Constrained parameter estimation with uncertain priors for Bayesian networks

Article / Letter to editorLeiden Inst Advanced Computer Science

Dirac structures on Hilbert spaces

For a real Hilbert space (H,〈,〉), a subspace L⊂H⊕H is said to be a Dirac structure on H if it is maximally isotropic with respect to the pairing 〈(x,y),(x′,y′)〉+=(1/2)(〈x,y′〉+〈x′,y〉). By investigating some basic properties of these structures, it is shown that Dirac structures on H are in one-to-one correspondence with isometries on H, and, any two Dirac structures are isometric. It is, also, proved that any Dirac structure on a smooth manifold in the sense of [1] yields a Dirac structure on some Hilbert space. The graph of any densely defined skew symmetric linear operator on a Hilbert space is, also, shown to be a Dirac structure. For a Dirac structure L on H, every z∈H is uniquely decomposed as z=p1(l)+p2(l) for some l∈L, where p1 and p2 are projections. When p1(L) is closed, for any Hilbert subspace W⊂H, an induced Dirac structure on W is introduced. The latter concept has also been generalized

Attenuation of serum laminin concentrations upon treatment of chronic hepatitis

Objectives: The aim of this work was to determine the serum laminin level cutoff point for predicting liver fibrosis highlighting its diagnostic value and determining the effect of treatment on serum laminin concentrations. Methods: Serum laminin concentrations in chronic hepatitis patients (n=62) and controls (n=20) were compared by ELISA and stages of fibrosis were assessed according to the modified Knodell score system. Results: Mean serum laminin concentration in patients (91.9 ± 20.9 ng/ml) was greater than controls (46.2 ± 10.2 ng/ml; p <0.001). Serum concentrations of laminin in all stages of hepatic fibrosis were significantly higher than those of healthy controls (p <0.05). A cutoff point of 52ng laminin/ml of serum was obtained for the discrimination of various stages of liver fibrosis showing a good sensitivity (96.8%) and specificity (80%). After 6 months of treatment, a gradual decrease in serum laminin concentrations were observed, however the level was still higher than that of the healthy group (p<0.05). Conclusions: Our findings suggest that the serum laminin concentration is a useful noninvasive marker of liver fibrosis and shows a strong positive correlation with different stages of the disease

Constrained parameter estimation with uncertain priors for Bayesian networks

Algorithms and the Foundations of Software technolog

Serum hyaluronic acid and laminin as potential tumor markers for upper gastrointestinal cancers

Background: Early diagnosis of patients with upper gastrointestinal cancer is important because many cases are diagnosed in advanced stages and have poor prognosis. Several studies have reported increased serum levels of hyaluronic acid and laminin in various cancers and the correlation of the levels with poor prognosis. However, little data on the use of serum hyaluronic acid and laminin levels for early detection of esophageal and gastric cancers are available. Methods: We assessed serum hyaluronic acid and laminin levels using enzyme-linked immunosorbent assay in 20 gastric cardia cancer, 23 gastric noncardia cancer and 20 esophageal squamous cell carcinoma incident cases and 25 controls in the Golestan Province, northern Iran, a high risk area for upper gastrointestinal cancers. Results: Mean serum hyaluronic acid and laminin concentrations in cancer cases were higher than in controls in crude analyses. Significant correlations were observed between hyaluronic acid levels and gastric noncardia cancer (Beta-coefficient = 0.390; P = 0.01) and esophageal squamous cell carcinoma (Beta-coefficient = 0.332; P = 0.05) and between laminin levels and gastric cardia cancer (Beta-coefficient = 0.454; P = 0.003) in multivariate models. For esophageal squamous cell carcinoma, gastric cardia cancer, and gastric noncardia cancer, area under ROC curve (AUC) of hyaluronic acid was 0.708, 0.694, and 0.770, and of laminin was 0.706, 0.828, and 0.671. Conclusions: Our study suggests that hyaluronic acid and laminin may be used to identify potentially high-risk groups of upper gastrointestinal cancers for further diagnostic work-ups, particularly in high incidence areas. Nevertheless, further studies with larger sample size and tumor staging information are warranted to clarify the clinical significance of hyaluronic acid and laminin in those cancers. © 2011 European Federation of Internal Medicine

Radiation-Induced Galectin-1 by Endothelial Cells: A Promising Molecular Target for Preferential Drug Delivery to the Tumor Vasculature

