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A characterization of the magnetic properties of amorphous Co40Fe40B20 thin films, developed for low damping applications in magnon spintronics, using vector network analyzer ferromagnetic resonance (VNA-FMR) and the magneto-optical Kerr effect is presented. Our films show a very weak uniaxial anisotropy and a low Gilbert damping parameter (α=0.0042). The saturation magnetization MS extracted from the FMR measurements is 1250 kA/m. The frequency dependence of the first perpendicular standing spin waves mode on the applied magnetic field is used to determine the exchange constant A for this alloy resulting in a value of 1.5×10-11 J/m. These values are discussed in comparison to literature values for different CoFeB compositions and other related alloys. [ABSTRACT FROM AUTHOR]

Adequate primary stability is a pre-requisite for the osseointegration and long-term success of dental implants. Primary stability depends essentially on the bone mechanical integrity at the implantation site. Clinically, a qualitative evaluation can be made on medical images, but finite element (FE) simulations can assess the primary stability of a bone-implant construct quantitatively based on high-resolution CT images. However, FE models lack experimental validation on clinically relevant bone anatomy. The aim of this study is to validate such an FE model on human jawbones. Forty-seven bone biopsies were extracted from human cadaveric jawbones. Dental implants of two sizes (Ø3.5 mm and Ø4.0 mm) were inserted and the constructs were subjected to a quasi-static bending-compression loading protocol. Those mechanical tests were replicated with sample-specific non-linear homogenized FE models. Bone was modeled with an elastoplastic constitutive law that included damage. Density-based material properties were mapped based on μCT images of the bone samples. The experimental ultimate load was better predicted by FE (R 2  = 0.83) than by peri-implant bone density (R 2  = 0.54). Unlike bone density, the simulations were also able to capture the effect of implant diameter. The primary stability of a dental implant in human jawbones can be predicted quantitatively with FE simulations. This method may be used for improving the design and insertion protocols of dental implants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Radioimmunotherapy (RIT) is a promising alternative to conventional treatment options. Here, we present experimental work on the synthesis, radiochemistry, and in vivo performance of a lanthanoid-selective nonadentate bispidine ligand suitable for 177 Lu 3+ ion complexation. The ligand (bisp,1) was derivatised with a photoactivatable aryl azide (ArN 3 ) group as a bioconjugation handle for light-induced labelling of proteins. Quantitative radiosynthesis of [ 177 Lu]Lu-1 + was accomplished in 10 minutes at 40 °C. Subsequent incubation of [ 177 Lu]Lu-1 + with trastuzumab, followed by irradiation with light at 365 nm for 15 min, at room temperature and pH 8.0-8.3, gave the radiolabelled mAb, [ 177 Lu]Lu-1-azepin-trastuzumab ([ 177 Lu]Lu-1-mAb) in a decay-corrected radiochemical yield of 14 %, and radiochemical purity (RCP)>90 %. Stability studies and cellular binding assays in vitro using the SK-OV-3 human ovarian cancer cells confirmed that [ 177 Lu]Lu-1-mAb remained biological active and displayed specific binding to HER2/neu. Experiments in immunocompromised female athymic nude mice bearing subcutaneous xenograft models of SK-OV-3 tumours revealed significantly higher tumour uptake in the normal group compared with the control block group (29.8±11.4 %ID g -1 vs. 14.8±6.1 %ID g -1 , respectively; P-value=0.037). The data indicate that bispidine-based ligand systems are suitable starting points for constructing novel, high-denticity chelators for specific complexation of larger radiotheranostic metal ion nuclides., (© 2023 Wiley-VCH GmbH.)

The front cover artwork is provided by the Institute of Analytical and Bioanalytical Chemistry and the Institute of Inorganic Chemistry I at Ulm University within the Collaborative Research Center TRR 234 CataLight. The image shows an algebraic approach to generically calculate and predict the turnover number (TON) and the endpoint of photocatalytic hydrogen gas evolution experiments. Read the full text of the Research Article at 10.1002/cphc.202300767., (© 2024 Wiley-VCH GmbH.)

