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

Myrtucommulone from Myrtus communis exhibits potent anti-inflammatory effectiveness in vivo.

Myrtucommulone a nonprenylated acylphloroglucinol contained in the leaves of myrtle (Myrtus communis), has been reported to suppress the biosynthesis of eicosanoids by inhibition of 5-lipoxygenase and cyclooxygenase-1 in vitro and to inhibit the release of elastase and the formation of reactive oxygen species in activated polymorphonuclear leukocytes. Here, in view of the ability of MC to suppress typical proinflammatory cellular responses in vitro, we have investigated the effects of MC in in vivo models of inflammation. MC was administered to mice intraperitoneally, and paw edema and pleurisy were induced by the subplantar and intrapleural injection of carrageenan, respectively. MC (0.5, 1.5, and 4.5 mg/kg i.p.) reduced the development of mouse carrageenan-induced paw edema in a dose-dependent manner. Moreover, MC (4.5 mg/kg i.p. 30 min before and after carrageenan) exerted anti-inflammatory effects in the pleurisy model. In particular, 4 h after carrageenan injection in the pleurisy model, MC reduced: 1) the exudate volume and leukocyte numbers; 2) lung injury (histological analysis) and neutrophil infiltration (myeloperoxidase activity); 3) the lung intercellular adhesion molecule-1 and P-selectin immunohistochemical localization; 4) the cytokine levels (tumor necrosis factor-α and interleukin-1 β in the pleural exudate and their immunohistochemical localization in the lung; 5) the leukotriene B 4, but not prostaglandin E2, levels in the pleural exudates; and 6) lung peroxidation (thiobarbituric acid-reactant substance) and nitrotyrosine and poly (ADP-ribose) immunostaining. In conclusion, our results demonstrate that MC exerts potent anti-inflammatory effects in vivo and offer a novel therapeutic approach for the management of acute inflammation. Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics

Vitamin E metabolites as potent inhibitors of 5-lipoxygenase

International audienc

Machine intelligence decrypts β-lapachone as an allosteric 5-lipoxygenase inhibitor.

Using machine learning, targets were identified for β-lapachone. Resorting to biochemical assays, β-lapachone was validated as a potent, ligand efficient, allosteric and reversible modulator of 5-lipoxygenase (5-LO). Moreover, we provide a rationale for 5-LO modulation and show that inhibition of 5-LO is relevant for the anticancer activity of β-lapachone. This work demonstrates the power of machine intelligence to deconvolute complex phenotypes, as an alternative and/or complement to chemoproteomics and as a viable general approach for systems pharmacology studies

Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/06)

In this trial, stopping bevacizumab after completion of induction chemotherapy was associated with a shorter time to progression, but no statistically significant difference in overall survival compared with the bevacizumab continuation strategy. Non-inferiority could not be demonstrated. Treatment costs are substantially higher for continuous bevacizumab treatmen

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

Adding cetuximab to capecitabine plus oxaliplatin (XELOX) in first-line treatment of metastatic colorectal cancer: a randomized phase II trial of the Swiss Group for Clinical Cancer Research SAKK

Background: To determine the activity and tolerability of adding cetuximab to the oxaliplatin and capecitabine (XELOX) combination in first-line treatment of metastatic colorectal cancer (MCC). Patients and methods: In a multicenter two-arm phase II trial, patients were randomized to receive oxaliplatin 130 mg/m2 on day 1 and capecitabine 1000 mg/m2 twice daily on days 1-14 every 3 weeks alone or in combination with standard dose cetuximab. Treatment was limited to a maximum of six cycles. Results: Seventy-four patients with good performance status entered the trial. Objective partial response rates after external review and radiological confirmation were 14% and 41% in the XELOX and in the XELOX + Cetuximab arm, respectively. Stable disease has been observed in 62% and 35% of the patients, with 76% disease control in both arms. Cetuximab led to skin rash in 65% of the patients. The median overall survival was 16.5 months for arm A and 20.5 months for arm B. The median time to progression was 5.8 months for arm A and 7.2 months for arm B. Conclusion: Differences in response rates between the treatment arms indicate that cetuximab may improve outcome with XELOX. The correct place of the cetuximab, oxaliplatin and fluoropyrimidine combinations in first-line treatment of MCC has to be assessed in phase III trial

Comprehensive Treatment Algorithms of the Swiss Peritoneal Cancer Group for Peritoneal Cancer of Gastrointestinal Origin.

Peritoneal cancer (PC) is a dire finding, yet in selected patients, long-term survival is possible. Complete cytoreductive surgery (CRS) together with combination immunochemotherapy is essential to achieve cure. Hyperthermic intraperitoneal chemotherapy (HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC) are increasingly added to the multimodal treatment. The Swiss Peritoneal Cancer Group (SPCG) is an interdisciplinary group of expert clinicians. It has developed comprehensive treatment algorithms for patients with PC from pseudomyxoma peritonei, peritoneal mesothelioma, gastric, and colorectal origin. They include multimodal neoadjuvant treatment, surgical resection, and palliative care. The indication for and results of CRS HIPEC and PIPAC are discussed in light of the current literature. Institutional volume and clinical expertise required to achieve best outcomes are underlined, while inclusion of patients considered for CRS HIPEC and PIPAC in a clinical registry is strongly advised. The present recommendations are in line with current international guidelines and provide the first comprehensive treatment proposal for patients with PC including intraperitoneal chemotherapy. The SPCG comprehensive treatment algorithms provide evidence-based guidance for the multimodal care of patients with PC of gastrointestinal origin that were endorsed by all Swiss clinicians routinely involved in the multimodal care of these challenging patients

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

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