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1.
Nat Methods ; 18(11): 1294-1303, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34725485

RESUMO

Spheroids are three-dimensional cellular models with widespread basic and translational application across academia and industry. However, methodological transparency and guidelines for spheroid research have not yet been established. The MISpheroID Consortium developed a crowdsourcing knowledgebase that assembles the experimental parameters of 3,058 published spheroid-related experiments. Interrogation of this knowledgebase identified heterogeneity in the methodological setup of spheroids. Empirical evaluation and interlaboratory validation of selected variations in spheroid methodology revealed diverse impacts on spheroid metrics. To facilitate interpretation, stimulate transparency and increase awareness, the Consortium defines the MISpheroID string, a minimum set of experimental parameters required to report spheroid research. Thus, MISpheroID combines a valuable resource and a tool for three-dimensional cellular models to mine experimental parameters and to improve reproducibility.

2.
Phys Med ; 89: 80-92, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34352679

RESUMO

MR fingerprinting (MRF) is an innovative approach to quantitative MRI. A typical disadvantage of dictionary-based MRF is the explosive growth of the dictionary as a function of the number of reconstructed parameters, an instance of the curse of dimensionality, which determines an explosion of resource requirements. In this work, we describe a deep learning approach for MRF parameter map reconstruction using a fully connected architecture. Employing simulations, we have investigated how the performance of the Neural Networks (NN) approach scales with the number of parameters to be retrieved, compared to the standard dictionary approach. We have also studied optimal training procedures by comparing different strategies for noise addition and parameter space sampling, to achieve better accuracy and robustness to noise. Four MRF sequences were considered: IR-FISP, bSSFP, IR-FISP-B1, and IR-bSSFP-B1. A comparison between NN and the dictionary approaches in reconstructing parameter maps as a function of the number of parameters to be retrieved was performed using a numerical brain phantom. Results demonstrated that training with random sampling and different levels of noise variance yielded the best performance. NN performance was at least as good as the dictionary-based approach in reconstructing parameter maps using Gaussian noise as a source of artifacts: the difference in performance increased with the number of estimated parameters because the dictionary method suffers from the coarse resolution of the parameter space sampling. The NN proved to be more efficient in memory usage and computational burden, and has great potential for solving large-scale MRF problems.


Assuntos
Aprendizado Profundo , Processamento de Imagem Assistida por Computador , Algoritmos , Encéfalo/diagnóstico por imagem , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Imagens de Fantasmas
3.
4.
Leukemia ; 35(10): 2813-2826, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34193978

RESUMO

Although targeting of cell metabolism is a promising therapeutic strategy in acute myeloid leukemia (AML), metabolic dependencies are largely unexplored. We aimed to classify AML patients based on their metabolic landscape and map connections between metabolic and genomic profiles. Combined serum and urine metabolomics improved AML characterization compared with individual biofluid analysis. At intracellular level, AML displayed dysregulated amino acid, nucleotide, lipid, and bioenergetic metabolism. The integration of intracellular and biofluid metabolomics provided a map of alterations in the metabolism of polyamine, purine, keton bodies and polyunsaturated fatty acids and tricarboxylic acid cycle. The intracellular metabolome distinguished three AML clusters, correlating with distinct genomic profiles: NPM1-mutated(mut), chromatin/spliceosome-mut and TP53-mut/aneuploid AML that were confirmed by biofluid analysis. Interestingly, integrated genomic-metabolic profiles defined two subgroups of NPM1-mut AML. One was enriched for mutations in cohesin/DNA damage-related genes (NPM1/cohesin-mut AML) and showed increased serum choline + trimethylamine-N-oxide and leucine, higher mutation load, transcriptomic signatures of reduced inflammatory status and better ex-vivo response to EGFR and MET inhibition. The transcriptional differences of enzyme-encoding genes between NPM1/cohesin-mut and NPM1-mut allowed in silico modeling of intracellular metabolic perturbations. This approach predicted alterations in NAD and purine metabolism in NPM1/cohesin-mut AML that suggest potential vulnerabilities, worthy of being therapeutically explored.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , Dano ao DNA/genética , Leucemia Mieloide Aguda/genética , Mutação/genética , Proteínas Nucleares/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromatina/genética , Feminino , Genômica/métodos , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
5.
Blood ; 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34125889

