Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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Insulin and disorders of behavioural flexibility
(Elsevier, 2023-04-27) Scholtz, Samantha; Glennon, Jeffrey C.; Sullivan, Mairead; Fernández Aranda, Fernando; Camacho Barcia, Lucía; Harkin, Andrew; Macrì, Simone; Mora Maltas, Bernat; Jiménez-Murcia, Susana; O'Leary, Aet; Ottomana, Angela Maria; Presta, Martina; Slattery, David
Behavioural inflexibility is a symptom of neuropsychiatric and neurodegenerative disorders such as Obsessive-Compulsive Disorder, Autism Spectrum Disorder and Alzheimer's Disease, encompassing the maintenance of a behaviour even when no longer appropriate. Recent evidence suggests that insulin signalling has roles apart from its regulation of peripheral metabolism and mediates behaviourally-relevant central nervous system (CNS) functions including behavioural flexibility. Indeed, insulin resistance is reported to generate anxious, perseverative phenotypes in animal models, with the Type 2 diabetes medication metformin proving to be beneficial for disorders including Alzheimer's Disease. Structural and functional neuroimaging studies of Type 2 diabetes patients have highlighted aberrant connectivity in regions governing salience detection, attention, inhibition and memory. As currently available therapeutic strategies feature high rates of resistance, there is an urgent need to better understand the complex aetiology of behaviour and develop improved therapeutics. In this review, we explore the circuitry underlying behavioural flexibility, changes in Type 2 diabetes, the role of insulin in CNS outcomes and mechanisms of insulin involvement across disorders of behavioural inflexibility.
A novel technique for computer-assisted dental autotransplantation: A case report with 42 months of follow-up
(Tabriz University of Medical Sciences (TUOMS), 2025-04-13) Chegeni, Ehsan; Marques, José; Barbosa de Figueiredo, Rui Pedro; Valmaseda Castellón, Eduardo; Kadkhodazadeh, Mahdi
Dental autotransplantation (DAT) is an effective technique for replacing missing teeth. This case report presents a novel computer-assisted approach using cone-beam computed tomography (CBCT) for 3D planning. A 15-year-old female with a hopeless molar due to failed endodontic treatment underwent DAT. Following 3D planning, the donor tooth was surgically extracted and transplanted into the prepared socket, followed by semi-rigid splinting. A meticulous 42-month clinical and radiographic follow-up demonstrated the success and stability of the procedure. This innovative method emphasizes the role of advanced computer technology and 3D imaging in enhancing surgical precision and treatment outcomes. Within the limitations of this case report, DAT, combined with computer-assisted planning, proved a reliable and predictable treatment option for replacing hopeless teeth, particularly in young patients. This approach showed the potential of DAT to transform tooth replacement strategies with better accuracy and decision-making.
Gene-Specific Detection Rate of Adenomas and Advanced Adenomas in Lynch Syndrome
(Elsevier, 2025-09-01) Sánchez Brualla, Alicia; Castillo Iturra, Joaquín; Balmaña, Judith; Brunet, Joan; Castells Sánchez, Alba; Capellá, G. (Gabriel); Ladabaum, Uri; Dekker, Evelien; Moreira, Luciana; Pellisé, M.; Balaguer Prunés, Francesc; López Fernández, Adrià; Salces, Inmaculada; Picó, María Dolores; Rivas, Laura; Bujanda, Luis; Garzon, Marta; Pizarro, Angeles; Martinez de Castro, Eva; Roos, V.H.; Dueñas, Nuria; Pineda Riu, Marta; Moreno Calle, Lorena; Rodríguez Alonso, Lorena; Ramon y Cajal, Teresa; Llort, Gemma; Piñol, Virginia; López Arias, María .Jesús; Poves, Carmen; Garau, Catalina; Rodríguez Alcalde, Daniel; Herraiz, Maite; Álvarez Urrutia, Cristina; Dacal, Andrés; Carrillo Palau, Marta; Cid, Lucía; Ponce, Marta; Barreiro Alonso, Eva; Saperas, Esteban; Aguirre, Elena; Bastiaansen, B.; Ocaña, Teresa; Carballal, Sabela; Rivero Sánchez, Liseth; Ortiz, Oswaldo; Daca Álvarez, María; Prat Galito, Ricard; Bessa, Xavier; Cubiella, Joaquin; Jover, Rodrigo; Rodríguez Moranta, Francisco
Background & Aims Colonoscopy is expected to reduce colorectal cancer (CRC) incidence in Lynch syndrome (LS) by detecting and removing adenomas. The existence of gene-specific differences in adenoma detection has been proposed yet remains insufficiently explored. This study aims to elucidate gene-specific adenoma detection rates and their association with post-colonoscopy CRC (PCCRC), which stands as an important issue in LS surveillance. Methods In this multicenter study, we analyzed 1072 LS carriers without prior CRC undergoing surveillance colonoscopy, evaluating adenoma and advanced adenoma (AA) detection rates by gene. The primary outcome was to compare adenoma detection rates in individuals without prior CRC carrying pathogenic variants in MLH1/MSH2 vs MSH6/PMS2. Subgroup analysis was performed to assess the intermediate risk profile in MSH6 carriers relative to MLH1/MSH2 and PMS2 carriers. We compared overall adenoma detection rates, adenoma burden, age at first adenoma occurrence, and 10-year cumulative detection rates. Risk factors for AA and PCCRC were also identified. Multiple testing and multivariate analyses were performed. Results The adenoma detection rates were similar across the 4 genes. However, MLH1/MSH2 carriers had a higher overall AA detection rate compared with MSH6/PMS2 carriers (14.5% vs 11.9%; P = .04) and showed higher cumulative AA detection rates over 10 years (21.6% vs 19.7%; P = .04). Subgroup analysis indicated that MSH6 carriers had an intermediate AA detection rate positioned between MLH1/MSH2 carriers and PMS2 carriers. Multivariate analysis indicated that AAs (odds ratio, 2.12; 95% confidence interval, 1.08–4.17; P=.03) and repeated AA detection (odds ratio, 4.62; 95% confidence interval, 1.70–12.57; P < .01) were independent risk factors for PCCRC. Conclusions Carriers of MLH1/MSH2 pathogenic variants are at a higher risk of developing AAs compared with those with MSH6/PMS2 mutations, with MSH6 carriers exhibiting an intermediate risk profile. AAs are an independent risk factor for PCCRC. LS patients with AAs should be identified as high risk and undergo enhanced colonoscopy surveillance.
