Optimal measurement budget allocation for particle filtering

Particle filtering is a powerful tool for target tracking. When the budget for observations is restricted, it is necessary to reduce the measurements to a limited amount of samples carefully selected. A discrete stochastic nonlinear dynamical system is studied over a finite time horizon. The problem of selecting the optimal measurement times for particle filtering is formalized as a combinatorial optimization problem. We propose an approximated solution based on the nesting of a genetic algorithm, a Monte Carlo algorithm and a particle filter. Firstly, an example demonstrates that the genetic algorithm outperforms a random trial optimization. Then, the interest of non-regular measurements versus measurements performed at regular time intervals is illustrated and the efficiency of our proposed solution is quantified: better filtering performances are obtained in 87.5% of the cases and on average, the relative improvement is 27.7%.Comment: 5 pages, 4 figues, conference pape

To calibrate or not to calibrate? A methodological dilemma in experimental pain research

To calibrate or not to calibrate? This question is raised by almost everyone designing an experimental pain study with supra-threshold stimulation. The dilemma is whether to individualize stimulus intensity to the pain threshold / supra-threshold pain level of each participant or whether to provide the noxious stimulus at a fixed intensity so that everyone receives the identical input. Each approach has unique pros and cons which need to be considered to i) accurately design an experiment, ii) enhance statistical inference in the given data and, iii) reduce bias and the influence of confounding factors in the individual study e.g., body composition, differences in energy absorption and previous experience. Individualization requires calibration, a procedure already irritating the nociceptive system but allowing to match the pain level across individuals. It leads to a higher variability of the stimulus intensity, thereby influencing the encoding of noxiousness by the central nervous system. Results might be less influenced by statistical phenomena such as ceiling/floor effects and the approach does not seem to rise ethical concerns. On the other hand, applying a fixed (standardized) intensity reduces the problem of intensity encoding leading to a large between-subjects variability in pain responses. Fixed stimulation intensities do not require pre-exposure. It can be proposed that one method is not preferable over another, however the choice depends on the study aim and the desired level of external validity. This paper discusses considerations for choosing the optimal approach for experimental pain studies and provides recommendations for different study designs. PERSPECTIVE: To calibrate pain or not? This dilemma is related to almost every experimental pain research. The decision is a trade-off between statistical power and greater control of stimulus encoding. The article decomposes both approaches and presents the pros and cons of either approach supported by data and simulation experiment

Neutrino suppression and extra dimensions: a minimal model

We study flavour neutrinos confined to our 4-dimensional world coupled to one "bulk" state, i.e. a Kaluza-Klein tower. We discuss the spatial development of the neutrino disappearance, the possibility of resurgence and the effective flavour transitions induced in this mechanism. We show that even a simple model can produce an energy-independent suppression at large distances, and relate this to experimental data.Comment: 14 pages, 8 figures; the exclusion of sterile neutrinos by SuperKamiokande is discussed; references adde

Hydrogen-Bonded Homoleptic Fluoride–Diarylurea Complexes::Structure, Reactivity, and Coordinating Power

Hydrogen-bonding with fluoride is a key interaction encountered when analyzing the mode of action of 5'-fluoro-5'-deoxyadenosine synthase, the only known enzyme capable of catalyzing the formation of a C-F bond from F-. Further understanding of the effect of hydrogen-bonding on the structure and reactivity of complexed fluoride is therefore important for catalysis and numerous other applications, such as anion supramolecular chemistry. Herein we disclose a detailed study examining the structure of 18 novel urea-fluoride complexes in the solid state, by X-ray and neutron diffraction, and in solution phase and explore the reactivity of these complexes as a fluoride source in SN2 chemistry. Experimental data show that the structure, coordination strength and reactivity of the urea-fluoride complexes are tunable by modifying substituents on the urea receptor. Hammett analysis of aryl groups on the urea indicates that fluoride bind-ing is dependent on [sigma]p and [sigma]m parameters with stronger binding being observed for electron-deficient urea ligands. For the first time, defined urea-fluoride complexes are used as fluoride-binding reagents for the nucleophilic substitution of a model alkyl bromide. The reaction is slower in comparison with known alcohol-fluoride complexes, but SN2 is largely favored over E2, at a ratio surpassing all hydrogen-bonded complexes documented in the literature for the model alkyl bromide employed. Increased second-order rate constants at higher dilution support the hypothesis that the reactive species is a 1:1 urea-fluoride complex of type [UF]- (U = urea) resulting from partial dissociation of the parent compound [U2F]- . The dissociation processes can be quantified through a combination of UV and NMR assays, including DOSY and HOESY analyses that illuminate the complexation state and H-bonding in solution

