Multiporphyrin coordination arrays based on complexation of magnesium(II) porphyrins with porphyrinylphosphine oxides

Di- and triporphyrin arrays consisting of 5,15-diphenylporphyrinatomagnesium(II) (MgDPP) coordinated to free- base and Ni( II) porphyrinyl mono- and bis-phosphine oxides, as well as the self-coordinating diphenyl[10,20-diphenylporphyrinatomagnesium(II)-5-yl]phosphine oxide [MgDPP(Ph2PO)], were synthesised in excellent yields and characterised by various spectroscopic techniques. Phosphine oxides stabilise Mg(II) coordination to porphyrins and the resulting complexes have convenient solubilities, while the Ni(II) complexes exhibit interesting intramolecular fluorescence quenching behaviour. The binding constant of MgDPP to triphenylphosphine oxide (5.3 +/- 0.1 x 10(5) M-1) and the very high self- association constant of [MgDPP(Ph2PO)] (5.5 +/- 0.5 x 10(8) M-1) demonstrate the strong affinity of phosphine oxides towards Mg(II) porphyrins. These complexes are the first strongly bound synthetic Mg(II) multiporphyrin complexes and could potentially mimic the "special pair" in the photosynthetic reaction centre

High Throughput, Polymeric Aqueous Two‐Phase Printing of Tumor Spheroids

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109304/1/adfm201401302-sup-0001-S1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/109304/2/adfm201401302.pd

Patient-specific RF safety assessment in MRI: Progress in creating surface-based human head and shoulder models

The interaction of electromagnetic (EM) fields with the human body during magnetic resonance imaging (MRI) is complex and subject specific. MRI radiofrequency (RF) coil performance and safety assessment typically includes numerical EM simulations with a set of human body models. The dimensions of mesh elements used for discretization of the EM simulation domain must be adequate for correct representation of the MRI coil elements, different types of human tissue, and wires and electrodes of additional devices. Examples of such devices include those used during electroencephalography, transcranial magnetic stimulation, and transcranial direct current stimulation, which record complementary information or manipulate brain states during MRI measurement. The electrical contact within and between tissues, as well as between an electrode and the skin, must also be preserved. These requirements can be fulfilled with anatomically correct surface-based human models and EM solvers based on unstructured meshes. Here, we report (i) our workflow used to generate the surface meshes of a head and torso model from the segmented AustinMan dataset, (ii) head and torso model mesh optimization for three-dimensional EM simulation in ANSYS HFSS, and (iii) several case studies of MRI RF coil performance and safety assessment

On the early and developed stages of surface condensation: competition mechanism between interfacial and condensate bulk thermal resistances

Financial supports from the National Natural Science Foundation of China (51406205), the Beijing Natural Science Foundation (3142021) and the Engineering and Physics Science Research Council (EPSRC) of the UK (EP/L001233/1) are acknowledged.Financial supports from the National Natural Science Foundation of China (51406205), the Beijing Natural Science Foundation (3142021) and the Engineering and Physics Science Research Council (EPSRC) of the UK (EP/L001233/1) are acknowledged.Financial supports from the National Natural Science Foundation of China (51406205), the Beijing Natural Science Foundation (3142021) and the Engineering and Physics Science Research Council (EPSRC) of the UK (EP/L001233/1) are acknowledged.We use molecular dynamics simulation to investigate the early and developed stages of surface condensation. We find that the liquid-vapor and solid-liquid interfacial thermal resistances depend on the properties of solid and fluid, which are time-independent, while the condensate bulk thermal resistance depends on the condensate thickness, which is time-dependent. There exists intrinsic competition between the interfacial and condensate bulk thermal resistances in timeline and the resultant total thermal resistance determines the condensation intensity for a given vapor-solid temperature difference. We reveal the competition mechanism that the interfacial thermal resistance dominates at the onset of condensation and holds afterwards while the condensate bulk thermal resistance gradually takes over with condensate thickness growing. The weaker the solid-liquid bonding, the later the takeover occurs. This competition mechanism suggests that only when the condensate bulk thermal resistance is reduced after it takes over the domination can the condensation be effectively intensified. We propose a unified theoretical model for the thermal resistance analysis by making dropwise condensation equivalent to filmwise condensation. We further find that near a critical point (contact angle being ca. 153°) the bulk thermal resistance has the least opportunity to take over the domination while away from it the probability increases.Financial supports from the National Natural Science Foundation of China (51406205), the Beijing Natural Science Foundation (3142021) and the Engineering and Physics Science Research Council (EPSRC) of the UK (EP/L001233/1) are acknowledged

On the analysis of the contact angle for impacting droplets using a polynomial fitting approach

ractical considerations on the measurement of the dynamic contact angle and the spreading diameter of impacting droplets are discussed in this paper. The contact angle of a liquid is commonly obtained either by a polynomial or a linear fitting to the droplet profile around the triple phase point. Previous works have focused on quasi-static or sessile droplets, or in cases where inertia does not play a major role on the contact angle dynamics. Here, we study the effect of droplet shape, the order of the fitting polynomial, and the fitting domain, on the measurement of the contact angle on various stages following droplet impact where the contact line is moving. Our results, presented in terms of the optical resolution and the droplet size, show that a quadratic fitting provides the most consistent results for a range of various droplet shapes. As expected, our results show that contact angle values are less sensitive to the fitting conditions for the cases where the droplet can be approximated to a spherical cap. Our experimental conditions include impact events with liquid droplets of different sizes and viscosities on various substrates. In addition, validating past works, our results show that the maximum spreading diameter can be parameterised by the Weber number and the rapidly advancing contact angle

Reversing Melanoma Cross-Resistance to BRAF and MEK Inhibitors by Co-Targeting the AKT/mTOR Pathway