Currently, most photosensitizers and catalysts used in the field of artificial photosynthesis are still based on rare earth metals and should thus be utilized as efficiently and economically as possible. While repair of an inactivated catalyst is a potential mitigation strategy, this remains a challenge. State-of-the-art methods are crucial for characterizing reaction products during photocatalysis and repair, and are currently based on invasive analysis techniques limiting real-time access to the involved mechanisms. Herein, we use an innovative in situ technique for detecting both initially evolved hydrogen and after active repair via advanced non-invasive rotational Raman spectroscopy. This facilitates unprecedently accurate monitoring of gaseous reaction products and insight into the mechanism of active repair during light-driven catalysis enabling the identification of relevant mechanistic details along with innovative repair strategies., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Objectives: To retrospectively evaluate all cone-beam computed tomography (CBCT) scans acquired from 2017 to 2022 in a Swiss university dental clinic with particular emphasis on radiation protection aspects., Material and Methods: Radiological databases at the dental clinic of the University of Bern, Switzerland, were explored using a self-developed search algorithm. Data of all acquired CBCT from 01.01.2017 to 27.06.2022 were screened. Exposure parameters (exposure time, exposure angle, milliampere (mA), kilovoltage (kV), field of view (FOV) size), dose area product (DAP), age, and sex of the patient were recorded anonymously. The collected data were analyzed mainly descriptively. Correlations measured the statistical relationships between the variables., Results: A total of 10,348 CBCT datasets were analyzed. Patient age ranged from 5 to 96 years (mean: 49.4 years, SD: 21.6 years). The number of CBCTs in patients under 25 years was around 20% each year. In total, 10,313 (99.7%) CBCTs were acquired in small to medium FOV (FOV up to 10 cm of height), and 35 (0.3%) in large FOV (height > 10 cm). DAPs of small FOVs were 518.3 ± 233.2 mGycm 2 (mean ± SD), of medium FOV 1233 ± 502.2 mGycm 2 , and of large FOV 2189 ± 368.7 mGycm 2 . DAP (ρ = 0.4048, p < 0.0001) and kV (ρ = 0.0210, p = 0.0327) correlated positively with age. Reduced scan angle correlated with young age (r pb 0.2729, p < 0.001). mA did not correlate with age (p = 0.3685)., Conclusions: This study demonstrates that certain well-known radiation protection aspects as the reduction of FOV, mA, kV, and scan angle were only partly considered., Clinical Relevance: Known radiation protection aspects, especially in young patients, should be fully applied in regular clinical practice., (© 2023. The Author(s).)

E-scooters have gained popularity worldwide in the last few years. Due to the increase in users, more accidents related to e-scooters can be observed. The present study aimed to analyse epidemiological data, characteristics, and severity of injuries in patients admitted to a Level I trauma centre in Switzerland (Inselspital Bern, University Hospital Bern) after accidents associated with e-scooters. This retrospective case series evaluated 23 patients who presented to the University Hospital of Bern between 1 of May 2019 and 31 of October 2021 after an e-scooter accident. Data were collected on patient demographics, time and cause of the accident, speed, alcohol consumption, helmet use, type and localisation of injury, number of injuries per patient, and outcome. Men were most frequently affected (61.9%). The mean age was 35.8 (STD 14.8) years. Slightly more than half (52.2%) of all accidents were self-inflicted. Most accidents were reported during the night (7 p.m. to 7 a.m., 60.9%) and in summer (43.5%). Alcohol consumption was reported in 43.5% of cases, with a mean blood alcohol level of 1.4 g/l. Most injuries were observed in the face (25.3%) and head/neck area (20.25%). Skin abrasions (56.5%) and traumatic brain injury (43.5%) were the most common types of traumata in terms of total number of patients. Only in one case it was reported that a protective helmet had been worn. Five patients required hospitalisation and four patients underwent surgery. Three patients underwent emergency orthopaedic surgery, and one patient underwent emergency neurosurgery. E-scooter accidents result in a significant number of facial and head/neck injuries. E-scooter riders would potentially benefit from a helmet to protect them in the event of an accident. Additionally, the results of this study indicate that a significant number of e-scooter accidents in Switzerland occurred under the influence of alcohol. Prevention campaigns to raise awareness of the risks of driving e-scooters under the influence of alcohol could help prevent future accidents.

