Evolution of magnetic surfboards and spin glass behavior in (Fe1-pGap)2TiO5.

The unusual anisotropy of the spin glass (SG) transition in the pseudobrookite system Fe2TiO5has been interpreted as arising from an induced, van der Waals-like, interaction among magnetic clusters. Here we present susceptibility (χ) and specific heat data (C) for Fe2TiO5diluted with non-magnetic Ga, (Fe1-pGap)2TiO5, for disorder parameterp= 0, 0.11, and 0.42, and elastic neutron scattering data forp= 0.20. A uniform suppression ofTgis observed upon increasingp, along with a value ofχTgthat increases asTgdecreases, i.e.dχ(Tg)/dTg<0We also observeCT∝T2in the low temperature limit. The observed behavior places (Fe1-pGap)2TiO5in the category of a strongly geometrically frustrated SG.

Magnetoquantum oscillations in the specific heat of a topological Kondo insulator.

Surprisingly, magnetoquantum oscillations (MQOs) characteristic of a metal with a Fermi surface have been observed in measurements of the topological Kondo insulator SmB6. As these MQO have only been observed in measurements of magnetic torque (dHvA) and not in measurements of magnetoresistance (SdH), a debate has arisen as to whether the MQO are an extrinsic effect arising from rare-earth impurities, defects, and/or aluminum inclusions or an intrinsic effect revealing the existence of charge-neutral excitations. We report here the first observation of MQO in the low-temperature specific heat of SmB6. The observed frequencies and their angular dependence for these flux-grown samples are consistent with previous results based on magnetic torque for SmB6but the inferred effective masses are significantly larger than previously reported. Such oscillations can only be observed if the MQO are of bulk thermodynamic origin; the measured magnetic-field dependent oscillation amplitude and effective mass allow us to rule out suggestions of an extrinsic, aluminum inclusion-based origin for the MQO.

Extremely Weakly Interacting ΔS_{z}=0 and ΔS_{z}=1 Excitations and Evidence for Fractional Quantization in a Magnetization Plateau: CeSb.

The plateau at 1/3 of the saturation magnetization M_{s} in the metamagnet CeSb is accompanied by a state of ferromagnetic layers of spins in an up-up-down sequence. We measured M and the specific heat C in the plateau, spin wave analyses of which reveal two distinct branches of excitations. Those with ΔS_{z}=1 as measured by M, coexist with a much larger population of ΔS_{z}=0 excitations measured by C but invisible to M. The large density of ΔS_{z}=0 excitations, their energy gap, and their seeming lack of interaction with ΔS_{z}=1 excitations suggest an analogy with astrophysical dark matter. Additionally, in the middle of the plateau three sharp jumps in M(H) are seen, the size of which, 0.15%M_{s}, is consistent with fractional quantization of magnetization per site in the down-spin layers.

Evidence for undoped Weyl semimetal charge transport in Y2Ir2O7.

Weyl fermions scattering from a random Coulomb potential are predicted to exhibit resistivity versus temperature [Formula: see text] in a single particle model. Here we show that, in closed-environment-grown polycrystalline samples of Y2Ir2O7, [Formula: see text] over four orders of magnitude in [Formula: see text]. While the measured prefactor, [Formula: see text], is obtained from the model using reasonable materials parameters, the [Formula: see text] behavior extends far beyond the model's range of applicability. In particular, the behavior extends into the low-temperature, high-resistivity region where the Ioffe-Regel parameter, [Formula: see text]. Strong on-site Coulomb correlations, instrumental for predicting a Weyl semimetal state in Y2Ir2O7, are the possible origin of such 'bad' Weyl semimetal behavior.

Local Moment Instability of Os in Honeycomb Li2.15Os0.85O3.

