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Cancer is one of the most complex and challenging human diseases, with rising incidences and cancer-related deaths despite improved diagnosis and personalized treatment options. Targeted alpha therapy (TαT) offers an exciting strategy emerging for cancer treatment which has proven effective even in patients with advanced metastatic disease that has become resistant to other treatments. Yet, in many cases, more sophisticated strategies are needed to stall disease progression and overcome resistance to TαT. The combination of two or more therapies which have historically been used as stand-alone treatments is an approach that has been pursued in recent years. This review aims to provide an overview on TαT and the four main pillars of therapeutic strategies in cancer management, namely external beam radiation therapy (EBRT), immunotherapy with checkpoint inhibitors (ICI), cytostatic chemotherapy (CCT), and brachytherapy (BT), and to discuss their potential use in combination with TαT. A brief description of each therapy is followed by a review of known biological aspects and state-of-the-art treatment practices. The emphasis, however, is given to the motivation for combination with TαT as well as the pre-clinical and clinical studies conducted to date.

Changes in cardiac metabolism typically precede cardiac dysfunction and therefore represent an important target for diagnosis and treatment designed to prevent progression to heart failure, a leading cause of death. Profound changes in pyruvate metabolism, including reduced expression of the mitochondrial pyruvate carrier (MPC), are increasingly recognized as early maladaptive alterations in cardiomyopathies, but no methods currently exist to determine MPC expression in vivo. We exposed mice to doxorubicin (DOX), an anthracycline chemotherapeutic known to perturb pyruvate metabolism, and demonstrated that cardiac tissue levels of MPC decrease within 4 weeks of initial DOX exposure. Using a combination of stable isotope tracing metabolomics, hyperpolarized [1- 13 C]pyruvate magnetic resonance imaging (MRI), and [3- 11 C]pyruvate positron emission tomography (PET), we found that loss of MPC and monocarboxylate transporter 1 (MCT1) resulted in decreased utilization of pyruvate for mitochondrial oxidative metabolism and resulted in decreased cardiac carbon-11 clearance. Despite recovery of expression levels of pyruvate transporters, including MPC, 16 weeks after initial DOX exposure, cardiac carbon-11 clearance still trends towards differences between control mice and the mice exposed to this chemotherapeutic. [3- 11 C]Pyruvate PET is therefore a promising approach to imaging cardiac pyruvate transport with potential applications to the identification of early maladaptive changes in pyruvate metabolism and monitoring response to therapy.

Purpose Treatment of pediatric cancers with doxorubicin is a common and predictable cause of cardiomyopathy. Early diagnosis of treatment-induced cardiotoxicity and intervention are major determinants for the prevention of advanced disease. The onset of cardiomyopathies is often accompanied by profound changes in lipid metabolism, including an enhanced uptake of short-chain fatty acids (SCFA). Therefore, we explored the utility of 2-[ 18 F]fluoropropionic acid ([ 18 F]FPA), an SCFA analog, as an imaging biomarker of cardiac injury in mice exposed to doxorubicin. Procedures Cardiotoxicity and cardiac dysfunction were induced in mice by an 8-dose regimen of doxorubicin (cumulative dose 24 mg/kg) administered over 14 days. The effects of doxorubicin exposure were assessed by measurement of heart weights, left ventricular ejection fractions, and blood cardiac troponin levels. Whole body and cardiac [ 18 F]FPA uptakes were determined by PET and tissue gamma counting in the presence or absence of AZD3965, a pharmacological inhibitor of monocarboxylate transporter 1 (MCT1). Radiation absorbed doses were estimated using tissue time-activity concentrations. Results Significantly higher cardiac [ 18 F]FPA uptake was observed in doxorubicin-treated animals. This uptake remained constant from 30 to 120 min post-injection. Pharmacological inhibition of MCT1-mediated transport by AZD3965 selectively decreased the uptake of [ 18 F]FPA in tissues other than the heart. Co-administration of [ 18 F]FPA and AZD3965 enhanced the imaging contrast of the diseased heart while reducing overall exposure to radioactivity. Conclusions [ 18 F]FPA, especially when co-administered with AZD3965, is a new tool for imaging changes in fatty acid metabolism occurring in response to doxorubicin-induced cardiomyopathy by PET.