Functional studies of primary cancer have been limited to animal models for a long time making it difficult to study aspects specific to human cancer biology. The development of organoid technology enabled us to culture human healthy and tumor cells as three-dimensional self-organizing structures in vitro for a prolonged time. Organoid cultures conserve the heterogeneity of the originating epithelium regarding cell types and tumor clonality. Therefore, organoids are considered an invaluable tool to study and genetically dissect various aspects of human cancer biology. In this review, we describe the applications, advantages, and limitations of organoids as human cancer models with the main emphasis on colorectal cancer.

Background/aims: It is unknown whether cancer stem cells respond differentially to treatment compared with progeny, potentially providing therapeutic vulnerabilities. Our program pioneered use of ultra-high single dose radiotherapy, which cures diverse metastatic diseases at a higher rate (90-95%) than conventional fractionation (~65%). Single dose radiotherapy engages a distinct biology involving microvascular acid sphingomyelinase/ceramide signaling, which, via NADPH oxidase-2-dependent perfusion defects, initiates an adaptive tumor SUMO Stress Response that globally-inactivates homologous recombination repair of double stand breaks, conferring cure. Accumulating data show diverse stem cells display heightened-dependence on homologous recombination repair to repair resolve double stand breaks., Methods: Here we use colorectal cancer patient-derived xenografts containing logarithmically-increased Lgr5+ stem cells to explore whether optimizing engagement of this acid sphingomyelinase dependent biology enhances stem cell dependent tumor cure., Results: We show radioresistant colorectal cancer patient-derived xenograft CLR27-2 contains radioresistant microvasculature and stem cells, whereas radiosensitive colorectal cancer patient-derived xenograft CLR1-1 contains radiosensitive microvasculature and stem cells. Pharmacologic or gene therapy enhancement of single dose radiotherapy-induced acid sphingomyelinase/ceramide-mediated microvascular dysfunction dramatically sensitizes CLR27-2 homologous recombination repair inactivation, converting Lgr5+ cells from the most resistant to most sensitive patient-derived xenograft population, yielding tumor cure., Conclusion: We posit homologous recombination repair represents a vulnerability determining colorectal cancer stem cell fate, approachable therapeutically using single dose radiotherapy., Competing Interests: Patents unrelated to this work: RK (US7195775B1, US7850984B2, US10052387B2, US10414533B2, US20140205543A1), RK/JAR (US8562993B2, US9592238B2, US10450385B2, US20150216971A1, US20170335014A1, US20190389970A1, US20190046538A1), RK/ZF (US20170333413A1, US20180015183A1), ZF (US10413533B2). RK/ZF are co-founders of Ceramedix Holding L.L.C. The remaining authors have declared that no conflicts of interest exist., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)

This work elaborates the effect of dynamic irradiation on light-driven molecular water oxidation to counteract deactivation. It highlights the importance of overall reaction engineering to overcome limiting factors in artificial photosynthesis reactions. Systematic investigation of a homogeneous three-component ruthenium-based water oxidation system revealed significant potential to enhance the overall catalytic efficiency by synchronizing the timescales of photoreaction and mass transport in a capillary flow reactor. The overall activity could be improved by a factor of more than 10 with respect to the turnover number and a factor of 31 referring to the external energy efficiency by controlling the local availability of photons. Detailed insights into the mechanism of light driven water oxidation could be obtained using complementary methods of investigation like Raman, IR, and UV/Vis/emission spectroscopy, unraveling the importance of avoiding high concentrations of excited photosensitizers., (© 2022 The Authors. ChemSusChem published by Wiley-VCH GmbH.)

