CD69-oxLDL ligand engagement induces Programmed Cell Death 1 (PD-1) expression in human CD4 + T lymphocytes

The mechanisms that control the inflammatory–immune response play a key role in tissue remodelling in cardiovascular diseases. T cell activation receptor CD69 binds to oxidized low-density lipoprotein (oxLDL), inducing the expression of anti-inflammatory NR4A nuclear receptors and modulating inflammation in atherosclerosis. To understand the downstream T cell responses triggered by the CD69-oxLDL binding, we incubated CD69-expressing Jurkat T cells with oxLDL. RNA sequencing revealed a differential gene expression profile dependent on the presence of CD69 and the degree of LDL oxidation. CD69-oxLDL binding induced the expression of NR4A receptors (NR4A1 and NR4A3), but also of PD-1. These results were confirmed using oxLDL and a monoclonal antibody against CD69 in CD69-expressing Jurkat and primary CD4 + lymphocytes. CD69-mediated induction of PD-1 and NR4A3 was dependent on NFAT activation. Silencing NR4A3 slightly increased PD-1 levels, suggesting a potential regulation of PD-1 by this receptor. Moreover, expression of PD-1, CD69 and NR4A3 was increased in human arteries with chronic inflammation compared to healthy controls, with a strong correlation between PD-1 and CD69 mRNA expression (r = 0.655 P < 0.0001). Moreover, PD-1 was expressed in areas enriched in CD3 infiltrating T cells. Our results underscore a novel mechanism of PD-1 induction independent of TCR signalling that might contribute to the role of CD69 in the modulation of inflammation and vascular remodelling in cardiovascular diseasesOpen Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was supported by grant S2017/BMD-3671-INFLAMUNE-CM from the Comunidad de Madrid, a grant from the Ramón Areces Foundation “Ciencias de la Vida y la Salud”, “La Caixa” Banking Foundation (HR17-00016) to FSM; grants PDC2021-121719-I00 and PDI-2020-120412RBI00 to FSM, and RTI2018-094727-B-100 to JMG funded by MCIN/ AEI/10.13039/501100011033 and by “ERDF A way of making Europe”; the Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR) (2017-SGR-00333) to JMG; and a grant from the Instituto de Salud Carlos III (PI18/0919) to CR. M. Jiménez-Fernández is supported by a FPI-Severo Ochoa-CNIC (PRE2019-087941); C. Ballester-Servera is supported by a FPU fellowship (Ministerio de Universidades). Data availability The data underlying this article are available in the article and in its online Supplementary material. Declarations Conflict of interest The authors have no confict of interest to declare. Ethical approval Written consent was obtained from all participating subjects. The procedure was approved by the Ethics Committee of the Hospital de la Santa Creu i Sant Pau (Barcelona, Spain) and was conducted in accordance with the Declaration of Helsinki. Consent for publication Consent to publish has been received from all participant

ID1 and ID4 Are Biomarkers of Tumor Aggressiveness and Poor Outcome in Immunophenotypes of Breast Cancer

Inhibitor of differentiation (ID) proteins are a family of transcription factors that contribute to maintaining proliferation during embryogenesis as they avoid cell differentiation. Afterward, their expression is mainly silenced, but their reactivation and contribution to tumor development have been suggested. In breast cancer (BC), the overexpression of ID1 has been previously described. However, whether the remaining ID genes have a specific role in this neoplasia is still unclear. We studied the mRNA expression of all ID genes by q RT-PCR in BC cell lines and 307 breast carcinomas, including all BC subtypes. Our results showed that ID genes are highly expressed in all cell lines tested. However, ID4 presented higher expression in BC cell lines compared to a healthy breast epithelium cell line. In accordance, ID1 and ID4 were predominantly overexpressed in Triple-Negative and HER2-enriched samples. Moreover, high levels of both genes were associated with larger tumor size, histological grade 3, necrosis and vascular invasion, and poorer patients’ outcomes. In conclusion, ID1 and ID4 may act as biomarkers of tumor aggressiveness and worse prognosis in breast cancer, and they could be used as potential targets for new treatments discover.This research was funded by the Alicante Institute for Health and Biomedical Research (ISABIAL) (UGP 16-149 and UGP 180184) and Navarro-Tripodi Foundation (BOLA00150). M.G.E. was supported by fellowships issued by the Valencian Government of Spain (GVA) and the European Social Fund (ACIF/2016/004)

Reseñas iberoamericanas

Reseñas iberoamericana

Reseñas iberoamericanas

Iberoamerican reviewsReseñas iberoamericana

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

Parámetros morfológicos y biológicos en el carcinoma ductal in situ de mama. Implicaciones pronósticas

