Bayesian Updating of Earthquake Vulnerability Functions with Application to Mortality Rates

Vulnerability functions often rely on data from expert opinion, post-earthquake investigations, or analytical simulations. Combining the information can be particularly challenging. In this paper a Bayesian statistical framework is presented to combining disparate information. The framework is illustrated through application to earthquake mortality data obtained from the 2005 Pakistan earthquake and from PAGER. Three different models are tested including an exponential, a combination of Bernoulli and exponential and Bernoulli and gamma fit to model respectively zero and non-zero mortality rates. A novel Bayesian model for the Bernoulli exponential and Bernoulli-gamma probability densities is introduced. It is found that the exponential distribution represents the zero casualties very poorly. The Bernoulli-exponential and Bernoulli-gamma models capture the data for both the zero and non-zero mortality rates. It is also shown that the Bernoulli-gamma model fits the 2005 Pakistan data the best and has uncertainties that are smaller than either the ones from the 2005 Pakistan data or the PAGER data.This research was partially supported by the Global Earthquake Model, by the National Science Foundation Grant CMMI 1233694 and the Shah Family Graduate Fellowship

The role of mTOR and phospho-p70S6K in pathogenesis and progression of gastric carcinomas: an immunohistochemical study on tissue microarray

<p>Abstract</p> <p>Background</p> <p>mTOR signaling pathway and its downstream serine/threonine kinase p70S6k were frequently activated in human cancers. The dysregulation of the mTOR pathway has been found to be a contributing factor of a variety of different cancer. To investigate the role of mTOR signal pathway in the stepwise development of gastric carcinomas, we analyzed the correlations between the mTOR and P70S6K expression and clinic pathological factors and studied its prognostic role in gastric carcinomas.</p> <p>Methods</p> <p>mTOR and phospho-p70S6K proteins were examined by immunohistochemistry on tissue microarray containing gastric carcinomas (n = 412), adenomas (n = 47) and non-neoplastic mucosa (NNM, n = 197) with a comparison of their expression with clinicopathological parameters of carcinomas.</p> <p>Results</p> <p>There was no difference of mTOR expression between these three tissues (p > 0.05). Cytoplasmic phospho(p)-P706SK was highly expressed in adenoma, compared with ANNMs (p < 0.05), whereas its nuclear expression was lower in gastric carcinomas than gastric adenoma and ANNMs (p < 0.05). These three markers were preferably expressed in the older patients with gastric cancer and intestinal-type carcinoma (p < 0.05). mTOR expression was positively correlated with the cytoplasmic and nuclear expression of p-P70S6K(p < 0.05). Nuclear P70S6K was inversely linked to tumor size, depth of invasion, lymph node metastasis and UICC staging (p < 0.05). Univariate analysis indicated that expression of mTOR and nuclear p-P70S6K was closely linked to favorable prognosis of the carcinoma patients (p < 0.05). Multivariate analysis showed that age, depth of invasion, lymphatic invasion, lymph node metastasis, Lauren's classification and mTOR expression were independent prognostic factors for overall gastric carcinomas (p < 0.05).</p> <p>Conclusion</p> <p>Aberrant expression of p-P70S6K possibly contributes to pathogenesis, growth, invasion and metastasis of gastric carcinomas. It was considered as a promising marker to indicate the aggressive behaviors and prognosis of gastric carcinomas.</p

TRPM2 channel deficiency prevents delayed cytosolic Zn²⁺ accumulation and CA1 pyramidal neuronal death after transient global ischemia

Transient ischemia is a leading cause of cognitive dysfunction. Postischemic ROS generation and an increase in the cytosolic Zn²⁺ level ([Zn²⁺]c) are critical in delayed CA1 pyramidal neuronal death, but the underlying mechanisms are not fully understood. Here we investigated the role of ROS-sensitive TRPM2 (transient receptor potential melastatin-related 2) channel. Using in vivo and in vitro models of ischemia-reperfusion, we showed that genetic knockout of TRPM2 strongly prohibited the delayed increase in the [Zn²⁺]c, ROS generation, CA1 pyramidal neuronal death and postischemic memory impairment. Time-lapse imaging revealed that TRPM2 deficiency had no effect on the ischemia-induced increase in the [Zn²⁺]c but abolished the cytosolic Zn²⁺ accumulation during reperfusion as well as ROS-elicited increases in the [Zn²⁺]c. These results provide the first evidence to show a critical role for TRPM2 channel activation during reperfusion in the delayed increase in the [Zn²⁺]c and CA1 pyramidal neuronal death and identify TRPM2 as a key molecule signaling ROS generation to postischemic brain injury