Identifying colorectal cancer patient populations responsive to chemotherapy or chemoradiation therapy before surgery remains a challenge. Recently validated mouse protocols for organoid irradiation employ the single hit multi-target (SHMT) algorithm, which yields a single value, the D0, as a measure of inherent tissue radiosensitivity. Here, we translate these protocols to human tissue to evaluate radioresponsiveness of patient-derived organoids (PDO) generated from normal human intestines and rectal tumors of patients undergoing neoadjuvant therapy. While PDOs from adenomas with a logarithmically expanded Lgr5+ intestinal stem cell population retain the radioresistant phenotype of normal colorectal PDOs, malignant transformation yields PDOs from a large patient subpopulation displaying marked radiosensitivity due to reduced homologous recombination-mediated DNA repair. A proof-of-principle pilot clinical trial demonstrated that rectal cancer patient responses to neoadjuvant chemoradiation, including complete response, correlate closely with their PDO D0 values. Overall, upon transformation to colorectal adenocarcinoma, broad radiation sensitivity occurs in a large subset of patients that can be identified using SHMT analysis of PDO radiation responses., Significance: Analysis of inherent tissue radiosensitivity of patient-derived organoids may provide a readout predictive of neoadjuvant therapy response to radiation in rectal cancer, potentially allowing pretreatment stratification of patients likely to benefit from this approach., (©2022 American Association for Cancer Research.)

Recent data establish a logarithmic expansion of leucine rich repeat containing G protein coupled receptor 5-positive (Lgr5+) colonic epithelial stem cells (CESCs) in human colorectal cancer (CRC). Complementary studies using the murine 2-stage azoxymethane-dextran sulfate sodium (AOM-DSS) colitis-associated tumor model indicate early acquisition of Wnt pathway mutations drives CESC expansion during adenoma progression. Here, subdivision of the AOM-DSS model into in vivo and in vitro stages revealed DSS induced physical separation of CESCs from stem cell niche cells and basal lamina, a source of Wnt signals, within hours, disabling the stem cell program. While AOM delivery in vivo under non-adenoma-forming conditions yielded phenotypically normal mucosa and organoids derived thereof, niche injury ex vivo by progressive DSS dose escalation facilitated outgrowth of Wnt-independent dysplastic organoids. These organoids contained 10-fold increased Lgr5+ CESCs with gain-of-function Wnt mutations orthologous to human CRC driver mutations. We posit CRC originates by niche injury-induced outgrowth of normally suppressed mutated stem cells, consistent with models of adaptive oncogenesis.

