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Background: Deferasirox (DFX) is commonly used to reduce the chronic iron overload (IO) in pediatric patients. However, the drug is characterized by a large pharmacokinetic variability and approximately 10% of patients may discontinue the treatment due to toxicities. Therefore, the present retrospective study investigated possible correlations between DFX pharmacokinetics and drug-associated toxicities in 39 children (26 males), aged 2–17 years, who underwent an allogeneic hematopoietic stem cell transplantation. Methods: IO was diagnosed by an abdominal magnetic resonance imaging and DFX was started at a median dose of 500 mg/day. DFX plasma concentrations were measured by a high performance liquid chromatographic method with UV detection and they were analysed by nonlinear mixed-effects modeling. Results: The pharmacometric analysis demonstrated that DFX pharmacokinetics were significantly influenced by lean body mass (bioavailability and absorption constant), body weight (volume of distribution), alanine and aspartate transaminases, direct bilirubin, and serum creatinine (clearance). Predicted DFX minimum plasma concentrations (Ctrough) accounted for 32.4 ± 23.2 mg/L (mean ± SD), and they were significantly correlated with hepatic/renal and hematological toxicities (p-value &lt, 0.0001, T-test and Fisher’s exact tests) when Ctrough threshold values of 7.0 and 11.5 mg/L were chosen, respectively. Conclusions: The population pharmacokinetic model described the interindividual variability and identified Ctrough threshold values that were predictive of hepatic/renal and hematological toxicities associated with DFX.

In recent years, the digital polymerase chain reaction has received increasing interest as it has emerged as a tool to provide more sensitive and accurate detection of minimal residual disease. In order to start the process of data alignment, we assessed the consistency of the BCR-ABL1 quantification results of the analysis of 16 RNA samples at different levels of disease. The results were obtained by two different laboratories that relied on The Qx100/Qx200 Droplet Digital PCR System (Bio-Rad) and Quant Studio 3D dPCR System (Thermofisher) platforms. We assessed the compatibility between the estimated values by linear regression, Bland–Altman bias-plot, and Mann–Whitney nonparametric test. The results confirmed the compatibility of the measures, allowing us tocompute an ‘alignment factor’ (AF), equal to 1.41, which was further validated by a different series of experiments. We conclude that the performed measurements by the two laboratories are comparable, and also equalized through the introduction of an alignment factor.

The advanced beam-driven FRC is a Field Reversed Configuration (FRC) with the addition of neutral beam (NB) injection, electrode biasing, and magnetic expander divertors. The resulting configuration has novel features that make it necessary to revisit many key results in FRC theory. Three of these features include (i) a large energetic ion population, (ii) in-principle capability to adjust the electric field and rotation profiles, and (iii) a combination of magnetic and electrostatic confinement of electrons in the SOL. In some fueling scenarios the electron density profile may exhibit a significant peak outside of the separatrix. To explore these features a hybrid fluid/kinetic equilibrium model has been used to reconstruct typical experimental profiles of the C-2W experiment. Results indicate that the energetic ions provide at least 50% of the total plasma pressure. These equilibrium profiles have been used as initial conditions for global, cross-separatrix, turbulent transport simulations using the 3D electrostatic particle-in-cell code ANC. Electrostatic fluctuations were found to nonlinearly saturate at an amplitude which is an order magnitude lower than that observed previously. The tokamak turbulence code GTC code has also been extended to handle FRC physics in the new GTC-X version, which has been used to perform simulations of turbulent transport in the SOL relevant to electrode biasing. It is found that equilibrium × flow shear significantly decreases ion temperature gradient saturation amplitude and ion heat transport. Also in the SOL, a 1D2V continuum code has been developed and applied to parallel electron heat transport. Results show the formation of pre-sheath potential and reduction of parallel electron heat loss close to the ideal ambipolar limit, a result which has been validated by experimental diagnostics. These transport modifications caused by the three novel configuration features help to explain the remarkable plasma performance of the C-2W experiment.