Changes in cardiac metabolism typically precede cardiac dysfunction and therefore represent an important target for diagnosis and treatment designed to prevent progression to heart failure, a leading cause of death. Profound changes in pyruvate metabolism, including reduced expression of the mitochondrial pyruvate carrier (MPC), are increasingly recognized as early maladaptive alterations in cardiomyopathies, but no methods currently exist to determine MPC expression in vivo. We exposed mice to doxorubicin (DOX), an anthracycline chemotherapeutic known to perturb pyruvate metabolism, and demonstrated that cardiac tissue levels of MPC decrease within 4 weeks of initial DOX exposure. Using a combination of stable isotope tracing metabolomics, hyperpolarized [1-13C]pyruvate magnetic resonance imaging (MRI), and [3-11C]pyruvate positron emission tomography (PET), we found that loss of MPC and monocarboxylate transporter 1 (MCT1) resulted in decreased utilization of pyruvate for mitochondrial oxidative metabolism and resulted in decreased cardiac carbon-11 clearance. Despite recovery of expression levels of pyruvate transporters, including MPC, 16 weeks after initial DOX exposure, cardiac carbon-11 clearance still trends towards differences between control mice and the mice exposed to this chemotherapeutic. [3-11C]Pyruvate PET is therefore a promising approach to imaging cardiac pyruvate transport with potential applications to the identification of early maladaptive changes in pyruvate metabolism and monitoring response to therapy.Changes in cardiac metabolism typically precede cardiac dysfunction and therefore represent an important target for diagnosis and treatment designed to prevent progression to heart failure, a leading cause of death. Profound changes in pyruvate metabolism, including reduced expression of the mitochondrial pyruvate carrier (MPC), are increasingly recognized as early maladaptive alterations in cardiomyopathies, but no methods currently exist to determine MPC expression in vivo. We exposed mice to doxorubicin (DOX), an anthracycline chemotherapeutic known to perturb pyruvate metabolism, and demonstrated that cardiac tissue levels of MPC decrease within 4 weeks of initial DOX exposure. Using a combination of stable isotope tracing metabolomics, hyperpolarized [1-13C]pyruvate magnetic resonance imaging (MRI), and [3-11C]pyruvate positron emission tomography (PET), we found that loss of MPC and monocarboxylate transporter 1 (MCT1) resulted in decreased utilization of pyruvate for mitochondrial oxidative metabolism and resulted in decreased cardiac carbon-11 clearance. Despite recovery of expression levels of pyruvate transporters, including MPC, 16 weeks after initial DOX exposure, cardiac carbon-11 clearance still trends towards differences between control mice and the mice exposed to this chemotherapeutic. [3-11C]Pyruvate PET is therefore a promising approach to imaging cardiac pyruvate transport with potential applications to the identification of early maladaptive changes in pyruvate metabolism and monitoring response to therapy.

Treatment of pediatric cancers with doxorubicin is a common and predictable cause of cardiomyopathy. Early diagnosis of treatment-induced cardiotoxicity and intervention are major determinants for the prevention of advanced disease. The onset of cardiomyopathies is often accompanied by profound changes in lipid metabolism, including an enhanced uptake of short-chain fatty acids (SCFA). Therefore, we explored the utility of 2-[18F]fluoropropionic acid ([18F]FPA), an SCFA analog, as an imaging biomarker of cardiac injury in mice exposed to doxorubicin.PURPOSETreatment of pediatric cancers with doxorubicin is a common and predictable cause of cardiomyopathy. Early diagnosis of treatment-induced cardiotoxicity and intervention are major determinants for the prevention of advanced disease. The onset of cardiomyopathies is often accompanied by profound changes in lipid metabolism, including an enhanced uptake of short-chain fatty acids (SCFA). Therefore, we explored the utility of 2-[18F]fluoropropionic acid ([18F]FPA), an SCFA analog, as an imaging biomarker of cardiac injury in mice exposed to doxorubicin.Cardiotoxicity and cardiac dysfunction were induced in mice by an 8-dose regimen of doxorubicin (cumulative dose 24 mg/kg) administered over 14 days. The effects of doxorubicin exposure were assessed by measurement of heart weights, left ventricular ejection fractions, and blood cardiac troponin levels. Whole body and cardiac [18F]FPA uptakes were determined by PET and tissue gamma counting in the presence or absence of AZD3965, a pharmacological inhibitor of monocarboxylate transporter 1 (MCT1). Radiation absorbed doses were estimated using tissue time-activity concentrations.PROCEDURESCardiotoxicity and cardiac dysfunction were induced in mice by an 8-dose regimen of doxorubicin (cumulative dose 24 mg/kg) administered over 14 days. The effects of doxorubicin exposure were assessed by measurement of heart weights, left ventricular ejection fractions, and blood cardiac troponin levels. Whole body and cardiac [18F]FPA uptakes were determined by PET and tissue gamma counting in the presence or absence of AZD3965, a pharmacological inhibitor of monocarboxylate transporter 1 (MCT1). Radiation absorbed doses were estimated using tissue time-activity concentrations.Significantly higher cardiac [18F]FPA uptake was observed in doxorubicin-treated animals. This uptake remained constant from 30 to 120 min post-injection. Pharmacological inhibition of MCT1-mediated transport by AZD3965 selectively decreased the uptake of [18F]FPA in tissues other than the heart. Co-administration of [18F]FPA and AZD3965 enhanced the imaging contrast of the diseased heart while reducing overall exposure to radioactivity.RESULTSSignificantly higher cardiac [18F]FPA uptake was observed in doxorubicin-treated animals. This uptake remained constant from 30 to 120 min post-injection. Pharmacological inhibition of MCT1-mediated transport by AZD3965 selectively decreased the uptake of [18F]FPA in tissues other than the heart. Co-administration of [18F]FPA and AZD3965 enhanced the imaging contrast of the diseased heart while reducing overall exposure to radioactivity.[18F]FPA, especially when co-administered with AZD3965, is a new tool for imaging changes in fatty acid metabolism occurring in response to doxorubicin-induced cardiomyopathy by PET.CONCLUSIONS[18F]FPA, especially when co-administered with AZD3965, is a new tool for imaging changes in fatty acid metabolism occurring in response to doxorubicin-induced cardiomyopathy by PET.

