PublicationStructural and Molecular Insight into Piperazine and Piperidine Derivatives as Histamine H3 and Sigma-1 Receptor Antagonists with Promising Antinociceptive Properties.(2021-12-15) Szczepańska, Katarzyna; Podlewska, Sabina; Dichiara, Maria; Gentile, Davide; Patamia, Vincenzo; Rosier, Niklas; Mönnich, Denise; Ruiz Cantero, Ma Carmen; Karcz, Tadeusz; Łażewska, Dorota; Siwek, Agata; Pockes, Steffen; Cobos, Enrique J; Marrazzo, Agostino; Stark, Holger; Rescifina, Antonio; Bojarski, Andrzej J; Amata, Emanuele; Kieć-Kononowicz, KatarzynaIn an attempt to extend recent studies showing that some clinically evaluated histamine H3 receptor (H3R) antagonists possess nanomolar affinity at sigma-1 receptors (σ1R), we selected 20 representative structures among our previously reported H3R ligands to investigate their affinity at σRs. Most of the tested compounds interact with both sigma receptors to different degrees. However, only six of them showed higher affinity toward σ1R than σ2R with the highest binding preference to σ1R for compounds 5, 11, and 12. Moreover, all these ligands share a common structural feature: the piperidine moiety as the fundamental part of the molecule. It is most likely a critical structural element for dual H3/σ1 receptor activity as can be seen by comparing the data for compounds 4 and 5 (hH3R Ki = 3.17 and 7.70 nM, σ1R Ki = 1531 and 3.64 nM, respectively), where piperidine is replaced by piperazine. We identified the putative protein-ligand interactions responsible for their high affinity using molecular modeling techniques and selected compounds 5 and 11 as lead structures for further evaluation. Interestingly, both ligands turned out to be high-affinity histamine H3 and σ1 receptor antagonists with negligible affinity at the other histamine receptor subtypes and promising antinociceptive activity in vivo. Considering that many literature data clearly indicate high preclinical efficacy of individual selective σ1 or H3R ligands in various pain models, our research might be a breakthrough in the search for novel, dual-acting compounds that can improve existing pain therapies. Determining whether such ligands are more effective than single-selective drugs will be the subject of our future studies. PublicationSynthesis, In Vitro Profiling, and In Vivo Evaluation of Benzohomoadamantane-Based Ureas for Visceral Pain: A New Indication for Soluble Epoxide Hydrolase Inhibitors.(2022-10-12) Codony, Sandra; Entrena, José M; Calvó-Tusell, Carla; Jora, Beatrice; González-Cano, Rafael; Osuna, Sílvia; Corpas, Rubén; Morisseau, Christophe; Pérez, Belén; Barniol-Xicota, Marta; Griñán-Ferré, Christian; Pérez, Concepción; Rodríguez-Franco, María Isabel; Martínez, Antón L; Loza, M Isabel; Pallàs, Mercè; Verhelst, Steven H L; Sanfeliu, Coral; Feixas, Ferran; Hammock, Bruce D; Brea, José; Cobos, Enrique J; Vázquez, SantiagoThe soluble epoxide hydrolase (sEH) has been suggested as a pharmacological target for the treatment of several diseases, including pain-related disorders. Herein, we report further medicinal chemistry around new benzohomoadamantane-based sEH inhibitors (sEHI) in order to improve the drug metabolism and pharmacokinetics properties of a previous hit. After an extensive in vitro screening cascade, molecular modeling, and in vivo pharmacokinetics studies, two candidates were evaluated in vivo in a murine model of capsaicin-induced allodynia. The two compounds showed an anti-allodynic effect in a dose-dependent manner. Moreover, the most potent compound presented robust analgesic efficacy in the cyclophosphamide-induced murine model of cystitis, a well-established model of visceral pain. Overall, these results suggest painful bladder syndrome as a new possible indication for sEHI, opening a new range of applications for them in the visceral pain field. PublicationDietary diversity and depression: cross-sectional and longitudinal analyses in Spanish adult population with metabolic syndrome. Findings from PREDIMED-Plus trial.