There are currently few data concerning the cerebrospinal fluid (CSF) penetration of daptomycin in patients with healthcare-associated meningitis. This study aims (1) to better characterize the pharmacokinetics of daptomycin in humans during a 7-day intravenous (IV) therapy course, and (2) to study the penetration of daptomycin in the CSF after IV infusion at the dose of 10 mg/kg. In this prospective observational study, we enrolled nine patients with an implanted external ventricular drainage and a diagnosis of a healthcare-associated meningitis. Daptomycin was administered at 10 mg/kg for a maximum of 7 days. The pharmacokinetic of daptomycin was studied using a two-compartment population/pharmacokinetic (POP/PK) model and by means of a nonlinear mixed effects modeling approach. A large inter-individual variability in plasma area under the curve (Range: 574.7–1366.3 h mg/L), paralleled by high-peak plasma concentration (Cmax) (all values > 60 mg/L), was noted. The inter-individual variability of CSF-AUC although significant (range: 1.17–6.81 h mg/L) was narrower than previously reported and with a late occurrence of CSF-Cmax (range: 6.04–9.54 h). The terminal half-life between plasma and CSF was similar. tmax values in CSF did not show a high inter-individual variability, and the fluctuations of predicted CSF concentrations were minimal. The mean value for daptomycin penetration obtained from our model was 0.45%. Our POP/PK model was able to describe the pharmacokinetics of daptomycin in both plasma and CSF, showing that daptomycin (up to 7 days at 10 mg/kg) has minimal penetration into central nervous system. Furthermore, the observed variability of AUC, tmax and predicted concentration in CSF was lower than what previously reported in the literature. Based on the present findings, it is unlikely that daptomycin could reach CSF concentrations high enough to have clinical efficacy; this should be tested in future studies.

TAE Technologies' research is devoted to producing high temperature, stable, long-lived field-reversed configuration (FRC) plasmas by neutral-beam injection (NBI) and edge biasing/control. The newly constructed C-2W experimental device (also called "Norman") is the world's largest compact-toroid (CT) device, which has several key upgrades from the preceding C-2U device such as higher input power and longer pulse duration of the NBI system as well as installation of inner divertors with upgraded electrode biasing systems. Initial C-2W experiments have successfully demonstrated a robust FRC formation and its translation into the confinement vessel through the newly installed inner divertor with adequate guide magnetic field. They also produced dramatically improved initial FRC states with higher plasma temperatures (Te ~250+ eV; total electron and ion temperature g1.5 keV, based on pressure balance) and more trapped flux (up to ~15 mWb, based on rigid-rotor model) inside the FRC immediately after the merger of collided two CTs in the confinement section. As for effective edge control on FRC stabilization, a number of edge biasing schemes have been tried via open field-lines, in which concentric electrodes located in both inner and outer divertors as well as end-on plasma guns are electrically biased independently. As a result of effective outer-divertor electrode biasing alone, FRC plasma diamagnetism duration has reached up to ~9 ms which is equivalent to C-2U plasma duration. Magnetic field flaring/expansion in both inner and outer divertors plays an important role in creating a thermal insulation on open field-lines to reduce a loss rate of electrons, which leads to improvement of the edge and core FRC confinement properties. Experimental campaign with inner-divertor magnetic-field flaring has just commenced and early result indicates that electron temperature of the merged FRC stays relatively high and increases for a short period of time, presumably by NBI and ExB heating.

Numerous efforts have been made at Tri-Alpha Energy (TAE) to theoretically explore the physics of microwave electron heating in field-reversed configuration (FRC) plasmas. For the fixed 2D profiles of plasma density and temperature for both electrons and thermal ions and equilibrium field of the C-2U machine, simulations with GENRAY-C ray-tracing code have been conducted for the ratios of ω/ω ci[D] in the range of 6 - 20. Launch angles and antenna radial and axial positions have been optimized in order to simultaneously achieve good wave penetration into the core of FRC plasmas and efficient power damping on electrons. It is found that in an optimal regime, single pass absorption efficiency is 100% and most of the power is deposited inside the separatrix of FRC plasmas, with power damping efficiency of about 72% on electrons and less than 19% on ions. Calculations have clearly demonstrated that substantial power absorption on electrons is mainly attributed to high beta enhancement of magnetic pumping; complete power damping occurs before Landau damping has a significant effect on power absorption.

