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The biology of human granzymes remains enigmatic in part due to our inability to probe their functions outside of in vitro assays or animal models with divergent granzyme species. We hypothesize that the biology of human granzymes could be better elaborated with a translational imaging technology to reveal the contexts in which granzymes are secreted and biochemically active in vivo. Here, we advance toward this goal by engineering a Granzyme targeting Restricted Interaction Peptide specific to family member B (GRIP B) to measure secreted granzyme B (GZMB) biochemistry with positron emission tomography. A proteolytic cleavage of 64Cu-labeled GRIP B liberates a radiolabeled form of Temporin L, which sequesters the radioisotope by binding to adjacent phospholipid bilayers. Thus, at extended time points postinjection (i.e., hours, not seconds), tissue biodistribution of the radioisotope in vivo reflects relative units of the GZMB activity. As a proof of concept, we show in three syngeneic mouse cancer models that 64Cu-GRIP B detects GZMB from T cells activated with immune checkpoint inhibitors (CPI). Remarkably, the radiotracer detects the proteolysis within tumors but also in lymphoid tissue, where immune cells are activated by a systemic CPI. Control experiments with an uncleavable analogue of 64Cu-GRIP B and tumor imaging studies in germline GZMB knockout mice were applied to show that 64Cu-GRIP B is specific for GZMB proteolysis. Furthermore, we explored a potential noncytotoxic function for GZMB by applying 64Cu-GRIP B to a model of pulmonary inflammation. In summary, we demonstrate that granzyme biochemistry can be assessed in vivo using an imaging modality that can be scaled vertically into human subjects., A protease-activated chemosensor for in vivo molecular imaging enables the detection of activated immune cells by specifically harnessing granzyme B catalysis.

Adapting hydrogen as a carbon-free fuel for industrial applications requires new, innovative approaches, especially when radiant heat transfer is required. One possible option is to dope hydrogen with bio-oils, containing aromatics that help produce highly sooting flames. This study investigates the potential doping effects of toluene on a hydrogen-nitrogen (1:1 vol) flames. Flames with 1–5% toluene, based on the mole concentration of hydrogen, are measured using a combination of techniques including: still photographs and laser-based techniques. Toluene was mixed with hydrogen-nitrogen fuel mixture as either a vapour carried by nitrogen, or as a dilute spray. Spray flames are found to produce substantially more polycylic aromatic hydrocarbons, with significantly more soot near the nozzle exit plane, than the prevaporised flames. Increasing the dopant concentration from 1 to 3% of the hydrogen has a marked effect on soot loading in the flame, although the further increasing the dopant concentration to 5% has a far smaller effect on the soot produced in the flame. Simulations of laminar flames using detailed chemical kinetics support the above findings and reveal details of the competition between soot precursor formation and hydrocarbon oxidation. Correlations of formation rates are non-linear with toluene concentration in cases where toluene represents less than 10% of the fuel, although expected linear relationships are noted beyond this regime up to 1:1 toluene/hydrogen blends. The study provides insight and explanation into effects of toluene as a dopant, comparison between flame doping in gaseous or liquid phases and suggests that flame doping and blending should be treated as different regimes for their global effect on flame sooting characteristics. Refereed/Peer-reviewed

Glycosaminoglycans (GAGs) such as heparan sulfate and chondroitin sulfate decorate all mammalian cell surfaces. These mucopolysaccharides act as coreceptors for extracellular ligands, regulating cell signaling, growth, proliferation, and adhesion. In glioblastoma, the most common type of primary malignant brain tumor, dysregulated GAG biosynthesis results in altered chain length, sulfation patterns, and the ratio of contributing monosaccharides. These events contribute to the loss of normal cellular function, initiating and sustaining malignant growth. Disruption of the aberrant cell surface GAGs with small molecule inhibitors of GAG biosynthetic enzymes is a potential therapeutic approach to blocking the rogue signaling and proliferation in glioma, including glioblastoma. Previously, 4-azido-xylose-α-UDP sugar inhibited both xylosyltransferase (XYLT-1) and β−1,4-galactosyltransferase-7 (β-GALT-7)—the first and second enzymes of GAG biosynthesis—when microinjected into a cell. In another study, 4-deoxy-4-fluoro-β-xylosides inhibited β-GALT-7 at 1 mM concentration in vitro. In this work, we seek to solve the enduring problem of drug delivery to human glioma cells at low concentrations. We developed a library of hydrophobic, presumed prodrugs 4-deoxy-4-fluoro-2,3-dibenzoyl-(α- or β-) xylosides and their corresponding hydrophilic inhibitors of XYLT-1 and β-GALT-7 enzymes. The prodrugs were designed to be activatable by carboxylesterase enzymes overexpressed in glioblastoma. Using a colorimetric MTT assay in human glioblastoma cell lines, we identified a prodrug–drug pair (4-nitrophenyl-α-xylosides) as lead drug candidates. The candidates arrest U251 cell growth at an IC(50) = 380 nM (prodrug), 122 μM (drug), and U87 cells at IC(50) = 10.57 μM (prodrug). Molecular docking studies were consistent with preferred binding of the α- versus β-nitro xyloside conformer to XYLT-1 and β-GALT-7 enzymes.

Non-invasive methods to study glucocorticoid receptor (GR) signaling are urgently needed to reveal the complexity of GR signaling in normal physiology and human disorders, as well as to identify selective GR modulators to treat diseases. Here, we report evidence supporting translational studies with (±)-[11C]-5-(4-fluorobenzyl)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f ]-quinoline (named as (±)-[11C]YJH08), a radioligand for positron emission tomography (PET) that engages the ligand binding domain on GR. Methods: (±)-[11C]YJH08 was synthesized by reacting the phenol precursor with [11C]methyl iodide. The biodistribution was studied in vivo with PET/CT and autoradiography. A library of analogues were synthesized and studied in vitro and in vivo to understand the (±)-[11C]YJH08 structure activity relationship. Rodent dosimetry studies were performed to estimate the human equivalent doses of (±)-[11C]YJH08. Results: (±)-[11C]YJH08 was synthesized by reaction of the phenolic precursor with [11C]methyl iodide giving a radiochemical yield of 51.7 ± 4.7% (decay corrected to starting [11C]methyl iodide). An analysis of the (±)-YJH08 structure-activity relationship with molecular dynamics simulations showed that (R)- and (S)-enantiomers occupy the ligand binding domain on GR with different binding modes and have indistinguishable patterns of biodistribution in vivo. Moreover, a focused chemical screen of analogues revealed that the aryl fluoride motif on YJH08 is essential for high affinity GR binding in vitro, high tissue uptake in vivo, and passage across the blood brain barrier. Lastly, we performed dosimetry studies in rodents, from which we showed estimated human equivalent doses of (±)-[11C]YJH08 to be commensurate with widely used carbon-11 and fluorine-18 tracers. Conclusion: In summary, these studies reveal the molecular determinants of a high affinity and selectivity ligand-receptor interaction and support the use of (±)-[11C]YJH08 PET to make the first measurements of GR expression in human subjects.