Compounds with honeycomb structures occupied by strong spin orbit coupled (SOC) moments are considered to be candidate Kitaev quantum spin liquids. Here we present the first example of Os on a honeycomb structure, Li2.15(3)Os0.85(3)O3 (C2/c, a = 5.09 Å, b = 8.81 Å, c = 9.83 Å, ß = 99.3°). Neutron diffraction shows large site disorder in the honeycomb layer and X-ray absorption spectroscopy indicates a valence state of Os (4.7 ± 0.2), consistent with the nominal concentration. We observe a transport band gap of Δ = 243 ± 23 meV, a large van Vleck susceptibility, and an effective moment of 0.85 µB, much lower than expected from 70% Os(+5). No evidence of long range order is found above 0.10 K but a spin glass-like peak in ac-susceptibility is observed at 0.5 K. The specific heat displays an impurity spin contribution in addition to a power law ∝T(0.63±0.06). Applied density functional theory (DFT) leads to a reduced moment, suggesting incipient itineracy of the valence electrons, and finding evidence that Li over stoichiometry leads to Os(4+)-Os(5+) mixed valence. This local picture is discussed in light of the site disorder and a possible underlying quantum spin liquid state.

Precision chemical heating for diagnostic devices.

Decoupling nucleic acid amplification assays from infrastructure requirements such as grid electricity is critical for providing effective diagnosis and treatment at the point of care in low-resource settings. Here, we outline a complete strategy for the design of electricity-free precision heaters compatible with medical diagnostic applications requiring isothermal conditions, including nucleic acid amplification and lysis. Low-cost, highly energy dense components with better end-of-life disposal options than conventional batteries are proposed as an alternative to conventional heating methods to satisfy the unique needs of point of care use.

Internal dosimetry through GATE simulations of preclinical radiotherapy using a melanin-targeting ligand.

The GATE Monte Carlo simulation platform based on the Geant4 toolkit is under constant improvement for dosimetric calculations. In this study, we explore its use for the dosimetry of the preclinical targeted radiotherapy of melanoma using a new specific melanin-targeting radiotracer labeled with iodine 131. Calculated absorbed fractions and S values for spheres and murine models (digital and CT-scan-based mouse phantoms) are compared between GATE and EGSnrc Monte Carlo codes considering monoenergetic electrons and the detailed energy spectrum of iodine 131. The behavior of Geant4 standard and low energy models is also tested. Following the different authors' guidelines concerning the parameterization of electron physics models, this study demonstrates an agreement of 1.2% and 1.5% with EGSnrc, respectively, for the calculation of S values for small spheres and mouse phantoms. S values calculated with GATE are then used to compute the dose distribution in organs of interest using the activity distribution in mouse phantoms. This study gives the dosimetric data required for the translation of the new treatment to the clinic.

Pharmacokinetic study of cystemustine, administered on a weekly schedule in cancer patients.

BACKGROUND: Cystemustine is a chloroethylnitrosourea mostly active in humans against glioma and melanoma. The present report describes the results of a new phase I trial with cystemustine administered on a weekly schedule. The pharmacokinetic and pharmacodynamic properties of cystemustine were investigated. PATIENTS AND METHODS: Forty-three patients entered this study. Cystemustine was administered at dose levels ranging from 30 to 60 mg/m2. The drug was given on days 1, 8, 15 and 22, followed by a 4-week rest period. RESULTS: Thrombocytopenia was the dose-limiting toxicity and appeared to be reversible, but probably cumulative. This toxicity appeared dose-related, both in frequency and severity. The maximum tolerated dose was 60 mg/m2. Nonhematological toxicity was generally mild. Three partial responses were observed at dose levels of 50 and 60 mg/m2. Pharmacokinetics analysis showed mono- or biphasic cystemustine blood disposition with a mean a half-life of 4 min and mean terminal half-life of 49 min. CONCLUSIONS: There was a clear linear relationship between the area under the blood drug concentration-time curve (AUC) and the dose of cystemustine (P < 0.001). There was also a significant relationship between the AUC and the toxic effects of cystemustine on platelets, granulocytes and leukocytes (P < 0.001). A reasonable starting dose for phase II studies is 40 mg/m2, with dose escalation based on blood cell counts.

Melanin affinity of N-(2-diethylaminoethyl)-4-iodobenzamide, an effective melanoma imaging agent.

