Defining new biotypes in Prostate Cancer for diagnosis, prognosis and therapeutic intervention

El cáncer de próstata (CaP) es el segundo tumor más frecuente en hombres y la sexta causa de muerte por cáncer. Así pues, esta enfermedad constituye un problema socio-sanitario prioritario para el sistema de Salud Pública. Actualmente, las herramientas para orientar el diagnóstico en CaP (PSA y DRE) no son cáncer específicas y presentan distintas limitaciones tales como el alto número de falsos positivos (aproximadamente un 70% en un rango de PSA de 4-10 ng/ml) que dan lugar a complicaciones asociadas con el proceso de biopsia. Además, un gran número de los CaP diagnosticados son tumores de bajo grado implicando un sobre-diagnóstico y sobre-tratamiento de esta enfermedad. Sin embargo, otros CaP tendrán un comportamiento pronóstico más agresivo que dará lugar a la progresión de la enfermedad y en último término a la muerte del paciente. Estas diferencias en el comportamiento clínico del CaP se explican por una alta heterogeneidad molecular presente en este tumor. En este contexto de heterogeneidad molecular nuestro objetivo se centra en la búsqueda de nuevos biomarcadores identificables mediante procedimientos no invasivos y capaces de clasificar a los pacientes con CaP de acuerdo a biotipos moleculares asociados con diferentes parámetros clínico-patológicos y distinto riesgo de progresión. En este trabajo exploramos el papel que tienen los miRNAs como nueva fuente de biomarcadores en CaP y encontramos que el miR-182 y el miR-187 juegan un papel clave en la patogénesis y el desarrollo del CaP en ambos contextos, el diagnóstico (miR-187) y el pronóstico (miR-182). Además, identificamos ALDH1A3, un gen regulado por andrógenos, como diana del miR-187 y como potencial biomarcador en CaP. En nuestra búsqueda de nuevos biomarcadores estudiamos también el papel que tiene el gen SPOP en CaP confirmando su pérdida de expresión y mutaciones en CaP y siendo el primer grupo en describir la asociación de estas alteraciones moleculares con el pronóstico en CaP. Además en nuestro trabajo también intentamos ofrecer nuevas alternativas terapéuticas para el tratamiento del CaP avanzado de acuerdo con el biotipo molecular. Así, nuestro hallazgo de la asociación directa entre IGF-IR y TMPRSS2-ERG y la mayor sensibilidad de este grupo a los inhibidores de IGF-IR nos llevaron a proponer este subgrupo de pacientes como población diana -biotipo- para la inhibición de IGF-IR.Prostate cancer (PCa) is the second most frequent tumor in men and the sixth cause of cancer death. Hence, this disease constitutes a primary socio-sanitary and Public Health problem. Currently, the tools to orientate the PCa diagnosis (PSA and DRE) are not cancer specific and present several limitations such as the high rate of false positives (approximately 70% in the PSA range 4-10 ng/ml) leading to biopsy-associated complications. Furthermore, a high percentage of diagnosed PCa are low-grade tumors meaning a high overdiagnosis and overtreatment. On the other hand, other PCa will have a more aggressive prognostic behavior that could lead to disease progression and patient death. This different clinical behavior is translated into a high molecular heterogeneity. In this context of molecular heterogeneity we aimed to find new biomarkers identifiable by non-invasive procedures able to classify PCa patients according to molecular biotypes associated with different clinico-pathological parameters and risk of progression. In this work we explored the role of miRNAs as a source of new biomarkers in PCa and we found that miR-182 and miR-187 play a key role in the pathogenesis and development of PCa in both the diagnostic (miR-187) and prognostic settings (miR-182). Furthermore, we identified ALDH1A3, an androgen-regulated gene, as a target of miR-187 that also plays a role as biomarker for PCa. In our search for new biomarkers we also assessed the role of SPOP gene in PCa confirming its loss of expression and mutations in PCa but also being the first group to describe the association of these molecular alterations with PCa prognosis. Moreover in our work we also tried to offer new therapeutic alternatives for advanced PCa treatment according to the molecular biotype. Our finding of a direct association between IGF-IR and TMPRSS2-ERG and the higher sensitivity of this group to IGF-IR inhibitor agents lead us to propose this subgroup of patients as a target candidate population -biotype- for IGF-IR inhibition

