Explainable artificial intelligence to predict and identify prostate cancer tissue by gene expression

This work was supported by the ERDF and the Ministry of Economy, Innovation and Science of the Regional Government of Andalusia (grant number P18-RT-2248)Background and Objective: Prostate cancer is one of the most prevalent forms of cancer in men worldwide. Traditional screening strategies such as serum PSA levels, which are not necessarily cancer-specific, or digital rectal exams, which are often inconclusive, are still the screening methods used for the disease. Some studies have focused on identifying biomarkers of the disease but none have been reported for diagnosis in routine clinical practice and few studies have provided tools to assist the pathologist in the decision-making process when analyzing prostate tissue. Therefore, a classifier is proposed to predict the occurrence of PCa that provides physicians with accurate predictions and understandable explanations. Methods: A selection of 47 genes was made based on differential expression between PCa and normal tissue, GO gene ontology as well as the literature to be used as input predictors for different machine learning methods based on eXplainable Artificial Intelligence. These methods were trained using different class-balancing strategies to build accurate classifiers using gene expression data from 550 samples from ’The Cancer Genome Atlas’. Our model was validated in four external cohorts with different ancestries, totaling 463 samples. In addition, a set of SHapley Additive exPlanations was provided to help clinicians understand the underlying reasons for each decision. Results: An in-depth analysis showed that the Random Forest algorithm combined with majority class downsampling was the best performing approach with robust statistical significance. Our method achieved an average sensitivity and specificity of 0.90 and 0.8 with an AUC of 0.84 across all databases. The relevance of DLX1, MYL9 and FGFR genes for PCa screening was demonstrated in addition to the important role of novel genes such as CAV2 and MYLK. Conclusions: This model has shown good performance in 4 independent external cohorts of different ancestries and the explanations provided are consistent with each other and with the literature, opening a horizon for its application in clinical practice. In the near future, these genes, in combination with our model, could be applied to liquid biopsy to improve PCa screening.European Union (EU)Ministry of Econ-omy, Innovation and Science of the Regional Government of Andalusia P18-RT-224

Genetic structure in the paternal lineages of South East Spain revealed by the analysis of 17 Y-STRs

Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-019-41580-9.The content of this article is part of the Ph.D. thesis of María Saiz which was conducted at the University of Granada under the doctoral programme “Biomedicine”. The authors thank all of the participants who donated buccal swabs and all those who helped in the sample collection—namely, María Luisa Aceituno Villalva, Leticia Olga Rubio Lamia, and Verónica Delgado López. In addition, the authors want to thank Xiomara Gálvez for the technical assistance in the laboratory.The genetic data of 17 Y chromosome short tandem repeats in 146 unrelated donor residents in the provinces of Granada, Málaga, and Almería (GMA) were analyzed to determine the genetic legacy of the male inhabitants of the former Kingdom of Granada. A total of 139 unique haplotypes were identified. Observed allele frequencies and haplogroup frequencies were also analyzed. By AMOVA and STRUCTURE analysis, the populations of the 3 provinces could be treated genetically as a single population. The most frequent haplogroup was R1b1b2 (58.22%). By network analysis of all individuals, we observed a distribution according to haplogroup assignment. To improve the characterization of GMA population, it was compared with those of North Africa, the Iberian Peninsula, and southern Europe. In our analysis of allele frequencies and genetic distances, the GMA population lay within the Spanish population group. Further, in the STRUCTURE analysis, there was no African component in the GMA population, confirming that, based on our genetic markers, the GMA population does not reflect any male genetic influence of the North African people. The presence of African haplogroups in the GMA population is irrelevant when their frequency is compared with those in other European populations

Overdamped deterministic ratchets driven by multifrequency forces

Presented at the XVIII Marian Smoluchowski Symposium on Statistical Physics, Zakopane, Poland, September 3–6, 2005We investigate a dissipative, deterministic ratchet model in the overdamped regime driven by a rectangular force. Extensive numerical calculations are presented in a diagram depicting the drift velocity as a function of a wide range of the driving parameter values. We also present some theoretical considerations which explain some features of the mentioned diagram. In particular, we proof the existence of regions in the driving parameter space with bounded particle motion possessing zero current. Moreover, we present an explicit analytical expression for the drift velocity in the adiabatic limit.Ministerio de Educación y Ciencia of Spain (FIS2005-02884) and the Junta de Andalucía. Also acknowledges the Ministerio de Educación y Ciencia o f Spain for a contract under the Juan de la Cierva program