Cold atmospheric plasma (CAP) has the potential to interact with tissue or cells leading to fast, painless and efficient disinfection and furthermore has positive effects on wound healing and tissue regeneration. For clinical implementation it is necessary to examine how CAP improves wound healing and which molecular changes occur after the CAP treatment. In the present study we used the second generation MicroPlaSter ß® in analogy to the current clinical standard (2 min treatment time) in order to determine molecular changes induced by CAP using in vitro cell culture studies with human fibroblasts and an in vivo mouse skin wound healing model. Our in vitro analysis revealed that the CAP treatment induces the expression of important key genes crucial for the wound healing response like IL-6, IL-8, MCP-1, TGF-ß1, TGF-ß2, and promotes the production of collagen type I and alpha-SMA. Scratch wound healing assays showed improved cell migration, whereas cell proliferation analyzed by XTT method, and the apoptotic machinery analyzed by protein array technology, was not altered by CAP in dermal fibroblasts. An in vivo wound healing model confirmed that the CAP treatment affects above mentioned genes involved in wound healing, tissue injury and repair. Additionally, we observed that the CAP treatment improves wound healing in mice, no relevant side effects were detected. We suggest that improved wound healing might be due to the activation of a specified panel of cytokines and growth factors by CAP. In summary, our in vitro human and in vivo animal data suggest that the 2 min treatment with the MicroPlaSter ß® is an effective technique for activating wound healing relevant molecules in dermal fibroblasts leading to improved wound healing, whereas the mechanisms which contribute to these observed effects have to be further investigated.

The clear-sky radiative effect of aerosol–radiation interactions is of relevance for our understanding of the climate system. The influence of aerosol on the surface energy budget is of high interest for the renewable energy sector. In this study, the radiative effect is investigated in particular with respect to seasonal and regional variations for the region of Germany and the year 2015 at the surface and top of atmosphere using two complementary approaches. First, an ensemble of clear-sky models which explicitly consider aerosols is utilized to retrieve the aerosol optical depth and the surface direct radiative effect of aerosols by means of a clear-sky fitting technique. For this, short-wave broadband irradiance measurements in the absence of clouds are used as a basis. A clear-sky detection algorithm is used to identify cloud-free observations. Considered are measurements of the short-wave broadband global and diffuse horizontal irradiance with shaded and unshaded pyranometers at 25 stations across Germany within the observational network of the German Weather Service (DWD). The clear-sky models used are the Modified MAC model (MMAC), the Meteorological Radiation Model (MRM) v6.1, the Meteorological–Statistical solar radiation model (METSTAT), the European Solar Radiation Atlas (ESRA), Heliosat-1, the Center for Environment and Man solar radiation model (CEM), and the simplified Solis model. The definition of aerosol and atmospheric characteristics of the models are examined in detail for their suitability for this approach. Second, the radiative effect is estimated using explicit radiative transfer simulations with inputs on the meteorological state of the atmosphere, trace gases and aerosol from the Copernicus Atmosphere Monitoring Service (CAMS) reanalysis. The aerosol optical properties (aerosol optical depth, Ångström exponent, single scattering albedo and asymmetry parameter) are first evaluated with AERONET direct sun and inversion products. The largest inconsistency is found for the aerosol absorption, which is overestimated by about 0.03 or about 30 % by the CAMS reanalysis. Compared to the DWD observational network, the simulated global, direct and diffuse irradiances show reasonable agreement within the measurement uncertainty. The radiative kernel method is used to estimate the resulting uncertainty and bias of the simulated direct radiative effect. The uncertainty is estimated to −1.5 ± 7.7 and 0.6 ± 3.5 W m−2 at the surface and top of atmosphere, respectively, while the annual-mean biases at the surface, top of atmosphere and total atmosphere are −10.6, −6.5 and 4.1 W m−2, respectively. The retrieval of the aerosol radiative effect with the clear-sky models shows a high level of agreement with the radiative transfer simulations, with an RMSE of 5.8 W m−2 and a correlation of 0.75. The annual mean of the REari at the surface for the 25 DWD stations shows a value of −12.8 ± 5 W m−2 as the average over the clear-sky models, compared to −11 W m−2 from the radiative transfer simulations. Since all models assume a fixed aerosol characterization, the annual cycle of the aerosol radiation effect cannot be reproduced. Out of this set of clear-sky models, the largest level of agreement is shown by the ESRA and MRM v6.1 models.

