A new conceptualization for Mikulicz's disease as an IgG4-related plasmacytic disease

Mikulicz's disease (MD) has been included within the diagnosis of primary Sjögren's syndrome (SS), but it represents a unique condition involving persistent enlargement of the lacrimal and salivary glands characterized by few autoimmune reactions and good responsiveness to glucocorticoids, leading to the recovery of gland function. Mikulicz's disease was recently reported to be associated with elevated immunoglobulin G4 (IgG4) concentrations in the serum and prominent infiltration of plasmacytes expressing IgG4 into the lacrimal and salivary glands. The following features were used for diagnosis: (1) visual confirmation of symmetrical and persistent swelling in more than two lacrimal and major salivary glands; (2) prominent mononuclear cell infiltration of lacrimal and salivary glands; and (3) exclusion of other diseases that present with glandular swelling, such as sarcoidosis and lymphoproliferative disease. These features are not observed in most SS cases. The complications of MD include autoimmune pancreatitis, retroperitoneal fibrosis, tubulointerstitial nephritis, autoimmune hypophysitis, and Riedel's thyroiditis, all of which show IgG4 involvement in their pathogenesis. Mikulicz's disease thus differs from SS and may be a systemic IgG4-related plasmacytic disease

Epigenetic inactivation of the LRFN5 gene encoding type I transmembrane glycoprotein in esophageal squamous cell carcinoma

Alcohol drinking and cigarette smoking are significantly associated with an increased risk of esophageal cancer. Promoter hypermethylation of tumor suppressor genes plays an important role in esophageal squamous cell carcinoma (ESCC). To profile methylation changes and to identify methylated genes in clinical ESCC samples in a high-throughput fashion, we carried out genomewide methylation analysis using the methylated CpG island amplifi cation microarray (MCAM) technique in paired samples of ESCC and adjacent non-cancerous tissue and normal esophageal mucosa. As a surrogate of genome-wide hypomethylation, levels of LINE-1 methylation were analyzed using bisulfi te pyrosequencing. The degree of genome-wide methylation of the majority of non-cancerous esophageal tissues was intermediate between that of ESCC tissues and that of normal esophageal mucosa of healthy volunteers. A total of 210 candidate genes that are hypermethylated in ESCCs were identifi ed by using the MCAM technique. Among the candidate genes, we found that the LRFN5 gene coding for a transmembrane protein was transcriptionally silenced by promoter CpG island hypermethylation in ESCC. LRFN5 CpG island hypermethylation was a relatively common event even in patients without drinking habits. LRFN5 expression levels were reduced in most of the ESCC cell lines and ESCC tissues, being correlated with hypemethylation.Methylation levels of LINE-1 were significantly lower in tumor tissues than in adjacent non-tumor tissues of ESCC and inversely correlated with LRFN5 methylation. Importantly, LRFN5 immunostaining was undetectable in 5/7 (71%) intramucosal ESCC tissues,suggesting that LRFN5 silencing is an early event in ESCC pathogenesis. Hypermethylation of the LRFN5 gene may provide a useful marker for detecting preinvasive and early-stage ESCC, especially in individuals without drinking habits.departmental bulletin pape

Prediction of postoperative liver failure and evaluation of modifi ed criteria for liver resection with computed volume analysis

Background/Aims: The exact resectable volume corresponding to liver function has never been elucidated for safe resection of a diseased liver. The aim of this study was to evaluate whether modifi ed criteria for safe liver resection could be used to predict postoperative liver failure/dysfunction.Methodology: Consecutive 86 patients who underwent liver resections were assessed. Clinical laboratory tests and liver volume were evaluated. The modifi ed criteria used to determine safe liver resection consisted of indocyanine green retention rate at 15 min (ICGR15), antithrombin III (ATIII), clearance index (HH15), and receptor index (LHL15). We compared clinical outcomes after liver resection using our modifi ed criteria and Makuuchi criteria. Results: There were 78 patients without liver failure and 8 with liver failure/dysfunction. ICGR15 (P < 0.001), ATIII (P = 0.036), operative time (P = 0.014), tumor type (P = 0.047), modifi ed criteria score (P = 0.037), lost liver volume (P = 0.006), and modifi ed criteria (P= 0.007) were signifi cantly different between the groups. Diagnostic probability of modifi ed criteria (P = 0.007) was better than the one of Makuuchi criteria (P = 0.271).Conclusions: Postoperative liver failure/dysfunction could be predicted using the modifi ed criteria. Furthermore, the criteria could be used to provide a putative liver volume for safe removal.departmental bulletin pape