RESUMO

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes very common in oldest-old individuals, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 oldest-old individuals enrolled in two population-based studies and investigate the relationships between CHIP and associated pathologies. Clonal mutations were observed in one third of oldest-old individuals and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, ASXL1 with additional genetic lesions) and variant allele frequency ≥0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1 or JAK2 (most occurring as single lesion) were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was a common finding in oldest-old population, the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly-specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of oldest-old subjects with cytopenia had presumptive evidence of myeloid neoplasm. In conclusion, specific mutational patterns define different risk of developing myeloid neoplasms vs. inflammatory-associated diseases in oldest-old population. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.

7.
Elife ; 102021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33941312

RESUMO

Extreme longevity is the paradigm of healthy aging as individuals who reached the extreme decades of human life avoided or largely postponed all major age-related diseases. In this study, we sequenced at high coverage (90X) the whole genome of 81 semi-supercentenarians and supercentenarians [105+/110+] (mean age: 106.6 ± 1.6) and of 36 healthy unrelated geographically matched controls (mean age 68.0 ± 5.9) recruited in Italy. The results showed that 105+/110+ are characterized by a peculiar genetic background associated with efficient DNA repair mechanisms, as evidenced by both germline data (common and rare variants) and somatic mutations patterns (lower mutation load if compared to younger healthy controls). Results were replicated in a second independent cohort of 333 Italian centenarians and 358 geographically matched controls. The genetics of 105+/110+ identified DNA repair and clonal haematopoiesis as crucial players for healthy aging and for the protection from cardiovascular events.


Assuntos
Hematopoiese Clonal/genética , Reparo do DNA , Longevidade/genética , Sequenciamento Completo do Genoma/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Patrimônio Genético , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Mutação , Sequenciamento Completo do Genoma/métodos
8.
Brief Bioinform ; 22(6)2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34010955

RESUMO

The complex web of macromolecular interactions occurring within cells-the interactome-is the backbone of an increasing number of studies, but a clear consensus on the exact structure of this network is still lacking. Different genome-scale maps of human interactome have been obtained through several experimental techniques and functional analyses. Moreover, these maps can be enriched through literature-mining approaches, and different combinations of various 'source' databases have been used in the literature. It is therefore unclear to which extent the various interactomes yield similar results when used in the context of interactome-based approaches in network biology. We compared a comprehensive list of human interactomes on the basis of topology, protein complexes, molecular pathways, pathway cross-talk and disease gene prediction. In a general context of relevant heterogeneity, our study provides a series of qualitative and quantitative parameters that describe the state of the art of human interactomes and guidelines for selecting interactomes in future applications.

9.
Brain Sci ; 11(4)2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33919984

RESUMO

Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental conditions characterized by impairments in social interaction and communication and restricted patterns of behavior, interests, and activities. Although the etiopathogenesis of idiopathic ASD has not been fully elucidated, compelling evidence suggests an interaction between genetic liability and environmental factors in producing early alterations of structural and functional brain development that are detectable by magnetic resonance imaging (MRI) at the group level. This work shows the results of a network-based approach to characterize not only variations in the values of the extracted features but also in their mutual relationships that might reflect underlying brain structural differences between autistic subjects and healthy controls. We applied a network-based analysis on sMRI data from the Autism Brain Imaging Data Exchange I (ABIDE-I) database, containing 419 features extracted with FreeSurfer software. Two networks were generated: one from subjects with autistic disorder (AUT) (DSM-IV-TR), and one from typically developing controls (TD), adopting a subsampling strategy to overcome class imbalance (235 AUT, 418 TD). We compared the distribution of several node centrality measures and observed significant inter-class differences in averaged centralities. Moreover, a single-node analysis allowed us to identify the most relevant features that distinguished the groups.

