miRNAs in cerebrospinal fluid associated with Alzheimer's disease: A systematic review and pathway analysis using a data mining and machine learning approach.

Alzheimer's disease (AD) is the most common type and accounts for 60%-70% of the reported cases of dementia. MicroRNAs (miRNAs) are small non-coding RNAs that play a crucial role in gene expression regulation. Although the diagnosis of AD is primarily clinical, several miRNAs have been associated with AD and considered as potential markers for diagnosis and progression of AD. We sought to match AD-related miRNAs in cerebrospinal fluid (CSF) found in the GeoDataSets, evaluated by machine learning, with miRNAs listed in a systematic review, and a pathway analysis. Using machine learning approaches, we identified most differentially expressed miRNAs in Gene Expression Omnibus (GEO), which were validated by the systematic review, using the acronym PECO-Population (P): Patients with AD, Exposure (E): expression of miRNAs, Comparison (C): Healthy individuals, and Objective (O): miRNAs differentially expressed in CSF. Additionally, pathway enrichment analysis was performed to identify the main pathways involving at least four miRNAs selected. Four miRNAs were identified for differentiating between patients with and without AD in machine learning combined to systematic review, and followed the pathways analysis: miRNA-30a-3p, miRNA-193a-5p, miRNA-143-3p, miRNA-145-5p. The pathways epidermal growth factor, MAPK, TGF-beta and ATM-dependent DNA damage response, were regulated by these miRNAs, but only the MAPK pathway presented higher relevance after a randomic pathway analysis. These findings have the potential to assist in the development of diagnostic tests for AD using miRNAs as biomarkers, as well as provide understanding of the relationship between different pathophysiological mechanisms of AD.

microRNAS no líquido cefalorraquidiano associados à doença de Alzheimer: uma revisão sistemática e análise de vias usando a abordagem de aprendizado de máquina / microRNAs in Cerebrospinal Fluid Associated with Alzheimer's Disease: A systematic review and pathway analysis using a machine learning approach

O aumento da expectativa de vida e o envelhecimento populacional têm contribuído para o crescimento da prevalência da doença de Alzheimer (DA), uma vez que o envelhecimento é um dos fatores de risco para o desenvolvimento da forma esporádica da doença. O diagnóstico da DA é essencialmente baseado na avaliação clínica e requer a experiência de profissionais altamente treinados para um diagnóstico conclusivo. No entanto, devido à complexidade da doença e à necessidade de métodos mais precisos, a pesquisa por biomarcadores tem ganhado uma crescente importância. Nos últimos tempos, tem-se observado um aumento significativo no interesse pelo papel dos microRNAs (miRNAs) na regulação da expressão gênica e sua associação com a DA. Os miRNAs são pequenas moléculas de RNA não codificantes que desempenham um papel crucial na regulação de processos celulares. Vários miRNAs foram identificados como potenciais marcadores para o diagnóstico e progressão da DA. O presente estudo objetivou realizar uma busca por miRNAs diferencialmente expressos em líquor cefalorraquidiano (LCR) de pacientes com DA comparados a indivíduos cognitivamente saudáveis, a partir de banco de dados públicos e usando ferramentas de aprendizado de máquina, com validação dos resultados em uma revisão sistemática e a proposição de vias biológicas reguladas. Para isso, a primeira busca foi realizada na plataforma GEO Database e aplicado o algoritmo LightGBM. Posteriormente, a revisão sistemática foi realizada utilizando o PECO ­ população (P): indivíduos idosos, exposição (E): doença de Alzheimer (C): indivíduos cognitivamente saudáveis, desfeixo ou outcome (O): miRNAs diferencialmente expressos no líquor, usando os repositórios eletrônicos: MEDLINE/PubMed (Medical Literature Analysis and Retrieve System Online), Scopus, Cinahl, Web of Science e Embase. A análise de vias foi feita no miRTarBase. Após a sobreposição dos resultados obtidos pelo algoritmo e pela revisão sistemática, foram identificados sete miRNAs mais diferencialmente expressos no líquor de indivíduos com DA: miRNA-1274a, miRNA-193a-5p, miRNA-28-3p, miRNA-30a-3p, miRNA-145, miRNA-19b e miRNA-143. Na análise de enriquecimento de vias, foram identificadas: resposta ao dano no DNA por ATM, sinalização ERBB, sinalização de mensageiro secundário intracelular, sinalização MAPK e sinalização TGF-beta, as quais possuem participação na fisiopatologia da DA. Os resultados sugerem que os miRNA-1274a, miRNA-193a-5p, miRNA-28-3p, miRNA-30a-3p, miRNA-145, miRNA-19b e miRNA-143 podem estar envolvidos nos mecanismos moleculares e nas vias biológicas envolvidas na doença e podem ser no futuro alvos terapêuticos para a DA.

