Arzanol, a prenylated heterodimeric phloroglucinyl pyrone, inhibits eicosanoid biosynthesis and exhibits anti-inflammatory efficacy in vivo.

Based on its capacity to inhibit in vitro HIV-1 replication in T cells and the release of pro-inflammatory cytokines in monocytes, the prenylated heterodimeric phloroglucinyl α-pyrone arzanol was identified as the major anti-inflammatory and anti-viral constituent from Helichrysum italicum. We have now investigated the activity of arzanol on the biosynthesis of pro-inflammatory eicosanoids, evaluating its anti-inflammatory efficacy in vitro and in vivo. Arzanol inhibited 5-lipoxygenase (EC 7.13.11.34) activity and related leukotriene formation in neutrophils, as well as the activity of cyclooxygenase (COX)-1 (EC 1.14.99.1) and the formation of COX-2-derived prostaglandin (PG)E(2)in vitro (IC(50)=2.3-9μM). Detailed studies revealed that arzanol primarily inhibits microsomal PGE(2) synthase (mPGES)-1 (EC 5.3.99.3, IC(50)=0.4μM) rather than COX-2. In fact, arzanol could block COX-2/mPGES-1-mediated PGE(2) biosynthesis in lipopolysaccharide-stimulated human monocytes and human whole blood, but not the concomitant COX-2-derived biosynthesis of thromboxane B(2) or of 6-keto PGF(1α), and the expression of COX-2 or mPGES-1 protein was not affected. Arzanol potently suppressed the inflammatory response of the carrageenan-induced pleurisy in rats (3.6mg/kg, i.p.), with significantly reduced levels of PGE(2) in the pleural exudates. Taken together, our data show that arzanol potently inhibits the biosynthesis of pro-inflammatory lipid mediators like PGE(2)in vitro and in vivo, providing a mechanistic rationale for the anti-inflammatory activity of H. italicum, and a rationale for further pre-clinical evaluation of this novel anti-inflammatory lead

Exceptional Points for Nonlinear Schroedinger Equations Describing Bose-Einstein Condensates of Ultracold Atomic Gases

The coalescence of two eigenfunctions with the same energy eigenvalue is not possible in Hermitian Hamiltonians. It is, however, a phenomenon well known from non-hermitian quantum mechanics. It can appear, e.g., for resonances in open systems, with complex energy eigenvalues. If two eigenvalues of a quantum mechanical system which depends on two or more parameters pass through such a branch point singularity at a critical set of parameters, the point in the parameter space is called an exceptional point. We will demonstrate that exceptional points occur not only for non-hermitean Hamiltonians but also in the nonlinear Schroedinger equations which describe Bose-Einstein condensates, i.e., the Gross-Pitaevskii equation for condensates with a short-range contact interaction, and with additional long-range interactions. Typically, in these condensates the exceptional points are also found to be bifurcation points in parameter space. For condensates with a gravity-like interaction between the atoms, these findings can be confirmed in an analytical way

Plectranthus zeylanicus: A rich source of secondary metabolites with antimicrobial, disinfectant and anti-inflammatory activities

Plectranthus zeylanicus Benth is used in Sri Lankan folk medicine as a remedy for inflammatory conditions and microbial infections. Our previous investigations revealed potent 5-lipoxygenase (5-LO) inhibitory activity in lipophilic extracts of this plant, supporting its anti-inflammatory potential. In-depth studies on the antimicrobial activity have not been conducted and the bioactive ingredients remained elusive. As a continuation of our previous work, the present investigation was undertaken to evaluate the antimicrobial activity of different extracts of P. zeylanicus and to isolate and characterize bioactive secondary metabolites. Different organic extracts of this plant were analyzed for their antibacterial activity, and the most active extract, i.e., dichloromethane extract, was subjected to bioactivity-guided fractionation, which led to the isolation of 7α-acetoxy-6β-hydroxyroyleanone. This compound displayed strong antibacterial activity against methicillin-resistant Staphylococcus aureus with a minimum inhibitory concentration of 62.5 µg/mL, and its disinfectant capacity was comparable to the potency of a commercial disinfectant. Moreover, 7α-acetoxy-6β-hydroxyroyleanone inhibits 5-LO with IC50 values of 1.3 and 5.1 µg/mL in cell-free and cell-based assays, respectively. These findings rationalize the ethnopharmacological use of P. zeylanicus as antimicrobial and anti-inflammatory remedy

Neoadjuvant chemoradiotherapy with or without panitumumab in patients with wild-type KRAS, locally advanced rectal cancer (LARC): a randomized, multicenter, phase II trial SAKK 41/07

Background We conducted a randomized, phase II, multicenter study to evaluate the anti-epidermal growth factor receptor (EGFR) mAb panitumumab (P) in combination with chemoradiotherapy (CRT) with standard-dose capecitabine as neoadjuvant treatment for wild-type KRAS locally advanced rectal cancer (LARC). Patients and methods Patients with wild-type KRAS, T3-4 and/or N+ LARC were randomly assigned to receive CRT with or without P (6 mg/kg). The primary end-point was pathological near-complete or complete tumor response (pNC/CR), defined as grade 3 (pNCR) or 4 (pCR) histological regression by Dworak classification (DC). Results Forty of 68 patients were randomly assigned to P + CRT and 28 to CRT. pNC/CR was achieved in 21 patients (53%) treated with P + CRT [95% confidence interval (CI) 36%-69%] versus 9 patients (32%) treated with CRT alone (95% CI: 16%-52%). pCR was achieved in 4 (10%) and 5 (18%) patients, and pNCR in 17 (43%) and 4 (14%) patients. In immunohistochemical analysis, most DC 3 cells were not apoptotic. The most common grade ≥3 toxic effects in the P + CRT/CRT arm were diarrhea (10%/6%) and anastomotic leakage (15%/4%). Conclusions The addition of panitumumab to neoadjuvant CRT in patients with KRAS wild-type LARC resulted in a high pNC/CR rate, mostly grade 3 DC. The results of both treatment arms exceeded prespecified thresholds. The addition of panitumumab increased toxicit

