Search

Acute myeloid leukemia (AML) is a clonal hematologic neoplasm characterized by rapid, uncontrolled cell growth of immature myeloid cells (blasts). There are numerous genetic abnormalities in AML, many of which are prognostic, but an increasing number are targets for drug therapy. One of the most common genetic abnormalities in AML are activating mutations in the FMS-like tyrosine kinase 3 receptor (FLT3). As a receptor tyrosine kinase, FLT3 was the first targetable genetic abnormality in AML. The first generation of FLT3 inhibitors were broad-spectrum kinase inhibitors that inhibited FLT3 among other proteins. Although clinically active, first-generation FLT3 inhibitors had limited success as single agents. This led to the development of a second generation of more selective FLT3 inhibitors. This review focuses on quizartinib, a potent second-generation FLT3 inhibitor. We discuss the clinical trial development, mechanisms of resistance, and the recent FDA decision to deny approval for quizartinib as a single agent in relapsed/refractory AML., Competing Interests: Dr. Elie Traer reports consulting honorarium from Astellas, Agios, Daiichi Sankyo, Abbvie, and ImmunoGen, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2020 Fletcher et al.)

Absence or reduced frequency of human regulatory T cells (Tregs) can limit the control of inflammatory responses, autoimmunity, and the success of transplant engraftment. Clinical studies indicate that use of Tregs as immunotherapeutics would require billions of cells per dose. The Quantum® Cell Expansion System (Quantum system) is a hollow-fiber bioreactor that has previously been used to grow billions of functional T cells in a short timeframe, 8-9 d. Here we evaluated expansion of selected Tregs in the Quantum system using a soluble activator to compare the effects of automated perfusion with manual diffusion-based culture in flasks. Treg CD4 + CD25 + cells from three healthy donors, isolated via column-free immunomagnetic negative/positive selection, were grown under static conditions and subsequently seeded into Quantum system bioreactors and into T225 control flasks in an identical culture volume of PRIME-XV XSFM medium with interleukin-2, for a 9-d expansion using a soluble anti-CD3/CD28/CD2 monoclonal antibody activator complex. Treg harvests from three parallel expansions produced a mean of 3.95 × 10 8 (range 1.92 × 10 8 to 5.58 × 10 8 ) Tregs in flasks (mean viability 71.3%) versus 7.00 × 10 9 (range 3.57 × 10 9 to 13.00 × 10 9 ) Tregs in the Quantum system (mean viability 91.8%), demonstrating a mean 17.7-fold increase in Treg yield for the Quantum system over that obtained in flasks. The two culture processes gave rise to cells with a memory Treg CD4 + CD25 + FoxP3 + CD45RO + phenotype of 93.7% for flasks versus 97.7% for the Quantum system. Tregs from the Quantum system demonstrated an 8-fold greater interleukin-10 stimulation index than cells from flask culture following restimulation. Quantum system-expanded Tregs proliferated, maintained their antigenic phenotype, and suppressed effector immune cells after cryopreservation. We conclude that an automated perfusion bioreactor can support the scale-up expansion of functional Tregs more efficiently than diffusion-based flask culture.

Nanostructured photoanodes are attractive materials for hydrogen production via water photo-electrolysis process. This study focused on the incorporation of carbon quantum dots doped with nitrogen as a photosensitizer into meso porous tungsten trioxide photoanodes (N-CQD/ meso -WO 3 ) using a surfactant self-assembly template approach. The crystal structure, composition, and morphology of pure and N-CQD- modified meso porous WO 3 photoanodes were investigated using scanning electron and transmission microscopy, X-ray diffraction, and X-ray photoelectron spectroscopy. Due to their high surface area, enhanced optical absorption, and charge-carrier separation and transfer, the resulting N-CQD/ meso -WO 3 photoanodes exhibited a significantly enhanced photocurrent density of 1.45 mA cm -2 at 1.23 V vs. RHE under AM 1.5 G illumination in 0.5 M Na 2 SO 4 without any co-catalysts or sacrificial reagent, which was about 2.23 times greater than its corresponding pure meso -WO 3 . Moreover, the oxygen evolution onset potential of the N-CQD/ meso -WO 3 photoanodes exhibited a negative shift of 95 mV, signifying that both the charge-carrier separation and transfer processes were promoted.

