved successfully. This case demonstrates the potential efficacy of a low-dose oral inotrope for treating an anticoagulation-resistant LAA thrombus.

The Shumiya cataract rat (SCR) is a model for hereditary cataract. Two-third of these rats develop lens opacity within 10-11-weeks. Onset of cataract is attributed to the synergetic effect of lanosterol synthase (Lss) and farnesyl-diphosphate farnesyltransferase 1 (Fdft1) mutant alleles that lead to cholesterol deficiency in the lenses, which in turn adversely affects lens biology including the growth and differentiation of lens epithelial cells (LECs). Nevertheless, the molecular events and changes in gene expression associated with the onset of lens opacity in SCR is poorly understood. In the present study, a microarray-based approach was employed to analyze comparative gene expression changes in LECs isolated from the pre-cataractous and cataractous stages of lenses of 5-, 8- and 10-week-old SCRs. The changes in gene expression observed in microarray results in the LECs were further validated using real-time PCR and western blot analyses. Lens opacity was not observed in 5-week-old rats. However, histological analysis revealed mild dysplasia in the anterior suture and poorly differentiated fiber cells at the bow region. Expression of approximately 100 genes, including major intrinsic protein of lens fiber (MIP and Aquaporin0), deoxyribonuclease II beta (Dnase2b), heat shock protein B1 (Hspb1), and crystallin γ (γCry) B, C, and F were found to be significantly downregulated (0.07-0.5 fold) in rat LECs derived from cataract lenses compared to that in noncataractous lenses (control). Thus, our study aimed to identify the gene expression patterns during cataract formation in SCRs, which may be responsible for cataractogenesis in SCR. We proposed that mutation in lanosterol synthase was responsible for the downregulation of genes associated with lens fiber differentiation, which in turn leads to the formation of cataract in these rats. Our findings may have wider implications in understanding the effect of cholesterol deficiency and the role of cholesterol-lowering therapeutics on cataractogenesis.

Renal fibrosis is a major factor in the progression of chronic kidney disease and the final common pathway of kidney injury. Therefore, the effective therapies against renal fibrosis are urgently needed. The objective of this study was to investigate the effect of Am80, a synthetic retinoic acid receptor (RAR) agonist, in the treatment of renal interstitial fibrosis using unilateral ureteral obstruction (UUO) mice. The findings indicate that Am80 treatment suppressed renal fibrosis and inflammation to the same degree as the naturally-occuring retinoic acid, all-trans retinoic acid (atRA). But the adverse effect of body weight loss in Am80-treated mice was lower compared to the atRA treatment. The hepatic mRNA levels of alpha-1-acid glycoprotein (AGP), a downstream molecule of RAR agonist, was increased following administration of Am80 to healthy mice. In addition, increased AGP mRNA expression was also observed in HepG2 cells and THP-1-derived macrophages that had been treated with Am80. AGP-knockout mice exacerbated renal fibrosis, inflammation and macrophage infiltration in UUO mice, indicating endogenous AGP played an anti-fibrotic and anti-inflammatory role during the development of renal fibrosis. We also found that no anti-fibrotic effect of Am80 was observed in UUO-treated AGP-knockout mice whereas atRA treatment tended to show a partial anti-fibrotic effect. These collective findings suggest that Am80 protects against renal fibrosis via being involved in AGP function.

E-cadherin is a main cell-to-cell adhesion molecule. A negative expression of E-cadherin correlates with distant metastasis in lung cancer. Recently, it was reported that there is an association between FDG uptake on PET and epithelial-mesenchymal transition (EMT) in non-small cell lung cancer. Downregulation of E-cadherin is one of the best markers of EMT. The purpose of this study was to compare E-cadherin expression with FDG uptake on PET, cell differentiation, aggressiveness and post-operative recurrence in patients with lung adenocarcinoma, and to investigate whether FDG uptake on PET is associated with E-cadherin expression. We retrospectively reviewed 40 lung adenocarcinoma patients who underwent thoracotomy and FDG PET before thoracotomy. These patients were evaluated FDG PET metrics such as standardized uptake value (SUV), the immunohistochemical expression of E-cadherin in surgical specimens, clinicopathological features, including tumor size, pathologic stage, cell differentiation, aggressiveness and post-operative recurrence. High FDG uptake correlated with negative E-cadherin expression (P = 0.043). SUVmax was higher in a negative E-cadherin expression lung adenocarcinoma than in a positive E-cadherin expression lung adenocarcinoma (P = 0.033). Patients with moderately poorly differentiated adenocarcinoma had frequent negative E-cadherin expression or high FDG uptake (P = 0.004, P = 0.0001, respectively). Patients with aggressive adenocarcinoma had frequent negative E-cadherin expression or high FDG uptake (P = 0.004, P = 0.001, respectively). Kaplan–Meier analysis revealed that negative E-cadherin expression or high FDG uptake were strongly correlated with shortened disease-free survival (P = 0.0153, P = 0.0001, respectively). High FDG uptake on PET was associated with negative E-cadherin expression in patients with lung adenocarcinoma. Both high FDG uptake and negative E-cadherin expression were strongly correlated with poor differentiation, aggressiveness, and post-operative recurrence. These findings may cause the association between high FDG uptake and negative E-cadherin expression.

