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After several decades of sustained increase, hydrogen chloride (HCl, the main reservoir forstratospheric chlorine) reached a maximum abundance around 1997. Since then, its decreasehas been documented, characterized by short-term variability which was attributed toatmospheric circulation changes, affecting mainly the lower stratosphere (Mahieu et al.,2014). This notably led to a temporary increase of HCl over 2007-2011, complicating thedetermination of the long-term HCl trend and the accurate verification of the success of theMontreal Protocol for the protection of the stratospheric ozone layer. Studies haveused other long-lived tracers to remove the effects of dynamical variability in thelower stratosphere (e.g., Stolarski et al., 2018), while other investigations havesuggested that trends in the upper stratosphere were potentially more appropriate forthe long-term characterization of the HCl decrease (e.g., Froidevaux et al., 2015;Bernath and Fernando, 2018), especially when dealing with satellite height-resolveddata. In this contribution, we use FTIR (Fourier Transform InfraRed) data from theJungfraujoch station (Swiss Alps, 3580 m a.s.l.), a site of the NDACC network(http://www.ndacc.org), to study the evolution of HCl in some detail. The SFIT-4 retrievalalgorithm implementing the Optimal Estimation Method of Rodgers (2000) is employed,providing HCl columns with good sensitivity from the tropopause up to about 40 km altitude.Moreover, the vertical resolution is sufficient to determine independent partial columns forthe lower and upper stratosphere. With the support of model simulations performed with the 3D-Chemistry TransportModel of the Belgian Assimilation System for Chemical ObsErvations (BASCOE; Chabrillatet al., 2018), driven by the ERA-Interim meteorological reanalysis, we investigate thepost-peak trend of HCl in the lower and upper stratosphere. We also determine the magnitudeof the uncertainties affecting the various trends, using bootstrap tools which are specificallydeveloped to take into account the auto-correlation present in our geophysical datasets. Acknowledgments This research has been primarily supported by the F.R.S. – FNRS (Brussels), underGrants T.0040.16 and J.0147.18. The vital supports from the Fédération Wallonie Bruxellesand the Swiss GAW-CH programme are further acknowledged. We thank the InternationalFoundation High Altitude Research Stations Jungfraujoch and Gornergrat (HFSJG, Bern) forsupporting the facilities needed to perform the observations. We gratefully acknowledgesupport by the Deutsche Forschungsgemeinschaft DFG within the SFB/Transregio 172(AC)3. References Bernath, P. and Fernando, A. M.: Trends in stratospheric HCl from the ACE satellitemission, J. Quant. Spectrosc. Radiat. Transf., 217, 126–129, doi:10.1016/j.jqsrt.2018.05.027,2018. Chabrillat, S., Vigouroux, C., Christophe, Y., et al.: Comparison of mean age of air in fivereanalyses using the BASCOE transport model, Atmos. Chem. Phys., 18(19), 14715–14735,doi:10.5194/acp-18-14715-2018, 2018. Froidevaux, L., Anderson, J., Wang, H. J., et al.: Global OZone Chemistry and Relatedtrace gas Data records for the Stratosphere (GOZCARDS): Methodology and sample resultswith a focus on HCl, H2O, and O3, Atmos. Chem. Phys., 15(18), 10471–10507,doi:10.5194/acp-15-10471-2015, 2015. Mahieu, E., Chipperfield, M. P., Notholt, J., et al.: Recent Northern Hemispherestratospheric HCl increase due to atmospheric circulation changes, Nature, 515(7525),104–107, doi:10.1038/nature13857, 2014. Rodgers, C.D.: Inverse methods for atmospheric sounding: theory and practice (Series onatmospheric, oceanic and planetary physics), Vol. 2. Singapore, 2000. Stolarski, R. S., Douglass, A. R. and Strahan, S. E.: Using satellite measurements of N2Oto remove dynamical variability from HCl measurements, Atmos. Chem. Phys., 18(8),5691–5697, doi:10.5194/acp-18-5691-2018, 2018. [ABSTRACT FROM AUTHOR]

