42 research outputs found
Explainable machine learning identifies a polygenic risk score as a key predictor of pancreatic cancer risk in the UK Biobank
No full textBackground: Predicting the risk of developing pancreatic ductal adenocarcinoma (PDAC) is of paramount importance, given its high mortality rate. Current PDAC risk prediction models rely on a limited number of variables, do not include genetics, and have a modest accuracy. Aim: This study aimed to develop an interpretable PDAC risk prediction model, based on machine learning (ML). Methods: Five ML models (Adaptive Boosting, eXtreme Gradient Boosting, CatBoost, Deep Forest and Random Forest) built on 56 exposome variables and a polygenic risk score (PRS) were tested in 654 PDAC cases and 1,308 controls of the UK Biobank. Additionally, SHapley Additive exPlanation (SHAP) and Global model Interpretation via the Recursive Partitioning (Girp) were employed to explain the models. Results: All models provided similar performance, but based on recall the best was CatBoost (77.10 %). SHAP highlighted age and the PRS as primary contributors across all models. Girp developed rules to discern cases from controls, identifying age, PRS, and pancreatitis in most of the rules. Conclusion: The predictive models tested have exhibited good performance, indicating their potential application in the clinical field in the near future, with the PRS playing a key role in identifying high-risk individuals as demonstrated by the explainers
Long or short? Telomere length and pancreatic cancer and its precursor lesions, a narrative review
No full textPancreatic ductal adenocarcinoma (PDAC) is the most common and lethal form of pancreatic cancer, with a survival approaching only 11% at 5 years after diagnosis. In the last 15 years, telomere length (TL) measured in leukocyte (LTL) has been studied in relation to PDAC risk. The majority of the studies reported an association between short LTL and increased PDAC risk, but the results are heterogeneous. Genome-wide association studies have identified several single-nucleotide polymorphisms (SNPs) in the telomerase reverse transcriptase (TERT) gene as susceptibility loci for PDAC. Polygenic risk scores computed using SNPs associated with LTL have been tested in relation to PDAC susceptibility with various methods and giving contrasting results. The aim of this review is to analyze all publications carried out specifically on LTL, considering LTL measured with qPCR and with genetic proxies, and PDAC risk. Additionally, we will give an overview of the most relevant associations between SNPs in telomere-associated genes and PDAC, to answer the question shorter or longer? Which one of the two is associated with PDAC risk
Physical Activity, Sedentary Behavior, and Pancreatic Cancer Risk: A Mendelian Randomization Study
No full textPancreatic cancer is currently the seventh leading cause of cancer death worldwide. Understanding whether modifiable factors increase or decrease the risk of this disease is central to facilitating primary prevention. Several epidemiological studies have described the benefits of physical activity, and the risks associated with sedentary behavior, in relation to cancer. This study aimed to assess evidence of causal effects of physical activity and sedentary behavior on pancreatic cancer risk. We conducted a two-sample Mendelian randomization study using publicly available data for genetic variants associated with physical activity and sedentary behavior traits and genetic data from the Pancreatic Cancer Cohort Consortium (PanScan), the Pancreatic Cancer Case-Control Consortium (PanC4), and the FinnGen study for a total of 10 018 pancreatic cancer cases and 266 638 controls. We also investigated the role of body mass index (BMI) as a possible mediator between physical activity and sedentary traits and risk of developing pancreatic cancer. We found evidence of a causal association between genetically determined hours spent watching television (hours per day) and increased risk of pancreatic cancer for each hour increment (PanScan-PanC4 odds ratio = 1.52, 95% confidence interval 1.17-1.98, P = .002). Additionally, mediation analysis showed that genetically determined television-watching time was strongly associated with BMI, and the estimated proportion of the effect of television-watching time on pancreatic cancer risk mediated by BMI was 54%. This study reports the first Mendelian randomization-based evidence of a causal association between a measure of sedentary behavior (television-watching time) and risk of pancreatic cancer and that this is strongly mediated by BMI. Summary: Pancreatic cancer is a deadly disease that is predicted to become the second leading cause of cancer-related deaths by 2030. Physical activity and sedentary behaviors have been linked to cancer risk and survival. However, there is limited research on their correlation with pancreatic cancer. To investigate this, we used a Mendelian randomization approach to examine the genetic predisposition to physical activity and sedentariness and their relation to pancreatic cancer risk, while excluding external confounders. Our findings revealed a causal link between the time spent watching television and an increased risk of pancreatic cancer. Additionally, we determined that over half of the effect of watching television on pancreatic risk is mediated by the individual's BMI