Early anticoagulation may improve preprocedural patency of the infarct-related artery in primary percutaneous coronary intervention.
(Elsevier España, 2013-02-01) Ariza Solé, Albert; Ferreiro Gutiérrez, José Luis; Sánchez Salado, Jose Carlos; Lorente, Victòria; Gómez Hospital, Joan Antoni; Cequier Fillat, Àngel R.
The aim of this study was to evaluate the impact of early administration of anticoagulation therapy (at diagnosis) compared with its application in the cardiac catheterization laboratory at the start of the procedure on the initial patency of the infarct-related artery (IRA) in patients undergoing pPCI as a reperfusion strategy.
Epigenetic inactivation of the 5-methylcytosine RNA methyltransferase NSUN7 is associated with clinical outcome and therapeutic vulnerability in liver cancer
(BioMed Central, 2023-05-12) Ortiz Barahona, Vanessa; Soler, Marta; Davalos, Veronica; García-Prieto, Carlos A.; Janin, Maxime; Setién, Fernando; Fernández-Rebollo, Irene; Bech-Serra, Joan J.; De La Torre, Carolina; Guil, Sonia; Villanueva Garatachea, Alberto; Zhang, Pei-Hong; Yang, Li; Guarnacci, Marco; Schumann, Ulrike; Preiss, Thomas; Balaseviciute, Ugne; Montal, Robert; Llovet i Bayer, Josep Maria; Esteller, Manel
Background: RNA modifications are important regulators of transcript activity and an increasingly emerging body of data suggests that the epitranscriptome and its associated enzymes are altered in human tumors. Methods: Combining data mining and conventional experimental procedures, NSUN7 methylation and expression status was assessed in liver cancer cell lines and primary tumors. Loss-of-function and transfection-mediated recovery experiments coupled with RNA bisulfite sequencing and proteomics determined the activity of NSUN7 in downstream targets and drug sensitivity. Results: In this study, the initial screening for genetic and epigenetic defects of 5-methylcytosine RNA methyltransferases in transformed cell lines, identified that the NOL1/NOP2/Sun domain family member 7 (NSUN7) undergoes promoter CpG island hypermethylation-associated with transcriptional silencing in a cancer-specific manner. NSUN7 epigenetic inactivation was common in liver malignant cells and we coupled bisulfite conversion of cellular RNA with next-generation sequencing (bsRNA-seq) to find the RNA targets of this poorly characterized putative RNA methyltransferase. Using knock-out and restoration-of-function models, we observed that the mRNA of the coiled-coil domain containing 9B (CCDC9B) gene required NSUN7-mediated methylation for transcript stability. Most importantly, proteomic analyses determined that CCDC9B loss impaired protein levels of its partner, the MYC-regulator Influenza Virus NS1A Binding Protein (IVNS1ABP), creating sensitivity to bromodomain inhibitors in liver cancer cells exhibiting NSUN7 epigenetic silencing. The DNA methylation-associated loss of NSUN7 was also observed in primary liver tumors where it was associated with poor overall survival. Interestingly, NSUN7 unmethylated status was enriched in the immune active subclass of liver tumors. Conclusion: The 5-methylcytosine RNA methyltransferase NSUN7 undergoes epigenetic inactivation in liver cancer that prevents correct mRNA methylation. Furthermore, NSUN7 DNA methylation-associated silencing is associated with clinical outcome and distinct therapeutic vulnerability.
The impact of nursing-led emotional preparation on mental health after total hip arthroplasty
(Frontiers Media, 2025-11-05) Ripoll-Romero, Elisabet; Agüera, Zaida; Puig Llobet, Montserrat; Galimany Masclans, Jordi
Background: Postoperative anxiety and depression are common following total hip arthroplasty (THA) and can negatively affect recovery. While pharmacological management is standard, non-pharmacological interventions may offer additional benefits without adverse side effects. Objective: To assess the effectiveness of a nurse-led video-based intervention on anxiety and depression symptoms and perceived quality of life in patients undergoing THA, compared to standard care. Methods: A quasi-randomized controlled trial was conducted with 131 participants undergoing elective THA, randomly assigned to an intervention group (IG; n = 67) receiving a preoperative nursing intervention focused on emotional preparation and information, and a control group (CG; n = 64) receiving usual care. Psychopathological symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS), and quality of life was measured using the EQ-5D-5L. Assessments occurred at baseline (pre-surgery), post-intervention (hospital discharge), and one-month follow-up. General Linear Model (GLM) analyses were used for within- and between-group comparisons. Results: No significant differences in anxiety or depression symptoms were found between baseline and hospital discharge in either group. Both groups showed significant improvement in HADS scores and all EQ-5D-5L dimensions at one-month follow-up. Although the IG initially appeared to show greater improvement in depression symptomatology and in the 'usual activities' dimension compared to the CG, these differences were no longer statistically significant after adjusting for baseline depression. No other significant between-group differences were observed. Conclusion: The nurse-led video-based intervention did not produce immediate emotional benefits but was associated with improved functional recovery at 1 month; however, it has not been shown to be more effective than usual care. These findings suggest that targeted nursing interventions may support postoperative recovery, particularly in functional outcomes, while emotional effects remain inconclusive and warrant further investigation. Importantly, the video format offers a more sustainable and cost-effective approach compared to printed materials, reducing the need for physical handouts while maintaining structured patient education.