The present study was aimed at investigating whether imatinib pharmacogenetics is related to its pharmacodynamics in patients affected by chronic myeloid leukemia. Through a procedure based on a sequence of classical statistics methods, we investigated the possible relationships between treatment efficacy/tolerability and combinations of time-independent variables as gender and genetic covariates in the form of single nucleotide polymorphisms (SNPs) or combinations thereof. Moreover, since the drug tolerability has a strong incidence on the discontinuation of the therapy, we investigated whether the time of manifestation of the most frequent toxic effects can be related to time-independent patients’ characteristics or not. We found that a combination of two polymorphisms, namely hOCT1 c.480C>G (rs683369) and ABCB1 c.3435C>T (rs1045642), seems to play the role of predictor for imatinib in both efficacy and toxicity. Furthermore, the time of manifestation of edema toxicity is found to be associated to a combination of gender and ABCB1 c.3435C>T, whereas the time of manifestation of cramp toxicity appears related to gender. The novelty of this study is dual: the achievement of results that potentially have a significant clinical interest and the demonstration that the adoption of composed covariates may represent a unique tool to study different aspects of the treatment with imatinib.

Conventional field-reversed configurations (FRC) face notable stability and confinement concerns, which can be ameliorated by introducing and maintaining a significant fast ion population in the system. This is the conjecture first introduced by Norman Rostoker multiple decades ago and adopted as the central design tenet in Tri Alpha Energy’s advanced beam driven FRC concept. In fact, studying the physics of such neutral beam (NB) driven FRCs over the past decade, considerable improvements were made in confinement and stability. Next to NB injection, the addition of axially streaming plasma guns, magnetic end plugs, as well as advanced surface conditioning lead to dramatic reductions in turbulence driven losses and greatly improved stability. In turn, fast ion confinement improved significantly and allowed for the build-up of a dominant fast particle population. This recently led to the breakthrough of sustaining an advanced beam driven FRC, thereby demonstrating successful maintenance of trapped magnetic flux, plasma dimensions and total pressure inventory for times much longer than all characteristic system time scales and only limited by hardware and electric supply constraints.

In this review, we overview the main features and functions of NK cells, focusing on their role in cell-mediated immune response to tumor cells. In parallel, we discuss the information available in the field of NK cell receptors and offer a wide general overview of functional aspects of cell targeting and killing, focusing on the recent acknowledgments on the efficacy of NK cells after cytokine and mAb administration in cancer therapy. Since efficacy of NK cell-based immunotherapy has been proven in KIR-mismatch regimens or in TRAIL-dependent apoptosis, the ability to manipulate the balance of activating and inhibitory receptors on NK cells and of their cognate ligands, as well as the sensitivity of tumor cells to apoptosis, opens new perspectives for NK cell-based immunotherapy.

Cytotoxic functions and susceptibility to apoptosis are crucial aspects of NK cells suitable to counter cancer after infusion in oncologic patients. To test the feasibility and the usefulness of infusing in vitro generated NK cells, these two features were investigated in NK cells developed in vitro from CD34⁺ hematopoietic progenitors. Purified CD34⁺ cells were cultured for 15-30 days with FLT-3 ligand (FLT3-L) and IL-15 with or without IL-21. To induce terminal differentiation, NK cells were cultured for further 15 days with IL-15, IL-21, or their combination. A CD56(dim) /CD16⁺ NK subset, expressing high level of perforin, granzymes, and LFA-1, appeared early in cultures with FLT3-L, IL-15, and IL-21, but it quickly died, indicating its predisposition to apoptosis. On the contrary, CD56(bright) NK cells generated after 30 days of culture with FLT3-L plus IL-15 did not show a considerable apoptosis, nevertheless only a subset of these cells expressed granzyme-B, perforin, LFA-1, and CD94-CD159a heterodimer, indicating a functional immaturity. Interestingly, further 15 days of culture with IL-21 plus IL-15 did not induce the generation of CD56(dim) cells from the CD56(bright) subset and actually inhibited IL-15-induced maturation/activation of this latter subset. In fact, IL-15 alone upregulated granzyme-B, TRAIL, Fas ligand, CD94-CD159a, LFA-1, CD16, KIRs, and TRAIL-R2 on CD56(bright) NK cells. Our results suggest that during differentiation CD56(bright) NK cells, similarly to mature activated NK cells, become highly cytotoxic and are relatively resistant to apoptosis induced by TNF family members.