Cancer patients often develop mental conditions, including anxiety and depressive disorder. And, patients with chemotherapy often exhibit mental changes including anxiety and depressive disorder. Furthermore, it is well known that the frequency of delirium is increased in cancer patients receiving terminal care. Thus, the psychiatric and cognitive functions of cancer survivors are significantly influenced by their quality of life. In this study, we performed a retrospective analysis to identify the risk factors for psychiatric disorders in lung cancer survivors. Most lung cancer survivors that were diagnosed with psychiatric disorders had stage 4 disease. In addition, it was found that an increase in disease stage and high doses of opioids are associated with an increased risk of psychiatric disorders in lung cancer survivors. These findings suggest that it is necessary to consider the mental changes experienced by lung cancer patients during disease progression.

Background: The prognosis of elderly patients with acute myeloid leukemia (AML) remains poor. Elderly patients are frequently intolerant to intensive chemotherapy due to poor performance status and co-morbidities. Moreover, considering the increase of genetic abnormalities, it is disputable whether conventional chemotherapy improves the prognosis of elderly AML patients. The purpose of this study is to identity patients who would benefit from conventional chemotherapy. Patients and Methods: We retrospectively analyzed the outcome of patients with AML aged over 65 years who received conventional chemotherapy based on the JALSG GML 200 protocol at our institution between December 2011 and January 2020. Patients with acute promyelocytic leukemia were excluded. No patients underwent hematopoietic cell transplantation (HCT). Dose reduction of each regimen was considered in patients over 70 years of age. MEC regimen was used for reinduction therapy in 70% of patients with induction failure. The primary end point was overall survival (OS) after induction therapy. Factors associated with the achievement of complete remission (CR) and overall mortality were analyzed using logistic regression and Cox proportional hazards models, respectively. Results: A total of 74 patients were analyzed. The median age was 72.8 years (range, 65-85). Nine patients (12%) had an ECOG performance status of 3-4. The most common AML subtype was AML with myelodysplasia-related changes (n=30, 41%) followed by AML with maturation (n=11, 15%). Twenty patients (27%) were previously diagnosed with myelodysplastic syndromes (MDS). According to the 2017 ELN stratification, 3 patients (4%) were classified as favorable-risk, 44 (60%) as intermediate-risk, and 27 (37%) as adverse-risk. Overall, 21 patients (28%) achieved CR after induction therapy. Among 53 patients with induction failure, 37 received reinduction therapy and 14 (38%) achieved CR. The ELN favorable- or intermediate-risk (OR, 23.2; 95% CI, 4.59-117.0, p Conclusions: Each two patient (age, performance status) and disease (ELN disease risk, history of MDS) factors were significantly associated with survival in elderly patients with AML. The prognostic scoring system based on the four factors clearly stratified survival, suggesting that it will be useful for making a treatment decision. Further large-scale studies are required to validate this system and a combination therapy with molecular targeted drugs should be established for patients with poor prognosis. Disclosures Seo: Janssen Pharmacuetical K.K.: Consultancy; Novartis: Speakers Bureau; Bristol Myers Squibb K.K.: Speakers Bureau; Meiji Seika Pharma.: Speakers Bureau. Ichikawa:Novartis, Takeda: Honoraria. Mitani:KYOWA KIRIN: Consultancy, Research Funding; CHUGAI: Research Funding; Takeda: Research Funding.

To the editor: Chronic myeloid leukemia (CML) represents a distinct subtype of myeloproliferative neoplasm originated from a deregulated hematopoietic stem cell, in which a constitutively activated breakpoint cluster region-Abelson (BCR-ABL) fusion kinase plays a crucial role.[1][1] Although its

