Production of Interferons and β-Chemokines by Placental Trophoblasts of HIV-1-Infected Women

Objective: The mechanism whereby the placental cells of a human immunodeficiency virus (HIV)-1-infected mother protect the fetus from HIV-1 infection is unclear. Interferons (IFNs) inhibit the replication of viruses by acting at various stages of the life cycle and may play a role in protecting against vertical transmission of HIV-1. In addition the β-chemokines RANTES (regulated on activation T cell expressed and secreted), macrophage inflammatory protein-1-α (MIP-1α), and MIP-1β can block HIV-1 entry into cells by preventing the binding of the macrophage-trophic HIV-1 strains to the coreceptorCCR5. In this study the production of IFNs and β-chemokines by placental trophoblasts of HIV-1-infected women who were HIV-1 non-transmitters was examined. Methods: Placental trophoblastic cells were isolated from 29 HIV-1-infected and 10 control subjects. Supernatants of trophoblast cultures were tested for the production of IFNs and β-chemokines by enzyme linked immunosorbent assay (ELISA). Additionally, HIV-1-gag and IFN-β transcripts were determined by a semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) assay. Results: All placental trophoblasts of HIV-1-infected women contained HIV-1-gag transcripts. There were no statistical differences in the median constitutive levels of IFN-α and IFN-γ produced by trophoblasts of HIV-1- infected and control subjects. In contrast, trophoblasts of HIV-1-infected women constitutively produced significantly higher levels of IFN-β protein than trophoblasts of control subjects. Furthermore, the median levels of β-chemokines produced by trophoblasts of HIV-infected and control women were similar. Conclusions: Since there was no correlation between the placental HIV load and the production of interferons or β-chemokines, the role of trophoblast-derived IFNs and β-chemokines in protecting the fetus from infection with HIV-1 is not clear

Use of bisulfite processing to generate high-β-O-4 content water-soluble lignosulfonates

This work was supported by EPSRC grants (EP/1518175), the Industrial Biotechnology Innovation Centre (IBioIC) (DMB Ph.D. studentship) and an EPSRC Doctoral Prize Fellowship (CSL).With lignin-first biorefineries likely to become a reality, controlled depolymerization of high-quality lignin streams to high value products has become a priority. Using bisulfite chemistry, access to a high-β-O-4 content water-soluble lignosulfonate has been achieved, allowing follow-on procedures in water to be conducted. We show that phenolic β-O-4 units preferential-ly react under acidic bisulfite conditions, whilst non-phenolic β-O-4 units react much more slowly. Exploiting this improved chemical understanding and inherent selectivity, a softwood lignosulfonate has been prepared in which phenolic β-O-4 α-sulfonation has occurred leaving significant native β-O-4 content. Use of an O-benzoylation protocol with lignin coupled with advanced 2D NMR methods has allowed detailed analysis of this and other commercial and industrial lignosulfonates. Conversion of the native β-O-4 to benzylic- oxidized β-O-4 units was followed by a selective reductive cleavage to give a premium aromatic monomer in pure form.Publisher PDFPeer reviewe

Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models.

Continuous de novo fatty acid synthesis is a common feature of cancer that is required to meet the biosynthetic demands of a growing tumor. This process is controlled by the rate-limiting enzyme acetyl-CoA carboxylase (ACC), an attractive but traditionally intractable drug target. Here we provide genetic and pharmacological evidence that in preclinical models ACC is required to maintain the de novo fatty acid synthesis needed for growth and viability of non-small-cell lung cancer (NSCLC) cells. We describe the ability of ND-646-an allosteric inhibitor of the ACC enzymes ACC1 and ACC2 that prevents ACC subunit dimerization-to suppress fatty acid synthesis in vitro and in vivo. Chronic ND-646 treatment of xenograft and genetically engineered mouse models of NSCLC inhibited tumor growth. When administered as a single agent or in combination with the standard-of-care drug carboplatin, ND-646 markedly suppressed lung tumor growth in the Kras;Trp53-/- (also known as KRAS p53) and Kras;Stk11-/- (also known as KRAS Lkb1) mouse models of NSCLC. These findings demonstrate that ACC mediates a metabolic liability of NSCLC and that ACC inhibition by ND-646 is detrimental to NSCLC growth, supporting further examination of the use of ACC inhibitors in oncology