The creation of discrete, covalent bonds between a protein and a functional molecule like a drug, fluorophore, or radiolabeled complex is essential for making state-of-the-art tools that find applications in basic science and clinical medicine. Photochemistry offers a unique set of reactive groups that hold potential for the synthesis of protein conjugates. Previous studies have demonstrated that photoactivatable desferrioxamine B (DFO) derivatives featuring a para-substituted aryl azide (ArN 3 ) can be used to produce viable zirconium-89-radiolabeled monoclonal antibodies ( 89 Zr-mAbs) for applications in noninvasive diagnostic positron emission tomography (PET) imaging of cancers. Here, we report on the synthesis, 89 Zr-radiochemistry, and light-triggered photoradiosynthesis of 89 Zr-labeled human serum albumin (HSA) using a series of 14 different photoactivatable DFO derivatives. The photoactive groups explore a range of substituted, and isomeric ArN 3 reagents, as well as derivatives of benzophenone, a para-substituted trifluoromethyl phenyl diazirine, and a tetrazole species. For the compounds studied, efficient photochemical activation occurs inside the UVA-to-visible region of the electromagnetic spectrum (∼365-450 nm) and the photochemical reactions with HSA in water were complete within 15 min under ambient conditions. Under standardized experimental conditions, photoradiosynthesis with compounds 1 - 14 produced the corresponding 89 ZrDFO-PEG 3 -HSA conjugates with decay-corrected isolated radiochemical yields between 18.1 ± 1.8% and 62.3 ± 3.6%. Extensive density functional theory (DFT) calculations were used to explore the reaction mechanisms and chemoselectivity of the light-induced bimolecular conjugation of compounds 1 - 14 to protein. The photoactivatable DFO-derivatives operate by at least five distinct mechanisms, each producing a different type of bioconjugate bond. Overall, the experimental and computational work presented here confirms that photochemistry is a viable option for making diverse, functionalized protein conjugates., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Clinical production of 89 Zr-radiolabeled antibodies ( 89 Zr-mAbs) for positron emission tomography imaging relies on the pre-conjugation of desferrioxamine B (DFO) to the purified protein, followed by isolation and characterization of the functionalized intermediate, and then manual radiosynthesis. Although highly successful, this route exposes radiochemists to a potentially large radiation dose and entails several technological and economic hurdles that limit access of 89 Zr-mAbs to just a specialist few Nuclear Medicine facilities worldwide. Here, we introduce a fully automated synthesis box that can produce individual doses of 89 Zr-mAbs formulated in sterile solution in < 25 min starting from [ 89 Zr(C 2 O 4 ) 4 ] 4- ( 89 Zr-oxalate), our good laboratory practice-compliant photoactivatable desferrioxamine-based chelate (DFO-PEG 3 -ArN 3 ), and clinical-grade antibodies without the need for pre-purification of protein. The automated steps include neutralization of the 89 Zr-oxalate stock, chelate radiolabeling, and light-induced protein conjugation, followed by 89 Zr-mAb purification, formulation, and sterile filtration. As proof-of-principle, 89 ZrDFO-PEG 3 -azepin-trastuzumab was synthesized directly from Herceptin in < 25 min with an overall decay-corrected radiochemical yield of 20.1 ± 2.4% (n = 3), a radiochemical purity > 99%, and chemical purity > 99%. The synthesis unit can also produce 89 Zr-mAbs via the conventional radiolabeling routes from pre-functionalized DFO-mAbs that are currently used in the clinic. This automated method will improve access to state-of-the-art 89 Zr-mAbs at the many Nuclear Medicine and research institutions that require automated devices for radiotracer production., (© 2022. The Author(s).)

Fluorescent protein conjugates are vital tools in a wide range of scientific disciplines from basic biochemical research to applications in clinical pathology and intraoperative surgery. We report the synthesis and characterization of photoactivatable fluorophores ( PhotoTags ) based on the functionalization of coumarin, fluorescein, BODIPY, rhodamine B, and cyanine dyes with a photochemically active aryl azide group. Photochemical labeling experiments using human serum albumin produced fluorescent proteins in high yields under irradiation with ultraviolet light for <15 min. We also synthesized DFO-RhodB-PEG 3 -ArN 3 ─a photoactivatable compound that can be radiolabeled with 89 Zr for applications in optical imaging and positron emission tomography. One-pot 89 Zr-radiolabeling and light-induced protein conjugation produced [ 89 Zr]ZrDFO-RhodB-PEG 3 -azepin-trastuzumab. Proof-of-concept studies in vitro and in vivo confirmed that [ 89 Zr]ZrDFO-RhodB-PEG 3 -azepin-trastuzumab is a potential dual-modality agent for detecting human epidermal growth factor receptor 2 (HER2/ neu ) expression. Overall, the PhotoTag technology represents a rapid, synthetically versatile, and user-friendly approach for generating novel protein conjugates.