The increase in life expectancy and the aging population have contributed to the growth in the prevalence of Alzheimer's disease (AD), as aging is one of the risk factors for the development of the sporadic form of the disease. The diagnosis of AD is primarily based on clinical evaluation and requires the expertise of highly trained professionals for a conclusive diagnosis. However, due to the complexity of the disease and the need for more precise methods, research on biomarkers has gained increasing importance. In recent times, there has been a significant increase in interest in the role of microRNAs (miRNAs) in gene expression regulation and their association with AD. MiRNAs are small non-coding RNA molecules that play a crucial role in regulating cellular processes. Several miRNAs have been identified as potential markers for the diagnosis and progression of AD. This study aimed to search for differentially expressed miRNAs in the cerebrospinal fluid (CSF) of AD patients compared to cognitively healthy individuals using public databases and machine learning tools, with the validation of the results in a systematic review and the proposal of regulated biological pathways. To do this, the initial search was conducted on the GEO Database platform, and the LightGBM algorithm was applied. Subsequently, the systematic review was performed using the PECO framework ­ Population (P): elderly individuals, Exposure (E): Alzheimer's disease, Control (C): cognitively healthy individuals, Outcome (O): differentially expressed miRNAs in CSF, utilizing the electronic repositories: MEDLINE/PubMed, Scopus, Cinahl, Web of Science, and Embase. Pathway analysis was conducted using miRTarBase. After overlapping the results obtained by the algorithm and the systematic review, seven miRNAs were identified as the most differentially expressed in the CSF of individuals with AD: miRNA-1274a, miRNA-193a-5p, miRNA-28-3p, miRNA-30a-3p, miRNA-145, miRNA-19b, and miRNA-143. In the pathway enrichment analysis, the following pathways were identified: DNA damage response by ATM, ERBB signaling, intracellular second messenger signaling, MAPK signaling, and TGF-beta signaling, all of which have a role in the pathophysiology of AD. The results suggest that miRNA-1274a, miRNA-193a-5p, miRNA-28-3p, miRNA-30a-3p, miRNA-145, miRNA-19b, and miRNA-143 may be involved in the molecular mechanisms and biological pathways associated with the disease and could potentially serve as therapeutic targets for AD in the future.

microRNAs associated to anthracycline-induced cardiotoxicity in women with breast cancer: A systematic review and pathway analysis.

BACKGROUND: Cardiotoxicity is a common and serious adverse effect of anthracycline therapy in breast cancer patients. The current criteria for cardiotoxicity are based on imaging and cardiac biomarkers. However, there is a need for new biomarkers to help with early diagnosis. MicroRNAs (miRNAs) are small non-coding RNA molecules that play an important role in the regulation of gene expression. Several miRNAs have been associated with cardiovascular diseases and are biomarkers under investigation for cancer treatment-related cardiotoxicity. METHODS: We performed a systematic literature search of Medline/PubMed, Cochrane Central Register of Controlled Trials, Scopus, Lilacs, Web of Science and Embase, until April 2020. Cohort studies that reported miRNA biomarkers in breast cancer patients with anthracycline-induced cardiotoxicity and non-cardiotoxicity patients were included. Moreover, we searched the miRTarBase for experimentally validated miRNA-target interactions. RESULTS: Among the 209 studies retrieved, five fulfilled the inclusion criteria. Let-7f, miR-1, miR-20a, miR-126 and miR-210 were validated in two population-based cohorts. The pro-angiogenic miRNAs let-7f, miR-20a, miR-126 and miR-210 were significantly down-regulated in epirubicin-cardiotoxicity when compared to the non-cardiotoxicity group. miR-1 has been shown to provide diagnostic and prognostic information in the setting of myocardial infarction, but changes in its levels are controversial in doxorubicin-treated breast cancer patients with cardiotoxicity. Reactome pathways relevant to cardiotoxicity were found from the target genes for let-7f, miR-1, miR-20a, miR-126 and miR-210 at miRTarBase. CONCLUSION: The data suggest that let-7f, miR-1, miR-20a, miR-126 and miR-210 are associated with anthracycline-based cardiotoxicity during chemotherapy in breast cancer patients.