Invasive fungal infections (IFI) are an important complication in hematologic malignancies and stem-cell transplantation (SCT). However, there are limited data characterizing IFI in children. The clinical feature of IFI after chemotherapy and SCT were analyzed in 334 pediatric patients treated at Hokkaido University Hospital from 1997 to 2006. The cumulative incidence of IFI was 6.9%; this comprised cases of proven, probable and possible IFI at rates of 1.2%, 3.0%, and 2.7%, respectively. The infected lesions were lung in 14 patients, liver in 5 patients, brain in 3 patients, fungemia in 2 patients, kidney in 1 patient, and endophthalmitis in 1 patient. The mortality of IFI was 48.2%, excluding patients who died due to relapse and interstitial pneumonitis; in particular, 71.4% patients with a lung lesion (10/14) died due to IFI. Fifty-nine pediatric patients died in our institution over the 10-year period of the study and IFI was the direct cause of death in 18.6% (11/59) of the patients. Risk factors for IFI with chemotherapy and SCT were also analyzed. Univariate analysis showed that age at diagnosis older than 10 years, relapse of original disease, long-term administration of broad-spectrum antibiotics, and acute myelogenous leukemia (AML) were the risk factors for IFI. All patients with IFI received long-term antibiotic therapy. AML was most strongly associated using a multivariate analysis. The prognosis of IFI has been expected poor; therefore, prevention of this condition, especially for older patients with AML, would be important.

Objective. To assess the efficacy and tolerability of hydroxychloroquine (HCQ) in patients with cutaneous lupus erythematosus (CLE), in a phase III clinical trial conducted in Japan.Methods. We conducted a double-blind, randomized, parallel-group clinical trial. This was a baselinecontrolled study, and the group differences were evaluated in an exploratory analysis. A total of 103 patients with active CLE (according to a Cutaneous Lupus Erythematosus Disease Area and Severity Index [CLASI] activity score of ‡4) were included. Patients were randomized 3:1 to receive HCQ or placebo during the 16-week doubleblind period, and all patients were given HCQ during the following 36-week single-blind period. The primary efficacy end point was a reduction in the CLASI activity score at week 16. The secondary end points included the central photo evaluation (5-point scale), patient's global assessment (7-point scale), the Skindex-29 score, and investigator's global assessment (7-point scale, based on the other 3 secondary end points). In patients with systemic lupus erythematosus, fatigue and musculoskeletal pain were assessed. Safety was assessed up to week 55.Results. The mean CLASI score at week 16 was significantly improved from baseline in both the HCQ group and the placebo group: mean change 24.6 (95% confidence interval [95% CI] 26.1, 23.1) (P < 0.0001), and mean change 23.2 (95% CI 25.1, 21.3) (P 5 0.002), respectively, without between-group difference (P 5 0.197). The investigator's global assessment demonstrated a greater proportion of "improved" and "remarkably improved" patients in the HCQ group (51.4% versus 8.7% in the placebo group [P 5 0.0002 between groups]). The other secondary end points supported the efficacy of HCQ. Cellulitis, drug eruption, hepatic dysfunction, and Stevens-Johnson syndrome ClinicalTrials.gov identifier: NCT01551069. Supported

Type 2 diabetes mellitus is a risk factor for symptomatic GERD. In DM patients, use of oral hypoglycemic agents, body mass index, disease duration and the quality of diabetic control influenced the incidence of GERD.

SummaryDeregulated expression of tripartite motif-containing protein 32 (TRIM32, an E3 ubiquitin-protein ligase) contributes to various diseases. Here we report, using quantitative proteomics and biochemistry, that 14-3-3 proteins bind to phosphorylated TRIM32 and prevent TRIM32 autoubiquitylation and the formation of TRIM32-containing cytoplasmic bodies, which are potential autoregulatory mechanisms that can reduce the concentration of soluble free TRIM32. The 14-3-3-TRIM32 interaction is dependent on protein-kinase-A-catalyzed phosphorylation of TRIM32 at Ser651. We found that the inhibitory effect of 14-3-3 is, in part, a consequence of disrupting the propensity of TRIM32 to undergo higher-order self-association without affecting its dimerization. Consequently, dimerized TRIM32 bound to 14-3-3 was sequestered in a distinct cytoplasmic pool away from the microtubule network, whereas a TRIM32 mutant that cannot bind 14-3-3 underwent multimerization and was unavailable to facilitate cell growth. Our results reveal a novel connection between ubiquitylation and phosphorylation pathways, which could modulate a variety of cell events by stimulating the formation of the 14-3-3-TRIM32 signaling complex.

Ataxia-telangiectasia (AT) is an autosomal recessive genetic disease characterized by immunological deficiencies, neurological degeneration, developmental abnormalities and an increased risk of cancer. Ataxia-telangiectasia group D (ATDC) was initially described as a gene related to AT. Ataxia-telangiectasia group D, also known as TRIM29, is structurally a member of the tripartite motif (TRIM) family of proteins, some of which have been reported to be highly expressed in some human carcinomas, but the involvement of TRIM29 in carcinogenesis has not been fully elucidated. In this study, we found by using yeast two-hybrid screening that TRIM29 binds to Tip60, which has been reported as a cellular acetyltransferase protein. Overexpression of TRIM29 promoted degradation and changed localization of Tip60 and reduced acetylation of p53 at lysine 120 by Tip60, resulting in enhancement of cell growth and transforming activity. In addition, we found that TRIM29 suppresses apoptosis induced by UV irradiation in HCT116 cell lines. These findings suggest that TRIM29 functions as an oncogene that promotes tumor growth.