Proteomic alteration in gastic adenocarcinomas from Japanese patients

BACKGROUND: Gastric adenocarcinomas comprise one of the common types of cancers in Asian countries including Japan. Comprehensive protein profiling of paired surgical specimens of primary gastric adenocarcinomas and nontumor mucosae derived from Japanese patients was carried out by means of two-dimensional gel electrophoresis (2D-EP) and liquid chromatography-electrospray ionic tandem mass spectrometry (LC-ESI-MS) to establish gastric cancer-specific proteins as putative clinical biomarkers and molecular targets for chemotherapy. RESULTS: Relatively common alterations in protein expression were revealed in the tumor tissues. Increases in manganese dismutase and nonhistone chromosomal protein HMG-1 (HMG-1) were observed, while decreases in carbonic anhydrases I and II, glutatione-S-transferase and foveolin precursor (gastrokine-1) (FOV), an 18-kDa stomach-specific protein with putative tumor suppressor activity, were detected. RT-PCR analysis also revealed significant down-regulation of FOV mRNA expression in tumor tissues. CONCLUSION: A possible pathological role for down-regulation of FOV in gastric carcinogenesis was demonstrated. Evaluation of the specific decreases in gene and protein expression of FOV in patients may be utilized as clinical biomarkers for effective diagnosis and assessment of gastric cancer

Elastogenesis in cultured dermal fibroblasts from patients with lysosomal β-galactosidase, protective protein/cathepsin A and neuraminidase-1 deficiencies

The human GLB1 gene encodes a lysosomal β-galactosidase (β-Gal) and an elastinbinding protein(EBP). Defect of the EBP as a chaperon for tropoelastin and a component of receptor complex amongneuraminidase-1 (NEU1) and protective protein/ cathepsin A(PPCA)is suggested responsible for impaired elastogenesis in autosomal recessive β-Gal, PPCA and NEU1 deficiencies. The purpose of this study is to determine effects ofGLB1, PPCA and NEU1gene mutations on elastogenesis in skin fibroblasts. Elastic fiber formation and the EBP mRNA expression were examined by immunofluorescence with an anti-tropoelastin antibody and RT-PCR selective for EBP in skin fibroblasts with these lysosomal enzyme deficiencies. Apparently normal elastogenesis and EBP mRNA expression were observed for fibroblasts from Morquio B disease cases with the GLB1 gene alleles (W273L/W273L, W273L/R482H andW273L/W509C substitutions, respectively), a galactosialidosis case with the PPCA allele (IVS7+3A/IVS7+3A) and a sialidosis case with the NEU1 allele (V217M/G243R) as well as normal subject. In this study, theW273L substitution in the EBP could impossibly cause the proposed defect of elastogenesis, and the typical PPCA splicing mutation and the V217M/G243R substitutions in the NEU1 might hardly have effects on elastic fiber formation in the dermal fibroblasts

NCRT with S-1 plus irinotecan for LALRC

Background and purpose: Preoperative 5-fluorouracil-based chemoradiotherapy is a standard treatment for locally advanced lower rectal cancer (LALRC). We performed a phase I study to develop a new regimen combining irinotecan and S-1. Materials and methods: Patients with LALRC (T3-4, N0-2) were studied. The radiation dose was 45 Gy in 25 fractions. S-1 (80 mg/m2/day) was administered on days 1–5, 8–12, 22–26, and 29–33. Irinotecan was administered on days 1, 8, 22, and 29. The dose of irinotecan was initially 60 mg/m2 (level 1). Surgery was performed 6–10 weeks after the chemoradiotherapy. Results: Twenty patients were enrolled, of whom 18 patients were analyzed. Dose-limiting toxicity (DLT) did not occur in the first 3 patients treated with irinotecan at 80 mg/m2 (level 2), but developed in 3 of the 6 patients who received irinotecan at 90 mg/m2 (level 3). Then DLT occurred in 3 other patients at level 2. At level 2 or 3, DLT comprised neutropenia, thrombocytopenia, and diarrhea. Level 2 was designated as the maximum tolerated dose, and level 1 as a recommended dose (RD). The pathological complete response rate was 28%, and the down-staging rate was 56%. Conclusions: Our results suggested that the RD of irinotecan when combined with preoperative S-1 and pelvic radiation was 60 mg/m2

Prognostic Impact of Genetic Polymorphism in Mineralocorticoid Receptor and Comorbidity With Hypertension in Androgen-Deprivation Therapy

