Joint Research Centre

Systematic studies of cancer genomes have provided unprecedented insights into the molecular nature of cancer. Using this information to guide the development and application of therapies in the clinic is challenging. Here, we report how cancer-driven alterations identified in 11,289 tumors from 29 tissues (integrating somatic mutations, copy number alterations, DNA methylation, and gene expression) can be mapped onto 1,001 molecularly annotated human cancer cell lines and correlated with sensitivity to 265 drugs. We find that cell lines faithfully recapitulate oncogenic alterations identified in tumors, find that many of these associate with drug sensitivity/resistance, and highlight the importance of tissue lineage in mediating drug response. Logic-based modeling uncovers combinations of alterations that sensitize to drugs, while machine learning demonstrates the relative importance of different data types in predicting drug response. Our analysis and datasets are rich resources to link genotypes with cellular phenotypes and to identify therapeutic options for selected cancer sub-populations.

Aberrant cell signaling can cause cancer and other diseases and is a focal point of drug research. A common approach is to infer signaling activity of pathways from gene expression. However, mapping gene expression to pathway components disregards the effect of post-translational modifications, and downstream signatures represent very specific experimental conditions. Here we present PROGENy, a method that overcomes both limitations by leveraging a large compendium of publicly available perturbation experiments to yield a common core of Pathway RespOnsive GENes. Unlike pathway mapping methods, PROGENy can (i) recover the effect of known driver mutations, (ii) provide or improve strong markers for drug indications, and (iii) distinguish between oncogenic and tumor suppressor pathways for patient survival. Collectively, these results show that PROGENy accurately infers pathway activity from gene expression in a wide range of conditions.

The prediction of transcription factor (TF) activities from the gene expression of their targets (i.e., TF regulon) is becoming a widely used approach to characterize the functional status of transcriptional regulatory circuits. Several strategies and data sets have been proposed to link the target genes likely regulated by a TF, each one providing a different level of evidence. The most established ones are (1) manually curated repositories, (2) interactions derived from ChIP-seq binding data, (3) in silico prediction of TF binding on gene promoters, and (4) reverse-engineered regulons from large gene expression data sets. However, it is not known how these different sources of regulons affect the TF activity estimations and, thereby, downstream analysis and interpretation. Here we compared the accuracy and biases of these strategies to define human TF regulons by means of their ability to predict changes in TF activities in three reference benchmark data sets. We assembled a collection of TF-target interactions for 1541 human TFs and evaluated how different molecular and regulatory properties of the TFs, such as the DNA-binding domain, specificities, or mode of interaction with the chromatin, affect the predictions of TF activity. We assessed their coverage and found little overlap on the regulons derived from each strategy and better performance by literature-curated information followed by ChIP-seq data. We provide an integrated resource of all TF-target interactions derived through these strategies, with confidence scores, as a resource for enhanced prediction of TF activities.

Prostate-specific membrane antigen (PSMA) is a promising target in prostate cancer. Recently, we started the first-in-human treatment with an α-radionuclide–labeled PSMA ligand. Although the case series is still ongoing, we here report in advance about two patients in highly challenging clinical situations who showed a complete response to ²²⁵Ac-PSMA-617 therapy. <b>Methods:</b>⁶⁸Ga-PSMA-11 PET/CT validated the presence of the PSMA-positive tumor phenotype. A 100-kBq activity of ²²⁵Ac-PSMA-617 per kilogram of body weight was administered bimonthly. Prostate-specific antigen response and hematologic toxicity were measured at least every 4 wk. Restaging was performed with ⁶⁸Ga-PSMA-11 PET/CT. <b>Results:</b> Both patients experienced a prostate-specific antigen decline to below the measurable level and showed a complete response on imaging. No relevant hematologic toxicity was observed. Xerostomia was the only mentionable clinical side effect. <b>Conclusion:</b> Targeted α-therapy with ²²⁵Ac-PSMA-617, although still experimental, obviously has strong potential to significantly benefit advanced-stage prostate cancer patients.

