Antimalarial 4(1H)-pyridones bind to the Qisite of cytochromebc1

Cytochrome bc1 is a proven drug target in the prevention and treatment of malaria. The rise in drug-resistant strains of Plasmodium falciparum, the organism responsible for malaria, has generated a global effort in designing new classes of drugs. Much of the design/redesign work on overcoming this resistance has been focused on compounds that are presumed to bind the Qo site (one of two potential binding sites within cytochrome bc1) using the known crystal structure of this large membrane-bound macromolecular complex via in silico modeling. Cocrystallization of the cytochrome bc1 complex with the 4(1H)-pyridone class of inhibitors, GSK932121 and GW844520, that have been shown to be potent antimalarial agents in vivo, revealed that these inhibitors do not bind at the Qo site but bind at the Qi site. The discovery that these compounds bind at the Qi site may provide a molecular explanation for the cardiotoxicity and eventual failure of GSK932121 in phase-1 clinical trial and highlight the need for direct experimental observation of a compound bound to a target site before chemical optimization and development for clinical trials. The binding of the 4(1H)-pyridone class of inhibitors to Qi also explains the ability of this class to overcome parasite Qo-based atovaquone resistance and provides critical structural information for future design of new selective compounds with improved safety profiles

Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer.

BackgroundT cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s.MethodsPatients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells). In trial C-9701 and C-9702, CART72 cells were administered in escalating doses up to 1010 total cells; in trial C-9701 CART72 cells were administered by intravenous infusion. In trial C-9702, CART72 cells were administered via direct hepatic artery infusion in patients with colorectal liver metastases. In both trials, a brief course of interferon-alpha (IFN-α) was given with each CART72 infusion to upregulate expression of TAG-72.ResultsFourteen patients were enrolled in C-9701 and nine in C-9702. CART72 manufacturing success rate was 100% with an average transduction efficiency of 38%. Ten patients were treated in CC-9701 and 6 in CC-9702. Symptoms consistent with low-grade, cytokine release syndrome were observed in both trials without clear evidence of on target/off tumor toxicity. Detectable, but mostly short-term (≤14 weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48 weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had 111Indium-labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum; there was a precipitous decline of TAG-72, but not CEA, in some patients due to induction of an interfering antibody to the TAG-72 binding domain of humanized CC49, reflecting an anti-CAR immune response. No radiologic tumor responses were observed.ConclusionThese findings demonstrate the relative safety of CART72 cells. The limited persistence supports the incorporation of co-stimulatory domains in the CAR design and the use of fully human CAR constructs to mitigate immunogenicity

A rare case of giant leiomyosarcoma in a filarial scrotum: a case report

Giant leiomyosarcoma of scrotum is a rare tumour. A case of scrotum leiomyosarcoma is presented in a 67 year old patient with scrotal filariasis which was managed successfully with total scrotectomy with bilateral orchidectomy, degloved penis reconstructed with rotation advancement supra pubic fasciocutaneous flap. We made a literature search proving the rarity of this lesion type. Only 36 cases have been described and the first case in a filarial scrotu

Optimal reaction coordinate as a biomarker for the dynamics of recovery from kidney transplant.

The evolution of disease or the progress of recovery of a patient is a complex process, which depends on many factors. A quantitative description of this process in real-time by a single, clinically measurable parameter (biomarker) would be helpful for early, informed and targeted treatment. Organ transplantation is an eminent case in which the evolution of the post-operative clinical condition is highly dependent on the individual case. The quality of management and monitoring of patients after kidney transplant often determines the long-term outcome of the graft. Using NMR spectra of blood samples, taken at different time points from just before to a week after surgery, we have shown that a biomarker can be found that quantitatively monitors the evolution of a clinical condition. We demonstrate that this is possible if the dynamics of the process is considered explicitly: the biomarker is defined and determined as an optimal reaction coordinate that provides a quantitatively accurate description of the stochastic recovery dynamics. The method, originally developed for the analysis of protein folding dynamics, is rigorous, robust and general, i.e., it can be applied in principle to analyze any type of biological dynamics. Such predictive biomarkers will promote improvement of long-term graft survival after renal transplantation, and have potentially unlimited applications as diagnostic tools

The effects on population health status of using dedicated property taxes to fund local public health agencies

<p>Abstract</p> <p>Background</p> <p>In the United States, a dedicated property tax describes the legal authority given to a local jurisdiction to levy and collect a tax for a specific purpose. We investigated for an association of locally dedicated property taxes to fund local public health agencies and improved health status in the eight states designated as the Mississippi Delta Region.</p> <p>Methods</p> <p>We analyzed the difference in health outcomes of counties with and without a dedicated public health tax after adjusting for a set of control variables using regression models for county level data from 720 counties of the Mississippi Delta Region.</p> <p>Results</p> <p>Levying a dedicated public health tax for counties with per capita income above $28,000 is associated with improved health outcomes of those counties when compared to counties without a dedicated property tax for public health. Alternatively, levying a dedicated property tax in counties with lower per capita income is associated with poor health outcomes.</p> <p>Conclusions</p> <p>There are both positive and negative consequences of using dedicated property taxes to fund public health. Policymakers should carefully examine both the positive association of improved health outcomes and negative impact of taxation on poor populations before authorizing the use of dedicated local property tax levies to fund public health agencies.</p

