Biology subjects

Leal, A.

Publications and source records attributed to Leal, A..

3 recordsLinked to original sources

bioRxiv2023

Elucidating the heterogeneity of immunotherapy response and immune-related toxicities by longitudinal ctDNA and immune cell compartment tracking in lung cancer

PurposeAlthough immunotherapy is the mainstay of therapy for advanced non-small cell lung cancer (NSCLC), robust biomarkers of clinical response are lacking. The heterogeneity of clinical responses together with the limited value of radiographic response assessments to timely and accurately predict therapeutic effect -especially in the setting of stable disease-call for the development of molecularly-informed real-time minimally invasive predictive biomarkers. In addition to capturing tumor regression, liquid biopsies may be informative in evaluating immune-related adverse events (irAEs). Experimental designWe investigated longitudinal changes in circulating tumor DNA (ctDNA) in patients with metastatic NSCLC who received immunotherapy-based regimens. Using ctDNA targeted error-correction sequencing together with matched sequencing of white blood cells and tumor tissue, we tracked serial changes in cell-free tumor load (cfTL) and determined molecular response for each patient. Peripheral T-cell repertoire dynamics were serially assessed and evaluated together with plasma protein expression profiles. ResultsMolecular response, defined as complete clearance of cfTL, was significantly associated with progression-free (log-rank p=0.0003) and overall survival (log-rank p=0.01) and was particularly informative in capturing differential survival outcomes among patients with radiographically stable disease. For patients who developed irAEs, peripheral blood T-cell repertoire reshaping, assessed by significant TCR clonotypic expansions and regressions were noted on-treatment. ConclusionsMolecular responses assist with interpretation of heterogeneous clinical responses especially for patients with stable disease. Our complementary assessment of the tumor and immune compartments by liquid biopsies provides an approach for monitoring of clinical benefit and immune-related toxicities for patients with NSCLC receiving immunotherapy. Statement of translational relevanceLongitudinal dynamic changes in cell-free tumor load and reshaping of the peripheral T-cell repertoire capture clinical outcomes and immune-related toxicities during immunotherapy for patients with non-small cell lung cancer.

genomics↗

bioRxiv2023

Ghrelin delays premature aging in Hutchinson-Gilford progeria syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal genetic condition arising from a single nucleotide alteration in the LMNA gene, which leads to the production of a defective lamin A protein known as progerin. The buildup of progerin hastens the onset of premature and expedited aging. Patients with HGPS exhibit short stature, low body weight, lipodystrophy, metabolic dysfunction, and skin and musculoskeletal abnormalities and, in most cases, die of cardiovascular disease by their early teenage years. Currently, no effective cure or treatment for the disease highlights the importance of discovering new therapeutic strategies. Herein, we present evidence that the hormone ghrelin, besides promoting autophagy and progerin clearance, rescued several cellular hallmarks of premature aging of human HGPS fibroblasts. Using an HGPS mouse model, LmnaG609G/G609G mice, we also show that ghrelin administration rescued the short-lived mice molecular and histopathological progeroid features, prevented progressive weight loss at later stages, reverted the lipodystrophic phenotype, and extended lifespan. Thus, we disclose that modulation of ghrelin signaling may give rise to new treatment targets and translational approaches that may improve outcomes and the health quality of HGPS patients and natural aging pathologies.

physiology↗

bioRxiv2020

Mutational Survivorship Bias: The case of PNKP

The molecular function of a protein relies on its structure. Understanding how mutations alter structure and function in multi-domain proteins, is key to elucidate how a pathological phenotype is generated. However, one may fall into the logical bias of assessing protein damage only based on the mutations that are viable (survivorship bias), which can lead to partial conclusions. This is the case of PNKP, an important nuclear and mitochondrial DNA repair enzyme with kinase and phosphatase function. Most mutations in PNKP are confined to the kinase domain, leading to a pathological spectrum of three apparently distinct clinical entities. Since proteins and domains may have a different tolerance to disease causing mutations, we evaluated whether mutations in PNKP are under survivorship bias. Even when all mutations in the kinase domain are deleterious, we found a mayor mutation tolerability landscape in terms of survival. Instead, the phosphatase domain is less tolerant due to its low mutation rates, higher degree of sequence conservation, lower dN/dS ratios, and more disease-propensity hotspots. Thus, in multi-domain proteins, we propose the term "Walds domain" for those who are not apparently more associated with disease, but that are less resistant to mutations in terms of survival. Together, our results support previous experimental evidence that demonstrated that the phosphatase domain is functionally more necessary and relevant for DNA repair, especially in the context of the development of the central nervous system. Thus, this bias should be taken into account when analyzing the mutational landscape in protein structure, function, and finally in disease.

molecular biology↗