TDP1/TOP1 ratio as a promising indicator for the response of small cell lung cancer to topotecan

BACKGROUND AND OBJECTIVE Small cell lung cancer (SCLC) is one of the most challenging tumors to treat due to high proliferation rate, early metastatic dissemination and rapid development of chemotherapy resistance. The current treatment protocols involve the use of topoisomerase 1 (TOP1) poisons such as irinotecan and topotecan in combination with platinum-based compounds. TOP1 poisons kill cancer cells by trapping TOP1 on DNA, generating lethal DNA double-strand breaks. A potential mechanism employed by cancer cells to resist killing by TOP1 poisons is to overexpress enzymes involved in the repair of TOP1-DNA breaks. Tyrosyl DNA phosphodiesterase 1 (TDP1) is a key player in this process and despite its importance, no data is currently available to correlate TDP1 protein and mRNA levels with catalytic activity in SCLC. In addition, it is not known if TDP1 and TOP1 protein levels correlate with the cellular response of SCLC to TOP1 based therapies. METHODS AND RESULTS We report a remarkable variation in TDP1 and TOP1 protein levels in a panel of SCLC cell lines. TDP1 protein level correlates well with TDP1 mRNA and TDP1 catalytic activity, as measured by two newly developed independent activity assays, suggesting the potential utility of immunohistochemistry in assessing TDP1 levels in SCLC tissues. We further demonstrate that whilst TDP1 protein level alone does not correlate with topotecan sensitivity, TDP1/TOP1 ratio correlates well with sensitivity in 8 out of 10 cell lines examined. CONCLUSION This study provides the first cellular analyses of TDP1 and TOP1 in SCLC and suggests the potential utility of TDP1/TOP1 ratio to assess the response of SCLC to topotecan. The establishment and validation of an easy-to-use TDP1 enzymatic assay in cell extracts could be exploited as a diagnostic tool in the clinic. These findings may help in stratifying patients that are likely to benefit from TOP1 poisons and TDP1 inhibitors currently under development

The Unfolding of the Relational Operant: A Real-time Analysis Using Electroencephalography and Reaction Time Measures

The current study attempted to capture in real time the unfolding of the relational operant using electroencephalography (EEG) and reaction time measures. Participants were exposed to relational pretraining to establish the contextual cues of Same and Opposite for two arbitrary stimuli. These cues were then used to establish a series of contextually controlled discriminations in order to create a simple relational network among a series of arbitrary stimuli. During the test for derived relations of Same and Opposite, EEG and reaction time measures were recorded for each individual test task during the acquisition of a stable derived relational response pattern. Participants were then exposed to an identical set of relational training and testing tasks with the important difference that an entirely different set of stimuli was used. EEG and reaction time measures were again recorded during the relational test phase. Results showed that reaction times decreased for all subjects across successive test tasks and from the first to the second stimulus set. EEG data also suggested that there was increasingly less higher cognitive activity during the derivation of successive stimulus relations within and across stimulus sets. Taken together these findings provide support for the idea that derived relational responding can be viewed as an operant activity that both develops and generalizes

Soliton solutions in an effective action for SU(2) Yang-Mills theory: including effects of higher-derivative term

The Skyrme-Faddeev-Niemi (SFN) model which is an O(3) $\sigma$ model in three dimensional space upto fourth-order in the first derivative is regarded as a low-energy effective theory of SU(2) Yang-Mills theory. One can show from the Wilsonian renormalization group argument that the effective action of Yang-Mills theory recovers the SFN in the infrared region. However, the thoery contains an additional fourth-order term which destabilizes the soliton solution. In this paper, we derive the second derivative term perturbatively and show that the SFN model with the second derivative term possesses soliton solutions.Comment: 7 pages, 3 figure

Small molecule inhibits T-cell acute lymphoblastic leukaemia oncogenic interaction through conformational modulation of LMO2