Adenosine A_2A receptor activation regulates Niemann-Pick C1 expression and localization in macrophages
(MDPI, 2023-06-07) Skopál, Adrienn; Újlaki, Gyula; Gerencsér, Attila Tibor; Bankó, Csaba; Bacsó, Zsolt; Ciruela Alférez, Francisco; Virág, László; Haskó, György; Kókai, Endre
Adenosine plays an important role in modulating immune cell function, particularly T cells and myeloid cells, such as macrophages and dendritic cells. Cell surface adenosine A2A receptors (A2AR) regulate the production of pro-inflammatory cytokines and chemokines, as well as the proliferation, differentiation, and migration of immune cells. In the present study, we expanded the A2AR interactome and provided evidence for the interaction between the receptor and the Niemann-Pick type C intracellular cholesterol transporter 1 (NPC1) protein. The NPC1 protein was identified to interact with the C-terminal tail of A2AR in RAW 264.7 and IPMФ cells by two independent and parallel proteomic approaches. The interaction between the NPC1 protein and the full-length A2AR was further validated in HEK-293 cells that permanently express the receptor and RAW264.7 cells that endogenously express A2AR. A2AR activation reduces the expression of NPC1 mRNA and protein density in LPS-activated mouse IPMФ cells. Additionally, stimulation of A2AR negatively regulates the cell surface expression of NPC1 in LPS-stimulated macrophages. Furthermore, stimulation of A2AR also altered the density of lysosome-associated membrane protein 2 (LAMP2) and early endosome antigen 1 (EEA1), two endosomal markers associated with the NPC1 protein. Collectively, these results suggested a putative A2AR-mediated regulation of NPC1 protein function in macrophages, potentially relevant for the Niemann-Pick type C disease when mutations in NPC1 protein result in the accumulation of cholesterol and other lipids in lysosomes.
Association of monetary diet cost of foods and diet quality in Spanish older adults
(Frontiers Media, 2023-07-25) García-Ríos, Antonio; Bouzas, Cristina; Pastor, Rosario; García, Silvia; Monserrat Mesquida, Margalida; Martínez-González, Miguel Ángel; Salas Salvadó, Jordi; Corella Piquer, Dolores; Schröder, Helmut; Martínez, J. Alfredo; Alonso-Gómez, Ángel M.; Wärnberg, Julia; Vioque, Jesús; Romaguera, Dora; Lopez-Miranda, José; Estruch Riba, Ramon; Tinahones, Francisco J.; Lapetra, José; Serra Majem, Lluís; Riquelme Gallego, Blanca; Romero-Secin, Anny; Pintó Sala, Xavier; Gaforio, José J.; Matía Martín, Pilar; Vidal i Cortada, Josep; Zapatero, Miriam; Daimiel, Lidia; Ros Rahola, Emilio; García-Arellano, Ana; Babio, Nancy; González Monje, Inmaculada; Castañer Niño, Olga; Abete, Itziar; Tojal Sierra, Lucas; Benavente Marín, Juan Carlos; Signes Pastor, Antonio J.; Konieczna, Jadwiga; Castro-Barquero, Sara; Fernández-García, José C.; Santos Lozano, Jose Manuel; Bes Rastrollo, Maira; Mestres, Cristina; Guillem Saiz, Patricia; Goday Arnó, Albert; Goicolea Güemez, Leire; Puig-Aguiló, Estanislao; Ruiz-Canela, Miguel; Palau Galindo, Antoni; Fitó, Montse; Tur, Josep A.
Background: A major barrier to a healthy diet may be the higher price of healthy foods compared to low-quality foods. Objectives: This study aimed to assess the association between the monetary cost of food and diet quality in Spanish older adults at high risk of cardiovascular disease. Methods: Cross-sectional analysis was carried out in Spanish older adults (n = 6,838; 48.6% female). A validated food frequency questionnaire was used to assess dietary intake. Metabolic syndrome severity, adherence to the Mediterranean diet (MedDiet), adherence to a provegetarian dietary pattern, and dietary inflammatory index were assessed. The economic cost of the foods was obtained from the Spanish Ministry of Agriculture Fisheries and Food database (2015-2017, the period of time when the participants were recruited). The total cost of diet adjusted per 1,000 kcal was computed. Results: The healthier dietary pattern was associated with a higher cost of the diet. Higher adherence to the MedDiet, anti-inflammatory diet, and the healthy version of the provegetarian dietary pattern were related to higher costs of the diet. Conclusion: Higher diet quality was associated with a higher dietary cost of the diet per 1,000 kcal/day. Food prices can be an important component of interventions and policies aimed at improving people's diets and preventing diet-related chronic diseases.