Background: The rapid evolution of cell-based immunotherapies such as chimeric antigen receptor T-cells for treatment of hematological cancers has precipitated the need for a platform to expand these cells ex vivo in a safe, efficient, and reproducible manner. In the Quantum ® Cell Expansion System (Quantum system) we evaluated the expansion of T-cells from healthy donors in a functionally-closed environment that reduces time and resources needed to produce a therapeutic dose., Methods: Mononuclear cells from leukapheresis products from 5 healthy donors were activated with anti-CD3/CD28 Dynabeads ® and expanded in the Quantum system for 8-9 days using xeno-free, serum-free medium and IL-2. Harvested cells were phenotyped by flow cytometry and evaluated for cytokine secretion by multiplex assays., Results: From starting products of 30 or 85 × 10 6 mononuclear cells, CD3 + T-cell populations expanded over 500-fold following stimulation to provide yields up to 25 × 10 9 cells within 8 days. T-cell yields from all donors were similar in terms of harvest numbers, viability and doubling times. Functionality (secretion of IFN-γ, IL-2 and TNF-α) was retained in harvested T-cells upon restimulation in vitro and T-cells displayed therapeutically-relevant less-differentiated phenotypes of naïve and central memory T-cells, with low expression of exhaustion markers LAG-3 and PD-1., Conclusions: The Quantum system has been successfully used to produce large quantities of functional T-cells at clinical dosing scale and within a short timeframe. This platform could have wide applicability for autologous and allogeneic cellular immunotherapies for the treatment of cancer.

We present the non-adiabatic, conical-intersection quantum dynamics of the title collision where reactants and products are in the ground electronic states. Initial-state-resolved reaction probabilities, total integral cross sections, and rate constants of two H 2 vibrational states, v 0 = 0 and 1, in the ground rotational state ( j 0 = 0) are obtained at collision energies E coll ≤ 3 eV. We employ the lowest two excited diabatic electronic states of HeH 2 + and their electronic coupling, a coupled-channel time-dependent real wavepacket method, and a flux analysis. Both probabilities and cross sections present a few groups of resonances at low E coll , whose amplitudes decrease with the energy, due to an ion-induced dipole interaction in the entrance channel. At higher E coll , reaction probabilities and cross sections increase monotonically up to 3 eV, remaining however quite small. When H 2 is in the v 0 = 1 state, the reactivity increases by ~2 orders of magnitude at the lowest energies and by ~1 order at the highest ones. Initial-state resolved rate constants at room temperature are equal to 1.74 × 10 -14 and to 1.98 × 10 -12 cm 3 s -1 at v 0 = 0 and 1, respectively. Test calculations for H 2 at j 0 = 1 show that the probabilities can be enhanced by a factor of ~1/3, that is ortho- H 2 seems ~4 times more reactive than para- H 2 .

The question of whether virtual quantum particles exist is considered here in light of previous critical analysis and under the assumption that there are particles in the world as described by quantum field theory. The relationship of the classification of particles to quantum-field-theoretic calculations and the diagrammatic aids that are often used in them is clarified. It is pointed out that the distinction between virtual particles and others and, therefore, judgments regarding their reality have been made on basis of these methods rather than on their physical characteristics. As such, it has obscured the question of their existence. It is here argued that the most influential arguments against the existence of virtual particles but not other particles fail because they either are arguments against the existence of particles in general rather than virtual particles per se , or are dependent on the imposition of classical intuitions on quantum systems, or are simply beside the point. Several reasons are then provided for considering virtual particles real, such as their descriptive, explanatory, and predictive value, and a clearer characterization of virtuality-one in terms of intermediate states-that also applies beyond perturbation theory is provided. It is also pointed out that in the role of force mediators, they serve to preclude action-at-a-distance between interacting particles. For these reasons, it is concluded that virtual particles are as real as other quantum particles.

