8,222 research outputs found

    Therapeutic and prognostic strategies in neuroblastoma : exploring nuclear hormone receptors, MYC targets, and DIAPH3

    Get PDF
    Neuroblastoma (NB) is a pediatric cancer derived from the cells of neural crest origin that form the sympathoadrenal system. Typically, the tumor cells migrate along the spinal cord and spread to the chest, neck, and/or abdomen. Different clinical behaviors are observed in this disease: some tumors spontaneously regress without treatment, while others are highly aggressive and resistant to current therapies. Approximately 40% of high-risk NB patients have MYCN amplification while 10% have MYC (i.e. encoding c-MYC) overexpression. These patients have undifferentiated tumors with a poor prognosis. Our group previously found that the expression and activation of nuclear hormone receptors (NHRs) estrogen receptor alpha (ERα) by 17-β-estradiol (E2), and the glucocorticoid receptor (GR) by dexamethasone (DEX), could trigger differentiation by disrupting the regulation of the miR-17 ~ 92 microRNA cluster by MYCN. In paper I, we sought to investigate whether the simultaneous activation of both ERα and GR has a more beneficial effect compared to the activation of either ERα or GR alone. We examined cell survival, alterations in cell shape as indicated by neurite extension, variations in metabolic pathways, accumulation of lipid droplets, and performed xenograft experiments. Our findings revealed that the simultaneous activation of GR and ERα, compared to their single activation, led to reduced viability and a more robust differentiation. This dual activation also caused changes in glycolysis and oxidative phosphorylation, increased lipid droplet accumulation, and decreased aggressiveness in mouse models. The triple activation with an additional activation of the retinoic acid receptor using all trans-retinoic acid (ATRA), amplified the differentiation phenotype. Bulk-sequencing analysis showed that patients with high levels of NHRs are related to favorable survival and clinical outcome. In summary, our data suggest that combination activation of these NHRs could be a potential differentiation induction treatment. Paper II investigates target genes of c-MYC and MYCN to explore if it is possible to obtain a better prognosis prediction using the expression of this group of genes, instead of the expression of MYC and/or MYCN alone. In addition, we analyzed if there are different prediction power capabilities between c-MYC and MYCN target genes, and their different role during sympathoadrenal development. We screened lists of target genes by using comprehensive approaches, including differential expression analysis between clinical risk groups, INSS stages, MYCN amplification status, progression status; Univariate Cox regression analysis to select the target genes related to prognosis prediction power, and protein interaction network analysis to select genes that share a meaningful biology function. Following the training and validation of (LASSO) regression prediction models in three different patient cohorts (SEQC, Kocak, and Versteeg), we found that a risk score computed on c-MYC/MYCN target genes with prognostic value, could effectively classify patients in groups with different survival probabilities. The high-risk group of patients exhibited unfavorable clinical outcomes and low survival rates. Further, single cell RNA sequencing analysis revealed that c-MYC and MYCN targets have different expression patterns during sympathoadrenal development. Notably, genes linked to adverse outcomes were predominantly expressed in sympathoblasts in comparison to chromaffin cells. In summary, our research provides new insights into the importance of c-MYC/MYCN target genes during sympathoadrenal development and their value in predicting patient outcome. In paper III we studied the function of one member of the formin protein family involved in cytoskeleton modulation: Diaphanous Related Formin 3 (DIAPH3). We found that high DIAPH3 expression in NB tumors are associated with MYCN amplification, higher stage, risk, progression and negative clinical outcome. Elevated DIAPH3 expression was also found in specific cells during mouse sympathoadrenal development and in progenitor cells of the post- natal human adrenal gland. Furthermore, the knockdown of DIAPH3 resulted in a slight decrease in cell growth and cell cycle arrest. Our study suggests that DIAPH3 could be a promising target for new therapeutic strategies

