Cisplatin: synthesis of some 2,3-diaminopropionic ester analogues: dichloro(hexadecyl 2,3-diaminopropionato) platinum(II) and dichloro(cyclohexyl 2,3-diaminopropionato) platinum(II)

The title compounds were prepared from ethyl cyanoacetate by the four-step procedure of conversion into the corresponding 2-hydroxyimino-derivative, transesterification with either hexadecanol or cyclohexanol, catalytic hydrogenation of the respective products to afford the diamino-dihydrochlorides, and complex formation of the latter pair with potassium tetrachloroplatinate. Assignment of the structures of the cis-platinum complexes was confirmed by infrared spectrometry

A nanoparticle-incorporated STING activator enhances antitumor immunity in PD-L1-insensitive models of triple-negative breast cancer

Triple-negative breast cancer (TNBC) has few therapeutic options, and alternative approaches are urgently needed. Stimulator of IFN genes (STING) is becoming an exciting target for therapeutic adjuvants. However, STING resides inside the cell, and the intracellular delivery of CDNs, such as cGAMP, is required for the optimal activation of STING. We show that liposomal nanoparticle-delivered cGAMP (cGAMP-NP) activates STING more effectively than soluble cGAMP. These particles induce innate and adaptive host immune responses to preexisting tumors in both orthotopic and genetically engineered models of basal-like TNBC. cGAMP-NPs also reduce melanoma tumor load, with limited responsivity to anti-PD-L1. Within the tumor microenvironment, cGAMP-NPs direct both mouse and human macrophages (M), reprograming from protumorigenic M2-like phenotype toward M1-like phenotype; enhance MHC and costimulatory molecule expression; reduce M2 biomarkers; increase IFN-γ-producing T cells; augment tumor apoptosis; and increase CD4+ and CD8+ T cell infiltration. Activated T cells are required for tumor suppression, as their depletion reduces antitumor activity. Importantly, cGAMP-NPs prevent the formation of secondary tumors, and a single dose is sufficient to inhibit TNBC. These data suggest that a minimal system comprised of cGAMP-NP alone is sufficient to modulate the tumor microenvironment to effectively control PD-L1-insensitive TNBC

TRY plant trait database – enhanced coverage and open access

Plant traits—the morphological, anatomical, physiological, biochemical and phenological characteristics of plants—determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits—almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Global DNA methylation analysis identifies key pathway differences between poor (low OCT-1 activity) and standard risk CP-CML patients at diagnosis

Abstract Abstract 3730 Background: DNA methylation, specifically CpG methylation, is an essential mediator of epigenetic gene expression which is of vital importance to many biological processes and human malignancies. DNA hypermethylation has been previously described in a small number of genes in chronic myeloid leukemia (CML); however, current published studies have only examined the methylation status of selected genes, often based on the results of studies in other malignancies. Therefore, the global DNA methylation profile of chronic phase-CML (CP-CML) remains poorly understood, as does the impact of the epigenome on patient response to tyrosine kinase inhibitors (TKIs) including imatinib. The organic cation transport-1 (OCT-1) protein is the major active protein involved in imatinib transport, and we have previously demonstrated that measuring its function in leukemic mononuclear cells, expressed as OCT-1 activity (OA), in patient cells prior to imatinib therapy, provides a strong prognostic indicator. Notably, very low OA (poor risk cohort) is associated with patients at significant risk for poor molecular response, mutation development and leukemic transformation on imatinib therapy. Therefore, it is of particular interest to ascertain whether epigenetic changes are distinct and potentially biologically relevant in these poor risk patients. Aim: To investigate the global DNA methylation profile in CP-CML patients with a particular focus on poor risk patients (very low OCT-1 activity), and to ascertain whether aberrant epigenetic programming may underlie their poor response. Method: Cells were isolated from the blood of 55 CP-CML patients at diagnosis and 5 normal individuals. CP-CML patients were classified according to their OA values, with 29 classified as poor (very low OA) and 26 standard risk (high OA). Whole genome DNA methylation analysis was performed using the Illumina Infinium® HumanMethylation450 BeadChip. Analysis of array data was performed with R v2.15.0, using the minfiBioconductor package. Results: The methylation profile of CP-CML was significantly different to that of normal individuals, as shown in Table 1. GeneGo enrichment analysis revealed a significant enrichment in CML for genes known to be involved in other leukemias (p=4.92e−26) particularly AML and CLL, suggesting similar pathways may be under epigenetic control in CML. A significant number of polycomb group (BMI1 and EZH2) target genes were also identified, suggesting the likely involvement of this pathway in CML. Table 1: Summary of significant CpGs and corresponding genes when comparisons of CP-CML to normal individuals, and poor to standard risk patients, are made using methylation profiles. A significant difference was also observed when the methylation profiles of poor and standard risk CP-CML patients were analysed (Table 1). GeneGo analysis again identified polycomb group (SUZ12 and EZH2) target enrichment and significant enrichment of NOTCH, Hedgehog and WNT signalling (p=7.93e−9, p=2.42e−5 and p=3.66e−5 respectively) in poor risk patients, indicating these pathways may play a significant role in the unfavourable responses observed in many of these patients. Of particular interest were the ten CpGs where a fold change >4 was observed between the methylation profiles of poor and standard risk patients. Using the Prediction Analysis of Microarrays supervised learning algorithm, a classifier for patient OA prediction based on this 10 CpG signature was evaluated. This classifier had an overall accuracy of 94% (sensitivity: 95%, specificity: 93%). Conclusion: We present a comprehensive global DNA methylation analysis of CP-CML that indicates significant and widespread changes to the CML epigenome, compared with that of normal individuals. Importantly, we have generated a classifier, which identifies the poor risk patient subgroup (very low OA) with 94% accuracy. Validation of this classifier is currently in progress. The epigenetic changes identified here may contribute to CML pathogenesis, and also to the response heterogeneity observed between CP-CML patients treated with TKI therapy. Disclosures: Hughes: Novartis Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. White:Novartis Oncology: Honoraria, Research Funding; BMS: Research Funding; CSL: Research Funding. Dale B. Watkins, Chung Hoow Kok, Richard J. D'Andrea, Timothy P. Hughes and Deborah L. Whit