The cellular uptake and incorporation in macromolecules of iodine-125 labelled N-(2-diethylaminoethyl)-4-iodobenzamide ([125I]BZA), a melanoma imaging agent, was studied using human melanoma cells M3Dau (amelanotic) and M4Beu (melanotic). The interaction between [125I]BZA and synthetic melanin was examined in various conditions of incubation. The results showed that uptake was high only for M4Beu, whereas the incorporation in trichloroacetic acid-precipitable proteins was very low for both model cell lines, with no correlation with melanin content. Experiments with synthetic melanin showed that BZA binding to melanin was saturable and reversible, and involved several types of interaction. The influence of the ionic environment indicated that electrostatic forces play a role in the affinity, and the decrease in binding produced by the presence of an alcohol in the medium suggested that hydrophobic interactions may be involved in the binding mechanism. This was supported by the Scatchard analysis, which revealed two classes of binding sites, and the determination of two association constants (K1 = 3.9 +/- 1.9 x 106/M and K2 = 2.9 +/- 0.9 x 104/M). The affinity of BZA for melanin might explain the good results obtained in a phase II clinical trial for the diagnosis of malignant melanoma metastases, in which the specificity was 100%.

Synthesis, characterization and comparative biodistribution study of a new series of p-iodine-125 benzamides as potential melanoma imaging agents.

Iodobenzamides are reported to possess some affinity for melanoma. In order to identify the compound having the most appropriate pharmacokinetic properties as a potential melanoma imaging agent, thirteen new [125I]radioiodobenzamides with a butylene amide-amine spacer and various substituents on the terminal amino group were investigated. Their synthesis, radioiodination and biodistribution in B16 melanoma bearing C57BL6 mice are described and compared to [125I] labeled N-(2-diethylaminoethyl)-4-iodobenzamide ([125I]BZA), our reference compound. Changes in the terminal amino constituents induced modifications of lipophilicity, tumor uptake and organ distribution. The dimethylaminobutyl iodobenzamide appeared to be the most promising radiopharmaceutical imaging agent for the detection of melanoma and its metastases.

Evaluation in mice of some iodinated melanoma imaging agents using cryosectioning and multi-wire proportional counting.

AMBIS 4000, a multi-wire proportional counter, was calibrated for iodine-125 measurements. The detector displayed a linear response over a wide dynamic range. Using whole-body mice cryosections, a linear relationship could be established between count rate per area (cpm/mm2) measured with the AMBIS 4000 detector and the count rate per gram (dpm/g) determined with an NaI(Tl) scintillation detector. A calibration curve could, thus be constructed. This new method allowed direct visual and quantitative evaluation of the biodistribution of a short series of 125I-labelled benzamides in melanoma-bearing mice. All the compounds studied showed good tumoral targeting ability. For one of them, ortho-N-(2-diethylaminoethyl)-4-iodobenzamide, liver and lung uptake decreased rapidly after dosing, making it a suitable tracer for scintigraphic detection of malignant melanoma.

Study of implanted biomaterial functionality by diphosphonate molecules labeled with radioactive 99mTc.

An implanted biomaterial can be transformed into young bone after some months, but it has not necessary reached full biofunctionality. Mineral concentration kinetics and crystal-structure studies, still being carried out in our group, are completed here by biofunctionality determinations. A natural coral is implanted in vivo at the cortical level of the femoral diaphyoff++ in rabbits. Diphosphonates molecules labeled with radioactive 99mTc are then injected in rabbits and the fixation of the radioactivity is analyzed in several sites for 8 mo after the implantation. Nuclear instruments and methods are used for the measurements. Four successive cycles of osseous remodeling are determined before reaching a biofunctional phase.

A new quantitative method to evaluate the biodistribution of a radiolabelled tracer for melanoma using whole-body cryosectioning and a gaseous detector: comparison with conventional tissue combustion technology.

Whole-body autoradiography (WBA) and multi-wire proportional counting allow for spatial imaging of the radioactive material present in the tissues and organs of dehydrated animal sections. AMBIS 4000 counting of whole-body cryosections offers a sensitive, accurate and reproducible novel method for the quantitative measurement of the tissue distribution of a [14C] radiopharmaceutical. Intensity of AMBIS 4000 counting (net cpm/mm2) and concentration of radioactivity (nCi/g) were linearly related, yielding a standard curve. Evaluating biodistribution (a) provides pharmacokinetic data for predicting the potential tissue deposition of an absorbed dose of radioactivity in man, and (b) allows visual and quantitative evaluation of radioactivity in small anatomical structures that otherwise could not be detected by conventional tissue combustion technology. This new method of WBA, coupled with AMBIS 4000 counting, should prove a valuable method for pharmacodynamic studies, and afford a predictive tool for nuclear medicine by assessing specific targeting of selected tissues.

Tissue distribution and metabolism in rat of an ethynesulphonamide with filaricidal activity.