PURPOSE: Detection of bacteria-specific metabolism via positron emission tomography (PET) is an emerging strategy to image human pathogens, with dramatic implications for clinical practice. In silico and in vitro screening tools have recently been applied to this problem, with several monosaccharides including L-arabinose showing rapid accumulation in E. coli and other organisms. Our goal for this study was to evaluate several synthetically viable arabinofuranose-derived (18)F analogues for their incorporation into pathogenic bacteria. PROCEDURES: We synthesized four radiolabelled arabinofuranose-derived sugars: 2-deoxy-2-[(18)F]fluoro-arabinofuranoses (D-2-(18)F-AF and L-2-(18)F-AF) and 5-deoxy-5-[(18)F]fluoro-arabinofuranoses (D-5-(18)F-AF and L5-(18)F-AF). The arabinofuranoses were synthesized from (18)F(-) via triflated, peracetylated precursors analogous to the most common radiosynthesis of 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG). These radiotracers were screened for their uptake into E. coli and S. aureus. Subsequently the sensitivity of D-2-(18)F-AF and L-2-(18)F-AF to key human pathogens was investigated in vitro. RESULTS: All (18)F radiotracer targets were synthesized in high radiochemical purity. In the screening study, D-2-(18)F-AF and L-2-(18)F-AF showed greater accumulation in E. coli than in S. aureus. When evaluated in a panel of pathologic microorganisms, both D-2-(18)F-AF and L-2-(18)F-AF demonstrated sensitivity to most gram-positive and gram-negative bacteria. CONCLUSIONS: Arabinofuranose-derived (18)F PET radiotracers can be synthesized with high radiochemical purity. Our study showed absence of bacterial accumulation for 5-substitued analogues, a finding which may have mechanistic implications for related tracers. Both D-2-(18)F-AF and L-2-(18)F-AF showed sensitivity to most gram-negative and gram-positive organisms. Future in vivo studies will evaluate the diagnostic accuracy of these radiotracers in animal models of infection.

International audience; AGuIX are emerging radiosensitizing nanoparticles (NPs) for precision radiotherapy (RT) under clinical evaluation (Phase 2). Despite being accompanied by MRI thanks to the presence of gadolinium (Gd) at its surface, more sensitive and quantifiable imaging technique should further leverage the full potential of this technology. In this study, it is shown that Zr-89 can be labeled on such NPs directly for positron emission tomography (PET) imaging with a simple and scalable method. The stability of such complexes is remarkable in vitro and in vivo. Using a glioblastoma orthotopic rat model, it is shown that injected Zr-89-AGuIX is detectable inside the tumor for at least 1 week. Interestingly, the particles seem to efficiently infiltrate the tumor even in necrotic areas, which places great hope for the treatment of radioresistant tumor. Lastly, the first PET/MR whole-body imaging is performed in non-human primate (NHP), which further demonstrates the translational potential of these bimodal NP.

A central challenge for any therapeutic is targeting diseased over normal cells. Proteolysis is frequently upregulated in disease and can generate proteoforms with unique neo-epitopes. We hypothesize that targeting proteolytic neo-epitopes can enable more effective and safer treatments, reflecting a conditional layer of disease-specific regulation. Here, we characterized the precise proteolytic isoforms of CUB domain containing protein 1 (CDCP1), a protein overexpressed and specifically cleaved in RAS-driven cancers. We validated that the N-terminal and C-terminal fragments of CDCP1 remain associated after proteolysis in vitro and on the surface of pancreatic cancer cells. Using a differential phage display strategy, we generated exquisitely selective recombinant antibodies that target cells harboring cleaved CDCP1 and not the full-length form using antibody-drug conjugates or a bi-specific T-cell engagers. We show tumor-specific localization and anti-tumor activity in a syngeneic pancreatic tumor model having superior safety profiles compared to a pan-CDCP1-targeting antibody. Our studies show proteolytic neo-epitopes can provide an orthogonal “AND” gate for disease-specific targeting.One-Sentence SummaryAntibody-based targeting of neo-epitopes generated by disease-associated proteolysis improves the therapeutic index

PURPOSE: The swell of new and diverse radiotracers to predict or monitor tumor response to cancer immunotherapies invites the opportunity for comparative studies to identify optimal platforms. To probe the significance of antibody format on image quality for PD-L1 imaging, we developed and studied the biodistribution of a library of antibodies based on the anti-PD-L1 IgG1 clone C4. PROCEDURE: A C4 minibody and scFv were cloned, expressed and characterized. The antibodies were functionalized with desferrioxamine and radiolabeled with Zr-89 to enable rigorous comparison to prior data collected using (89)Zr-labeled C4 IgG1. The biodistribution of the radiotracers was evaluated in C57Bl6/J or nu/nu mice bearing B16F10 or H1975 tumors, respectively, which are models that represent high and low tumor autonomous PD-L1 expression. RESULTS: The tumor uptake of the (89)Zr-C4 minibody was higher than (89)Zr-C4 scFv, and equivalent to previous data collected using (89)Zr-C4 IgG1. However, the peak tumor to normal tissue ratios were generally higher for (89)Zr-C4 scFv compared to (89)Zr-C4 minibody and (89)Zr-IgG1. Moreover, an exploratory study showed that the rapid clearance of (89)Zr-C4 scFv enabled detection of endogenous PD-L1 on a genetically engineered and orthotopic model of hepatocellular carcinoma. CONCLUSION: In summary, these data support the use of low molecular weight constructs for PD-L1 imaging, especially for tumor types that manifest in abdominal organs that are obstructed by the clearance of high molecular weight radioligands.

The complexity of glucocorticoid receptor (GR) signaling cannot be measured with direct tissue analysis in living subjects, which has stifled our understanding of GR’s role in human physiology or disease and impeded the development of selective GR modulators. Herein, we report 18F-5-(4-fluorobenzyl)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline (18F-YJH08), a radioligand that enables noninvasive measurements of tissue autonomous GR expression levels in vivo with positron emission tomography (PET). YJH08 potently binds GR (Ki ∼ 0.4 nM) with ∼100-fold selectivity compared to nuclear hormone receptors in the same subfamily. 18F-YJH08 was prepared via Cu(OTf)2(py)4-mediated radiofluorination of an arylboronic acid pinacol ester with ∼12% decay corrected radiochemical yield from the starting 18F-fluoride ion. We applied treatment with the tissue-wide GR agonist dexamethasone and adrenalectomy and generated an adipocyte specific GR knockout mouse to show that 18F-YJH08 specifically binds GR in normal mouse tissues, including those for which aberrant GR expression is thought to drive severe diseases (e.g., brain, adipose tissue, kidneys). Remarkably, 18F-YJH08 PET also revealed that JG231, a potent and bioavailable HSP70 inhibitor, selectively degrades GR only in the adipose tissue of mice, a finding that foreshadows how GR targeted PET might be integrated into drug discovery to screen for selective GR modulation at the tissue level, beyond the historical screening that was performed at the transcriptional level. In summary, 18F-YJH08 enables a quantitative assessment of GR expression levels in real time among multiple tissues simultaneously, and this technology is a first step toward unraveling the daunting complexity of GR signaling and rationally engineering tissue specific therapeutic modulators in vivo.

This study compares the flame structure of ethanol and dimethyl ether (DME) in a hot and diluted oxidiser experimentally and computationally. Experiments were conducted on a Jet in Hot Coflow (JHC) burner, with the fuel jet issuing into a 1250-K coflow at three oxygen levels. Planar measurements using OH-LIF, CH2O-LIF, and Rayleigh scattering images reveal that the overall spatial distribution and evolution of OH, CH2O, and temperature were quite similar for the two fuels. For both the ethanol and the DME flames, a transitional flame structure occurred as the coflow oxygen level increased from 3% to 9%. This indicates that the flames shift away from the MILD combustion regime. Reaction flux analyses of ethanol and DME were performed with the OPPDIF code, and ethane (C2H6) was also included in the analyses for comparison. These analyses reveal that the H-2/O-2 pathways are very important for both ethanol and DME in the 3% O-2 cases. In contrast, the importance of fuel-specific reactions overtakes that of H-2/O-2 reactions when fuels are burnt in the cold air or in the vitiated oxidant stream with 9% 02. Unsteady laminar flamelet analyses were also performed to investigate the ignition processes and help interpret experimental results. Flamelet equations were solved in time and mixture fraction field, which was provided by non-reactive Large-Eddy Simulation (LES). (C) 2018 The Combustion Institute. Published by Elsevier Inc. All rights reserved. Refereed/Peer-reviewed