The local environment and germline genetic variation predict cancer risk in the UK Biobank prospective cohort
No full textBackground: There is a growing body of evidence on the effect of the local environment exposure on cancer susceptibility. Nonetheless, several of the associations remain controversial. Moreover, our understanding of the possible interaction between the local environment and the genetic variability is still very limited. Objective: The aim of this study was to clarify the role of the local environment and its possible interplay with genetics on common cancers development.Methods: Using the UK Biobank (UKBB) prospective cohort, we selected 12 local environment exposures: nitrogen oxides, nitrogen dioxides, particulate matter (10 and 2.5 mu m), noise pollution, urban traffic, living distance from the coast, percentage of greenspace, natural environment, water, and domestic garden within 1000 m from the residential coordinates of each participant. All these exposures were tested for association with 17 different types of cancer for a total of 53,270 cases and 302,645 controls. Additionally, a polygenic score (PGS) was computed for each cancer, to test possible gene-environment interactions. Finally, mediation analyses were carried out.Results: Thirty-six statistically significant associations considering multiple testing (p < 2.19 x 10(-4)) were observed. Among the novel associations we observed that individuals living farther from the coast had a higher risk of developing prostate cancer (OR = 1.13, CI95% = 1.06-1.20, P = 1.98 x 10(-4)). This association was partially mediated by physical activity (indirect effect (IE) =-8.48 x 10(-7)) and the time spent outdoor (IE = 9.07 x 10(-6)). All PGSs showed statistically significant associations. Finally, genome-environment interaction analysis showed that local environment and genetic variability affect cancer risk independently.Discussion: Living close to the coast and air pollution were associated with a decreased risk of prostate cancer and skin melanoma, respectively. These findings from the UKBB support the role of the local environment on cancer development, which is independent from genetics and may be mediated by several lifestyle factors
Big data analysis to discover genetic and environmental pancreatic cancer risk factors.
No full textL'adenocarcinoma duttale pancreatico (PDAC) è una malattia complessa che insorge dall'interazione tra la componente genetica e l’esposizione ambientale. Sebbene la conoscenza sui fattori di rischio del PDAC sia limitata, nessuno studio ha esaminato in modo esaustivo l'esposoma (definito come la misura di tutte le esposizioni ai fattori di rischio) in combinazione con la variabilità genetica in relazione alla suscettibilità della malattia. Comprendere l'epidemiologia del PDAC sarebbe fondamentale per identificarne l'eziologia e mettere a punto una strategia di prevenzione.
Questo progetto di dottorato mira ad ampliare le conoscenze sui fattori di rischio genetici e non genetici del PDAC, analizzando la suscettibilità genetica, l’esposoma e l'interazione tra i loci di suscettibilità noti e i fattori ambientali. Per raggiungere gli obiettivi di questo progetto, è stato adottato un approccio multidisciplinare che integra analisi secondarie, metodologie epidemiologiche classiche e approcci di intelligenza artificiale (IA). Le analisi secondarie si basano su ipotesi biologiche postulate a priori. Questo progetto ne indaga due: l'impatto dell'attività ormonale femminile e l'autofagia come potenziali fattori di rischio per il PDAC. I metodi epidemiologici classici (come l'analisi di associazione, il punteggio di rischio poligenico (PRS) e l'interazione gene-ambiente (G×E)), insieme a modelli di IA spiegabili, sono stati utilizzati per identificare nuovi fattori di rischio ambientali per il PDAC, per scoprire l'interazione tra la componente genetica e ambientale e per costruire un modello predittivo del rischio di PDAC. Tutti questi approcci sono stati applicati nel contesto di una delle più grandi coorti prospettiche disponibili ad oggi, UK Biobank.
