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Environmental Health Perspectives Jan 2024The organochlorine dichlorodiphenyltrichloroethane (DDT) is banned worldwide owing to its negative health effects. It is exceptionally used as an insecticide for malaria...
BACKGROUND
The organochlorine dichlorodiphenyltrichloroethane (DDT) is banned worldwide owing to its negative health effects. It is exceptionally used as an insecticide for malaria control. Exposure occurs in regions where DDT is applied, as well as in the Arctic, where its endocrine disrupting metabolite, dichlorodiphenyldichloroethylene (DDE) accumulates in marine mammals and fish. DDT and DDE exposures are linked to birth defects, infertility, cancer, and neurodevelopmental delays. Of particular concern is the potential of DDT use to impact the health of generations to come via the heritable sperm epigenome.
OBJECTIVES
The objective of this study was to assess the sperm epigenome in relation to DDE serum levels between geographically diverse populations.
METHODS
In the Limpopo Province of South Africa, we recruited 247 VhaVenda South African men and selected 50 paired blood serum and semen samples, and 47 Greenlandic Inuit blood and semen paired samples were selected from a total of 193 samples from the biobank of the INUENDO cohort, an EU Fifth Framework Programme Research and Development project. Sample selection was based on obtaining a range of -DDE serum levels (). We assessed the sperm epigenome in relation to serum -DDE levels using MethylC-Capture-sequencing (MCC-seq) and chromatin immunoprecipitation followed by sequencing (ChIP-seq). We identified genomic regions with altered DNA methylation (DNAme) and differential enrichment of histone H3 lysine 4 trimethylation (H3K4me3) in sperm.
RESULTS
Differences in DNAme and H3K4me3 enrichment were identified at transposable elements and regulatory regions involved in fertility, disease, development, and neurofunction. A subset of regions with sperm DNAme and H3K4me3 that differed between exposure groups was predicted to persist in the preimplantation embryo and to be associated with embryonic gene expression.
DISCUSSION
These findings suggest that DDT and DDE exposure impacts the sperm epigenome in a dose-response-like manner and may negatively impact the health of future generations through epigenetic mechanisms. Confounding factors, such as other environmental exposures, genetic diversity, and selection bias, cannot be ruled out. https://doi.org/10.1289/EHP12013.
Topics: Humans; Male; Cross-Sectional Studies; DDT; Dichlorodiphenyl Dichloroethylene; Epigenome; Inuit; Semen; South Africa; Spermatozoa; Black People
PubMed: 38294233
DOI: 10.1289/EHP12013 -
Cancer Letters Mar 2024The highly heterogenous nature of colorectal cancer can significantly hinder its early and accurate diagnosis, eventually contributing to high mortality rates. The... (Review)
Review
The highly heterogenous nature of colorectal cancer can significantly hinder its early and accurate diagnosis, eventually contributing to high mortality rates. The adenoma-carcinoma sequence and serrated polyp-carcinoma sequence are the two most common sequences in sporadic colorectal cancer. Genetic alterations in adenomatous polyposis coli (APC), v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and tumour protein 53 (TP53) genes are critical in adenoma-carcinoma sequence, whereas v-Raf murine sarcoma viral oncogene homolog B (BRAF) and MutL Homolog1 (MLH1) are driving oncogenes in the serrated polyp-carcinoma sequence. Sporadic mutations in these genes contribute differently to colorectal cancer pathogenesis by introducing distinct alterations in several signalling pathways that rely on the endosome-lysosome system. Unsurprisingly, the endosome-lysosome system plays a pivotal role in the hallmarks of cancer and contributes to specialised colon function. Thus, the endosome-lysosome system might be distinctively influenced by different mutations and these alterations may contribute to the heterogenous nature of sporadic colorectal cancer. This review highlights potential connections between major sporadic colorectal cancer mutations and the diverse pathogenic mechanisms driven by the endosome-lysosome system in colorectal carcinogenesis.
Topics: Animals; Mice; Humans; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Colorectal Neoplasms; Mutation; Adenoma; Carcinoma
PubMed: 38290660
DOI: 10.1016/j.canlet.2024.216639 -
Gene May 2024To examine the therapeutic mechanism of astragaloside IV (AS-IV) in the management of retinal ganglion cell (RGC) injury induced by high glucose (HG), a comprehensive...
OBJECTIVE
To examine the therapeutic mechanism of astragaloside IV (AS-IV) in the management of retinal ganglion cell (RGC) injury induced by high glucose (HG), a comprehensive approach involving the integration of network pharmacology and conducting in vitro and in vivo experiments was utilized.
