The impact of COVID-19 on "biological aging".

The global impact of the SARS-CoV-2 pandemic has been unprecedented, posing a significant public health challenge. Chronological age has been identified as a key determinant for severe outcomes associated with SARS-CoV-2 infection. Epigenetic age acceleration has previously been observed in various diseases including human immunodeficiency virus (HIV), Cytomegalovirus (CMV), cardiovascular diseases, and cancer. However, a comprehensive review of this topic is still missing in the field. In this review, we explore and summarize the research work focusing on biological aging markers, i.e., epigenetic age and telomere attrition in COVID-19 patients. From the reviewed articles, we identified a consistent pattern of epigenetic age dysregulation and shortened telomere length, revealing the impact of COVID-19 on epigenetic aging and telomere attrition.

Deep Learning in Colorectal Cancer Classification: A Scoping Review.

Colorectal cancer (CRC) is one of the most common cancers worldwide, and its diagnosis and classification remain challenging for pathologists and imaging specialists. The use of artificial intelligence (AI) technology, specifically deep learning, has emerged as a potential solution to improve the accuracy and speed of classification while maintaining the quality of care. In this scoping review, we aimed to explore the utilization of deep learning for the classification of different types of colorectal cancer. We searched five databases and selected 45 studies that met our inclusion criteria. Our results show that deep learning models have been used to classify colorectal cancer using various types of data, with histopathology and endoscopy images being the most common. The majority of studies used CNN as their classification model. Our findings provide an overview of the current state of research on deep learning in the classification of colorectal cancer.

Predicting Overall Survival in METABRIC Cohort Using Machine Learning.

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer that presents very high relapse and mortality. However, due to differences in the genetic architecture associated with TNBC, patients have different outcomes and respond differently to available treatments. In this study, we predicted the overall survival of TNBC patients in the METABRIC cohort employing supervised machine learning to identify important clinical and genetic features that are associated with better survival. We achieved a slightly higher Concordance index than the state of art and identified biological pathways related to the top genes considered important by our model.

Computational Methods for the Analysis and Prediction of EGFR-Mutated Lung Cancer Drug Resistance: Recent Advances in Drug Design, Challenges and Future Prospects.

Lung cancer is a major cause of cancer deaths worldwide, and has a very low survival rate. Non-small cell lung cancer (NSCLC) is the largest subset of lung cancers, which accounts for about 85% of all cases. It has been well established that a mutation in the epidermal growth factor receptor (EGFR) can lead to lung cancer. EGFR Tyrosine Kinase Inhibitors (TKIs) are developed to target the kinase domain of EGFR. These TKIs produce promising results at the initial stage of therapy, but the efficacy becomes limited due to the development of drug resistance. In this paper, we provide a comprehensive overview of computational methods, for understanding drug resistance mechanisms. The important EGFR mutants and the different generations of EGFR-TKIs, with the survival and response rates are discussed. Next, we evaluate the role of important EGFR parameters in drug resistance mechanism, including structural dynamics, hydrogen bonds, stability, dimerization, binding free energies, and signaling pathways. Personalized drug resistance prediction models, drug response curve, drug synergy, and other data-driven methods are also discussed. Recent advancements in deep learning; such as AlphaFold2, deep generative models, big data analytics, and the applications of statistics and permutation are also highlighted. We explore limitations in the current methodologies, and discuss strategies to overcome them. We believe this review will serve as a reference for researchers; to apply computational techniques for precision medicine, analyzing structures of protein-drug complexes, drug discovery, and understanding the drug response and resistance mechanisms in lung cancer patients.

Machine learning based personalized drug response prediction for lung cancer patients.

