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The therapeutic application of drugs often faces challenges due to non-specific distribution, inadequate dosification and degradation, which limits their efficacy. Two primary strategies are employed to overcome these issues: the use of derivatives of the active substances and incorporation of those into porous materials. The latter, involving materials such as zeolites, metal–organic frameworks (MOFs), and hydrogels, has shown promising results in protecting the active ingredients from degradation and enabling a controlled release. This study focuses on supramolecular metal–organic frameworks (SMOFs), which leverage supramolecular interactions for enhanced pore size control. [Cu6Cr(μ-adeninato-κN3:κN9)6(μ3-OH)6(μ-OH2)6](SO4)1.5·nH2O (Cu6Cr) was chosen for its flexible porous structure, water-stability, and paramagnetic properties. Magnetic sustentation studies showed that this compound was able to capture several drug molecules: 5-fluorouracil (5-FU), 5-aminosalicylic acid (5-ASA), 4-aminosalicylic acid (4-ASA) and theophylline (THEO). Their release follows a pseudo-first-order kinetics with desorption half-lives ranging from 2.2 to 4.7 hours. In this sense, a novel approach is proposed using bulkier raffinose and cholesterol as pore-blocking molecules. Cholesterol exhibited the best performance as a blocking molecule increasing the desorption half-life up to 8.2 hours. Cytotoxicity and RNA-seq transcriptomic assays carried out on human colorectal cancer cell cultures showed, on one hand, that the Cu6Cr porous material exhibits a proliferative effect, probably coming from the over-expression of MIR1248 and SUMO2 genes, and on the other hand, that there is a delay in the emergence of the cytotoxicity of 5-FU as expected for a slower release. [ABSTRACT FROM AUTHOR]

Strong epigenetic pan-cancer biomarkers are required to meet several current, urgent clinical needs and to further improve the present chemotherapeutic standard. We have concentrated on the investigation of epigenetic alteration of the hTERT gene, which is frequently epigenetically dysregulated in a number of cancers in specific developmental stages. Distinct DNA methylation profiles were identified in our data on early urothelial cancer. An efficient EpihTERT assay could be developed utilizing suitable combinations with sequence-dependent thermodynamic parameters to distinguish between differentially methylated states. We infer from this data set, the epigenetic context, and the related literature that a CpG-rich, 2800 bp region, a prominent CpG island, surrounding the transcription start of the hTERT gene is the crucial epigenetic zone for the development of a potent biomarker. In order to accurately describe this region, we have named it "Acheron" (Ἀχέρων). In Greek mythology, this is the river of woe and misery and the path to the underworld. Exploitation of the DNA methylation profiles focused on this region, e.g., idiolocal normalized Methylation Specific PCR (IDLN-MSP), opens up a wide range of new possibilities for diagnosis, determination of prognosis, follow-up, and detection of residual disease. It may also have broad implications for the choice of chemotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer treatment could be revolutionized by using particular CAR-T-cell therapies for all solid tumors. Finding appropriate CAR-T-cell antigens for every tumor entity would be necessary for this though. Our findings provide new insight into the possibility of employing CAR-T-cell therapy to treat nearly all cancers, as genome-wide screening following consistent occurring DNA hypomethylations may uncover novel antigens for every cancer entity. Based on the impressive success of Car-T-cell therapy in the treatment of hematological malignancies, a broad application for solid tumors also appears promising. However, some important hurdles need to be overcome. One of these is certainly the identification of specific target antigens on cancer cells. Hypomethylation is a characteristic epigenetic aberration in many tumor entities. Genome-wide screenings for consistent DNA hypomethylations in tumors enable the identification of aberrantly upregulated transcripts, which might result in cell surface proteins. Thus, this approach provides a new perspective for the discovery of potential new Car-T-cell target antigens for almost every tumor entity. First, we focus on this approach as a possible treatment for prostate cancer. [ABSTRACT FROM AUTHOR]