Scientific questions in fields such as catalysis, monitoring of biological processes, or environmental chemistry demand analytical technologies combining orthogonal spectroscopies. Combined spectroscopic concepts facilitate in situ online monitoring of dynamic processes providing a better understanding of the involved reaction pathways. In the present study, a low-liquid-volume multispectroscopic platform was developed based on infrared attenuated total reflection (IR-ATR) spectroscopy combined with Raman spectroscopy and luminescence sensing. To demonstrate the measurement capabilities, exemplary analyte systems including water/heavy water and aqueous solutions of ammonium sulfate were analyzed as proof-of-principle studies. It was successfully demonstrated that three optical techniques may be integrated into a single analytical platform without interference providing synchronized and complementary data sets by probing the same minute sample volume. In addition, the developed assembly provides a gastight lid sealing the headspace above the probed liquid for monitoring the concentration of molecular oxygen also in the gas phase via luminescence quenching. Hence, the entire assembly may be operated at inert conditions, as required, for example, during the analysis of photocatalytic processes., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

We report IR and UV/Vis spectroscopic signatures that allow discriminating between the oxidation states of the manganese-based water oxidation catalyst [(Mn 4 O 4 )(V 4 O 13 )(OAc) 3 ] 3- . Simulated IR spectra show that V=O stretching vibrations in the 900-1000 cm -1 region shift consistently by about 20 cm -1 per oxidation equivalent. Multiple bands in the 1450-1550 cm -1 region also change systematically upon oxidation/reduction. The computed UV/Vis spectra predict that the spectral range above 350 nm is characteristic of the managanese-oxo cubane oxidation state, whereas transitions at higher energy are due to the vanadate ligand. The presence of absorption signals above 680 nm is indicative of the presence of Mn III atoms. Spectroelectrochemical measurements of the oxidation from [Mn 2 III Mn 2 IV ] to [Mn 4 IV ] showed that the change in oxidation state can indeed be tracked by both IR and UV/Vis spectroscopy., (© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Despite their technological importance for water splitting, the reaction mechanisms of most water oxidation catalysts (WOCs) are poorly understood. This paper combines theoretical and experimental methods to reveal mechanistic insights into the reactivity of the highly active molecular manganese vanadium oxide WOC [Mn 4 V 4 O 17 (OAc) 3 ] 3- in aqueous acetonitrile solutions. Using density functional theory together with electrochemistry and IR-spectroscopy, we propose a sequential three-step activation mechanism including a one-electron oxidation of the catalyst from [Mn 2 3+ Mn 2 4+ ] to [Mn 3+ Mn 3 4+ ], acetate-to-water ligand exchange, and a second one-electron oxidation from [Mn 3+ Mn 3 4+ ] to [Mn 4 4+ ]. Analysis of several plausible ligand exchange pathways shows that nucleophilic attack of water molecules along the Jahn-Teller axis of the Mn 3+ centers leads to significantly lower activation barriers compared with attack at Mn 4+ centers. Deprotonation of one water ligand by the leaving acetate group leads to the formation of the activated species [Mn 4 V 4 O 17 (OAc) 2 (H 2 O)(OH)] - featuring one H 2 O and one OH ligand. Redox potentials based on the computed intermediates are in excellent agreement with electrochemical measurements at various solvent compositions. This intricate interplay between redox chemistry and ligand exchange controls the formation of the catalytically active species. These results provide key reactivity information essential to further study bio-inspired molecular WOCs and solid-state manganese oxide catalysts., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Most experimental work in the space of bioconjugation chemistry focuses on using new methods to construct covalent bonds between a cargo molecule and a protein of interest such as a monoclonal antibody (mAb). Bond formation is important for generating new diagnostic tools, yet when these compounds advance to preclinical in vitro and in vivo studies, and later for translation to the clinic, understanding the fate of potential metabolites that arise from chemical or enzymatic degradation of the construct is important to obtain a full picture of the pharmacokinetic performance of a new compound. In the context of designing new bioconjugate methods for labeling antibodies with the positron-emitting radionuclide 89 Zr, we previously developed a photochemical process for making 89 Zr-mAbs. Experimental studies on [ 89 Zr]ZrDFO-PEG 3 -azepin-mAb constructs revealed that incorporation of the tris-polyethylene glycol (PEG 3 ) linker improved the aqueous phase solubility and radiochemical conversion. However, the use of a PEG 3 linker also has an impact on the whole-body residence time of the construct, leading to a more rapid excretion of the 89 Zr activity when compared with radiotracers that lack the PEG 3 chain. In this work, we investigated the metabolic fate of eight possible metabolites that arise from the logical disconnection of [ 89 Zr]ZrDFO-PEG 3 -azepin-mAb at bonds which are susceptible to chemical or enzymatic cleavage. Synthesis combined with 89 Zr-radiolabeling, small-animal positron emission tomography imaging at multiple time points from 0 to 20 h, and measurements of the effective half-life for whole-body excretion are reported. The conclusions are that the use of a PEG 3 linker is non-innocent in terms of its impact on enhancing the metabolism of [ 89 Zr]ZrDFO-PEG 3 -azepin-mAbs. In most cases, degradation can produce metabolites that are rapidly eliminated from the body, thereby enhancing image contrast by reducing nonspecific accumulation and retention of 89 Zr in background organs such as the liver, spleen, kidney, and bone.

