Open Access
ONECUT2 is a druggable driver of luminal to basal breast cancer plasticity
(Sringer, 2024-05-31) Zamora Álvarez, Irene; Gutiérrez Núñez, Mirian; Pascual, Alex; Pajares Villandiego, María Josefa; Barajas Vélez, Miguel Ángel; Perez, Lillian M.; You, Sungyong; Knudsen, Beatrice S.; Freeman, Michael R.; Encío Martínez, Ignacio; Rotinen Díaz, Mirja Sofia; Ciencias de la Salud; Osasun Zientziak; Institute for Multidisciplinary Research in Applied Biology - IMAB; Gobierno de Navarra / Nafarroako Gobernua
Purpose: tumor heterogeneity complicates patient treatment and can be due to transitioning of cancer cells across phenotypic cell states. This process is associated with the acquisition of independence from an oncogenic driver, such as the estrogen receptor (ER) in breast cancer (BC), resulting in tumor progression, therapeutic failure and metastatic spread. The transcription factor ONECUT2 (OC2) has been shown to be a master regulator protein of metastatic castration-resistant prostate cancer (mCRPC) tumors that promotes lineage plasticity to a drug-resistant neuroendocrine (NEPC) phenotype. Here, we investigate the role of OC2 in the dynamic conversion between different molecular subtypes in BC. Methods: we analyze OC2 expression and clinical significance in BC using public databases and immunohistochemical staining. In vitro, we perform RNA-Seq, RT-qPCR and western-blot after OC2 enforced expression. We also assess cellular effects of OC2 silencing and inhibition with a drug-like small molecule in vitro and in vivo. Results: OC2 is highly expressed in a substantial subset of hormone receptor negative human BC tumors and tamoxifen-resistant models, and is associated with poor clinical outcome, lymph node metastasis and heightened clinical stage. OC2 inhibits ER expression and activity, suppresses a gene expression program associated with luminal differentiation and activates a basal-like state at the gene expression level. We also show that OC2 is required for cell growth and survival in metastatic BC models and that it can be targeted with a small molecule inhibitor providing a novel therapeutic strategy for patients with OC2 active tumors. Conclusions: the transcription factor OC2 is a driver of BC heterogeneity and a potential drug target in distinct cell states within the breast tumors.
Open Access
Randomized clinical trial: bone bioactive liquid improves implant stability and osseointegration
(MDPI, 2024-10-01) Al Madhoun, Ashraf; Meshal, Khaled; Carrió, Neus; Ferrés‐Amat, Eduard; Ferrés-Amat, Elvira; Barajas Vélez, Miguel Ángel; Jiménez-Escobar, Ana Leticia; Al-Madhoun, Areej Said; Saber, Alaa; Abou Alsamen, Yazan; Marti, Carles; Atari, Maher; Ciencias de la Salud; Osasun Zientziak; Institute for Multidisciplinary Research in Applied Biology - IMAB; Universidad Pública de Navarra / Nafarroako Unibertsitate Publikoa
Implant stability can be compromised by factors such as inadequate bone quality and infection, leading to potential implant failure. Ensuring implant stability and longevity is crucial for patient satisfaction and quality of life. In this multicenter, randomized, double-blind clinical trial, we assessed the impact of a bone bioactive liquid (BBL) on the Galaxy TS implant's performance, stability, and osseointegration. We evaluated the impact stability, osseointegration, and pain levels using initial stability quotient (ISQ) measurements, CBCT scans, and pain assessment post-surgery. Surface analysis was performed using scanning electron microscopy (SEM) and atomic force microscopy (AFM). In vitro studies examined the BBL's effects on dental pulp pluripotent stem cells' (DPPSCs') osteogenesis and inflammation modulation in human macrophages. All implants successfully osseointegrated, as demonstrated by the results of our clinical and histological studies. The BBL-treated implants showed significantly lower pain scores by day 7 (p < 0.00001) and improved stability by day 30 (ISQ > 62.00 ± 0.59, p < 8 × 10-7). By day 60, CBCT scans revealed an increased bone area ratio in BBL-treated implants. AFM images demonstrated the BBL's softening and wettability effect on implant surfaces. Furthermore, the BBL promoted DPPSCs' osteogenesis and modulated inflammatory markers in human primary macrophages. This study presents compelling clinical and biological evidence that BBL treatment improves Galaxy TS implant stability, reduces pain, and enhances bone formation, possibly through surface tension modulation and immunomodulatory effects. This advancement holds promise for enhancing patient outcomes and implant longevity.