Incomplete Punishment Networks in Public Goods Games: Experimental Evidence

Abundant evidence suggests that high levels of contributions to public goods can be sustained through self-governed monitoring and sanctioning. This experimental study investigates the effectiveness of decentralized sanctioning institutions in alternative punishment networks. Our results show that the structure of punishment network significantly affects allocations to the public good. In addition, we observe that network configurations are more important than punishment capacities for the levels of public good provision, imposed sanctions and economic efficiency. Lastly, we show that targeted revenge is a major driver of anti-social punishment

Model checking for symbolic-heap separation logic with inductive predicates

We investigate the model checking problem for symbolic-heap separation logic with user-defined inductive predicates, i.e., the problem of checking that a given stack-heap memory state satisfies a given formula in this language, as arises e.g. in software testing or runtime verification. First, we show that the problem is decidable; specifically, we present a bottom-up fixed point algorithm that decides the problem and runs in exponential time in the size of the problem instance. Second, we show that, while model checking for the full language is EXPTIME-complete, the problem becomes NP-complete or PTIME-solvable when we impose natural syntactic restrictions on the schemata defining the inductive predicates. We additionally present NP and PTIME algorithms for these restricted fragments. Finally, we report on the experimental performance of our procedures on a variety of specifications extracted from programs, exercising multiple combinations of syntactic restrictions

Phase I Dose Escalation Study of Sodium Stibogluconate (SSG), a Protein Tyrosine Phosphatase Inhibitor, Combined with Interferon Alpha for Patients with Solid Tumors

Purpose: Sodium stibogluconate (SSG), a small molecule inhibitor of protein tyrosine phosphatases, combined with IFN-alpha-2b (IFN-α) inhibited solid tumor cell line growth in vitro. We conducted a phase I clinical trial with SSG plus IFN-α in advanced cancer patients to assess tolerance, maximum tolerated dose (MTD) and immune system effects

Circulating tumor cells in newly diagnosed inflammatory breast cancer

Circulating tumor cells (CTCs) are an independent prognostic factor for progression-free survival (PFS) and overall survival (OS) in patients with metastatic breast cancer. Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. The prognostic value of a CTC count in newly diagnosed IBC has not been established. The aim of this study was to assess the prognostic value of a baseline CTC count in patients with newly diagnosed IBC

Circulating tumor cells as early predictors of metastatic spread in breast cancer patients with limited metastatic dissemination.

IntroductionTraditional factors currently used for prognostic stratification do not always predict adequately treatment response and disease evolution in advanced breast cancer patients. Therefore, the use of blood-based markers, such as circulating tumor cells (CTCs), represents a promising complementary strategy for disease monitoring. In this retrospective study, we explored the role of CTC counts as predictors of disease evolution in breast cancer patients with limited metastatic dissemination.Methods492 advanced breast cancer patients who had a CTC count assessed by CellSearch prior to starting a new line of systemic therapy were eligible for this analysis. Using the threshold of 5 cells/7.5 mL of blood, pretreatment CTC counts were correlated in the overall population with metastatic site distribution, evaluated at baseline and at the time of treatment failure, using the Fisher¿s Exact test. Time to visceral progression, as well as, time to the development of new metastatic lesions and sites were estimated in patients with non-visceral metastases and with single-site metastatic disease, respectively, by the Kaplan-Meier method. Survival times were compared among groups according to pretreatment CTC count by log-Rank test.ResultsIn the overall population, pretreatment CTCs¿¿¿5 were associated with increased baseline number of metastatic sites, compared with CTCs