BACKGROUND The correlation of the growth hormone (GH) and insulin-like growth factor-1 (IGF-1) with non-alcoholic fatty liver disease (NAFLD) has been reported in epidemiological studies. However, the mechanisms of molecular and inter-organ systems that render these factors to influence on NAFLD have not been elucidated. In this study, we examined the induction of ghrelin which is the GH-releasing hormone and IGF-1, and involvement of autonomic neural circuits, in the pathogenesis of NAFLD. METHODS The expression of gastric and hypothalamic ghrelin, neural activation in the brain, and serum IGF-1 were examined in NAFLD models of choline-deficient defined l-amino-acid diet-fed, melanocortin 4 receptor knockout mice, and partial hepatectomy mice with or without the blockades of autonomic nerves to test the contribution of neural circuits connecting the brain, liver, and stomach. KEY RESULTS The fatty changes in the liver increased the expression of gastric ghrelin through the autonomic pathways which sends the neural signals to the arcuate nucleus in the hypothalamus through the afferent vagal nerve which reached the pituitary gland to release GH and then stimulate the IGF-1 release from the liver. In addition, high levels of ghrelin expression in the arcuate nucleus were correlated with NAFLD progression regardless of the circuits. CONCLUSIONS Our study demonstrated that the fatty liver stimulates the autonomic nervous signal circuits which suppress the progression of the disease by activating the gastric ghrelin expression, the neural signal transduction in the brain, and the release of IGF-1 from the liver.

Fibroblasts are the commonest type of cancer stromal cells. Inflammation occurs in cancer tissue, and the inflammatory process has been suggested to be caused by interactions between immune cells and cancer cells. In this study, we clarified that site-specific fibroblasts regulate the formation of a site-specific inflammatory niche according to the depth of gastric cancer cell invasion. Immunohistochemistry was performed with paraffin-embedded tissues. The numbers of immune cells and the fibroblast area were calculated according to the cancer depth. The gene expression patterns of submucosal fibroblasts and subperitoneal fibroblasts stimulated with HSC44PE-conditioned medium were analyzed with a microarray. To examine the effects on the cancer microenvironment of differences in gene expressions between HSC44PE-stimulated submucosal fibroblasts and subperitoneal fibroblasts, assays of HSC44PE proliferation, T cell migration, and M2-like macrophage differentiation were performed. The distributions of immune cells differed between the submucosal layer and the subserosal layer. The number of M2 macrophages was significantly higher and the fibroblast area was significantly larger in the subserosal layer compared with the submucosal layer. High expression levels of IL1B, TNFSF15, and CCL13 were observed in HSC44PE-stimulated submucosal fibroblasts, and higher expression levels of TGFB2, CSF1, CCL8, and CXCL5 were found in HSC44PE-stimulated subperitoneal fibroblasts. HSC44PE-stimulated subperitoneal fibroblast medium promoted the differentiation of monocytes into M2-like macrophages, whereas HSC44PE-stimulated submucosal fibroblasts significantly induced the migration of Jurkat cells and the growth of HSC44PE cells. The dynamic states of immune cells differ between the submucosal and subserosal layers in cancer tissues. Site-specific fibroblasts regulate site-specific inflammatory niche formation according to the depth of cancer cell invasion.

The RUNX1-EVI1 gene generated by the t(3;21) translocation encodes a chimeric transcription factor and is a causative gene in the development of de novo acute megakaryoblastic leukemia and leukemic transformation of hematopoietic stem cell tumors. Heterozygous RUNX1-EVI1 knock-in mice die in utero due to hemorrhage in the central nervous system and spinal cord and complete abolishment of definitive hematopoiesis in the fetal liver. On the other hand, the chimeric knock-in mouse develops acute megakaryoblastic leukemia. We created another mouse model of RUNX1-EVI1 using transplantation of retrovirus-infected bone marrow cells. Some mice transplanted with RUNX1-EVI1-expressing bone marrow cells developed acute megakaryoblastic leukemia within eight months, and the other non-leukemic mice showed thrombocytosis at around a year. In the non-leukemic mice, dysplastic megakaryocytes proliferated in the bone marrow and frequently infiltrated into the spleen, which was not associated with marrow fibrosis. In the leukemic mice, their tumor cells were positive for c-kit and CD41, and negative for TER119. Although they were negative for platelet peroxidase in the electron microscopic analysis, they had multiple centrioles in the cytoplasm, which are characteristic of megakaryocytes that undergo endomitosis. The leukemic cells were serially transplantable, and gene-expression analyses using quantitative RT-PCR arrays revealed that they showed significantly elevated expression of stem cell, primitive hematopoietic cell and endothelial cell-related genes compared with normal bone marrow cells. All these data suggested that RUNX1-EVI1 caused dysplastic hematopoiesis or leukemia of the megakaryocytic lineage and endowed gene expression profiles distinctive of immature hematopoietic cells.