Cigarettes vs. e-cigarettes: Passive exposure at home measured by means of airborne marker and biomarkers
(Elsevier, 2014-09-27) Ballbè i Gibernau, Montse; Martínez Sánchez, José M.; Sureda, Xisca; Fu Balboa, Marcela; Pérez Ortuño, Raúl; Pascual, José A.; Saltó, Esteve; Fernández Muñoz, Esteve
Background: There is scarce evidence about passive exposure to the vapour released or exhaled from electronic cigarettes (e-cigarettes) under real conditions. The aim of this study is to characterise passive exposure to nicotine from e-cigarettes' vapour and conventional cigarettes' smoke at home among non-smokers under real-use conditions. Methods: We conducted an observational study with 54 non-smoker volunteers from different homes: 25 living at home with conventional smokers, 5 living with nicotine e-cigarette users, and 24 from control homes (not using conventional cigarettes neither e-cigarettes). We measured airborne nicotine at home and biomarkers (cotinine in saliva and urine). We calculated geometric mean (GM) and geometric standard deviations (GSD). We also performed ANOVA and Student's t tests for the log-transformed data. We used Bonferroni-corrected t-tests to control the family error rate for multiple comparisons at 5%. Results: The GMs of airborne nicotine were 0.74 μg/m(3) (GSD=4.05) in the smokers' homes, 0.13 μg/m(3) (GSD=2.4) in the e-cigarettes users' homes, and 0.02 μg/m(3) (GSD=3.51) in the control homes. The GMs of salivary cotinine were 0.38 ng/ml (GSD=2.34) in the smokers' homes, 0.19 ng/ml (GSD=2.17) in the e-cigarettes users' homes, and 0.07 ng/ml (GSD=1.79) in the control homes. Salivary cotinine concentrations of the non-smokers exposed to e-cigarette's vapour at home (all exposed ≥ 2 h/day) were statistically significant different that those found in non-smokers exposed to second-hand smoke ≥ 2 h/day and in non-smokers from control homes. Conclusions: The airborne markers were statistically higher in conventional cigarette homes than in e-cigarettes homes (5.7 times higher). However, concentrations of both biomarkers among non-smokers exposed to conventional cigarettes and e-cigarettes' vapour were statistically similar (only 2 and 1.4 times higher, respectively). The levels of airborne nicotine and cotinine concentrations in the homes with e-cigarette users were higher than control homes (differences statistically significant). Our results show that non-smokers passively exposed to e-cigarettes absorb nicotine.
Positive mental health questionnaire-short form (PMHQ-SF18): Psychometric properties of the spanish version
(MDPI, 2025-11-07) Lluch Canut, Ma. Teresa; Puig Llobet, Montserrat; Sanchez-Ortega, M. Aurelia; Moreno Arroyo, M. Carmen; Moreno Poyato, Antonio Rafael; Roldán Merino, Juan Francisco; Hidalgo Blanco, Miguel Ángel; Ferré Grau, Carmen; Albacar Riobóo, Núria; Sequeira, Carlos; Sanchez-Balcells, Sara; Mantas Jiménez, Susana; Prats Arimon, Marta; Agüera, Zaida
Background: The construct of positive mental health (PMH) is defined as the basis of individuals' psychological well-being and their ability to function effectively and cope with life's challenges. The Positive Mental Health Questionnaire (PMHQ) is a reliable tool for assessing the PMH factors, but its length (39 items) can pose challenges in certain contexts and populations. This highlights the need for an abridged version of the questionnaire that requires less time to administer. Therefore, the main aim was to validate the Spanish 18 item-shortened version of the PMHQ (PMHQ-SF18). Methods: The sample consisted of 574 nursing students. Psychometric analyses were carried out based on construct validity, criterion validity, and internal consistency. A confirmatory factor analysis was conducted to ascertain whether the internal structure was consistent with the model of the previously validated Portuguese brief version. Results: The results supported the good psychometric properties of the instrument, with adequate validity and reliability. Confirmatory factor analysis revealed optimal goodness-of-fit values, supporting the six-factor structure. The overall Cronbach's alpha was 0.83. Conclusions: The findings suggest that the PMHQ-SF18 is a valid and reliable instrument, comparable to the original version, but with the added benefits of being shorter, quicker, and easier to administer. Consequently, it may be particularly useful for population-based screening studies and for monitoring change following positive mental health promotion interventions. Its abridged format makes it particularly suitable for assessing individuals with specific characteristics or in contexts where time is limited, and more concise instruments are required, for example, in primary care or critical care.
Neural cell diversity in the light of single-cell transcriptomics
(CRC Press, Taylor and Francis Group, 2024-01-17) Fernandez Moya, Sandra M.; Jaya Ganesh, Akshay; Plass, Mireya
The development of highly parallel and affordable high-throughput single-cell transcriptomics technologies has revolutionized our understanding of brain complexity. These methods have been used to build cellular maps of the brain, its different regions, and catalog the diversity of cells in each of them during development, aging and even in disease. Now we know that cellular diversity is way beyond what was previously thought. Single-cell transcriptomics analyses have revealed that cell types previously considered homogeneous based on imaging techniques differ depending on several factors including sex, age and location within the brain. The expression profiles of these cells have also been exploited to understand which are the regulatory programs behind cellular diversity and decipher the transcriptional pathways driving them. In this review, we summarize how single-cell transcriptomics have changed our view on the cellular diversity in the human brain, and how it could impact the way we study neurodegenerative diseases. Moreover, we describe the new computational approaches that can be used to study cellular differentiation and gain insight into the functions of individual cell populations under different conditions and their alterations in disease.