Long-lived tracer concentrations in the lower stratosphere are affected by short time scale circulation variability as highlighted by recent papers (e.g., Mahieu et al., 2014). Many tracers, such as hydrogen chloride (HCl) or hydrogen fluoride (HF) have now been successfully used to investigate or identify this variability (e.g., Harrison et al., 2016).In this work, the main reservoirs of inorganic fluorine [i.e., HF, carbonyl fluoride (COF2) and carbonyl chloride fluoride (COClF)] and their sum (total inorganic fluorine, Fy) are used to investigate the lower stratospheric circulation changes. We use Fourier Transform InfraRed (FTIR) ground-based observations conducted in the framework of the NDACC network (http://www.ndacc.org) to derive column abundances of HF and COF2, thus providing a good proxy for Fy. To support this research, we also include satellite observations from HALOE (HF available) and ACE-FTS (HF, COF2 and COClF available). Moreover, we use the Chemical-Transport Model (CTM) BASCOE (Belgian Assimilation System for Chemical ObsErvations; Chabrillat et al., 2018) to evaluate the representation of the investigated circulation changes in state-of-the-art meteorological reanalyses. We also evaluate if WACCM4 (Whole Atmosphere Community Climate Model version 4) is able to reproduce these changes through a free dynamics and free chemistry run. Finally, SLIMCAT CTM (Chipperfield et al., 2015) simulations are included to provide information on the partitioning between the main Fy reservoirs.ReferencesChabrillat, S., Vigouroux, C., Christophe, Y., et al.: Comparison of mean age of air in five reanalyses using the BASCOE transport model, Atmos. Chem. Phys., 18(19), 14715–14735, doi:10.5194/acp-18-14715-2018, 2018.Chipperfield, M. P., Dhomse, S. S., Feng, W., et al.: Quantifying the ozone and ultraviolet benefits already achieved by the Montreal Protocol, Nature Communications, 6(7233), 1-8, https://doi.org/10.1038/ncomms8233, 2015Harrison, J. J., Chipperfield, M. P., Boone, et al.: Satellite observations of stratospheric hydrogen fluoride and comparisons with SLIMCAT calculations, Atmos. Chem. Phys., 16(16), 10501–10519, doi:10.5194/acp-16-10501-2016, 2016.Mahieu, E., Chipperfield, M. P., Notholt, J., et al.: Recent Northern Hemisphere stratospheric HCl increase due to atmospheric circulation changes, Nature, 515(7525), 104–107, doi:10.1038/nature13857, 2014. [ABSTRACT FROM AUTHOR]

The article focuses on a study related to lymphangiogenesis in melanoma during pregnancy in correlation with the prolactin signalling pathway. The study states that the computer-assisted morphometric analysis showed increase in the lymphatic vessels of pregnant women. The study concludes that the lymphatic vessel relative surface area at the periphery of the tumor is high in pregnant patients with melanoma compared to non-pregnant women.

Background: c-MET is a transmembrane receptor involved in many biological processes and contributes to cell proliferation and migration during cancer invasion process. Its expression is measured by immunehistochemistry on tissue biopsy in clinic, although this technique has its limitations. PET-CT could allow in vivo mapping of lesions expressing c-MET, providing whole-body detection. A number of radiopharmaceuticals are under development for this purpose but are not yet in routine clinical use. EMP100 is a cyclic oligopeptide bound to a DOTA chelator, with nanomolar affinity for c-MET. The aim of this project was to develop an automated method for radiolabelling the radiopharmaceutical [68Ga]Ga-EMP100. Results: The main results showed an optimal pH range between 3.25 and 3.75 for the complexation reaction and a stabilisation of the temperature at 90 °C, resulting in an almost complete incorporation of gallium-68 after 10 min of heating. In these experiments, 90 µg of EMP-100 peptide were initially used and then lower amounts (30, 50, 75 µg) were explored to determine the minimum required for sufficient synthesis yield. Radiolysis impurities were identified by radio-HPLC and ascorbic acid and ethanol were used to improve the purity of the compound. Three batches of [68Ga]Ga-EMP100 were then prepared according to the optimised parameters and all met the established specifications. Finally, the stability of [68Ga]Ga-EMP100 was assessed at room temperature over 3 h with satisfactory results in terms of appearance, pH, radiochemical purity and sterility. Conclusions: For the automated synthesis of [68Ga]Ga-EMP100, the parameters of pH, temperature, precursor peptide content and the use of adjuvants for impurity management were efficiently optimised, resulting in the production of three compliant and stable batches according to the principles of good manufacturing practice. [68Ga]Ga-EMP100 was successfully synthesised and is now available for clinical development in PET-CT imaging. [ABSTRACT FROM AUTHOR]