Synthesis of Tin Nitride SnxNyNanowires by Chemical Vapour Deposition

Tin nitride (SnxNy) nanowires have been grown for the first time by chemical vapour deposition on n-type Si(111) and in particular by nitridation of Sn containing NH4Cl at 450 °C under a steady flow of NH3. The SnxNynanowires have an average diameter of 200 nm and lengths ≥5 μm and were grown on Si(111) coated with a few nm’s of Au. Nitridation of Sn alone, under a flow of NH3is not effective and leads to the deposition of Sn droplets on the Au/Si(111) surface which impedes one-dimensional growth over a wide temperature range i.e. 300–800 °C. This was overcome by the addition of ammonium chloride (NH4Cl) which undergoes sublimation at 338 °C thereby releasing NH3and HCl which act as dispersants thereby enhancing the vapour pressure of Sn and the one-dimensional growth of SnxNynanowires. In addition to the action of dispersion, Sn reacts with HCl giving SnCl2which in turn reacts with NH3leading to the formation of SnxNyNWs. A first estimate of the band-gap of the SnxNynanowires grown on Si(111) was obtained from optical reflection measurements and found to be ≈2.6 eV. Finally, intricate assemblies of nanowires were also obtained at lower growth temperatures

Nonlinear Sigma Model for Disordered Media: Replica Trick for Non-Perturbative Results and Interactions

In these lectures, given at the NATO ASI at Windsor (2001), applications of the replicas nonlinear sigma model to disordered systems are reviewed. A particular attention is given to two sets of issues. First, obtaining non-perturbative results in the replica limit is discussed, using as examples (i) an oscillatory behaviour of the two-level correlation function and (ii) long-tail asymptotes of different mesoscopic distributions. Second, a new variant of the sigma model for interacting electrons in disordered normal and superconducting systems is presented, with demonstrating how to reduce it, under certain controlled approximations, to known ``phase-only'' actions, including that of the ``dirty bosons'' model.Comment: 25 pages, Proceedings of the NATO ASI "Field Theory of Strongly Correlated Fermions and Bosons in Low - Dimensional Disordered Systems", Windsor, August, 2001; to be published by Kluwe

Hierarchical information clustering by means of topologically embedded graphs

We introduce a graph-theoretic approach to extract clusters and hierarchies in complex data-sets in an unsupervised and deterministic manner, without the use of any prior information. This is achieved by building topologically embedded networks containing the subset of most significant links and analyzing the network structure. For a planar embedding, this method provides both the intra-cluster hierarchy, which describes the way clusters are composed, and the inter-cluster hierarchy which describes how clusters gather together. We discuss performance, robustness and reliability of this method by first investigating several artificial data-sets, finding that it can outperform significantly other established approaches. Then we show that our method can successfully differentiate meaningful clusters and hierarchies in a variety of real data-sets. In particular, we find that the application to gene expression patterns of lymphoma samples uncovers biologically significant groups of genes which play key-roles in diagnosis, prognosis and treatment of some of the most relevant human lymphoid malignancies.Comment: 33 Pages, 18 Figures, 5 Table

Regenerative Potential of Low-Concentration SDS-Decellularized Porcine Aortic Valved Conduits In Vivo

The aims of this study were to determine the functional biocompatibility of low-concentration SDS-decellularized porcine aortic roots in vivo. A previously developed process was modified for 9- and 15-mm-diameter aortic roots to facilitate implantation into the porcine abdominal aorta (n=3) and juvenile sheep right ventricular outflow tract (n=7), respectively. Native allogeneic aortic roots were used as controls. Acellular porcine roots explanted from pigs at weeks were largely repopulated with stromal cells of appropriate phenotype, and there was evidence that macrophages were involved in the regenerative process. Native allogeneic roots were subject to a classic allograft rejection response. Acellular porcine roots explanted from sheep at 6 months showed evidence of appropriate cellular repopulation, again with evidence of a role for macrophages in the regenerative process. There was some degree of calcification of two of the explanted acellular roots, likely due to incomplete removal of DNA before implantation. Native allogeneic ovine roots were subject to a classic allograft rejection response involving T cells, which resulted in overtly calcified and damaged tissues. The study highlighted (1) the importance of removal of DNA from acellular porcine valved roots to avoid calcification and (2) a role for macrophages in the regeneration of low-concentration SDS-decellularized aortic roots, as has been reported for other acellular biological extracellular matrix scaffolds