Lung cancers with a mutated epidermal growth factor receptor (EGFR) are a major contributor to cancer fatalities globally. Targeted tyrosine kinase inhibitors (TKIs) have been developed against EGFR and show encouraging results for survival rate and quality of life. However, drug resistance may affect treatment plans and treatment efficacy may be lost after about a year. Predicting the response to EGFR-TKIs for EGFR-mutated lung cancer patients is a key research area. In this study, we propose a personalized drug response prediction model (PDRP), based on molecular dynamics simulations and machine learning, to predict the response of first generation FDA-approved small molecule EGFR-TKIs, Gefitinib/Erlotinib, in lung cancer patients. The patient's mutation status is taken into consideration in molecular dynamics (MD) simulation. Each patient's unique mutation status was modeled considering MD simulation to extract molecular-level geometric features. Moreover, additional clinical features were incorporated into machine learning model for drug response prediction. The complete feature set includes demographic and clinical information (DCI), geometrical properties of the drug-target binding site, and the binding free energy of the drug-target complex from the MD simulation. PDRP incorporates an XGBoost classifier, which achieves state-of-the-art performance with 97.5% accuracy, 93% recall, 96.5% precision, and 94% F1-score, for a 4-class drug response prediction task. We found that modeling the geometry of the binding pocket combined with binding free energy is a good predictor for drug response. However, we observed that clinical information had a little impact on the performance of the model. The proposed model could be tested on other types of cancers. We believe PDRP will support the planning of effective treatment regimes based on clinical-genomic information. The source code and related files are available on GitHub at:   https://github.com/rizwanqureshi123/PDRP/ .

Long non-coding RNA and RNA-binding protein interactions in cancer: Experimental and machine learning approaches.

Understanding the complex and specific roles played by non-coding RNAs (ncRNAs), which comprise the bulk of the genome, is important for understanding virtually every hallmark of cancer. This large group of molecules plays pivotal roles in key regulatory mechanisms in various cellular processes. Regulatory mechanisms, mediated by long non-coding RNA (lncRNA) and RNA-binding protein (RBP) interactions, are well documented in several types of cancer. Their effects are enabled through networks affecting lncRNA and RBP stability, RNA metabolism including N6-methyladenosine (m6A) and alternative splicing, subcellular localization, and numerous other mechanisms involved in cancer. In this review, we discuss the reciprocal interplay between lncRNAs and RBPs and their involvement in epigenetic regulation via histone modifications, as well as their key role in resistance to cancer therapy. Other aspects of RBPs including their structural domains, provide a deeper knowledge on how lncRNAs and RBPs interact and exert their biological functions. In addition, current state-of-the-art knowledge, facilitated by machine and deep learning approaches, unravels such interactions in better details to further enhance our understanding of the field, and the potential to harness RNA-based therapeutics as an alternative treatment modality for cancer are discussed.

ALLD: Acute Lymphoblastic Leukemia Detector.

Acute Lymphoblastic Leukemia (ALL) is a life-threatening type of cancer wherein mortality rate is unquestionably high. Early detection of ALL can reduce both the rate of fatality as well as improve the diagnosis plan for patients. In this study, we developed the ALL Detector (ALLD), which is a deep learning-based network to distinguish ALL patients from healthy individuals based on blast cell microscopic images. We evaluated multiple DL-based models and the ResNet-based model performed the best with 98% accuracy in the classification task. We also compared the performance of ALLD against state-of-the-art tools utilized for the same purpose, and ALLD outperformed them all. We believe that ALLD will support pathologists to explicitly diagnose ALL in the early stages and reduce the burden on clinical practice overall.

Recent Developments in Artificial Intelligence-Based Techniques for Prostate Cancer Detection: A Scoping Review.

Artificial intelligence (AI) techniques can contribute to the early diagnosis of prostate cancer. Recently, there has been a sharp increase in the literature on AI techniques for prostate cancer diagnosis. This review article presents a summary of the AI methods that detect and diagnose prostate cancer using different medical imaging modalities. Following the PRISMA-ScR principle, this review covers 69 studies selected from 1441 searched papers published in the last three years. The application of AI methods reported in these articles can be divided into three broad categories: diagnosis, grading, and segmentation of tissues that have prostate cancer. Most of the AI methods leveraged convolutional neural networks (CNNs) due to their ability to extract complex features. Some studies also reported traditional machine learning methods, such as support vector machines (SVM), decision trees for classification, LASSO, and Ridge regression methods for features extraction. We believe that the implementation of AI-based tools will support clinicians to provide better diagnosis plans for prostate cancer.

Cardiovascular Diseases in Qatar: Smoking, Food Habits and Physical Activities Perspectives.

