Unifying Different Cancer Theories in a Unique TumourModel: Chronic Inflammation and Deaminases as Meeting Points

The increase in cancer incidences shows that there is a need to better understand tumour heterogeneity to achieve efficient treatments. Interestingly, there are several common features among almost all types of cancers, with chronic inflammation induction and deaminase dysfunctions singled out. Deaminases are a family of enzymes with nucleotide-editing capacity, which are classified into two main groups: DNA-based and RNA-based. Remarkably, a close relationship between inflammation and the dysregulation of these molecules has been widely documented, which may explain the characteristic intratumor heterogeneity, both at DNA and transcriptional levels. Indeed, heterogeneity in cancer makes it difficult to establish a unique tumour progression model. Currently, there are three main cancer models—stochastic, hierarchic, and dynamic—although there is no consensus on which one better resembles cancer biology because they are usually overly simplified. Here, to accurately explain tumour progression, we propose interactions among chronic inflammation, deaminases dysregulation, intratumor genetic heterogeneity, cancer phenotypic plasticity, and even the previously proposed appearance of cancer stem-like cell populations in the edges of advanced solid tumour masses (instead of being the cells of origin of primary malignancies). The new tumour development model proposed in this study does not contradict previously accepted models and it may open up a window to interesting therapeutic approaches.FPU grant from the Ministry of Education, Culture and SportUniversity of Jaen, Accion I apoyo a la investigacion BIO-349Excellence Research Unit "Modeling Nature" (MNat)Junta de Andalucia European Commission SOMM17/6109/UGRConsejeria de Salud y Familias de la Junta de Andalucia (FEDER funds) PEMP-0205-2020Ministry of Economy and Competitiveness (FEDER funds) PIE16/00045Ministry of Science, Innovation and Universities RTI2018-101309-B-C22Chair "Doctors Galera-Requena in cancer stem cell research" CMC-CTS96

Rationale and design of the Concordance study between FFR and iFR for the assessment of lesions in the left main coronary artery. The ILITRO-EPIC-07 Trial

Introduction and objectives: Patients with left main coronary artery (LMCA) stenosis have been excluded from the trials that support the non-inferiority of the instantaneous wave-free ratio (iFR) compared to the fractional flow reserve (FFR) in the decision-making process of coronary revascularization. This study proposes to prospectively assess the concordance between the two indices in LMCA lesions and to validate the iFR cut-off value of 0.89 for clinical use. Methods: National, prospective, and observational multicenter registry of 300 consecutive patients with intermediate lesions in the LMCA (angiographic stenosis, 25% to 60%. A pressure gudiewire study and determination of the RFF and the iFR will be performed: in the event of a negative concordant result (FFR > 0.80/iFR > 0.89), no treatment will be performed; in case of a positive concordant result (FFR 0.80/iFR 0.89), an intravascular echocardiography will be performed and revascularization will be delayed if the minimum lumen area is > 6 mm(2). The primary clinical endpoint will be a composite of cardiovascular death, LMCA lesion-related non-fatal infarction or need for revascularization of the LMCA lesion at 12 months. Conclusions: Confirm that an iFR-guided decision-making process in patients with intermediate LMCA stenosis is clinically safe and would have a significant clinical impact. Also, justify its systematic use when prescribing treatment in these potentially high-risk patients

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Cancer: a mirrored room between tumor bulk and tumor microenvironment

Pablo Hernandez-Camarero is supported by a FPU grant from the Ministry of Education, Culture and Sport. This work has been partially funded by the University of Jaen, Accion I apoyo a la investigacion (BIO-349); Consejeria de Economia, Conocimiento, Empresas y Universidad de la Junta de Andalucia and European Regional Development Fund (ERDF), ref. SOMM17/6109/UGR, and with grants from the Ministry of Economy and Competitiveness (FEDER funds, projects no. PIE16/00045), from the Ministry of Science, Innovation and Universities (ref. RTI2018-101309-B-C22), and from the Chair "Doctors Galera-Requena in cancer stem cell research" (CMC-CTS963).It has been well documented that the tumor microenvironment (TME) plays a key role in the promotion of drug resistance, the support of tumor progression, invasiveness, metastasis, and even the maintenance of a cancer stemlike phenotype. Here, we reviewed TME formation presenting it as a reflection of a tumor’s own organization during the different stages of tumor development. Interestingly, functionally different groups of stromal cells seem to have specific spatial distributions within the TME that change as the tumor evolves into advanced stage progression which correlates with the fact that cancer stem-like cells (CSCs) are located in the edges of solid tumor masses in advanced tumors. We also focus on the continuos feedback that is established between a tumor and its surroundings. The “talk” between tumor mass cells and TME stromal cells, marks the evolution of both interlocuting cell types. For instance, the metabolic and functional transformations that stromal cells undergo due to tumor corrupting activity. Moreover, the molecular basis of metastatic spread is also approached, making special emphasis on the site-specific pre-metastatic niche formation as another reflection of the primary tumor molecular signature. Finally, several therapeutic approaches targeting primary TME and pre-metastatic niche are suggested. For instance, a systematic analysis of the TME just adjacent to the tumor mass to establish the proportion of myofibroblasts-like cancer-associated fibroblasts (CAFs) which may in turn correspond to stemness and metastases-promotion. Or the implementation of “re-education” therapies consisting of switching tumor-supportive stromal cells into tumorsuppressive ones. In summary, to improve our clinical management of cancer, it is crucial to understand and learn how to manage the close interaction between TME and metastasis.FPU grant from the Ministry of Education, Culture and SportUniversity of Jaen, Accion I apoyo a la investigacion BIO-349Junta de Andalucia European Commission SOMM17/6109/UGRMinistry of Economy and Competitiveness (FEDER) PIE16/00045Ministry of Science, Innovation and Universities RTI2018-101309-B-C22Chair "Doctors Galera-Requena in cancer stem cell research" CMC-CTS96