The Gibbs Paradox is essentially a set of open questions as to how sameness of gases or fluids (or masses, more generally) are to be treated in thermodynamics and statistical mechanics. They have a variety of answers, some restricted to quantum theory (there is no classical solution), some to classical theory (the quantum case is different). The solution offered here applies to both in equal measure, and is based on the concept of particle indistinguishability (in the classical case, Gibbs' notion of 'generic phase'). Correctly understood, it is the elimination of sequence position as a labelling device, where sequences enter at the level of the tensor (or Cartesian) product of one-particle state spaces. In both cases it amounts to passing to the quotient space under permutations. 'Distinguishability', in the sense in which it is usually used in classical statistical mechanics, is a mathematically convenient, but physically muddled, fiction.

A fully quantitative theory connecting protein conformation and optical spectroscopy would facilitate deeper insights into biophysical and simulation studies of protein dynamics and folding. The web server DichroCalc (http://comp.chem.nottingham.ac.uk/dichrocalc) allows one to compute from first principles the electronic circular dichroism spectrum of a (modeled or experimental) protein structure or ensemble of structures. The regular, repeating, chiral nature of secondary structure elements leads to intense bands in the far-ultraviolet (UV). The near-UV bands are much weaker and have been challenging to compute theoretically. We report some advances in the accuracy of calculations in the near-UV, realized through the consideration of the vibrational structure of the electronic transitions of aromatic side chains. The improvements have been assessed over a set of diverse proteins. We illustrate them using bovine pancreatic trypsin inhibitor and present a new, detailed analysis of the interactions which are most important in determining the near-UV circular dichroism spectrum., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

MicroRNA (miRNA) is the noncoding gene: therefore, the miRNA gene inheritably controls protein gene expression through transcriptional and post-transcriptional levels. Aberrant expression of miRNA genes causes various human diseases, especially cancers. Although cancer is a complex disease, cancer/miRNA implication has yet been grasped from the perspective of miRNA profile in bed side. Since miRNA is the mobile genetic element, the clinical verification of miRNA in microvesicle of blood is too much straggle to predict potential cancer/miRNA associations without bioinformatical computing. Further, experimental investigation of miRNA/cancer pathways is expensive and time-consuming. While the accumulated data (big data) of miRNA profiles has been on line as the databases in cancers, using the database algorithms for miRNA target prediction have reduced required time for conventional experiments and have cut the cost. Computational prediction of miRNA/target mRNA has shown numerous significant outcomes that are unobtainable only by experimental approaches. However, ID of miRNA in the annotation is an arbitrary number and the ID is not related with miRNA its functions. Therefore, it has not been physicochemically shown why multiple miRNAs in blood or tissues are useful for diagnosis and porgnosis of human diseases or why function of single miRNA in cancer is rendered to oncomir or tumopr suppressor. In addition, it is less cleared why environmental factors, such as temperature, radiation, therapeutic anti-cancer immune or chemical agents can alter the expression of miRNAs in the cell. The ceRNA theory would not be enough for the investigation of such subjects. Given miRNA/target prediction tools, to elucidate such issues with computer simulation we have previously introduced the quantum miRNA/miRNA interaction as a new scoring using big database. The quantum score was implicated in miRNA synergisms in cancer and participated in the miRNA/target interaction on human diseases. On the other hand, ribosomal RNA (rRNA) is the dominant RNA species of the cells. It is well known that ribosomopathies, such as Diamond-Blackfan anemia, dyskeratiosis congenital, Shwachman-Diamond syndrome, 5q-myelodysplastic syndrome, Treacher Collins syndrome, cartilage-hair hypoplasia, North American Indian childhood cirrhosis, isolated congenital asplenia, Bowen-Conradi syndrome and cancer are caused by altered expression of ribosomal proteins or rRNA genes. We have proposed the hypothesis that the interaction among miRNAs from rRNA and/or other cellular miRNAs would be involved into cancer as the ribosomopathy. Subsequently, we found rRNA-derived miRNAs (rmiRNAs) by using the sequence homology search (miPS) with miRNA database (miRBase). Further, the pathway related with cancer between rmiRNA/target protein gene was predicted by miRNA entangling target sorting (METS) algorithm. In this chapter, we describe about the usage of in silico miRNA identification program, miRNA/target prediction search through the database and quantum language of miRNA by the METS, and the ontology analysis. In particular, the METS algorithm according to the quantum value would be useful simulator to discover a new therapeutic target aganist cancer. It may also partly contribute to the elucidation of complex mechanisms and development of agents of anti-cancer.