Mineralocorticoid receptor (MR) signaling which is closely associated with hypertension plays important roles in resistance to antiandrogen therapy in prostate cancer. However, its impact on the prognosis in androgen-deprivation therapy (ADT) has not been elucidated. Then, we investigated the impact of genetic variation in MR and comorbidity with hypertension on the prognosis in ADT. This study included 182 Japanese patients with prostate cancer treated with ADT, whose comorbidity status with hypertension were available. The associations of MR polymorphism (rs5522) and comorbidity with hypertension with clinicopathological parameters as well as progression-free survival and overall survival were examined. Clinicopathological characteristics were comparable between genetic variation in MR. However, homozygous variant in MR was associated with shorter time to castration resistance (P = 0.014) and any-cause death (P = 0.024). In patients' background, presence of comorbidity with hypertension showed the trend with lower PSA level at diagnosis and lower biopsy Gleason score, as well as significant association with less incidence of N1. Comorbidity with hypertension was associated with longer time to castration resistance (P = 0.043) and any-cause death (P = 0.046), which was diminished on multivariate analysis including age, PSA level at diagnosis, biopsy Gleason score, clinical stage, and the modality of hormonal therapy. Genetic variation in MR (rs5522) and comorbidity with hypertension were significantly and potentially associated with prognosis when treated with ADT, respectively. This suggests that the individual intensity of MR signaling may be associated with resistance to ADT and a promising biomarker in ADT

RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems

The immune system consists of two evolutionarily different but closely related responses, innate immunity and adaptive immunity. Each of these responses has characteristic receptors-Toll-like receptors (TLRs) for innate immunity and antigen-specific receptors for adaptive immunity. Here we show that the caspase recruitment domain (CARD)-containing serine/threonine kinase Rip2 (also known as RICK, CARDIAK, CCK and Ripk2)(1-4) transduces signals from receptors of both immune responses. Rip2 was recruited to TLR2 signalling complexes after ligand stimulation. Moreover, cytokine production in Rip2-deficient cells was reduced on stimulation of TLRs with lipopolysaccharide, peptidoglycan and double-stranded RNA, but not with bacterial DNA, indicating that Rip2 is downstream of TLR2/3/4 but not TLR9. Rip2-deficient cells were also hyporesponsive to signalling through interleukin (IL)-1 and IL-18 receptors, and deficient for signalling through Nod proteins-molecules also implicated in the innate immune response. Furthermore, Rip2-deficient T cells showed severely reduced NF-kappaB activation, IL-2 production and proliferation on T-cell-receptor (TCR) engagement, and impaired differentiation to T-helper subtype 1 (T(H)1) cells, indicating that Rip2 is required for optimal TCR signalling and T-cell differentiation. Rip2 is therefore a signal transducer and integrator of signals for both the innate and adaptive immune systems.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62842/1/416194a.pd

Characteristics of local wind force and wind response of a building under short-rise-time gusts

This paper was reviewed and accepted by the APCWE-IX Programme Committee for Presentation at the 9th Asia-Pacific Conference on Wind Engineering, University of Auckland, Auckland, New Zealand, held from 3-7 December 2017

Isotopic Evidence for Microbial Nitrogen Cycling in a Glacier Interior of High-Mountain Asia

Glaciers are now acknowledged as an important biome globally, but biological processes in the interior of the glacier (englacial) are thought to be slow and to play only a minor role in biogeochemical cycles. In this study, we demonstrate extensive, microbially driven englacial nitrogen cycling in an Asian glacier using the stable isotopes (δ15N, δ18O, and Δ17O values) of nitrate. Apparent decreases in Δ17O values of nitrate in an 8 m shallow firn core from the accumulation area indicate that nitrifiers gradually replaced ∼80% of atmospheric nitrate with nitrate from microbial nitrification on a decadal scale. Nitrate concentrations did not increase with depth in this core, suggesting the presence of nitrate sinks by microbial assimilation and denitrification within the firn layers. The estimated englacial metabolic rate using isotopic mass balance was classified as growth metabolism, which is approximately 2 orders of magnitude more active than previously known cold-environment metabolisms. In a 56 m ice core from the interior of the ablation area, we found less nitrification but continued microbial nitrate consumption, implying that organic matter is microbially accumulated over centuries before appearing on the ablating surface. Such englacial microbial products may support supraglacial microbes, potentially promoting glacial darkening and melting. With predicted global warming and higher nitrogen loads, englacial nutrient cycling and its roles may become increasingly important in the future