Biology subjects

Medeiros, M.

Publications and source records attributed to Medeiros, M..

4 recordsLinked to original sources

bioRxiv2026

Absolute quantitative proteomics guides patient-stratified drug repurposing in clear cell and papillary renal cell carcinoma.

BackgroundRenal cell carcinoma (RCC) is a highly heterogeneous disease in which distinct molecular subtypes exhibit characteristic genomic, metabolic, and microenvironmental features that influence therapeutic response. Substantial inter-patient variability exists within each subtype, resulting in markedly different clinical outcomes even among tumours of the same histological category. Proteomics provides a direct readout of tumour biology and pathway activity, complementing genomic information and enabling the identification of patient-specific actionable vulnerabilities. We applied a Total Protein Approach (TPA)-based prescriptomics framework that integrates absolute quantitative proteomics with curated drug-target knowledge to nominate patient-specific drug-repurposing options, positioned as coadjuvants to the prevailing standard of care. MethodsSeventeen human kidney tissue specimens, seven clear cell RCC (ccRCC), five papillary RCC (pRCC), and five normal adjacent tissues (NAT), were retrieved from the publicly available PRIDE repository (PXD023296) and reanalysed by TPA-based absolute quantification applied to previously acquired label-free LC-MS/MS data. Differential expression analysis between each tumour subtype and NAT identified subtype-specific upregulated proteins, wich were intersected with Therapeutic Target Database (TTD) to nominate FDA-approved drugs targeting dysregulated proteins as candidate repurposing strategies. ResultsccRCC and pRCC produced distinct proteome-wide upregulation profiles consistent with their known biological drivers. TPA index stratification nominated bempedoic acid (ACLY inhibitor) and tipiracil hydrochloride (TYMP inhibitor) as patient-stratified candidates for ccRCC, and auranofin (TXNRD1 inhibitor), bempedoic acid, and mipomersen (APOB-directed antisense oligonucleotide) for pRCC. ACLY was the only top-priority target shared across both subtypes, pointing to a candidate cross-subtype metabolic vulnerability. Secondary candidates emerged from protein-protein interaction network analysis in both subtypes.. ConclusionsThis study presents a quantitative proteomics framework for translating individual-patient proteomic dysregulation into coadjuvant drug-repurposing hypotheses across the principal RCC subtypes. By combining the TPA for absolute protein quantification with prescriptomics-guided drug-target mapping, we show that ccRCC and pRCC harbour distinct, individually stratifiable therapeutic vulnerabilities. These findings provide a proof-of-concept for proteomics-based treatment stratification in RCC and establish a scalable framework that, pending functional validation, could inform personalised therapeutic decision-making across RCC subtypes.

biochemistry↗

bioRxiv2024

A single-cell eQTL atlas of the human cerebellum reveals vulnerability of oligodendrocytes in essential tremor

Essential tremor (ET) is a movement disorder characterized by an upper-limb postural and action tremor. It is one of the most common neurological disorders, affecting 1% of the worldwide population. Despite strong evidence for genetic factors driving the aetiology of ET, the underlying pathophysiology remains poorly understood. To understand the effects of genetic risk factors in ET on the cerebellum, the brain region thought to be affected by the disease, we built a population-scale single-cell atlas of the human cerebellar cortex comprised of over 1 million cells from 109 individuals. Using single-cell expression quantitative trait loci and mendelian randomization, we found evidence of ET-associated variants in the BACE2 locus causally linked to its downregulation in cerebellar oligodendrocytes. We highlight a genetically vulnerable population of BACE2-expressing immature oligodendrocytes, suggestive of demyelination. We also find dysfunctional processes affecting interactions between Golgi cells, Purkinje layer interneurons, and oligodendrocytes in ET. Our study suggests a crucial role for cerebellar oligodendrocytes in the pathogenesis of ET.

genomics↗

bioRxiv2021

Pathway centered analysis to guide clinical decision-making in precision medicine

Changes in the human proteome caused by disease before, during and after medical care is phenotype-dependent, so the proteome of each individual at any time point is a snapshot of the bodys response to disease and to disease treatment. Here, we introduce a new concept named differential Personal Pathway index (dPPi). This tool extracts and summates comprehensive disease-specific information contained within an individuals proteome as a holistic way to follow the response to disease and medical care over time. We demonstrate the principle of the dPPi algorithm on proteins found in urine from patients suffering from neoplasia of the bladder. The relevance of the dPPi results to the individual clinical cases is described. The dPPi concept can be extended to other malignant and non-malignant diseases, and to other types of biopsies, such as plasma, serum or saliva. We envision the dPPi as a tool for clinical decision-making in precision medicine.

biochemistry↗

bioRxiv2019

Analysis of the testis transcriptome of the Chagas’ disease vector Rhodnius prolixus

Rhodnius prolixus is amongst the most important vectors of Trypanosoma cruzi in the Americas, putting thousands of people at risk of contracting Chagas Disease. This insect is also one of the most important models in insect physiology, especially regarding the blood-feeding process. However, studies on R. prolixus genetics lagged, and our understanding on the regulation of gene expression is incipient. Transcriptomes have the power to study the expression of thousands of genes in a single experiment. A comprehensive R. prolixus transcriptome was performed in 2014, sequencing RNA from different tissues (anterior gut, midgut, posterior gut, rectum, ovaries, fat body, maphigian tubules, and testicles). However, on that occasion, only the gut transcriptome was deeply analysed. Here we evaluated the results of the testicles transcriptome of R. prolixus with the objective to find and understand genes that could have an important role in male reproduction. We found, that from the 25,673 transcripts assembled in the whole transcriptome, 5,365 have a testicle specific expression pattern. As expected, amongst the most abundant families of transcripts, are those related to spermatogenesis and male fertility, such as myosins, actins, and dyneins. To our surprise, lipocalins, serine protease inhibitors (serpins), and lysozymes also were highly abundant in testicles. The role of these classes of genes are well known in other tissues, such as salivary glands and gut, but very little is known on their role in male reproduction (and we proposed here a few hypothesis that could be tested to address the role of these genes in male fertility). It would be interesting to study further the role of these genes on R. prolixus male fertility. Finally, as a reflection of the lack of knowledge on triatomine genetics, we found that almost half of the transcripts in R. prolixus testicles have no similarities to any other genes on reference databases. Our study shows that we still have a lot to know and to understand about reproduction in triatomine, especially in males. Besides the large number of genes without described function (possibly novel genes), there are those in which the function is known for other tissues, and we can only guess, at best, the role and importance of such genes for triatomine male fertility. Author SummaryThe understanding of the biology of insects vectors of parasitic diseases is key to the development of strategies of public health. For decades, the studies on the biology of male insects vectors of diseases was neglected, since in many cases female insects are those with relevant role in the spread of diseases. With the development of genomics, large scale studies to compare differential gene expression (transcriptomics) among different tissues, developmental stages, and sex became accessible. In this study, we looked at the physiology of the male reproductive organs of the vector of Chagas disease Rhodnius prolixus. This is a first glimpse, from a perspective of genes differentially expressed in male gonads, in such insects. We also performed an effort to link all identified genes with the insect genome published in 2015. We found ~14,000 genes expressed in the testicles, from which 5,635 genes are expressed exclusively in male reproductive organs. From the ~14,000 genes, we were able to attribute putative biological functions to 6,372 genes, which allowed us to draw a bigger picture on how these genes contribute to male fertility. This study now opens the door for further in-depth studies to find key genes for R. prolixus reproductive biology.

genomics↗