Sorafenib is a multi-kinase inhibitor that has been proven effective for the treatment of unresectable hepatocellular carcinoma (HCC). However, its precise mechanisms of action and resistance have not been well established. We have developed high-density fluorescence reverse-phase protein arrays and used them to determine the status of 180 phosphorylation sites of signaling molecules in the 120 pathways registered in the NCI-Nature curated database in 23 HCC cell lines. Among the 180 signaling nodes, we found that the level of ribosomal protein S6 phosphorylated at serine residue 235/236 (p-RPS6 S235/236) was most significantly correlated with the resistance of HCC cells to sorafenib. The high expression of p-RPS6 S235/236 was confirmed immunohistochemically in biopsy samples obtained from HCC patients who responded poorly to sorafenib. Sorafenib-resistant HCC cells showed constitutive activation of the mammalian target of rapamycin (mTOR) pathway, but whole-exon sequencing of kinase genes revealed no evident alteration in the pathway. p-RPS6 S235/236 is a potential biomarker that predicts unresponsiveness of HCC to sorafenib. The use of mTOR inhibitors may be considered for the treatment of such tumors.

N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is an endogenous antifibrotic peptide. We found that suppression of AcSDKP and induction of dipeptidyl peptidase-4 (DPP-4), which is associated with insufficient levels of antifibrotic microRNA (miR)s in kidneys, were imperative to understand the mechanisms of fibrosis in the diabetic kidneys. Analyzing streptozotocin (STZ)-induced diabetic mouse strains, diabetic CD-1 mice with fibrotic kidneys could be differentiated from less-fibrotic diabetic 129Sv mice by suppressing AcSDKP and antifibrotic miRs (miR-29s and miR-let-7s), as well as by the prominent induction of DPP-4 protein expression/activity and endothelial to mesenchymal transition. In diabetic CD-1 mice, these alterations were all reversed by AcSDKP treatment. Transfection studies in culture endothelial cells demonstrated crosstalk regulation of miR-29s and miR-let-7s against mesenchymal activation program; such bidirectional regulation could play an essential role in maintaining the antifibrotic program of AcSDKP. Finally, we observed that AcSDKP suppression in fibrotic mice was associated with induction of both interferon-γ and transforming growth factor-β signaling, crucial molecular pathways that disrupt antifibrotic miRs crosstalk. The present study provides insight into the physiologically relevant antifibrotic actions of AcSDKP via antifibrotic miRs; restoring such antifibrotic programs could demonstrate potential utility in combating kidney fibrosis in diabetes.

Hypoxia is a key element involved in the development and progression of tumors. HIF-1α may transiently induce and mediate the response to acute and severe hypoxia, while HIF-2α may induce a longer response and may control the response to chronic and moderate hypoxia. Hypoxia increases the cellular uptake of FDG. Therefore, HIF may play an important role in the process of the cellular uptake of FDG. The aim of this study was to compare HIF-1α/HIF-2α expression with FDG uptake, Glut-1 expression, and prognosis in the patients with lung adenocarcinoma and to investigate the role of HIF-1α/HIF-2α in the uptake of FDG in lung adenocarcinoma. In the current work, we compared the immunohistochemical expression of HIF-1α and HIF-2α in surgical specimens of 44 patients with lung adenocarcinoma. The relationships between HIF-α expression and Glut-1 expression, FDG uptake, and clinicopathological factors, including prognosis, were analyzed. There was a marginal association between HIF-1α and HIF-2α expressions (P = 0.076). We found a significant correlation between HIF-2α expression and FDG uptake (P = 0.0001). HIF-1α expression showed a marginal association with FDG uptake (P = 0.066). FDG uptake correlated more significantly with HIF-2α expression than with HIF-1α expression. A significant correlation was noticed between Glut-1 expression and both HIF-1α and HIF-2α expressions (P = 0.005 and P = 0.003, respectively). Univariate analysis of disease-free survival demonstrated that FDG uptake and HIF-2α expression, but not HIF-1α expression, were related to recurrence (P

Background A closed chamber evaporimeter is suitable for measuring transepidermal water loss (TEWL) in cats because of the compact device size, tolerance to sudden movement and short measuring time. TEWL is a representative parameter for skin barrier dysfunction, which is one of the clinical signs of atopic dermatitis in humans and dogs. Measurement of feline TEWL has been reported, but applicability of this parameter has not been validated. Hypothesis/Objectives The aims of this study were to determine if tape stripping is a valid experimental model in cats for studying TEWL and to determine if a closed chambered system is a suitable measurement tool for cats. Animals Ten clinically normal cats. Methods In order to evaluate variation of the measured values, TEWL was measured at the right and left side of the three clipped regions (axillae, lateral thigh and groin). Subsequently, TEWL was measured using sequential tape stripping of the stratum corneum as a model of acute barrier disruption. Results The variations between both sides of the three regions showed no significant difference. Sequential tape stripping was associated with increasing values for TEWL. Conclusions and clinical importance Feline TEWL was shown to reflect changes in the skin barrier in an experimental model using a closed chamber system and has the potential for evaluating skin barrier function in cats with skin diseases.