Le analisi secondarie hanno confermato associazioni già note, come quella con il gene NR5A2 (p=4.08×10-5) considerando solo le donne con PDAC, ma anche quella con i geni TP53 (p=2.50×10-4) e TP63 (p=8.43×10-9) e il rischio di PDAC. Per quanto riguarda la suscettibilità ambientale, è stato osservato un totale di 147 associazioni a p<0.05 e 54 sotto la soglia di significatività ottenuta con la correzione di Bonferroni di p<1.37×10-4. I nostri risultati sottolineano l'importanza dello stress e dei comportamenti sedentari nella suscettibilità del PDAC, suggerendo che cambiamenti nello stile di vita potrebbero essere utili per ridurre il rischio della malattia. Infine, abbiamo integrato la componente genetica con quella ambientale per sviluppare un modello predittivo per il PDAC che ha ottenuto delle buone performance (accuratezza complessiva di CatBoost=85,24% e recall sui casi=77,10%).
Il nostro studio ha confermato alcuni fattori genetici e scoperto nuovi fattori ambientali associati al rischio di sviluppare PDAC, fondamentali per sviluppare un futuro screening sui soggetti ad alto rischio. Inoltre, abbiamo calcolato un modello predittivo per la valutazione del rischio di PDAC, che potrebbe essere utilizzato come strumento di screening su una popolazione più ampia
Susceptibility loci for pancreatic cancer in genes involved in mitochondrial metabolism.
No full textIl pancreas è un organo che presenta una componente endocrina ed una esocrina da cui possono svilupparsi differenti tumori: dalla parte esocrina insorge l’adenocarcinoma duttale pancratico (PDAC), mentre dalla parte endocrina si sviluppano i tumori neuroendocrini pancreatici (PNET). Il cancro al pancreas è attualmente la settima causa di morte dovuta a tumori nel mondo e la quarta in Europa. I principali fattori di rischio ambientali epidemiologici per lo sviluppo del cancro al pancreas comprendono età, sesso, fumo, etnia, diabete e la pancreatite cronica. Una parte del rischio di sviluppare il cancro al pancreas è associato a mutazioni ad alta penetranza che però sono estremamente rare nella popolazione e quindi spiegano soltanto una piccola frazione dei tumori sporadici pancreatici. Gli Studi di Associazione Genome-Wide (GWAS) hanno identificato 27 varianti comuni, a bassa penetranza, che contribuiscono all‘insorgenza della patologia, tuttavia queste varianti rappresentano soltanto una piccola parte dell’ereditabilità della patologia sottolineando la necessità di identificare nuovi loci di suscettibilità. La maggior parte degli studi sulla di associazione condotti per determinare il coinvolgimento genetico nello sviluppo del PDAC sono stati condotti utilizzando esclusivamente il genoma nucleare. Tuttavia, in diversi studi è stato dimostrato il coinvolgimento di mutazioni mitocondriali e di varianti di geni nucleari coinvolti nel metabolismo mitocondriale nello sviluppo patologie metaboliche, diabete ed obesità, che sono fattori di rischio accertati per il cancro al pancreas. Per questo motivo, lo scopo di questo studio è stato approfondire le nostre conoscenze sulla suscettibilità genetica del PDAC focalizzandoci su varianti di geni nucleari coinvolti nel metabolismo mitocondriale
Analysis of exposome and genetic variability suggests stress as a major contributor for development of pancreatic ductal adenocarcinoma
No full textBackground: The current knowledge on pancreatic ductal adenocarcinoma (PDAC) risk factors is limited and no study has comprehensively tested the exposome in combination with the genetic variability in relation to the disease susceptibility. Aim: The aim of this study was to analyze the exposome and its interaction with known genetic susceptibility loci, in relation to PDAC risk. Methods: A case-control study nested in UK Biobank cohort was conducted on 816 PDAC cases and 302,645 controls. A total of 347 exposure variables, and a polygenic risk score (PRS) were analyzed through logistic regression. Gene-environment interaction analyses were conducted. Results: A total of 52 associations under the Bonferroni corrected threshold of p < 1.46 × 10−4 were observed. Known risk factors such as smoking, pancreatitis, diabetes, PRS, heavy alcohol drinking and overweight were replicated in this study. As for novel associations, a clear indication for length and intensity of mobile phone use and the stress-related factors and stressful events with increase of PDAC risk was observed. Although the PRS was associated with PDAC risk (P = 2.09 × 10−9), statistically significant gene-exposome interactions were not identified. Conclusion: In conclusion, our results suggest that a stressful lifestyle and sedentary behaviors may play a major role in PDAC susceptibility independently from the genetic background