Urinary Transforming Growth Factor-beta 1 as a marker of response to immunosuppressive treatment, in patients with crescentic nephritis

BACKGROUND: Crescentic nephritis is characterized by formation of cellular crescents that soon become fibrotic and result in irreversible damage, unless an effective immunosuppressive therapy is rapidly commenced. TGF-β(1 )is involved in the development of crescents through various pathways. The aim of this study was to identify whether the determination of urinary TGF-β(1 )levels in patients with crescentic nephritis could be used as a marker of response to treatment. METHODS: Fifteen patients with crescentic nephritis were included in the study. The renal expression of TGF-β(1 )was estimated in biopsy sections by immunohistochemistry and urinary TGF-β(1 )levels were determined by quantitative sandwich enzyme immunoassay (EIA). TGF-β(1 )levels were determined at the time of renal biopsy, before the initiation of immunosuppressive treatment (corticosteroids, cyclophosphamide and plasma exchange). Twelve patients with other types of proliferative glomerulonephritis and ten healthy subjects were used as controls. RESULTS: Improvement of renal function with immunosuppressive therapy was observed in 6 and stabilization in 4 patients (serum creatinine from 3.2 ± 1.5 to 1.4 ± 0.1 mg/dl and from 4.4 ± 1.2 to 4.1 ± 0.6 mg/dl, respectively). In 5 patients, with severe impairment of renal function who started on dialysis, no improvement was noted. The main histological feature differentiating these 5 patients from others with improved or stabilized renal function was the percentage patients with poor response to treatment were the percentage of glomeruli with crescents and the presence of ruptured Bowman's capsule and glomerular necrosis. Urinary TGF-β(1 )levels were significantly higher in patients who showed no improvement of renal function with immunosuppressive therapy (930 ± 126 ng/24 h vs. 376 ± 84 ng/24 h, p < 0.01). TGF-β(1 )was identified in crescents and tubular epithelial cells, whereas a significant correlation of TGF-β(1 )immunostaining with the presence of fibrocellular cresents was observed (r = 0.531, p < 0,05). CONCLUSION: Increased TGF-β(1 )renal expression and urinary excretion that is related to the response to immunosuppressive therapy was observed in patients with crescentic nephritis. Evaluation of urinary TGF-β(1 )levels may be proved a useful marker of clinical outcome in patients with crescentic nephritis

The mTOR inhibitor rapamycin down-regulates the expression of the ubiquitin ligase subunit Skp2 in breast cancer cells

INTRODUCTION: Loss of the cyclin-dependent kinase inhibitor p27 is associated with poor prognosis in breast cancer. The decrease in p27 levels is mainly the result of enhanced proteasome-dependent degradation mediated by its specific ubiquitin ligase subunit S phase kinase protein 2 (Skp2). The mammalian target of rapamycin (mTOR) is a downstream mediator in the phosphoinositol 3' kinase (PI3K)/Akt pathway that down-regulates p27 levels in breast cancer. Rapamycin was found to stabilize p27 levels in breast cancer, but whether this effect is mediated through changes in Skp2 expression is unknown. METHODS: The expression of Skp2 mRNA and protein levels were examined in rapamycin-treated breast cancer cell lines. The effect of rapamycin on the degradation rate of Skp2 expression was examined in cycloheximide-treated cells and in relationship to the anaphase promoting complex/Cdh1 (APC\C) inhibitor Emi1. RESULTS: Rapamycin significantly decreased Skp2 mRNA and protein levels in a dose and time-dependent fashion, depending on the sensitivity of the cell line to rapamycin. The decrease in Skp2 levels in the different cell lines was followed by cell growth arrest at G1. In addition, rapamycin enhanced the degradation rate of Skp2 and down-regulated the expression of the APC\C inhibitor Emi1. CONCLUSION: These results suggest that Skp2, an important oncogene in the development and progression of breast cancer, may be a novel target for rapamycin treatment

Decreased expression of the Augmenter of Liver Regeneration results in increased apoptosis and oxidative damage in human-derived glioma cells

