A personalised medicine approach for ponatinib-resistant chronic myeloid leukaemia.

BACKGROUND: Chronic myeloid leukaemia (CML) is characterised by the presence of a fusion driver oncogene, BCR-ABL1, which is a constitutive tyrosine kinase. Tyrosine kinase inhibitors (TKIs) are the central treatment strategy for CML patients and have significantly improved survival rates, but the T315I mutation in the kinase domain of BCR-ABL1 confers resistance to all clinically approved TKIs, except ponatinib. However, compound mutations can mediate resistance even to ponatinib and remain a clinical challenge in CML therapy. Here, we investigated a ponatinib-resistant CML patient through whole-genome sequencing (WGS) to identify the cause of resistance and to find alternative therapeutic targets. PATIENTS AND METHODS: We carried out WGS on a ponatinib-resistant CML patient and demonstrated an effective combination therapy against the primary CML cells derived from this patient in vitro. RESULTS: Our findings demonstrate the emergence of compound mutations in the BCR-ABL1 kinase domain following ponatinib treatment, and chromosomal structural variation data predicted amplification of BCL2. The primary CD34(+) CML cells from this patient showed increased sensitivity to the combination of ponatinib and ABT-263, a BCL2 inhibitor with a negligible effect against the normal CD34(+) cells. CONCLUSION: Our results show the potential of personalised medicine approaches in TKI-resistant CML patients and provide a strategy that could improve clinical outcomes for these patients

Direct Interaction of PP2A Phosphatase with GABAB Receptors Alters Functional Signaling

Addictive drugs usurp the brain's intrinsic mechanism for reward, leading to compulsive and destructive behaviors. In the ventral tegmental area (VTA), the center of the brain's reward circuit, GABAergic neurons control the excitability of dopamine (DA) projection neurons and are the site of initial psychostimulant-dependent changes in signaling. Previous work established that cocaine/methamphetamine exposure increases protein phosphatase 2A (PP2A) activity, which dephosphorylates the GABABR2 subunit, promotes internalization of the GABAB receptor (GABABR) and leads to smaller GABABR-activated G-protein-gated inwardly rectifying potassium (GIRK) currents in VTA GABA neurons. How the actions of PP2A become selective for a particular signaling pathway is poorly understood. Here, we demonstrate that PP2A can associate directly with a short peptide sequence in the C terminal domain of the GABABR1 subunit, and that GABABRs and PP2A are in close proximity in rodent neurons (mouse/rat; mixed sexes). We show that this PP2A-GABABR interaction can be regulated by intracellular Ca2+ Finally, a peptide that potentially reduces recruitment of PP2A to GABABRs and thereby limits receptor dephosphorylation increases the magnitude of baclofen-induced GIRK currents. Thus, limiting PP2A-dependent dephosphorylation of GABABRs may be a useful strategy to increase receptor signaling for treating diseases.SIGNIFICANCE STATEMENT Dysregulation of GABAB receptors (GABABRs) underlies altered neurotransmission in many neurological disorders. Protein phosphatase 2A (PP2A) is involved in dephosphorylating and subsequent internalization of GABABRs in models of addiction and depression. Here, we provide new evidence that PP2A B55 regulatory subunit interacts directly with a small region of the C-terminal domain of the GABABR1 subunit, and that this interaction is sensitive to intracellular Ca2+ We demonstrate that a short peptide corresponding to the PP2A interaction site on GABABR1 competes for PP2A binding, enhances phosphorylation GABABR2 S783, and affects functional signaling through GIRK channels. Our study highlights how targeting PP2A dependent dephosphorylation of GABABRs may provide a specific strategy to modulate GABABR signaling in disease conditions

All-Versus-Nothing Proof of Einstein-Podolsky-Rosen Steering

Einstein-Podolsky-Rosen steering is a form of quantum nonlocality intermediate between entanglement and Bell nonlocality. Although Schr\"odinger already mooted the idea in 1935, steering still defies a complete understanding. In analogy to "all-versus-nothing" proofs of Bell nonlocality, here we present a proof of steering without inequalities rendering the detection of correlations leading to a violation of steering inequalities unnecessary. We show that, given any two-qubit entangled state, the existence of certain projective measurement by Alice so that Bob's normalized conditional states can be regarded as two different pure states provides a criterion for Alice-to-Bob steerability. A steering inequality equivalent to the all-versus-nothing proof is also obtained. Our result clearly demonstrates that there exist many quantum states which do not violate any previously known steering inequality but are indeed steerable. Our method offers advantages over the existing methods for experimentally testing steerability, and sheds new light on the asymmetric steering problem.Comment: 7 pages, 2 figures. Accepted in Sci. Re

