Biology subjects

Burgos, A.

Publications and source records attributed to Burgos, A..

5 recordsLinked to original sources

bioRxiv2025

Age-dependent chemotherapy response and vitamin D impact in paired patient-derived normal and tumor colorectal organoids

Early-onset colorectal cancer (EO-CRC, <50 years) incidence is rising worldwide. Using paired patient-derived colorectal normal and tumor organoids, we demonstrate the therapeutic window of three standard chemotherapies. Normal organoids were more resistant than tumor organoids to 5-fluorouracil (5-FU) and oxaliplatin in both EO-CRC and late-onset CRC (LO-CRC) patients. However, for SN38, this therapeutic window was observed in LO-CRC but not in EO-CRC patients, revealing age-dependent differences in drug resistance. We also evaluated the effect of calcitriol, the active vitamin D metabolite with anti-CRC activity, on drug sensitivity. Calcitriol reduced the cytotoxicity of 5-FU and SN38 in normal organoids regardless of patient age, while it selectively decreased their cytotoxicity in EO-CRC but not in LO-CRC tumor organoids. This protective effect correlated with calcitriol antiproliferative action and transcriptional effects on drug-metabolism pathways. These findings identify clinically relevant age-dependent differences in chemotherapy response and support vitamin D-based strategies to design age-tailored precision treatments.

cancer biology↗

bioRxiv2024

CD4+ T Cell Depletion Before Primary Dengue and/or Secondary Zika Infection Reveals Mechanistic Correlates of Antibody Functionality in Rhesus Macaques.

Dengue (DENV) virus and Zika virus (ZIKV) are two flaviviruses of major public health concern. One drawback designing effective vaccines is our limited understanding of the mechanisms ruling protection or harm among DENV serotypes, or between DENV and ZIKV. Here, we depleted rhesus macaques of CD4+ T cells in vivo before primary DENV infection and/or secondary ZIKV challenge to recreate a sub-optimal priming of the humoral immune response. Our results support that CD4+ T cells are needed to induce a quantitative and type-specific effective humoral immune response against primary DENV, but also against secondary ZIKV in DENV-experimented subjects. Our results also indicate a limited contribution of the DENV-Memory B cells to anti-ZIKV response. Furthermore, our results suggest that a suboptimal B cell priming during a primary DENV infection does differentially impact different antibody (Abs) properties. While binding or neutralization of ZIKV or DENV during a subsequent exposure to ZIKV is not affected by the lack of CD4+ T - B cells interaction during a primary DENV infection, that interaction is critical to guarantee the Abs specificity. Also, we found that depleting CD4+ T cells before DENV primary infection but not before ZIKV challenge significantly increases Abs cross-reactivity against DENV-EDIII domain and DENV-NS1 protein but not against ZIKV-EDIII domain or NS1 protein. Furthermore, there was more cross-reactivity among the DENV-NS1 proteins than against DENV-EDIII domains, suggesting that during a primary DENV infection CD4+ T cells have a different weight in the responses against EDIII domain and NS1 protein. The proper Abs binding and neutralization with increased cross-reactivity profile was associated with limited frequency of circulating peripheral T helper cells (pTfh) with T helper 1 phenotype (CD4+/CXCR5+/CXCR3+) and expressing markers related to B cell activation (CXCR5+/CXCR3+/PD-1+/ICOS+) in the group depleted of CD4+ T cells only before primary DENV infection. However, memory B cells - but not Antibody Secreting Cells (ASC) activation 7 days after the infection - positively correlate with those two populations of pTfh. Finally, when Abs cross-reactivity values were incorporated in a Principal Component Analysis (PCA), the DENV-CD4+ T depleted group separates from the other two groups with similar Abs binding and neutralization profiles. Our result strongly suggests that during a heterologous sequential DENV/ZIKV infections Abs binding, and neutralization, may be regulated by different factors than their specificity. Before, the induction of cross-neutralizing Abs has been described in the context of secondary DENV infection. Here, for the first time, we are reproducing the experimental conditions leading to the generation of such Abs population in vivo. In summary, we show that suboptimal immune priming during a primary flavivirus infection has functional consequences during a secondary heterologous infection. Finally, we shown that CD8+ T cells are essential to guarantee an optimal Abs neutralization activity. These results have huge implications understanding the immune response to DENV vaccines (and maybe ZIKV), including why an optimal vaccine or natural-induced neutralizing response not necessarily protects or enhances pathogenesis during a subsequent natural heterologous exposure.

immunology↗

bioRxiv2022

Age-related differences in ocular features of a naturalistic free-ranging population of rhesus macaques