Open Access
Experimental pilot study after surgery on a food supplement for athletes to protect articular knee cartilage. A functional and biochemical study
(Federación Española de Medicina del Deporte, 2021) Alfaro Adrián, Jesús; Araña Ciordia, Miriam; Barajas Vélez, Miguel Ángel; Ciencias de la Salud; Osasun Zientziak
En este estudio experimental doble ciego se evalúa la eficacia de la suplementación condroprotectora (Carticure Plus®, 5000 mg Colágeno (Péptidos Bioactivos) altamente asimilable, 1500 mg Glucosamina clorhidrato, 1200 mg Condroitín sulfato, 1,1 mg Cobre, 80 mg Vitamina C, 2 mg Manganeso) en pacientes con patología ligamentosa y meniscal que han requerido cirugía artroscópica. Se seleccionaron 12 pacientes con lesión ligamentosa y 12 pacientes con meniscopatía a los que se les procedió a la medición de distintos marcadores inflamatorios mediante ELISA, colágeno 2A y ácido hialurónico, además de a la evalua¬ción del dolor así como la funcionalidad y calidad de vida a través de EVA (Escala Visual Analógica), WOMAC (Western Ontario McMaster Universities Osteoarthritis Index) y KOOS (Knee Injury and Osteoarthritis Outcome Score). Se observaron diferencias estadísticamente significativas de mejoría clínica a favor de Carticure Plus®, con una mejora de la capacidad funcional de la escala WOMAC del 76 % frente a un 53% del placebo para el conjunto de pacientes y con una clara mejoría en el primer mes en lesión meniscal, en mejora de las actividades de la vida diaria (KOOS), Carticure Plus® 31% frente a placebo -1%, actividad deportiva (Carticure Plus® 41% vs Placebo 13,2%), actividades deportivas y recreativas (Carticure Plus® 128% vs Placebo 10,4%). Por otro lado, en lesión ligamentosa se observa una mejoría en calidad de vida (KOOS) Carticure Plus® 75% vs Placebo -8,8% y dolor (KOOS) Carticure Plus® 49,6% vs Placebo 0,3% en el primer mes respecto al basal. En el conjunto de pacientes, el dolor (KOOS) Carticure Plus® 31,4% vs Placebo 1,3% y actividades de la vida diaria (KOOS) Carticure Plus® 43,9% vs Placebo 27,1% en el tercer mes respecto al basal se asocian a una mejora a Carticure Plus® en comparación al placebo. A pesar del pequeño tamaño muestral, es destacable el hecho de haber encontrado diferencias estadísticamente significativas que podría presu¬poner la eficacia de Carticure Plus®.
Open Access
Lactiplantibacillus plantarum DSM20174 attenuates the progression of non-alcoholic fatty liver disease by modulating gut microbiota, improving metabolic risk factors, and attenuating adipose inflammation
(MDPI, 2022) Riezu Boj, José I.; Barajas Vélez, Miguel Ángel; Pérez Sánchez, Tania; Pajares Villandiego, María Josefa; Araña Ciordia, Miriam; Milagro Yoldi, F. I.; Urtasun Alonso, Raquel; Ciencias de la Salud; Osasun Zientziak
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease, reaching epidemic proportions worldwide. Targeting the gut–adipose tissue–liver axis by modulating the gut microbiota can be a promising therapeutic approach in NAFLD. Lactiplantibacillus plantarum, a potent lactic-acid-producing bacterium, has been shown to attenuate NAFLD. However, to our knowledge, the possible effect of the Lactiplantibacillus plantarum strain DSM20174 (L.p. DSM20174) on the gut–adipose tissue axis, diminishing inflammatory mediators as fuel for NAFLD progression, is still unknown. Using a NAFLD mouse model fed a high-fat, high-fructose (HFHF) diet for 10 weeks, we show that L.p DSM20174 supplementation of HFHF mice prevented weight gain, improved glucose and lipid homeostasis, and reduced white adipose inflammation and NAFLD progression. Furthermore, 16S rRNA gene sequencing of the faecal microbiota suggested that treatment of HFHF-fed mice with L.p DSM20174 changed the diversity and altered specific bacterial taxa at the levels of family, genus, and species in the gut microbiota. In conclusion, the beneficial effects of L.p DSM20174 in preventing fatty liver progression may be related to modulations in the composition and potential function of gut microbiota associated with lower metabolic risk factors and a reduced M1-like/M2-like ratio of macrophages and proinflammatory cytokine expression in white adipose tissue and liver.