Background Prostate-specific membrane antigen (PSMA)-based positron emission tomography (PET) imaging is a highly sensitive tool for the detection of prostate cancer metastases. However, the effect of primary and secondary androgen deprivation therapy (ADT) on PSMA PET uptake has not been described. Objective To prospectively evaluate changes in 68Ga-PSMA-11 PET uptake on initiation of androgen receptor (AR)-targeted therapy. Design, setting, and participants Prospective single-institution study of patients with metastatic castration-sensitive (n = 4) and castration-resistant prostate cancer (n = 4) starting treatment with ADT and enzalutamide, respectively, who underwent serial 68Ga-PSMA-11 PET imaging before and after treatment initiation. Outcome measurements and statistical analysis The percentage change in 68Ga-PSMA-11 PET uptake from baseline was descriptively reported and graphically represented. Results and limitations Early increases in PSMA PET tracer uptake in at least one metastatic lesion were observed in six out of seven patients who achieved subsequent prostate-specific antigen declines of >50% from baseline. Overall, 22 of 45 metastatic lesions (49%) exhibited early increases in PSMA uptake that were indicative of a flare effect rather than disease progression. Considerable intra- and interpatient heterogeneity was observed in the temporal pattern of PSMA uptake on treatment initiation. Study limitations include the sample size, the variable timing for scan acquisition, and limited long-term follow up. Conclusions Tumor flare in PSMA PET tracer uptake in the absence of disease progression is variably observed on initiation of AR-targeted treatment. Further studies are needed to delineate the factors controlling PSMA expression to optimize the diagnostic yield. Patient summary Flares of increased prostate-specific membrane antigen (PSMA) tracer uptake on positron emission tomography scans are variably observed following initiation of hormone therapy for prostate cancer and do not necessarily represent disease progression. There was considerable variability in PSMA expression between patients, and further studies are needed to understand the factors controlling PSMA expression.

This paper presents the design, fabrication, and measurement of a plasmonic thin-film terahertz photoconductive antenna. Conventional terahertz photoconductive antennas suffer from poor optical-to-terahertz conversion efficiency, often on the order of 10−4. This is due to the low quantum efficiency of the device. The goal of this work is to demonstrate enhanced terahertz emission from a plasmonic thin-film device architecture. The combination of plasmonic nanodisks, a 120-nm low-temperature-grown gallium arsenide thin-film, and a bottom-located bowtie antenna has demonstrated the feasibility of producing such devices. Fabrication attempts and failure analysis is discussed in this work. Experimental characterization measuring the peak-to-peak electric field values of the terahertz pulses emitted from the device prototypes showed approximately five times improvement in plasmonic thin-film devices compared to conventional devices. The plasmonic thin-film devices had a measureable terahertz bandwidth of ∼5 THz. This indicates that the plasmonic thin-film architecture has a potential for producing high optical-to-terahertz conversion efficiencies across a wide frequency range.

Resistance to clinical antiandrogens has plagued the evolution of effective therapeutics for advanced prostate cancer. As with the first-line therapeutic bicalutamide (Casodex), resistance to newer antiandrogens (enzalutamide, ARN-509) develops quickly in patients, despite the fact that these drugs have ∼10-fold better affinity for the androgen receptor than bicalutamide. Improving affinity alone is often not sufficient to prevent resistance, and alternative strategies are needed to improve antiandrogen efficacy. Covalent and reversible covalent drugs are being used to thwart drug resistance in other contexts, and activated aryl nitriles are among the moieties being exploited for this purpose. We capitalized on the presence of an aryl nitrile in bicalutamide, and the existence of a native cysteine residue (Cys784) in the androgen receptor ligand binding pocket, to develop 5N-bicalutamide, a cysteine-reactive antiandrogen. 5N-bicalutamide exhibits a 150-fold improvement in Ki and 20-fold improvement in IC5...

Turbulent flames in the moderate or intense low oxygen dilution (MILD) combustion regime have previously exhibited less susceptibility to lift-off than conventional autoignitive flames in a jet-in-hot-coflow (JHC) burner. This has been demonstrated through laser-based diagnostics and examination of CH* chemiluminescence. New experimental observations are presented of turbulent flames of natural gas, ethylene and blends of the two fuels, in coflows with temperatures from 1250-1385 K and oxygen concentrations from 3-11% (vol./vol.). Zero- and one-dimensional simulations, as well as turbulent flame modelling, are used to explain the trends seen experimentally with different coflows and fuels. Numerical simulations using simplified batch reactors and opposed-flow flames demonstrate that blending of methane and ethylene fuels is most significant near 1100 K. Near this temperature, pure ethylene exhibits a transition between high and low temperature ignition pathways. Further analyses show that a 1:1 methane/ethylene blend behaves more like ethylene near MILD combustion conditions, and more like methane in conventional autoignition conditions. Two-dimensional modelling results of the turbulent flames are then discussed and explained in the context of the simplified reactor results. The flames confined by the lean flammability-limit in the coflow and high strain-rates in jet shear layer, in agreement with previous work using a semi-empirical jet model. The two-dimensional modelling is additionally able to qualitatively replicate the trends in lift-off height, with normalised heat release rate profiles reproducing, and serving to explain, the effects seen in experimental campaigns. (C) 2017 Elsevier Ltd. All rights reserved. Refereed/Peer-reviewed

Purpose: mTOR regulates many normal physiological processes and when hyperactive can drive numerous cancers and human diseases. However, it is very challenging to detect and quantify mTOR signaling noninvasively in clinically relevant animal models of disease or man. We hypothesized that a nuclear imaging tool measuring intracellular mTOR activity could address this unmet need. Experimental Design: Although the biochemical activity of mTOR is not directly amenable to nuclear imaging probe development, we show that the transferrin receptor can be used to indirectly measure intracellular changes in mTOR activity. Results: After verifying that the uptake of radiolabeled transferrin (the soluble ligand of the transferrin receptor) is stimulated by active mTORC1 in vitro, we showed that 89Zr-labeled transferrin (Tf) can measure mTORC1 signaling dynamics in normal and cancerous mouse tissues with PET. Finally, we show that 89Zr-Tf can detect the upregulation of mTORC1 by tumor cells to escape the antitumor effects of a standard-of-care antiandrogen, which is to our knowledge the first example of applying PET to interrogate the biology of treatment resistant cancer. Conclusions: In summary, we have developed the first quantitative assay to provide a comprehensive measurement of mTOR signaling dynamics in vivo, in specific normal tissues, and during tumor development in genetically engineered animal models using a nuclear imaging tool that is readily translatable to man. Clin Cancer Res; 23(12); 3045–52. ©2016 AACR.

The moderate or intense low oxygen dilution (MILD) combustion regime offers reductions in pollutant emissions and improvements in efficiency. The implementation of MILD combustion in non-premixed systems, however, still requires a significantly improved understanding of the effects of the oxidant stream composition in both the MILD combustion regime, and in the transition from MILD combustion to conventional spontaneous-ignition. This paper presents a numerical study of two-dimensional flames near the transition between MILD combustion and conventional spontaneous-ignition. The numerical study is performed with a detailed kinetic mechanism, using the laminarSMOKE code to provide insight into the chemical structure of flames with a hot and diluted coflow. This study is complemented by new experimental observations of laminar flames in similar coflows, which demonstrate a non-monotonic change in lift-off height with changing oxidant O-2 concentration. This change occurs in conjunction with a transition from spatially gradual ignition to well-defined flame bases, with increasing coflow O-2 level. The simulated flames are compared to a previous definition of MILD combustion in a hot coflow as an edge flame without a tribrachial flame structure. The different structures of simulated CH4 flames are consistent with the observed experimental behaviour under similar conditions, however comparisons between experimental observations and simulations of C2H4 flames highlight the importance of the flow-field, even in a simple streaming flow. The simulations show that equilibrium levels of the OH radical (< 10 ppm) in the oxidant stream significantly intensifies a MILD CH4 reaction zone, by increasing CH3 oxidation, however such levels have little effect on tribrachial, spontaneously-igniting flames. Conversely, increasing the ratio of CO2 to H2O in the coflow reduces the intensity of a MILD CH4 reaction zone. Neither the inclusion of equilibrium concentrations of OH, nor the change in CO2 to H2O ratio, in the oxidant results in a transition between MILD reaction zones to tribrachial spontaneously-igniting flames, despite significantly affecting the temperature of reaction zones in the MILD combustion regime. The results show that the intensity of MILD combustion is strongly dependent on the different chemical species in the oxidant stream. Tribrachial spontaneously-igniting flames are, in contrast, relatively resilient against changes other than temperature and O-2 level. (C) 2016 The Combustion Institute. Refereed/Peer-reviewed