The mammalian growth factor erv1-like (GFER) gene encodes a sulfhydryl oxidase enzyme, named Augmenter of Liver Regeneration (ALR). Recently it has been demonstrated that ALR supports cell proliferation acting as an anti-apoptotic factor. This effect is determined by ALR ability to support the anti-apoptotic gene expression and to preserve cellular normoxic conditions. We recently demonstrated that the addition of recombinant ALR (rALR) in the culture medium of H2O2-treated neuroblastoma cells reduces the lethal effects induced by the hydrogen peroxide. Similar data have been reported in the regenerating liver tissue from partially hepatectomized rats treated with rALR. The purpose of the present study was to evaluate the effect of the GFER inhibition, via the degradation of the complementary mRNA by the specific siRNA, on the behaviour of the apoptosis (apoptotic gene and caspase expression and apoptotic cell number) and of the oxidative stress-induced parameters (reactive oxygen species (ROS), clusterin expression and mitochondrial integrity) in T98G glioma cells. The results revealed a reduction of (i) ALR, (ii) clusterin and (iii) bcl-2 and an increase of (iv) caspase-9, activated caspase-3, ROS, apoptotic cell number and mitochondrial degeneration. These data confirm the anti-apoptotic role of ALR and its anti-oxidative properties, and shed some light on the molecular pathways through which ALR modulates its biological effects

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Metastatic lymph node in gastric cancer; Is it a real distant metastasis?

<p>Abstract</p> <p>Background</p> <p>Currently, the TNM staging system is a widely accepted method for assessing the prognosis of the disease and planning therapeutic strategies for cancer. Of the TNM system, the extent of lymph node involvement is the most important independent prognostic factor for gastric cancer. The aim of our study is to evaluate the survival and prognosis of gastric cancer patients with LN#12 or #13 involvement only and to assess the impact of anatomic regions of primary gastric tumor on survival in this particular subset of patients.</p> <p>Methods</p> <p>Among data of 1,008 stage IV gastric cancer patients who received curative R0 gastrectomy, a total of 79 patients with LN#12 (n = 68) and/or #13 (n = 11) were identified. All patients performed gastrectomy with D2 or D3 lymph node dissection.</p> <p>Results</p> <p>In 79 patients with LN#12/13 involvement, the estimated one-, three- and five-year survival rate was 77.2%, 41.8% and 26.6% respectively. When we compared the patients with LN#12/13 involvement to those without involvement, there was no significant difference in OS (21.0 months vs. 25.0 months, respectively; P = 0.140). However, OS was significantly longer in patients with LN#12/13 involvement only than in those with M1 lymph node involvement (14.3 months; P = 0.001). There was a significant difference in survival according to anatomic locations of the primary tumor (lower to mid-body vs. high body or whole stomach): 26.5 vs. 9.2 months (P = 0.009). In Cox proportional hazard analysis, only N stage (p = 0.002) had significance to predict poor survival.</p> <p>Conclusion</p> <p>In this study we found that curatively resected gastric cancer patients with pathologic involvement of LN #12 and/or LN #13 had favorable survival outcome, especially those with primary tumor location of mid-body to antrum. Prospective analysis of survival in gastric cancer patients with L N#12 or #13 metastasis is warranted especially with regards to primary tumor location.</p

Expression of the progenitor marker NG2/CSPG4 predicts poor survival and resistance to ionising radiation in glioblastoma

Glioblastoma (GBM) is a highly aggressive brain tumour, where patients respond poorly to radiotherapy and exhibit dismal survival outcomes. The mechanisms of radioresistance are not completely understood. However, cancer cells with an immature stem-like phenotype are hypothesised to play a role in radioresistance. Since the progenitor marker neuron-glial-2 (NG2) has been shown to regulate several aspects of GBM progression in experimental systems, we hypothesised that its expression would influence the survival of GBM patients. Quantification of NG2 expression in 74 GBM biopsies from newly diagnosed and untreated patients revealed that 50% express high NG2 levels on tumour cells and associated vessels, being associated with significantly shorter survival. This effect was independent of age at diagnosis, treatment received and hypermethylation of the O6-methylguanine methyltransferase (MGMT) DNA repair gene promoter. NG2 was frequently co-expressed with nestin and vimentin but rarely with CD133 and the NG2 positive tumour cells harboured genetic aberrations typical for GBM. 2D proteomics of 11 randomly selected biopsies revealed upregulation of an antioxidant, peroxiredoxin-1 (PRDX-1), in the shortest surviving patients. Expression of PRDX-1 was associated with significantly reduced products of oxidative stress. Furthermore, NG2 expressing GBM cells showed resistance to ionising radiation (IR), rapidly recognised DNA damage and effectuated cell cycle checkpoint signalling. PRDX-1 knockdown transiently slowed tumour growth rates and sensitised them to IR in vivo. Our data establish NG2 as an important prognostic factor for GBM patient survival, by mediating resistance to radiotherapy through induction of ROS scavenging enzymes and preferential DNA damage signalling