Open Access
Histologic and histomorphometric evaluation of a new bioactive liquid bbl on implant surface: a preclinical study in foxhound dogs
(MDPI, 2021) Ferrés‐Amat, Eduard; Al Madhoun, Ashraf; Ferrés-Amat, Elvira; Al Demour, Saddam; Ababneh, Mera A.; Ferrés-Padró, Eduard; Marti, Carles; Carrió, Neus; Barajas Vélez, Miguel Ángel; Atari, Maher; Ciencias de la Salud; Osasun Zientziak
Background: bioactive chemical surface modifications improve the wettability and osse-ointegration properties of titanium implants in both animals and humans. The objective of this animal study was to investigate and compare the bioreactivity characteristics of titanium implants (BLT) pre‐treated with a novel bone bioactive liquid (BBL) and the commercially available BLT‐SLA active. Methods: forty BLT‐SLA titanium implants were placed in in four foxhound dogs. Animals were divided into two groups (n = 20): test (BLT‐SLA pre‐treated with BBL) and control (BLT‐SLA active) implants. The implants were inserted in the post extraction sockets. After 8 and 12 weeks, the animals were sacrificed, and mandibles were extracted, containing the implants and the surrounding soft and hard tissues. Bone‐to‐implant contact (BIC), inter‐thread bone area percentage (ITBA), soft tissue, and crestal bone loss were evaluated by histology and histomorphometry. Results: all animals were healthy with no implant loss or inflammation symptoms. All implants were clinically and histologically osseo‐integrated. Relative to control groups, test implants demon-strated a significant 1.5‐ and 1.7‐fold increase in BIC and ITBA values, respectively, at both assessment intervals. Crestal bone loss was also significantly reduced in the test group, as compared with controls, at week 8 in both the buccal crests (0.47 ± 0.32 vs 0.98 ± 0.51 mm, p < 0.05) and lingual crests (0.39* ± 0.3 vs. 0.89 ± 0.41 mm, p < 0.05). At week 12, a pronounced crestal bone loss improvement was observed in the test group (buccal, 0.41 ± 0.29 mm and lingual, 0.54 ± 0.23 mm). Tissue thickness showed comparable values at both the buccal and lingual regions and was significantly improved in the studied groups (0.82–0.92 mm vs. 33–48 mm in the control group). Conclusions: Relative to the commercially available BLT‐SLA active implants, BLT‐SLA pre‐treated with BBL showed improved histological and histomorphometric characteristics indicating a reduced titanium surface roughness and improved wettability, promoting healing and soft and hard tissue regeneration at the implant site.
Open Access
From lipid signatures to cellular responses: unraveling the complexity of melanoma and furthering its diagnosis and treatment
(MDPI, 2024) Díaz Grijuela, Elisa; Hernández, Agustín; Caballero, Claudia; Fernández, Roberto; Urtasun Alonso, Raquel; Gulak, Marina; Astigarraga, Egoitz; Barajas Vélez, Miguel Ángel; Barreda-Gómez, Gabriel; Ciencias de la Salud; Osasun Zientziak
Recent advancements in mass spectrometry have significantly enhanced our understanding of complex lipid profiles, opening new avenues for oncological diagnostics. This review highlights the importance of lipidomics in the comprehension of certain metabolic pathways and its potential for the detection and characterization of various cancers, in particular melanoma. Through detailed case studies, we demonstrate how lipidomic analysis has led to significant breakthroughs in the identification and understanding of cancer types and its potential for detecting unique biomarkers that are instrumental in its diagnosis. Additionally, this review addresses the technical challenges and future perspectives of these methodologies, including their potential expansion and refinement for clinical applications. The discussion underscores the critical role of lipidomic profiling in advancing cancer diagnostics, proposing a new paradigm in how we approach this devastating disease, with particular emphasis on its application in comparative oncology.
Open Access
Integrative multi-omics analysis for etiology classification and biomarker discovery in stroke: advancing towards precision medicine
(MDPI, 2024) Labarga Gutiérrez, Alberto; Martínez-González, Judith; Barajas Vélez, Miguel Ángel; Ciencias de la Salud; Osasun Zientziak
Recent advancements in high-throughput omics technologies have opened new avenues for investigating stroke at the molecular level and elucidating the intricate interactions among various molecular components. We present a novel approach for multi-omics data integration on knowledge graphs and have applied it to a stroke etiology classification task of 30 stroke patients through the integrative analysis of DNA methylation and mRNA, miRNA, and circRNA. This approach has demonstrated promising performance as compared to other existing single technology approaches.