Pollutant accumulation patterns in nestlings of an avian top predator: biochemical and metabolic effects

The exposure to persistent pollutants such as organochlorine compounds (OCs) or metals has been associated with declines in top predator populations, which can accumulate high amounts of these pollutants from their prey. However, understanding how variation in OC and metal accumulation in wild species affects their biochemical and physiological responses is a big challenge, especially for endangered predators like the Bonelli's eagle (Aquila fasciata). This bird of prey is an interesting study model because the differences in diet composition among populations and territories can account for important pollutant uptake variations. We compared OC and metal accumulation in blood of Bonelli's eagle nestlings from three populations across Spain as a function of origin, age class (nestlings vs. adults), sex and number of siblings per nest, and related accumulation patterns to responses indicative of body condition, biochemistry and antioxidant status. Nestlings from Catalonia, the most industrialized area, showed the highest concentrations of PCBs and arsenic, and the lowest concentrations of zinc. The two former substances, together with DDTs, exerted an overall influence on nestling's physiology. PCBs and arsenic were associated with reduced retinol levels, pointing to oxidative damage in exposed individuals, which was also consistent with the low zinc levels in individuals from the polluted region. Increased plasma DDT levels were related to reduced body condition and lower levels of triglycerides. Mercury accumulation in Castile and Leon was higher in nestlings that were alone in the nest than in nestlings that shared it with a sibling; this suggests an increased mercury uptake from secondary prey in territories where preferred prey (i.e. rabbits) are scarce, which are also the territories where productivity is reduced. Overall, the results reveal a spatial variation in pollutant accumulation patterns and associated physiological effects, and suggest the major role that territory quality may have in such patterns

Justificación y diseño del estudio Concordancia entre RFF e iFR en lesiones del tronco común.: Estudio iLITRO-EPIC-07

Introduction and objectives: Patients with left main coronary artery (LMCA) stenosis have been excluded from the trials that support the non-inferiority of the instantaneous wave-free ratio (iFR) compared to the fractional flow reserve (FFR) in the decision-making process of coronary revascularization. This study proposes to prospectively assess the concordance between the two indices in LMCA lesions and to validate the iFR cut-off value of 0.89 for clinical use. Methods: National, prospective, and observational multicenter registry of 300 consecutive patients with intermediate lesions in the LMCA (angiographic stenosis, 25% to 60%. A pressure gudiewire study and determination of the RFF and the iFR will be performed: in the event of a negative concordant result (FFR > 0.80/iFR > 0.89), no treatment will be performed; in case of a positive concordant result (FFR ≤ 0.80/iFR ≤ 0.89), revascularization will be performed; In the event of a discordant result (FFR> 0.80/iFR ≤ 0.89 or FFR ≤ 0.80/iFR> 0.89), an intravascular echocardiography will be performed and revascularization will be delayed if the minimum lumen area is > 6 mm2. The primary clinical endpoint will be a composite of cardiovascular death, LMCA lesion-related non-fatal infarction or need for revascularization of the LMCA lesion at 12 months. Conclusions: Confirm that an iFR-guided decision-making process in patients with intermediate LMCA stenosis is clinically safe and would have a significant clinical impact. Also, justify its systematic use when prescribing treatment in these potentially high-risk patients. Registered at ClinicalTrials.gov ( Identifier: NCT03767621).Introducción y objetivos: Los pacientes con estenosis en el tronco coronario izquierdo (TCI) han sido excluidos de los ensayos que apoyan la no inferioridad del cociente de presiones en el índice diastólico instantáneo sin ondas (iFR) respecto a la reserva fraccional de flujo (RFF) en la toma de decisiones sobre revascularización coronaria. El presente estudio propone valorar de manera prospectiva la concordancia entre los dos índices en lesiones del TCI y validar el valor de corte del iFR de 0,89 para su uso clínico. Métodos: Registro multicéntrico nacional, prospectivo, observacional, con la inclusión de 300 pacientes consecutivos con lesiones intermedias (estenosis angiográfica 25-60%) en el TCI. Se realizará un estudio con guía de presión y determinación de RFF e iFR. En caso de resultado concordante negativo (RFF > 0,80 / iFR > 0,89), no se realizará tratamiento; en caso de resultado concordante positivo (RFF ≤ 0,80 / iFR ≤ 0,89), se realizará revascularización; en caso de resultado discordante (RFF > 0,80 / iFR ≤ 0,89 o RFF ≤ 0,80 / iFR > 0,89), se realizará estudio con ecocardiografía intravascular y se considerará diferir la revascularización si el área luminal mínima es > 6 mm2. El criterio de valoración clínico primario será la incidencia del combinado de muerte cardiovascular, infarto no mortal relacionado con la lesión del TCI o necesidad de revascularización de la lesión del TCI a los 12 meses. Conclusiones: La demostración de la seguridad clínica en la toma de decisiones del iFR en pacientes con lesiones intermedias en el TCI tendría un impacto clínico importante y justificaría su uso sistemático para la decisión del tratamiento en estos pacientes de potencial alto riesgo. Registrado en ClinicalTrials.gov (identificador: NCT03767621)