Energy substrate metabolism, mitochondrial structure and oxidative stress after cardiac ischemia-reperfusion in mice lacking UCP3.
(Elsevier B.V., 2023-08-20) Sánchez-Pérez, Patricia; Mata, Ana; Torp, May-Kristin; López Bernardo, Elia; Heiestad, Christina M.; Aronsen, Jan Magnus; Molina-Iracheta, Antonio; Jiménez-Borreguero, Luis J.; García-Roves, Pablo M. (Pablo Miguel); Costa, Ana S.H.; Frezza, Christian; Murphy, Michael P.; Stenslokken, Kåre-Olav; Cadenas, Susana
Myocardial ischemia-reperfusion (IR) injury may result in cardiomyocyte dysfunction. Mitochondria play a critical role in cardiomyocyte recovery after IR injury. The mitochondrial uncoupling protein 3 (UCP3) has been proposed to reduce mitochondrial reactive oxygen species (ROS) production and to facilitate fatty acid oxidation. As both mechanisms might be protective following IR injury, we investigated functional, mitochondrial structural, and metabolic cardiac remodeling in wild-type mice and in mice lacking UCP3 (UCP3-KO) after IR. Results showed that infarct size in isolated perfused hearts subjected to IR ex vivo was larger in adult and old UCP3-KO mice than in equivalent wild-type mice, and was accompanied by higher levels of creatine kinase in the effluent and by more pronounced mitochondrial structural changes. The greater myocardial damage in UCP3-KO hearts was confirmed in vivo after coronary artery occlusion followed by reperfusion. S1QEL, a suppressor of superoxide generation from site IQ in complex I, limited infarct size in UCP3-KO hearts, pointing to exacerbated superoxide production as a possible cause of the damage. Metabolomics analysis of isolated perfused hearts confirmed the reported accumulation of succinate, xanthine and hypoxanthine during ischemia, and a shift to anaerobic glucose utilization, which all recovered upon reoxygenation. The metabolic response to ischemia and IR was similar in UCP3-KO and wild-type hearts, being lipid and energy metabolism the most affected pathways. Fatty acid oxidation and complex I (but not complex II) activity were equally impaired after IR. Overall, our results indicate that UCP3 deficiency promotes enhanced superoxide generation and mitochondrial structural changes that increase the vulnerability of the myocardium to IR injury.
Prediagnostic selenium status, selenoprotein gene variants and association with breast cancer risk in a European cohort study
(Elsevier BV, 2023-11-01) J. Hughes, David; Schomburg, Lutz; Jenab, Mazda; Biessy, Carine; Méplan, Catherine; Moskal, Aurelie; Sun, Qian; Demircan, Kamil; Fedirko, Veronika; Weiderpass, Elisabete; Mukhtar, Maryam; Olsen, Anja; Tjønneland, Anne; Overvad, Kim; Schulze, Matthias; Haugdahl Nøst, Therese; Skeie, Guri; Standahl Olsen, Karina; Ricceri, Fulvio; Grioni, Sara; Palli, Domenico; Masala, Giovanna; Tumino, Rosario; Pasanisi, Fabrizio; Amiano, Pilar; M. Colorado Yohar, Sandra; Agudo, Antonio; Sánchez, Maria-jose; Ardanaz, Eva; Sund, Malin; Andersson, Anne; Perez-cornago, Aurora; Travis, Ruth; K. Heath, Alicia; Dossus, Laure
Selenium (Se) may help prevent breast cancer (BC) development. Owing to limited observational evidence, we investigated whether prediagnostic Se status and/or variants in the selenoprotein genes are associated with BC risk in a large European cohort. Se status was assessed by plasma measures of Se and its major circulating proteins, selenoprotein P (SELENOP) and glutathione peroxidase 3 (GPX3), in matched BC case-control pairs (2208 for SELENOP; 1785 for GPX3 and Se) nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). Single nucleotide polymorphisms (SNPs, n = 452) in 55 selenoprotein and Se metabolic pathway genes and an additional 18 variants previously associated with Se concentrations were extracted from existing genotyping data within EPIC for 1564 case-control pairs. Multivariable-adjusted logistic regression models were used to calculate the odds ratios (ORs) and 95 % confidence intervals (CIs) of the association be-tween Se status markers, SNP variants and BC risk. Overall, there was no statistically significant association of Se status with BC risk. However, higher GPX3 activity was associated with lower risk of premenopausal BC (4th versus 1st quartile, OR = 0.54, 95 % CI: 0.30-0.98, Ptrend= 0.013). While none of the genetic variant associations (P <= 0.05) retained significance after multiple testing correction, rs1004243 in the SELENOM selenoprotein gene and two SNPs in the related antioxidant TXN2 gene (rs4821494 and rs5750261) were associated with respective lower and higher risks of BC at a significance threshold of P <= 0.01. Fourteen SNPs in twelve Se pathway genes (P <= 0.01) in interaction with Se status were also associated with BC risk. Higher Se status does not appear to associated with BC risk, although activity of the selenoenzyme GPX3 may be inversely associated with pre-menopausal BC risk, and SNPs in the Se pathway alone or in combination with suboptimal Se status may in-fluence BC risk.
