LEE011 and ruxolitinib: a synergistic drug combination for natural killer/T-cell lymphoma (NKTCL).

Natural killer/T-cell lymphoma (NKTCL) is an aggressive non-Hodgkin lymphoma that has been facing limited success with conventional treatments, urging for the discovery of alternative strategies. Recent studies including ours have revealed that EZH2 and JAK-STAT signalling pathways are key contributors to NKTCL pathogenesis. In particular, we found that EZH2 is overexpressed and directly transcriptionally activates the CCND1 gene to confer growth advantage. CCND1 codes for cyclin D1, which complexes with CDK4/6 to promote G1 to S phase transition. Therefore in this study we investigated whether inhibiting both JAK1/2 and CDK4/6, using LEE011 and ruxolitinib respectively is effective in NKTL. We first demonstrate that separate LEE011 and ruxolitinib treatment is sufficient to cause growth inhibition of NKTCL cells. More importantly, we found that there is synergistic growth inhibitory effects on NKTCL cells with combination treatment of LEE011 and ruxolitinib. The results obtained shows that the targeting of both CDK4/6 and JAK1/2 are promising to develop better treatment alternatives for NKTCL.This study was supported by the National Medical Research Council (NMRC) grants NMRC/Clinician Scientist-Individual Research/1343/2012 (WJC), NMRC/Basic Research Grant-New Investigator/2021/2014 (JY) and the Singapore Ministry of Education Academic Research Fund Tier 2 grant MOE2015-T2-2-119 (DN). WJC was also supported by the NMRC Clinician Scientist Investigator Award

Isolated heart models for studying cardiac electrophysiology: a historical perspective and recent advances

Experimental models used in cardiovascular research range from cellular to whole heart preparations. Isolated whole hearts show higher levels of structural and functional integration than lower level models such as tissues or cellular fragments. Cardiovascular diseases are multi-factorial problems that are dependent on highly organized structures rather than on molecular or cellular components alone. This article first provides a general introduction on the animal models of cardiovascular diseases. It is followed by a detailed overview and a historical perspective of the different isolated heart systems with a particular focus on the Langendorff perfusion method for the study of cardiac arrhythmias. The choice of species, perfusion method, and perfusate composition are discussed in further detail with particular considerations of the theoretical and practical aspects of experimental settings

Mouse models of atherosclerosis: a historical perspective and recent advances.

Atherosclerosis represents a significant cause of morbidity and mortality in both the developed and developing countries. Animal models of atherosclerosis have served as valuable tools for providing insights on its aetiology, pathophysiology and complications. They can be used for invasive interrogation of physiological function and provide a platform for testing the efficacy and safety of different pharmacological therapies. Compared to studies using human subjects, animal models have the advantages of being easier to manage, with controllable diet and environmental risk factors. Moreover, pathophysiological changes can be induced either genetically or pharmacologically to study the harmful effects of these interventions. There is no single ideal animal model, as different systems are suitable for different research objectives. A good understanding of the similarities and differences to humans enables effective extrapolation of data for translational application. In this article, we will examine the different mouse models for the study and elucidation of the pathophysiological mechanisms underlying atherosclerosis. We also review recent advances in the field, such as the role of oxidative stress in promoting endoplasmic reticulum stress, mitochondrial dysfunction and mitochondrial DNA damage, which can result in vascular inflammation and atherosclerosis. Finally, novel therapeutic approaches to reduce vascular damage caused by chronic inflammation using microRNA and nano-medicine technology, are discussed.YC is supported by a project grant from the ESRC for her doctoral studies at the University of Cambridge. GT was supported by the BBSRC Doctoral Training Award and Assistant Professorships from The Croucher Foundation of Hong Kong

Isolated heart models for studying cardiac electrophysiology: a historical perspective and recent advances

Experimental models used in cardiovascular research range from cellular to whole heart preparations. Isolated whole hearts show higher levels of structural and functional integration than lower level models such as tissues or cellular fragments. Cardiovascular diseases are multi-factorial problems that are dependent on highly organized structures rather than on molecular or cellular components alone. This article first provides a general introduction on the animal models of cardiovascular diseases. It is followed by a detailed overview and a historical perspective of the different isolated heart systems with a particular focus on the Langendorff perfusion method for the study of cardiac arrhythmias. The choice of species, perfusion method, and perfusate composition are discussed in further detail with particular considerations of the theoretical and practical aspects of experimental settings.published_or_final_versio