Recently, increased computational power and data availability, as well as algorithmic advances, have led machine learning (ML) techniques to impressive results in regression, classification, data generation and reinforcement learning tasks. Despite these successes, the proximity to the physical limits of chip fabrication alongside the increasing size of datasets is motivating a growing number of researchers to explore the possibility of harnessing the power of quantum computation to speed up classical ML algorithms. Here we review the literature in quantum ML and discuss perspectives for a mixed readership of classical ML and quantum computation experts. Particular emphasis will be placed on clarifying the limitations of quantum algorithms, how they compare with their best classical counterparts and why quantum resources are expected to provide advantages for learning problems. Learning in the presence of noise and certain computationally hard problems in ML are identified as promising directions for the field. Practical questions, such as how to upload classical data into quantum form, will also be addressed., Competing Interests: The authors declare no competing interests.

Despite certain quantum concepts, such as superposition states, entanglement, 'spooky action at a distance' and tunnelling through insulating walls, being somewhat counterintuitive, they are no doubt extremely useful constructs in theoretical and experimental physics. More uncertain, however, is whether or not these concepts are fundamental to biology and living processes. Of course, at the fundamental level all things are quantum, because all things are built from the quantized states and rules that govern atoms. But when does the quantum mechanical toolkit become the best tool for the job? This review looks at four areas of 'quantum effects in biology'. These are biosystems that are very diverse in detail but possess some commonality. They are all (i) effects in biology: rates of a signal (or information) that can be calculated from a form of the 'golden rule' and (ii) they are all protein-pigment (or ligand) complex systems. It is shown, beginning with the rate equation, that all these systems may contain some degree of quantum effect, and where experimental evidence is available, it is explored to determine how the quantum analysis aids in understanding of the process., Competing Interests: I declare I have no competing interests.

Fe3+ and Mn2+ capped ZnS quantum dots were synthesized using the chemical precipitation method at room temperature in aqueous media. The effect of 2-Mercaptoethanol and Chitosan as capping agents and dopants were investigated using Fourier Transform Infra-Red (FTIR), X-ray Diffraction (XRD), UV-Visible and Field Emission Scanning Electron Microscopy (FESEM) analysis of the nanocrystals. FTIR revealed the presence of respective capping agents and FESEM micrograph identifies the particles as poly-dispersed. TEM images showed agglomerated particles with crystal sized ˜3 nm. Particles were analyzed as cubic structured with peaks indexed at (1 1 1), (2 2 1) and (3 1 1) and an average crystalline size of 2.49±0.06 nm. Blue shift is obtained by both doping agents, and band gap values of ranging from 3.75–4.95 eV were reported. Characterizations suggests 2-mercaptoethanol as better capping agent compared to chitosan and has a greater potential for photocatalytic applications.

A sufficiently complex set of molecules, if subject to perturbation, will self-organize and show emergent behaviour. If such a system can take on information it will become subject to natural selection. This could explain how self-replicating molecules evolved into life and how intelligence arose. A pivotal step in this evolutionary process was of course the emergence of the eukaryote and the advent of the mitochondrion, which both enhanced energy production per cell and increased the ability to process, store and utilize information. Recent research suggest that from its inception life embraced quantum effects such as 'tunnelling' and 'coherence' while competition and stressful conditions provided a constant driver for natural selection. We believe that the biphasic adaptive response to stress described by hormesis-a process that captures information to enable adaptability, is central to this whole process. Critically, hormesis could improve mitochondrial quantum efficiency, improving the ATP/ROS ratio, whereas inflammation, which is tightly associated with the aging process, might do the opposite. This all suggests that to achieve optimal health and healthy aging, one has to sufficiently stress the system to ensure peak mitochondrial function, which itself could reflect selection of optimum efficiency at the quantum level., (© 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.)