Introduction: Bipolar disorder (BD) is a chronically progressive mental condition, associated with a reduced quality of life and greater disability. Patient admissions are preventable events with a considerable impact on global functioning and social adjustment. While machine learning (ML) approaches have proven prediction ability in other diseases, little is known about their utility to predict patient admissions in this pathology. Aim: To develop prediction models for hospital admission/readmission within 5 years of diagnosis in patients with BD using ML techniques. Methods: The study utilized data from patients diagnosed with BD in a major healthcare organization in Colombia. Candidate predictors were selected from Electronic Health Records (EHRs) and included sociodemographic and clinical variables. ML algorithms, including Decision Trees, Random Forests, Logistic Regressions, and Support Vector Machines, were used to predict patient admission or readmission. Survival models, including a penalized Cox Model and Random Survival Forest, were used to predict time to admission and first readmission. Model performance was evaluated using accuracy, precision, recall, F1 score, area under the receiver operating characteristic curve (AUC) and concordance index. Results: The admission dataset included 2,726 BD patients, with 354 admissions, while the readmission dataset included 352 patients, with almost half being readmitted. The best-performing model for predicting admission was the Random Forest, with an accuracy score of 0.951 and an AUC of 0.98. The variables with the greatest predictive power in the Recursive Feature Elimination (RFE) importance analysis were the number of psychiatric emergency visits, the number of outpatient follow-up appointments and age. Survival models showed similar results, with the Random Survival Forest performing best, achieving an AUC of 0.95. However, the prediction models for patient readmission had poorer performance, with the Random Forest model being again the best performer but with an AUC below 0.70. Conclusion: ML models, particularly the Random Forest model, outperformed traditional statistical techniques for admission prediction. However, readmission prediction models had poorer performance. This study demonstrates the potential of ML techniques in improving prediction accuracy for BD patient admissions. [ABSTRACT FROM AUTHOR]

Cell-free extrachromosomal circular DNA (cf-eccDNA) has been proposed as a promising early biomarker for disease diagnosis, progression and drug response. Its established biomarker features are changes in the number and length distribution of cf-eccDNA. Another novel promising biomarker is a set of eccDNA excised from a panel of genes specific to a condition compared to a control. Deficiencies in two endonucleases that specifically target DNA, Dnase1 and Dnase1l3, are associated with systemic lupus erythematosus (SLE). To study the genic eccDNA profiles in the case of their deficiencies, we mapped sequenced eccDNA data from plasma, liver and buffy coat from Dnase1 and Dnase1l3 knockouts (KOs), and wild type controls in mouse. Next, we performed an eccDNA differential analysis between KO and control groups using our DifCir algorithm. We found a specific genic cf-eccDNA fingerprint of the Dnase1l3 group compared to the wild type controls involving 131 genes; 26% of them were associated with human chromosomal fragile sites (CFSs) and with a statistically significant enrichment of CFS-associated genes. We found six genes in common with the genic cf-eccDNA profile of SLE patients with DNASE1L3 deficiency, namely Rorb, Mvb12b, Osbpl10, Fto, Tnik and Arhgap10; all of them were specific and present in all human plasma samples, and none of them were associated with CFSs. A not so distinctive genic cf-eccDNA difference involving only seven genes was observed in the case of the Dnase1 group compared to the wild type. In tissue—liver and buffy coat—we did not detect the same genic eccDNA difference observed in the plasma samples. These results point to a specific role of a set of genic eccDNA in plasma from DNase KOs, as well as a relation with CFS genes, confirming the promise of the genic cf-eccDNA in studying diseases and the need for further research on the relationship between eccDNA and CFSs. [ABSTRACT FROM AUTHOR]

Background: Numerous genes, including SOD1, mutated in familial and sporadic amyotrophic lateral sclerosis (f/sALS) share a role in DNA damage and repair, emphasizing genome disintegration in ALS. One possible outcome of chromosomal instability and repair processes is extrachromosomal circular DNA (eccDNA) formation. Therefore, eccDNA might accumulate in f/sALS with yet unknown function. Methods: We combined rolling circle amplification with linear DNA digestion to purify eccDNA from the cervical spinal cord of 9 co-isogenic symptomatic hSOD1G93A mutants and 10 controls, followed by deep short-read sequencing. We mapped the eccDNAs and performed differential analysis based on the split read signal of the eccDNAs, referred as DifCir, between the ALS and control specimens, to find differentially produced per gene circles (DPpGC) in the two groups. Compared were eccDNA abundances, length distributions and genic profiles. We further assessed proteome alterations in ALS by mass spectrometry, and matched the DPpGCs with differentially expressed proteins (DEPs) in ALS. Additionally, we aligned the ALS-specific DPpGCs to ALS risk gene databases. Results: We found a six-fold enrichment in the number of unique eccDNAs in the genotoxic ALS-model relative to controls. We uncovered a distinct genic circulome profile characterized by 225 up-DPpGCs, i.e., genes that produced more eccDNAs from distinct gene sequences in ALS than under control conditions. The inter-sample recurrence rate was at least 89% for the top 6 up-DPpGCs. ALS proteome analyses revealed 42 corresponding DEPs, of which 19 underlying genes were itemized for an ALS risk in GWAS databases. The up-DPpGCs and their DEP tandems mainly impart neuron-specific functions, and gene set enrichment analyses indicated an overrepresentation of the adenylate cyclase modulating G protein pathway. Conclusions: We prove, for the first time, a significant enrichment of eccDNA in the ALS-affected spinal cord. Our triple circulome, proteome and genome approach provide indication for a potential importance of certain eccDNAs in ALS neurodegeneration and a yet unconsidered role as ALS biomarkers. The related functional pathways might open up new targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]