Total columns of the trace gases nitric acid (HNO3) and hydrogen chloride (HCl) are sensitive to variations in the lower stratospheric age of air, a quantity that describes transport time scales in the stratosphere. Analyses of HNO3 and HCl columns from the Network for the Detection of Atmospheric Composition Change panning 77°S to 79°N have detected changes in the extratropical stratospheric transport circulation from 1994 to 2018. The HNO3 and HCl analyses combined with the age of air from a simulation using the MERRA2 reanalysis show that the Southern Hemisphere lower stratosphere has become 1 month/decade younger relative to the Northern Hemisphere, largely driven by the Southern Hemisphere transport circulation. The analyses reveal multiyear anomalies with a 5‐ to 7‐year period driven by interactions between the circulation and the quasi‐biennial oscillation in tropical winds. This hitherto unrecognized variability is large relative to hemispheric transport trends and may bias ozone trend regressions. Plain Language Summary: Our analyses of the 25‐year Network for the Detection of Atmospheric Composition Change column HNO3 and HCl data records from nine stations provide observational evidence that air in the Southern Hemisphere lower stratosphere has been getting younger relative to the Northern Hemisphere at a rate of 1 month/decade since 1994. This stands in contrast to several model studies that predict that Antarctic ozone hole recovery in this century will increase the Southern Hemisphere age of air relative to the Northern Hemisphere. The analyses also reveal extratropical variability with a 5‐ to 7‐year period driven by interactions between the circulation and tropical winds. This previously unrecognized, low‐frequency variability is much larger than hemispheric transport trends and is likely to cause bias in trends calculated using data records shorter than about two decades. Understanding and quantifying changes in the transport circulation matters to our ability to model how our protective O3 layer will evolve in the future. Key Points: Trace gas data show southern stratospheric air is getting younger relative to the Northern Hemisphere, in contrast to model predictionsBoth extratropical hemispheres have dynamically driven 5‐ to 7‐year periodicity with large amplitude relative to the age trendMultidecadal data sets are required to quantify transport trends that are not confounded by large extratropical variability [ABSTRACT FROM AUTHOR]

Peptide-based imaging agents targeting prostate-specific membrane antigen (PSMA) have revolutionized the evaluation of biochemical recurrence of prostate cancer (PCa) but lacks sensitivity at very low serum prostate specific antigen (PSA) levels. Once recurrence is suspected, other positron emission tomography (PET) radiotracers could be of interest to discriminate between local and distant relapse. We studied 18F]fluorodeoxyglucose (18F]FDG) targeting glucose metabolism, 18F]fluorocholine (18F]FCH) targeting membrane metabolism and peptide-based imaging agents 68Ga]Ga-PSMA-11, 68Ga]Ga-AMBA, 68Ga]Ga-NODAGA-RGD and 68Ga]Ga-DOTA-NT-20.3 targeting PSMA, gastrin releasing peptide receptor (GRPr), αvβ3 integrin and neurotensin type 1 receptor (NTSR1) respectively, in different PCa tumour models. Mice were xenografted with 22Rv1, an androgen-receptor (AR)-positive, PCa cell line that expresses PSMA and PC3, an AR-negative one that does not express PSMA. PET imaging using the different radiotracers was performed sequentially and the uptake characteristics compared to one other. NTSR1 and PSMA expression levels were analysed in tumours by immunohistochemistry. 18F]FDG displayed low but sufficient uptake to visualize PC3 and 22Rv1 derived tumours. We also observed a low efficacy of 18F]FCH PET imaging and a low 68Ga]Ga-NODAGA-RGD tumour uptake in those tumours. As expected, an elevated tumour uptake was obtained for 68Ga]Ga-PSMA-11 in 22Rv1 derived tumour although no uptake was measured in the androgen independent cell line PC3, derived from a bone metastasis of a high-grade PCa. Moreover, in PC3 cell line, we obtained good tumour uptake, high tumour-to-background contrast using 68Ga]Ga-AMBA and 68Ga]Ga-DOTA-NT-20.3. Immunohistochemistry analysis confirmed high NTSR1 expression in PC3 derived tumours and conversely high PSMA expression in 22Rv1 derived tumours. PET imaging using 68Ga]Ga-AMBA and 68Ga]Ga-DOTA-NT-20.3 demonstrates that GRPr and NTSR1 could represent viable alternative targets for diagnostic or therapeutic applications in PCa with limited PSMA expression levels. More preclinical and clinical studies will follow to explore this potential. Peptide-based imaging agents targeting PSMA represent a major progress in the evaluation of biochemical recurrence of PCa but sometimes yield false negative results in some lesions. Continuing efforts have thus been made to evaluate other radiotracers. Our preclinical results suggest that 68Ga]labelled bombesin and neurotensin analogues could serve as alternative PET radiopharmaceuticals for diagnostic or therapy in cases of PSMA-negative PCa. [ABSTRACT FROM AUTHOR]