METHODS
A rat model of diabetic retinopathy (DR) injury was created by administering streptozotocin through intraperitoneal injection. Additionally, a model of RGC injury induced by HG was established using a glucose concentration of 0.3 mmol/mL. Optical coherence tomography (OCT) images were captured 8 weeks after the injection of AS-IV. AS-IV and FBS were added to the culture medium and incubated for 48 h. The viability of cells was assessed using a CCK-8 assay, while the content of reactive oxygen species (ROS) was measured using DCFH-DA. Apoptosis was evaluated using Annexin V-PI. To identify the targets of AS-IV, hyperglycemia, and RGC, publicly available databases were utilized. The Metascape platform was employed for conducting GO and KEGG enrichment analyses. The STRING database in conjunction with Cytoscape 3.7.2 was used to determine common targets of protein-protein interactions (PPIs) and to identify the top 10 core target proteins in the RGC based on the MCC algorithm. qRT-PCR was used to measure the mRNA expression levels of the top10 core target proteins in RGCs.
RESULTS
OCT detection indicated that the thickness of the outer nucleus, and inner and outer accessory layers of the retina increased in the AS-IV treated retina compared to that in the DM group but decreased compared to that in the CON group. Coculturing RGC cells with AS-IV after HG induction resulted in a significant increase in cell viability and a decrease in ROS and apoptosis, suggesting that AS-IV can reduce damage to RGC cells caused by high glucose levels by inhibiting oxidative stress. There were 14 potential targets of AS-IV in the treatment of RGC damage induced by high glucose levels. The top 10 core target proteins identified by the MCC algorithm were HIF1α, AKT1, CTNNB1, SMAD2, IL6, SMAD3, IL1β, PPARG, TGFβ1, and NOTCH3. qRT-PCR analysis showed that AS-IV could upregulate the mRNA expression levels of SMAD3, TGF-β1, and NOTCH3, and downregulate the mRNA expression levels of HIF1α, AKT1, CTNNB1, SMAD2, SMAD3, and IL-1β in high glucose-induced RGC cells.
CONCLUSION
The findings of this study validate the efficacy of astragaloside IV in the treatment of DR and shed light on the molecular network involved. Specifically, HIF1α, AKT1, CTNNB1, SMAD2, SMAD3, and IL-1β were identified as the crucial candidate molecules responsible for the protective effects of astragaloside IV on RGCs.
Topics: Rats; Animals; Retinal Ganglion Cells; Reactive Oxygen Species; Apoptosis; Diabetic Retinopathy; Glucose; Computational Biology; RNA, Messenger; Saponins; Triterpenes
PubMed: 38286267
DOI: 10.1016/j.gene.2024.148219 -
Clinical Genetics Jun 2024Multiple congenital contractures (MCC) due to fetal akinesia manifest across a broad spectrum of diseases, ranging from mild distal arthrogryposis to lethal fetal...
Multiple congenital contractures (MCC) due to fetal akinesia manifest across a broad spectrum of diseases, ranging from mild distal arthrogryposis to lethal fetal akinesia deformation sequence. We hereby present a series of 26 fetuses displaying severe MCC phenotypes from 18 families and describe detailed prenatal ultrasound findings, postmortem clinical evaluations, and genetic investigations. Most common prenatal findings were abnormal facial profile (65%), central nervous system abnormalities (62%), polyhydramnios (50%), increased nuchal translucency (50%), and fetal hydrops (35%). Postmortem examinations unveiled additional anomalies including facial dysmorphisms, dysplastic skeletal changes, ichthyosis, multiple pterygia, and myopathy, allowing preliminary diagnosis of particular Mendelian disorders in multiple patients. Evaluation of the parents revealed maternal grip myotonia in one family. By exome sequencing and targeted testing, we identified causative variants in ACTC1, CHST14, COG6, DMPK, DOK7, HSPG2, KLHL7, KLHL40, KIAA1109, NEB, PSAT1, RAPSN, USP14, and WASHC5 in 15 families, and one patient with a plausible diagnosis associated with biallelic NEB variants. Three patients received a dual diagnosis. Pathogenic alterations in newly discovered genes or in previously known genes recently linked to new MCC phenotypes were observed in 44% of the cohort. Our results provide new insights into the clinical and molecular landscape of lethal MCC phenotypes.
Topics: Humans; Female; Male; Arthrogryposis; Phenotype; Fetus; Exome Sequencing; Contracture; Pregnancy; Ultrasonography, Prenatal; Mutation; Abnormalities, Multiple
PubMed: 38278647
DOI: 10.1111/cge.14490 -
PeerJ 2024Intrahepatic cholangiocarcinoma (ICC) is a malignancy with a dismal prognosis, thus the discovery of promising diagnostic markers and treatment targets is still...