Ectopic expression in T-cell precursors of LIM only protein 2 (LMO2), a key factor in hematopoietic development, has been linked to the onset of T-cell acute lymphoblastic leukaemia (T-ALL). In the T-ALL context, LMO2 drives oncogenic progression through binding to erythroid-specific transcription factor SCL/TAL1 and sequestration of E-protein transcription factors, normally required for T-cell differentiation. A key requirement for the formation of this oncogenic protein-protein interaction (PPI) is the conformational flexibility of LMO2. Here we identify a small molecule inhibitor of the SCL-LMO2 PPI, which hinders the interaction in vitro through direct binding to LMO2. Biophysical analysis demonstrates that this inhibitor acts through a mechanism of conformational modulation of LMO2. Importantly, this work has led to the identification of a small molecule inhibitor of the SCL-LMO2 PPI, which can provide a starting point for the development of new agents for the treatment of T-ALL. These results suggest that similar approaches, based on the modulation of protein conformation by small molecules, might be used for therapeutic targeting of other oncogenic PPIs

The Impact of Tumour pH on Cancer Progression; Strategies for Clinical Intervention

Dysregulation of cellular pH is frequent in solid tumours and provides potential opportunities for therapeutic intervention. The acidic microenvironment within a tumour can promote migration, invasion and metastasis of cancer cells through a variety of mechanisms. Pathways associated with the control of intracellular pH that are under consideration for intervention include carbonic anhydrase IX, the monocarboxylate transporters (MCT, MCT1 and MCT4), the vacuolar-type H(+)-ATPase proton pump, and the sodium-hydrogen exchanger 1. This review will describe progress in the development of inhibitors to these targets

Synthesis and luminescence properties of cyclometalated iridium(III) complexes incorporating conjugated benzotriazole units

The stepwise synthesis of imidazo[4,5-f]-1,10-phenanthroline-based ligands that incorporate conjugated benzotriazole units are described. Corresponding cyclometalated Ir(III) complexes of the type [Ir(CˆN)2(L)]BF4 (where CˆN = cyclometalating ligand; L = phenanthroline type ligand) are reported. The complexes were characterized using a variety of techniques, including IR, NMR, UV-vis. spectroscopies, mass spectrometry and cyclic voltammetry. The [Ir(ppy)2(L)]BF4 complexes display luminescence in the visible region with the benzotriazole variants showing blue shifted emission around 495 nm. Supporting TD-DFT calculations predict that a mixture of MLCT and LLCT character may contribute to the HOMO-LUMO transition of the benzotriazole derivatives

Development of 2-(4-pyridyl)-benzimidazoles as PKN2 chemical tools to probe cancer

Kinases are signalling proteins which have proven to be successful targets for the treatment of a variety of diseases, predominantly in cancers. However, only a small proportion of kinases (<20%) have been investigated for their therapeutic viability, likely due to the lack of available chemical tools across the kinome. In this work we describe initial efforts in the development of a selective chemical tool for protein kinase N2 (PKN2), a relatively unexplored kinase of interest in several types of cancer. The most successful compound, 5, has a measured IC50 of 0.064 μM against PKN2, with ca. 17-fold selectivity over close homologue, PKN1

Low-Voltage Polymer/Small-Molecule Blend Organic Thin-Film Transistors and Circuits Fabricated via Spray Deposition

Organic thin-film electronics have long been considered an enticing candidate in achieving high-throughput manufacturing of low-power ubiquitous electronics. However, to achieve this goal, more work is required to reduce operating voltages and develop suitable mass-manufacture techniques. Here, we demonstrate low-voltage spray-cast organic thin-film transistors based on a semiconductor blend of 2,8-difluoro- 5,11-bis (triethylsilylethynyl) anthradithiophene and poly(triarylamine). Both semiconductor and dielectric films are deposited via successive spray deposition in ambient conditions (air with 40%–60% relative humidity) without any special precautions. Despite the simplicity of the deposition method, p-channel transistors with hole mobilities of \u3e1 cm2/Vs are realized at −4 V operation, and unipolar inverters operating at −6 V are demonstrated