1. The tissue distribution and metabolism of a new filaricidal agent P903 (N-[(2-phenylethynyl)sulfonyl]morpholine) were studied in rat. 2. After s.c. administration of 14C and 13C P903, the Tmax in the blood was observed on day 2. Elimination was slow and > 95% was bound to protein. Radioactivity was distributed in the whole organism but particularly in erythrocytes and the lymphatic channel. Four days later, > 60% of the radioactivity was excreted in urine and faeces at equal amounts and 15% remained at the injection point. 3. In all biological fluids tested no P903 was found but only its metabolites. 4. One principal metabolite, the N-[(2-phenyloxo-2-ethane) sulphonyl] morpholine or oxosulphonamide was identified in blood, urine and faeces as compared with the reference compound by GC/MS and NMR. This latter molecule was detected following hydrolysis by hydrochloric acid but not with beta glucuronidase/sulphatase. 5. Unconjugated and conjugated oxosulphonamide represented > 85% of the radioactivity at all times tested in blood but only 38 and 35% respectively of urinary and faecal radioactivity on day 1 after the administration of the labelled drug. 6. Thus, P903 is rapidly converted to a reactive metabolite, probably an oxirene, which is then conjugated with endogenous components to form conjugated oxosulphonamide and an unknown metabolite. The role of this reactive metabolite in antifilarial activity seems to be very important in understanding the mechanism of action of P903.

Synthesis, radiolabeling, and preliminary evaluation in mice of some (N-diethylaminoethyl)-4-iodobenzamide derivatives as melanoma imaging agents.

N-(2-Diethylaminoethyl)-4-iodobenzamide (BZA) is a radiopharmaceutical recently developed in our laboratory for the scintigraphic detection of melanoma and metastases. Optimal time for imaging was between 18-24 h p.i. of [123I] BZA. With a view to selecting compounds able to provide quality images shortly after the injection, synthesis of an initial series of BZA derivatives and their evaluation in B16 melanoma bearing mice have been carried out. The [125I] radiolabeled products were obtained by a simple isotopic exchange procedure with high radiochemical yields (85-95%). After i.v. administration of the compounds we observed a good tumoral targeting ability. Tumoral activity peaked at 2.6 to 7.70% injected dose per g within 1 h post-injection. One of the benzamides with a blood clearance faster than that of BZA--0.06 vs. 0.2% I D/g--6 h p.i. gave the same tumor to blood and to organ ratios as BZA at 12-18 h p.i. Based on these preclinical data we hope to obtain good tumoral images 6 h p.i. in scintigraphic studies in man.

Disposition and metabolism of O6-alkylguanine-DNA alkyltransferase inhibitor in nude mice bearing human melanoma.

Tumor resistances to chloroethylnitrosourea (CENU) are mainly due to O6-alkylguanine-DNA alkyltransferase (AGT). Our laboratory has synthesized a new water-soluble AGT inhibitor. O6-benzyl-N-acetylguanosine (BNAG). We have shown that this compound is able to deplete AGT activity on M4Beu human melanoma cells and to enhance the antitumor power of CENU N'-[2-chloroethyl]-N-[2-(methylsulfonyl)ethyl]-N'-nitrosourea (cystemustine) towards the M4Beu melanoma grafted on nude mice. With a view to determining the best combination BNAG/CENUs conditions, we have studied the distribution and metabolism of BNAG in nude mice bearing M4Beu human melanoma. BNAG, labelled with carbon-14 on the benzyl group, was administered by single i.v. dose of 40 mg/kg. Blood analysis showed that the main radioactive compound was unchanged molecule, and only a small part was found as hippuric acid resulting from the metabolic cleavage of the benzyl group. BNAG and hippuric acid were mainly eliminated in the urine. Unchanged BNAG blood kinetics showed three phases: blood epuration (t1/2 (1) = 13 min), reabsorption and elimination (t1/2 (2) = 1.7 hr). This kinetic profile is probably due to an enterohepatic cycle. BNAG is distributed in several tissues (kidney, liver, skin, duodenum, colon, tumor) but not in the central nervous system, suggesting a poor blood-brain crossing. Because an important part of the administered dose is not metabolized, high unchanged BNAG level remains in most tissues, including M4Beu tumor, and AGT depletion can occur several hours after dosing.