Objective Bone morphogenetic protein 6 (BMP6) has been identified as crucial regulator of iron homeostasis. However, its further role in liver pathology including non-alcoholic fatty liver disease (NAFLD) and its advanced form non-alcoholic steatohepatitis (NASH) is elusive. The aim of this study was to investigate the expression and function of BMP6 in chronic liver disease. Design BMP6 was analysed in hepatic samples from murine models of chronic liver injury and patients with chronic liver diseases. Furthermore, a tissue microarray comprising 110 human liver tissues with different degree of steatosis and inflammation was assessed. BMP6-deficient (BMP6−/−) and wild-type mice were compared in two dietary NASH-models, that is, methionine choline-deficient (MCD) and high-fat (HF) diets. Results BMP6 was solely upregulated in NAFLD but not in other murine liver injury models or diseased human livers. In NAFLD, BMP6 expression correlated with hepatic steatosis but not with inflammation or hepatocellular damage. Also, in vitro cellular lipid accumulation in primary human hepatocytes induced increased BMP6 expression. MCD and HF diets caused more hepatic inflammation and fibrosis in BMP6−/− compared with wild-type mice. However, only in the MCD and not in the HF diet model BMP6−/− mice developed marked hepatic iron overload, suggesting that further mechanisms are responsible for protective BMP6 effect. In vitro analysis revealed that recombinant BMP6 inhibited the activation of hepatic stellate cells (HSCs) and reduced proinflammatory and profibrogenic gene expression in already activated HSCs. Conclusions Steatosis-induced upregulation of BMP6 in NAFLD is hepatoprotective. Induction of BMP6-signalling may be a promising antifibrogenic strategy.

Kidney transplantation (ktx) in mice is used to learn about rejection and to develop new treatment strategies. Past studies have mainly been based on histological or molecular biological methods. Imaging techniques to monitor allograft pathology have rarely been used. Here we investigated mice after isogenic and allogenic ktx over time with functional MRI with diffusion-weighted imaging (DWI) and mapping of T2-relaxation time (T2-mapping) to assess graft inflammation and edema formation. To characterize graft pathology, we used PAS-staining, counted CD3-positive T-lymphocytes, analyzed leukocytes by means flow cytometry. DWI revealed progressive restriction of diffusion of water molecules in allogenic kidney grafts. This was paralleled by enhanced infiltration of the kidney by inflammatory cells. Changes in tissue diffusion were not seen following isogenic ktx. T2-times in renal cortex were increased after both isogenic and allogenic transplantation, consistent with tissue edema due to ischemic injury following prolonged cold ischemia time of 60 minutes. Lack of T2 increase in the inner stripe of the inner medulla in allogenic kidney grafts matched loss of tubular autofluorescence and may result from rejection-driven reductions in tubular water content due to tubular dysfunction and renal functional impairment. Functional MRI is a valuable non-invasive technique for monitoring inflammation, tissue edema and tubular function. It permits on to differentiate between acute rejection and ischemic renal injury in a mouse model of ktx.

Subjective cognitive decline (SCD) is proposed as an indicator of transitional disease stage 2 in the Alzheimer’s disease (AD) continuum. However, molecular and particularly longitudinal fluid biomarker data for this stage are still limited. This study aimed to determine whether blood-based biomarkers in amyloid-positive individuals with SCD (A + SCD) support the notion of stage 2 as a distinct stage between stages 1 and 3 of AD and to identify those at high risk for clinical progression. In a prospective multicenter study (DELCODE) involving 457 participants across the AD continuum, we analyzed plasma phospho-tau 181 (p181) and neurofilament light chain (NfL) and assessed their association with longitudinal cognition, hippocampal atrophy, and AD clinical stage transition. The results showed that baseline plasma p181 levels were elevated and increased more rapidly in A + SCD individuals compared to amyloid-positive cognitively unimpaired (A + CU) individuals (stage 1). NfL levels rose across A + CU, A + SCD, and amyloid-positive mild cognitive impairment (A + MCI, stage 3). In A + SCD, but not in A + CU, higher p181 levels predicted cognitive decline (PACC5) and transition to MCI. In conclusion, plasma p181 provides molecular biomarker evidence supporting A + SCD as a pre-dementia AD stage (stage 2) distinct from A + CU (stage 1) and helps identify individuals at risk for cognitive decline early in the AD continuum.