Intrahepatic cholangiocarcinoma (ICC) is a malignancy with a dismal prognosis, thus the discovery of promising diagnostic markers and treatment targets is still required. In this study, 1,852 differentially expressed genes (DEGs) were identified in the GSE45001 dataset for weighted gene co-expression network analysis (WGCNA), and the turquoise module was confirmed as the key module. Next, the subnetworks of the 1,009 genes in the turquoise module analyzed by MCODE, MCC, and BottleNeck algorithms identified nine overlapping genes (CAT, APOA1, APOC2, HSD17B4, EHHADH, APOA2, APOE4, ACOX1, AGXT), significantly associated with lipid metabolism pathways, such as peroxisome and cholesterol metabolism. Among them, APOE4 exhibited a potential tumor-suppressive role in ICC and high diagnostic value for ICC in both GSE45001 and GSE32879 datasets. experiments demonstrated Apolipoprotein E4 (APOE4) overexpression suppressed ICC cell proliferation, migration, and invasion, knockdown was the opposite trend. And in ICC modulated lipid metabolism, notably decreasing levels of TG, LDL-C, and HDL-C, while concurrently increasing the expressions of TC. Further, APOE4 also downregulated lipid metabolism-related genes, suggesting a key regulatory role in maintaining cellular homeostasis, and regulating the expression of the membrane protein ATP-binding cassette transporter A1 (ABCA1). These findings highlighted the coordinated regulation of lipid metabolism by APOE4 and ABCA1 in ICC progression, providing new insights into ICC mechanisms and potential therapeutic strategies.
Topics: Humans; Apolipoprotein E4; Lipid Metabolism; Gene Expression Profiling; Cholangiocarcinoma; ATP Binding Cassette Transporter 1
PubMed: 38274331
DOI: 10.7717/peerj.16740 -
Cardiovascular Drugs and Therapy Jan 2024Sparstolonin B (SsnB) is characterized as a new toll-like receptor (TLR)-2/4 antagonist. However, the effects of SsnB on different inflammatory diseases have not been...
BACKGROUND
Sparstolonin B (SsnB) is characterized as a new toll-like receptor (TLR)-2/4 antagonist. However, the effects of SsnB on different inflammatory diseases have not been systemically reviewed.
METHODS
We investigated the effects of SsnB on inflammatory diseases with data mining and network analysis of literature, including frequency description, cluster analysis, association rule mining, functional enrichment, and protein-protein interaction (PPI) mining.
RESULTS
A total of 27 experimental reports were included. The ARRIVE 2.0 guidelines were used to evaluate the quality of animal studies. Frequency analysis revealed 13 different diseases (cardio-cerebrovascular system diseases account for 23.53%), 12 pharmacological effects (anti-inflammatory effect accounts for 53.85%), and 67 therapeutic targets. The overview of investigation sequence of SsnB studies was depicted by Sankey diagram. Cluster analysis classified the therapeutic targets for SsnB into four main categories: (1) NF-κB; (2) IL-1β, IL-6, and TNF-α; (3) TLR2, TLR4, and MyD88; (4) the other targets. Moreover, the Apriori association discovered two main association pairs: (1) TNF-α, IL-1β, and IL-6 and (2) TLR2, TLR4, and MyD88 (support range 33.33-50%, confidence range 83.33-88.89%). Functional enrichment of the therapeutic targets for SsnB showed that the top enriched items in the biological process were mainly the response to lipopolysaccharide (LPS)/bacterial origin and regulation of cytokine production. Finally, the PPI network and hub gene selection by maximal clique centrality (MCC) algorithm indicated the top ranked proteins were TNF-α, IL-1β, IL-6, AKT1, PPAR-γ, TLR4, CCL2, and TLR2.
CONCLUSION
These results emphasized the importance of TLR2/TLR4-MyD88-NF-κB-IL-1β/IL-6/TNF-α pathways as therapeutic targets of SsnB in inflammatory diseases.
PubMed: 38270691
DOI: 10.1007/s10557-023-07535-z -
Computers in Biology and Medicine Mar 2024A framework is developed for gene expression analysis by introducing fuzzy Jaccard similarity (FJS) and combining Łukasiewicz implication with it through weights in...