EL ADN ANTIGUO UNA HERRAMIENTA PARA DESCIFRAR LA HISTORIA

The evolution of biomolecular techniques, as the PCR; has improved the quality of genetic analysis in f ields like forensic science and biomedicine. To these days, it is possible to obtain DNA  from  extinguished  species;  called  ancient  DNA  (aDNA).  The  analysis  of  aDNA  has been really helpful in  anthropology and forensic sciences. Some important historical cases have been elucidated through these techniques  as the identif ication of remains of Christopher Columbus  and  the  Romanov  dynasty.  The  main  aim  of  this  paper  is  to  introduce  in  detail ancient  DNA,  its applications  and  the  main  advantages  and  disadvantages  of working  with this type of DNA.Gracias a la evolución de las técnicas biomoleculares  como la PCR, campos como la medicina forense y la biomedicina han mejorado la calidad de los análisis genéticos. Actualmente, incluso es posible obtener ADN de especies  ya extinguidas;  este tipo de ADN se llama ADN antiguo (aDNA).  El  análisis del aDNA ha sido de gran ayuda en la antropología  y la ciencia forense. Importantes casos históricos han sido resueltos gracias a este tipo de técnicas como la identif icación  de los restos  óseos  de  Cristóbal  Colón  y la dinastía  Romanov  entre  otros. El principal objetivo de este artículo es hacer una  introducción detallada del aDNA, sus aplicaciones  y  las  principales  ventajas  e  inconvenientes  que  se  encuentran  al  trabajar  con este tipo de ADN

Bisphenol A Analogues in Food and Their Hormonal and Obesogenic Effects: A Review

Bisphenol A (BPA) is the most well-known compound from the bisphenol family. As BPA has recently come under pressure, it is being replaced by compounds very similar in structure, but data on the occurrence of these BPA analogues in food and human matrices are limited. The main objective of this work was to investigate human exposure to BPA and analogues and the associated health effects. We performed a literature review of the available research made in humans, in in vivo and in vitro tests. The findings support the idea that exposure to BPA analogues may have an impact on human health, especially in terms of obesity and other adverse health effects in children.This research was funded by Plan Estatal de I+D+I 2013-2016 Proyecto cofinanciado FEDER-ISCIII PI17/01758 and by Fundación Mapfre MAPFRE2018

Interplay between genetics and lifestyle on pain susceptibility in women with fibromyalgia: the al-Ándalus project

This work was supported by the Spanish Ministry of Economy and Competitiveness (I + D+i DEP2010-15639, I + D+i DEP2013-40908-R to M.D.-F.; BES-2014-067612 to F.E.-L.), the Spanish Ministry of Education (FPU13/03410 to D.S.-T.; FPU15/0002 to B.G.-C.), the Consejeria de Turismo, Comercio y Deporte, Junta de Andalucia (CTCD-201000019242-TRA to M.D.-F.), the Consejeria de Salud, Junta de Andalucia (PI-0520-2016 to M.D.-F.) and the University of Granada, Plan Propio de Investigacion 2016, Excellence actions: Units of Excellence; Unit of Excellence on Exercise and Health (UCEES). The funders of the present study did not have any role in the study design, data collection and analyses, decision to publish or preparation of the manuscript.Objectives. It is widely acknowledged that the experience of pain is promoted by both genetic susceptibility and environmental factors such as engaging in physical activity (PA), and that pain-related cognitions are also important. Thus, the purpose of the present study was to test the association of 64 polymorphisms (34 candidate genes) and the gene–gene, gene–PA and gene–sedentary behaviour interactions with pain and pain-related cognitions in women with FM. Methods. Saliva samples from 274 women with FM [mean (S.D.) age 51.7 (7.7) years] were collected for extracting DNA. We measured PA and sedentary behaviour by accelerometers for a week, pain with algometry and questionnaires, and pain-related cognitions with questionnaires. To assess the robustness of the results, a meta-analysis was also performed. Results. The rs6311 and rs6313 polymorphisms (5-hydroxytryptamine receptor 2A, HTR2A) were individually related to algometer scores. The interaction of rs4818 (catechol-O-methyltransferase, COMT) and rs1799971 (opioid receptor l gene, OPRM1) was related to pain catastrophizing. Five gene–behaviour interactions were significant: the interactions of sedentary behaviour with rs1383914 (adrenoceptor alpha 1A, ADRA1A), rs6860 (charged multivesicular body protein 1A, CHMP1A), rs4680 (COMT), rs165599 (COMT) and rs12994338 (SCN9A) on bodily pain subscale of the Short Form 36. Furthermore, the meta-analysis showed an association between rs4680 (COMT) and severity of FM symptoms (codominant model, P-value 0.032). Conclusion. The HTR2A gene (individually), COMT and OPRM1 gene–gene interaction, and the interactions of sedentary behaviour with ADRA1A, CHMP1A, COMT and SCN9A genes were associated with pain-related outcomes. Collectively, findings from the present study indicate a modest contribution of genetics and gene– sedentary behaviour interaction to pain and pain catastrophizing in women with FM. Future research should examine whether reducing sedentary behaviour is particularly beneficial for reducing pain in women with genetic susceptibility to pain.Spanish Government I + D+i DEP2010-15639 I + D+i DEP2013-40908-R BES-2014-067612 FPU13/03410 FPU15/0002Junta de Andalucia CTCD-201000019242-TRA PI-0520-2016University of Granada, Plan Propio de InvestigacionUnit of Excellence on Exercise and Health (UCEES

