Biology subjects

Ramos, A.

Publications and source records attributed to Ramos, A..

23 records · Page 2Linked to original sources

bioRxiv2020

Immune profiling of gliomas reveals a connection with Tau function and the tumor vasculature.

BackgroundGliomas remain refractory to all attempted treatments, including those using immune checkpoint inhibitors. The characterization of the tumor (immune) microenvironment has been recognized as an important challenge to get a mechanistic explanation for this lack of response and to improve the therapy of glial tumors. MethodsWe designed a prospective analysis of the immune cells of gliomas by flow cytometry. Tumors with or without isocytrate dehydrogenase 1/2 (IDH1/2) mutations were included in the study. The genetic profile and the presence of different molecular and cellular features of the gliomas were analyzed in parallel. The findings were validated in mouse glioma models. ResultsWe observed that few immune cells infiltrate mutant IDH1/2 gliomas and we distinguished two different profiles in their IDH1/2 wild-type counterparts. The first one has an important immune component, particularly enriched in myeloid cells with immunosuppressive features. The second group is more similar to mutant IDH1/2 gliomas, with few immune cells and a less immunosuppressive profile. Notably, we observed a direct correlation between the immune content and the presence of vascular alterations, which were associated with a reduced expression of Tau, a microtubule-binding-protein that controls the formation of tumor vessels in gliomas. Furthermore, overexpression of Tau was able to reduce the immune content in orthotopic mouse glioma models, delaying tumor growth. ConclusionsThere is a correlation between vascular alterations and the immune profile of gliomas, which could be exploited for the design of more successful clinical trials with immunomodulatory molecules. Key pointsO_LIMutant IDH1/2 gliomas harbor few immune cells in the tumor microenviroment. C_LIO_LIWe distinguished two different profiles in the IDH1/2 wild-type gliomas. C_LIO_LIThere is a correlation between Tau expression, vascular alterations and the immune profile. C_LI Importance of the StudyIn the present work we have confirmed that IDHmut gliomas are "cold" tumors and we have identified a subgroup of IDHwt GBMs that also contains a low immune infiltrate. By contrast, a large subgroup of IDHwt GBMs are characterized by an important immune component, particularly enriched in myeloid cells, and an elevated expression of the ligand of PD-L1 in the immune compartment. Notably, we have observed a direct correlation between the immune content and the presence of vascular alterations, as well as with the reduced expression of Tau, a microtubule-binding protein that we described as a negative regulator of angiogenesis. Here, we add that overexpression of Tau reduces the immune content in orthotopic glioma models, delaying tumor growth. This correlation between the vascular phenotype and the entrance and/or the function of the immune cells on gliomas, where Tau could play a central role, opens new venues to find synergistic treatments.

cancer biology↗

bioRxiv2019

Nuclear GAPDH signaling mediates pathological cardiac hypertrophy

Here we report that stress-induced nuclear translocation of GAPDH mediates heart hypertrophy via Brahma-Related-Gene-1 (BRG1)-associated chromatin remodelling. In response to pressure overload elicited by transverse aortic constriction, we observed nuclear translocation of GAPDH in the mouse heart. We also demonstrated a robust nuclear localization of GAPDH in cardiomyocytes from patients with dilated hypertrophic cardiomyopathy, whereas negligible GAPDH in the nucleus in control subjects. This is the first demonstration of disease-associated nuclear GAPDH directly in living patients. Using immunohistochemical methods and a pharmacological way that selectively blocks GAPDH nuclear translocation (RR compound), we proved the causal involvement of GAPDH cysteine-150 modification in this translocation in Gq-induced cell model for heart hypertrophy. Accordingly, both pharmacological and genetic interventions proved that the same mechanism played a causal role for heart hypertrophy and dysfunction in vivo. We discovered that, upon nuclear translocation, GAPDH augmented the protein interaction of BRG1 and histone deacetylase 2 (HDAC2), which further facilitated the Myh7/Myh6 isoform ratio from the mature to immature status, an essential mechanism for heart hypertrophy. Beyond medical implications, we provide a novel mechanism of stress-induced reversion of a cellular phenotype from adult to fetal state, which is mediated by a "moonlighting" function of GAPDH.

molecular biology↗

bioRxiv2019

Lifetime changes in CD4 count, viral load suppression and adherence among adolescents living with HIV in urban Peru