Gene expression signature that predicts early molecular response failure in chronic-phase CML patients on frontline imatinib

In chronic-phase chronic myeloid leukemia (CP-CML) patients treated with frontline imatinib, failure to achieve early molecular response (EMR; EMR failure: BCR-ABL1 >10% on the international scale at 3 months) is predictive of inferior outcomes. Identifying patients at high-risk of EMR failure at diagnosis provides an opportunity to intensify frontline therapy and potentially avoid EMR failure. We studied blood samples from 96 CP-CML patients at diagnosis and identified 365 genes that were aberrantly expressed in 13 patients who subsequently failed to achieve EMR, with a gene signature significantly enriched for stem cell phenotype (eg, Myc, β-catenin, Hoxa9/Meis1), cell cycle, and reduced immune response pathways. We selected a 17-gene panel to predict EMR failure and validated this signature on an independent patient cohort. Patients classified as high risk with our gene expression signature (HR-GES) exhibited significantly higher rates of EMR failure compared with low-risk (LR-GES) patients (78% vs 5%; P < .0001), with an overall accuracy of 93%. Furthermore, HR-GES patients who received frontline nilotinib had a relatively low rate of EMR failure (10%). However, HR-GES patients still had inferior deep molecular response achievement rate by 24 months compared with LR-GES patients. This novel multigene signature may be useful for selecting patients at high risk of EMR failure on standard therapy who may benefit from trials of more potent kinase inhibitors or other experimental approaches.Chung H. Kok, David T. Yeung, Liu Lu, Dale B. Watkins, Tamara M. Leclercq, Phuong Dang, Verity A. Saunders, John Reynolds, Deborah L. White and Timothy P. Hughe

An integrated on-line learning system for evolving programmable logic array controllers

Abstract. This paper presents an integrated on-line learning system to evolve programmable logic array (PLA) controllers for navigating an autonomous robot in a two-dimensional environment. The integrated online learning system consists of two learning modules: one is the module of reinforcement learning based on temporal-di erence learning methods, and the other is the module of evolutionary learning based on genetic algorithms. The control rules extracted from the module of reinforcement learning can be used as input to the module of evolutionary learning, and quickly implemented by the PLA through on-line evolution. The on-line evolution has shown promise as a method of learning systems in complex environment. The evolved PLA controllers can successfully navigate the robot to a target in the two-dimensional environment while avoiding collisions with randomly positioned obstacles.

Signaling via a novel integral plasma membrane pool of a serine/threonine protein kinase PRK1 in mammalian cells

10.1096/fj.04-1876fjeFASEB Journal18141722-1724FAJO

Contrast Gain Control in Auditory Cortex

The auditory system must represent sounds with a wide range of statistical properties. One important property is the spectrotemporal contrast in the acoustic environment: the variation in sound pressure in each frequency band, relative to the mean pressure. We show that neurons in ferret auditory cortex rescale their gain to partially compensate for the spectrotemporal contrast of recent stimulation. When contrast is low, neurons increase their gain, becoming more sensitive to small changes in the stimulus, although the effectiveness of contrast gain control is reduced at low mean levels. Gain is primarily determined by contrast near each neuron's preferred frequency, but there is also a contribution from contrast in more distant frequency bands. Neural responses are modulated by contrast over timescales of ∼100 ms. By using contrast gain control to expand or compress the representation of its inputs, the auditory system may be seeking an efficient coding of natural sounds