PurposeRhesus macaques (Macaca mulatta) are the premier nonhuman primate model for studying human health and disease. We aimed to investigate if age was associated with ocular features of clinical relevance in a large cohort of free-ranging rhesus macaques from Cayo Santiago, Puerto Rico. MethodsWe evaluated 120 rhesus macaques (73 males, 47 females) aged from 0 to 29 years old (mean{+/-}SD: 12.6{+/-}6.4) from September to December, 2021. The ophthalmic evaluation included IOP assessment, corneal pachymetry, anterior segment biomicroscopy, A-Scan biometry, automated refraction, and fundus photography after pupil dilation. The effects of age on the outcome variables were investigated through multilevel mixed-effects models adjusted for sex and weight. ResultsOn average, IOP, pachymetry, axial length, and automated refraction spherical equivalent were 15.47{+/-}2.47 mmHg, 474.43{+/-}32.21 m, 19.49{+/-}1.24 mm, and 0.30{+/-}1.70 D, respectively. Age was significantly associated with pachymetry (Coef.= -1.20; 95%CI: -2.27 to -0.14; p=0.026), axial length (Coef.= 0.03; 95%CI: 0.01 to 0.05; p=0.002), and spherical equivalent (Coef.= -0.12; 95%CI: -0.22 to -0.02; p=0.015). No association was detected between age and IOP. The prevalence of cataracts in either eye was 10.83% (95% CI: 6.34 - 17.89%) and was significantly associated with age (OR= 1.20; 95%CI: 1.06 - 1.36; p=0.004). Retinal drusen in either eye was observed in 15.00% (95% CI: 9.60 - 22.68%) of the animals, which was also significantly associated with age (OR=1.14; 95%CI: 1.02 - 1.27; p=0.020). ConclusionsRhesus macaques exhibit age-related ocular associations similar to those observed in human aging, including decreased corneal thickness, increased axial length, myopic shift, and higher occurrence of cataract and retinal drusen.

systems biology↗

bioRxiv2021

Recombinant Fasciola hepatica fatty acid binding protein (Fh15) as a novel anti-inflammatory biotherapeutic in an acute gram-negative non-human primate sepsis model

AO_SCPLOWBSTRACTC_SCPLOWDue to their phylogenetic proximity to human, non-human primates (NHP) are considered an adequate choice for basic and pre-clinical model of sepsis. Gram-negative bacteria are the primary causative of sepsis. During infection bacteria continuously release the potent toxin lipopolysaccharide (LPS) into the bloodstream, which triggers an uncontrolled systemic inflammatory response leading to death. Our previous research has demonstrated in vitro and in vivo using a mouse model of septic shock that Fh15, a recombinant variant of the Fasciola hepatica fatty acid binding protein, acts as an antagonist of TLR4 suppressing the LPS-induced pro-inflammatory cytokine storm. The present study aimed to demonstrate that Fh15 suppress the cytokine storm and other inflammatory markers during the early phase of an endotoxemia induced in rhesus macaques by i.v. infusion with lethal doses of live E. coli. Fh15 was administrated as isotonic infusion 30 min prior to the bacterial infusion. Among the novel findings reported in this communication, I) Fh15 significantly prevented bacteremia, suppressed LPS levels in plasma and the production of C-reactive protein and procalcitonin, which are key signature of inflammation and bacterial infection, respectively, II) notably reduced the production of pro-inflammatory cytokines, and III) increased innate immune cell populations in blood, which suggest a role in promoting a prolonged steady state in rhesus macaques even in the presence of inflammatory stimuli. This is the first report demonstrating that a F. hepatica-derived molecule possesses potential as anti-inflammatory drug against endotoxemia in an NHP-model. TO_SCPLOWWEETC_SCPLOWThis is the first communication demonstrating that a F. hepatica-derived molecule possesses potential as anti-inflammatory drug against endotoxemia in an NHP-model. IO_SCPLOWMPORTANCEC_SCPLOWSepsis caused by Gram-negative bacteria affect 1.7 million adults annually in the United States and is one of the most important causes of death at intensive care units. Although the effective use of antibiotics has resulted in improved prognosis of sepsis, the pathological and deathly effects has been attributed to the persistent inflammatory cascade. There is a present need to develop anti-inflammatory agents that can suppress or neutralize the inflammatory responses and prevent the lethal consequences of sepsis. We demonstrated herein that a small molecule of 14.5kDa can suppress the bacteremia, endotoxemia and many other inflammatory markers in a rhesus macaque model. These results reinforce the notion that Fh15 constitute an excellent candidate for drug development against sepsis.

microbiology↗

bioRxiv2019

Integrins protect nociceptive neurons in models of paclitaxel-mediated peripheral sensory neuropathy

Chemotherapy induced peripheral neuropathy (CIPN) is a major side effect from cancer treatment with no known method for prevention or cure in clinics. CIPN primarily affects unmyelinated nociceptive sensory terminals. Despite the high prevalence of CIPN, molecular and cellular mechanisms that lead to CIPN are still poorly understood. Here, we used a genetically tractable Drosophila model and primary sensory neurons isolated from adult mouse to examine the mechanisms underlying CIPN and identify protective pathways. We found that chronic treatment of Drosophila larvae with paclitaxel caused sensory neuron degeneration, altered the terminal branching pattern of nociceptive neurons, and reduced thermal nociceptive responses. We found that nociceptive neuron-specific overexpression of integrins, which are known to support neuronal maintenance in several systems, conferred protection from paclitaxel-mediated cellular and behavioral phenotypes. Live imaging and superresolution approaches provide evidence that paclitaxel treatment causes cellular changes that are consistent with alterations in endosome-mediated trafficking of integrins. We used primary dorsal root ganglia neuron cultures to test conservation of integrin-mediated protection. We show that overexpression of a human integrin {beta} subunit 1 (ITGB1) also prevented degeneration following paclitaxel treatment. Altogether, our study supports conserved mechanisms of paclitaxel-induced perturbation of integrin trafficking and a therapeutic potential of restoring integrin levels to antagonize paclitaxel-mediated toxicity in sensory neurons.

neuroscience↗