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Epithelial cell rests of Malassez (ERM) are quiescent epithelial remnants of the Hertwig's epithelial root sheath (HERS) that are involved in the formation of tooth roots. ERM cells are unique epithelial cells that remain in periodontal tissues throughout adult life. They have a functional role in the repair/regeneration of cement or enamel. Here, we isolated odontogenic epithelial cells from ERM in the periodontal ligament, and the cells were spontaneously immortalized. Immortalized odontogenic epithelial (iOdE) cells had the ability to form spheroids and expressed stem cell-related genes. Interestingly, iOdE cells underwent osteogenic differentiation, as demonstrated by the mineralization activity in vitro in mineralization-inducing media and formation of calcification foci in iOdE cells transplanted into immunocompromised mice. These findings suggest that a cell population with features similar to stem cells exists in ERM and that this cell population has a differentiation capacity for producing calcifications in a particular microenvironment. In summary, iOdE cells will provide a convenient cell source for tissue engineering and experimental models to investigate tooth growth, differentiation, and tumorigenesis.

We previously reported that the pVHL-atypical PKC-JunB pathway contributed to promotion of cell invasiveness and angiogenesis in clear cell renal cell carcinoma (ccRCC), and we detected chemokine (C-C motif) ligand-2 (CCL2) as one of downstream effectors of JunB. CCL2 plays a critical role in tumorigenesis in other types of cancer, but its role in ccRCC remains unclear. In this study, we investigated the roles and therapeutic potential of CCL2 in ccRCC. Immunohistochemical analysis of CCL2 expression for ccRCC specimens showed that upregulation of CCL2 expression correlated with clinical stage, overall survival, and macrophage infiltration. For functional analysis of CCL2 in ccRCC cells, we generated subclones of WT8 cells that overexpressed CCL2 and subclones 786-O cells in which CCL2 expression was knocked down. Although CCL2 expression did not affect cell proliferation in vitro, CCL2 overexpression enhanced and CCL2 knockdown suppressed tumor growth, angiogenesis, and macrophage infiltration in vivo. We then depleted macrophages from tumor xenografts by administration of clodronate liposomes to confirm the role of macrophages in ccRCC. Depletion of macrophages suppressed tumor growth and angiogenesis. To examine the effect of inhibiting CCL2 activity in ccRCC, we administered CCL2 neutralizing antibody to primary RCC xenografts established from patient surgical specimens. Inhibition of CCL2 activity resulted in significant suppression of tumor growth, angiogenesis, and macrophage infiltration. These results suggest that CCL2 is involved in angiogenesis and macrophage infiltration in ccRCC, and that CCL2 could be a potential therapeutic target for ccRCC., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Both autoimmunity and tumor immunity are immune responses against self-tissues or cells. However, the precise similarity or difference between them remains unclear. In this study, to understand a novel mechanism of tumor immunity, we performed transplantation experiments with a murine autoimmune model, C57BL/6J (B6)/lpr mice. A melanoma cell line, B16F10 cells, or granulocyte macrophage colony-stimulating factor- overexpressing B16F10 (B16F10/mGM) cells were transplanted into B6 or B6/lpr mice. Tumor growth by transplanted B16F10/mGM cells was significantly accelerated in B6/lpr mice compared with that in B6 mice. The accumulation of M1 macrophages in the tumor tissues of B6/lpr recipient mice was significantly lower compared with that in the control mice. In vitro co-culture experiment showed that impaired differentiation into M1 macrophages was observed in B6/lpr mice. The number of tumor vessels and vascular endothelial growth factor (VEGF) expression were also significantly enhanced in the tumor tissues of B6/lpr mice compared with those in the B6 mice. Moreover, VEGF expression was correlated with the increased expression of hypoxia-inducible factor-1α in the tumor tissues of B6/lpr mice. These results suggest that dysfunctional tumor immunity and enhanced angiogenesis in autoimmunity influence tumor growth.

Diphenylarsinic acid (DPAA) was detected as the primary compound responsible for the arsenic poisoning that occurred in Kamisu, Ibaraki, Japan, where people using water from a well that was contaminated with a high level of arsenic developed neurological (mostly cerebellar) symptoms and dysregulation of regional cerebral blood flow. To understand the underlying molecular mechanism of DPAA-induced cerebellar symptoms, we focused on astrocytes, which have a brain-protective function. Incubation with 10 µM DPAA for 96 h promoted cell proliferation, increased the expression of antioxidative stress proteins (heme oxygenase-1 and heat shock protein 70), and induced the release of cytokines (MCP-1, adrenomedullin, FGF2, CXCL1, and IL-6). Furthermore, DPAA overpoweringly increased the phosphorylation of three major mitogen-activated protein kinases (MAPKs) (ERK1/2, p38MAPK, and SAPK/JNK), which indicated MAPK activation, and subsequently induced expression and/or phosphorylation of transcription factors (Nrf2, CREB, c-Jun, and c-Fos) in cultured rat cerebellar astrocytes. Structure-activity relationship analyses of DPAA and other related pentavalent organic arsenicals revealed that DPAA at 10 µM activated astrocytes most effective among organic arsenicals tested at the same dose. These results suggest that in a cerebellum exposed to DPAA, abnormal activation of the MAPK-transcription factor pathway and irregular secretion of these neuroactive, glioactive, and/or vasoactive cytokines in astrocytes can be the direct/indirect cause of functional abnormalities in surrounding neurons, glial cells, and vascular cells: This in turn might lead to the onset of cerebellar symptoms and disruption of cerebral blood flow., (© The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Regulatory T (Treg) cells play key roles in various immune responses. For example, Treg cells contribute to the complex pathogenesis of inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis during onset or development of that disease. Many animal models of IBD have been used to investigate factors such as pathogenic cytokines, pathogenic bacteria, and T-cell functions, including those of Treg cells. In addition, analyses of patients with IBD facilitate our understanding of the precise mechanism of IBD. This review article focuses on the role of Treg cells and outlines the pathogenesis and therapeutic strategies of IBD based on previous reports.

Allergic contact hypersensitivity to metals is a delayed-type allergy. Although various metals are known to produce an allergic reaction, nickel is the most frequent cause of metal allergy. Researchers have attempted to elucidate the mechanisms of metal allergy using animal models and human patients. Here, the immunological and molecular mechanisms of metal allergy are described based on the findings of previous studies, including those that were recently published. In addition, the adsorption and excretion of various metals, in particular nickel, is discussed to further understand the pathogenesis of metal allergy.

The objective of the study was to evaluate strategies and barriers to recruiting Asians and Pacific Islanders (API) with type 2 diabetes, into clinical trials. Descriptive statistics and content analysis were utilized to analyze reasons for non-participation. A "talk story" interview method was employed to recruit participants and uncover reasons for non-participation. A total of 1891 potential participants were identified and 340 declined participation. Eighty who declined were randomly selected to provide their reasons for non-participation. Socioeconomic issues faced by this population, such as earning wages to meet basic needs and care giving took precedence over altruistic participation in research.