Boron neutron capture therapy (BNCT) is a therapeutic modality which has been used for the treatment of cancers, including brain and head and neck tumors. For effective treatment via BNCT, efficient and selective delivery of a high boron dose to cancer cells is needed. Prostate specific membrane antigen (PSMA) is a target for prostate cancer imaging and drug delivery. In this study, we conjugated boronic acid or carborane functional groups to a well-established PSMA inhibitor scaffold to deliver boron to prostate cancer cells and prostate tumor xenograft models. Eight boron-containing PSMA inhibitors were synthesized. All of these compounds showed strong binding affinity to PSMA in a competition radioligand binding assay (IC(50) from 555.7 nM-20.3 nM). Three selected compounds 1a, 1d and 1f were administered to mice, and their in vivo blocking of (68)Ga-PSMA-11 uptake was demonstrated through a positron emission tomography (PET) imaging and biodistribution experiment. Biodistribution analysis demonstrated boron uptake of 4–7 μg/gram in 22Rv1 prostate xenograft tumors and similar tumor/muscle ratios compared to the ratio for the most commonly used BNCT compound, 4-borono-L-phenylalanine (BPA). Taken together, this data suggest a potential role for PSMA targeted BNCT agents in prostate cancer therapy following suitable optimization.

Background Biologics account for a substantial portion of drug spending in rheumatoid arthritis (RA). Variability in the U.S. in biologic prescribing patterns (and therefore variability in cost of care), and factors that correlate with that variability, remain largely undefined. Objectives We used data from the RISE registry to perform a cross-sectional analysis among U.S. rheumatologists of prescription patterns for biologic DMARDs and tofacitinib and their relationship to RA disease activity. Methods RISE is a U.S. registry that passively collects data on all patients seen by participating practices, thereby reducing selection bias present in single-insurer claims databases. As of December 2017, RISE held validated data from 1.257 providers in 236 practices, representing an estimated 25% of the U.S. clinical rheumatology workforce. We identified patients with available demographic and disease activity information who were assigned ≥2 codes for RA ≥30 days apart between January and December 2017. Practices with 1 of these drugs were assigned to the first drug prescribed and therefore counted only once. We used a hierarchical linear model to predict the probability of receiving a prescription for a biologic based on the patient’s most recent disease activity score (moderate or high disease activity vs. low disease activity or remission) and age from 2016, accounting for clustering by practice. Results We analyzed 53.850 patients from 104 practices. Overall, 29% of patients were prescribed a biologic DMARD or tofacitinib in 2017. TNF inhibitors were most commonly prescribed, followed by abatacept (4.5% of patients), tofacitinib (4.2%), tocilizumab (3.4%), and rituximab (2.5%). We found significant variation within practices in the proportion of patients prescribed any of these drugs (range 0%-100%). In the adjusted analysis, we found that patients with higher disease activity in 2016 were more likely to receive biologics in 2017 (OR 1.56, 95% CI (1.51, 1.62)). Within a practice, as shown in the figure, the risk-adjusted likelihood of receiving a biologic prescription still showed significant variation (between 0%-83% of patients in each practice received a biologic; model c-statistic 0.61). Conclusion In this large sample of U.S. rheumatology practices, higher RA disease activity correlated with the likelihood that a patient would receive a prescription for a biologic, but did not account for all of the variability in biologic prescription patterns. These results suggest that there may be other factors in addition to RA disease activity that account for practice-to-practice variability in biologic prescription patterns. Disclaimer: These data were collected from the ACR’s RISE Registry; however, the views expressed represent those of the authors, not necessarily those of the ACR. Disclosure of Interests Douglas White Grant/research support from: Abbott 2006-2009, Pfizer 2017-2019 (unrelated to this work), Consultant for: Crescendo advisory board 2013-2014, Employee of: Genomyx (Genentech) 1991, Speakers bureau: None since 2008, Michael Evans: None declared, Tracy Johansson: None declared, Rachel Myslinski: None declared, Jinoos Yazdany Grant/research support from: Pfizer, Consultant for: AstraZeneca, Gabriela Schmajuk Grant/research support from: Investigator initiated award from Pfizer from 2015-2018, unrelated to this work

For ultra-fine pixel pitch focal plane array (FPA) applications, flip-chip hybridization has advantages including high I/O density and short distance between the photodiode array (PDA) and the readout integrated circuit (ROIC). Indium has become the primary interconnect material because of its high ductility at low temperature. Successful mating of large format die becomes increasingly difficult, however, for finer pitch applications where bumps are shorter, as tolerance for bowing is low. Simultaneously, the epoxy filling process for large image format, hybridized focal planes becomes more challenging. These constraints call for tall indium bumps with high aspect ratio to accommodate die bowing and provide larger openings for the flow of fill epoxy. A process for the fabrication of highly uniform, high aspect ratio (height:diameter) indium bumps has been developed by Sensors Unlimited Inc. (SUI), a Collins Aerospace Company. The grain size of the deposited indium metal is minimized by optimizing process parameters as well as introducing intermediate metal layers underneath the indium bumps. Anisotropic deposition has been achieved by optimizing deposition rate and controlling substrate parameters. Indium bumps with aspect ratios over 2:1 and flat bump heads have been achieved. The developed bump process has been successfully applied to the fabrication of high resolution indium gallium arsenide (InGaAs) FPAs. Key control parameters for bump formation will be discussed in this paper.

[Image: see text] Redox cycling of iron powers various enzyme functions crucial for life, making the study of iron acquisition, storage, and disposition in the whole organism a worthy topic of inquiry. However, despite its important role in biology and disease, imaging iron in animals with oxidation-state specificity remains an outstanding problem in biology and medicine. Here we report a first-generation reactivity-based probe of labile ferrous iron suitable for positron emission tomography studies in live animals. The responses of this reagent to systemic changes in labile iron disposition were revealed using iron supplementation and sequestration treatments in mice, while the potential of this approach for in vivo imaging of cancer was demonstrated using genetically and pathologically diverse mouse models, including spontaneous tumors arising in a genetically engineered model of prostate cancer driven by loss of PTEN.

The scenario of fuel injected into hot surrounds is found in a range of practical combustion applications. These flame conditions have been emulated using a jet-in-hot-coflow-burner using prevaporised n-heptane and mixtures of n-heptane and toluene, relevant to gasoline and diesel fuel surrogates. This paper reports measurements of six lifted, turbulent flames, with a constant jet flow of a prevaporised fuel/N2 mixture at 380 K into various hot and vitiated coflow conditions. Five of these flames issued into coflows generated by the combustion of different mixtures of ethylene/air and one had a coflow from a natural gas/air flame. Two n-heptane/toluene fuel blends were also measured to study the effect of soot propensity. Gas sampling, non-linear excitation regime two-line atomic fluorescence (NTLAF) and laser-induced incandescence (LII) were used to characterise the flames, investigate the mixing between the hot coflow and the surrounding air, and measure the flame temperature for the different coflow configurations. A comparison of results of the flames issuing into hot coflows is presented, indicating that the hottest flame is not associated with the coflow containing the highest concentration of O2, but with the minimum soot loading and, consequently, the minimum radiative heat loss. Subsequent numerical simulations of canonical opposed-flow flames demonstrate that the soot loading in the downstream region of the flames is strongly dependent on PAH formation in the hot coflow region and further analyses reveal the chemical pathways which are most impacted by small variations in hot coflow composition. Refereed/Peer-reviewed

There has been significant and rapid growth in the development of amino acid-based molecular imaging agents (e.g., peptides, proteins, and antibody constructs) largely due to facile library preparation and high throughput screening. Positron-emitting fluorine-18 (half-life = 109.7 min) has a unique set of properties that match well with the pharmacokinetics of smaller sized constructs. Several indirect fluorine-18 labeling approaches have been developed yet only a few have advanced to human trials. Enzymatically catalyzed radiofluorination utilizing lipoic acid ligase shows promise as a mild site-specific method for coupling fluorine-18-labeled carboxylate substrates with biomolecules. Methods for preparation of two [18F]fluorocarboxylates and their ligation to a specific peptide sequence (LAP peptide) are presented herein.