10.
J Clin Oncol ; 39(11): 1223-1233, 2021 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-33539200

RESUMO

PURPOSE: Recurrently mutated genes and chromosomal abnormalities have been identified in myelodysplastic syndromes (MDS). We aim to integrate these genomic features into disease classification and prognostication. METHODS: We retrospectively enrolled 2,043 patients. Using Bayesian networks and Dirichlet processes, we combined mutations in 47 genes with cytogenetic abnormalities to identify genetic associations and subgroups. Random-effects Cox proportional hazards multistate modeling was used for developing prognostic models. An independent validation on 318 cases was performed. RESULTS: We identify eight MDS groups (clusters) according to specific genomic features. In five groups, dominant genomic features include splicing gene mutations (SF3B1, SRSF2, and U2AF1) that occur early in disease history, determine specific phenotypes, and drive disease evolution. These groups display different prognosis (groups with SF3B1 mutations being associated with better survival). Specific co-mutation patterns account for clinical heterogeneity within SF3B1- and SRSF2-related MDS. MDS with complex karyotype and/or TP53 gene abnormalities and MDS with acute leukemia-like mutations show poorest prognosis. MDS with 5q deletion are clustered into two distinct groups according to the number of mutated genes and/or presence of TP53 mutations. By integrating 63 clinical and genomic variables, we define a novel prognostic model that generates personally tailored predictions of survival. The predicted and observed outcomes correlate well in internal cross-validation and in an independent external cohort. This model substantially improves predictive accuracy of currently available prognostic tools. We have created a Web portal that allows outcome predictions to be generated for user-defined constellations of genomic and clinical features. CONCLUSION: Genomic landscape in MDS reveals distinct subgroups associated with specific clinical features and discrete patterns of evolution, providing a proof of concept for next-generation disease classification and prognosis.


Assuntos
Genômica/métodos , Síndromes Mielodisplásicas/classificação , Feminino , Humanos , Masculino , Síndromes Mielodisplásicas/genética , Prognóstico , Estudos Retrospectivos
11.
BMC Bioinformatics ; 22(1): 60, 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33563206

RESUMO

BACKGROUND: Current high-throughput technologies-i.e. whole genome sequencing, RNA-Seq, ChIP-Seq, etc.-generate huge amounts of data and their usage gets more widespread with each passing year. Complex analysis pipelines involving several computationally-intensive steps have to be applied on an increasing number of samples. Workflow management systems allow parallelization and a more efficient usage of computational power. Nevertheless, this mostly happens by assigning the available cores to a single or few samples' pipeline at a time. We refer to this approach as naive parallel strategy (NPS). Here, we discuss an alternative approach, which we refer to as concurrent execution strategy (CES), which equally distributes the available processors across every sample's pipeline. RESULTS: Theoretically, we show that the CES results, under loose conditions, in a substantial speedup, with an ideal gain range spanning from 1 to the number of samples. Also, we observe that the CES yields even faster executions since parallelly computable tasks scale sub-linearly. Practically, we tested both strategies on a whole exome sequencing pipeline applied to three publicly available matched tumour-normal sample pairs of gastrointestinal stromal tumour. The CES achieved speedups in latency up to 2-2.4 compared to the NPS. CONCLUSIONS: Our results hint that if resources distribution is further tailored to fit specific situations, an even greater gain in performance of multiple samples pipelines execution could be achieved. For this to be feasible, a benchmarking of the tools included in the pipeline would be necessary. It is our opinion these benchmarks should be consistently performed by the tools' developers. Finally, these results suggest that concurrent strategies might also lead to energy and cost savings by making feasible the usage of low power machine clusters.