Quantum nature of laser light

All compositions of a mixed-state density operator are equivalent for the prediction of the probabilities of future outcomes of measurements. For retrodiction, however, this is not the case. The retrodictive formalism of quantum mechanics provides a criterion for deciding that some compositions are fictional. Fictional compositions do not contain preparation device operators, that is operators corresponding to states that could have been prepared. We apply this to Molmer's controversial conjecture that optical coherences in laser light are a fiction and find agreement with his conjecture. We generalise Molmer's derivation of the interference between two lasers to avoid the use of any fictional states. We also examine another possible method for discriminating between conerent states and photon number states in laser light and find that it does not work, with the equivalence for prediction saved by entanglement

Lumbar spinal stenosis treatment with aperius perclid interspinous system

The purpose of this study is to report clinical outcome and imaging changes of percutaneous Aperius stand-alone implant in patients with degenerative lumbar spinal stenosis and neurogenic intermittent claudication, which did not respond to conservative treatment.Between January 2008 and July 2010, 37 patients (20 males and 17 females) with mean age of 64.3 years underwent surgery for the onset of claudicatio spinalis with Aperius PercLID interspinous device (Medtronic). In all patients, the diagnosis was: foraminal stenosis, in one case (2.7 \%) it was associated to a degenerative anterior listhesis (I grade), in three cases (8.1 \%) it was associated to an intraforaminal disc herniation. The mean follow-up was of 18 months (range 2-35 months). The patients were evaluated through the Oswestry disability index, Zurich Claudication Questionnaire (ZCQ), VAS scales. In all cases were obtained preoperative and in postoperative radiographs and magnetic resonance imaging.The VAS score decreased significantly after surgery: the patients presented a mean VAS of seven preoperatively and two postoperatively (p < 0.001). The ZCQ score significantly decreased postoperatively, with an average reduction of 21.89 \% (p < 0.001). The ODI score as well showed a significant reduction postoperatively of an average 26.09 \% (p < 0.001).Despite of the brief follow up, the preliminary results are encouraging, showing a significantly decrease of the disability parameters, a marked improvement of the function with the vanishing of the claudicatio spinalis and the following increase of the free interval during the walk. Aperius PercLID system seems to offer an alternative to the traditional decompression surgery

Testing foundations of quantum mechanics with photons

The foundational ideas of quantum mechanics continue to give rise to counterintuitive theories and physical effects that are in conflict with a classical description of Nature. Experiments with light at the single photon level have historically been at the forefront of tests of fundamental quantum theory and new developments in photonics engineering continue to enable new experiments. Here we review recent photonic experiments to test two foundational themes in quantum mechanics: wave-particle duality, central to recent complementarity and delayed-choice experiments; and Bell nonlocality where recent theoretical and technological advances have allowed all controversial loopholes to be separately addressed in different photonics experiments.Comment: 10 pages, 5 figures, published as a Nature Physics Insight review articl

The Brain Health Index: Towards a combined measure of neurovascular and neurodegenerative structural brain injury

Background: A structural magnetic resonance imaging measure of combined neurovascular and neurodegenerative burden may be useful as these features often coexist in older people, stroke and dementia. Aim: We aimed to develop a new automated approach for quantifying visible brain injury from small vessel disease and brain atrophy in a single measure, the brain health index. Materials and methods: We computed brain health index in N = 288 participants using voxel-based Gaussian mixture model cluster analysis of T1, T2, T2*, and FLAIR magnetic resonance imaging. We tested brain health index against a validated total small vessel disease visual score and white matter hyperintensity volumes in two patient groups (minor stroke, N = 157; lupus, N = 51) and against measures of brain atrophy in healthy participants (N = 80) using multiple regression. We evaluated associations with Addenbrooke’s Cognitive Exam Revised in patients and with reaction time in healthy participants. Results: The brain health index (standard beta = 0.20–0.59, P &#60; 0.05) was significantly and more strongly associated with Addenbrooke’s Cognitive Exam Revised, including at one year follow-up, than white matter hyperintensity volume (standard beta = 0.04–0.08, P &#62; 0.05) and small vessel disease score (standard beta = 0.02–0.27, P &#62; 0.05) alone in both patient groups. Further, the brain health index (standard beta = 0.57–0.59, P &#60; 0.05) was more strongly associated with reaction time than measures of brain atrophy alone (standard beta = 0.04–0.13, P &#62; 0.05) in healthy participants. Conclusions: The brain health index is a new image analysis approach that may usefully capture combined visible brain damage in large-scale studies of ageing, neurovascular and neurodegenerative disease