A multi-step procedure has been described which afforded satisfactory yields of N,N′ -disubstituted cinnamamides derived from N -Boc-protected amino acids (Boc-Gly, Boc-Val, Boc-Phe). The key step of this synthesis was a regioselective RedAl reduction of an amide function in presence of a carbamate group. Next, these cinnamamides were evaluated in co-admnistration with ciprofloxacin as efflux pump inhibitors against two S. aureus strains, NorA overexpressing SA1199B and wild type SA1199. In parallel, their intrinsic toxicity was appreciated on human lung fibroblast MRC5 cells. Therefore, the cinnamamide combining both carbamate and indol-3-yl groups, was found to be the most active and one of the less toxic EPI and constituted a promising hit. [ABSTRACT FROM AUTHOR]

Bivalent ligands, i.e., molecules having two ligands covalently connected by a linker, have been gathering attention since the first description of their pharmacological potential in the early 80s. However, their synthesis, particularly of labeled heterobivalent ligands, can still be cumbersome and time-consuming. We herein report a straightforward procedure for the modular synthesis of labeled heterobivalent ligands (HBLs) using dual reactive 3,6-dichloro-1,2,4,5-tetrazine as a starting material and suitable partners for sequential S N Ar and inverse electron-demand Diels-Alder (IEDDA) reactions. This assembly method conducted in a stepwise or in a sequential one-pot manner provides quick access to multiple HBLs. A conjugate combining ligands toward the prostate-specific membrane antigen (PSMA) and the gastrin-releasing peptide receptor (GRPR) was radiolabeled, and its biological activity was assessed in vitro and in vivo (receptor binding affinity, biodistribution, imaging) as an illustration that the assembly methodology preserves the tumor targeting properties of the ligands., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

Neurotensin receptor 1 (NTS 1 ) is involved in the development and progression of numerous cancers, which makes it an interesting target for the development of diagnostic and therapeutic agents. A small molecule NTS 1 antagonist, named [ 177 Lu]Lu-IPN01087, is currently evaluated in phase I/II clinical trials for the targeted therapy of neurotensin receptor-positive cancers. In this study, we synthesized seven compounds based on the structure of NTS 1 antagonists, bearing different chelating agents, and radiolabeled them with gallium-68 for PET imaging. These compounds were evaluated in vitro and in vivo in mice bearing a HT-29 xenograft. The compound [ 68 Ga]Ga-bisNODAGA- 16 showed a promising biodistribution profile with mainly signal in tumor (4.917 ± 0.776%ID/g, 2 h post-injection). Its rapid clearance from healthy tissues led to high tumor-to-organ ratios, resulting in highly contrasted PET images. These results were confirmed on subcutaneous xenografts of AsPC-1 tumor cells, a model of NTS 1 -positive human pancreatic adenocarcinoma.