Quantitative and Qualitative Analysis of Blood-based Liquid Biopsies to Inform Clinical Decision-making in Prostate Cancer

ADN tumoral circulant; Medicina de precisió; Càncer de pròstataADN tumoral circulante; Medicina de precisión; Cáncer de próstataCirculating tumor DNA; Precision medicine; Prostate cancerContext Genomic stratification can impact prostate cancer (PC) care through diagnostic, prognostic, and predictive biomarkers that aid in clinical decision-making. The temporal and spatial genomic heterogeneity of PC together with the challenges of acquiring metastatic tissue biopsies hinder implementation of tissue-based molecular profiling in routine clinical practice. Blood-based liquid biopsies are an attractive, minimally invasive alternative. Objective To review the clinical value of blood-based liquid biopsy assays in PC and identify potential applications to accelerate the development of precision medicine. Evidence acquisition A systematic review of PubMed/MEDLINE was performed to identify relevant literature on blood-based circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and extracellular vesicles (EVs) in PC. Evidence synthesis Liquid biopsy has emerged as a practical tool to profile tumor dynamics over time, elucidating features that evolve (genome, epigenome, transcriptome, and proteome) with tumor progression. Liquid biopsy tests encompass analysis of DNA, RNA, and proteins that can be detected in CTCs, ctDNA, or EVs. Blood-based liquid biopsies have demonstrated promise in the context of localized tumors (diagnostic signatures, risk stratification, and disease monitoring) and advanced disease (response/resistance biomarkers and prognostic markers). Conclusions Liquid biopsies have value as a source of prognostic, predictive, and response biomarkers in PC. Most clinical applications have been developed in the advanced metastatic setting, where CTC and ctDNA yields are significantly higher. However, standardization of assays and analytical/clinical validation is necessary prior to clinical implementation

Diffusion MRI signal cumulants and hepatocyte microstructure at fixed diffusion time: insights from simulations, 9.4T imaging, and histology

Histology; Liver; MicrostructureHistología; Hígado; MicroestructuraHistologia; Fetge; MicroestructuraPurpose Relationships between diffusion-weighted MRI signals and hepatocyte microstructure were investigated to inform liver diffusion MRI modeling, focusing on the following question: Can cell size and diffusivity be estimated at fixed diffusion time, realistic SNR, and negligible contribution from extracellular/extravascular water and exchange? Methods Monte Carlo simulations were performed within synthetic hepatocytes for varying cell size/diffusivity L / D0 , and clinical protocols (single diffusion encoding; maximum b-value: {1000, 1500, 2000} s/mm2; 5 unique gradient duration/separation pairs; SNR = { ∞ , 100, 80, 40, 20}), accounting for heterogeneity in (D0,L) and perfusion contamination. Diffusion ( D ) and kurtosis ( K ) coefficients were calculated, and relationships between (D0,L) and (D,K) were visualized. Functions mapping (D,K) to (D0,L) were computed to predict unseen (D0,L) values, tested for their ability to classify discrete cell-size contrasts, and deployed on 9.4T ex vivo MRI-histology data of fixed mouse livers Results Relationships between (D,K) and (D0,L) are complex and depend on the diffusion encoding. Functions mapping (D,K) to (D0,L) captures salient characteristics of D0(D,K) and L(D,K) dependencies. Mappings are not always accurate, but they enable just under 70% accuracy in a three-class cell-size classification task (for SNR = 20, bmax = 1500 s/mm2, δ = 20 ms, and Δ = 75 ms). MRI detects cell-size contrasts in the mouse livers that are confirmed by histology, but overestimates the largest cell sizes. Conclusion Salient information about liver cell size and diffusivity may be retrieved from minimal diffusion encodings at fixed diffusion time, in experimental conditions and pathological scenarios for which extracellular, extravascular water and exchange are negligible.This project was supported by Fundació La Caixa and by the investigator-initiated PREdICT study at the Vall d'Hebron Institute of Oncology (Barcelona), funded by AstraZeneca and supporting FG. FG has received funding from the postdoctoral fellowships programme Beatriu de Pinós (2020 BP 00117), funded by the Secretary of Universities and Research (Government of Catalonia). KB is funded by a Beatriu de Pinós post-doctoral grant (2019 BP 00182). RPL is supported by a CRIS Foundation Talent Award (TALENT19-05), the Instituto de Salud Carlos III-Investigación en Salud (PI18/01395), Spanish Ministry for Science, Innovation and Universities (RTI2018-095209-B-C21, FIS-G64384969), Prostate Cancer Foundation Young Investigator Award and Fero Foundation. ICS is supported by a fellowship from Fundació ”la Caixa” (ID 100010434) and the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 847648, fellowship code LCF/BQ/PI20/117600