    Mobile Device Background Sensors: Authentication vs Privacy

    Get PDF
    The increasing number of mobile devices in recent years has caused the collection of a large amount of personal information that needs to be protected. To this aim, behavioural biometrics has become very popular. But, what is the discriminative power of mobile behavioural biometrics in real scenarios? With the success of Deep Learning (DL), architectures based on Convolutional Neural Networks (CNNs) and Recurrent Neural Networks (RNNs), such as Long Short-Term Memory (LSTM), have shown improvements compared to traditional machine learning methods. However, these DL architectures still have limitations that need to be addressed. In response, new DL architectures like Transformers have emerged. The question is, can these new Transformers outperform previous biometric approaches? To answers to these questions, this thesis focuses on behavioural biometric authentication with data acquired from mobile background sensors (i.e., accelerometers and gyroscopes). In addition, to the best of our knowledge, this is the first thesis that explores and proposes novel behavioural biometric systems based on Transformers, achieving state-of-the-art results in gait, swipe, and keystroke biometrics. The adoption of biometrics requires a balance between security and privacy. Biometric modalities provide a unique and inherently personal approach for authentication. Nevertheless, biometrics also give rise to concerns regarding the invasion of personal privacy. According to the General Data Protection Regulation (GDPR) introduced by the European Union, personal data such as biometric data are sensitive and must be used and protected properly. This thesis analyses the impact of sensitive data in the performance of biometric systems and proposes a novel unsupervised privacy-preserving approach. The research conducted in this thesis makes significant contributions, including: i) a comprehensive review of the privacy vulnerabilities of mobile device sensors, covering metrics for quantifying privacy in relation to sensitive data, along with protection methods for safeguarding sensitive information; ii) an analysis of authentication systems for behavioural biometrics on mobile devices (i.e., gait, swipe, and keystroke), being the first thesis that explores the potential of Transformers for behavioural biometrics, introducing novel architectures that outperform the state of the art; and iii) a novel privacy-preserving approach for mobile biometric gait verification using unsupervised learning techniques, ensuring the protection of sensitive data during the verification process

    Advances in machine learning algorithms for financial risk management

    Get PDF
    In this thesis, three novel machine learning techniques are introduced to address distinct yet interrelated challenges involved in financial risk management tasks. These approaches collectively offer a comprehensive strategy, beginning with the precise classification of credit risks, advancing through the nuanced forecasting of financial asset volatility, and ending with the strategic optimisation of financial asset portfolios. Firstly, a Hybrid Dual-Resampling and Cost-Sensitive technique has been proposed to combat the prevalent issue of class imbalance in financial datasets, particularly in credit risk assessment. The key process involves the creation of heuristically balanced datasets to effectively address the problem. It uses a resampling technique based on Gaussian mixture modelling to generate a synthetic minority class from the minority class data and concurrently uses k-means clustering on the majority class. Feature selection is then performed using the Extra Tree Ensemble technique. Subsequently, a cost-sensitive logistic regression model is then applied to predict the probability of default using the heuristically balanced datasets. The results underscore the effectiveness of our proposed technique, with superior performance observed in comparison to other imbalanced preprocessing approaches. This advancement in credit risk classification lays a solid foundation for understanding individual financial behaviours, a crucial first step in the broader context of financial risk management. Building on this foundation, the thesis then explores the forecasting of financial asset volatility, a critical aspect of understanding market dynamics. A novel model that combines a Triple Discriminator Generative Adversarial Network with a continuous wavelet transform is proposed. The proposed model has the ability to decompose volatility time series into signal-like and noise-like frequency components, to allow the separate detection and monitoring of non-stationary volatility data. The network comprises of a wavelet transform component consisting of continuous wavelet transforms and inverse wavelet transform components, an auto-encoder component made up of encoder and decoder networks, and a Generative Adversarial Network consisting of triple Discriminator and Generator networks. The proposed Generative Adversarial Network employs an ensemble of unsupervised loss derived from the Generative Adversarial Network component during training, supervised loss and reconstruction loss as part of its framework. Data from nine financial assets are employed to demonstrate the effectiveness of the proposed model. This approach not only enhances our understanding of market fluctuations but also bridges the gap between individual credit risk assessment and macro-level market analysis. Finally the thesis ends with a novel proposal of a novel technique or Portfolio optimisation. This involves the use of a model-free reinforcement learning strategy for portfolio optimisation using historical Low, High, and Close prices of assets as input with weights of assets as output. A deep Capsules Network is employed to simulate the investment strategy, which involves the reallocation of the different assets to maximise the expected return on investment based on deep reinforcement learning. To provide more learning stability in an online training process, a Markov Differential Sharpe Ratio reward function has been proposed as the reinforcement learning objective function. Additionally, a Multi-Memory Weight Reservoir has also been introduced to facilitate the learning process and optimisation of computed asset weights, helping to sequentially re-balance the portfolio throughout a specified trading period. The use of the insights gained from volatility forecasting into this strategy shows the interconnected nature of the financial markets. Comparative experiments with other models demonstrated that our proposed technique is capable of achieving superior results based on risk-adjusted reward performance measures. In a nut-shell, this thesis not only addresses individual challenges in financial risk management but it also incorporates them into a comprehensive framework; from enhancing the accuracy of credit risk classification, through the improvement and understanding of market volatility, to optimisation of investment strategies. These methodologies collectively show the potential of the use of machine learning to improve financial risk management