Echoes are ubiquitous phenomena in several branches of physics, ranging from acoustics, optics, condensed matter and cold atoms to geophysics. They are at the base of a number of very useful experimental techniques, such as nuclear magnetic resonance, photon echo and time-reversal mirrors. Particularly interesting physical effects are obtained when the echo studies are performed on complex systems, either classically chaotic, disordered or many-body. Consequently, the term Loschmidt echo has been coined to designate and quantify the revival occurring when an imperfect time-reversal procedure is applied to a complex quantum system, or equivalently to characterize the stability of quantum evolution in the presence of perturbations. Here, we present the articles which discuss the work that has shaped the field in the past few years., (© 2016 The Author(s).)

Using semiclassical methods, it is possible to construct very accurate approximations in the short-wavelength limit of quantum dynamics that rely exclusively on classical dynamical input. For systems whose classical realization is strongly chaotic, there is an exceedingly short logarithmic Ehrenfest time scale, beyond which the quantum and classical dynamics of a system necessarily diverge, and yet the semiclassical construction remains valid far beyond that time. This fact leads to a paradox if one ponders the reversibility and predictability properties of quantum and classical mechanics. They behave very differently relative to each other, with classical dynamics being essentially irreversible/unpredictable, whereas quantum dynamics is reversible/stable. This begs the question: 'How can an accurate approximation to a reversible/stable dynamics be constructed from an irreversible/unpredictable one?' The resolution of this incongruity depends on a couple of key ingredients: a well-known, inherent, one-way structural stability of chaotic systems; and an overlap integral not being amenable to the saddle point method., (© 2016 The Author(s).)

We obtain a general connection between a large quantum advantage in communication complexity and Bell nonlocality. We show that given any protocol offering a sufficiently large quantum advantage in communication complexity, there exists a way of obtaining measurement statistics that violate some Bell inequality. Our main tool is port-based teleportation. If the gap between quantum and classical communication complexity can grow arbitrarily large, the ratio of the quantum value to the classical value of the Bell quantity becomes unbounded with the increase in the number of inputs and outputs.

In this paper we explore the boundary shared by biology and formal systems., (Copyright © 2015. Published by Elsevier Ltd.)

As a direct consequence of the no-cloning theorem, the deterministic amplification as in classical communication is impossible for unknown quantum states. This calls for more advanced techniques in a future global quantum network, e.g., for cloud quantum computing. A unique solution is the teleportation of an entangled state, i.e., entanglement swapping, representing the central resource to relay entanglement between distant nodes. Together with entanglement purification and a quantum memory it constitutes a so-called quantum repeater. Since the aforementioned building blocks have been individually demonstrated in laboratory setups only, the applicability of the required technology in real-world scenarios remained to be proven. Here we present a free-space entanglement-swapping experiment between the Canary Islands of La Palma and Tenerife, verifying the presence of quantum entanglement between two previously independent photons separated by 143 km. We obtained an expectation value for the entanglement-witness operator, more than 6 SDs beyond the classical limit. By consecutive generation of the two required photon pairs and space-like separation of the relevant measurement events, we also showed the feasibility of the swapping protocol in a long-distance scenario, where the independence of the nodes is highly demanded. Because our results already allow for efficient implementation of entanglement purification, we anticipate our research to lay the ground for a fully fledged quantum repeater over a realistic high-loss and even turbulent quantum channel.