The present study reports on a new strategy for selective, radiation therapy-amplified drug delivery using an antiangiogenic 33-a.a., tumor vasculature-targeting ligand, anginex, to improve the therapeutic ratio for strategies developed against solid tumors. Our findings indicate that galectin-1 is (a) one of the major receptors for anginex (b) overexpressed by tumor neovasculature and (c) further specifically upregulated in endothelial cells in response to radiation exposure as low as 0.5 Gy. An investigation of [18]-F-labeled anginex biodistribution in SCK tumors indicates that anginex is an effective targeting molecule for image and radiation-guided therapy of solid tumors. An anginex-conjugated liposome capable of being loaded with drug was shown to selectively target endothelial cells post-radiation. The presence of endothelial cells in a three-dimensional co-culture system with tumor cells developed to study tumor/endothelial cell interactions in vitro led to higher levels of galectin-1 and showed a further increase in expression upon radiation exposure when compared to tumor cell spheroids alone. Similar increase in galectin-1 was observed in tumor tissue originating from the tumor‐endothelial cell spheroids in vivo and radiation exposure further induced galectin-1 in these tumors. The overall results suggest feasibility of using a clinical or subclinical radiation dose to increase expression of the galectin-1 receptor on the tumor microvasculature to promote delivery of therapeutics via the anginex peptide. This approach may reduce systemic toxicity, overcome drug resistance, and improve the therapeutic efficacy of conventional chemo/radiation strategies

E2F-1 induces melanoma cell apoptosis via PUMA up-regulation and Bax translocation

BACKGROUND: PUMA is a pro-apoptotic Bcl-2 family member that has been shown to be involved in apoptosis in many cell types. We sought to ascertain whether induction of PUMA plays a crucial role in E2F-1-induced apoptosis in melanoma cells. METHODS: PUMA gene and protein expression levels were detected by real-time PCR and Western blot in SK-MEL-2 and HCT116 cell lines after Ad-E2F-1 infection. Activation of the PUMA promoter by E2F-1 overexpression was detected by dual luciferase reporter assay. E2F-1-induced Bax translocation was shown by immunocytochemistry. The induction of caspase-9 activity was measured by caspase-9 colorimetric assay kit. RESULTS: Up-regulation of the PUMA gene and protein by E2F-1 overexpression was detected by real-time PCR and Western blot analysis in the SK-MEL-2 melanoma cell line. In support of this finding, we found six putative E2F-1 binding sites within the PUMA promoter. Subsequent dual luciferase reporter assay showed that E2F-1 expression could increase the PUMA gene promoter activity 9.3 fold in SK-MEL-2 cells. The role of PUMA in E2F-1-induced apoptosis was further investigated in a PUMA knockout cell line. Cell viability assay showed that the HCT116 PUMA-/- cell line was more resistant to Ad-E2F-1-mediated cell death than the HCT116 PUMA+/+ cell line. Moreover, a 2.2-fold induction of the PUMA promoter was also noted in the HCT116 PUMA+/+ colon cancer cell line after Ad-E2F-1 infection. Overexpression of a truncated E2F-1 protein that lacks the transactivation domain failed to up-regulate PUMA promoter, suggesting that PUMA may be a transcriptional target of E2F-1. E2F-1-induced cancer cell apoptosis was accompanied by Bax translocation from the cytosol to mitochondria and the induction of caspase-9 activity, suggesting that E2F-1-induced apoptosis is mediated by PUMA through the cytochrome C/Apaf-1-dependent pathway. CONCLUSION: Our studies strongly demonstrated that E2F-1 induces melanoma cell apoptosis via PUMA up-regulation and Bax translocation. The signaling pathways provided here will further enhance insights on the mechanisms of E2F-1-induced cancer cell apoptosis as a strategy for cancer therapy

α-Synuclein Genetic Variants Predict Faster Motor Symptom Progression in Idiopathic Parkinson Disease

Currently, there are no reported genetic predictors of motor symptom progression in Parkinson’s disease (PD). In familial PD, disease severity is associated with higher α-synuclein (SNCA) expression levels, and in postmortem studies expression varies with SNCA genetic variants. Furthermore, SNCA is a well-known risk factor for PD occurrence. We recruited Parkinson’s patients from the communities of three central California counties to investigate the influence of SNCA genetic variants on motor symptom progression in idiopathic PD. We repeatedly assessed this cohort of patients over an average of 5.1 years for motor symptom changes employing the Unified Parkinson’s Disease Rating Scale (UPDRS). Of 363 population-based incident PD cases diagnosed less than 3 years from baseline assessment, 242 cases were successfully re-contacted and 233 were re-examined at least once. Of subjects lost to follow-up, 69% were due to death. Adjusting for covariates, risk of faster decline of motor function as measured by annual increase in motor UPDRS exam score was increased 4-fold in carriers of the REP1 263bp promoter variant (OR 4.03, 95%CI:1.57–10.4). Our data also suggest a contribution to increased risk by the G-allele for rs356165 (OR 1.66; 95%CI:0.96–2.88), and we observed a strong trend across categories when both genetic variants were considered (p for trend  = 0.002). Our population-based study has demonstrated that SNCA variants are strong predictors of faster motor decline in idiopathic PD. SNCA may be a promising target for therapies and may help identify patients who will benefit most from early interventions. This is the first study to link SNCA to motor symptom decline in a longitudinal progression study