Assuntos
Biologia Computacional , Sequenciamento de Nucleotídeos em Larga Escala , Software , Sequenciamento Completo do Exoma , Sequenciamento de Cromatina por Imunoprecipitação , Biologia Computacional/métodos , Sequenciamento Completo do Exoma/normas , Fluxo de Trabalho
12.
Sci Rep ; 11(1): 3030, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33542369

RESUMO

In this paper we compared taxonomic results obtained by metataxonomics (16S rRNA gene sequencing) and metagenomics (whole shotgun metagenomic sequencing) to investigate their reliability for bacteria profiling, studying the chicken gut as a model system. The experimental conditions included two compartments of gastrointestinal tracts and two sampling times. We compared the relative abundance distributions obtained with the two sequencing strategies and then tested their capability to distinguish the experimental conditions. The results showed that 16S rRNA gene sequencing detects only part of the gut microbiota community revealed by shotgun sequencing. Specifically, when a sufficient number of reads is available, Shotgun sequencing has more power to identify less abundant taxa than 16S sequencing. Finally, we showed that the less abundant genera detected only by shotgun sequencing are biologically meaningful, being able to discriminate between the experimental conditions as much as the more abundant genera detected by both sequencing strategies.


Assuntos
Bactérias/genética , Microbioma Gastrointestinal/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Metagenoma/genética , Bactérias/classificação , Humanos , Metagenômica , Microbiota/genética , Filogenia , RNA Ribossômico 16S/genética , Análise de Sequência de DNA
14.
Nature ; 589(7840): 131-136, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33239787

RESUMO

The liver connects the intestinal portal vasculature with the general circulation, using a diverse array of immune cells to protect from pathogens that translocate from the gut1. In liver lobules, blood flows from portal triads that are situated in periportal lobular regions to the central vein via a polarized sinusoidal network. Despite this asymmetry, resident immune cells in the liver are considered to be broadly dispersed across the lobule. This differs from lymphoid organs, in which immune cells adopt spatially biased positions to promote effective host defence2,3. Here we used quantitative multiplex imaging, genetic perturbations, transcriptomics, infection-based assays and mathematical modelling to reassess the relationship between the localization of immune cells in the liver and host protection. We found that myeloid and lymphoid resident immune cells concentrate around periportal regions. This asymmetric localization was not developmentally controlled, but resulted from sustained MYD88-dependent signalling induced by commensal bacteria in liver sinusoidal endothelial cells, which in turn regulated the composition of the pericellular matrix involved in the formation of chemokine gradients. In vivo experiments and modelling showed that this immune spatial polarization was more efficient than a uniform distribution in protecting against systemic bacterial dissemination. Together, these data reveal that liver sinusoidal endothelial cells sense the microbiome, actively orchestrating the localization of immune cells, to optimize host defence.


Assuntos
Microbioma Gastrointestinal/imunologia , Fígado/imunologia , Fígado/microbiologia , Simbiose/imunologia , Animais , Bactérias/imunologia , Bactérias/isolamento & purificação , Separação Celular , Quimiocina CXCL9/imunologia , Células Endoteliais/citologia , Células Endoteliais/imunologia , Feminino , Humanos , Macrófagos do Fígado/citologia , Macrófagos do Fígado/imunologia , Macrófagos do Fígado/metabolismo , Fígado/irrigação sanguínea , Fígado/citologia , Linfócitos/imunologia , Masculino , Camundongos , Modelos Imunológicos , Imagem Molecular , Células Mieloides/imunologia , Fator 88 de Diferenciação Mieloide/metabolismo , Transdução de Sinais , Simbiose/genética , Transcriptoma
15.
J Comput Biol ; 28(3): 257-268, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33370157

RESUMO

In a series of previous studies, we provided a stochastic description of a theory of synaptic plasticity. This theory, called BCM from the names of the three authors, has been formulated in two ways: the original formulation, where the plasticity threshold is defined as the square of the time-averaged neuronal activity, and a newer formulation, where the plasticity threshold is defined as the time average of the square of the neuronal activity. The newest formulation of the BCM rule of synaptic activity has interesting statistical properties, derived from a risk (or energy) function, the minimization of which leads to seeking of interesting projections in high-dimensional space. Moreover, these two rules, if implemented by a chemical master equation approach, show another interesting difference: the original rule satisfies the detailed balance, whereas the other not. Based on this different behavior, we found a continuous parameterization between these two rules. This parameterization shows a minimum that corresponds to maximum negative eigenvalues of the Jacobian matrix. In addition, the newest rule, due to the fact that it is in a nonequilibrium steady state (NESS), shows a higher level of plasticity than the original rule. This higher level of plasticity has to be interpreted in the framework of open thermodynamical systems and we show that entropy production and energy consumption in the newest rule are both less than in the original BCM rule.