Technological advances, namely the integration of quantum cascade lasers (QCLs) within an infrared (IR) microscope, are enabling the development of valuable label-free biomedical-imaging tools capable of targeting and detecting salient chemical species within practical clinical timeframes., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: We describe the experimental design for a methodological approach to determine whether directed adaptive mutation occurs in mammalian cells. Identification of directed adaptive mutation would have profound practical significance for a wide variety of biomedical problems, including disease development and resistance to treatment. In adaptive mutation, the genetic or epigenetic change is not random; instead, the presence and type of selection influences the frequency and character of the mutation event. Adaptive mutation can contribute to the evolution of microbial pathogenesis, cancer, and drug resistance, and may become a focus of novel therapeutic interventions., Objective: Our experimental approach was designed to distinguish between 3 types of mutation: (1) random mutations that are independent of selective pressure, (2) undirected adaptive mutations that arise when selective pressure induces a general increase in the mutation rate, and (3) directed adaptive mutations that arise when selective pressure induces targeted mutations that specifically influence the adaptive response. The purpose of this report is to introduce an experimental design and describe limited pilot experiment data (not to describe a complete set of experiments); hence, it is an early report., Methods: An experimental design based on immortalization of mouse embryonic fibroblast cells is presented that links clonal cell growth to reversal of an inactivating polyadenylation site mutation. Thus, cells exhibit growth only in the presence of both the countermutation and an inducing agent (doxycycline). The type and frequency of mutation in the presence or absence of doxycycline will be evaluated. Additional experimental approaches would determine whether the cells exhibit a generalized increase in mutation rate and/or whether the cells show altered expression of error-prone DNA polymerases or of mismatch repair proteins., Results: We performed the initial stages of characterizing our system and have limited preliminary data from several pilot experiments. Cell growth and DNA sequence data indicate that we have identified a cell clone that exhibits several suitable characteristics, although further study is required to identify a more optimal cell clone., Conclusions: The experimental approach is based on a quantum biological model of basis-dependent selection describing a novel mechanism of adaptive mutation. This project is currently inactive due to lack of funding. However, consistent with the objective of early reports, we describe a proposed study that has not produced publishable results, but is worthy of report because of the hypothesis, experimental design, and protocols. We outline the project's rationale and experimental design, with its strengths and weaknesses, to stimulate discussion and analysis, and lay the foundation for future studies in this field.

Background: The use of bone marrow-derived mesenchymal stromal cells (MSCs) as a cellular therapy for various diseases, such as graft-versus-host disease, diabetes, ischemic cardiomyopathy and Crohn's disease, has produced promising results in early-phase clinical trials. However, for widespread application and use in later phase studies, manufacture of these cells must be cost-effective, safe and reproducible. Current methods of manufacturing in flasks or cell factories are labor-intensive, involve a large number of open procedures and require prolonged culture times., Methods: We evaluated the Quantum Cell Expansion System for the expansion of large numbers of MSCs from unprocessed bone marrow in a functionally closed system and compared the results with a flask-based method currently in clinical trials., Results: After only two passages, we were able to expand a mean of 6.6 × 10(8) MSCs from 25 mL of bone marrow reproducibly. The mean expansion time was 21 days, and cells obtained were able to differentiate into all three lineages: chondrocytes, osteoblasts and adipocytes. The Quantum was able to generate the target cell number of 2.0 × 10(8) cells in an average of 9 fewer days and in half the number of passages required during flask-based expansion. We estimated that the Quantum would involve 133 open procedures versus 54,400 in flasks when manufacturing for a clinical trial. Quantum-expanded MSCs infused into an ischemic stroke rat model were therapeutically active., Conclusions: The Quantum is a novel method of generating high numbers of MSCs in less time and at lower passages when compared with flasks. In the Quantum, the risk of contamination is substantially reduced because of the substantial decrease in open procedures., (Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

We discuss the possible nature and role of non-physical entanglement, and the classical vs. non-classical interface, in models of human decision-making. We also introduce an experimental setting designed after the double-slit experiment in physics, and discuss how it could be used to discriminate between classical and non-classical interference effects in human decisions., (Copyright © 2013 Cognitive Science Society, Inc.)