Incidence, associated disease burden and healthcare utilization due to Staphylococcus aureus prosthetic joint infection in European hospitals: the COMBACTE-NET ARTHR-IS multi-centre study
(Elsevier BV, 2023-10-04) Espíndola, R.; Vella, V.; Benito, N.; Mur, I.; Tedeschi, S.; Zamparini, E.; Hendriks, J.g.e.; Sorlí, L.; Murillo, O.; Soldevila, L.; Scarborough, M.; Scarborough, C.; Kluytmans, J.; Ferrari, M.c.; Pletz, M.w.; Mcnamara, I.; Escudero-sanchez, R.; Arvieux, C.; Batailler, C.; Dauchy, F.-a.; Liu, W.-y.; Lora-tamayo, J.; Praena, J.; Ustianowski, A.; Cinconze, E.; Pellegrini, M.; Bagnoli, F.; Rodríguez-baño, J.; Del-toro-lópez, M.-d.
Background: The aim of this study was to estimate the incidence, associated disease burden and healthcare utilization due to Staphylococcus aureus prosthetic joint infections (SA-PJI) after primary hip and knee arthroplasty in European centres. Methods: This study was conducted in patients who underwent primary hip and knee arthroplasty in 19 European hospitals between 2014 and 2016. The global incidence of PJI and SA-PJI was calculated. The associated disease burden was measured indirectly as infection-related mortality plus loss of function. For healthcare utilization, number and duration of hospitalizations, number and type of surgical procedures, duration of anti-biotic treatments, and number of outpatient visits were collected. Subgroup and regres-sion analyses were used to evaluate the impact of SA-PJI on healthcare utilization, controlling for confounding variables. Results: The incidence of PJI caused by any micro-organism was 1.41%, and 0.40% for SA-PJI. Among SA-PJI, 20.7% were due to MRSA with substantial regional differences, and were more frequent in partial hip arthroplasty (PHA). Related deaths and loss of function occurred in 7.0% and 10.2% of SA-PJI cases, respectively, and were higher in patients with PHA. Compared with patients without PJI, patients with SA-PJI had a mean of 1.4 more readmissions, 25.1 more days of hospitalization, underwent 1.8 more surgical procedures, and had 5.4 more outpatient visits, controlling for confounding variables. Healthcare utilization was higher in patients who failed surgical treatment of SA-PJI. Conclusions: This study confirmed that the SA-PJI burden is high, especially in PHA, and provided a solid basis for planning interventions to prevent SA-PJI. 2023 The Author(s). Published by Elsevier Ltd on behalf of The Healthcare Infection Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Patritumab deruxtecan in untreated hormone receptor-positive/HER2-negative early breast cancer: final results from part A of the window-of- opportunity SOLTI TOT-HER3 pre-operative study
(Oxford University Press, 2023-05-19) Santhanagopal, Anu; Sellami, Dalila; Villacampa, Guillermo; Ferrero Cafiero, Juan Manuel; Pascual, Tomás; Prat Aparicio, Aleix; Vidal Espinar, Miquel; Martínez Sáez, Olga; Paré Brunet, Laia; González Farré, Blanca; Sanfeliu, Esther; Ciruelos, Eva; Espinosa Bravo, Martin; Pernas, Sònia; Izarzugaza, Y.; Esker, Stephen; Oliveira, Mafalda; Falato, Claudette; Cejalvo Andújar, Juan Miguel; Margelí Vila, Mireia; Tolosa, Pablo; Salvador Bofill, Francisco Javier; Cruz Jurado, Josefina; Arumi de Dios, Miriam; Luna Barrera, Ana María; Guerra, Juan Antonio; Fan, Pang-dian; Parul, Patel
Background: Patritumab deruxtecan (HER3-DXd) is a human epidermal growth factor receptor 3 (HER3)-directed antibody-drug conjugate composed of a fully human anti-HER3 monoclonal antibody (patritumab) covalently linked to a topoisomerase I inhibitor payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. TOT-HER3 is a window-of-opportunity study designed to assess the biological activity, measured by CelTIL score [= -0.8 × tumor cellularity (in %) + 1.3 × tumor-infiltrating lymphocytes (TILs) (in %)], and clinical activity of HER3-DXd during short-term (21 days) pre-operative treatment in patients with primary operable HER2-negative early breast cancer. Patients and methods: Patients with previously untreated hormone receptor-positive/HER2-negative tumors were allocated to one of four cohorts according to baseline ERBB3 messenger RNA expression. All patients received one dose of HER3-DXd 6.4 mg/kg. The primary objective was to evaluate change from baseline in CelTIL score. Results: Seventy-seven patients were evaluated for efficacy. A significant change in CelTIL score was observed, with a median increase from baseline of 3.5 (interquartile range, -3.8 to 12.7; P = 0.003). Among patients assessable for clinical response (n = 62), an overall response rate of 45% was observed (tumor measurement by caliper), with a trend toward an increase in CelTIL score among responders compared with non-responders (mean difference, +11.9 versus +1.9). Change in CelTIL score was independent of baseline ERBB3 messenger RNA and HER3 protein levels. Genomic changes occurred, including switching toward a less proliferative tumor phenotype based on PAM50 subtypes, suppression of cell proliferation genes, and induction of genes associated with immunity. Treatment-emergent adverse events were observed in 96% of patients (14% grade ≥3); most common were nausea, fatigue, alopecia, diarrhea, vomiting, abdominal pain, and neutrophil count decrease. Conclusions: A single dose of HER3-DXd was associated with clinical response, increased immune infiltration, suppression of proliferation in hormone receptor-positive/HER2-negative early breast cancer, and a tolerable safety profile consistent with previously reported results. These findings support further study of HER3-DXd in early breast cancer.