The aim of this study was to develop a treatment protocol for ²²⁵Ac-PSMA-617 α-radiation therapy in advanced-stage, metastatic castration-resistant prostate cancer patients with prostate-specific membrane antigen (PSMA)–positive tumor phenotype. <b>Methods:</b> A dosimetry estimate was calculated on the basis of time–activity curves derived from serially obtained ¹⁷⁷Lu-PSMA-617 scans extrapolated to the physical half-life of ²²⁵Ac, assuming instant decay of unstable daughter nuclides. Salvage therapies empirically conducted with 50 (<i>n</i> = 4), 100 (<i>n</i> = 4), 150 (<i>n</i> = 2), and 200 kBq/kg (<i>n</i> = 4) of ²²⁵Ac-PSMA-617 were evaluated retrospectively regarding toxicity and treatment response. Eight of 14 patients received further cycles in either 2- or 4-mo intervals with identical or deescalated activities. <b>Results:</b> Dosimetry estimates for 1 MBq of ²²⁵Ac-PSMA-617 assuming a relative biologic effectiveness of 5 revealed mean doses of 2.3 Sv for salivary glands, 0.7 Sv for kidneys, and 0.05 Sv for red marrow that are composed of 99.4% α, 0.5% β, and 0.1% photon radiation, respectively. In clinical application, severe xerostomia became the dose-limiting toxicity if treatment activity exceeded 100 kBq/kg per cycle. At 100 kBq/kg, the duration of prostate-specific antigen decline was less than 4 mo, but if therapy was repeated every 2 mo patients experienced additive antitumor effects. Treatment activities of 50 kBq/kg were without toxicity but induced insufficient antitumor response in these high-tumor-burden patients. Remarkable antitumor activity by means of objective radiologic response or tumor marker decline was observed in 9 of 11 evaluable patients. <b>Conclusion:</b> For advanced-stage patients, a treatment activity of 100 kBq/kg of ²²⁵Ac-PSMA-617 per cycle repeated every 8 wk presents a reasonable trade-off between toxicity and biochemical response.

Unlike beta particle-emitting isotopes, alpha emitters can selectively kill individual cancer cells with a single atomic decay. HuM195, a humanized anti-CD33 monoclonal antibody, specifically targets myeloid leukemia cells and has activity against minimal disease. When labeled with the beta-emitters (131)I and (90)Y, HuM195 can eliminate large leukemic burdens in patients, but it produces prolonged myelosuppression requiring hematopoietic stem cell transplantation at high doses. To enhance the potency of native HuM195 yet avoid the nonspecific cytotoxicity of beta-emitting constructs, the alpha-emitting isotope (213)Bi was conjugated to HuM195. Eighteen patients with relapsed and refractory acute myelogenous leukemia or chronic myelomonocytic leukemia were treated with 10.36 to 37.0 MBq/kg (213)Bi-HuM195. No significant extramedullary toxicity was seen. All 17 evaluable patients developed myelosuppression, with a median time to recovery of 22 days. Nearly all the (213)Bi-HuM195 rapidly localized to and was retained in areas of leukemic involvement, including the bone marrow, liver, and spleen. Absorbed dose ratios between these sites and the whole body were 1000-fold greater than those seen with beta-emitting constructs in this antigen system and patient population. Fourteen (93%) of 15 evaluable patients had reductions in circulating blasts, and 14 (78%) of 18 patients had reductions in the percentage of bone marrow blasts. This study demonstrates the safety, feasibility, and antileukemic effects of (213)Bi-HuM195, and it is the first proof-of-concept for systemic targeted alpha particle immunotherapy in humans.

The aim of this evaluation was to identify the first indicators of efficacy for ²²⁵Ac-labeled prostate-specific membrane antigen (PSMA)–617 therapy in a retrospectively analyzed group of patients. <b>Methods:</b> Forty patients with metastatic castration-resistant prostate cancer were selected for treatment with three 100 kBq/kg cycles of ²²⁵Ac-PSMA-617 at 2-mo intervals. Prostate-specific antigen (PSA) and blood cell count were measured every 4 wk. PSMA PET/CT or PSMA SPECT/CT were used for baseline staging and imaging follow-up at month 6. Follow-up included the duration of PSA response and radiologic progression-free survival at month 6. Patient histories were reviewed for the duration of previous treatment lines, and a swimmer plot was used to intraindividually compare the duration of tumor control by PSMA therapy versus prior treatment modalities. <b>Results:</b> Thirty-one of 40 patients were treated per protocol. Five patients discontinued treatment because of nonresponse, and 4 because of xerostomia. Of the 38 patients surviving at least 8 wk, 24 (63%) had a PSA decline of more than 50%, and 33 (87%) had a PSA response of any degree. The median duration of tumor control under ²²⁵Ac-PSMA-617 last-line therapy was 9.0 mo; 5 patients had an enduring response of more than 2 y. Because all patients had advanced disease, this result compares favorably with the tumor control rates associated with earlier-phase disease; the most common preceding first-, second-, third-, and fourth-line therapies were abiraterone (median duration 10.0 mo), docetaxel (6.5 mo), enzalutamide (6.5 mo), and cabazitaxel (6.0 mo), respectively. <b>Conclusion:</b> A positive response for surrogate parameters demonstrates remarkable antitumor activity for ²²⁵Ac-PSMA-617. Swimmer-plot analysis indicates a promising duration of tumor control, especially considering the unfavorable prognostic profile of the selected advanced-stage patients. Xerostomia was the main reason patients discontinued therapy or refused additional administrations and was in the same dimension as nonresponse; this finding indicates that further modifications of the treatment regimen with regard to side effects might be necessary to further enhance the therapeutic range.