16.
Microorganisms ; 8(12)2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33255715

RESUMO

An inter-laboratory proficiency test was organized to assess the ability of participants to perform shotgun metagenomic sequencing of cold smoked salmon, experimentally spiked with a mock community composed of six bacteria, one parasite, one yeast, one DNA, and two RNA viruses. Each participant applied its in-house wet-lab workflow(s) to obtain the metagenomic dataset(s), which were then collected and analyzed using MG-RAST. A total of 27 datasets were analyzed. Sample pre-processing, DNA extraction protocol, library preparation kit, and sequencing platform, influenced the abundance of specific microorganisms of the mock community. Our results highlight that despite differences in wet-lab protocols, the reads corresponding to the mock community members spiked in the cold smoked salmon, were both detected and quantified in terms of relative abundance, in the metagenomic datasets, proving the suitability of shotgun metagenomic sequencing as a genomic tool to detect microorganisms belonging to different domains in the same food matrix. The implementation of standardized wet-lab protocols would highly facilitate the comparability of shotgun metagenomic sequencing dataset across laboratories and sectors. Moreover, there is a need for clearly defining a sequencing reads threshold, to consider pathogens as detected or undetected in a food sample.

17.
Sci Rep ; 10(1): 19756, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-33184391

RESUMO

Photoplethysmography (PPG) measured by smartphone has the potential for a large scale, non-invasive, and easy-to-use screening tool. Vascular aging is linked to increased arterial stiffness, which can be measured by PPG. We investigate the feasibility of using PPG to predict healthy vascular aging (HVA) based on two approaches: machine learning (ML) and deep learning (DL). We performed data preprocessing, including detrending, demodulating, and denoising on the raw PPG signals. For ML, ridge penalized regression has been applied to 38 features extracted from PPG, whereas for DL several convolutional neural networks (CNNs) have been applied to the whole PPG signals as input. The analysis has been conducted using the crowd-sourced Heart for Heart data. The prediction performance of ML using two features (AUC of 94.7%) - the a wave of the second derivative PPG and tpr, including four covariates, sex, height, weight, and smoking - was similar to that of the best performing CNN, 12-layer ResNet (AUC of 95.3%). Without having the heavy computational cost of DL, ML might be advantageous in finding potential biomarkers for HVA prediction. The whole workflow of the procedure is clearly described, and open software has been made available to facilitate replication of the results.


Assuntos
Envelhecimento/patologia , Aprendizado Profundo , Redes Neurais de Computação , Fotopletismografia/métodos , Smartphone/estatística & dados numéricos , Doenças Vasculares/diagnóstico , Adolescente , Adulto , Idoso , Feminino , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Processamento de Sinais Assistido por Computador , Adulto Jovem
18.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 2520-2523, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018519

RESUMO

Non-contact galvanotaxis as a way to drive the cells migration could be a promising tool for a variety of biomedical applications, such as wound healing control, avoiding the interaction between electrodes and cell cultures. To this regard, the efficacy of this electrical stimulus application has to be deeper studied to control physiological migratory phenomena in a remote way.Aim of this work is to provide an experimental investigation on the mobility of cells exposed to a static electric field in a "noncontact" mode, supported by a suitable modeling of the electric field distribution inside the experimental setup. In particular, scratch assays have been carried out placing the electrodes outside the cells medium support and changing the cells holder to study more than one configuration.Clinical Relevance- In this study the in vitro experiments on the non-contact galvanotaxis, together with the numerical simulations of the exposure setup, provide a way to investigate the effects that could affect an electrically drive cell migration.