In multiple sclerosis, activated CD4(+) T cells initiate an immune response in the brain and spinal cord, resulting in demyelination, degeneration and progressive paralysis. Repulsive guidance molecule-a (RGMa) is an axon guidance molecule that has a role in the visual system and in neural tube closure. Our study shows that RGMa is expressed in bone marrow-derived dendritic cells (BMDCs) and that CD4(+) T cells express neogenin, a receptor for RGMa. Binding of RGMa to CD4(+) T cells led to activation of the small GTPase Rap1 and increased adhesion of T cells to intracellular adhesion molecule-1 (ICAM-1). Neutralizing antibodies to RGMa attenuated clinical symptoms of mouse myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) and reduced invasion of inflammatory cells into the CNS. Silencing of RGMa in MOG-pulsed BMDCs reduced their capacity to induce EAE following adoptive transfer to naive C57BL/6 mice. CD4(+) T cells isolated from mice treated with an RGMa-specific antibody showed diminished proliferative responses and reduced interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-4 and IL-17 secretion. Incubation of PBMCs from patients with multiple sclerosis with an RGMa-specific antibody reduced proliferative responses and pro-inflammatory cytokine expression. These results demonstrate that an RGMa-specific antibody suppresses T cell responses, and suggest that RGMa could be a promising molecular target for the treatment of multiple sclerosis.

Myelin components that inhibit axonal regeneration are believed to contribute significantly to the lack of axonal regeneration noted in the adult central nervous system. Three proteins found in myelin, Nogo, myelin-associated glycoprotein, and oligodendrocyte-myelin glycoprotein, inhibit neurite outgrowth in vitro. All of these proteins interact with the same receptors, namely, the Nogo receptor (NgR) and paired immunoglobulin-like receptor B (PIR-B). As per previous reports, corticospinal tract (CST) regeneration is not enhanced in NgR-knock-out mice after spinal cord injury. Therefore, we assessed CST regeneration in PIR-B-knock-out mice. We found that hindlimb motor function, as assessed using the Basso mouse scale, footprint test, inclined plane test, and beam walking test, did not differ between the PIR-B-knock-out and wild-type mice after dorsal hemisection of the spinal cord. Further, tracing of the CST fibers after injury did not reveal enhanced axonal regeneration or sprouting in the CST of the PIR-B-knock-out mice. Systemic administration of NEP1–40, a NgR antagonist, to PIR-B knock-out mice did not enhance the regenerative response. These results indicate that PIR-B knock-out is not sufficient to induce extensive axonal regeneration after spinal cord injury.

Accumulating evidence indicates that oxidative stress plays a critical role in initiating the progression of inflammatory and fibrotic liver diseases, including cholestatic hepatitis. Peroxiredoxin 4 (PRDX4) is a secretory antioxidase that protects against oxidative damage by scavenging reactive oxygen species (ROS) in both the intracellular compartments and extracellular space. In this study, we examined the in vivo net effects of PRDX4 overexpression in a murine model of cholestasis. To induce cholestatic liver injury, we subjected C57BL/6J wild-type (WT) or human PRDX4 (hPRDX4) transgenic (Tg) mice to sham or bile duct ligation (BDL) surgery for seven days. Our results showed that the liver necrosis area was significantly suppressed in Tg BDL mice with a reduction in the severity of liver injuries. Furthermore, PRDX4 overexpression markedly reduced local and systemic oxidative stress generated by BDL. In addition, suppression of inflammatory cell infiltration, reduced proliferation of hepatocytes and intrahepatic bile ducts, and less fibrosis were also found in the liver of Tg BDL mice, along with a reduced mortality rate after BDL surgery. Interestingly, the composition of the hepatic bile acids (BAs) was more beneficial for Tg BDL mice than for WT BDL mice, suggesting that PRDX4 overexpression may affect BA metabolism during cholestasis. These features indicate that PRDX4 plays an important role in protecting against liver injury following BDL and might be a promising therapeutic modality for cholestatic diseases.

The Barthel Index (BI) cannot be used to measure initial stroke severity or by extension, to stratify patients by severity in acute stroke trials because most patients are bedbound in the first few hours after stroke, either by their deficit or by medical direc- tive. Our objectives were to clarify the threshold of acute BI for use in the prediction of subsequent independence in activities of daily living (ADL) and to assist in the defini- tion of acute stroke rehabilitation goals. Subjects comprised 78 patients out of 191 inpa- tients admitted with acute stroke at our hospital during 2006-2007. The BI ADL score was divided into 2 ranges (BI 60 and 40), in a process similar to previous studies. During the acute period (from onset to approximately 3 weeks), all patients with a BI 40 could im- prove their ADL in 6 months. Patients with a BI 40 exhibited two ADL recovery out- comes (improved and no change) at 6 months. We also found that the skill level of basic activities related to standing was significant indicator of BI improvement (P