(2022-07-19) Cano-Ibáñez, Naomi; Serra-Majem, Lluis; Martín-Peláez, Sandra; Martínez-González, Miguel Ángel; Salas-Salvadó, Jordi; Corella, Dolores; Lassale, Camille; Martínez, Jose Alfredo; Alonso-Gómez, Ángel M; Wärnberg, Julia; Vioque, Jesús; Romaguera, Dora; López-Miranda, José; Estruch, Ramon; Gómez-Pérez, Ana María; Lapetra, José; Fernández-Aranda, Fernando; Bueno-Cavanillas, Aurora; Tur, Josep A; Cubelos, Naiara; Pintó, Xavier; Gaforio, José Juan; Matía-Martín, Pilar; Vidal, Josep; Calderón, Cristina; Daimiel, Lidia; Ros, Emilio; Gea, Alfredo; Babio, Nancy; Gimenez-Alba, Ignacio Manuel; Zomeño-Fajardo, María Dolores; Abete, Itziar; Tojal Sierra, Lucas; Romero-Galisteo, Rita P; García de la Hera, Manoli; Martín-Padillo, Marian; García-Ríos, Antonio; Casas, Rosa M; Fernández-García, J C; Santos-Lozano, José Manuel; Toledo, Estefanía; Becerra-Tomas, Nerea; Sorli, Jose V; Schröder, Helmut; Zulet, María A; Sorto-Sánchez, Carolina; Diez-Espino, Javier; Gómez-Martínez, Carlos; Fitó, Montse; Sánchez-Villegas, AlmudenaTo examine the cross-sectional and longitudinal (2-year follow-up) associations between dietary diversity (DD) and depressive symptoms. An energy-adjusted dietary diversity score (DDS) was assessed using a validated FFQ and was categorised into quartiles (Q). The variety in each food group was classified into four categories of diversity (C). Depressive symptoms were assessed with Beck Depression Inventory-II (Beck II) questionnaire and depression cases defined as physician-diagnosed or Beck II >= 18. Linear and logistic regression models were used. Spanish older adults with metabolic syndrome (MetS). A total of 6625 adults aged 55-75 years from the PREDIMED-Plus study with overweight or obesity and MetS. Total DDS was inversely and statistically significantly associated with depression in the cross-sectional analysis conducted; OR Q4 v. Q1 = 0·76 (95 % CI (0·64, 0·90)). This was driven by high diversity compared to low diversity (C3 v. C1) of vegetables (OR = 0·75, 95 % CI (0·57, 0·93)), cereals (OR = 0·72 (95 % CI (0·56, 0·94)) and proteins (OR = 0·27, 95 % CI (0·11, 0·62)). In the longitudinal analysis, there was no significant association between the baseline DDS and changes in depressive symptoms after 2 years of follow-up, except for DD in vegetables C4 v. C1 = (β = 0·70, 95 % CI (0·05, 1·35)). According to our results, DD is inversely associated with depressive symptoms, but eating more diverse does not seem to reduce the risk of future depression. Additional longitudinal studies (with longer follow-up) are needed to confirm these findings. PublicationIndoor Built Environment and Older Adults' Activity: A Systematic Review(Cambridge univ press, 2022-07-18) Azim, Farah T.; Ariza-Vega, Patrocinio; Gardiner, Paul A.; Ashe, Maureen C.; [Azim, Farah T.] Univ British Columbia, Dept Family Practice, Vancouver, BC, Canada; [Ashe, Maureen C.] Univ British Columbia, Dept Family Practice, Vancouver, BC, Canada; [Ariza-Vega, Patrocinio] Univ Granada, Ibs Granada, Fac Hlth Sci, Granada, Spain; [Gardiner, Paul A.] Univ Southern Queensland, Sch Hlth & Med Sci, Ipswich, Qld, Australia; Canada Research Chairs Program for career support of Professor AsheAlthough the physical environment can influence people's activity, there are few knowledge syntheses for indoor environments and older adults' daily life routines. Therefore, we conducted a systematic review of peer-reviewed evidence to inform future research and practice. Inclusion criteria were studies with any research designs, across all years and languages focused on older adults 60 years of age or more, on physical activity/sedentary behaviour and the indoor environment. After searching five databases, two authors completed title/abstract and full-text screening. The last search was on December 19, 2020. We screened 1,367 citations, and included 23 studies situated in private or collective dwellings (e.g., assisted living). We identified physical activity-supportive indoor features across three domains: campus (e.g., amenities, pathways), building (e.g., area, floor level), and fixtures (e.g., elevators, hallways). Knowledge of indoor environmental factors for older adults' engagement in daily activities can guide future research and policy on housing design. PublicationArthrospira (Spirulina) platensis feeding reduces the early stage of chemically induced rat colon carcinogenesis.