Open Access
Development, analysis, and sensory evaluation of improved bread fortified with a plant-based fermented food product
(MDPI, 2023) Cabello Olmo, Miriam; Krishnan, Padmanaban G.; Araña Ciordia, Miriam; Oneca Agurruza, María; Díaz, Jesús Vicente; Barajas Vélez, Miguel Ángel; Rovai, Maristela; Ciencias de la Salud; Osasun Zientziak
In response to the demand for healthier foods in the current market, this study aimed to develop a new bread product using a fermented food product (FFP), a plant-based product composed of soya flour, alfalfa meal, barley sprouts, and viable microorganisms that showed beneficial effects in previous studies. White bread products prepared with three different substitution levels (5, 10, and 15%) of FFP were evaluated for physical characteristics (loaf peak height, length, width), color indices (lightness, redness/greenness, yellowness/blueness), quality properties (loaf mass, volume, specific volume), protein content, crumb digital image analysis, and sensory characteristics. The results revealed that FFP significantly affected all studied parameters, and in most cases, there was a dose–response effect. FFP supplementation affected the nutritional profile and increased the protein content (p < 0.001). The sensory test indicated that consumer acceptance of the studied sensory attributes differed significantly between groups, and bread with high levels of FFP (10 and 15% FFP) was generally more poorly rated than the control (0%) and 5% FFP for most of the variables studied. Despite this, all groups received acceptable scores (overall liking score ≥ 5) from consumers. The sensory analysis concluded that there is a possible niche in the market for these improved versions of bread products.
Open Access
Nutritional interventions with bacillus coagulans improved glucose metabolism and hyperinsulinemia in mice with acute intermittent porphyria
(MDPI, 2023) Longo, Miriam; Jericó, Daniel; Córdoba, Karol M.; Riezu Boj, José I.; Urtasun Alonso, Raquel; Solares, Isabel; Sampedro, Ana; Collantes, María; Peñuelas, Iván; Moreno Aliaga, María J.; Ávila, Matías A.; Di Pierro, Elena; Barajas Vélez, Miguel Ángel; Milagro Yoldi, F. I.; Dongiovanni, Paola; Fontanellas, Antonio; Ciencias de la Salud; Osasun Zientziak
Acute intermittent porphyria (AIP) is a metabolic disorder caused by mutations in the porphobilinogen deaminase (PBGD) gene, encoding the third enzyme of the heme synthesis pathway. Although AIP is characterized by low clinical penetrance (~1% of PBGD mutation carriers), patients with clinically stable disease report chronic symptoms and frequently show insulin resistance. This study aimed to evaluate the beneficial impact of nutritional interventions on correct carbohydrate dysfunctions in a mouse model of AIP that reproduces insulin resistance and altered glucose metabolism. The addition of spores of Bacillus coagulans in drinking water for 12 weeks modified the gut microbiome composition in AIP mice, ameliorated glucose tolerance and hyperinsulinemia, and stimulated fat disposal in adipose tissue. Lipid breakdown may be mediated by muscles burning energy and heat dissipation by brown adipose tissue, resulting in a loss of fatty tissue and improved lean/fat tissue ratio. Probiotic supplementation also improved muscle glucose uptake, as measured using Positron Emission Tomography (PET) analysis. In conclusion, these data provide a proof of concept that probiotics, as a dietary intervention in AIP, induce relevant changes in intestinal bacteria composition and improve glucose uptake and muscular energy utilization. Probiotics may offer a safe, efficient, and cost-effective option to manage people with insulin resistance associated with AIP.
Open Access
Influence of storage temperature and packaging on bacteria and yeast viability in a plant-based fermented food
(MDPI, 2020) Cabello Olmo, Miriam; Oneca Agurruza, María; Torre Hernández, Paloma; Díaz, Jesús Vicente; Encío Martínez, Ignacio; Barajas Vélez, Miguel Ángel; Araña Ciordia, Miriam; Ciencias de la Salud; Osasun Zientziak; Agronomía, Biotecnología y Alimentación; Agronomia, Bioteknologia eta Elikadura; Gobierno de Navarra / Nafarroako Gobernua
Optimization of food storage has become a central issue for food science and biotechnology, especially in the field of functional foods. The aim of this work was to investigate the influence of different storage strategies in a fermented food product (FFP) and further determine whether the regular storage (room temperature (RT) and standard packaging (SP)) could be refined. Eight experimental conditions (four different temperatures × two packaging) were simulated and changes in FFP’s microbial ecology (total bacteria, lactic acid bacteria (LAB), and yeasts) and physicochemical characteristics (pH and moisture content (MC)) were determined following 1, 3, 6, and 12 months. All conditions tested showed a decline in microbial content due to the effect of the temperature, 37 ◦C being the most detrimental condition, while −20 and 4 ◦C seemed to be better than RT in some parameters. Vacuum packaging (VP) only had a major effect on MC and we found that VP preserved greater MC values than SP at 3, 6, and 12 months. The correlation analysis revealed that total bacteria, LAB, and yeasts were positively associated, and also both pH and MC showed a correlation. According to our results and with the purpose to maintain the load of viable microorganisms, we observed that the best storage conditions should contemplate SP and freezing or cooling temperature during a period no longer than 3 months.