Common molecular machineries between hematopoietic stem cell (HSC) maintenance and leukemia prevention have been highlighted. The tumor suppressor Fbxw7 (F-box and WD-40 domain protein 7), a subunit of an SCF-type ubiquitin ligase complex, induces the degradation of positive regulators of the cell cycle. We demonstrate that inactivation of Fbxw7 in hematopoietic cells causes premature depletion of HSCs due to active cell cycling and p53-dependent apoptosis. Interestingly, Fbxw7 deletion also confers a selective advantage to cells with suppressed p53 function, eventually leading to development of T-cell acute lymphoblastic leukemia (T-ALL). Thus, Fbxw7 functions as a fail-safe mechanism against both premature HSC loss and leukemogenesis.

Corrigendum: Ecto-domain phosphorylation promotes functional recovery from spinal cord injury

Dermatophytosis, cryptococcosis and sporotrichosis are dermatological zoonosis caused by fungi. Control of dermatophytosis is still difficult, although it is well known as a transmittable disease from animal to human. Exotic animals such as hamster, guinea pig and rabbit, some imported from foreign countries, have become a frequent source of human dermatophytosis, and the emergence of fungal pathogens followed. The nasal cavity of dogs and cats is an important reservoir of pathogens of cryptococcosis, in addition to bird droppings. Though there have been many reports of human sporotrichosis caused by patients' pet, especially cats in Europe and U.S., since there has been no report of zoonotic transmission of sporotrichosis, zoonosis is not believed do be present in Japan. The interrelation and cooperation of medical and veterinary doctors and all other scientists involved is therefore required to prevent fungal zoonosis, because the condition may be partly due to changes in the environments of human and animal life and the more intimate relationships between humans and animals.

Inhibition of Nogo-66 receptor (NgR) can promote recovery following spinal cord injury. The ecto-domain of NgR can be phosphorylated by protein kinase A (PKA), which blocks activation of the receptor. Here, we found that infusion of PKA plus ATP into the damaged spinal cord can promote recovery of locomotor function. While significant elongation of cortical-spinal axons was not detectable even in the rats showing enhanced recovery, neuronal precursor cells were observed in the region where PKA plus ATP were directly applied. NgR1 was expressed in neural stem/progenitor cells (NSPs) derived from the adult spinal cord. Both an NgR1 antagonist NEP1-40 and ecto-domain phosphorylation of NgR1 promote neuronal cell production of the NSPs, in vitro. Thus, inhibition of NgR1 in NSPs can promote neuronal cell production, which could contribute to the enhanced recovery of locomotor function following infusion of PKA and ATP.

Kidney fibrosis is the final common pathway of all progressive chronic kidney diseases, of which diabetic nephropathy is the leading cause. Endothelial-to-mesenchymal transition (EndMT) has emerged as one of the most important origins of matrix-producing fibroblasts. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been introduced into the market as antidiabetes drugs. Here, we found that the DPP-4 inhibitor linagliptin ameliorated kidney fibrosis in diabetic mice without altering the blood glucose levels associated with the inhibition of EndMT and the restoration of microRNA 29s. Streptozotocin-induced diabetic CD-1 mice exhibited kidney fibrosis and strong immunoreactivity for DPP-4 by 24 weeks after the onset of diabetes. At 20 weeks after the onset of diabetes, mice were treated with linagliptin for 4 weeks. Linagliptin-treated diabetic mice exhibited a suppression of DPP-4 activity/protein expression and an amelioration of kidney fibrosis associated with the inhibition of EndMT. The therapeutic effects of linagliptin on diabetic kidneys were associated with the suppression of profibrotic programs, as assessed by mRNA microarray analysis. We found that the induction of DPP-4 observed in diabetic kidneys may be associated with suppressed levels of microRNA 29s in diabetic mice; linagliptin restored microRNA 29s and suppressed DPP-4 protein levels. Using cultured endothelial cells, we found that linagliptin inhibited TGF-β2–induced EndMT, and such anti-EndMT effects of linagliptin were mediated through microRNA 29 induction. These results indicate the possible novel pleiotropic action of linagliptin to restore normal kidney function in diabetic patients with renal impairment.