A high temperature field reversed configuration (FRC) has been produced in the newly built, world’s largest compact toroid (CT) facility, C-2, by colliding and merging two high-β CTs produced using the advanced field-reversed θ-pinch technology. This long-lived, stable merged state exhibits the following key properties: (1) apparent increase in the poloidal flux from the first pass to the final merged state, (2) significantly improved confinement compared to conventional θ-pinch FRCs with flux decay rates approaching classical values in some cases, (3) strong conversion from kinetic energy into thermal energy with total temperature (Te + Ti) exceeding 0.5 keV, predominantly into the ion channel. Detailed modeling using a new 2-D resistive magnetohydrodynamic (MHD) code, LamyRidge, has demonstrated, for the first time, the formation, translation, and merging/reconnection dynamics of such extremely high-β plasmas.

A hot stable field-reversed configuration (FRC) has been produced in the C-2 experiment by colliding and merging two high-β plasmoids preformed by the dynamic version of field-reversed θ-pinch technology. The merging process exhibits the highest poloidal flux amplification obtained in a magnetic confinement system (over tenfold increase). Most of the kinetic energy is converted into thermal energy with total temperature (T{i}+T{e}) exceeding 0.5 keV. The final FRC state exhibits a record FRC lifetime with flux confinement approaching classical values. These findings should have significant implications for fusion research and the physics of magnetic reconnection.

CD56(bright) natural killer (NK) cells, generated in vitro from CD34+ hematopoietic progenitor cells, were characterized after a 30-day culture with flt3 ligand plus IL-15. Virtually, all CD56(bright) cells expressed CD117, CD25, natural cytotoxicity receptors (NCRs), NKG2D, CD161, and CD244, while only a subset expressed CD18-CD11a (LFA-1), and CD94 molecule, defining an immature CD56(bright)/NCRs+/NKG2D+/LFA-1(-)/CD94(-) subset. Another small subset of cells expressing CD94 but not LFA-1 integrin was also identified, suggesting that during NK differentiation LFA-1 might be upregulated later than CD94. To verify this hypothesis in vivo, we evaluated the NK cell expression of LFA-1 in both peripheral and umbilical cord blood samples. Interestingly, in these blood fluids, we have identified a lineage negative CD34(-)/LFA-1(low)/NKp46(dim)/NKG2D(dim)/CD94(-) subset that resembled an immature stage of NK cells present in lymph nodes. Altogether, the results indicate that CD18-CD11a integrin, as well as CD11b in mice, may be a useful marker to identify immature stages of NK cell differentiation.