    AGI-P: A Gender Identification Framework for Authorship Analysis Using Customized Fine-Tuning of Multilingual Language Model

    Get PDF
    In this investigation, we propose a solution for the author’s gender identification task called AGI-P. This task has several real-world applications across different fields, such as marketing and advertising, forensic linguistics, sociology, recommendation systems, language processing, historical analysis, education, and language learning. We created a new dataset to evaluate our proposed method. The dataset is balanced in terms of gender using a random sampling method and consists of 1944 samples in total. We use accuracy as an evaluation measure and compare the performance of the proposed solution (AGI-P) against state-of-the-art machine learning classifiers and fine-tuned pre-trained multilingual language models such as DistilBERT, mBERT, XLM-RoBERTa, and Multilingual DEBERTa. In this regard, we also propose a customized fine-tuning strategy that improves the accuracy of the pre-trained language models for the author gender identification task. Our extensive experimental studies reveal that our solution (AGI-P) outperforms the well-known machine learning classifiers and fine-tuned pre-trained multilingual language models with an accuracy level of 92.03%. Moreover, the pre-trained multilingual language models, fine-tuned with the proposed customized strategy, outperform the fine-tuned pre-trained language models using an out-of-the-box fine-tuning strategy. The codebase and corpus can be accessed on our GitHub page at: https://github.com/mumairhassan/AGI-

    Artificial intelligence for predictive biomarker discovery in immuno-oncology: a systematic review

    Get PDF
    Background: The widespread use of immune checkpoint inhibitors (ICIs) has revolutionised treatment of multiple cancer types. However, selecting patients who may benefit from ICI remains challenging. Artificial intelligence (AI) approaches allow exploitation of high-dimension oncological data in research and development of precision immuno-oncology. Materials and methods: We conducted a systematic literature review of peer-reviewed original articles studying the ICI efficacy prediction in cancer patients across five data modalities: genomics (including genomics, transcriptomics, and epigenomics), radiomics, digital pathology (pathomics), and real-world and multimodality data. Results: A total of 90 studies were included in this systematic review, with 80% published in 2021-2022. Among them, 37 studies included genomic, 20 radiomic, 8 pathomic, 20 real-world, and 5 multimodal data. Standard machine learning (ML) methods were used in 72% of studies, deep learning (DL) methods in 22%, and both in 6%. The most frequently studied cancer type was non-small-cell lung cancer (36%), followed by melanoma (16%), while 25% included pan-cancer studies. No prospective study design incorporated AI-based methodologies from the outset; rather, all implemented AI as a post hoc analysis. Novel biomarkers for ICI in radiomics and pathomics were identified using AI approaches, and molecular biomarkers have expanded past genomics into transcriptomics and epigenomics. Finally, complex algorithms and new types of AI-based markers, such as meta-biomarkers, are emerging by integrating multimodal/multi-omics data. Conclusion: AI-based methods have expanded the horizon for biomarker discovery, demonstrating the power of integrating multimodal data from existing datasets to discover new meta-biomarkers. While most of the included studies showed promise for AI-based prediction of benefit from immunotherapy, none provided high-level evidence for immediate practice change. A priori planned prospective trial designs are needed to cover all lifecycle steps of these software biomarkers, from development and validation to integration into clinical practice

    Computational models for predicting liver toxicity in the deep learning era

    Get PDF
    Drug-induced liver injury (DILI) is a severe adverse reaction caused by drugs and may result in acute liver failure and even death. Many efforts have centered on mitigating risks associated with potential DILI in humans. Among these, quantitative structure-activity relationship (QSAR) was proven to be a valuable tool for early-stage hepatotoxicity screening. Its advantages include no requirement for physical substances and rapid delivery of results. Deep learning (DL) made rapid advancements recently and has been used for developing QSAR models. This review discusses the use of DL in predicting DILI, focusing on the development of QSAR models employing extensive chemical structure datasets alongside their corresponding DILI outcomes. We undertake a comprehensive evaluation of various DL methods, comparing with those of traditional machine learning (ML) approaches, and explore the strengths and limitations of DL techniques regarding their interpretability, scalability, and generalization. Overall, our review underscores the potential of DL methodologies to enhance DILI prediction and provides insights into future avenues for developing predictive models to mitigate DILI risk in humans