Endothelial-to-mesenchymal transition (EndMT) emerges as an important source of fibroblasts. MicroRNA let-7 exhibits anti-EndMT effects and fibroblast growth factor (FGF) receptor has been shown to be an important in microRNA let-7 expression. The endogenous antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is a substrate of angiotensin-converting enzyme (ACE). Here, we found that AcSDKP inhibited the EndMT and exhibited fibrotic effects that were associated with FGF receptor-mediated anti-fibrotic program. Conventional ACE inhibitor plus AcSDKP ameliorated kidney fibrosis and inhibited EndMT compared to therapy with the ACE inhibitor alone in diabetic CD-1 mice. The endogenous AcSDKP levels were suppressed in diabetic animals. Cytokines induced cultured endothelial cells into EndMT; coincubation with AcSDKP inhibited EndMT. Expression of microRNA let-7 family was suppressed in the diabetic kidney; antifibrotic and anti-EndMT effects of AcSDKP were associated with the restoration of microRNA let-7 levels. AcSDKP restored diabetes- or cytokines-suppressed FGF receptor expression/phosphorylation into normal levels both in vivo and in vitro. These results suggest that AcSDKP is an endogenous antifibrotic molecule that has the potential to cure diabetic kidney fibrosis via an inhibition of the EndMT associated with the restoration of FGF receptor and microRNA let-7.

Sporothrix schenckii is pathogenic to human and animals. To detect S. schenckii in the tissue, we designed specific oligonucleotide primers based on the chitin synthase gene. Amplification products were selectively obtained from S. schenckii DNA. Polymerase chain reaction analysis with the primer pair S2-R2 was able to detect 10 pg genomic DNA of S. schenckii with ethidium bromide staining. This detection system will be useful as a microbiological tool for the diagnosis of human and animal sporotrichosis.

Yeasts of Malassezia , members of the microbiologic flora of the skin, cause pityriasis versicolor and have also been implicated in the pathogenesis of other superficial dermatoses; the most important ones are seborrheic dermatitis, folliculitis, and atopic dermatitis. The mechanisms by which the yeasts cause these dermatoses¸ however, are not yet clear, and there have been no studies on the interaction between fungi and keratinocytes, especially the effects of fungi on the production of cytokines by human keratinocytes. Recently, the genus Malassezia has been expanded to seven species based on molecular data. In this study, we estimated the effects of Malassezia yeasts on cytokine (interleukins 1β, 6, and 8, monocyte chemotactic protein-1, and tumor necrosis factor-α) production by human keratinocytes in order to examine whether the pathogenicity of the respective Malassezia yeasts is different from each other and to elucidate the mechanism by which Malassezia yeasts cause the dermatoses with different clinical and pathologic manifestations. Variable levels of interleukin 6 and 8, and tumor necrosis factor-α in the supernatants in response to Malassezia yeasts (except M. furfur ) increased from 1 to 24 h co-culture, but the monocyte chemotactic protein-1 was undetectable. Furthermore, cytokine levels in the supernatants were undetectable 1–24 h after the keratinocytes were harvested with only supernatants of Malassezia . These results indicate that Malassezia stimulates cytokine production by keratinocytes, the cytokine production needs the presence of Malassezia , and there are differences in ability to induce cytokine production by human keratinocytes among Malassezia yeasts. These differences may reflect the different inflammatory responses in Malassezia -associated dermatoses, resulting in different clinical and pathologic manifestations.

Ten free-ranging female sika deer (Cervus nippon) were captured to obtain the reference values for acid-base status and blood gas when immobilized with the combination of medetomidine and ketamine. The mean +/- SE of PaCO2, PaO2, and HCO3- were 58.1 +/- 6.1 mmHg, 58.8 +/- 6.4 mmHg, and 36.0 +/- 4.4 mmol/l, respectively. Although acidosis and alkalosis occurred in three and two animals, respectively, no serious conditions were observed. The blood values, however, suggest that some degree of hypoxemia and respiratory acidosis with metabolic alkalosis are developed. The trapped deer showed a significantly higher than normal rectal temperature reflective of exertion.

We report 2 cases with acute brainstem and brainstem-cerebellar infarction showed improvement of their signs and symptoms after administration of edaravone. Case 1, a 74-year-old woman who experienced sudden vertigo, also had dysarthria and left hemiplegia. Magnetic resonance imaging (MRI) showed an abnormal region in the right ventrolateral medulla oblongata. The patient's vertigo and hemiplegia improved completely after treatment. Case 2, a 50-year-old man who experienced sudden vertigo and sensorineural hearing loss (SNHL), developed dysarthria after admission. MRI revealed acute infarction in the right cerebellar hemisphere. Magnetic resonance angiography revealed dissection of the basilar artery and occlusion of the right anterior inferior cerebellar artery. The patient's vertigo and hearing remarkably improved. We have described 2 patients whose early symptoms were vertigo and sudden SNHL, but who were later shown to have ischemic lesions of the central nervous system. Edaravone is neuroprotective drug with free radical-scavenging actions. Free radicals in the ear are responsible for ischemic damage. Edaravone, a free radical scavenger, may be useful in the treatment of vertigo and SNHL.