Asian Americans and Pacific Islanders are twice as likely to be diagnosed with type 2 diabetes compared to Caucasians. The objective was to determine the effect of cognitive behavioral therapy on quality of life, general health perceptions, depressive symptoms, and glycemia in Asians and Pacific Islanders with type 2 diabetes. The design was a randomized controlled clinical trial comparing cognitive behavioral therapy to diabetes education and support for six weekly sessions. Participants were recruited from two endocrinology practices; 207 were enrolled. The cognitive behavioral therapy group was provided self-management tools which included biofeedback, breathing exercises, and stress relievers, while the diabetes education and support group included diabetes education and group discussions. Assessments of psychosocial and clinical outcomes were obtained before and after sessions and 12 months PostSession. Differences between the two groups were examined using linear mixed-effects models with linear contrasts. The cognitive behavioral therapy group had improved depressive symptom scores from PreSession to EndSession compared to the diabetes education and support group (P < .03), but the improvement did not extend to 12 months PostSession. Similar results were observed with misguided support scores in the Multidimensional Diabetes Questionnaire (P < .03) and susceptibility in health beliefs (P < .01), but no significant differences in HbA1c improvement were found between the two groups. Both interventions improved outcomes from baseline but were not sustained for 1 year.

Neonatal thymectomy in certain mouse strains is known to induce organ-specific autoimmunity due to impaired functions of T cells, including Foxp3(+) regulatory T (Treg) cells in the thymus. The precise mechanism underlying the induction of autoimmunity by neonatal thymectomy remains unclear. One possibility is that depletion of Treg cells breaks down peripheral tolerance. We examined the functions of Treg cells by using a murine Sjögren syndrome model of NFS/sld mice that underwent neonatal thymectomy. The ratio of Treg cells to effector memory phenotype T cells in thymectomy mice was significantly lower than that of nonthymectomy mice. In addition, in vitro induction of peripherally induced Treg cells by transforming growth factor-β (TGF-β) using naive T cells from Sjögren syndrome model mice was severely impaired. The mRNA expression of TGF-β receptor I and II and Smad3 and -4 in the TGF-β-induced signal transduction pathway of Treg cells in this Sjögren syndrome model were lower than those of control mice. In addition, Treg cells in this Sjögren syndrome model exhibited an interferon-γ-producing Th1-like phenotype that resembled effector T cells. In conclusion, these results suggest that abnormal expansion and differentiation of Treg cells and inflammatory cytokines produced by Treg cells contribute to the development of autoimmunity., (Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objectives: The extent of visceral malperfusion due to acute type A aortic dissection remains difficult to assess in view of the clinical signs that typically present at a late stage. We suspected that visceral malperfusion can persist after proximal aortic graft replacement despite redirecting blood flow into the true lumen. We therefore evaluated the operative outcomes of visceral malperfusion complicated with acute type A aortic dissection., Methods: Among 121 patients with acute type A aortic dissection treated at our hospital between January 2000 and December 2014, 10 (8.2%) were preoperatively complicated with visceral malperfusion. Eight of them had been treated by visceral arterial branch bypass followed by central repair, and 2 with circulatory instability had undergone central repair followed by laparotomy., Results: The 2 patients who underwent initial central repair required extensive intestinal resection due to necrosis and died of multiple organ failure related to visceral necrosis in hospital (hospital mortality rate, 20.0%). The ischaemic time (interval between the onset of dissection and visceral arterial revascularization) was significantly longer for patients who initially underwent central repair compared with those who were initially treated by visceral arterial revascularization. However, base excess and lactate levels did not significantly differ between the two groups., Conclusions: We believe that if visceral ischaemia is severe and extensive in patients with type A aortic dissection, abdominal surgery should proceed before the aorta is surgically approached to avoid further irreversible ischaemic damage caused by circulatory arrest in organs with compromised perfusion., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background and Objectives: Molecular data suggests that adiponectin may directly regulate urinary albumin excretion. In the Diabetes Prevention Program (DPP) we measured adiponectin and albuminuria before and after intervention, and we previously reported increases in adiponectin with interventions. Here we have used the DPP dataset to test the hypothesis that treatment-related increases in adiponectin may reduce albuminuria in obesity., Design, Setting, Participants and Methods: We evaluated cross-sectional correlations between plasma adiponectin and urinary albumin excretion at baseline, and the relationship of treatment-related changes in adiponectin and albuminuria. Baseline and follow-up urine albumin to creatinine ratios (ACR (albumin to creatinine ratio)) and plasma adiponectin concentration were available in 2553 subjects., Results: Adjusting for age, sex and race/ethnicity, we observed a statistically significant but weak inverse relationship between adiponectin and ACR at baseline (conditional Spearman's rho = (-) 0.04, p = 0.04). Although DPP treatments significantly increased plasma adiponectin, there were no treatment effects on ACR and no differences in ACR across treatment groups. There was a weak direct (not inverse) association between change in adiponectin and change in albuminuria (adjusted Spearman's rho = (+) 0.04, p = 0.03)., Conclusions: In a large, well-characterized cohort of obese dysglycemic subjects we observed a weak inverse association between circulating adiponectin concentrations and urinary albumin excretion at baseline. Contrary to the hypothesized effect, treatment-related increases in plasma adiponectin were not associated with a reduction in ACR. The association of change in adiponectin with change in ACR should be assessed in populations with overt albuminuria before excluding a beneficial effect of increasing adiponectin to reduce ACR in obesity.

Aurora-A is a well-known mitotic kinase that regulates mitotic entry, spindle formation, and chromosome maturation as a canonical role. During mitosis, Aurora-A protein is stabilized by its phosphorylation at Ser51 via blocking anaphase-promoting complex/cyclosome-mediated proteolysis. Importantly, overexpression and/or hyperactivation of Aurora-A is involved in tumorigenesis via aneuploidy and genomic instability. Recently, the novel function of Aurora-A for DNA replication has been revealed. In mammalian cells, DNA replication is strictly regulated for preventing over-replication. Pre-replication complex (pre-RC) formation is required for DNA replication as an initiation step occurring at the origin of replication. The timing of pre-RC formation depends on the protein level of geminin, which is controlled by the ubiquitin-proteasome pathway. Aurora-A phosphorylates geminin to prevent its ubiquitin-mediated proteolysis at the mitotic phase to ensure proper pre-RC formation and ensuing DNA replication. In this review, we introduce the novel non-canonical role of Aurora-A in DNA replication.