Identification of MiRNAs as Viable Aggressiveness Biomarkers for Prostate Cancer

MiRNAs play a relevant role in PC (prostate cancer) by the regulation in the expression of several pathways’ AR (androgen receptor), cellular cycle, apoptosis, MET (mesenchymal epithelium transition), or metastasis. Here, we report the role of several miRNAs’ expression patterns, such as miR-miR-93-5p, miR-23c, miR-210-3p, miR-221-3p, miR-592, miR-141, miR-375, and miR-130b, with relevance in processes like cell proliferation and MET. Using Trizol® extraction protocol and TaqMan™ specific probes for amplification, we performed miRNAs’ analysis of 159 PC fresh tissues and 60 plasmas from peripheral blood samples. We had clinical data from all samples including PSA, Gleason, TNM, and D’Amico risk. Moreover, a bioinformatic analysis in TCGA (The Cancer Genome Atlas) was included to analyze the effect of the most relevant miRNAs according to aggressiveness in an extensive cohort (n = 531). We found that miR-210-3p, miR-23c, miR-592, and miR-93-5p are the most suitable biomarkers for PC aggressiveness and diagnosis, respectively. In fact, according with our results, miR93-5p seems the most promising non-invasive biomarker for PC. To sum up, miR-210-3p, miR-23c, miR-592, and miR93-5p miRNAs are suggested to be potential biomarkers for PC risk stratification that could be included in non-invasive strategies such as liquid biopsy in precision medicine for PC management.Regional Ministry of Health and Families of the Andalusian Government (ref: PI-0319-2018)FIBAO (Andalusian Public Foundation for Biomedical Research in Eastern Andalusia, “Alejandro Otero”

Determination of Exosome Mitochondrial DNA as a Biomarker of Renal Cancer Aggressiveness

This study is partially supported by ID#53169721 project funded by Pfizer and the exosomes characterization was financed thanks to the grant PY20_00241 (FEDER/Junta de Andalucia-Regional Ministry of Economic Transformation, Industry, Knowledge and Universities).Here, the role of non-invasive biomarkers in liquid biopsy was evaluated, mainly in exosomes and mitochondrial DNA (mtDNA) as promising, novel, and stable biomarkers for renal cell carcinoma (RCC). A total of 140 fractions (named from B to F) obtained by ultracentrifugations of whole blood samples from 28 individuals (13 patients and 15 controls) were included. Nanoparticle Tracking Analysis (NTA) was conducted to characterized exosomal fraction. Subsequently, an analysis of digital PCR (dPCR) using the QuantStudio (TM) 3D Digital PCR platform was performed and the quantification of mtDNA copy number by QuantStudioTM 12K Flex Real-Time PCR System (qPCR) was developed. Moreover, Next Generation Sequencing (NGS) analyses were included using MiSeq system (Illumina, San Diego, CA, USA). An F fraction, which contains all exosome data and all mitochondrial markers, was identified in dPCR and qPCR with statistically significant power (adjusted p values <= 0.03) when comparing cases and controls. Moreover, present analysis in mtDNA showed a relevant significance in RCC aggressiveness. To sum up, this is the first time a relation between exosomal mtDNA markers and clinical management of RCC is analyzed. We suggest a promising strategy for future liquid biopsy RCC analysis, although more analysis should be performed prior to application in routine clinical practice.Pfizer 53169721FEDER/Junta de Andalucia-Regional Ministry of Economic Transformation, Industry, Knowledge and Universities PY20_0024