Aberrant expression of MIR9 predicts a poor prognosis in acute myelogenous leukemia. To evaluate its clinical significance in acute lymphoblastic leukemia, we analyzed expression levels of MIR9 in bone marrow samples from patients with acute lymphoblastic leukemia and compared them to those in normal bone marrow cells. Approximately 20% of them showed higher expression compared with controls. There was a tendency that patients who showed overexpression of MIR9 underwent worse clinical courses, but without statistical significance. However, when the analyses were restricted to patients who did not receive a stem cell transplant, overexpression of MIR9 was significantly associated with worse overall survival. Interestingly, exaggerated MIR9 expression and higher white blood cell count at presentation were independent unfavorable prognostic factors in all patients for overall survival by multivariate analysis. The presence of higher MIR9 expression could be a useful indicator for treatment stratifica...

A yeast-like fungus isolated from a granulomatous and ulcerative skin lesion in a mongrel cat was mycologically examined. The isolate was identified as Sporothrix schenckii from the morphological findings and its pathogenicity in a mouse, confirming the first case of feline sporotrichosis in Japan. Fortunately, no transmission to humans occurred in this case, however the risk of humans contracting Sporothrix schenckii infection increases with the increase in the number of animals with sporotrichosis. Consequently when handling such animals protective clothing such as gloves should be worn to reduce the risk of transmission of the fungus through open wounds.

Introduction: αv integrins are a class of adhesion molecules which play a role in tumor progression and metastasis, and have been found to be highly expressed in various cancer types. A phase I/II study of anti-αv integrin antibody Abituzumab showed prolonged overall survival in the subgroup of colorectal cancer (CRC) patients, in which tumor highly expressed αvß6. Here, we examined the expression of integrins in surgical resected specimens by immunohistochemistry and evaluated the relationship between integrin expression and clinicopathological features of Japanese patients with types of cancers which show high prevalence in Asian countries. Materials and methods: Immunohistochemical (IHC) staining for integrin αvβ3, αvβ5, αvβ6, αvβ8, pan-αv, and CD31 was conducted for formalin fixed paraffin embedded surgical specimen of Japanese patients with five different types of cancers, including gastric cancer (GC), esophageal squamous cell cancer (ESCC), biliary tract cancer (BTC), hepatocellular carcinoma (HCC), and CRC. All samples were collected at the National Cancer Research Center Hospital East between 2000 and 2014. The total number of samples was 250. Fifty samples of each cancer type were examined. IHC staining of each sample was evaluated by pathologists. Histoscores (H-score; range: 0 - 300) were used to describe the intensity and prevalence of signal. H-scores were determined separately for membrane and cytoplasm, both in tumor cells and normal adjacent cells. Results: Pan-αv expression patterns were found in most tumor cells of all tumor entities with a tendency towards moderate or strong staining. Expression of αvβ6 was observed in tumor cells of all tumor types other than HCC. Especially, BTC and ESCC tumor cells showed elevated intensity and higher prevalence of αvβ6 expression both in membranous and cytoplasmic compared to CRC tumor samples. In addition, BTC and ESCC tumor cells showed stronger intensity and higher proportion of αvβ6 compared to normal tissues. In CRC, the cases with higher expression of αvβ6 showed stronger tumor invasion or lymph node metastasis. In BTC and ESCC, high expression of αvβ6 was detected regardless of T-stage or lymph node metastasis status. ESCC cases with high expression of αvβ6 had a poor prognosis compared to cases with low expression. Conclusions: These data demonstrated that the expression of αvβ6 integrin correlated with clinicopathological features of BTC, ESCC, and CRC. High expression of αvβ6 in ESCC was associated with the poor prognosis. These data indicate that αv integrin may be an attractive target in cancer treatment. Citation Format: Yasutoshi Kuboki, Yuka Nakamura, Takeshi Kuwata, Satoshi Fujii, Motohiro Kojima, Toshio Kuronita, Morihiro Watanabe, Josef Straub, Atsushi Ochiai. Immunohistochemical analysis of integrin αv families in solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A126.

Two human cases of tinea corporis due to Arthroderma benhamiae (teleomorph of Trichophyton mentagrophytes) were described. They acquired the infection from their cross-bred rabbit. The three clinical isolates from a human couple and a pet rabbit had been identified as A. benhamiae by chitin synthase 1 (CHS1) gene analysis as well as by mating experiments. There was no previous isolate of A. benhamiae from humans in Japan, although we had reported the first isolate of A. benhamiae from a rabbit in 1998. Therefore, this is the first report on human ringworm cases caused by A. benhamiae in Japan. It is anticipated that the human and animal cases of A. benhamiae infection could rise in number.