Genomic Biomarkers and Genome-Wide Loss-of-Heterozygosity Scores in Metastatic Prostate Cancer Following Progression on Androgen-Targeting Therapies

Genomic biomarkers; Prostate cancer; Targeting therapiesBiomarcadores genómicos; Cáncer de próstata; Terapias dirigidasBiomarcadors genòmics; Càncer de pròstata; Teràpies dirigidesPURPOSE To study the impact of standard-of-care hormonal therapies on metastatic prostate cancer (mPC) clinical genomic profiles in real-world practice, with a focus on homologous recombination-repair (HRR) genes. PATIENTS AND METHODS Targeted next-generation sequencing of 1,302 patients with mPC was pursued using the FoundationOne or FoundationOne CDx assays. Longitudinal clinical data for correlative analysis were curated via technology-enabled abstraction of electronic health records. Genomic biomarkers, including individual gene aberrations and genome-wide loss-of-heterozygosity (gLOH) scores, were compared according to biopsy location and time of sample acquisition (androgen deprivation therapy [ADT]-naïve, ADT-progression and post-ADT, and novel hormonal therapies [NHT]-progression), using chi-square and Wilcoxon rank-sum tests. Multivariable analysis used linear regression. False-discovery rate of 0.05 was applied to account for multiple comparisons. RESULTS Eight hundred forty (65%), 132 (10%), and 330 (25%) biopsies were ADT-naïve, ADT-progression, and NHT-progression, respectively. Later-stage samples were enriched for AR, MYC, TP53, PTEN, and RB1 aberrations (all adjusted P values < .05), but prevalence of HRR-related BRCA2, ATM, and CDK12 aberrations remained stable. Primary and metastatic ADT-naïve biopsies presented similar prevalence of TP53 (36% v 31%) and BRCA2 (8% v 7%) aberrations; 81% of ADT-naïve BRCA2-mutated samples presented BRCA2 biallelic loss. Higher gLOH scores were independently associated with HRR genes (BRCA2, PALB2, and FANCA), TP53, and RB1 aberrations, and with prior exposure to hormonal therapies in multivariable analysis. CONCLUSION Prevalence of HRR-gene aberrations remains stable along mPC progression, supporting the use of diagnostic biopsies to guide poly (ADP-ribose) polymerase inhibitor treatment in metastatic castration-resistant prostate cancer. gLOH scores increase with emerging resistance to hormonal therapies, independently of individual HRR gene mutations

Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-alpha 2 in 10 patients: IFN-alpha 2 only in three, IFN-alpha 2 plus IFN-omega in five, and IFN-alpha 2, IFN-omega plus IFN-beta in two; IFN-omega only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-alpha 2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-omega in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-alpha 2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-. only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-omega and/or IFN-alpha 2

Insulin-like growth factor 1 receptor affects the survival of primary prostate cancer patients depending on TMPRSS2-ERG status

Abstract Background Prostate cancer (PCa) is characterized by clinical and biological heterogeneity and has differential outcomes and mortality rates. Therefore, it is necessary to identify molecular alterations to define new therapeutic strategies based on the risk of progression. In this study, the prognostic relevance of the insulin-like growth factor (IGF) system was examined in molecular subtypes defined by TMPRSS2-ERG (T2E) gene fusion within a series of patients with primary localized PCa. Methods A cohort of 270 formalin-fixed and paraffin-embedded (FFPE) primary PCa samples from patients with more than 5 years’ follow-up was collected. IGF-1R, IGF-1, IGFBP-3 and INSR expression was analyzed using quantitative RT-PCR. The T2E status and immunohistochemical ERG findings were considered in the analyses. The association with both biochemical and clinical progression-free survival (BPFS and PFS, respectively) was evaluated for the different molecular subtypes using the Kaplan-Meier proportional risk log-rank test and the Cox proportional hazards model. Results An association between IGF-1R overexpression and better BPFS was found in T2E-negative patients (35.3% BPFS, p-value = 0.016). Multivariate analysis demonstrated that IGF-1R expression constitutes an independent variable in T2E-negative patients [HR: 0.41. CI 95% (0.2–0.82), p = 0.013]. These data were confirmed using immunohistochemistry of ERG as subrogate of T2E. High IGF-1 expression correlated with prolonged BPFS and PFS independent of the T2E status. Conclusions IGF-1R, a reported target of T2E, constitutes an independent factor for good prognosis in T2E-negative PCa. Quantitative evaluation of IGF-1/IGF-1R expression combined with molecular assessment of T2E status or ERG protein expression represents a useful marker for tumor progression in localized PCa