We report the complete GNO solar neutrino results for the measuring periods GNO III, GNO II, and GNO I. The result for GNO III (last 15 solar runs) is [54.3−9.3+9.9(stat)±2.3(syst)]SNU (1σ) or [54.3−9.6+10.2(incl. syst)]SNU (1σ) with errors combined. The GNO experiment is now terminated after altogether 58 solar exposure runs that were performed between 20 May 1998 and 9 April 2003. The combined result for GNO (I + II + III) is [62.9−5.3+5.5(stat)±2.5(syst)]SNU (1σ) or [62.9−5.9+6.0]SNU (1σ) with errors combined in quadrature. Overall, gallium based solar observations at LNGS (first in GALLEX, later in GNO) lasted from 14 May 1991 through 9 April 2003. The joint result from 123 runs in GNO and GALLEX is [69.3±5.5(incl. syst)]SNU (1σ). The distribution of the individual run results is consistent with the hypothesis of a neutrino flux that is constant in time. Implications from the data in particle- and astrophysics are reiterated.

The number of publications on environmental footprint indicators has been growing rapidly, but with limited efforts to integrate different footprints into a coherent framework. Such integration is important for comprehensive understanding of environmental issues, policy formulation and assessment of trade-offs between different environmental concerns. Here, we systematize published footprint studies and define a family of footprints that can be used for the assessment of environmental sustainability. We identify overlaps between different footprints and analyse how they relate to the nine planetary boundaries and visualize the crucial information they provide for local and planetary sustainability. In addition, we assess how the footprint family delivers on measuring progress towards Sustainable Development Goals (SDGs), considering its ability to quantify environmental pressures along the supply chain and relating them to the water-energy-food-ecosystem (WEFE) nexus and ecosystem services. We argue that the footprint family is a flexible framework where particular members can be included or excluded according to the context or area of concern. Our paper is based upon a recent workshop bringing together global leading experts on existing environmental footprint indicators.

Molecular knowledge of biological processes is a cornerstone in omics data analysis. Applied to single-cell data, such analyses provide mechanistic insights into individual cells and their interactions. However, knowledge of intercellular communication is scarce, scattered across resources, and not linked to intracellular processes. To address this gap, we combined over 100 resources covering interactions and roles of proteins in inter- and intracellular signaling, as well as transcriptional and post-transcriptional regulation. We added protein complex information and annotations on function, localization, and role in diseases for each protein. The resource is available for human, and via homology translation for mouse and rat. The data are accessible via OmniPath's web service (https://omnipathdb.org/), a Cytoscape plug-in, and packages in R/Bioconductor and Python, providing access options for computational and experimental scientists. We created workflows with tutorials to facilitate the analysis of cell-cell interactions and affected downstream intracellular signaling processes. OmniPath provides a single access point to knowledge spanning intra- and intercellular processes for data analysis, as we demonstrate in applications studying SARS-CoV-2 infection and ulcerative colitis.

Background: Recent reports of the remarkable therapeutic efficacy of 225Ac-labeled PSMA- 617 for therapy of metastatic castration-resistant prostate cancer have underlined the clinical potential of targeted alpha therapy. Objective and Conclusion: This review describes methods for the production of 225Ac and its daughter nuclide 213Bi and summarizes the current clinical experience with both alpha emitters with particular focus on recent studies of targeted alpha therapy of bladder cancer, brain tumors, neuroendocrine tumors and prostate cancer. Keywords: Targeted alpha therapy, alpha emitter, actinium-225, bismuth-213, nuclide production, clinical application.