International audience; AGuIX® are sub-5 nm nanoparticles made of a polysiloxane matrix and gadolinium chelates. This nanoparticle has been recently accepted in clinical trials in association with radiotherapy. This review will summarize the principal preclinical results that have led to first in man administration. No evidence of toxicity has been observed during regulatory toxicity tests on two animal species (rodents and monkeys). Biodistributions on different animal models have shown passive uptake in tumours due to enhanced permeability and retention effect combined with renal elimination of the nanoparticles after intravenous administration. High radiosensitizing effect has been observed with different types of irradiations in vitro and in vivo on a large number of cancer types (brain, lung, melanoma, head and neck…). The review concludes with the second generation of AGuIX nanoparticles and the first preliminary results on human.

31 Background: Transferrin receptor (TFRC) expression is controlled by the PI3K and MYC signaling pathways, which are frequently dysregulated in prostate cancer (PC). Gallium-68 citrate (68Ga-citrate) is an iron biomimetic, which can be used to image PC in a TFRC dependent fashion. We performed a single-center pilot imaging study to investigate the use of 68Ga-citrate PET in patients with metastatic castration-resistant PC (mCRPC). Methods: Following written informed consent, mCRPC patients were prospectively enrolled and underwent 68Ga-citrate PET imaging. Optional metastatic tumor biopsies were undertaken at the time of imaging. Results: 34 mCRPC patients underwent 68Ga-citrate PET imaging. The median age was 67.5 years old. Median duration of castration resistance was 17.5 months; 14.7% of patients were post-docetaxel. Median serum PSA was 35.2 ng/dL. A total of 483 lesions were detected on conventional imaging (CT, 99mTc-HDP) or 68Ga-citrate PET, including 420 osseous and 63 soft tissue (nodal and visceral) lesions (Table). 67.3% of all lesions were detected on 68Ga-citrate PET, including 74.5% of all osseous lesions but only 19.0% of all soft tissue lesions (p68Ga-citrate PET imaging only. Per-lesion average SUVmax (SUVmax,avg) was 6.7. Metastatic biopsies of PET avid lesions were performed in 20 patients (59%); adenocarcinoma histology was confirmed in 14 (70%) cases, treatment-emergent small cell neuroendocrine cancer (t-SCNC) in 6 (30%). There was no significant difference in SUVmax,avg between patients with adenocarcinoma or t-SCNC (SUVmax,avg 7.3 vs 7.6, respectively; Table). Serial 68Ga-citrate PET perfomed in a patient with biopsy-confirmed t-SCNC after 2 cycles of carboplatin/cabazitaxel demonstrated an early metabolic response (28.5% decrease in average SUVmax) confirmed on subsequent conventional imaging. Conclusions: 68Ga-citrate PET detects mCRPC bone metastases in patients with biopsy-proven prostatic adenocarcinoma or t-SCNC, distinguishing it from lineage dependent agents such as PSMA tracers. Detection of an early metabolic response in the bone of a treated t-SCNC patient was observed. Further prospective studies are ongoing coupling serial Ga-citrate PET with investigational agents targeting the MYC signaling pathway. Clinical trial information: NCT02391025. [Table: see text]

Chromatin modifying proteins are attractive drug targets in oncology, given the fundamental reliance of cancer on altered transcriptional activity. Multiple transcription factors can be impacted downstream of primary target inhibition, thus making it challenging to understand the driving mechanism of action of pharmacologic inhibition of chromatin modifying proteins. This in turn makes it difficult to identify biomarkers predictive of response and pharmacodynamic tools to optimize drug dosing. In this report, we show that (89)Zr-transferrin, an imaging tool we developed to measure MYC activity in cancer, can be used to identify cancer models that respond to broad spectrum inhibitors of transcription primarily due to MYC inhibition. As a proof of concept, we studied inhibitors of BET bromodomain containing proteins, as they can impart antitumor effects in a MYC dependent or independent fashion. In vitro, we show that transferrin receptor biology is inhibited in multiple MYC positive models of prostate cancer and double hit lymphoma when MYC biology is impacted. Moreover, we show that bromodomain inhibition in one lymphoma model results in transferrin receptor expression changes large enough to be quantified with (89)Zr-transferrin and positron emission tomography (PET) in vivo. Collectively, these data further underscore the diagnostic utility of the relationship between MYC and transferrin in oncology, and provide the rationale to incorporate transferrin-based PET into early clinical trials with bromodomain inhibitors for the treatment of solid tumors.

Formaldehyde (FA) is a reactive carbonyl species (RCS) that plays a broad spectrum of roles in epigenetics, toxicology, and progression of diseases ranging from cancer to diabetes to neurodegeneration, motivating the development of translatable technologies for FA imaging. Here we report formaldehyde-caged-[18F]fluorodeoxyglucose-1 ([18F]FAC-FDG-1), an aza-Cope-based reactivity probe for in vivo FA imaging using positron emission tomography (PET). [18F]FAC-FDG-1 reacts selectively with FA over potentially competing analytes to generate [18F]FDG, allowing its FA-dependent uptake and retention in cell culture as well as in animal models. The relative uptake of [18F]FAC-FDG-1 was evaluated using FA-treated PC3 prostate cancer and U87-MG glioblastoma cells demonstrating a dose-dependent response to exogenously added FA. Moreover, [18F]FAC-FDG-1 is capable of FA detection in vivo using a PC3 tumor xenograft model. In addition to providing a unique tool for monitoring FA in living animals, these data establish a general approach for translatable detection of FA and other reactive biological analytes in vivo by exploiting the widely-available clinical [18F]FDG tracer as a masked aldehyde that can be caged by analyte-responsive triggers.

© 2015 American Chemical Society. Solid tumors are hypoxic with altered metabolism, resulting in secretion of acids into the extracellular matrix and lower relative pH, a feature associated with local invasion and metastasis. Therapeutic and diagnostic agents responsive to this microenvironment may improve tumor-specific delivery. Therefore, we pursued a general strategy whereby caged small-molecule drugs or imaging agents liberate their parent compounds in regions of low interstitial pH. In this manuscript, we present a new acid-labile prodrug method based on the glycosylamine linkage, and its application to a class of positron emission tomography (PET) imaging tracers, termed [18F]FDG amines. [18F]FDG amines operate via a proposed two-step mechanism, in which an acid-labile precursor decomposes to form the common radiotracer 2-deoxy-2-[18F]fluoro-d-glucose, which is subsequently accumulated by glucose avid cells. The rate of decomposition of [18F]FDG amines is tunable in a systematic fashion, tracking the pKaof the parent amine. In vivo, a 4-phenylbenzylamine [18F]FDG amine congener showed greater relative accumulation in tumors over benign tissue, which could be attenuated upon tumor alkalinization using previously validated models, including sodium bicarbonate treatment, or overexpression of carbonic anhydrase. This new class of PET tracer represents a viable approach for imaging acidic interstitial pH with potential for clinical translation.