Quantitative and Qualitative Analysis of Blood-based Liquid Biopsies to Inform Clinical Decision-making in Prostate Cancer.

ContextGenomic stratification can impact prostate cancer (PC) care through diagnostic, prognostic, and predictive biomarkers that aid in clinical decision-making. The temporal and spatial genomic heterogeneity of PC together with the challenges of acquiring metastatic tissue biopsies hinder implementation of tissue-based molecular profiling in routine clinical practice. Blood-based liquid biopsies are an attractive, minimally invasive alternative.ObjectiveTo review the clinical value of blood-based liquid biopsy assays in PC and identify potential applications to accelerate the development of precision medicine.Evidence acquisitionA systematic review of PubMed/MEDLINE was performed to identify relevant literature on blood-based circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and extracellular vesicles (EVs) in PC.Evidence synthesisLiquid biopsy has emerged as a practical tool to profile tumor dynamics over time, elucidating features that evolve (genome, epigenome, transcriptome, and proteome) with tumor progression. Liquid biopsy tests encompass analysis of DNA, RNA, and proteins that can be detected in CTCs, ctDNA, or EVs. Blood-based liquid biopsies have demonstrated promise in the context of localized tumors (diagnostic signatures, risk stratification, and disease monitoring) and advanced disease (response/resistance biomarkers and prognostic markers).ConclusionsLiquid biopsies have value as a source of prognostic, predictive, and response biomarkers in PC. Most clinical applications have been developed in the advanced metastatic setting, where CTC and ctDNA yields are significantly higher. However, standardization of assays and analytical/clinical validation is necessary prior to clinical implementation.Patient summaryTraces of tumors can be isolated from blood samples from patients with prostate cancer either as whole cells or as DNA fragments. These traces provide information on tumor features. These minimally invasive tests can guide diagnosis and treatment selection

Extracción de atributos faciales mediante redes convolucionales

This project focuses on the extraction of facial attributes {namely, gender, age and some other minor features{ using convolutional neu- ral networks. We build on previous work [11] that has developed an eficient, accurate architecture for the task of face recognition and aim to use this architecture as a feature extractor on which to de- velop our classification networks. On this basis, our gender classifi- cation network achieves state of the art results on the CelebA test set [37]. The next facet of our project aims to check if a multi-label model could outperform independently trained networks with the same data by taking advantage of correlations between these attributes on the training data; for example taking advantage of the gender- specific age characteristics and age-specific gender characteristics inherent to facial images. The results, although not managing to overcome the individually trained models, fall really close behind, proving at least that this architecture is able to learn to classify multiple attributes without a mayor loss of accuracy. ---RESUMEN--- Este trabajo se centra en la extracción de atributos faciales { género y edad entre otros{ mediante redes neuronales convoluciona- les. Nos basamos en un trabajo previo [11] que desarrolla una red de gran eficiencia y precisión en la tares de reconocimiento facial y lo usamos como extractor de características para construir sobre este nuestros sistemas clasificadores. De esta forma obtenemos una red de clasificación de género que alcanza el estado del arte en el conjunto de evaluación de CelebA [37]. La siguiente parte de nuestro proyecto trata de comprobar si una red multi-etiqueta puede obtener mejores resultados que redes entrenadas independientemente con los mismos datos aprovechando la correlación entre estos atributos en los datos de entrenamiento; por ejemplo la clasificación de género debe tener en cuenta carac- terísticas que son dependientes de la edad, y viceversa. Aunque los resultados no han probado esta hipótesis, si se han quedado lo su- ficientemente cerca como para afirmar que esta red tiene capacidad como para clasificar múltiples atributos simultáneamente sin sufrir grandes pérdidas de precisión