A significant volume of research clearly shows that disease-related methylation changes can be used as biomarkers at all stages of clinical disease management, including risk assessment and predisposition screening through early diagnostics to personalization of patient care and monitoring of the relapse and chronic disease. Thus diseaserelated methylation changes are an attractive source of the biomarkers that can have significant impact on precision medicine. However, the translation of the research findings in methylation biomarkers field to clinical practice is at the very least not satisfactory. That is mainly because the evidence generated in research studies indicating the utility of the disease-related methylation change to predict clinical outcome is in majority of the cases not sufficient to postulate the diagnostic use of the biomarker. The research studies need to be followed by well-designed and systematic investigations of clinical utility of the biomarker that produce data of sufficient quality to meet regulatory approval for the test to be used to make clinically valid decision. In this review, we describe methylation-based IVD tests currently approved for IVD use or at the advanced stages of the development for the diagnostic use. For each of those tests, we analyze the technologies that the test utilizes for methylation detection as well as describe the types of the clinical studies that were performed to show clinical validity of the test and warrant regulatory approval. The examples reviewed here should help with planning of clinical investigations and delivery of the clinical evidence required for the regulatory approval of potential methylation biomarker based IVD tests.
The anticancer activity of bortezomib (BTZ) has been increasingly studied in a number of indications and promising results for the use of this treatment have been shown in neuroblastoma. As BTZ treatment is usually administered in cycles, the development of resistance and side effects in patients undergoing therapy with BTZ remains a major challenge for the clinical usage of this compound. Common resistance development also means that certain cells are able to survive BTZ treatment and bypass molecular mechanisms that render BTZ anticancer activity. We studied the methylome of neuroblastoma cells that survived BTZ treatment. Our results indicate that BTZ induces pronounced genome wide methylation changes in cells which recovered from the treatment. Functional analyses of identified methylation changes demonstrated they were involved in key cancer pathology pathways. These changes may allow the cells to bypass the primary anticancer activity of BTZ and develop a treatment resistant and proliferative phenotype. To study whether cells surviving BTZ treatment acquire a proliferative phenotype, we repeatedly treated cells which recovered from the first round of BTZ treatment. The repetitive treatment led to induction of the extraordinary proliferative potential of the cells, that increased with subsequent treatments. As we did not observe similar effects in cells that survived treatment with lenalidomide, and non-treated cells cultured under the same experimental conditions, this phenomenon seems to be BTZ specific. Overall, our results indicate that methylation changes may play major role in the development of BTZ resistance.
Covalent modifications of nucleotides in genetic material have been known from the beginning of the last century. Currently, one of those modifications referred to as DNA methylation, is impacting personalised medicine both as a treatment target and a biomarker source for clinical disease management. In this short review, we describe landmark discoveries that led to the elucidation of the DNA methylation importance in the cell’s physiology and clarification of its role as one of the major processes in disease pathology. We also describe turning points in the development of methodologies to study this modification, which ultimately resulted in the development of in-vitro diagnostic kits targeting disease related DNA methylation changes as biomarkers.
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Non-alcoholic fatty liver disease (NAFLD) is associated with dysfunction of the intestinal microbiota and its metabolites. We aimed to assess whether replacing bread with high-fiber buns beneficially changes the metabolome in NAFLD patients. This study involved 27 adult patients with NAFLD validated by FibroScan® (CAP ≥ 234 dB/m). Patients were asked to replace their existing bread for two meals with high-fiber buns. In this way, the patients ate two rolls every day for 2 months. The following parameters were analysed (at the beginning and after 2 months): the anthropometric data (BIA), eating habits (24 h food recalls), gut barrier markers (lipopolysaccharide S and liposaccharide binding protein (LPS, LBP)), serum short-chain fatty acids (SCFAs) and branched chain fatty acids (BCFAs) by GC/MS chromatography, as well as serum metabolites (by 1H NMR spectroscopy). After 2 months of high-fiber roll consumption, the reduction of liver steatosis was observed (change Fibroscan CAP values from 309–277 dB/m). In serum propionate, acetate, isovaleric, and 2-methylbutyric decrease was observed. Proline, choline and one unknown molecule had higher relative concentration in serum at endpoint. A fiber-targeted dietary approach may be helpful in the treatment of patients with NAFLD, by changing the serum microbiota metabolome.
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