Evidence and Policy in Aid-Dependent Settings

This chapter examines how the political dynamics of aid relationships can affect the use of evidence within health policymaking. Empirical examples from Cambodia, Ethiopia and Ghana illustrate how relationships between national governments and donor agencies influence the ways in which evidence is generated, selected, or utilised to inform policymaking. We particularly consider how relationships with donors influence the underlying systems and processes of evidence use. We find a number of issues affecting which bodies or forms of evidence are taken to be policy relevant, including: levels of local technical capacity to utilise or synthesise evidence; differing stakeholder framing of issues; and the influence of non-state actors on sector-wide systems of agenda setting. The chapter also reflects on some of the key governance implications of these arrangements in which global actors promote forms of evidence use – often under a banner of technical efficiency – with limited consideration for local representation or accountability

Letrozole as upfront endocrine therapy for postmenopausal women with hormone-sensitive breast cancer: BIG 1-98

The BIG 1-98 trial is a large, randomized, independently conducted clinical trial designed to compare the efficacy of upfront letrozole versus tamoxifen monotherapy and to compare sequential or up-front use of letrozole and/or tamoxifen as an early adjuvant therapy for patients with early breast cancer. We report on the results from the primary core analysis of the BIG 1-98 trial of 8,010 patients, which compares monotherapy with letrozole versus tamoxifen. This pre-planned core analysis allowed the use of patient data from the monotherapy arms of letrozole and tamoxifen and from the sequential arms prior to the drug switch point. Patients randomized to letrozole had a 19% improved disease-free survival (hazard ratio [HR] = 0.81; P = 0.003), due especially to reduced distant metastases (HR = 0.73; P = 0.001). A 14% risk reduction of fatal events in favor of letrozole was also observed (P = NS). The results from the monotherapy arms alone confirmed the findings from the primary core analysis. Based on the results from this trial, the aromatase inhibitor letrozole (Femara®) is currently recommended as a part of standard adjuvant therapy for postmenopausal women with endocrine-responsive breast cancer and has recently been approved in the early adjuvant setting in both Europe and the United States. A subsequent analysis after additional follow-up will address the question of monotherapy versus sequential therapy

Interpreting breast international group (BIG) 1-98: a randomized, double-blind, phase III trial comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive, early breast cancer

The Breast International Group (BIG) 1-98 study is a four-arm trial comparing 5 years of monotherapy with tamoxifen or with letrozole or with sequences of 2 years of one followed by 3 years of the other for postmenopausal women with endocrine-responsive early invasive breast cancer. From 1998 to 2003, BIG -98 enrolled 8,010 women. The enhanced design f the trial enabled two complementary analyses of efficacy and safety. Collection of tumor specimens further enabled treatment comparisons based on tumor biology. Reports of BIG 1-98 should be interpreted in relation to each individual patient as she weighs the costs and benefits of available treatments

Exploration of Long-Chain Vitamin E Metabolites for the Discovery of a Highly Potent, Orally Effective, and Metabolically Stable 5-LOX Inhibitor that Limits Inflammation.

Endogenous long-chain metabolites of vitamin E (LCMs) mediate immune functions by targeting 5-lipoxygenase (5-LOX) and increasing the systemic concentrations of resolvin E3, a specialized proresolving lipid mediator. SAR studies on semisynthesized analogues highlight α-amplexichromanol (27a), which allosterically inhibits 5-LOX, being considerably more potent than endogenous LCMs in human primary immune cells and blood. Other enzymes within lipid mediator biosynthesis were not substantially inhibited, except for microsomal prostaglandin E2 synthase-1. Compound 27a is metabolized by sulfation and β-oxidation in human liver-on-chips and exhibits superior metabolic stability in mice over LCMs. Pharmacokinetic studies show distribution of 27a from plasma to the inflamed peritoneal cavity and lung. In parallel, 5-LOX-derived leukotriene levels decrease, and the inflammatory reaction is suppressed in reconstructed human epidermis, murine peritonitis, and experimental asthma in mice. Our study highlights 27a as an orally active, LCM-inspired drug candidate that limits inflammation with superior potency and metabolic stability to the endogenous lead

The two sides of cytokine signaling and glaucomatous optic neuropathy

The mechanistic study of glaucoma pathogenesis has shifted to seeking to understand the effects of immune responses on retinal ganglion cell damage and protection. Cytokines are the hormonal factors that mediate most of the biological effects in both the immune and nonimmune systems. CD4-expressing T helper cells are a major source of cytokine production and regulation. Type 1 helper T (Th1) cells are characterized by the production of proinflammatory cytokines such as interferon-gamma, interleukin (IL)-2, IL-12, IL-23, and tumor necrosis factor-alpha while type 2 helper T (Th2) cells are characterized by the production of IL-4, IL-5, IL-6, and IL-10. The balance of Th1/Th2 cytokine production influences many pathological processes and plays both causative and protective roles in neuron damages. Growing evidence indicates that imbalances of Th1/Th2 cytokine production are involved in neural damage or protection in many neurological diseases. In this review, we discuss the possible roles of Th1/Th2 cytokine production and imbalance of Th1/Th2 cytokines in retina, especially glaucomatous optic neuropathy