Evaluation and Clinical Validity of a New Questionnaire for Mikulicz's Disease

Objectives. The characteristic features of Mikulicz's disease (MD) are diffuse enlargement of the lacrimal and submandibular glands, elevated levels of serum immunoglobulin (Ig)G4, and abundant infiltration of IgG4-positive plasmacytes into both glands. No disease index is available to properly evaluate MD, so we developed a functional assessment of MD, the Mikulicz's disease activity questionnaire (MAQ), and evaluated its clinical efficacy. Methods. We selected 18 patients who were either being treated for MD or who had presented with recurrence. The patients completed a self-assessment and were scored according to the MAQ sheet during each visit between December 2009 and August 2011. Assessment items were in regard to increases or decreases in lacrimal and salivary gland enlargement and severity of sicca symptoms. Results. On the first visits, MAQ scores were high, but scores decreased rapidly as treatment progressed. When doses of glucocorticoid were reduced, some patients showed increased scores. Dry-symptom scores increased initially. MAQ scores for patients with recurrent MD gradually increased over several months before relapse. However, some patients displayed no elevation in MAQ scores due to relapses at other sites. Conclusion. MAQ score can be used to quantify flares and treatment response and is useful for functional assessment of MD

Epigenetic biomarkers for prediction of sensitivity to chemotherapeutic drugs in multiple myeloma

Multiple myeloma continues to be a lethal malignancy despite the development of treatments such as high-dose chemotherapy combined with stem cell transplantation. Multiple myeloma arises through an accumulation of multiple genetic anges, including immunoglobulin gene rearrangements involved in Cyclin D. The main difficulties in multiple myeloma treatments are drug-resistance. DNA methylation of the5\u27 CpG islands of genes is often found in multiple myeloma. To screen for he genes involved in tumorigenesis of multiple myeloma, which are silenced by DNA methylation, we performed cDNA microarray analysis using multiple myeloma cell lines treated with demethylating agent5-aza-2-deoxycytidine (DAC), and entified RASD1, a dexamethasone (Dex)-inducible gene, as one of the targets of epigenetic changes. Inactivation of RASD1 was found to correlate with resistance to Dex, and treatment of multiple myeloma cells with DAC restored sensitivity to Dex. These findings suggest the involvement of epigenetic gene silencing in multiple myeloma progression and drug-resistance, and the usefulness of demethylation therapy for multiple myeloma treatment. Furthermore, DNA methylation can be an epigenetic biomarker for multiple myeloma

Clinical Study Evaluation and Clinical Validity of a New Questionnaire for Mikulicz&apos;s Disease

Objectives. The characteristic features of Mikulicz&apos;s disease (MD) are diffuse enlargement of the lacrimal and submandibular glands, elevated levels of serum immunoglobulin (Ig)G4, and abundant infiltration of IgG4-positive plasmacytes into both glands. No disease index is available to properly evaluate MD, so we developed a functional assessment of MD, the Mikulicz&apos;s disease activity questionnaire (MAQ), and evaluated its clinical efficacy. Methods. We selected 18 patients who were either being treated for MD or who had presented with recurrence. The patients completed a self-assessment and were scored according to the MAQ sheet during each visit between December 2009 and August 2011. Assessment items were in regard to increases or decreases in lacrimal and salivary gland enlargement and severity of sicca symptoms. Results. On the first visits, MAQ scores were high, but scores decreased rapidly as treatment progressed. When doses of glucocorticoid were reduced, some patients showed increased scores. Dry-symptom scores increased initially. MAQ scores for patients with recurrent MD gradually increased over several months before relapse. However, some patients displayed no elevation in MAQ scores due to relapses at other sites. Conclusion. MAQ score can be used to quantify flares and treatment response and is useful for functional assessment of MD