A framework is developed for gene expression analysis by introducing fuzzy Jaccard similarity (FJS) and combining Łukasiewicz implication with it through weights in hybrid ensemble framework (WCLFJHEF) for gene selection in cancer. The method is called weighted combination of Łukasiewicz implication and fuzzy Jaccard similarity in hybrid ensemble framework (WCLFJHEF). While the fuzziness in Jaccard similarity is incorporated by using the existing Gödel fuzzy logic, the weights are obtained by maximizing the average F-score of selected genes in classifying the cancer patients. The patients are first divided into different clusters, based on the number of patient groups, using average linkage agglomerative clustering and a new score, called WCLFJ (weighted combination of Łukasiewicz implication and fuzzy Jaccard similarity). The genes are then selected from each cluster separately using filter based Relief-F and wrapper based SVMRFE (Support Vector Machine with Recursive Feature Elimination). A gene (feature) pool is created by considering the union of selected features for all the clusters. A set of informative genes is selected from the pool using sequential backward floating search (SBFS) algorithm. Patients are then classified using Naïve Bayes'(NB) and Support Vector Machine (SVM) separately, using the selected genes and the related F-scores are calculated. The weights in WCLFJ are then updated iteratively to maximize the average F-score obtained from the results of the classifier. The effectiveness of WCLFJHEF is demonstrated on six gene expression datasets. The average values of accuracy, F-score, recall, precision and MCC over all the datasets, are 95%, 94%, 94%, 94%, and 90%, respectively. The explainability of the selected genes is shown using SHapley Additive exPlanations (SHAP) values and this information is further used to rank them. The relevance of the selected gene set are biologically validated using the KEGG Pathway, Gene Ontology (GO), and existing literatures. It is seen that the genes that are selected by WCLFJHEF are candidates for genomic alterations in the various cancer types. The source code of WCLFJHEF is available at http://www.isical.ac.in/~shubhra/WCLFJHEF.html.
Topics: Humans; Bayes Theorem; Gene Expression Profiling; Algorithms; Neoplasms; Software
PubMed: 38262204
DOI: 10.1016/j.compbiomed.2024.107981 -
The British Journal of Dermatology May 2024Merkel cell carcinoma (MCC) is an aggressive malignant neuroendocrine tumour. There are two subsets of MCC, one related to Merkel cell polyomavirus (MCPyV) and the other...
BACKGROUND
Merkel cell carcinoma (MCC) is an aggressive malignant neuroendocrine tumour. There are two subsets of MCC, one related to Merkel cell polyomavirus (MCPyV) and the other to ultraviolet radiation (UVR). MCPyV-positive and MCPyV-negative MCCs have been considered to be different tumours, as the former harbour few DNA mutations and are not related to UVR, and the latter usually arise in sun-exposed areas and may be found in conjunction with other keratinocytic tumours, mostly squamous cell carcinomas. Two viral oncoproteins, large T antigen (LT; coded by MCPyV_gp3) and small T antigen (sT; coded by MCPyV_gp4), promote different carcinogenic pathways.
OBJECTIVES
To determine which genes are differentially expressed in MCPyV-positive and MCPyV-negative MCC; to describe the mutational burden and the most frequently mutated genes in both MCC subtypes; and to identify the clinical and molecular factors that may be related to patient survival.
METHODS
Ninety-two patients with a diagnosis of MCC were identified from the medical databases of participating centres. To study gene expression, a customized panel of 172 genes was developed. Gene expression profiling was performed with nCounter technology. For mutational studies, a customized panel of 26 genes was designed. Somatic single nucleotide variants (SNVs) were identified following the GATK Best Practices workflow for somatic mutations.
RESULTS
The expression of LT enabled the series to be divided into two groups (LT positive, n = 55; LT negative, n = 37). Genes differentially expressed in LT-negative patients were related to epithelial differentiation, especially SOX9, or proliferation and the cell cycle (MYC, CDK6), among others. Congruently, LT displayed lower expression in SOX9-positive patients, and differentially expressed genes in SOX9-positive patients were related to epithelial/squamous differentiation. In LT-positive patients, the mean SNV frequency was 4.3; in LT-negative patients it was 10 (P = 0.03). On multivariate survival analysis, the expression of SNAI1 [hazard ratio (HR) 1.046, 95% confidence interval (CI) 1.007-1.086; P = 0.02] and CDK6 (HR 1.049, 95% CI 1.020-1.080; P = 0.001) were identified as risk factors.
CONCLUSIONS
Tumours with weak LT expression tend to co-express genes related to squamous differentiation and the cell cycle, and to have a higher mutational burden. These findings are congruent with those of earlier studies.