Proyecto de Innovación Docente Básico Aplicación de la Bioquímica al contexto profesional para los alumnos del Grado de Ciencias de la Actividad Física y el Deporte del campus de Granada y Melilla

Se agradece la colaboración del Centro de Salud y Deporte BuenaVida.Algunos alumnos del Grado de Fisioterapia y del Grado de Ciencias de la Actividad Física y el Deporte, carecen de conocimientos previos de Bioquímica, lo que dificulta la comprensión de dicha asignatura. Por ello, algunos de estos alumnos abandonan la asignatura desde el inicio de curso, lo que interfiere también en el aprendizaje de otras asignaturas, cuyos conocimientos están interconectados con la Bioquímica, como la Fisiología, Biofísica y Nutrición. Además, un porcentaje elevado de estos alumnos piensa que los conocimientos de Bioquímica no tienen aplicabilidad en su futuro ejercicio profesional. Nuestro principal objetivo es que el alumno desde el inicio de las clases de Bioquímica se entusiasme por la asignatura, y para ello es imprescindible que pueda ver la aplicabilidad de la Bioquímica en su futura vida laboral. La metodología que vamos a emplear se basa en casos prácticos reales, para que el alumno esté “in situ” en uno de sus posibles escenarios profesionales. Con este fin, los casos prácticos serán planteados por personal sanitario y pacientes de la Clínicas de rehabilitación “Fisionat, Osteopatía y Fisioterapia” y por los profesionales y usuarios del Centro de Salud y Deporte Buena Vida de Granada”. Las preguntas de los casos prácticos podrán tratar temas, tales como los aspectos metabólicos que, mediante el ejercicio o la nutrición pueden interferir en la salud o las bases metabólicas de algunas enfermedades. Para ello, utilizaremos la aplicación libre y de código abierto para la grabación de vídeo “OBS-Studio” y, posteriormente, el video será subtitulado para garantizar la integración plena de todo el alumnado. Dicho material será subido al Youtube en modo privado y accesible sólo para nuestros alumnos. Las nuevas tecnologías parecen un entorno amigable para los alumnos y le predispondrán favorablemente al desarrollo de esta actividad. Asimismo, mediante esta metodología el alumno también desarrollará la capacidad crítica y autorreflexiva, discusión y defensa de un saber, y mejorará su comunicación oral

Follow-Up Biomarkers in the Evolution of Prostate Cancer, Levels of S100A4 as a Detector in Plasma

The management and screening of prostate cancer (PC) is still the main problem in clinical practice. In this study, we investigated the role of aggressiveness genetic markers for PC stratification. We analyzed 201 plasma samples from PC patients and controls by digital PCR. For selection and validation, 26 formalin-fixed paraffin-embedded tissues, 12 fresh tissues, and 24 plasma samples were characterized by RNA-Seq, immunochemistry, immunofluorescence, Western blot, and extracellular-vesicles analyses. We identified three novel non-invasive biomarkers; all with an increased expression pattern in patients (PCA3: p = 0.002, S100A4: p <= 0.0001 and MRC2: p = 0.005). S100A4 presents the most informative AUC (area under the curve) (0.735). Combination of S100A4, MRC2, and PCA3 increases the discriminatory power between patients and controls and between different more and less aggressive stages (AUC = 0.761, p <= 0.0001). However, although a sensitivity of 97.47% in PCA3 and a specificity of 90.32% in S100A4 was reached, the detection signal level could be variable in some analyses owing to tumor heterogeneity. This is the first time that the role of S100A4 and MRC2 has been described in PC aggressiveness. Moreover, the combination of S100A4, MRC2, and PCA3 has never been described as a non-invasive biomarker for PC screening and aggressiveness.Ministry of Health, Andalusia Government Leonardo de la Pena 2020 research grant - Urology Research Foundation (FIU) PI-0319-201