Dataset Information

Genetics in Cartilage Lesions: Basic Science and Therapy Approaches.

ABSTRACT: Cartilage lesions have a multifactorial nature, and genetic factors are their strongest determinants. As biochemical and genetic studies have dramatically progressed over the past decade, the molecular basis of cartilage pathologies has become clearer. Several homeostasis abnormalities within cartilaginous tissue have been found, including various structural changes, differential gene expression patterns, as well as altered epigenetic regulation. However, the efficient treatment of cartilage pathologies represents a substantial challenge. Understanding the complex genetic background pertaining to cartilage pathologies is useful primarily in the context of seeking new pathways leading to disease progression as well as in developing new targeted therapies. A technology utilizing gene transfer to deliver therapeutic genes to the site of injury is quickly becoming an emerging approach in cartilage renewal. The goal of this work is to provide an overview of the genetic basis of chondral lesions and the different approaches of the most recent systems exploiting therapeutic gene transfer in cartilage repair. The integration of tissue engineering with viral gene vectors is a novel and active area of research. However, despite promising preclinical data, this therapeutic concept needs to be supported by the growing body of clinical trials.

SUBMITTER: Szwedowski D

PROVIDER: S-EPMC7432875 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Genetics in Cartilage Lesions: Basic Science and Therapy Approaches.

Szwedowski Dawid D Szczepanek Joanna J Paczesny Łukasz Ł Pękała Przemysław P Zabrzyński Jan J Kruczyński Jacek J

International journal of molecular sciences 20200730 15

Cartilage lesions have a multifactorial nature, and genetic factors are their strongest determinants. As biochemical and genetic studies have dramatically progressed over the past decade, the molecular basis of cartilage pathologies has become clearer. Several homeostasis abnormalities within cartilaginous tissue have been found, including various structural changes, differential gene expression patterns, as well as altered epigenetic regulation. However, the efficient treatment of cartilage pat ...[more]

PMID: 32751537

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Project description:Maintenance therapy (MT) with oral methotrexate (MTX) and 6-mercaptopurine (6-MP) is essential for the cure of acute lymphoblastic leukemia (ALL). MTX and 6-MP interfere with nucleotide synthesis and salvage pathways. The primary cytotoxic mechanism involves the incorporation of thioguanine nucleotides (TGNs) into DNA (as DNA-TG), which may be enhanced by the inhibition of de novo purine synthesis by other MTX/6-MP metabolites. Co-medication during MT is common. Although Pneumocystis jirovecii prophylaxis appears safe, the benefit of glucocorticosteroid/vincristine pulses in improving survival and of allopurinol to moderate 6-MP pharmacokinetics remains uncertain. Numerous genetic polymorphisms influence the pharmacology, efficacy, and toxicity (mainly myelosuppression and hepatotoxicity) of MTX and thiopurines. Thiopurine S-methyltransferase (encoded by TPMT) decreases TGNs but increases methylated 6-MP metabolites (MeMPs); similarly, nudix hydrolase 15 (encoded by NUDT15) also decreases TGNs available for DNA incorporation. Loss-of-function variants in both genes are currently used to guide MT, but do not fully explain the inter-patient variability in thiopurine toxicity. Because of the large inter-individual variations in MTX/6-MP bioavailability and metabolism, dose adjustments are traditionally guided by the degree of myelosuppression, but this does not accurately reflect treatment intensity. DNA-TG is a common downstream metabolite of MTX/6-MP combination chemotherapy, and a higher level of DNA-TG has been associated with a lower relapse hazard, leading to the development of the Thiopurine Enhanced ALL Maintenance (TEAM) strategy-the addition of low-dose (2.5-12.5 mg/m2/day) 6-thioguanine to the 6-MP/MTX backbone-that is currently being tested in a randomized ALLTogether1 trial (EudraCT: 2018-001795-38). Mutations in the thiopurine and MTX metabolism pathways, and in the mismatch repair genes have been identified in early ALL relapses, providing valuable insights to assist the development of strategies to detect imminent relapse, to facilitate relapse salvage therapy, and even to bring about changes in frontline ALL therapy to mitigate this relapse risk.

Project description:Background Many HIV databases and applications focus on a limited domain of HIV knowledge. Since even a “simple” organism like HIV represents a very complex system with many interacting elements, the fractured structure of existing databases and applications likely limits our ability to investigate and understand HIV. To facilitate research, therefore, we have built HIVToolbox, which integrates much of the knowledge about HIV proteins and presents the data in an interactive web application. HIVToolbox allows quick and convenient hypotheses generation, experiment interpretation, and potential new drug structure creation. Methods HIVToolbox was built as a standard three-tier J2EE web application, consisting of 1) an underlying relational MySQL database, 2) a set of standard Java data access objects that pull data from the database, and 3) a set of dynamic web pages the user interacts with. HIV-1 data from external sources such as the Protein Data Bank, NCBI, Los Alamos, etc. was collected, curated, and stored in the HIVToolbox database. Additional data, such as homology and position statistics matrices, was generated from existing data. Since version 1, drug binding site and drug resistant mutation data has also been added. Results HIVToolbox was used to create several new hypotheses about HIV-1 integrase, including predicting the location of a CK2 phosphorylation site, which was later confirmed by experiment. A new version of HIVToolbox support display of the 3D locations of drug resistant mutations on surface plots of HIV proteins and the drug binding sites for structures of complexes of HIV proteins with drugs. Conclusion HIVToolbox is an open-access web application that allows virologists and structural biologists to access detailed information about HIV-1 proteins, such as sequence, structure, functional sites and relationships, homology, drug binding sites, and drug resistant mutations, and to immediately see the relationships between any or all of them. Weblink: [http://hivtoolbox.bio-toolkit.com]

Dataset Information

Genetics in Cartilage Lesions: Basic Science and Therapy Approaches.

Publications

Genetics in Cartilage Lesions: Basic Science and Therapy Approaches.

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