El Carcinoma ductal in situ de mama es una entidad cada vez más frecuente en nuestros días, sobre todo tras la implantación y mejoras en el cribado del cáncer de mama. En mujeres que han sido sometidas a tumorectomía en el CDIS todavía no se conoce o no se ha estratificado a las pacientes según las características clínicas e histológicas en un grupo cuyo riesgo de recurrencia garantice o justifique la no administración de tratamientos adyuvantes. Una manera de mejorar el sistema de clasificación del CDIS y la relación con la evolución a CMI podría ser la incorporación de los marcadores moleculares a medida que demuestren su importancia en la predicción de recaída local. Sería muy interesante que la clasificación del perfil molecular mediante IHQ en el CDIS fuese capaz de predecir la recurrencia local, ya sea a CDIS o a CMI, ya que se podría mejorar la planificación terapéutica de las pacientes y de esta manera evitar tanto el sobre como el infra-tratamiento que existe actualmente. Por eso surge y se plantea el presente estudio. Se han podido identificar los perfiles IHQ en nuestra serie de CDIS. Comparado con el fenotipo Luminal A, el resto de perfiles (Luminal B Her-2 negativo, Luminal B Her-2 positivo, Her-2 y triple negativo) presenta un riesgo de recaída mayor, sin diferencias en supervivencia libre de recaída. El subgrupo Luminal B Her-2 positivo es el que presenta un peor pronóstico, dado que su HR es de 6,3 (resultado estadísticamente significativo). Entre los marcadores IHQ (de manera independiente), sólo el Her-2 positivo tiene mayor riesgo de recaída: si el CDIS es Her-2 ++ el riesgo de recaída está aumentado 4,5 veces. Ninguna variable de las clásicas conocidas en el CDIS (edad, grado histológico, márgenes, tipo comedo y tamaño) han demostrado tener relación con la recaída

Presence of human papillomavirus DNA in breast cancer: a Spanish case-control study

Abstract Background Breast cancer is one of the most important neoplasia among women. It was recently suggested that biological agents could be the etiological cause, particularly Human Papilloma Virus (HPV). The aim of this study was to explore the presence of HPV DNA in a case-control study. Methods We performed our study including 251 cases (breast cancer) and 186 controls (benign breast tumors), using three different molecular techniques with PCR (GP5/GP6, CLART® and DIRECT FLOW CHIP®). Results HPV DNA was evidenced in 51.8% of the cases and in 26.3% of the controls (p < 0.001). HPV-16 was the most prevalent serotype. The odds ratio (OR) of HPV within a multivariate model, taking into account age and breastfeeding, was 4.034. Conclusions Our study, with methodological rigour and a sample size not previously found in the literature, demonstrate a significant presence of HPV DNA in breast cancer samples. A possible causal relationship, or mediation or not as a cofactor, remains to be established by future studies

Variable Intrinsic Expression of Immunoregulatory Biomarkers in Breast Cancer Cell Lines, Mammospheres, and Co-Cultures

Advances in immunotherapy have increased interest in knowing the role of the immune system in breast cancer (BC) pathogenesis. Therefore, immune checkpoints (IC) and other pathways related to immune regulation, such as JAK2 and FoXO1, have emerged as potential targets for BC treatment. However, their intrinsic gene expression in vitro has not been extensively studied in this neoplasia. Thus, we evaluated the mRNA expression of tumor-cell-intrinsic CTLA-4, PDCD1 (PD1), CD274 (PD-L1), PDCD1LG2 (PD-L2), CD276 (B7-H3), JAK2, and FoXO1 in different BC cell lines, derived mammospheres, and co-cultures with peripheral blood mononuclear cells (PBMCs) by real-time quantitative polymerase chain reaction (qRT-PCR). Our results showed that intrinsic CTLA-4, CD274 (PD-L1), and PDCD1LG2 (PD-L2) were highly expressed in triple-negative cell lines, while CD276 was predominantly overexpressed in luminal cell lines. In contrast, JAK2 and FoXO1 were under-expressed. Moreover, high levels of CTLA-4, PDCD1 (PD1), CD274 (PD-L1), PDCD1LG2 (PD-L2), and JAK2 were found after mammosphere formation. Finally, the interaction between BC cell lines and peripheral blood mononuclear cells (PBMCs) stimulates the intrinsic expression of CTLA-4, PCDC1 (PD1), CD274 (PD-L1), and PDCD1LG2 (PD-L2). In conclusion, the intrinsic expression of immunoregulatory genes seems very dynamic, depending on BC phenotype, culture conditions, and tumor-immune cell interactions.This research was funded by the Alicante Institute for Health and Biomedical Research (ISABIAL) (NR-180202; NR-19-292; 2020-0324; 2021-0389; 2021-0453)