Clinicopathological and molecular characteristics of gastric papillary adenocarcinoma.

Papillary adenocarcinoma is defined as carcinoma with a well-defined papillary or villous structure. Despite sharing clinicopathological and morphological features with tubular adenocarcinomas, papillary adenocarcinomas frequently show microsatellite instability. The present study aimed to clarify the clinicopathological features, molecular classification, and programmed death-ligand 1 (PD-L1) expression characteristics of papillary adenocarcinoma, especially tumors with microsatellite instability. We examined the microsatellite status and expression of mucin core proteins and PD-L1 as well as the clinicopathological features in 40 gastric papillary adenocarcinomas. Surrogate immunohistochemical analysis of p53 and mismatch repair proteins along with Epstein-Barr virus-encoded RNA in situ hybridization were performed for molecular classification. Female predominance and frequent microsatellite instability were observed in papillary adenocarcinoma in comparison with tubular adenocarcinoma. The presence of microsatellite instability in papillary adenocarcinoma was significantly correlated with older age, tumor-infiltrating lymphocytes, and Crohn's-like lymphoid reactions. Surrogate examination demonstrated that the genomically stable type (17 cases, 42.5%) was the most common, followed by the microsatellite-unstable type (14 cases, 35%). Among the seven cases showing PD-L1-positive expression in tumor cells, four involved carcinomas with microsatellite instability. These results reveal the clinicopathological and molecular characteristics of gastric papillary adenocarcinoma.

Serum amyloid A3 binds MD-2 to activate p38 and NF-κB pathways in a MyD88-dependent manner.

Serum amyloid A (SAA) 3 is a major component of the acute phase of inflammation. We previously reported that SAA3 served as an endogenous peptide ligand for TLR4 to facilitate lung metastasis. Because these experiments were performed with SAA3 recombinant proteins purified from Escherichia coli or mammalian cells, we could not rule out the possibility of LPS contamination. In this study, we used SAA3 synthetic peptides to eliminate the presence of LPS in SAA3. We found that the SAA3 synthetic peptide (aa 20-86) (20-86) stimulated cell migration and activated p38 in a manner dependent on TLR4, MD-2, and MyD88. SAA3 (20-86) also activated NF-κB and Rho small GTPase. Using surface plasmon resonance analysis, the binding constant KD values between SAA3 (20-86) or SAA3 (43-57) and TLR4/MD-2 protein highly purified by the baculovirus system were 2.2 and 30 µM, respectively. FLAG-tagged SAA3 tightly bound to protein A-tagged MD-2, but not to TLR4 in baculovirus coinfection experiments. Although SAA3 (20-86) caused a low, but appreciable level of endocytosis in TLR4, it induced the upregulation of both IL-6 and TNF-α, but not IFN-ß1. An i.v. injection of SAA3 (43-57) induced the lung recruitment of CD11b(+)Gr-1(+) cells at an estimated serum concentration around its KD value toward TLR4/MD-2. Taken together, these results suggest that SAA3 directly binds MD-2 and activates the MyD88-dependent TLR4/MD-2 pathway.

Ephrin-A1 expression induced by S100A8 is mediated by the toll-like receptor 4.

The deregulation of Eph/ephrin protein expression has been shown to lead to tumor development and progression. Both mRNA and protein expression analyses using clinical samples have demonstrated that ephrin-A1 is over-expressed in various cancers and positively correlates with a poor prognosis for cancer patients. The prognosis of cancer patients depends on metastasis to distant organs. We previously demonstrated that ADAM12 metalloproteinase cleaved ephrin-A1 and ADAM12-cleaved ephrin-A1 enhanced vascular permeability by degrading VE-cadherin and the EphA2 receptor at the plasma membrane. An increase of soluble ephrin-A1 levels in the serum facilitated tumor cell recruitment to the lungs, which resulted in lung metastasis. We also found that ephrin-A1 was overexpressed in 3LL tumors, a highly metastatic tumor, in mice and TNFα, an authentic positive regulator of ephrin-A1, was not elevated in the tumors, whereas S100A8 was. Moreover, S100A8 induced ephrin-A1 expression mediated by the toll-like receptor 4 (TLR4). S100A8 is known to be an endogenous ligand for TLR4 and its expression was shown to be increased in the lungs at the premetastatic phase. Thus, S100A8 and ephrin-A1 contribute to lung metastasis. Therefore, elucidating the regulation mechanism of ephrin-A1 overexpression is of importance and may lead to the development of therapeutic drugs against tumor growth and metastasis.