Immunostimulatory gene therapy targeting CD40, 4-1BB and IL-2R activates DCs and stimulates antigen-specific T-cell and NK-cell responses in melanoma models
(Springer Science and Business Media LLC, 2023-07-27) Wenthe, Jessica; Eriksson, Emma; Hellström, Ann-charlotte; Moreno, Rafael; Ullenhag, Gustav; Alemany, Ramon; Lövgren, Tanja; Loskog, Angelica
BackgroundThe activation of dendritic cells (DCs) is pivotal for generating antigen-specific T-cell responses to eradicate tumor cells. Hence, immunotherapies targeting this interplay are especially intriguing. Moreover, it is of interest to modulate the tumor microenvironment (TME), as this harsh milieu often impairs adaptive immune responses. Oncolytic viral therapy presents an opportunity to overcome the immunosuppression in tumors by destroying tumor cells and thereby releasing antigens and immunostimulatory factors. These effects can be further amplified by the introduction of transgenes expressed by the virus.MethodsLokon oncolytic adenoviruses (LOAd) belong to a platform of chimeric serotype Ad5/35 viruses that have their replication restricted to tumor cells, but the expression of transgenes is permitted in all infected cells. LOAd732 is a novel oncolytic adenovirus that expresses three essential immunostimulatory transgenes: trimerized membrane-bound CD40L, 4-1BBL and IL-2. Transgene expression was determined with flow cytometry and ELISA and the oncolytic function was evaluated with viability assays and xenograft models. The activation profiles of DCs were investigated in co-cultures with tumor cells or in an autologous antigen-specific T cell model by flow cytometry and multiplex proteomic analysis. Statistical differences were analyzed with Kruskal-Wallis test followed by Dunn's multiple comparison test.ResultsAll three transgenes were expressed in infected melanoma cells and DCs and transgene expression did not impair the oncolytic activity in tumor cells. DCs were matured post LOAd732 infection and expressed a multitude of co-stimulatory molecules and pro-inflammatory cytokines crucial for T-cell responses. Furthermore, these DCs were capable of expanding and stimulating antigen-specific T cells in addition to natural killer (NK) cells. Strikingly, the addition of immunosuppressive cytokines TGF-& beta;1 and IL-10 did not affect the ability of LOAd732-matured DCs to expand antigen-specific T cells and these cells retained an enhanced activation profile.ConclusionsLOAd732 is a novel immunostimulatory gene therapy based on an oncolytic adenovirus that expresses three transgenes, which are essential for mediating an anti-tumor immune response by activating DCs and stimulating T and NK cells even under imunosuppressive conditions commonly present in the TME. These qualities make LOAd732 an appealing new immunotherapy approach.
XV Reunión Post-ECTRIMS: revisión de las novedades presentadas en el Congreso ECTRIMS 2022 (II)
(IMR Press, 2023-07-01) Fernández, O.; Montalban, X.; Agüera, E.; Aladro, Y.; Alonso, A.; Arroyo, R.; Brieva, L.; Calles, C.; Costa-frossard, L.; Eichau, S.; García-domínguez, J. M.; Hernández, M. A.; Landete, L.; Llaneza, M.; Llufriu, S.; Meca-lallana, J. E.; Meca-lallana, V.; Mongay-ochoa, N.; Moral, E.; Oreja-guevara, C.; Ramió-torrentà, Ll.; Téllez, N.; Romero-pinel, L.; Rodríguez-antigüedad, A.
Introduction. On 4 and 5 November 2022, Madrid hosted the 15th edition of the Post-ECTRIMS Meeting, where neurologists specialised in multiple sclerosis outlined the latest developments presented at the 2022 ECTRIMS Congress, held in Amsterdam from 26 to 28 October. Aim. To synthesise the content presented at the 15th edition of the Post-ECTRIMS Meeting, in an article broken down into two parts. Development. This second part describes the new developments in terms of therapeutic strategies for escalation and de-escalation of disease-modifying therapies (DMT), when and in whom to initiate or switch to highly effective DMT, the definition of therapeutic failure, the possibility of treating radiologically isolated syndrome and the future of personalised treatment and precision medicine. It also considers the efficacy and safety of autologous haematopoietic stem cell transplantation, different approaches in clinical trial design and outcome measures to assess DMT in progressive stages, challenges in the diagnosis and treatment of cognitive impairment, and treatment in special situations (pregnancy, comorbidity and the elderly). In addition, results from some of the latest studies with oral cladribine and evobrutinib presented at ECTRIMS 2022 are shown.