Noninvasive tools that target tumor cells could improve the management of glioma. Cancer generally has a high demand for Fe(III), an essential nutrient for a variety of biochemical processes. We tested whether 68Ga-citrate, an Fe(III) biomimetic that binds to apo-transferrin in blood, detects glioma in preclinical models and patients using hybrid PET/MRI. Mouse PET/CT studies showed that 68Ga-citrate accumulates in subcutaneous U87MG xenografts in a transferrin receptor-dependent fashion within 4 hours after injection. Seventeen patients with WHO grade III or IV glioma received 3.7-10.2 mCi 68Ga-citrate and were imaged with PET/MR 123-307 minutes after injection to establish that the radiotracer can localize to human tumors. Multiple contrast-enhancing lesions were PET avid, and tumor to adjacent normal white matter ratios were consistently greater than 10:1. Several contrast-enhancing lesions were not PET avid. One minimally enhancing lesion and another tumor with significantly reduced enhancement following bevacizumab therapy were PET avid. Advanced MR imaging analysis of one patient with contrast-enhancing glioblastoma showed that metabolic hallmarks of viable tumor spatially overlaid with 68Ga-citrate accumulation. These early data underscore that high-grade glioma may be detectable with a radiotracer that targets Fe(III) transport.

The swell of experimental imaging technologies to non-invasively measure immune checkpoint protein expression presents the opportunity for rigorous comparative studies toward identifying a gold standard. (89)Zr-atezolizumab is currently in man, and early data show tumor targeting but also abundant uptake in several normal tissues. Therefore, we conducted a reverse translational study, both to understand if tumor to normal tissue ratios for (89)Zr-atezolizumab could be improved, and to make direct comparisons to (89)Zr-C4, a radiotracer that we showed can detect a large dynamic range of tumor-associated PD-L1 expression. PET/CT and biodistribution studies in tumor bearing immunocompetent and nu/nu mice revealed that high specific activity (89)Zr-atezolizumab (~2 μCi/μg) binds to PD-L1 on tumors, but also results in very high uptake in many normal mouse tissues, as expected. Unexpectedly, (89)Zr-atezolizumab uptake was generally higher in normal mouse tissues compared to (89)Zr-C4, and lower in H1975, a tumor model with modest PD-L1 expression. Also unexpectedly, reducing the specific activity at least 15 fold suppressed (89)Zr-atezo uptake in normal mouse tissues, but increased tumor uptake to levels observed with high specific activity (89)Zr-C4. In summary, these data reveal that low specific activity (89)Zr-atezo may be necessary for accurately measuring PD-L1 in the tumor microenvironment, assuming a threshold can be identified that preferentially suppresses binding in normal tissues without reducing binding to tumors with abundant expression. Alternatively, high specific activity approaches like (89)Zr-C4 PET may be simpler to implement clinically to measure the broad dynamic range of PD-L1 expression known to manifest among tumors.

High sensitivity imaging tools could provide a more holistic view of target antigen expression to improve the identification of patients who might benefit from cancer immunotherapy. We developed for immunoPET a novel recombinant human IgG1 (termed C4) that potently binds an extracellular epitope on human and mouse PD-L1 and radiolabeled the antibody with zirconium-89. Small animal PET/CT studies showed that 89Zr-C4 detected antigen levels on a patient derived xenograft (PDX) established from a non-small-cell lung cancer (NSCLC) patient before an 8-month response to anti-PD-1 and anti-CTLA4 therapy. Importantly, the concentration of antigen is beneath the detection limit of previously developed anti-PD-L1 radiotracers, including radiolabeled atezolizumab. We also show that 89Zr-C4 can specifically detect antigen in human NSCLC and prostate cancer models endogenously expressing a broad range of PD-L1. 89Zr-C4 detects mouse PD-L1 expression changes in immunocompetent mice, suggesting that endogenous PD-1/2 will not confound human imaging. Lastly, we found that 89Zr-C4 could detect acute changes in tumor expression of PD-L1 due to standard of care chemotherapies. In summary, we present evidence that low levels of PD-L1 in clinically relevant cancer models can be imaged with immunoPET using a novel recombinant human antibody.

Moderate or intense low oxygen dilution (MILD) combustion has been established as a combustion regime with improved thermal efficiency and decreased pollutant emissions, including NOx and soot. MILD combustion has been the subject of numerous experimental studies, and presents a challenge for computational modeling due to the strong turbulence-chemistry coupling within the homogeneous reaction zone. Models of flames in the jet in hot coflow (JHC) burner have typically had limited success using the eddy dissipation concept (EDC) combustion model, which incorporates finite-rate kinetics at low computational expense. A modified EDC model is presented, which successfully simulates an ethylene-nitrogen flame in a 9% O-2 coflow. It is found by means of a systematic study in which adjusting the parameters C-tau and C-xi from the default 0.4082 and 2.1377 to 3.0 and 1.0 gives significantly improved performance of the EDC model under these conditions. This modified EDC model has subsequently been applied to other ethylene-and methane-based fuel jets in a range of coflow oxidant stream conditions. The modified EDC offers results comparable to the more sophisticated, and computationally expensive, transport probability density function (PDF) approach. The optimized EDC models give better agreement with experimental measurements of temperature, hydroxyl (OH), and formaldehyde (CH2O) profiles. The visual boundary of a chosen flame is subsequently defined using a kinetic mechanism for OH* and CH*, showing good agreement with experimental observations. This model also appears more robust to variations in the fuel jet inlet temperature and turbulence intensity than the standard EDC model trialed in previous studies. The sensitivity of the newly modified model to the chemical composition of the heated coflow boundary also demonstrates robustness and qualitative agreement with previous works. The presented modified EDC model offers improved agreement with experimental data profiles than has been achieved previously, and offers a viable alternative to significantly more computationally expensive modeling methods for lifted flames in a heated and vitiated coflow. Finally, the visually lifted flame behavior observed experimentally in this configuration is replicated, a phenomenon that has not been successfully reproduced using the EDC model in the past. Refereed/Peer-reviewed

Here we report the radiosynthesis of an endogenous redox pair, [(11)C]ascorbic acid ([(11)C]VitC) and [(11)C]dehydroascorbic acid ([(11)C]DHA), the reduced and oxidized forms of vitamin C, and their application to ROS sensing. These results provide the basis for in vivo detection of ROS using positron emission tomography (PET).

Noninvasive biomarkers that detect the activity of important oncogenic drivers could significantly improve cancer diagnosis and management of treatment. The goal of this study was to determine whether 68Ga-citrate (which avidly binds to circulating transferrin) can detect MYC-positive prostate cancer tumors, as the transferrin receptor is a direct MYC target gene. PET imaging paired with 68Ga-citrate and molecular analysis of preclinical models, human cell-free DNA (cfDNA), and clinical biopsies were conducted to determine whether 68Ga-citrate can detect MYC-positive prostate cancer. Importantly, 68Ga-citrate detected human prostate cancer models in a MYC-dependent fashion. In patients with castration-resistant prostate cancer, analysis of cfDNA revealed that all patients with 68Ga-citrate avid tumors had a gain of at least one MYC copy number. Moreover, biopsy of two PET avid metastases showed molecular or histologic features characteristic of MYC hyperactivity. These data demonstrate that 68Ga-citrate targets prostate cancer tumors with MYC hyperactivity. A larger prospective study is ongoing to demonstrate the specificity of 68Ga-citrate for tumors with hyperactive MYC. Implications: Noninvasive measurement of MYC activity with quantitative imaging modalities could substantially increase our understanding of the role of MYC signaling in clinical settings for which invasive techniques are challenging to implement or do not characterize the biology of all tumors in a patient. Moreover, measuring MYC activity noninvasively opens the opportunity to study changes in MYC signaling in patients under targeted therapeutic conditions thought to indirectly inhibit MYC. Mol Cancer Res; 15(9); 1221–9. ©2017 AACR.