Anti-glomerular basement membrane disease developing 3 years after the development of Sweet syndrome and 1 year after the development of anti-neutrophil cytoplasmic antibody-associated vasculitis: a case report.

A 73-year-old Japanese woman, with a history of Sweet syndrome diagnosed 3 years earlier and anti-myeloperoxidase (MPO) antibody anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis diagnosed 1 year earlier, presented with an episode of rapidly progressive glomerulonephritis (RPGN) with anti-glomerular basement membrane (GBM) disease. At the time of diagnosis of the ANCA-associated vasculitis 1 year earlier, serological testing yielded a negative result for anti-GBM antibody. However, at the present visit, serology for anti-MPO antibody was negative, while that for anti-GBM antibody was positive. This is the first report of anti-GBM disease developing sequentially after Sweet syndrome and ANCA-associated vasculitis. This case may provide clues to the potential immunological links among these three distinct conditions.

Accelerated telomere shortening in adrenal zona reticularis in patients with prolonged critical illness.

Background: The number of patients with prolonged critical illness (PCI) has been increasing in many countries, and the adrenal gland plays an important role in maintaining homeostasis during PCI. Chronic disease burden is reportedly associated with shorter telomere lengths in human tissues. Telomere shortening in human somatic cells is largely dependent on cell divisions, and critically short telomeres lead to cellular dysfunction and aging. However, the association between PCI and telomere lengths in human adrenal cells is poorly understood. In this study, we investigated this association to assess whether the burden of PCI could accelerate the aging process in adrenal cells. Methods: Adrenocortical tissues from patients who died after PCI usually show a diffuse pattern of intracellular cholesterol ester depletion (i.e., lipid depletion). This study examined near-normal adrenal glands obtained from autopsied patients who died suddenly (control group) and lipid-depleted adrenal glands obtained from autopsied patients who died after PCI (PCI group). The control group included 7 men aged 80 to 94 years (mean age: 85.3 years) and 7 women aged 84 to 94 years (mean age: 87.7 years). The PCI group included 10 men aged 71 to 88 years (mean age: 78.8 years) and 8 women aged 77 to 95 years (mean age: 85.6 years). By using quantitative fluorescence in situ hybridization, relative telomere lengths (RTLs) were determined in the parenchymal cells of the three adrenocortical zones (zona glomerulosa, zona fasciculata, and zona reticularis [ZR]) and in the chromaffin cells of the medulla. The number of adrenal parenchymal cells was determined by immunohistochemistry and digital image analysis. Results: RTLs in ZR cells were significantly shorter in the PCI group than in the control group for both men and women (P = 0.0001 for men and P = 0.0012 for women). However, RTLs in the remaining three types of adrenal cells did not differ between the control and PCI groups for both men and women. The number of ZR cells was higher in the PCI group than in the control group for both men and women (P < 0.0001 for both men and women). The proportion of the number of ZR cells to the total number of adrenocortical parenchymal cells was also higher in the PCI group than in the control group (P < 0.0001 for both men and women). The Ki-67 proliferation index in ZR cells was higher in the PCI group than in the control group (P = 0.0039 for men and P = 0.0063 for women). Conclusions: This study demonstrated ZR cell-specific telomere shortening in patients with adrenal lipid depletion who died after PCI. Our results suggest that the reactive proliferation of ZR cells accelerates the telomere shortening and aging process in ZR cells in these patients. The results of our study may contribute to the understanding of adrenal aging during PCI.

Painting image browser applying an associate-rule-aware multidimensional data visualization technique.

Exploration of artworks is enjoyable but often time consuming. For example, it is not always easy to discover the favorite types of unknown painting works. It is not also always easy to explore unpopular painting works which looks similar to painting works created by famous artists. This paper presents a painting image browser which assists the explorative discovery of user-interested painting works. The presented browser applies a new multidimensional data visualization technique that highlights particular ranges of particular numeric values based on association rules to suggest cues to find favorite painting images. This study assumes a large number of painting images are provided where categorical information (e.g., names of artists, created year) is assigned to the images. The presented system firstly calculates the feature values of the images as a preprocessing step. Then the browser visualizes the multidimensional feature values as a heatmap and highlights association rules discovered from the relationships between the feature values and categorical information. This mechanism enables users to explore favorite painting images or painting images that look similar to famous painting works. Our case study and user evaluation demonstrates the effectiveness of the presented image browser.