Mechanical circulatory support as a cornerstone in advanced heart failure and transplantation
(Frontiers Media SA, 2025-10-24) Braga, Marta; Pinho, Ana Isabel; Jorde, Ulrich P. ; González-Costello, José
Orthotopic heart transplantation remains the gold standard for managing selected patients with end-stage heart failure (HF) who are unresponsive to conventional therapies. Mechanical circulatory support (MCS), encompassing durable (dMCS) and temporary (tMCS) devices, has become a cornerstone in bridging patients to transplant (BTT) and also addressing the increasing burden of advanced HF with dMCS destination therapy. Each type of MCS offers distinct advantages tailored to specific patient needs and clinical scenarios. This review summarizes the features of MCS devices, their implications in clinical practice, and their impact on patient outcomes. Evidence demonstrates that dMCS, including the widely used durable left ventricular assist device HeartMate 3, significantly improves the prognosis of waitlisted patients and is associated with better post-transplant outcomes compared to tMCS when used as a BTT strategy. However, recent trends in allocation systems favor prioritizing tMCS-supported patients to improve outcomes for sicker individuals, underscoring the complexity of resource allocation. In this context, recent tMCs devices such as the Impella 5.5 have demonstrated promising early results as BTT, and ongoing larger studies with long-term follow-up will be crucial to better define their optimal indications and patient selection. Additional research is required to ascertain whether urgency-based models provide the most equitable distribution of resources while optimizing both pre- and post-transplant outcomes. Continued innovation in MCS technology, alongside the development of personalized treatment strategies, is vital to address the evolving needs of the growing advanced HF population. Future advancements should prioritize creating devices that are easier to implant, feature wireless power sources, and provide more physiological support, ultimately enhancing the care and outcomes of patients with advanced HF.
Activity of imipenem/relebactam against Enterobacterales and Pseudomonas aeruginosa in Spain. SMART 2016-2020
(Sociedad Espanola de Quimioterapia, 2023-03-22) García Fernández, Sergio; Calvo, Jorge; Cercenado, Emilia; Suárez Barrenechea, Ana Isabel; Fernández Billón, María; Castillo, Francisco Javier; Gálvez Benítez, Lydia; Tubau, Fe; Figueroa Cerón, Ruth Esther; Hernández Cabezas, Alicia; González Romo, Fernando; Fariñas, María Carmen; Gómez, Maria; Díaz Regañón, Jazmín; Cantón, Rafael
Objectives. To determine susceptibility to the novel beta-lactam/beta-lactamase inhibitor combination imipenem/relebactam in clinical isolates recovered from intra-abdominal (IAI), urinary (UTI), respiratory (RTI) and bloodstream (BSI) infections in the SMART (Study for Monitoring Antimicrobial Resistance Trends) study in SPAIN during 2016 - 2020. Methods. Broth microdilution MICs for imipenem/relebactam and comparators were determined by a central laboratory against isolates of Enterobacterales and Pseudomonas aeruginosa. MICs were interpreted using EUCAST-2021 breakpoints. Results. In total, 5,210 Enterobacterales and 1,418 P. aeruginosa clinical isolates were analyzed. Imipenem/relebactam inhibited 98.8% of Enterobacterales. Distinguishing by source of infection susceptibility was 99.1% in BSI, 99.2% in IAI, 97.9% in RTI, and 99.2% in UTI. Of intensive care unit isolates (ICU) 97.4% were susceptible and of non-ICU isolates 99.2% were susceptible. In Enterobacterales, activity against Class A, Class B and Class D carbapenemases was 96.2%, 15.4% and 73.2%, respectively. In P. aeruginosa, imipenem/relebactam was active in 92.2% of isolates. By source of infection it was 94.8% in BSI, 92.9% in IAI, 91.7% in RTI, and 93.1% in UTI. An 88.7% of ICU isolates and 93.6% of non-ICU isolates were susceptible to imipenem/relebactam. Imipenem/relebactam remained active against P. aeruginosa ceftazidime-resistant (76.3%), cefepime-resistant (73.6%), imipenem-resistant (71.5%) and piperacillin-resistant (78.7%) isolates. Of all multidrug-resistant or difficult-to-treat resistance P. aeruginosa isolates, 75.1% and 46.2%, respectively, were susceptible to imipenem/relebactam. Conclusions. Imipenem/relebactam showed high rates of susceptibility in Enterobacterales and P. aeruginosa isolates from different sources of infection as well as depending on patients' location (ICU or non-ICU scenarios).
Follicular helper T-cell lymphomas: disease spectrum, relationship with clonal hematopoiesis, and mimics. A report of the 2022 EA4HP/SH lymphoma workshop
(Springer Science and Business Media LLC, 2023-07-27) L Ondrejka, Sarah; Amador, Catalina; Climent, Fina; Ng, Siok-bian; Soma, Lorinda; Zamo, Alberto; Dirnhofer, Stefan; Quintanilla-martinez, Leticia; Wotherspoon, Andrew; Leoncini, Lorenzo; De Leval, Laurence
Follicular helper T-cell lymphomas (TFH lymphomas) were discussed in session V of the lymphoma workshop of the European Association for Haematopathology (EA4HP)/Society for Hematopathology (SH) 2022 meeting in Florence, Italy. The session focused on the morphologic spectrum of TFH lymphoma, including its three subtypes: angioimmunoblastic-type (AITL), follicular-type, and not otherwise specified (NOS). The submitted cases encompassed classic examples of TFH lymphoma and unusual cases such as those with early or indolent presentations, associated B-cell proliferations, or Hodgkin/Reed-Sternberg-like cells. The relationship between TFH lymphoma and clonal hematopoiesis was highlighted by several cases documenting divergent evolution of myeloid neoplasm and AITL from shared clonal mutations. The distinction between TFH lymphoma and peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), was stressed, and many challenging examples were presented. Various cases highlighted the difficulties of differentiating TFH lymphoma from other established types of lymphoma and reactive conditions. Cutaneous T-cell lymphoma expressing TFH markers, particularly when resulting in lymph node involvement, should be distinguished from TFH lymphomas. Additional immunophenotyping and next-generation sequencing studies were performed on various cases in this session, highlighting the importance of these technologies to our current understanding and classification of TFH lymphomas.

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