Vascular endothelial growth factor (VEGF) and mammalian target of rapamycin are well-known therapeutic targets for renal cell carcinoma (RCC). Sunitinib is an agent that targets VEGF receptors and is considered to be a standard treatment for metastatic or unresectable clear cell RCC (ccRCC). However, ccRCC eventually develops resistance to sunitinib in most cases, and the mechanisms underlying this resistance are not fully elucidated. In the present study, we established unique primary xenograft models, KURC1 (Kyoto University Renal Cancer 1) and KURC2, from freshly isolated ccRCC specimens. The KURC1 xenograft initially responded to sunitinib treatment, however finally acquired resistance. KURC2 retained sensitivity to sunitinib for over 6 months. Comparing gene expression profiles between the two xenograft models with different sensitivity to sunitinib, we identified interleukin 13 receptor alpha 2 (IL13RA2) as a candidate molecule associated with the acquired sunitinib-resistance in ccRCC. And patients with high IL13RA2 expression in immunohistochemistry in primary ccRCC tumor tends to have sunitinib-resistant metastatic site. Next, we showed that sunitinib-sensitive 786-O cells acquired resistance in vivo when IL13RA2 was overexpressed. Conversely, shRNA-mediated knockdown of IL13RA2 successfully overcame the sunitinib-resistance in Caki-1 cells. Histopathological analyses revealed that IL13RA2 repressed sunitinib-induced apoptosis without increasing tumor vasculature in vivo. To our knowledge, this is a novel mechanism of developing resistance to sunitinib in a certain population of ccRCC, and these results indicate that IL13RA2 could be one of potential target to overcome sunitinib resistance.

Several autoimmune diseases are known to develop in postmenopausal women. However, the mechanism by which estrogen deficiency influences autoimmunity is unknown. Aromatase is an enzyme that converts androgens to estrogens. Herein, we used female aromatase gene knockout (ArKO) mice as a model of estrogen deficiency to investigate the molecular mechanism that underlies the onset and development of autoimmunity. Histological analyses showed that inflammatory lesions in the lacrimal and salivary glands of ArKO mice increased with age. Adoptive transfer of spleen cells or bone marrow cells from ArKO mice into recombination activating gene 2 knockout mice failed to induce the autoimmune lesions. Expression of mRNA encoding proinflammatory cytokines and monocyte chemotactic protein-1 increased in white adipose tissue of ArKO mice and was significantly higher than that in wild-type mice. Moreover, an increased number of inflammatory M1 macrophages was observed in white adipose tissue of ArKO mice. A significantly increased monocyte chemotactic protein-1 mRNA expression of the salivary gland tissue in ArKO was found together with adiposity. Furthermore, the autoimmune lesions in a murine model of Sjögren syndrome were exacerbated by administration of an aromatase inhibitor. These results suggest that aromatase may play a key role in the pathogenesis of Sjögren syndrome-like lesions by controlling the target organ and adipose tissue-associated macrophage., (Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: To compare the efficacy and safety of dulaglutide, a once-weekly GLP-1 receptor agonist, with placebo and exenatide in type 2 diabetic patients. The primary objective was to determine superiority of dulaglutide 1.5 mg versus placebo in HbA1c change at 26 weeks., Research Design and Methods: This 52-week, multicenter, parallel-arm study (primary end point: 26 weeks) randomized patients (2:2:2:1) to dulaglutide 1.5 mg, dulaglutide 0.75 mg, exenatide 10 μg, or placebo (placebo-controlled period: 26 weeks). Patients were treated with metformin (1,500-3,000 mg) and pioglitazone (30-45 mg). Mean baseline HbA1c was 8.1% (65 mmol/mol)., Results: Least squares mean ± SE HbA1c change from baseline to the primary end point was -1.51 ± 0.06% (-16.5 ± 0.7 mmol/mol) for dulaglutide 1.5 mg, -1.30 ± 0.06% (-14.2 ± 0.7 mmol/mol) for dulaglutide 0.75 mg, -0.99 ± 0.06% (-10.8 ± 0.7 mmol/mol) for exenatide, and -0.46 ± 0.08% (-5.0 ± 0.9 mmol/mol) for placebo. Both dulaglutide doses were superior to placebo at 26 weeks (both adjusted one-sided P < 0.001) and exenatide at 26 and 52 weeks (both adjusted one-sided P < 0.001). Greater percentages of patients reached HbA1c targets with dulaglutide 1.5 mg and 0.75 mg than with placebo and exenatide (all P < 0.001). At 26 and 52 weeks, total hypoglycemia incidence was lower in patients receiving dulaglutide 1.5 mg than in those receiving exenatide; no dulaglutide-treated patients reported severe hypoglycemia. The most common gastrointestinal adverse events for dulaglutide were nausea, vomiting, and diarrhea. Events were mostly mild to moderate and transient., Conclusions: Both once-weekly dulaglutide doses demonstrated superior glycemic control versus placebo and exenatide with an acceptable tolerability and safety profile., (© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

The management of symptomatic hyperthyroidism in patients with end stage renal disease (ESRD) is challenging because of altered clearance of medications and iodine with dialysis; moreover, many patients meeting these criteria are medically fragile. A 77-year-old man with type 2 diabetes and ESRD requiring hemodialysis, with dilated cardiomyopathy and paroxysmal atrial fibrillation, was found to have subclinical hyperthyroidism. Over a 2-year period he became clinically hyperthyroid with serum TSH level of <0.05 mIU/L and free T4 level of 4.3 ng/dL, attributed to toxic multinodular goiter. Despite antithyroid medication, he developed rapid ventricular rate from his atrial fibrillation that resulted in decompensated heart failure and multiple hospitalizations. His hyperthyroidism was successfully controlled with high dose methimazole and potassium iodide treatment, which were eventually discontinued after prolonged use. Nearly 6 months off medications, his hyperthyroidism recurred but was readily resolved when methimazole was restarted. Hyperthyroidism in the medically fragile ESRD patient may precipitate emergent conditions. Antithyroid medications are effective and should be considered as primary therapy for the treatment of hyperthyroidism in patients with hemodialysis. Moreover, clinical guidelines for the characterization and management of individuals with ESRD and subclinical hyperthyroidism should be developed.

Background: Topical therapy is effective for dry eye, and its prolonged effects should help in maintaining the quality of life of patients with dry eye. We previously reported that the oral administration of rebamipide (Reb), a mucosal protective agent, had a potent therapeutic effect on autoimmune lesions in a murine model of Sjögren's syndrome (SS). However, the effects of topical treatment with Reb eyedrops on the ocular lesions in the murine model of SS are unknown., Methods and Finding: Reb eyedrops were administered to the murine model of SS aged 4-8 weeks four times daily. Inflammatory lesions of the extraorbital and intraorbital lacrimal glands and Harderian gland tissues were histologically evaluated. The direct effects of Reb on the lacrimal glands were analyzed using cultured lacrimal gland cells. Tear secretions of Reb-treated mice were significantly increased compared with those of untreated mice. In addition to the therapeutic effect of Reb treatment on keratoconjunctivitis, severe inflammatory lesions of intraorbital lacrimal gland tissues in this model of SS were resolved. The mRNA expression levels of IL-10 and mucin 5Ac in conjunctival tissues from Reb-treated mice was significantly increased compared with those of control mice. Moreover, lactoferrin production from lacrimal gland cells was restored by Reb treatment., Conclusion: Topical Reb administration had an anti-inflammatory effect on the ocular autoimmune lesions in the murine model of SS and a protective effect on the ocular surfaces.