Localizing triplet periodicity in DNA and cDNA sequences

<p>Abstract</p> <p>Background</p> <p>The protein-coding regions (coding exons) of a DNA sequence exhibit a triplet periodicity (TP) due to fact that coding exons contain a series of three nucleotide codons that encode specific amino acid residues. Such periodicity is usually not observed in introns and intergenic regions. If a DNA sequence is divided into small segments and a Fourier Transform is applied on each segment, a strong peak at frequency 1/3 is typically observed in the Fourier spectrum of coding segments, but not in non-coding regions. This property has been used in identifying the locations of protein-coding genes in unannotated sequence. The method is fast and requires no training. However, the need to compute the Fourier Transform across a segment (window) of arbitrary size affects the accuracy with which one can localize TP boundaries. Here, we report a technique that provides higher-resolution identification of these boundaries, and use the technique to explore the biological correlates of TP regions in the genome of the model organism <it>C. elegans</it>.</p> <p>Results</p> <p>Using both simulated TP signals and the real <it>C. elegans </it>sequence F56F11 as an example, we demonstrate that, (1) Modified Wavelet Transform (MWT) can better define the boundary of TP region than the conventional Short Time Fourier Transform (STFT); (2) The scale parameter (a) of MWT determines the precision of TP boundary localization: bigger values of a give sharper TP boundaries but result in a lower signal to noise ratio; (3) RNA splicing sites have weaker TP signals than coding region; (4) TP signals in coding region can be destroyed or recovered by frame-shift mutations; (5) 6 bp periodicities in introns and intergenic region can generate false positive signals and it can be removed with 6 bp MWT.</p> <p>Conclusions</p> <p>MWT can provide more precise TP boundaries than STFT and the boundaries can be further refined by bigger scale MWT. Subtraction of 6 bp periodicity signals reduces the number of false positives. Experimentally-introduced frame-shift mutations help recover TP signal that have been lost by possible ancient frame-shifts. More importantly, TP signal has the potential to be used to detect the splice junctions in fully spliced mRNA sequence.</p

Environmental DNA signatures distinguish between tsunami and storm deposition in overwash sand

AbstractSandy onshore deposits from tsunamis are difficult to distinguish from storm deposits, which makes it difficult to assess coastal hazards from the geological record. Here we analyse environmental DNA from microbial communities preserved in known tsunami and storm-deposited sediments and intercalating soils and non-marine sediments near Cuddalore, India, and Phra Thong Island, Thailand. Both sites were impacted by the 2004 Indian Ocean Tsunami and a subsequent storm flooding event (2011 Cyclone Thane at Cuddalore and a 2007 storm at Phra Thong Island). We show that the microbial communities in the overwash deposits are significantly different from soil and sediments that are not derived by overwash processes at both locations. Our method also successfully discriminates between modern tsunami deposits and storm deposits. We suggest molecular techniques have the potential to accurately discriminate overwash deposits from catastrophic natural events.</jats:p

Ductility by shear band delocalization in the nano-layer of gradient structure

Nanostructured (NS) metals typically fail soon after yielding, starting with the formation of narrow shear bands. Here we report the observation of shear band delocalization in gradient metals. Shear bands were nucleated and delocalized in the NS layers by propagating along the gage length soon after yielding, converting the shear band into a localized strain zone (LSZ). Synergistic work hardening was developed in the LSZ by regaining dislocation hardening capability, and by back-stress hardening from the strain gradients in the axial and depth directions, which helped with enhancing global ductility. [GRAPHICS

Observation of a ppb mass threshoud enhancement in \psi^\prime\to\pi^+\pi^-J/\psi(J/\psi\to\gamma p\bar{p}) decay

The decay channel $\psi^\prime\to\pi^+\pi^-J/\psi(J/\psi\to\gamma p\bar{p})$ is studied using a sample of $1.06\times 10^8$ $\psi^\prime$ events collected by the BESIII experiment at BEPCII. A strong enhancement at threshold is observed in the $p\bar{p}$ invariant mass spectrum. The enhancement can be fit with an $S$-wave Breit-Wigner resonance function with a resulting peak mass of $M=1861^{+6}_{-13} {\rm (stat)}^{+7}_{-26} {\rm (syst)} {\rm MeV/}c^2$ and a narrow width that is $\Gamma<38 {\rm MeV/}c^2$ at the 90% confidence level. These results are consistent with published BESII results. These mass and width values do not match with those of any known meson resonance.Comment: 5 pages, 3 figures, submitted to Chinese Physics

Polyclonal rabbit anti-murine plasmacytoma cell globulins induce myeloma cells apoptosis and inhibit tumour growth in mice

Multiple myelomas (MMs) are etiologically heterogeneous and there are limited treatment options; indeed, current monoclonal antibody therapies have had limited success, so more effective antibodies are urgently needed. Polyclonal antibodies are a possible alternative because they target multiple antigens simultaneously. In this study, we produced polyclonal rabbit anti-murine plasmacytoma cell immunoglobulin (PAb) by immunizing rabbits with the murine plasmacytoma cell line MPC-11. The isolated PAb bound to plasma surface antigens in several MM cell lines, inhibited their proliferation as revealed by MTT assay, and induce apoptosis as indicated by flow cytometry, microscopic observation of apoptotic changes in morphology, and DNA fragmentation on agarose gels. The cytotoxicity of PAb on MPC-11 cell lines was both dose-dependent and time-dependent; PAb exerted a 50% inhibitory effect on MPC-11 cell viability at a concentration of 200 µg/ml in 48 h. Flow cytometry demonstrated that PAb treatment significantly increased the number of apoptotic cells (48.1%) compared with control IgG (8.3%). Apoptosis triggered by PAb was confirmed by activation of caspase-3, -8, and -9. Serial intravenous or intraperitoneal injections of PAb inhibited tumour growth and prolonged survival in mice bearing murine plasmacytoma, while TUNEL assay demonstrated that PAb induced statistically significant apoptosis (P < 0.05) compared to control treatments. We conclude that PAb is an effective agent for in vitro and in vivo induction of apoptosis in multiple myeloma and that exploratory clinical trials may be warranted