Correlation Between Telomere Attrition of Zona Fasciculata and Adrenal Weight Reduction in Older Men.

CONTEXT: Although numerous theories are reported on sex differences in longevity, the underlying biological mechanisms remain unknown. We previously reported that telomere length in the zona reticularis cells of the human adrenal cortex was significantly longer in older than that in younger subjects. However, we could not evaluate sex differences in the telomere lengths. OBJECTIVE: To compare the telomere lengths of adrenocortical and adrenal medullar cells between men and women from infancy through older adulthood. METHODS: Adrenal glands of 30 male (aged 0 to 100 years) and 25 female (aged 0 to 104 years) autopsied subjects were retrieved from autopsy files. Using quantitative fluorescence in situ hybridization, relative telomere lengths were determined in the parenchymal cells of the 3 adrenocortical zones and medulla. Age-related changes in the weight of adrenal glands were also investigated. MAIN RESULTS: Older male subjects (aged 65 years or older) had significantly shorter telomere lengths in zona fasciculata (ZF) cells compared to the corresponding female subjects. In men, older subjects exhibited a significant age-related reduction in adrenal weight; however, no age-related changes in adrenal weight were detected in women. CONCLUSION: Telomere attrition of ZF cells was correlated with adrenal weight reduction in older men but not in older women, suggesting a decreased number of ZF cells in older men. This may help us understand the possible biological mechanisms of sex difference in longevity of humans.

[Effect of clinical pathway in the treatment of inpatients with ischemic colitis].

Based on the results of a retrospective review of clinical data on inpatients with ischemic colitis treated at our hospital, we created a clinical pathway and evaluated its usefulness. We used the clinical pathway for 21 inpatients, and the patient who fulfilled the criteria consisted of 18 inpatients. The fasting period after the onset and the duration of hospitalization were compared with those of 60 patients before implementation of the clinical pathway. The fasting period after the onset before and after implementation were 6.20+/- 3.42 days (mean+/- SD), and 5.28+/- 1.27 days, respectively. The duration of hospitalization before and after implementation was 10.37+/- 7.32 days, 8.37+/- 2.89 days, respectively. The clinical pathway is useful for shortening the duration of hospitalization, enhancing the uniformity of treatment and controlling the treatment risk.

Genetic analysis of root elongation induced by phosphorus deficiency in rice (Oryza sativa L.): fine QTL mapping and multivariate analysis of related traits.

Root elongation induced by phosphorus deficiency has been reported as one of the adaptive mechanisms in plants. Genetic differences were found in rice for the root elongation under phosphorus deficiency (REP), for which a distinct quantitative trait locus (QTL) was detected on the long arm of chromosome 6. Subsequently, the effect and position of the QTL, designated as qREP-6, were confirmed using chromosome segment substitution lines (CSSLs), in which the background of a japonica cultivar, 'Nipponbare' with non-REP, was partially substituted by chromosomal segments from an indica cultivar, 'Kasalath' with remarkable REP. Out of 54 CSSLs, two lines (CSSL28 and CSSL29) that retain a common 'Kasalath'-derived segment on the long arm of chromosome 6 showed a significantly high REP. The high REP lines also showed high adaptabilities such as enhanced tillering ability and shoot phosphorus content. Accordingly, conditional dependencies between the related traits were assessed using a graphical Gaussian model (GGM). Direct interactions between REP and root length, and between root length and tiller number were detected under P deficiency in CSSLs. Furthermore, qREP-6 for REP and qTNP-6 for tiller number under P deficiency were fine-mapped with an F(2) population of a cross between Nipponbare and CSSL29. A region containing qREP-6 accounted for more than half of the phenotypic variance, the most plausible interval of which contained 37 candidate genes. The result provides a foundation for cloning of the qREP-6 gene which will be applicable to study P deficiency-dependent response and to improve rice's adaptability to P deficiency stress.