For the control of immunity in COVID-19 survivors and vaccinated subjects, there is an urgent need for reliable and rapid serological assays. Based on samples from 63 COVID-19 survivors up to 7 months after symptom onset, and on 50 serum samples taken before the beginning of the pandemic, we compared the performances of three commercial immunoassays for the detection of SARS-CoV-2 IgA and IgG antibodies (Euroimmun SARS-COV-2 IgA/IgG, Mikrogen recom Well SARS-CoV-2 IgA/IgG, and Serion ELISA agile SARS-CoV-2 IgA/IgG) and three rapid lateral flow (immunochromatographic) tests (Abbott PanBio COVID-19 IgG/IgM, Nadal COVID-19 IgG/IgM, and Cleartest Corona 2019-nCOV IgG/IgM) with a 50% plaque-reduction neutralization test (PRNT50) representing the gold standard. Fifty-seven out of 63 PCR-confirmed COVID-19 patients (90%) showed neutralizing antibodies. The sensitivity of the seven assays ranged from 7.0% to 98.3%, and the specificity ranged from 86.0% to 100.0%. Only one commercial immunoassay showed a sensitivity and specificity of greater than 98%.

We report the synthesis of the first transplatin-BODIPY conjugates for application in photodynamic therapy (PDT). The distyryl BODIPYs containing two iodine atoms were designed to absorb in the red region, easily undergo intersystem crossing for efficient singlet oxygen generation, and additionally offer the possibility for coordination with mono-activated transplatin. We were able to demonstrate that coordination of the BODIPYs with a mono-activated transplatin increases the phototoxic index of the photosensitizers significantly, giving rise to highly phototoxic distyryl BODIPY derivatives, of which one was shown to have the highest ever reported phototoxic index against any cell line. Furthermore, the photophysical mechanism of singlet oxygen generation in distyryl BODIPYs undergoing intramolecular charge transfer was studied experimentally and using time-dependent density functional theory., (© 2020 Wiley-VCH GmbH.)

The synthesis, characterisation and application of radiolabelled compounds for use in diagnostic and therapeutic medicine requires a diverse skill set. This article highlights a selection of our ongoing projects that aim to provide new synthetic methods and radiochemical tools for building molecular imaging agents with various radionuclides.