Cardiovascular diseases (CVDs) trigger a high number of deaths across the world. In this study, we investigate the food, drinking, smoking, and lifestyle-related habits for a Qatari CVD cohort to understand the implication of these factors on CVD. Statistical analysis shows that the CVD group is consuming a lower amount of fast foods, soft drinks, snacks, and meats compared to the control group. Alarmingly, the level of smoking is still higher in the CVD group, and the consumption level of healthy items (e.g., cereal, cornflakes) in breakfast is relatively lower compared to the control group. Interestingly, the CVD cohort is spending more time walking and avoiding heavy sports, compared to the control group, but their involvement in moderate physical activities is lower than the control group. Overall, we conclude that the Qatari CVD cohort is following most of the standard guidelines related to food items and heavy sports; however, the cohort should reduce smoking habits, and may modify the moderate level of physical activity based on physician guidelines.

Transcriptional landscape of Mycobacterium tuberculosis infection in macrophages.

Mycobacterium tuberculosis (Mtb) infection reveals complex and dynamic host-pathogen interactions, leading to host protection or pathogenesis. Using a unique transcriptome technology (CAGE), we investigated the promoter-based transcriptional landscape of IFNγ (M1) or IL-4/IL-13 (M2) stimulated macrophages during Mtb infection in a time-kinetic manner. Mtb infection widely and drastically altered macrophage-specific gene expression, which is far larger than that of M1 or M2 activations. Gene Ontology enrichment analysis for Mtb-induced differentially expressed genes revealed various terms, related to host-protection and inflammation, enriched in up-regulated genes. On the other hand, terms related to dis-regulation of cellular functions were enriched in down-regulated genes. Differential expression analysis revealed known as well as novel transcription factor genes in Mtb infection, many of them significantly down-regulated. IFNγ or IL-4/IL-13 pre-stimulation induce additional differentially expressed genes in Mtb-infected macrophages. Cluster analysis uncovered significant numbers, prolonging their expressional changes. Furthermore, Mtb infection augmented cytokine-mediated M1 and M2 pre-activations. In addition, we identified unique transcriptional features of Mtb-mediated differentially expressed lncRNAs. In summary we provide a comprehensive in depth gene expression/regulation profile in Mtb-infected macrophages, an important step forward for a better understanding of host-pathogen interaction dynamics in Mtb infection.

Redefining the transcriptional regulatory dynamics of classically and alternatively activated macrophages by deepCAGE transcriptomics.

Classically or alternatively activated macrophages (M1 and M2, respectively) play distinct and important roles for microbiocidal activity, regulation of inflammation and tissue homeostasis. Despite this, their transcriptional regulatory dynamics are poorly understood. Using promoter-level expression profiling by non-biased deepCAGE we have studied the transcriptional dynamics of classically and alternatively activated macrophages. Transcription factor (TF) binding motif activity analysis revealed four motifs, NFKB1_REL_RELA, IRF1,2, IRF7 and TBP that are commonly activated but have distinct activity dynamics in M1 and M2 activation. We observe matching changes in the expression profiles of the corresponding TFs and show that only a restricted set of TFs change expression. There is an overall drastic and transient up-regulation in M1 and a weaker and more sustainable up-regulation in M2. Novel TFs, such as Thap6, Maff, (M1) and Hivep1, Nfil3, Prdm1, (M2) among others, were suggested to be involved in the activation processes. Additionally, 52 (M1) and 67 (M2) novel differentially expressed genes and, for the first time, several differentially expressed long non-coding RNA (lncRNA) transcriptome markers were identified. In conclusion, the finding of novel motifs, TFs and protein-coding and lncRNA genes is an important step forward to fully understand the transcriptional machinery of macrophage activation.

How to find a leucine in a haystack? Structure, ligand recognition and regulation of leucine-aspartic acid (LD) motifs.

LD motifs (leucine-aspartic acid motifs) are short helical protein-protein interaction motifs that have emerged as key players in connecting cell adhesion with cell motility and survival. LD motifs are required for embryogenesis, wound healing and the evolution of multicellularity. LD motifs also play roles in disease, such as in cancer metastasis or viral infection. First described in the paxillin family of scaffolding proteins, LD motifs and similar acidic LXXLL interaction motifs have been discovered in several other proteins, whereas 16 proteins have been reported to contain LDBDs (LD motif-binding domains). Collectively, structural and functional analyses have revealed a surprising multivalency in LD motif interactions and a wide diversity in LDBD architectures. In the present review, we summarize the molecular basis for function, regulation and selectivity of LD motif interactions that has emerged from more than a decade of research. This overview highlights the intricate multi-level regulation and the inherently noisy and heterogeneous nature of signalling through short protein-protein interaction motifs.