Assuntos
Eletricidade , Resposta Táctica , Bioensaio , Movimento Celular , Eletricidade Estática
19.
PLoS One ; 15(10): e0237207, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33125392

RESUMO

In this work we propose an index to estimate the gut microbiota biodiversity using a modeling approach with the aim of describing its relationship with health and aging. The gut microbiota, a complex ecosystem that links nutrition and metabolism, has a pervasive effect on all body organs and systems, undergoes profound changes with age and life-style, and substantially contributes to the pathogenesis of age-related diseases. For these reasons, the gut microbiota is a suitable candidate for assessing and quantifying healthy aging, i.e. the capability of individuals to reach an advanced age, avoiding or postponing major age-related diseases. The importance of the gut microbiota in health and aging has been proven to be related not only to its taxonomic composition, but also to its ecological properties, namely its biodiversity. Following an ecological approach, here we intended to characterize the relationship between the gut microbiota biodiversity and healthy aging through the development a parsimonious model of gut microbiota from which biodiversity can be estimated. We analysed publicly available metagenomic data relative to subjects of different ages, countries, nutritional habits and health status and we showed that a hybrid niche-neutral model well describes the observed patterns of bacterial relative abundance. Moreover, starting from such ecological modeling, we derived an estimate of the gut microbiota biodiversity that is consistent with classical indices, while having a higher statistical power. This allowed us to unveil an increase of the gut microbiota biodiversity during aging and to provide a good predictor of health status in old age, dependent on life-style and aging disorders.


Assuntos
Envelhecimento , Microbioma Gastrointestinal , Modelos Biológicos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Envelhecimento/fisiologia , Biodiversidade , Criança , Pré-Escolar , Bases de Dados de Ácidos Nucleicos , Feminino , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/fisiologia , Nível de Saúde , Envelhecimento Saudável/genética , Envelhecimento Saudável/fisiologia , Humanos , Lactente , Recém-Nascido , Masculino , Metagenoma , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética , Adulto Jovem
20.
EJNMMI Phys ; 7(1): 63, 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33044651

RESUMO

BACKGROUND: Internal dosimetry evaluation consists of a multi-step process ranging from imaging acquisition to absorbed dose calculations. Assessment of uncertainty is complicated and, for that reason, it is commonly ignored in clinical routine. However, it is essential for adequate interpretation of the results. Recently, the EANM published a practical guidance on uncertainty analysis for molecular radiotherapy based on the application of the law of propagation of uncertainty. In this study, we investigated the overall uncertainty on a sample of a patient following the EANM guidelines. The aim of this study was to provide an indication of the typical uncertainties that may be expected from performing dosimetry, to determine parameters that have the greatest effect on the accuracy of calculations and to consider the potential improvements that could be made if these effects were reduced. RESULTS: Absorbed doses and the relative uncertainties were calculated for a sample of 49 patients and a total of 154 tumours. A wide range of relative absorbed dose uncertainty values was observed (14-102%). Uncertainties associated with each quantity along the absorbed dose calculation chain (i.e. volume, recovery coefficient, calibration factor, activity, time-activity curve fitting, time-integrated activity and absorbed dose) were estimated. An equation was derived to describe the relationship between the uncertainty in the absorbed dose and the volume. The largest source of error was the VOI delineation. By postulating different values of FWHM, the impact of the imaging system spatial resolution on the uncertainties was investigated. DISCUSSION: To the best of our knowledge, this is the first analysis of uncertainty in molecular radiotherapy based on a cohort of clinical cases. Wide inter-lesion variability of absorbed dose uncertainty was observed. Hence, a proper assessment of the uncertainties associated with the calculations should be considered as a basic scientific standard. A model for a quick estimate of uncertainty without implementing the entire error propagation schema, which may be useful in clinical practice, was presented. Ameliorating spatial resolution may be in future the key factor for accurate absorbed dose assessment.

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