Over the past several decades, radionuclides have matured from largely esoteric and experimental technologies to indispensible components of medical diagnostics. Driving this transition, in part, have been mutually necessary advances in biomedical engineering, nuclear medicine, and cancer biology. Somewhat unsung has been the seminal role of inorganic chemistry in fostering the development of new radiotracers. In this regard, the purpose of this Forum Article is to more visibly highlight the significant contributions of inorganic chemistry to nuclear imaging by detailing the development of five metal-based imaging agents: (64)Cu-ATSM, (68)Ga-DOTATOC, (89)Zr-transferrin, (99m)Tc-sestamibi, and (99m)Tc-colloids. In a concluding section, several unmet needs both in and out of the laboratory will be discussed to stimulate conversation between inorganic chemists and the imaging community.

The effective management of tumors in the brain imposes several unique clinical challenges. For example, the complete surgical resection of a primary brain tumor—a critical factor influencing prognosis—is often complicated by atypical tumor margins or proximity to essential neurologic tissue (1,2). Moreover, because the blood–brain barrier can obstruct the delivery of systemically administered therapeutics, the pharmacokinetic limitations of drugs designed to address primary or metastatic brain tumors can severely dampen clinical responses (3). With some success, noninvasive imaging modalities have been invoked to address these challenges. One of the most visible examples of progress has been the use of MR imaging to localize a tumor mass or to monitor tumor burden after therapy (4). However, the low sensitivity of this modality, and its inability to distinguish tumors from nonmalignant pathologies (infection), precludes its application to some common clinical issues (e.g., detection of residual or recurrent subclinical disease). Because of its comparatively lower detection limit, and its ability to intercalate tumor biology independent of morphologic changes, nuclear medicine technologies (e.g., PET) are regarded as an attractive complement to anatomic imaging. Indeed, several clinical studies have been conducted with common (18F-FDG) and investigational radiotracers (3′-deoxy-3′-18F-fluorothymidine, 11C-labeled amino acids), resulting in some degree of disease contrast and effectively establishing proof of concept (5). However, shortcomings have been documented and are generally attributed to obfuscating uptake in normal brain tissue, ongoing questions concerning mechanism of action, and the practical limitations of studying radiotracers with rapid decay kinetics. On the basis of these observations, we hypothesized that 89Zr-transferrin, a radiotracer we previously developed to target transferrin receptor (TFRC) in prostate cancer (6), could be a generally useful tool for the detection and monitoring of tumor burden in the brain. Indeed, there is a known tropism of transferrin for primary and metastatic brain tumors (7,8), leading several groups to exploit this property therapeutically by coupling transferrin to anticancer drugs to foster tumor-specific delivery (9–12). Moreover, our previous work with this radiotracer (and with 89Zr-labeled monoclonal antibodies) resulted in high-contrast images of tumors, with generally low uptake in normal tissues (13,14). Part of the success can be attributed to 89Zr itself—the radionuclide has highly attractive physical properties such as its long half-life (~78 h), which is well suited to the length of time required for large biomolecules such as transferrin to distribute in vivo (15). Collectively, these observations led us to profile the avidity of primary brain tumor models for 89Zr-transferrin.

International audience; The ultrasmall nanoparticle AGuIX is a versatile platform that tolerates a range of chemical diversity for theranostic applications. Our previous work showed that AGuIX clears rapidly from normal tissues, while durably accumulating within the tumor microenvironment. On this basis, AGuIX was used to detect tumor tissue with Gd3+ enhanced MRI and can sensitize tumors to radiation therapy. As we begin the translation of AGuIX, we appreciated that coupling AGuIX to a long-lived radioisotope would help to more completely measure the magnitude and duration of its retention within the tumor microenvironment. Therefore, we developed 89Zr-DFO-AGuIX. AGuIX was coupled to DFO and then to 89Zr in ∼99% radiochemical yield. Stability studies showed that 89Zr-DFO-AGuIX did not dissociate after 72 h. In animals bearing U87MG xenografts, it was detectable at levels above background for 72 h. Lastly, 89Zr-DFO-AGuIX did not accumulate in inflammatory abscesses in vivo, highlighting its specificity for well vascularized tumors.

We present an aza-Cope-based reactivity probe for imaging formaldehyde in vivo using positron emission tomography., Formaldehyde (FA) is a reactive carbonyl species (RCS) that plays a broad spectrum of roles in epigenetics, toxicology, and progression of diseases ranging from cancer to diabetes to neurodegeneration, motivating the development of translatable technologies for FA imaging. Here we report formaldehyde-caged-[18F]fluorodeoxyglucose-1 ([18F]FAC-FDG-1), an aza-Cope-based reactivity probe for in vivo FA imaging using positron emission tomography (PET). [18F]FAC-FDG-1 reacts selectively with FA over potentially competing analytes to generate [18F]FDG, allowing its FA-dependent uptake and retention in cell culture as well as in animal models. The relative uptake of [18F]FAC-FDG-1 was evaluated using FA-treated PC3 prostate cancer and U87-MG glioblastoma cells demonstrating a dose-dependent response to exogenously added FA. Moreover, [18F]FAC-FDG-1 is capable of FA detection in vivo using a PC3 tumor xenograft model. In addition to providing a unique tool for monitoring FA in living animals, these data establish a general approach for translatable detection of FA and other reactive biological analytes in vivo by exploiting the widely-available clinical [18F]FDG tracer as a masked aldehyde that can be caged by analyte-responsive triggers.

New methodologies for site-specifically radiolabeling proteins with the PET isotope [ 18 F] are required to generate high quality radiotracers for imaging in both the preclinical and clinical settings. The enzymatic radiofluorination overcomes many of the limitations encountered to date with purely chemical approaches. The bacterial enzyme lipoic acid ligase was used to conjugate [ 18 F]-fluorooctanoic acid to both a small peptide and a Fab antibody fragment. Labeling was site-specific and highly efficient under mild aqueous conditions using small amounts of peptide/protein (1-10 nmol). The labeled construct retained full epitope binding affinity and was stable in mouse serum. Using an optimized reaction scheme, mCi quantities of [ 18 F]-Fab were generated, an amount sufficient for human imaging.

The present paper is focused on prevaporised ethanol flames in the transition from conventional combustion to the MILD combustion regime. Photographs and imaging of OH * chemiluminescence reveal a distinctive flame structure when ethanol carried by air burns in a 3% O 2 coflow (typical of MILD combustion), differing from that at higher oxygen levels. In comparison to flames carried by air in a 9% O 2 coflow, the spatial gradient and the peak in the OH * signal profile are significantly reduced in the 3% O 2 coflow, indicating a more uniform distribution of heat release and temperature. The use of N 2 as a carrier gas renders the OH * profile for the 6% O 2 coflow case similar to that of flames carried by air in the 3% O 2 coflow. The experimental results indicate a transition from conventional combustion to MILD combustion with the decrease of coflow O 2 level and/or the use of N 2 as a carrier gas. Calculations reveal that a substantial drop in the peak heat release rate and/or overall net heat release rate might contribute to the lack of luminosity of flames in the 3% O 2 coflow, suggesting a need for threshold values of these two in defining MILD combustion. A series of laminar flame calculations are performed to identify the MILD combustion regime based on the absence of a negative heat release region. The absence of a negative heat release region is found to be strain rate dependent at a given temperature and O 2 level of the oxidant stream. This is mainly a result of the enhanced transportation of O 2 across the reaction zone at a higher strain rate. At low strain rates, the negative heat release region is more likely to disappear in a 3% O 2 oxidant flow due to a combination of low flame temperature and high availability of O 2 .