Ni is the most frequent cause of contact allergy induced by metals. However, the underlying mechanism of this induction is unknown. Our previous research demonstrates that activation of dendritic cells (DCs) through p38MAPK/MKK6 is required for Ni-induced allergy in mice. In the current study, we investigated the cellular and molecular mechanisms underlying Ni-induced allergy using a mouse model that involves injecting Ni into the ear, with or without Freund's incomplete or complete adjuvants. Nickel had greater potential to cause allergic reactions compared with palladium and gold. Among the proteins expressed at higher levels in mice with Ni-induced allergy, we focused on thymic stromal lymphopoietin (TSLP), which is produced in abundance by keratinocytes. We detected increased expression of the TSLP receptor (TSLPR) in DCs from cervical lymph nodes of mice with Ni-induced allergy, suggesting that DCs in ear tissues were activated through TSLPR signaling induced by keratinocyte-derived TSLP. Furthermore, delayed-type hypersensitivity reactions in mice with Ni-induced allergy were decreased significantly by injection of a Tslp-short interfering RNA along with atelocollagen in the ear skin. These results suggest that Ni allergy may be triggered by a TSLP/TSLPR-mediated interaction between epithelial and immune cells.

Fungi have been recently recognized as organisms able to grow in presence of high salt concentration with halophilic and halotolerance properties and their ligninolytic enzyme complex have an unspecific action enabling their use to degradation of a number of xenobiotic compounds. In this work, both the effect of salt and polyols on growth of the basidiomycetes strains, on their ability to produce ligninolytic enzyme and diuron degradation were evaluated. Results showed that the presence of NaCl in the culture medium affected fungal specimens in different ways. Seven out of ten tested strains had growth inhibited by salt while Dacryopinax elegans SXS323, Polyporus sp MCA128 and Datronia stereoides MCA167 fungi exhibited higher biomass production in medium containing 0.5 and 0.6 mol.L(-1) of NaCl, suggesting to be halotolerant. Polyols such as glycerol and mannitol added into the culture media improved the biomass and ligninases production by D. elegans but the fungus did not reveal consumption of these polyols from media. This fungus degraded diuron in medium control, in presence of NaCl as well as polyols, produced MnP, LiP and laccase.

A 68-year-old man lost consciousness while speaking. Computed tomography of the head revealed no hemorrhage or areas of hypodensity. Recombinant tissue plasminogen activator was administered. Neck duplex scanning showed dissecting intima of the right common carotid artery. Chest computed tomography disclosed Stanford type A aortic dissection. We performed emergency surgery because the right common carotid artery was severely stenosed. Despite 8 h of surgery due to coagulopathy, the patient was discharged without neurological deficits.

Objectives: To identify the patient subgroups benefitting the most from the modern strategy including molecular-targeted therapy among patients with metastatic renal cell carcinoma (mRCC) in clinical practice., Methods: Retrospective analysis of 144 patients with mRCC diagnosed between 1992 and 2011 at Kyoto University Hospital was conducted. Multivariate analysis using the Cox proportional hazards model was conducted to identify prognostic factors associated with overall survival (OS). Subgroup analysis was conducted to identify patients who benefitted the most from molecular-targeted therapy., Results: Independent factors associated with worse OS are: tumors of histological type other than clear-cell, decreased hemoglobin (Hb), elevated lactate dehydrogenase (LDH), elevated C-reactive protein (CRP), and metastases at ≥ 3 sites. Median OS of patients treated with molecular-targeted therapy alone or with prior immunotherapy and those treated with immunotherapy alone was 57, 45 and 28 months, respectively. Molecular-targeted therapy had more effect on OS than immunotherapy alone among female patients, patients with Memorial Sloan-Kettering Cancer Center (MSKCC) intermediate risk features, and patients with metastatic progression less than 1 year after initial diagnosis of RCC, compared with their counterparts., Conclusions: The modern strategy including molecular-targeted therapy may improve OS in patients with mRCC and MSKCC intermediate risk features in clinical practice, relative to those with other risk features. However, the prognosis for patients with tumors of histological type other than clear-cell, decreased Hb, elevated LDH, elevated CRP, or metastases at ≥ 3 sites remains poor even in the modern molecular-targeted era. Novel treatment strategies are necessary to improve prognosis in these patients.

Activation-induced cell death (AICD) of T cells is a process for regulating the peripheral immune system. The fate of a T cell is controlled by numerous signals derived from various stimuli, such as antigens, cytokines, and chemokines. In healthy humans, overactivated or autoreactive T cells are harmful and are eliminated to maintain the immune system. AICD in T cells by Fas/FasL-mediated apoptosis is triggered by the switch from life to death through several signaling molecules. The control or distribution of Fas or FasL expression largely affects AICD of T cells. Although autoimmune diseases are considered to be induced by multiple factors, an impaired immune system with AICD by Fas/FasL-mediated apoptosis leads to the onset or development of autoimmunity. Based on published reports, this review describes the regulatory mechanisms involved in AICD of T cells by Fas/ FasL-mediated apoptosis and the associations between AICD and autoimmunity in humans and animal models.

Objective: To assess speech alterations in mouth-breathing children, and to correlate them with the respiratory type, etiology, gender, and age., Method: A total of 439 mouth-breathers were evaluated, aged between 4 and 12 years. The presence of speech alterations in children older than 5 years was considered delayed speech development. The observed alterations were tongue interposition (TI), frontal lisp (FL), articulatory disorders (AD), sound omissions (SO), and lateral lisp (LL). The etiology of mouth breathing, gender, age, respiratory type, and speech disorders were correlated., Results: Speech alterations were diagnosed in 31.2% of patients, unrelated to the respiratory type: oral or mixed. Increased frequency of articulatory disorders and more than one speech disorder were observed in males. TI was observed in 53.3% patients, followed by AD in 26.3%, and by FL in 21.9%. The co-occurrence of two or more speech alterations was observed in 24.8% of the children., Conclusion: Mouth breathing can affect speech development, socialization, and school performance. Early detection of mouth breathing is essential to prevent and minimize its negative effects on the overall development of individuals., (Copyright © 2013 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

Objectives: Postoperative infection control is one of the most important issues for infected aortic aneurysms, and the methods of preventing recurrent infection remain controversial. We previously reported that omental flaps could prevent or reduce the occurrence of infection after implanting an artificial aortic graft. However, the long-term outcomes of this strategy are unknown. We used imaging modalities to evaluate whether wrapping prosthetic grafts with omentum prevents postoperative graft infection over the long-term., Methods: We surgically treated 521 patients with thoracic aortic aneurysm (TAA) at our hospital between July 1995 and May 2012. Of these, 22 (3.9%) (male, n = 17; mean age, 68.2 ± 11.4 years) had infectious TAA. All infectious aneurysms were resected, all patients received in-situ grafts and 16 grafts were wrapped with omentum. We followed up all survivors annually using computed tomography. We also used angiography to investigate blood circulation in omental flaps over the long-term., Results: Five patients died in-hospital (operative mortality, 26.3%). The operative mortality rates of patients with and without omental wrapping were 12.5 and 50.0%, respectively (P = 0.06, NS), and the 5-year event-free survival rates were 84.6 and 33.3% (P = 0.025), respectively. Omental flaps around prosthetic grafts and their blood circulation were well-preserved over the long-term., Conclusions: Wrapping implanted artificial aortic grafts with omental flaps could prevent or reduce the occurrence of subsequent infection. Furthermore, blood circulation in the flaps must be well-preserved to improve the long-term outcomes.