Methods that provide rapid access to radiolabeled antibodies are vital in the development of diagnostic and radiotherapeutic agents for PET or radioimmunotherapy. The human hepatocyte growth factor receptor (c-MET) signaling pathway is dysregulated in several malignancies, including gastric cancer, and is an important biomarker in drug discovery. Here, we used a photoradiochemical approach to produce 89 Zr-radiolabeled onartuzumab (a monovalent, antihuman c-MET antibody), starting directly from the fully formulated drug (MetMAb). Methods: Simultaneous 89 Zr-radiolabeling and protein conjugation was performed in one-pot reactions containing 89 Zr-oxalate, the photoactive chelate desferrioxamine B (DFO)-aryl azide (DFO-ArN 3 ), and MetMAb to give 89 Zr-DFO-azepin-onartuzumab. As a control, 89 Zr-DFO-benzyl Bn-isothiocyanate Bn-NCS-onartuzumab was prepared via a conventional two-step process using prepurified onartuzumab and DFO-Bn-NCS. Radiotracers were purified by using size-exclusion methods and evaluated by radiochromatography. Radiochemical stability was studied in human serum, and immunoreactivity was determined by cellular binding assays using MKN-45 gastric carcinoma cells. PET imaging at multiple time points (0-72 h) was performed on female athymic nude mice bearing subcutaneous MKN-45 xenografts. Biodistribution experiments were performed after the final image was obtained. The tumor specificity of 89 Zr-DFO-azepin-onartuzumab was assessed in vivo by competitive inhibition (blocking) studies. Results: Initial photoradiosynthesis experiments produced 89 Zr-DFO-azepin-onartuzumab in less than 15 min, with an isolated decay-corrected radiochemical yield (RCY) of 24.8%, a radiochemical purity of approximately 90%, and a molar activity of approximately 1.5 MBq nmol -1 Reaction optimization improved the radiochemical conversion of 89 Zr-DFO-azepin-onartuzumab to 56.9% ± 4.1% ( n = 3), with isolated RCYs of 41.2% ± 10.6% ( n = 3) and radiochemical purity of more than 90%. Conventional methods produced 89 Zr-DFO-Bn-NCS-onartuzumab with an isolated RCY of more than 97%, radiochemical purity of more than 97% and molar activity of approximately 14.0 MBq nmol -1 Both radiotracers were immunoreactive and stable in human serum. PET imaging and biodistribution studies showed high tumor uptake for both radiotracers. By 72 h, tumor and liver uptake (percentage injected dose [%ID]) reached 15.37 ± 5.21 %ID g -1 and 6.56 ± 4.03 %ID g -1 , respectively, for 89 Zr-DFO-azepin-onartuzumab ( n = 4) and 21.38 ± 11.57 %ID g -1 and 18.84 ± 6.03 %ID g -1 , respectively, for 89 Zr-DFO-Bn-NCS-onartuzumab ( n = 4). Blocking experiments gave a statistically significant reduction in tumor uptake (6.34 ± 0.47 %ID g -1 ) of 89 Zr-DFO-azepin-onartuzumab ( n = 4). Conclusion: The experiments demonstrated that photoradiosynthesis is a viable alternative approach for producing 89 Zr-radiolabeled antibodies directly in protein formulation buffer, reducing protein aggregation and liver uptake., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Tissue survival responses to ionizing radiation are nonlinear with dose, rather yielding tissue-specific descending curves that impede straightforward analysis of biologic effects. Apoptotic cell death often occurs at low doses, while at clinically relevant intermediate doses, double-strand break misrepair yields mitotic death that determines outcome. As researchers frequently use a single low dose for experimentation, such strategies may inaccurately depict inherent tissue responses. Cutting edge radiobiology has adopted full dose survival profiling and devised mathematical algorithms to fit curves to observed data to generate highly reproducible numerical data that accurately define clinically relevant inherent radiosensitivities. Here, we established a protocol for irradiating organoids that delivers radiation profiles simulating the organ of origin. This technique yielded highly similar dose-survival curves of small and large intestinal crypts in vivo and their cognate organoids analyzed by the single-hit multi-target (SHMT) algorithm, outcomes reflecting the inherent radiation profile of their respective Lgr5 + stem cell populations. As this technological advance is quantitative, it will be useful for accurate evaluation of intestinal (patho)physiology and drug screening. SIGNIFICANCE: These findings establish standards for irradiating organoids that deliver radiation profiles that phenocopy the organ of origin. See related commentary by Muschel et al., p. 927 ., (©2019 American Association for Cancer Research.)