Imipramine blue sensitively and selectively targets FLT3-ITD positive acute myeloid leukemia cells.

Aberrant cytokine signaling initiated from mutant receptor tyrosine kinases (RTKs) provides critical growth and survival signals in high risk acute myeloid leukemia (AML). Inhibitors to FLT3 have already been tested in clinical trials, however, drug resistance limits clinical efficacy. Mutant receptor tyrosine kinases are mislocalized in the endoplasmic reticulum (ER) of AML and play an important role in the non-canonical activation of signal transducer and activator of transcription 5 (STAT5). Here, we have tested a potent new drug called imipramine blue (IB), which is a chimeric molecule with a dual mechanism of action. At 200-300 nM concentrations, IB is a potent inhibitor of STAT5 through liberation of endogenous phosphatase activity following NADPH oxidase (NOX) inhibition. However, at 75-150 nM concentrations, IB was highly effective at killing mutant FLT3-driven AML cells through a similar mechanism as thapsigargin (TG), involving increased cytosolic calcium. IB also potently inhibited survival of primary human FLT3/ITD+ AML cells compared to FLT3/ITDneg cells and spared normal umbilical cord blood cells. Therefore, IB functions through a mechanism involving vulnerability to dysregulated calcium metabolism and the combination of fusing a lipophilic amine to a NOX inhibiting dye shows promise for further pre-clinical development for targeting high risk AML

Gall Bladder And Common Bile Duct Stones – When Is Direct Cholangiography Indicated?

The medical records of 277 consecutive patients who underwent cholecystectomy for benign gall stone disease, were reviewed to determine the incidence and cause of biliary tract obstructuion

Comparative genomic analysis of Mycobacterium avium subspecies obtained from multiple host species

<p>Abstract</p> <p>Background</p> <p><it>Mycobacterium avium </it>(<it>M. avium</it>) subspecies vary widely in both pathogenicity and host specificity, but the genetic features contributing to this diversity remain unclear.</p> <p>Results</p> <p>A comparative genomic approach was used to identify large sequence polymorphisms among <it>M. avium </it>subspecies obtained from a variety of host animals. DNA microarrays were used as a platform for comparing mycobacterial isolates with the sequenced bovine isolate <it>M. avium </it>subsp. <it>paratuberculosis </it>(MAP) K-10. Open reading frames (ORFs) were classified as present or divergent based on the relative fluorescent intensities of the experimental samples compared to MAP K-10 DNA. Multiple large polymorphic regions were found in the genomes of MAP isolates obtained from sheep. One of these clusters encodes glycopeptidolipid biosynthesis enzymes which have not previously been identified in MAP. <it>M. avium </it>subsp. <it>silvaticum </it>isolates were observed to have a hybridization profile very similar to yet distinguishable from <it>M. avium </it>subsp. <it>avium</it>. Isolates obtained from cattle (n = 5), birds (n = 4), goats (n = 3), bison (n = 3), and humans (n = 9) were indistinguishable from cattle isolate MAP K-10.</p> <p>Conclusion</p> <p>Genome diversity in <it>M. avium </it>subspecies appears to be mediated by large sequence polymorphisms that are commonly associated with mobile genetic elements. Subspecies and host adapted isolates of <it>M. avium </it>were distinguishable by the presence or absence of specific polymorphisms.</p

Magnetic properties of copper amalgams

Magnetic properties of dilute as well as concentrated amalgams have been investigated. It has been shown that when dilute amalgams are prepared by prolonged electrolysis at room temperature the diamagnetic susceptibilty of the amalgams prepared is lower than that calculated on the mixture law and the results are in line with those of Venkataramiah; but if the amalgams are prepared at low temperature, 0° C., within 4-5 hours or by grinding the components according to the method of Terry and Wright susceptibility value of the amalgams obeys the mixture law. This difference in the susceptibility has been explained by the authors, by suggesting the formation of paragmanetic oxides formed during prolonged electrolysis at high temperatures. Amalgams of higher concentrations prepared by grinding method, when fresh obey the mixture law but on keeping, even under vacuum, become less diamagnetic and the maximum difference, in susceptibility values between a fresh and an aged amalgam is observed in one which contains 34 per cent. copper. This is supposed to be due to the formation of compound

The play's the thing

For very understandable reasons phenomenological approaches predominate in the field of sensory urbanism. This paper does not seek to add to that particular discourse. Rather it takes Rorty’s postmodernized Pragmatism as its starting point and develops a position on the role of multi-modal design representation in the design process as a means of admitting many voices and managing multidisciplinary collaboration. This paper will interrogate some of the concepts underpinning the Sensory Urbanism project to help define the scope of interest in multi-modal representations. It will then explore a range of techniques and approaches developed by artists and designers during the past fifty years or so and comment on how they might inform the question of multi-modal representation. In conclusion I will argue that we should develop a heterogeneous tool kit that adopts, adapts and re-invents existing methods because this will better serve our purposes during the exploratory phase(s) of any design project that deals with complexity

Transfer Learning for Domain Adaptation in MRI: Application in Brain Lesion Segmentation

Magnetic Resonance Imaging (MRI) is widely used in routine clinical diagnosis and treatment. However, variations in MRI acquisition protocols result in different appearances of normal and diseased tissue in the images. Convolutional neural networks (CNNs), which have shown to be successful in many medical image analysis tasks, are typically sensitive to the variations in imaging protocols. Therefore, in many cases, networks trained on data acquired with one MRI protocol, do not perform satisfactorily on data acquired with different protocols. This limits the use of models trained with large annotated legacy datasets on a new dataset with a different domain which is often a recurring situation in clinical settings. In this study, we aim to answer the following central questions regarding domain adaptation in medical image analysis: Given a fitted legacy model, 1) How much data from the new domain is required for a decent adaptation of the original network?; and, 2) What portion of the pre-trained model parameters should be retrained given a certain number of the new domain training samples? To address these questions, we conducted extensive experiments in white matter hyperintensity segmentation task. We trained a CNN on legacy MR images of brain and evaluated the performance of the domain-adapted network on the same task with images from a different domain. We then compared the performance of the model to the surrogate scenarios where either the same trained network is used or a new network is trained from scratch on the new dataset.The domain-adapted network tuned only by two training examples achieved a Dice score of 0.63 substantially outperforming a similar network trained on the same set of examples from scratch.Comment: 8 pages, 3 figure

Boltzmann-Shannon Entropy: Generalization and Application

The paper deals with the generalization of both Boltzmann entropy and distribution in the light of most-probable interpretation of statistical equilibrium. The statistical analysis of the generalized entropy and distribution leads to some new interesting results of significant physical importance.Comment: 5 pages, Accepted in Mod.Phys.Lett.

Cosymmetries and Nijenhuis recursion operators for difference equations

In this paper we discuss the concept of cosymmetries and co--recursion operators for difference equations and present a co--recursion operator for the Viallet equation. We also discover a new type of factorisation for the recursion operators of difference equations. This factorisation enables us to give an elegant proof that the recursion operator given in arXiv:1004.5346 is indeed a recursion operator for the Viallet equation. Moreover, we show that this operator is Nijenhuis and thus generates infinitely many commuting local symmetries. This recursion operator and its factorisation into Hamiltonian and symplectic operators can be applied to Yamilov's discretisation of the Krichever-Novikov equation