Introduction: IL-1 plays key roles in the biological functions of various cells. In particular, many roles of IL-1 in the immune system have been discovered by numerous studies. This review focuses on the association of IL-1 with the pathogenesis of autoimmunity., Areas Covered: An overview of the biological functions of the IL-1 family and the IL-1 receptors (IL-1Rs), including the maintenance of systemic or local homeostasis, and the signaling pathway through IL-1/IL-1R in various immune systems are described. Several functions of IL-1 in the pathogenesis of Sjögren's syndrome (SS) have been demonstrated with a focus on the immune responses and target tissues in SS. In addition to the role of IL-1 in the immune responses in SS, the function of IL-1 in ocular mucosa lesions in SS has been described. Lastly, there is an overview of possible therapeutic strategies for IL-1 inhibition in SS., Expert Opinion: IL-1 plays critical roles in the onset and development of SS by controlling systemic or local immune responses and maintaining the survival and mucosal defense of target epithelial cells. The inhibition of the pathogenic functions of IL-1 may be beneficial for treating SS.

Peripheral T cells are maintained by the apoptosis of activated T cells through the Fas-Fas ligand system. Although it is well known that normal T cells fail to survive in the Fas-deficient immune condition, the molecular mechanism for the phenomenon has yet to be elucidated. In this study, we demonstrate that rapid cell death and clearance of normal T cells were induced by Fas-deficient lpr macrophages. Transfer of normal T cells into lpr mice revealed that Fas expression on donor T cells was promptly enhanced through the IFN-γ/IFN-γR. In addition, Fas ligand expression and phagocytic activity of lpr macrophages were promoted through increased NF-κB activation. Controlling Fas expression on macrophages plays an essential role in maintaining T cell homeostasis in the peripheral immune system. Our data suggest a critical implication to the therapeutic strategies such as transplantation and immunotherapy for immune disorder or autoimmunity related to abnormal Fas expression.

Objective: To report an uncommon case of diabetic ketoacidosis in a patient with acromegaly, and present the clinical response to treatment., Methods: Patient evaluation and literature review., Results: A 23-year-old Japanese male with no prior medical history, presented with diabetic ketoacidosis (DKA) and found to have acromegaly. His growth hormone (GH) level was 115 ng/ml, serum insulin-like growth factor-1 (IGF-1) was 1118 ng/ml, and cranial MRI showed a non-enhancing 2.4 x 1.7 x 2.0 cm pituitary mass. After transphenoidal hypophysectomy, his GH level decreased but his IGF-1 level remained unchanged, yet he required no anti-hyperglycemic medications and attained near normal A1c level of 5.8%. He subsequently underwent stereotactic radiotherapy, and additional treatment with bromocriptine and octreotide acetate were not effective, but pegvisomant therapy lowered his IGF-1 concentration to targeted levels., Conclusion: The cause of DKA in this patient with acromegaly is most likely due to glucotoxicity and lipotoxicity, which cause severe but partially reversible β-cell dysfunction; possibly categorized within the syndromes of Ketosis-Prone Diabetes Mellitus (KPD). Diabetic ketoacidosis is an uncommon initial presentation of acromegaly. Successful reduction of GH excess appears to control and resolve hyperglycemia.

We report the case of a 31-day-old girl presenting with severe respiratory distress and cutaneous lesions from Sweet syndrome. Pulmonary symptoms unresponsive to antibiotics in patients with Sweet syndrome should raise suspicion for neutrophilic infiltration., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Vascular endothelial growth factor (VEGF)-targeted therapies show significant antitumor effects for advanced clear cell renal cell carcinomas (CC-RCCs). Previous studies using VEGF inhibitors in mice models revealed that VEGF-dependent capillaries were characterized by the existence of endothelial fenestrations (EFs). In this study, we revealed that capillaries with abundant EFs did exist, particularly in CC-RCCs harboring VHL mutation. This finding was recapitulated in mice xenograft models, in which tumors from VHL null cells showed more abundant EFs compared to those from VHL wild-type cells. Importantly, treatment with bevacizumab resulted in a significant decrease of tumor size established from VHL null cells. Additionally, a significant reduction of EFs and microvessel density was observed in VHL null tumors. Indeed, xenograft from 786-O/mock (pRC3) cells developed four times more abundant EFs than that from 786-O/VHL (WT8). However, introduction of the constitutively active form of hypoxia-inducible factor (HIF)-2α to WT8 cells failed to either augment the number of EFs or restore the sensitivity to bevacizumab in mice xenograft, irrespective of the equivalent production of VEGF to 786-O/mock cells. These results indicated that HIF-2α independent factors also play significant roles in the development of abundant EFs. In fact, several angiogenesis-related genes including CCL2 were upregulated in 786-O cells in a HIF-2α independent manner. Treatment with CCL2 neutralizing antibody caused significant reduction of capillaries with EFs in 786-O xenograft, indicating that they were also sensitive to CCL2 inhibition as well as VEGF. Collectively, these results strongly indicated that capillaries with distinctive phenotype developed in VHL null CC-RCCs are potent targets for anti-angiogenic therapy., (© 2012 Japanese Cancer Association.)

A right-sided aortic arch associated with an aberrant subclavian artery is a rare anomaly. Regardless, this condition is clinically relevant because mortality is associated with rupture, morbidity results from compression of mediastinal structures, and the surgery is complex. We describe the successful surgical repair of this vascular anomaly by totally debranching the neck vessels and placing an endovascular stent-graft to exclude the ruptured Kommerell's diverticulum.

A number of patients with benign prostatic hyperplasia can not undergo surgical therapy because of advanced age, concomitant diseases, and other reasons. Since 1980, various types of urethral stents have been used for high-risk patients with benign prostatic hyperplasia. We report our experience with the use of urethral stents (Memotherm®). Between July 2002 and December 2010, we implanted urethral stents in 36 patients. The average follow-up period was 24.0 months. After stent implantation, 34 of the 36 patients were able to micturate. The average residual urine volume was 24.7 ml (0-250 ml), and the maximal urinary flow rate was 10.7 ml/s (3-24 ml/s). One stent had to be removed due to bladder tamponade, and one had to be exchanged due to dislocation. In 2 patients, a stone formed at the bladder end of the stent, and one of these patients underwent transurethral lithotripsy. Our results suggest that therapy with the Memotherm® urethral stent is a good option for patients suffering from urinary retention due to benign prostatic hyperplasia.