IntroductionViral load suppression and adherence to combined antiretroviral therapy (cART) have been shown to be lower in adolescents than in other age groups; however, this relationship has not been documented longitudinally from childhood to adolescence and has rarely been examined outside of high-resource settings and sub-Saharan Africa. To address this knowledge gap, we quantified longitudinal changes in CD4 cell count, viral load suppression, and cART adherence in adolescents living with HIV in urban, Peru.\n\nMethodsWe conducted a retrospective chart review among adolescents ages 10-18 years on cART and receiving care at a large, public sector pediatric hospital as of December 2015. We abstracted clinical notes indicating nonadherence and viral load and CD4 counts from childhood to adolescence. We modeled the association between age and each outcome with restricted cubic splines accounting for multiple observations per person, and graphed study outcomes by age.\n\nResultsA median of 7.7 years (25th percentile=4.9, 75th percentile=10.2) of follow up were observed for 128 adolescents. Nearly 70% of patients had at least one nonadherence note and the proportion with nonadherence increased log-linearly with age (p<0.0001). The peak proportion with viral load suppression was 84% (95% CI: 79, 88) at age 13, which dropped to 67% (95% CI: 47, 83) by age 18. Mean CD4 count decreased at age 13, dropping from 723 cells/mm3 (95% CI: 666, 784) to 429 cells/mm3 (95% CI: 356, 517) by age 18.\n\nConclusionThis is the first report from Latin America to examine longitudinal changes in HIV outcomes from childhood into adolescence. Consistent with the limited evidence from other settings, decreases in viral load suppression and mean CD4 count occurred in early adolescence in tandem with increases in nonadherence. Adolescent-friendly cART adherence support interventions to target this critical period are urgently needed.

epidemiology↗

bioRxiv2018

The role of control region mitochondrial DNA mutations in cardiovascular disease: stroke and myocardial infarction

Recent studies associated certain type of cardiovascular disease (CVD) with specific mitochondrial DNA (mtDNA) defects, mainly driven by the central role of mitochondria in cellular metabolism. Considering the importance of the control region (CR) on the regulation of the mtDNA gene expression, the aim of the present study was to investigate the role of the mtDNA CR mutations in two CVDs: stroke and myocardial infarction (MI). Both, fixed and heteroplasmy mutations of the mtDNA CR in two population samples of demographically-matched case and controls, were analysed using 154 stroke cases, 211 MI cases and their corresponding control individuals. Significant differences were found between cases and controls, reporting the m.16145G>A and m.16311T>C as a potential genetic risk factors for stroke (conditional logistic regression: p=0.038 and p=0.018, respectively), whereas the m.72T>C, m.73A>G and m.16356T>C could act as possible beneficial genetic factors for MI (conditional logistic regression: p=0.001, p=0.009 and p=0.016, respectively). Furthermore, our findings also showed a high percentage of point heteroplasmy in MI controls (logistic regression: p=0.046; OR= 0.209, 95% CI [0.045-0.972]). These results demonstrate the possible role of mtDNA mutations in the CR on the pathogenesis of stroke and MI, and show the importance of including this regulatory region in genetic association studies.\n\nAuthor SummaryGiven the association between cardiovascular disease and specific mitochondrial DNA (mtDNA) defects and considering the importance of the control region of this genome on the regulation of mtDNA gene expression, here, we investigate the role of mutations in mitochondrial DNA control region in two cardiovascular diseases: stroke and myocardial infarction. In this study we found five mitochondrial genetic variants related to cardiovascular disease, based on single nucleotide polymorphisms (SNPs), which are located in the control region of mtDNA. Despite the abundance of work on the role of mitochondrial DNA in relation to cardiovascular disease, little literature has been published on the variation that this genome expresses in relation to this disease. For this reason, our study provides significant insight of the genetic variability that determines normality or pathology in relation to the genetic risk of cardiovascular disease. The results obtained demonstrate the possible role of mtDNA mutations in the control region on the pathogenesis of stroke and myocardial infarction, and show the importance of including this regulatory region in genetic association studies.

genetics↗

bioRxiv2018

Reappraising the human mitochondrial DNA recombination dogma

With the \"mitochondrial Eve\" theory proposed by Rebecca Cann in the eighties, human mitochondrial DNA (mtDNA) has been used as a tool in studying human variation and evolution. Although the existence of recombination in human mtDNA has been previously advocated, studies dealing with human variation and evolution have assumed that human mtDNA does not recombine and should be considered as pathological or very infrequent. Using both direct and indirect approaches, we provide consistent evidence of mtDNA recombination in humans. We applied the single molecule PCR procedure to directly test for recombination in multiheteroplasmic individuals without any overt pathology. Moreover, we searched for past recombination events in the whole mitochondrial genomes of more than 15,000 individuals. Results from our study update and expand both the seminal indirect findings and the scarce direct evidence observed to date, paving the way for the definitive rejection of the non-recombination dogma for human mtDNA. Acknowledgment of recombination as a frequent event in mtDNA will require the description of the population recombination rate(s) and to apply it to past and future studies involving mtDNA. MtDNA recombination affects our knowledge of human evolutionary history, regarding haplogroup divergence times, as well as the time to the mitochondrial most recent common ancestor. Finally, mtDNA recombination will have a substantial impact on our understanding of the etiology and transmission of mitochondrial diseases.

molecular biology↗