    Sound Event Detection by Exploring Audio Sequence Modelling

    Get PDF
    Everyday sounds in real-world environments are a powerful source of information by which humans can interact with their environments. Humans can infer what is happening around them by listening to everyday sounds. At the same time, it is a challenging task for a computer algorithm in a smart device to automatically recognise, understand, and interpret everyday sounds. Sound event detection (SED) is the process of transcribing an audio recording into sound event tags with onset and offset time values. This involves classification and segmentation of sound events in the given audio recording. SED has numerous applications in everyday life which include security and surveillance, automation, healthcare monitoring, multimedia information retrieval, and assisted living technologies. SED is to everyday sounds what automatic speech recognition (ASR) is to speech and automatic music transcription (AMT) is to music. The fundamental questions in designing a sound recognition system are, which portion of a sound event should the system analyse, and what proportion of a sound event should the system process in order to claim a confident detection of that particular sound event. While the classification of sound events has improved a lot in recent years, it is considered that the temporal-segmentation of sound events has not improved in the same extent. The aim of this thesis is to propose and develop methods to improve the segmentation and classification of everyday sound events in SED models. In particular, this thesis explores the segmentation of sound events by investigating audio sequence encoding-based and audio sequence modelling-based methods, in an effort to improve the overall sound event detection performance. In the first phase of this thesis, efforts are put towards improving sound event detection by explicitly conditioning the audio sequence representations of an SED model using sound activity detection (SAD) and onset detection. To achieve this, we propose multi-task learning-based SED models in which SAD and onset detection are used as auxiliary tasks for the SED task. The next part of this thesis explores self-attention-based audio sequence modelling, which aggregates audio representations based on temporal relations within and between sound events, scored on the basis of the similarity of sound event portions in audio event sequences. We propose SED models that include memory-controlled, adaptive, dynamic, and source separation-induced self-attention variants, with the aim to improve overall sound recognition

    Toward a new era of cancer detection: patient-friendly solutions

    Get PDF
    SUMMARY High cancer mortality rates and the rising cancer burden worldwide prioritize the development of innovative methods that facilitate the early and accurate detection of cancer. Combining patient-friendly sampling methods with reliable biomarker testing offers a method that is convenient for patients and effective in detecting cancer at a curable stage, with improved patient outcomes as an ultimate goal. This thesis assessed the feasibility of DNA methylation testing in urine as a diagnostic tool for different cancer types, including endometrial, ovarian, and lung cancer. For endometrial and ovarian cancer, the value of DNA methylation testing in self-collected cervicovaginal samples and clinician-taken cervical scrapes was also investigated. Part 1: Endometrial and ovarian cancer detection in patient-friendly samples Part 1 describes the detection of endometrial and ovarian cancer in urine, cervicovaginal self-samples, and clinician-taken cervical scrapes. The outcomes of Part 1 revealed the value of methylation analysis in patient-friendly sample types for endometrial cancer detection of all stages. Convenient modes of sample collection offer the possibility of at-home collection with high patient acceptability. This approach is clinically useful to screen patient populations at risk for endometrial cancer and to streamline who needs to undergo invasive endometrial tissue sampling. Although promising, the clinical effectiveness of this approach requires further confirmation in additional cohorts, including individuals presenting with postmenopausal bleeding and asymptomatic women at risk for endometrial cancer. The presence of ovarian cancer-derived DNA in the urine provides the first steps toward urine-based diagnostics for ovarian cancer. Further research is needed to further explore and refine the use of urine biomarkers for ovarian cancer diagnostics. Part 2: Non-small cell lung cancer detection in urine In Part 2 of this thesis, the diagnostic potential of urine as a liquid biopsy for non-small cell lung cancer (NSCLC) detection was evaluated. The outcomes of Part 2 demonstrate the technical feasibility of detecting NSCLC in the urine using DNA methylation markers. Further research, including larger patient cohorts and controls with benign pulmonary nodules, is needed to validate the clinical usefulness of this approach. The considerable variability between urine samples highlights the need for a more thorough understanding of cfDNA dynamics and enhancements in test development to ensure reliability. Upon further refinement, this test has the potential to serve as a valuable complementary diagnostic tool to low-dose CT screening to guide clinical decisions in patients with pulmonary nodules
    • …
    corecore