Background. In spite of the dramatically positive changes in the outcome of Chronic Myeloid Leukemia (CML) patients due to the introduction of imatinib, several aspects of both the pharmacokinetics and pharmacodynamics of this TKI remain unclear. In particular, the possible relations between patients' specific characteristics and the efficacy and toxicity of treatment are still matter of debate. Aim of the study. The purpose of this study was twofold: 1) set up an innovative and unsupervised mathematical model that helps in explaining the variability of imatinib plasma levels through the analysis of the main pharmacokinetic parameters in terms of patient-specific features as BMI, renal and hepatic function, alpha1-acid glycoprotein, age, sex and polymorphisms of transporters; 2) set up a specifically tailored analysis of variance technique which allows to detect in limited databases also possible correlations between efficacy, toxicity and genetic covariates either as single SNP or in the form of more complex combinations of different polymorphisms. Patients and Methods. The study has been carried out on 53 CML adult patients (30 males and 23 females) receiving imatinib as first-line therapy at the Section of Hematology of the Department of Clinical and Experimental Medicine of the University of Pisa and from the Department of Internal Medicine of Orbassano, Turin. Patients gave their informed consent to the participation to the study before enrollment. The pharmacokinetic model has been constructed following the indication of the Factor Analysis of Mixed Data (FAMD), a procedure that permitted us to select the possible important covariates and eventually which of them aggregate in a single factor using an unsupervised approach. For what concerns imatinib pharmacodynamics, we studied first the possible relation between treatment efficacy and genetic covariates (either as single SNPs or diplotypes) and then whether the pharmacogenetic variables obtained are also relevant for the tolerability of the drug. The genetic variables considered were represented by the following polymorphisms: rs72552763 [MI420I], rs12208357 [c.181C>T] and rs683369 [c.480C>G] (hOCT1), rs1128503 [c.1236C>T], rs2032582 [c.2677G>T/A] and rs1045642 [c.3435C>T] (ABCB1), rs4149117 [c.334G>T] (SLCO1B3). Results. The FAMD procedure allowed us to identify three main factors (single or aggregated covariates) which properly included in the pharmacokinetic model reduced significantly the uncertainties on all pharmacokinetic parameters. The selected factors are: hOCT1 polymorphism c.480C>G, a combination of BMI and gender and the glomerular filtration rate. Such a procedure led to ka = 0.786 ± 5.9 %, c1 = 0.0282 ± 24.5 %, where ka and c1 are the absorption and elimination rate, respectively. Through our investigation of the pharmacodynamics, we found that both the complete cytogenetic response (CCyR) and the maximum toxicity are related to a particular combination of hOCT1 rs683369 [c.480C>G] and ABCB1 rs1045642 [c.3435C>T] polymorphisms. Furthermore, since the toxic effects of the drug have a strong incidence on the discontinuation of the therapy, we have studied whether the manifestation and the onset time of the most frequent specific toxic effects of Imatinib can be associated to the genetic characteristics of the patients and/or to a combination of them. Edema toxicity has resulted to be correlated with combinations between c.3435C>T and gender or ABCB1 rs1128503 [c.1236C>T]. Cramp toxicity has resulted to be correlated to gender alone or in combination with SCLO1B3 rs4149117 [c.334G>T]. Discussion. Results of this study obtained provide relevant insights on the role of covariates in imatinib treatment and suggest that FAMD analyses in combination with ANOVA tests may allow the unsupervised identification of covariates that significantly affect drug disposition and pharmacodynamics. Figure 1. Color map of the mean values (left) and coefficient of variation (right) of contributions of ten covariates on the first five dimensions. In the color map of the mean values, greater is the value (darker color), more important is the role of the covariate in the dimension. Figure 1. Color map of the mean values (left) and coefficient of variation (right) of contributions of ten covariates on the first five dimensions. In the color map of the mean values, greater is the value (darker color), more important is the role of the covariate in the dimension. Disclosures No relevant conflicts of interest to declare.

Conventional field-reversed configurations (FRCs), high-beta, prolate compact toroids embedded in poloidal magnetic fields, face notable stability and confinement concerns. These can be ameliorated by various control techniques, such as introducing a significant fast ion population. Indeed, adding neutral beam injection into the FRC over the past half-decade has contributed to striking improvements in confinement and stability. Further, the addition of electrically biased plasma guns at the ends, magnetic end plugs, and advanced surface conditioning led to dramatic reductions in turbulence-driven losses and greatly improved stability. Together, these enabled the build-up of a well-confined and dominant fast-ion population. Under such conditions, highly reproducible, macroscopically stable hot FRCs (with total plasma temperature of ∼1 keV) with record lifetimes were achieved. These accomplishments point to the prospect of advanced, beam-driven FRCs as an intriguing path toward fusion reactors. This paper reviews key results and presents context for further interpretation.

The aim of this work is to characterize the complexity of nematic liquid crystal auto-organizing structures. The formation of these kinds of frames is due to the application of a particular electric field to the sample. Varying this control parameter, the structures evolve from very regular frames to very disorderly ones. For all these different cases we had acquired a string of data. We manage to classify these sequences, taken on the liquid crystal, according to their degree of complexity through an entropy method, the Diffusion Entropy Method.