Objective: Macrophage activation by monosodium urate (MSU) and calcium pyrophosphate (CPP) crystals mediates an interleukin (IL)-1β-dependent inflammation during gout and pseudo-gout flare, respectively. Since metabolic reprogramming of macrophages goes along with inflammatory responses dependently on stimuli and tissue environment, we aimed to decipher the role of glycolysis and oxidative phosphorylation in the IL-1β-induced microcrystal response., Methods: Briefly, an in vitro study (metabolomics and real-time extracellular flux analysis) on MSU and CPP crystal-stimulated macrophages was performed to demonstrate the metabolic phenotype of macrophages. Then, the role of aerobic glycolysis in IL-1β production was evaluated, as well in vitro as in vivo using 18 F-fluorodeoxyglucose positron emission tomography imaging and glucose uptake assay, and molecular approach of glucose transporter 1 (GLUT1) inhibition., Results: We observed that MSU and CPP crystals led to a metabolic rewiring toward the aerobic glycolysis pathway explained by an increase in GLUT1 plasma membrane expression and glucose uptake on macrophages. Also, neutrophils isolated from human synovial fluid during gout flare expressed GLUT1 at their plasma membrane more frequently than neutrophils isolated from bloodstream. Both glucose deprivation and treatment with either 2-deoxyglucose or GLUT1 inhibitor suppressed crystal-induced NLRP3 activation and IL-1β production, and microcrystal inflammation in vivo., Conclusion: In conclusion, we demonstrated that GLUT1-mediated glucose uptake is instrumental during the inflammatory IL-1β response induced by MSU and CPP crystals. These findings open new therapeutic paths to modulate crystal-related inflammation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background & Aims: In one-third of hepatocellular carcinomas (HCCs), cancer cells have mutations that activate β-catenin pathway. These cells have alterations in glutamine, bile, and lipid metabolism. We investigated whether positron emission tomography (PET) imaging allows identification of altered metabolic pathways that might be targeted therapeutically., Methods: We studied mice with activation of β-catenin in liver (Apc ko-liv mice) and male C57Bl/6 mice given injections of diethylnitrosamine, which each develop HCCs. Mice were fed a conventional or a methionine- and choline-deficient diet or a choline-deficient (CD) diet. Choline uptake and metabolism in HCCs were analyzed by micro-PET imaging of mice; livers were collected and analyzed by histologic, metabolomic, messenger RNA quantification, and RNA-sequencing analyses. Fifty-two patients with HCC underwent PET imaging with 18 F-fluorodeoxyglucose, followed by 18 F-fluorocholine tracer metabolites. Human HCC specimens were analyzed by immunohistochemistry, quantitative polymerase chain reaction, and DNA sequencing. We used hepatocytes and mouse tumor explants for studies of incorporation of radiolabeled choline into phospholipids and its contribution to DNA methylation. We analyzed HCC progression in mice fed a CD diet., Results: Livers and tumors from Apc ko-liv mice had increased uptake of dietary choline, which contributes to phospholipid formation and DNA methylation in hepatocytes. In patients and in mice, HCCs with activated β-catenin were positive in 18 F-fluorocholine PET, but not 18 F-fluorodeoxyglucose PET, and they overexpressed the choline transporter organic cation transporter 3. The HCC cells from Apc ko-liv mice incorporated radiolabeled methyl groups of choline into phospholipids and DNA. In Apc ko-liv  mice, the methionine- and choline-deficient diet reduced proliferation and DNA hypermethylation of hepatocytes and HCC cells, and the CD diet reduced long-term progression of tumors., Conclusions: In mice and humans, HCCs with mutations that activate β-catenin are characterized by increased uptake of a fluorocholine tracer, but not 18 F-fluorodeoxyglucose, revealed by PET. The increased uptake of choline by HCCs promotes phospholipid formation, DNA hypermethylation, and hepatocyte proliferation. In mice, the CD diet reverses these effects and promotes regression of HCCs that overexpress β-catenin., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)