The sustained clinical activity of the BRAF inhibitor vemurafenib (PLX4032/RG7204) in patients with BRAF(V600) mutant melanoma is limited primarily by the development of acquired resistance leading to tumor progression. Clinical trials are in progress using MEK inhibitors following disease progression in patients receiving BRAF inhibitors. However, the PI3K/AKT pathway can also induce resistance to the inhibitors of MAPK pathway.The sensitivity to vemurafenib or the MEK inhibitor AZD6244 was tested in sensitive and resistant human melanoma cell lines exploring differences in activation-associated phosphorylation levels of major signaling molecules, leading to the testing of co-inhibition of the AKT/mTOR pathway genetically and pharmacologically. There was a high degree of cross-resistance to vemurafenib and AZD6244, except in two vemurafenib-resistant cell lines that acquired a secondary mutation in NRAS. In other cell lines, acquired resistance to both drugs was associated with persistence or increase in activity of AKT pathway. siRNA-mediated gene silencing and combination therapy with an AKT inhibitor or rapamycin partially or completely reversed the resistance.Primary and acquired resistance to vemurafenib in these in vitro models results in frequent cross resistance to MEK inhibitors, except when the resistance is the result of a secondary NRAS mutation. Resistance to BRAF or MEK inhibitors is associated with the induction or persistence of activity within the AKT pathway in the presence of these drugs. This resistance can be potentially reversed by the combination of a RAF or MEK inhibitor with an AKT or mTOR inhibitor. These combinations should be available for clinical testing in patients progressing on BRAF inhibitors

PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro

Abstract Introduction Alterations in cell cycle regulators have been implicated in human malignancies including breast cancer. PD 0332991 is an orally active, highly selective inhibitor of the cyclin D kinases (CDK)4 and CDK6 with ability to block retinoblastoma (Rb) phosphorylation in the low nanomolar range. To identify predictors of response, we determined the in vitro sensitivity to PD 0332991 across a panel of molecularly characterized human breast cancer cell lines. Methods Forty-seven human breast cancer and immortalized cell lines representing the known molecular subgroups of breast cancer were treated with PD 0332991 to determine IC50 values. These data were analyzed against baseline gene expression data to identify genes associated with PD 0332991 response. Results Cell lines representing luminal estrogen receptor-positive (ER+) subtype (including those that are HER2 amplified) were most sensitive to growth inhibition by PD 0332991 while nonluminal/basal subtypes were most resistant. Analysis of variance identified 450 differentially expressed genes between sensitive and resistant cells. pRb and cyclin D1 were elevated and CDKN2A (p16) was decreased in the most sensitive lines. Cell cycle analysis showed G0/G1 arrest in sensitive cell lines and Western blot analysis demonstrated that Rb phosphorylation is blocked in sensitive lines but not resistant lines. PD 0332991 was synergistic with tamoxifen and trastuzumab in ER+ and HER2-amplified cell lines, respectively. PD 0332991 enhanced sensitivity to tamoxifen in cell lines with conditioned resistance to ER blockade. Conclusions These studies suggest a role for CDK4/6 inhibition in some breast cancers and identify criteria for patient selection in clinical studies of PD 0332991

Negative feedback regulation of the ERK1/2 MAPK pathway

The extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signalling pathway regulates many cellular functions, including proliferation, differentiation, and transformation. To reliably convert external stimuli into specific cellular responses and to adapt to environmental circumstances, the pathway must be integrated into the overall signalling activity of the cell. Multiple mechanisms have evolved to perform this role. In this review, we will focus on negative feedback mechanisms and examine how they shape ERK1/2 MAPK signalling. We will first discuss the extensive number of negative feedback loops targeting the different components of the ERK1/2 MAPK cascade, specifically the direct posttranslational modification of pathway components by downstream protein kinases and the induction of de novo gene synthesis of specific pathway inhibitors. We will then evaluate how negative feedback modulates the spatiotemporal signalling dynamics of the ERK1/2 pathway regarding signalling amplitude and duration as well as subcellular localisation. Aberrant ERK1/2 activation results in deregulated proliferation and malignant transformation in model systems and is commonly observed in human tumours. Inhibition of the ERK1/2 pathway thus represents an attractive target for the treatment of malignant tumours with increased ERK1/2 activity. We will, therefore, discuss the effect of ERK1/2 MAPK feedback regulation on cancer treatment and how it contributes to reduced clinical efficacy of therapeutic agents and the development of drug resistance

Targeted agents and immunotherapies: optimizing outcomes in melanoma

Treatment options for patients with metastatic melanoma, and especially BRAF-mutant melanoma, have changed dramatically in the past 5 years, with the FDA approval of eight new therapeutic agents. During this period, the treatment paradigm for BRAF-mutant disease has evolved rapidly: the standard-of-care BRAF-targeted approach has shifted from single-agent BRAF inhibition to combination therapy with a BRAF and a MEK inhibitor. Concurrently, immunotherapy has transitioned from cytokine-based treatment to antibody-mediated blockade of the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and, now, the programmed cell-death protein 1 (PD-1) immune checkpoints. These changes in the treatment landscape have dramatically improved patient outcomes, with the median overall survival of patients with advanced-stage melanoma increasing from approximately 9 months before 2011 to at least 2 years - and probably longer for those with BRAF-V600-mutant disease. Herein, we review the clinical trial data that established the standard-of-care treatment approaches for advanced-stage melanoma. Mechanisms of resistance and biomarkers of response to BRAF-targeted treatments and immunotherapies are discussed, and the contrasting clinical benefits and limitations of these therapies are explored. We summarize the state of the field and outline a rational approach to frontline-treatment selection for each individual patient with BRAF-mutant melanoma