Background: Although autoimmunity in MRL/lpr mice occurs due to a defect in Fas-mediated cell death of T cells, the role of Fas-independent apoptosis in pathogenesis has rarely been investigated. We have recently reported that receptor activator of nuclear factor (NF)-κB ligand (RANKL)-activated dendritic cells (DCs) play a key role in the pathogenesis of rheumatoid arthritis (RA) in MRL/lpr mice. We here attempted to establish a new therapeutic strategy with RANKL-activated DCs in RA by controlling apoptosis of peripheral T cells. Repeated transfer of RANKL-activated DCs into MRL/lpr mice was tested to determine whether this had a therapeutic effect on autoimmunity., Methods and Finding: Cellular and molecular mechanisms of Fas-independent apoptosis of T cells induced by the DCs were investigated by in vitro and in vivo analyses. We demonstrated that repeated transfers of RANKL-activated DCs into MRL/lpr mice resulted in therapeutic effects on RA lesions and lymphoproliferation due to declines of CD4(+) T, B, and CD4(-)CD8(-) double negative (DN) T cells. We also found that the Fas-independent T-cell apoptosis was induced by a direct interaction between tumor necrosis factor (TNF)-related apoptosis-inducing ligand-receptor 2 (TRAIL-R2) on T cells and TRAIL on Fas-deficient DCs in MRL/lpr mice., Conclusion: These results strongly suggest that a novel Fas-independent apoptosis pathway in T cells maintains peripheral tolerance and thus controls autoimmunity in MRL/lpr mice.

Forkhead box p3-positive (Foxp3(+)) regulatory T cells (T(reg) cells) participate in maintaining peripheral immune tolerance and suppressing autoimmunity. We recently reported that in situ patrolling by C-C-chemokine receptor 7 (CCR7)(+) T(reg) cells in target organs is essential for controlling autoimmune lesions in Sjögren's syndrome. In the present study, the molecular mechanism underlying CCR7-mediated T(reg) cell migration was investigated in a mouse model. The impaired migratory response of Ccr7(-/-) T(reg) cells to sphingosine 1-phosphate (S1P) occurred because of defective association of S1P receptor 1 (S1P(1)) with a G coupled-protein. In addition, T-cell receptor (TCR)- and S1P(1)-mediated Ras-related C3 botulinum toxin substrate 1 (Rac-1), extracellular signal-related kinase (ERK), and c-Jun phosphorylation required for activator protein 1 (AP-1) transcriptional activity were significantly impaired in Ccr7(-/-) T(reg) cells. Surprisingly, the abnormal nuclear localization of Foxp3 was detected after abrogation of the c-Jun and Foxp3 interaction in the nucleus of Ccr7(-/-) T(reg) cells. These results indicate that CCR7 essentially controls the migratory function of T(reg) cells through S1P(1)-mediated AP-1 signaling, which is regulated through its interaction with Foxp3 in the nucleus., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

The purpose of this study was to explore the perceptions of Asians and Pacific Islanders (API) with Type 2 diabetes related to diet and exercise. A descriptive content analysis was conducted on verbalized responses from 15 participants in focus groups who were asked "What role does your culture play in what, when, and how much you eat?" and "If and/or how much you exercise and what type of exercise you do?" The participants recorded responses were transcribed verbatim and analyzed for themes utilizing the social ecological framework.The families, environment, and the local culture in Hawai'i greatly affect the dietary and physical activities of the participants. Psychosocial themes related to diet included depression, denial, and lack of self control. Physical activities were impacted by motivation and awareness of complications of diabetes. Family upbringing, social events, food portions and variety, and reciprocity contributed to eating behaviors of the participants. Family values in sports and role expectations of gender influenced physical activities.This study identified social ecological influences on health behavior among Asians and Pacific Islanders. The findings suggest various efforts for physicians and other health care providers to assist API in taking care of their diabetes.

We report a case of renal arteriovenous fistula, which was found during treatment for pyelonephritis. A 61-year-old woman was referred to our hospital because of lumbar backache and infectious fever. The computed tomographic scan showed right hydronephrosis and perinephritis. We treated her conservatively for pyelonephritis, but 5 days later, the contrast-enhanced computed tomographic scan showed retroperitoneal hemorrhage. Renal angiography demonstrated an arteriovenous fistula in the central portion of the right kidney. Superselective transcatheter arterial embolization of the AVF was performed. Hemostasis was possible by embolization. She has not had any recurrence of renal arteriovenous fistula. To our knowledge, this is the 5th report of a rupture in the retroperitoneum of an arteriovenous fistula, and renal arteriovenous fistula with the pyelonephritis is very rare.

Background: Although the activation of dermal dendritic cells (DCs) or Langerhans cells (LCs) via p38 mitogen-activated protein kinase (MAPK) plays a crucial role in the pathogenesis of metal allergy, the in vivo molecular mechanisms have not been identified and a possible therapeutic strategy using the control of dermal DCs or LCs has not been established. In this study, we focused on dermal DCs to define the in vivo mechanisms of metal allergy pathogenesis in a mouse nickel (Ni) allergy model. The effects of DC therapy on Ni allergic responses were also investigated., Methods and Finding: The activation of dermal DCs via p38 MAPK triggered a T cell-mediated allergic immune response in this model. In the MAPK signaling cascade in DCs, Ni potently phosphorylated MAP kinase kinase 6 (MKK6) following increased DC activation. Ni-stimulated DCs could prime T cell activation to induce Ni allergy. Interestingly, when MKK6 gene-transfected DCs were transferred into the model mice, a more pronounced allergic reaction was observed. In addition, injection of short interfering (si) RNA targeting the MKK6 gene protected against a hypersensitivity reaction after Ni immunization. The cooperative action between T cell activation and MKK6-mediated DC activation by Ni played an important role in the development of Ni allergy., Conclusions: DC activation by Ni played an important role in the development of Ni allergy. Manipulating the MKK6 gene in DCs may be a good therapeutic strategy for dermal Ni allergy.

Objective: Late cardiac and aortic reoperation after CABG is indispensable for patients with atherosclerotic disease, but reoperations are still associated with high morbidity rates., Patients and Methods: Between January 2002 and December 2010, 459 patients underwent coronary artery bypass grafting. Six patients (males; mean age, 65.0 ± 5.7 years) with previous arterial bypass grafts (mean, 2.8 ± 1.2 per patient) required reoperation for cardiac and aortic disease (3, valvular disease; 3, acute type I aortic dissection) during long-term follow-up. The mean interval between the initial operation and reoperation was 5.4 ± 2.0 years. Grafts visualized by preoperative enhanced computed tomography were harvested as pedicles and clamped for myocardial protection. The total arch or ascending aorta was replaced in three patients. The aortic valve was replaced in two patients, and the aortic and mitral valves were replaced in one., Results: Durations for surgery, total cardiopulmonary bypass, and cardiac ischemia were 611.5 ± 172.6, 223.2 ± 88.4, and 133.4 ± 58.0 minutes, respectively. Perioperative myocardial infarction did not develop, and all patients recovered uneventfully with no neurological deficits., Conclusion: Bypass grafts should be preoperatively visualized and carefully exposed. Cardiac damage must be avoided during reoperation after coronary artery bypass grafting.