Anomalies and Fermion Content of Grand Unified Theories in Extra Dimensions

The restrictions imposed by anomaly cancellation on the chiral fermion content of nonsupersymmetric gauge theories based on various groups are studied in spacetime dimension D=6, 8, and 10. In particular, we show that the only mathematically consistent chiral SU(5) theory in D=6 contains three nonidentical generations.Comment: 15 pages, revtex. v2: references added to match published versio

Synthesis and PET Imaging Biodistribution Studies of Radiolabeled Iododiflunisal, a Transthyretin Tetramer Stabilizer, Candidate Drug for Alzheimer’s Disease

The small-molecule iododiflunisal (IDIF) is a transthyretin (TTR) tetramer stabilizer and acts as a chaperone of the TTR-Amyloid beta interaction. Oral administration of IDIF improves Alzheimer’s Disease (AD)-like pathology in mice, although the mechanism of action and pharmacokinetics remain unknown. Radiolabeling IDIF with positron or gamma emitters may aid in the in vivo evaluation of IDIF using non-invasive nuclear imaging techniques. In this work, we report an isotopic exchange reaction to obtain IDIF radiolabeled with 18F. [19F/18F]exchange reaction over IDIF in dimethyl sulfoxide at 160 °C resulted in the formation of [18F]IDIF in 7 ± 3% radiochemical yield in a 20 min reaction time, with a final radiochemical purity of >99%. Biodistribution studies after intravenous administration of [18F]IDIF in wild-type mice using positron emission tomography (PET) imaging showed capacity to cross the blood-brain barrier (ca. 1% of injected dose per gram of tissue in the brain at t > 10 min post administration), rapid accumulation in the liver, long circulation time, and progressive elimination via urine. Our results open opportunities for future studies in larger animal species or human subjects

[123I]CC1: A PARP-Targeting, Auger Electron–Emitting Radiopharmaceutical for Radionuclide Therapy of Cancer

Poly(adenosine diphosphate ribose) polymerase (PARP) has emerged as an effective therapeutic strategy against cancer that targets the DNA damage repair enzyme. PARP-targeting compounds radiolabeled with an Auger electron–emitting radionuclide can be trapped close to damaged DNA in tumor tissue, where high ionizing potential and short range lead Auger electrons to kill cancer cells through the creation of complex DNA damage, with minimal damage to surrounding normal tissue. Here, we report on [123I]CC1, an 123I-labeled PARP inhibitor for radioligand therapy of cancer. Methods: Copper-mediated 123I iododeboronation of a boronic pinacol ester precursor afforded [123I]CC1. The level and specificity of cell uptake and the therapeutic efficacy of [123I]CC1 were determined in human breast carcinoma, pancreatic adenocarcinoma, and glioblastoma cells. Tumor uptake and tumor growth inhibition of [123I]CC1 were assessed in mice bearing human cancer xenografts (MDA-MB-231, PSN1, and U87MG). Results: In vitro and in vivo studies showed selective uptake of [123I]CC1 in all models. Significantly reduced clonogenicity, a proxy for tumor growth inhibition by ionizing radiation in vivo, was observed in vitro after treatment with as little as 10 Bq [123I]CC1. Biodistribution at 1 h after intravenous administration showed PSN1 tumor xenograft uptake of 0.9 ± 0.06 percentage injected dose per gram of tissue. Intravenous administration of a relatively low amount of [123I]CC1 (3 MBq) was able to significantly inhibit PSN1 xenograft tumor growth but was less effective in xenografts that expressed less PARP. [123I]CC1 did not cause significant toxicity to normal tissues. Conclusion: Taken together, these results show the potential of [123I]CC1 as a radioligand therapy for PARP-expressing cancers