BACKGROUND: Many functional analysis tools have been developed to extract functional and mechanistic insight from bulk transcriptome data. With the advent of single-cell RNA sequencing (scRNA-seq), it is in principle possible to do such an analysis for single cells. However, scRNA-seq data has characteristics such as drop-out events and low library sizes. It is thus not clear if functional TF and pathway analysis tools established for bulk sequencing can be applied to scRNA-seq in a meaningful way. RESULTS: To address this question, we perform benchmark studies on simulated and real scRNA-seq data. We include the bulk-RNA tools PROGENy, GO enrichment, and DoRothEA that estimate pathway and transcription factor (TF) activities, respectively, and compare them against the tools SCENIC/AUCell and metaVIPER, designed for scRNA-seq. For the in silico study, we simulate single cells from TF/pathway perturbation bulk RNA-seq experiments. We complement the simulated data with real scRNA-seq data upon CRISPR-mediated knock-out. Our benchmarks on simulated and real data reveal comparable performance to the original bulk data. Additionally, we show that the TF and pathway activities preserve cell type-specific variability by analyzing a mixture sample sequenced with 13 scRNA-seq protocols. We also provide the benchmark data for further use by the community. CONCLUSIONS: Our analyses suggest that bulk-based functional analysis tools that use manually curated footprint gene sets can be applied to scRNA-seq data, partially outperforming dedicated single-cell tools. Furthermore, we find that the performance of functional analysis tools is more sensitive to the gene sets than to the statistic used.

Abstract Background A remarkable therapeutic efficacy has been demonstrated with 225 Ac-prostate-specific membrane antigen (PSMA)-617 in heavily pre-treated metastatic castration-resistant prostate cancer (mCRPC) patients. We report our experience with 225 Ac-PSMA-617 therapy in chemotherapy-naïve patients with advanced metastatic prostate carcinoma. Methods Seventeen patients with advanced prostate cancer were selected for treatment with 225 Ac-PSMA-617 in 2-month intervals, with initial activity of 8 MBq, then de-escalation to 7 MBq, 6 MBq or 4 MBq in cases of good response. In one patient, activity was escalated to 13 MBq in the third cycle. Fourteen patients had three treatment cycles administered, while in three patients treatment was discontinued after two cycles due to good response. Six out of 17 patients received additional treatments after the third cycle. Prostate-specific antigen (PSA) was measured every 4 weeks for PSA response assessment. 68 Ga-PSMA-PET/CT was used for functional response assessment before each subsequent treatment cycle. Serial full blood count, renal function test, and liver function were obtained to determine treatment-related side effects. Results Good antitumor activity assessed by serum PSA level and 68 Ga-PSMA-PET/CT was seen in 16/17 patients. In 14/17 patients, PSA decline ≥90% was seen after treatment, including seven patients with undetectable serum PSA following two (2/7) or three cycles (5/7) cycles of 225 Ac-PSMA-617. Fifteen of 17 patients had a &gt; 50% decline in lesions avidity for tracer on 68 Ga-PSMA-PET/CT including 11 patients with complete resolution (PET-negative and either stable sclerosis on CT for bone or resolution of lymph node metastases) of all metastatic lesions. Grade 1/2 xerostomia was seen in all patients, and none was severe enough to lead to discontinuation of treatment. One patient had with extensive bone marrow metastases and a background anemia developed a grade 3 anemia while another patient with solitary kidney and pre-treatment grade 3 renal failure developed grade 4 renal toxicity following treatment. The group presented with significant palliation of bone pain and reduced toxicity to salivary glands due to de-escalation. Conclusions 225 Ac-PSMA-617 RLT of chemotherapy-naïve patients with advanced metastatic prostate carcinoma led to a ≥ 90% decline in serum PSA in 82% of patients including 41% of patients with undetectable serum PSA who remained in remission 12 months after therapy. The remarkable therapeutic efficacy reported in this study could be achieved with reduced toxicity to salivary glands due to de-escalation of administered activities in subsequent treatment cycles. This necessitates further exploration for informing clinical practice and clinical trial design.

A comprehensive review of the thermodynamic properties of the oxide compounds of the lanthanide and actinide elements is presented. The available literature data for the solid, liquid, and gaseous state have been analysed and recommended values are presented. In case experimental data are missing, estimates have been made based on the trends in the two series, which are extensively discussed.

During its operating life in the core of a nuclear reactor nuclear fuel is subjected to significant restructuring processes determined by neutron irradiation directly through nuclear reactions and indirectly through the thermo-mechanical conditions established as a consequence of such reactions. In today's light water reactors, starting after ∼4 years of operation the cylindrical UO2 fuel pellet undergoes a transformation that affects its outermost radial region. The discovery of a newly forming structure necessitated the answering of important questions concerning the safety of extended fuel operation and still today poses the fascinating scientific challenge of fully understanding the microstructural mechanisms responsible for its formation.