A 43-year-old female was referred to our hospital from a local doctor. Her chief complaints were weight gain and abdominal fullness. Computed tomography and magnetic resonance imaging showed a huge tumor in the right retroperitoneal space, which adhered to the right kidney. It was resected with concomitant resection of the right kidney. It measured 30×15 cm and weighed 3.0 kg. Histological examination revealed well differentiated liposarcoma with metaplastic bone formation. She has survived 22 months since the operation with no evidence of recurrence. A retoroperitoneal liposarcoma with metaplastic bone formation is rare. Twenty cases have been reported in Japan including our case.

A 82-year-old female was referred to our department for close examination and treatment of a right renal tumor incidentally found by computed tomography. Her past history included partial thyroidectomy for follicular thyroid carcinoma 20 years earlier. Enhanced computed tomography showed a hypervascular mass with a diameter of 3 cm at the lower pole of the right kidney. We carried out radical nephrectomy for diagnosis of renal cell carcinoma. Pathological findings revealed a metastatic renal tumor of follicular thyroid carcinoma. It is rare to find metastatic renal tumors arising from thyroid carcinoma in clinical practice. Thirty cases have been reported in the Japanese literature.

Background: Type 1 diabetes (T1D) is an autoimmune disease resulting from defects in central and peripheral tolerance and characterized by T cell-mediated destruction of islet β cells. To determine whether specific lysosomal proteases might influence the outcome of a T cell-mediated autoimmune response, we examined the functional significance of cathepsin inhibition on autoimmune T1D-prone non-obese diabetic (NOD) mice., Methods and Findings: Here it was found that specific inhibition of cathepsin L affords strong protection from cyclophosphamide (CY)-induced insulitis and diabetes of NOD mice at the advanced stage of CD8(+) T cell infiltration via inhibiting granzyme activity. It was discovered that cathepsin L inhibition prevents cytotoxic activity of CD8(+) T cells in the pancreatic islets through controlling dipeptidyl peptidase I activity. Moreover, the gene targeting for cathepsin L with application of in vivo siRNA administration successfully prevented CY-induced diabetes of NOD mice. Finally, cathepsin L mRNA expression of peripheral CD8(+) T cells from NOD mice developing spontaneous T1D was significantly increased compared with that from control mice., Conclusions: Our results identified a novel function of cathepsin L as an enzyme whose activity is essential for the progression of CD8(+) T cell-mediated autoimmune diabetes, and inhibition of cathepsin L as a powerful therapeutic strategy for autoimmune diabetes.

The nucleolar material of Chariesterus armatus was analyzed during spermiogenesis in cell preparations impregnated with silver nitrate. Nucleolar corpuscles were observed in spermatids at the beginning of the process, showing that this organoid is also maintained after meiosis. In addition, nucleoli were seen in the round spermatids connected to the X-chromosome (bearer of the nucleolar organizer in C. armatus), indicating de novo synthesis of nucleolar material. This differs from the reorganization of ribosomal granules, transported from meiotic spermatocytes to round spermatids, where they would support protein synthesis, which is reported for other species. We also observed connections of nucleolar corpuscles to the nuclear membrane regions where the tail and the acrosome will be formed, suggesting close involvement of the nucleolar material in the formation of these structures. In addition to the nucleolar bodies, we detected silver-positive structures, which will require new approaches to clarify their role. One of these structures, observed in the cytoplasm, appears to correspond to the chromatoid body, which has been found in several organisms, but is still poorly understood; another is a complex structure to which the tail appears to be connected. We conclude that C. armatus is an appropriate model for understanding not only the synthesis of rRNA in the spermiogenesis, but also the functional meaning of the close relationship of nucleolar material with other structures during this process.

Background: Insulin glargine and lispro mix 75/25 (75% insulin lispro protamine suspension and 25% insulin lispro injection [LM75/25]) represent 2 common starter insulin regimen classes: basal and premixed. After initiation of starter insulin therapy, if patients with type 2 diabetes mellitus (DM) are unable to achieve a glycosylated hemoglobin (HbA1c) level <7.0%, insulin intensification may be indicated. The DURABLE (Assessing Durability of Basal Versus Lispro Mix 75/25 Insulin Efficacy) trial was designed to compare initiating insulin therapy with analogue basal insulin versus premixed analogue insulin in patients unable to achieve good glycemic control while taking multiple oral antihyperglycemic drugs (OADs)., Objective: To provide objective information about insulin intensification, the DURABLE trial also included a substudy evaluating a systematic approach to advancing insulin therapy in those patients who did not achieve glycemic control with their initial insulin regimen. This substudy, the results of which are reported here, tested the hypothesis that advancing insulin therapy with premixed insulin is noninferior to basal-bolus therapy (BBT) in patients with type 2 DM unable to achieve an HbA1c level < or = 7.0% after 6 months of starter insulin therapy., Methods: In the main DURABLE study, 2091 patients (age range, 30-80 years) with type 2 DM and HbA1c values >7.0% receiving > or = 2 OADs were randomized to receive insulin glargine (n = 1046) or LM75/25 (n = 1045), both in combination with prestudy OADs. After 6 months, patients with HbA1c levels >7.0% could enter this intensification substudy; OADs except sulfonylureas were continued. Patients originally receiving insulin glargine were enrolled in intensification arm A and were randomized to receive BBT (insulin glargine once daily plus mealtime insulin lispro TID) or LM75/25 BID. Patients originally receiving LM75/25 were enrolled in intensification arm B and randomized to receive BBT or mealtime 50% insulin lispro protamine suspension and 50% insulin lispro injection (LM50/50) TID. Insulin doses were adjusted based on preprandial plasma glucose levels. The primary end point was noninferiority of premixed therapy versus BBT with respect to end-point HbA1c. Secondary end points included change in HbA1c and weight, percentage of patients reaching HbA1c target levels, total daily insulin dose, and rates of hypoglycemia. The safety profile was also assessed., Results: Of the 475 patients in the insulin glargine + OAD arm of the main study who had HbA1c levels >7.0% at 6 months, 399 (84%) entered intensification arm A. The mean age was 57 years, 53% of the patients were male, and mean (SD) HbA1c was 8.0% (1.0%) at baseline. Of those patients, 199 were randomly assigned to receive BBT and 200 were assigned to receive LM75/25. Of the 411 patients in the LM75/25 + OAD arm of the main study who had an HbA1c level >7.0% at 6 months, 345 (84%) entered intensification arm B. The mean age was 55 years, 51% of the patients were male, and mean (SD) HbA1c was 8.0% (0.9%) at baseline. Of those patients, 171 were randomly assigned to receive BBT and 174 were assigned to receive LM50/50. At end point, noninferiority of LM75/25 or LM50/50 to BBT was supported, with a 95% CI of -0.10 to 0.37 and -0.25 to 0.25, respectively. At 6 months, HbA1c did not differ significantly from baseline in any group. Regardless of treatment group, <20% of patients achieved an HbA1c level <7.0%. There were no significant differences between groups in total daily insulin dose, weight gain, incidence or rate of hypoglycemia, or incidence of serious adverse events., Conclusions: No group had significant improvement from baseline in HbA1c. Our study results suggest that premixed therapy, dosed 2 times per day (LM75/25) or 3 times per day (LM50/50), was noninferior to BBT (4 injections/d) in this population of adult patients with type 2 DM previously uncontrolled with OADs plus basal insulin or twice-daily premixed insulin. Clinical-Trials.gov identifier: NCT00279201., (Copyright 2010 Excerpta Medica Inc. All rights reserved.)

