Synthesis, Biological Evaluation, and Molecular Modeling Studies of 1-Aryl-1H-pyrazole-Fused Curcumin Analogues as Anticancer Agents

Addressing the growing burden of cancer and the shortcomings of chemotherapy in cancer treatment are the current research goals. Research to overcome the limitations of curcumin and to improve its anticancer activity via its heterocycle-fused monocarbonyl analogues (MACs) has immense potential. In this study, 32 asymmetric MACs fused with 1-aryl-

An Electronic Health Record Model for Predicting Risk of Hepatic Fibrosis in Primary Care Patients

BackgroundOne challenge for primary care providers caring for patients with nonalcoholic fatty liver disease is to identify those at the highest risk for clinically significant liver disease.AimTo derive a risk stratification tool using variables from structured electronic health record (EHR) data for use in populations which are disproportionately affected with obesity and diabetes.MethodsWe used data from 344 participants who underwent Fibroscan examination to measure liver fat and liver stiffness measurement [LSM]. Using two approaches, multivariable logistic regression and random forest classification, we assessed risk factors for any hepatic fibrosis (LSM > 7 kPa) and significant hepatic fibrosis (> 8 kPa). Possible predictors included data from the EHR for age, gender, diabetes, hypertension, FIB-4, body mass index (BMI), LDL, HDL, and triglycerides.ResultsOf 344 patients (56.4% women), 34 had any hepatic fibrosis, and 15 significant hepatic fibrosis. Three variables (BMI, FIB-4, diabetes) were identified from both approaches. When we used variable cut-offs defined by Youden's index, the final model predicting any hepatic fibrosis had an AUC of 0.75 (95% CI 0.67-0.84), NPV of 91.5% and PPV of 40.0%. The final model with variable categories based on standard clinical thresholds (i.e., BMI ≥ 30 kg/m2; FIB-4 ≥ 1.45) had lower discriminatory ability (AUC 0.65), but higher PPV (50.0%) and similar NPV (91.3%). We observed similar findings for predicting significant hepatic fibrosis.ConclusionsOur results demonstrate that standard thresholds for clinical risk factors/biomarkers may need to be modified for greater discriminatory ability among populations with high prevalence of obesity and diabetes

Decoration of T-independent antigen with ligands for CD22 and Siglec-G can suppress immunity and induce B cell tolerance in vivo

Autoreactive B lymphocytes first encountering self-antigens in peripheral tissues are normally regulated by induction of anergy or apoptosis. According to the "two-signal" model, antigen recognition alone should render B cells tolerant unless T cell help or inflammatory signals such as lipopolysaccharide are provided. However, no such signals seem necessary for responses to T-independent type 2 (TI-2) antigens, which are multimeric antigens lacking T cell epitopes and Toll-like receptor ligands. How then do mature B cells avoid making a TI-2-like response to multimeric self-antigens? We present evidence that TI-2 antigens decorated with ligands of inhibitory sialic acid-binding Ig-like lectins (siglecs) are poorly immunogenic and can induce tolerance to subsequent challenge with immunogenic antigen. Two siglecs, CD22 and Siglec-G, contributed to tolerance induction, preventing plasma cell differentiation or survival. Although mutations in CD22 and its signaling machinery have been associated with dysregulated B cell development and autoantibody production, previous analyses failed to identify a tolerance defect in antigen-specific mutant B cells. Our results support a role for siglecs in B cell self-/nonself-discrimination, namely suppressing responses to self-associated antigens while permitting rapid "missing self"-responses to unsialylated multimeric antigens. The results suggest use of siglec ligand antigen constructs as an approach for inducing tolerance

Quenched Hadrons using Wilson and O(a)-Improved Fermion Actions at beta=6.2

We present the first study of the light hadron spectrum and decay constants for quenched QCD using an O(a)-improved nearest-neighbour Wilson fermion action at \beta=6.2. We compare the results with those obtained using the standard Wilson fermion action, on the same set of 18 gauge field configurations of a 24^3 times 48 lattice. For pseudoscalar meson masses in the range 330-800 MeV, we find no significant difference between the results for the two actions. The scales obtained from the string tension and mesonic sector are consistent, but differ from that derived from baryon masses. The ratio of the pseudoscalar decay constant to the vector meson mass is roughly independent of quark mass as observed experimentally, and in approximate agreement with the measured value.Comment: 11 page

Two-Higgs doublet models from TeV-scale supersymmetric extra U(1) models

We investigate the reduction of a general TeV-scale supersymmetric extra U(1) model to a 2HDM below the TeV- scale through the tree level non-decoupling. Portions of the parameter space of the extra U(1) model appropriate for obtaining a 2HDM are identified. Various properties of the resulting 2HDM are connected to the parameter space of the underlying model. PACS: 12.60.Jv, 12.60.Cn, 12.60.FrComment: 12 pages, 4 postscript figures, to appear in Phys. Rev.

SUSY GUTs contributions and model independent extractions of CP phases

We consider the origin of new phases in supersymmetric grand unification model, and show how significant new contributions arise from the gluino mediated diagram. We then present a more general model independent analysis of various modes of B-decays suggested previously for measurement of the CKM phases and point out what they really measure. It is in principle possible to separate out all the phases.Comment: 13 pages (Latex), 2 PS figures, a few remarks are added and a typo is corrected. To appear in Phys. Rev. Let

Intermediate scale as a source of lepton flavor violation in SUSY SO(10)

In supersymmetric SO(10) grand unified models, we examine the lepton flavor violation process $\mu \rightarrow e\gamma$ from having the SU(2)$_R\times$U(1)$_{B-L}$ gauge symmetry broken at an intermediate scale $M_I$ below the SO(10) grand unification scale $M_G$. Even in the case that supersymmetry is broken by universal soft terms introduced at the scale $M_G$, we find significant rates for $\mu\rightarrow e\gamma$ with $M_I \sim 10^{12}$ GeV or less. These rates are further enhanced if the universal soft terms appear at a scale greater than $M_G$.Comment: 12 pages (Latex), 3 PS Figures (uuencoded, epsf.tex), small addition to discussion in the text, as to appear in Phys. Rev. D Rapid Communication

Measurements of Fast Confined Alphas on TFTR

This Letter reports the first measurements of the fast confined α-particle energy distribution in a fusion plasma. The pellet charge exchange technique shows the fusion generated α\u27s in the core of the Tokamak Fusion Test Reactor plasma slow down classically, and appear to be well confined. Preliminary indications are that stochastic ripple effects are responsible for steepening the energy distribution outside the plasma core (r/a0.35). Sawteeth mixing of fast α\u27s is suggested in data during the post-beam-heating plasma decay. © 1995 The American Physical Society