The Joint Research Centre of the European Commission (JRC), in partnership with 30 institutions, has produced a global land cover map for the year 2000, the GLC 2000 map. The validation of the GLC2000 product has now been completed. The accuracy assessment relied on two methods: a confidence-building method (quality control based on a comparison with ancillary data) and a quantitative accuracy assessment based on a stratified random sampling of reference data. The sample site stratification used an underlying grid of Landsat data and was based on the proportion of priority land cover classes and on the landscape complexity. A total of 1265 sample sites have been interpreted. The first results indicate an overall accuracy of 68.6%. The GLC2000 validation exercise has provided important experiences. The design-based inference conforms to the CEOS Cal-Val recommendations and has proven to be successful. Both the GLC2000 legend development and reference data interpretations used the FAO Land Cover Classification System (LCCS). Problems in the validation process were identified for areas with heterogeneous land cover. This issue appears in both in the GLC2000 (neighborhood pixel variations) and in the reference data (cartographic and thematic mixed units). Another interesting outcome of the GLC2000 validation is the accuracy reporting. Error statistics are provided from both the producer and user perspective and incorporates measures of thematic similarity between land cover classes derived from LCCS

Extreme sea levels (ESLs) in Europe could rise by as much as one metre or more by the end of this century due to climate change. This poses significant challenges to safeguard coastal communities. Here we present a comprehensive analysis of economically efficient protection scenarios along Europe's coastlines during the present century. We employ a probabilistic framework that integrates dynamic simulations of all ESL components and flood inundation, impact modelling and a cost-benefit analysis of raising dykes. We find that at least 83% of flood damages in Europe could be avoided by elevating dykes in an economically efficient way along 23.7%-32.1% of Europe's coastline, specifically where high value conurbations exist. The European mean benefit to cost ratio of the investments varies from 8.3 to 14.9 while at country level this ranges between 1.6 and 34.3, with higher efficiencies for a scenario with high-end greenhouse gas emissions and strong socio-economic growth.

The structural high-pressure properties of $\mathrm{Th}{\mathrm{O}}_{2}$ and $\mathrm{U}{\mathrm{O}}_{2}$ have been studied in diamond-anvil cells up to maximum pressures of 80 and 69 GPa, respectively. These results show that both thorium and uranium dioxides exhibit an identical sequence of structural transitions under pressure; both transform rather sluggishly to the cotunnite-type (orthorhombic $Pnma$) high-pressure structure. This study which was performed under better hydrostatic conditions than previous experiments has enabled us to determine reliable compressibility parameters for the two dioxides: $\mathrm{Th}{\mathrm{O}}_{2}$: ${B}_{0}=198(2)\phantom{\rule{0.3em}{0ex}}\mathrm{GPa}$ and ${B}_{0}^{\ensuremath{'}}=4.6(3)$; $\mathrm{U}{\mathrm{O}}_{2}$: ${B}_{0}=207(2)\phantom{\rule{0.3em}{0ex}}\mathrm{GPa}$ and ${B}_{0}^{\ensuremath{'}}=4.5(4)$. In the case of $\mathrm{U}{\mathrm{O}}_{2}$ the ambient pressure cubic phase was still found to be present at $69\phantom{\rule{0.3em}{0ex}}\mathrm{GPa}$, which is in contradiction with earlier measurements. With regards to these results and re-calculations performed on other actinide dioxides $\mathrm{Pu}{\mathrm{O}}_{2}$ and $\mathrm{Am}{\mathrm{O}}_{2}$, we obtain a different evolution of the bulk moduli through the actinide dioxide series.

Abstract The first and basic step in gas release is single gas atom diffusion. The lattice location of rare gas atoms in the UO2 lattice and the mechanism of this diffusion process are discussed. Trapping of single gas atoms is important for out-of-pile laboratory work and helps to explain much of the scatter in the reported data. It is less important in-pile due to irradiation induced resolution. The experimental techniques used to measure gas diffusion and release are critically discussed. The available data on fission gas bubble mobility are reviewed. The reliable knowledge is scarce. The effect of burn-up (change in O/M-ratio, in-growth of fission products) is treated. The relative contributions of single gas atom diffusion, fission gas bubble mobility, sweeping and inter-granular bubble growth are discussed for the cases of highly rated fast breeder fuel and moderately rated water reactor fuel. It is argued that single gas atom diffusion is contributing essentially to release in LMFBR fuel, whereas trapping is not typical for in-pile conditions. Finally, some implications on empirical gas release relations and computer codes are given.

The logical (or logic) formalism is increasingly used to model regulatory and signaling networks. Complementing these applications, several groups contributed various methods and tools to support the definition and analysis of logical models. After an introduction to the logical modeling framework and to several of its variants, we review here a number of recent methodological advances to ease the analysis of large and intricate networks. In particular, we survey approaches to determine model attractors and their reachability properties, to assess the dynamical impact of variations of external signals, and to consistently reduce large models. To illustrate these developments, we further consider several published logical models for two important biological processes, namely the differentiation of T helper cells and the control of mammalian cell cycle.