Although a number of autoimmune diseases are known to develop in postmenopausal women, the mechanisms by which estrogen deficiency influences autoimmunity remain unclear. Previously, we found that tissue-specific apoptosis in the exocrine glands in estrogen-deficient mice may contribute to the development of autoimmune exocrinopathy. We found that RbAp48 overexpression induces p53-mediated apoptosis in the exocrine glands depending on estrogen deficiency. RbAp48-inducible transfectants result in rapid apoptosis with p53 phosphorylation (Ser9), and alpha-fodrin cleavage. Indeed, transgenic expression of the RbAp48 gene induced apoptosis in the exocrine glands, resulting in the development of autoimmune exocrinopathy resembling Sjögren's syndrome (SS). CD4(+) T-cell-mediated autoimmune lesions were aggravated with age, in association with production of autoantibodies against SS-A, SS-B and alpha-fodrin. These findings demonstrated that estrogen deficiency initiates tissue-specific apoptosis in the exocrine gland cells through RbAp48 overexpression and exerts a possible gender-based risk of autoimmune exocrinopathy in postmenopausal women. Thus, these data indicate RbAp48 to be a novel immunotherapeutic target for preventing epithelial cell apoptosis and the development of gender-based autoimmune exocrinopathy.

The impact of hypercortisolism on multiple metabolic conditions is well recognized; the metabolic manifestations of Cushing's syndrome overlap with those seen in type 2 diabetes and the metabolic syndrome. Ketoconazole (KTZ), a widely used antifungal agent that inhibits various enzymes in adrenal cortisol synthesis, is effective in treating hypercortisolemia, but its use is limited by toxicities. KTZ is a racemic compound of two cis-enantiomers: (2R,4S)-(+)-KTZ and (2S,4R)-(-)-KTZ. The consideration of an enantiomer with selective effect but minimal metabolic toxicity has driven the development of DIO-902 ([2S,4R]-[-]-KTZ) for the treatment of patients with type 2 diabetes and the metabolic syndrome. To evaluate the safety profile and effect of KTZ enantiomer, (2S,4R)-(-)-KTZ, on cortisol production, glycemia, and lipid profiles in patients with type 2 diabetes. Review of multiple published studies and examination of preliminary results from a Phase IIb clinical trial. Twelve weeks of treatment with DIO-902 resulted in reduced levels of HbA1c, FPG, total and LDL cholesterol as well as weight loss and decreased BP. In a previously conducted Phase IIa study, C-reactive protein levels decreased with DIO-902 treatment. Unfortunately, the development of this agent has been terminated due to unacceptable safety profiles.

Background: Migration of T cells, including regulatory T (Treg) cells, into the secondary lymph organs is critically controlled by chemokines and adhesion molecules. However, the mechanisms by which Treg cells regulate organ-specific autoimmunity via these molecules remain unclear. Although we previously reported autoimmune exocrinopathy resembling Sjögren's syndrome (SS) in the lacrimal and salivary glands from C-C chemokine receptor 7 (CCR7)-deficient mice, it is still unclear whether CCR7 signaling might specifically affect the dynamics and functions of Treg cells in vivo. We therefore investigated the cellular mechanism for suppressive function of Treg cells via CCR7 in autoimmunity using mouse models and human samples., Methods and Findings: Patrolling Treg cells were detected in the exocrine organs such as lacrimal and salivary glands from normal mice that tend to be targets for autoimmunity while the Treg cells were almost undetectable in the exocrine glands of CCR7(-/-) mice. In addition, we found the significantly increased retention of CD4(+)CD25(+)Foxp3(+) Treg cells in the lymph nodes of CCR7(-/-) mice with aging. Although Treg cell egress requires sphingosine 1-phosphate (S1P), chemotactic function to S1P of CCR7-/- Treg cells was impaired compared with that of WT Treg cells. Moreover, the in vivo suppression activity was remarkably diminished in CCR7(-/-) Treg cells in the model where Treg cells were co-transferred with CCR7(-/-) CD25(-)CD4(+) T cells into Rag2(-/-) mice. Finally, confocal analysis showed that CCR7(+)Treg cells were detectable in normal salivary glands while the number of CCR7(+)Treg cells was extremely decreased in the tissues from patients with Sjögren's syndrome., Conclusions: These results indicate that CCR7 essentially governs the patrolling functions of Treg cells by controlling the traffic to the exocrine organs for protecting autoimmunity. Characterization of this cellular mechanism could have clinical implications by supporting development of new diagnosis or treatments for the organ-specific autoimmune diseases such as Sjögren's syndrome and clarifying how the local immune system regulates autoimmunity.

Although 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been shown to influence immune responses, the effects of low-dose TCDD on the development of autoimmunity are unclear. In this study, using NFS/sld mice as a model for human Sjögren's syndrome, in which the lesions are induced by the thymectomy on day 3 after birth, the autoimmune lesions in the salivary glands, and in later phase, inflammatory cell infiltrations in the other organs were developed by neonatal exposure to nonapoptotic dosage of TCDD without thymectomy on day 3 after birth. We found disruption of thymic selection, but not thymic atrophy, in TCDD-administered mice. The endogenous expression of aryl hydrocarbon receptor in the neonatal thymus was significantly higher than that in the adult thymus, suggesting that the neonatal thymus may be much more sensitive to TCDD compared with the adult thymus. In addition, the production of T(H)1 cytokines such as IL-2 and IFN-gamma from splenic CD4(+) T cells and the autoantibodies relevant for Sjögren's syndrome in the sera from TCDD-exposed mice were significantly increased compared with those in control mice. These results suggest that TCDD/aryl hydrocarbon receptor signaling in the neonatal thymus plays an important role in the early thymic differentiation related to autoimmunity.