Topics: Humans; Carcinoma, Merkel Cell; Merkel cell polyomavirus; Skin Neoplasms; Male; Aged; Female; Polyomavirus Infections; Tumor Virus Infections; SOX9 Transcription Factor; Antigens, Viral, Tumor; Aged, 80 and over; Middle Aged; Mutation; Gene Expression Regulation, Neoplastic; Gene Expression Profiling
PubMed: 38261397
DOI: 10.1093/bjd/ljae033 -
Journal of Chemical Information and... Apr 2024Bacterial promoters play a crucial role in gene expression by serving as docking sites for the transcription initiation machinery. However, accurately identifying...
Bacterial promoters play a crucial role in gene expression by serving as docking sites for the transcription initiation machinery. However, accurately identifying promoter regions in bacterial genomes remains a challenge due to their diverse architecture and variations. In this study, we propose MLDSPP (Machine Learning and Duplex Stability based Promoter prediction in Prokaryotes), a machine learning-based promoter prediction tool, to comprehensively screen bacterial promoter regions in 12 diverse genomes. We leveraged biologically relevant and informative DNA structural properties, such as DNA duplex stability and base stacking, and state-of-the-art machine learning (ML) strategies to gain insights into promoter characteristics. We evaluated several machine learning models, including Support Vector Machines, Random Forests, and XGBoost, and assessed their performance using accuracy, precision, recall, specificity, F1 score, and MCC metrics. Our findings reveal that XGBoost outperformed other models and current state-of-the-art promoter prediction tools, namely Sigma70pred and iPromoter2L, achieving F1-scores >95% in most systems. Significantly, the use of one-hot encoding for representing nucleotide sequences complements these structural features, enhancing our XGBoost model's predictive capabilities. To address the challenge of model interpretability, we incorporated explainable AI techniques using Shapley values. This enhancement allows for a better understanding and interpretation of the predictions of our model. In conclusion, our study presents MLDSPP as a novel, generic tool for predicting promoter regions in bacteria, utilizing original downstream sequences as nonpromoter controls. This tool has the potential to significantly advance the field of bacterial genomics and contribute to our understanding of gene regulation in diverse bacterial systems.
Topics: Tool Use Behavior; Bacteria; DNA; Machine Learning; Promoter Regions, Genetic
PubMed: 38258978
DOI: 10.1021/acs.jcim.3c02017 -
BMC Health Services Research Jan 2024Chimeric antigen receptor T cells (CAR-T) represent an innovation but raise issues for healthcare payers because of the uncertainty on impact at market launch, high cost...
BACKGROUND
Chimeric antigen receptor T cells (CAR-T) represent an innovation but raise issues for healthcare payers because of the uncertainty on impact at market launch, high cost and important organisational impact. The literature has focused on their assessment, appraisal and market access solutions. No evidence on the costs sustained to implement CAR-T is available and a few studies reported the cost of the CAR-T clinical pathway, including the activities that are remunerated through inpatient or outpatient fee-for-service/episode. This paper aims at filling the information gap, assessing the cost of implementing CAR-T activity and the full cost of managing the CAR-T clinical pathway.
METHODS
Cost analysis relied on the Activity Based Costing approach, which was applied to two Italian healthcare organisations, both CAR-T Centres authorized by the regional governments with a minimum of 20 patients treated with the first two CAR-T therapies launched on the market.
RESULTS
The cost of implementing CAR-T was estimated at €1.31 million (calculated for one of the organizations with complete data). Most of these costs (77%) were generated by quality assurance activity. The mean cost per patient entering the CAR-T pathway (59 and 27) and surviving at follow-up (21 and 5) ranges from €48K to €57K and from €96K to €106K, respectively. Fees for hospitalization and infusion of gene therapy accounts for more than 70% of these costs. The actual hospitalisation cost varies greatly across patients and is in general lower than the fee-for-episode paid by the region to the hospital.
CONCLUSIONS
Despite its limitations (exploratory nature; the time spent by staff on activities which are not remunerated through fees was estimated through interviews with the CAR-T coordinators; cost items are not fully comparable), this research highlighted the relevant organisational and economic impact of CAR-T and provided important insights for policy makers and healthcare managers: the necessity to invest resources in CAR-T implementation; the need for assessing activities which are not remunerated through fees for service / episode; the opportunity to shift from fee-for-episode / service to bundled payments for CAR-T clinical pathway.
Topics: Humans; Receptors, Chimeric Antigen; Inpatients; Outpatients; Administrative Personnel; Costs and Cost Analysis
PubMed: 38254079
DOI: 10.1186/s12913-023-10443-5