Experiments of autoignitive jet flames in a hot and vitiated coflow have previously shown various flame behaviors, spanning lifted flames to moderate or intense low oxygen dilution (MILD) combustion. For better understanding the behavior of flames in this configuration, regime diagrams and ignition delay results are presented from well-stirred reactor calculations across a wide range of operating conditions for methane and ethylene fuels. In conjunction with two-dimensional calculations, the importance of flame precursors and oxygen penetration across the reaction zone is revealed. It is found that widely accepted definitions and regime diagrams are inadequate to classify and reconcile the different flame behaviors that are observed experimentally. For accurate prediction of the ignition process, it is necessary to incorporate boundary conditions that capture minor species in the oxidizer. The role of fuel type also has a major impact on the ignition process and flame appearance. Refereed/Peer-reviewed

Early life is a dynamic period of growth for the lung and immune system. We hypothesized that ambient ozone exposure during postnatal development can affect the innate immune response to other environmental challenges in a persistent fashion. To test this hypothesis, we exposed infant rhesus macaque monkeys to a regimen of 11 ozone cycles between 30 days and 6 mo of age; each cycle consisted of ozone for 5 days (0.5 parts per million at 8 h/day) followed by 9 days of filtered air. Animals were subsequently housed in filtered air conditions and challenged with a single dose of inhaled LPS at 1 yr of age. After completion of the ozone exposure regimen at 6 mo of age, total peripheral blood leukocyte and polymorphonuclear leukocyte (PMN) numbers were reduced, whereas eosinophil counts increased. In lavage, total cell numbers at 6 mo were not affected by ozone, however, there was a significant reduction in lymphocytes and increased eosinophils. Following an additional 6 mo of filtered air housing, only monocytes were increased in blood and lavage in previously exposed animals. In response to LPS challenge, animals with a prior history of ozone showed an attenuated peripheral blood and lavage PMN response compared with controls. In vitro stimulation of peripheral blood mononuclear cells with LPS resulted in reduced secretion of IL-6 and IL-8 protein in association with prior ozone exposure. Collectively, our findings suggest that ozone exposure during infancy can result in a persistent effect on both pulmonary and systemic innate immune responses later in life.

Li 2 PtH 6 , the missing member of the complex transition metal hydride series A 2 PtH 6 ( A =alkali metal), was prepared by reacting mixtures of LiH and Pt in the presence of BH 3 NH 3 as hydrogen source at pressures above 8 GPa. According to powder X-ray diffraction analysis, Li 2 PtH 6 is isostructural to its heavier homologues and crystallizes in the cubic K 2 PtCl 6 structure (space group Fm 3¯ m , a =6.7681(3), Z =4). However, PtH 6 2− octahedral complexes in Li 2 PtH 6 approach each other closely and its structure may likewise be regarded as a defective perovskite structure where half of the octahedrally coordinated atoms (cations) are missing. The IR spectrum of Li 2 PtH 6 reveals the Pt–H T 1u stretch and bend at 1840 and 889 cm −1 , respectively.

Background: Non-invasive tools that measure the activity of central oncogenes could be broadly useful for cancer detection and management. We have shown that radiolabeled transferrin molecules can be used to measure mTORC1 and MYC signaling in prostate cancer models, because the transferrin receptor is a MYC target gene. The purpose of this study was to complete the preclinical assessment of 89Zr-transferrin, as well as demonstrate that clinical disease harbors avidity for transferrin using 68Ga-citrate. Methods: Human prostate cancer cell lines have been manipulated pharmacologically and genetically to alter mTORC1 and/or MYC signaling, and radiolabeled transferrin has been used to study the impact of aberrant oncogene signaling on transferrin biology. A first in man study with 68Ga-transferrin PET was also performed at UCSF using a GE SIGNA PET/MR. A dose escalation study was performed in eight patients with castration resistant prostate cancer to identify the optimal signal to noise ratio. Results: Activation of mTORC1 or MYC resulted in higher transferrin receptor expression and higher transferrin uptake into cells, as expected. Pharmacological inhibition of either oncogene suppressed transferrin uptake in vitro and in vivo. 68Ga-transferrin PET/MR resolved ~75% of lesions that were detectable by CT or bone scan. Approximately 4 mCi and >3.5 hours post injection was required to visualize tumor lesions. Conclusions: These experiments establish that like MYC, mTOR activity can be quantified in prostate cancer models with 89Zr-transferrin. Moreover, our first in human study with 68Ga-transferrin shows that human disease is generally avid for the radiotracer, but the uptake is variable among lesions, consistent with a molecularly diverse disease. Citation Format: Michael J. Evans, Charles Truillet, Davide Ruggero, Jason S. Lewis, Rahul Aggarwal, Spencer C. Behr. Measuring oncogene signaling with transferrin-based PET: From bench to bedside [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3694.

The quaternary aluminium hydrides SrAlGeH and BaAlGeH were synthesized from either hydrogenating the intermetallic AlB2-type precursors SrAlGe and BaAlGe or reacting SrH2 with a mixture of Al and G ...

Vibrational properties of the gallium monohydrides SrGaGeH, BaGaSiH, BaGaGeH, and BaGaSnH (AeGaTtH) have been investigated by means of inelastic neutron scattering (INS) and first principles calculations. The compounds contain separated Ga–H units being part of a two dimensional polyanionic layer, [TtGaH]2− (Tt=Si, Ge, Sn). The INS spectra show internal Ga–H bending and stretching modes at frequencies around 900 and 1200 cm−1, respectively. While the stretching mode is virtually invariant with respect to the variable chemical environment of the Ga–H unit, the bending mode frequency varies and is highest for BaGaSiH and lowest for BaGaSnH. The stretching mode is a direct measure of the Ga–H bond strength, whereas the bending mode reflects indirectly the strength of alkaline earth metal–hydrogen interaction. Accordingly, the terminal Ga–H bond in solid state AeGaTtH is distinct, but—compared to molecular gallium hydrides—very weak.

Asthma is a worldwide health problem that affects 300 million people, as estimated by the World Health Organization. A key question in light of this statistic is: “what is the most appropriate laboratory animal model for human asthma?” The present authors used stereological methods to assess airways in adults and during post-natal development, and their response to inhaled allergens to compare rodents and nonhuman primates to responses in humans. An epithelial–mesenchymal trophic unit was defined in which all of the compartments interact with each other. Asthma manifests itself by altering not only the epithelial compartment but also other compartments ( e.g. interstitial, vascular, immunological and nervous). All of these compartments show significant alteration in an airway generation-specific manner in rhesus monkeys but are limited to the proximal airways in mice. The rhesus monkey model shares many of the key features of human allergic asthma including the following: 1) allergen-specific immunoglobulin (Ig)E and skin-test positivity; 2) eosinophils and IgE+ cells in airways; 3) a T-helper type 2 cytokine profile in airways; 4) mucus cell hyperplasia; 5) subepithelial fibrosis; 6) basement membrane thickening; and 7) persistent baseline hyperreactivity to histamine or methacholine. In conclusion, the unique responses to inhaled allergens shown in rhesus monkeys make it the most appropriate animal model of human asthma.

Inner city children exposed to high levels of ozone suffer from an increased prevalence of respiratory diseases. Lung development in children is a long-term process, and there is a significant period of time during development when children growing up in urban areas are exposed to oxidant air pollution. This study was designed to test whether repeating cycles of injury and repair caused by episodes of ozone exposure lead to chronic airway disease and decreased lung function by altering normal lung maturation. We evaluated postnatal lung morphogenesis and function of infant monkeys after 5 mo of episodic exposure of 0.5 parts per million ozone beginning at 1 mo of age. Nonhuman primates were chosen because their airway structure and postnatal lung development is similar to those of humans. Airway morphology and structure were evaluated at the end of the 5-mo exposure period. Compared with control infants, ozone-exposed animals had four fewer nonalveolarized airway generations, hyperplastic bronchiolar epithelium, and altered smooth muscle bundle orientation in terminal and respiratory bronchioles. These results suggest that episodic exposure to environmental ozone compromises postnatal morphogenesis of tracheobronchial airways.