RAPCON Project: Sustainable Concrete Made with Recycled Asphalt Pavement
No full textThis paper reports some of the outcomes of RAPCON, a 3-year-project
financed by Fondazione Cariplo in the framework of the 2019 Call “Scientific
Research – Circular Economy for a Sustainable Future”. The main objectives of
RAPCON project were (i) the investigation of the use of RAP (Reclaimed Asphalt
Pavement) as replacement of natural aggregates in concrete to study mechanical,
microstructural and durability performances of RAP-based concrete; (ii) the
assessment of the expected service life of concrete with increasing RAP content
and determination of relevant environmental impacts by life cycle analysis
(LCA); (iii) draft proposal of an European Assessment Document (EAD) aimed
at the certification procedures of RAP as aggregate for concrete.
RAPCONproject allowed the analysis of a complete scenario related to the use
of RAP as replacement of natural aggregates for structural concrete, highlighting
the advantages and limitations related to the material, environmental and cost
impacts and industrialization
A genome-wide association study identifies eight loci associated with intraductal papillary mucinous neoplasm progression toward malignancy
No full textBackground: Intraductal papillary mucinous neoplasms (IPMNs) are precursors to pancreatic cancer, but not all IPMNs progress to cancer. The objective of this study was to identify the germline genetic variants associated with IPMN clinical progression by conducting the first genome-wide association study (GWAS) and computing a polygenic hazard score (PHS) in 338 patients with IPMN. Methods: The study population was divided into two subsets, and a Cox analysis adjusted for sex, age, cyst size at diagnosis, and the top 10 principal components was performed. A PHS was calculated using the genotypes of common variants associated with IPMN progression identified. Results: Eight loci with significant associations (p < 5 × 10−8) were identified, and the most significant was 7q21.11-rs117620617 (hazard ratio, 16.35; 95% confidence interval, 6.93–38.60; p = 1.80 × 10−10). All variants were associated with inflammatory processes, suggesting that alleles that predispose to an inflammatory prone phenotype may promote progression. The PHS indicated a statistically significant association (hazard ratio, 18.05; 95% confidence interval, 7.96–45.80; p = 6.18 × 10−11) with IPMN progression among individuals who had the highest number of effect alleles (fourth quartile) compared with those who had the lowest number (first quartile). Conclusions: The current results study advance the understanding of individual predisposition to IPMN progression and underscore the potential use of genetics in the stratification of patients who have IPMN
The worst enemy of science: clarifying polemics issues on Paul Feyerabend’s Epistemology in teacher training
No full textMany of the objections to Feyerabend's epistemology arise from
misinterpretations of ideas by this author. Terms and expressions as epistemological
anarchism, irrationality, control of science and anything goes can give the false
impression that the author's arguments are chaotic and unsustainable. This paper
discusses these concepts, opposing the misconceptions about them. In initial and
continuing teacher education, this reflection can be useful both for the deconstruction of
certain misleading images about the nature of science and for the upbringing of critical
citizens acquaintated to the concepts of modern philosophy of science