Imaging PARP with [18F]rucaparib in pancreatic cancer models

Supplementary Information is available online at: https://link.springer.com/article/10.1007/s00259-022-05835-4#Sec18 .Purpose: Rucaparib, an FDA-approved PARP inhibitor, is used as a single agent in maintenance therapy to provide promising treatment efficacy with an acceptable safety profile in various types of BRCA-mutated cancers. However, not all patients receive the same benefit from rucaparib-maintenance therapy. A predictive biomarker to help with patient selection for rucaparib treatment and predict clinical benefit is therefore warranted. With this aim, we developed [18F]rucaparib, an 18F-labelled isotopologue of rucaparib, and employed it as a PARP-targeting agent for cancer imaging with PET. Here, we report the in vitro and in vivo evaluation of [18F]rucaparib in human pancreatic cancer models. Method: We incorporated the positron-emitting 18F isotope into rucaparib, enabling its use as a PET imaging agent. [18F]rucaparib binds to the DNA damage repair enzyme, PARP, allowing direct visualisation and measurement of PARP in cancerous models before and after PARP inhibition or other genotoxic cancer therapies, providing critical information for cancer diagnosis and therapy. Proof-of-concept evaluations were determined in pancreatic cancer models. Results: Uptake of [18F]rucaparib was found to be mainly dependent on PARP1 expression. Induction of DNA damage increased PARP expression, thereby increasing uptake of [18F]rucaparib. In vivo studies revealed relatively fast blood clearance of [18F]rucaparib in PSN1 tumour-bearing mice, with a tumour uptake of 5.5 ± 0.5%ID/g (1 h after i.v. administration). In vitro and in vivo studies showed significant reduction of [18F]rucaparib uptake by addition of different PARP inhibitors, indicating PARP-selective binding. Conclusion: Taken together, we demonstrate the potential of [18F]rucaparib as a non-invasive PARP-targeting imaging agent for pancreatic cancers.This research was supported by Cancer Research UK through the Oxford Institute for Radiation Oncology, Medical Research Council (MRC) (MR/R01695X/1, G.D. and F.G., and H3R00580, C.Y.C) and Pancreatic Cancer UK (PCUK H3R00510, C.Y.C)

Radiofluorination of a highly potent ATM inhibitor as a potential PET imaging agent

Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.Supplementary Information is available online at: https://ejnmmires.springeropen.com/articles/10.1186/s13550-022-00920-z#Sec11 .Purpose: Ataxia telangiectasia mutated (ATM) is a key mediator of the DNA damage response, and several ATM inhibitors (ATMi) are currently undergoing early phase clinical trials for the treatment of cancer. A radiolabelled ATMi to determine drug pharmacokinetics could assist patient selection in a move towards more personalised medicine. The aim of this study was to synthesise and investigate the first 18F-labelled ATM inhibitor [18F]1 for non-invasive imaging of ATM protein and ATMi pharmacokinetics. Methods: Radiofluorination of a confirmed selective ATM inhibitor (1) was achieved through substitution of a nitro-precursor with [18F]fluoride. Uptake of [18F]1 was assessed in vitro in H1299 lung cancer cells stably transfected with shRNA to reduce expression of ATM. Blocking studies using several non-radioactive ATM inhibitors assessed binding specificity to ATM. In vivo biodistribution studies were performed in wild-type and ATM-knockout C57BL/6 mice using PET/CT and ex vivo analysis. Uptake of [18F]1 in H1299 tumour xenografts was assessed in BALB/c nu/nu mice. Results: Nitro-precursor 2 was synthesised with an overall yield of 12%. Radiofluorination of 2 achieved radiochemically pure [18F]1 in 80 ± 13 min with a radiochemical yield of 20 ± 13% (decay-corrected) and molar activities up to 79.5 GBq/μmol (n = 11). In vitro, cell-associated activity of [18F]1 increased over 1 h, and retention of [18F]1 dropped to 50% over 2 h. [18F]1 uptake did not correlate with ATM expression, but could be reduced significantly with an excess of known ATM inhibitors, demonstrating specific binding of [18F]1 to ATM. In vivo, fast hepatobiliary clearance was observed with tumour uptake ranging 0.13–0.90%ID/g after 1 h. Conclusion: Here, we report the first radiofluorination of an ATM inhibitor and its in vitro and in vivo biological evaluations, revealing the benefits but also some limitations of 18F-labelled ATM inhibitors.This research was supported by MRC (MR/R01695X/1) and CRUK though the Oxford Institute for Radiation Oncology