Surgical benefits of liver hanging maneuver for hepatectomy of huge liver tumor

In hepatic surgery, it is very important to control bleeding during liver resection. However, in hepatectomy for a huge liver tumor it is often difficult to reduce bleeding volume and maintain an excellent surgical view. The anterior pproach, which is hepatectomy done using the liver hanging maneuver, has beneficial effects reducing bleeding volume and preventing scattering of cancer cells from huge liver tumors. W e investigated the surgical benefits of the liver anging maneuver during hepatectomy for huge liver tumors in our department.

Oxidative Stress Impairs the Heat Stress Response and Delays Unfolded Protein Recovery

Background: Environmental changes, air pollution and ozone depletion are increasing oxidative stress, and global warming threatens health by heat stress. We now face a high risk of simultaneous exposure to heat and oxidative stress. However, there have been few studies investigating their combined adverse effects on cell viability. Principal Findings: Pretreatment of hydrogen peroxide (H2O2) specifically and highly sensitized cells to heat stress, and enhanced loss of mitochondrial membrane potential. H 2O 2 exposure impaired the HSP40/HSP70 induction as heat shock response (HSR) and the unfolded protein recovery, and enhanced eIF2a phosphorylation and/or XBP1 splicing, land marks of ER stress. These H2O2-mediated effects mimicked enhanced heat sensitivity in HSF1 knockdown or knockout cells. Importantly, thermal preconditioning blocked H 2O 2–mediated inhibitory effects on refolding activity and rescued HSF1 +/+ MEFs, but neither blocked the effects nor rescued HSF1-/- MEFs. These data strongly suggest that inhibition of HSR and refolding activity is crucial for H2O2–mediated enhanced heat sensitivity. Conclusions: H2O2 blocks HSR and refolding activity under heat stress, thereby leading to insufficient quality control and enhancing ER stress. These uncontrolled stress responses may enhance cell death. Our data thus highlight oxidative stres

Interferon-α/β and Anti-Fibroblast Growth Factor Receptor 1 Monoclonal Antibody Suppress Hepatic Cancer Cells In Vitro and In Vivo

Hepatocellular carcinoma (HCC) is the most commonly occurring primary liver cancer and ranks as the fifth most frequently occurring cancer, overall, and the third leading cause of cancer deaths, worldwide. At present, effective therapeutic options available for HCC are limited; consequently, the prognosis for these patients is poor. Our aim in the present study was to identify a novel target for antibody therapy against HCC..Our results suggest that the combined use of an anti-FGFR1 antibody and interferon-α/β is a promising approach to the treatment of HCC

Cytoplasmic RASSF2A is a proapoptotic mediator whose expression is epigenetically silenced in gastric cancer

Gastric cancer cells often show altered Ras signaling, though the underlying molecular mechanism is not fully understood. We examined the expression profile of eight ras-association domain family (RASSF) genes plus MST1/2 and found that RASSF2A is the most frequently downregulated in gastric cancer. RASSF2A was completely silenced in 6 of 10 gastric cancer cell lines as a result of promoter methylation, and expression was restored by treating the cells with 5-aza-2′-deoxycytidine. Introduction of RASSF2A into non-expressing cell lines suppressed colony formation and induced apoptosis. These effects were associated with the cytoplasmic localization of RASSF2A and morphological changes to the cells. Complementary DNA microarray analysis revealed that RASSF2A suppresses the expression of inflammatory cytokines, which may in turn suppress angiogenesis and invasion. In primary gastric cancers, aberrant methylation of RASSF2A was detected in 23 of 78 (29.5%) cases, and methylation correlated significantly with an absence of the lymphatic invasion, absence of venous invasion, absence of lymph node metastasis, less advanced stages, Epstein–Barr virus, absence of p53 mutations and the presence of the CpG island methylator phenotype-high. These results suggest that epigenetic inactivation of RASSF2A is required for tumorigenesis in a subset of gastric cancers