(2022-05-04) Amadeu, Simone Oliveira; Sarmiento-Machado, Luis Manuel; Bartolomeu, Ariane Rocha; Chaves, María Angel García; Romualdo, Guilherme Ribeiro; de Moura, Nelci Antunes; Barbisan, Luis FernandoColorectal cancer is the third most diagnosed cancer worldwide and linked to dietary/lifestyle factors. Arthrospira (Spirulina) platensis (AP) contains bioactive compounds with beneficial effects in vivo/in vitro. We evaluated the effects of AP feeding against 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis. Male Sprague Dawley rats were given subcutaneous injections of DMH (4 × 40 mg/kg body weight) (G1-G3) or vehicle (G4-G5) twice a week (weeks 3-4). During weeks 1-4, animals were fed a diet containing 1 % (G2) or 2 % (G3-G4) AP powder (w/w). After this period, all groups received a balanced diet until week 12. Some animals were euthanised after the last DMH injection (week 4) for histological, immunohistochemical (Ki-67, γ-H2AX and caspase-3) and molecular analyses (real time-PCR for 91 genes), while other animals were euthanised at week 12 for preneoplastic aberrant crypt foci (ACF) analysis. Both AP treatments (G2-G3) significantly decreased the DMH-induced increase in γ-H2AX (DNA damage) and caspase 3 (DNA damage-induced cell death) in colonic crypts at week 4. In addition, Cyp2e1 (Drug metabolism), Notch1, Notch2 and Jag1 genes (Notch pathway) and Atm, Wee1, Chek2, Mgmt, Ogg1 and Xrcc6 genes (DNA repair) were also down-regulated by 2 % AP feeding (G3) at week 4. A significant reduction in ACF development was observed in both AP-treated groups (G2-G3) at week 12. In conclusion, findings indicate that AP feeding reduced acute colonic damage after DMH, resulting in fewer preneoplastic lesions. Our study provided mechanistic insights on dietary AP-preventive effects against early colon carcinogenesis. PublicationMilk intake and incident stroke and CHD in populations of European descent: a Mendelian randomisation study.(2021-10-21) Vissers, L E T; Sluijs, I; Burgess, S; Forouhi, N G; Freisling, H; Imamura, F; Nilsson, T K; Renström, F; Weiderpass, E; Aleksandrova, K; Dahm, C C; Perez-Cornago, A; Schulze, M B; Tong, T Y N; Aune, D; Bonet, C; Boer, J M A; Boeing, H; Chirlaque, M D; Conchi, M I; Imaz, L; Jäger, S; Krogh, V; Kyrø, C; Masala, G; Melander, O; Overvad, K; Panico, S; Sánches, M J; Sonestedt, E; Tjønneland, A; Tzoulaki, I; Verschuren, W M M; Riboli, E; Wareham, N J; Danesh, J; Butterworth, A S; van der Schouw, Y THigher milk intake has been associated with a lower stroke risk, but not with risk of CHD. Residual confounding or reverse causation cannot be excluded. Therefore, we estimated the causal association of milk consumption with stroke and CHD risk through instrumental variable (IV) and gene-outcome analyses. IV analysis included 29 328 participants (4611 stroke; 9828 CHD) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD (eight European countries) and European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) case-cohort studies. rs4988235, a lactase persistence (LP) SNP which enables digestion of lactose in adulthood was used as genetic instrument. Intake of milk was first regressed on rs4988235 in a linear regression model. Next, associations of genetically predicted milk consumption with stroke and CHD were estimated using Prentice-weighted Cox regression. Gene-outcome analysis included 777 024 participants (50 804 cases) from MEGASTROKE (including EPIC-CVD), UK Biobank and EPIC-NL for stroke, and 483 966 participants (61 612 cases) from CARDIoGRAM, UK Biobank, EPIC-CVD and EPIC-NL for CHD. In IV analyses, each additional LP allele was associated with a higher intake of milk in EPIC-CVD (β = 13·7 g/d; 95 % CI 8·4, 19·1) and EPIC-NL (36·8 g/d; 95 % CI 20·0, 53·5). Genetically predicted milk intake was not associated with stroke (HR per 25 g/d 1·05; 95 % CI 0·94, 1·16) or CHD (1·02; 95 % CI 0·96, 1·08). In gene-outcome analyses, there was no association of rs4988235 with risk of stroke (OR 1·02; 95 % CI 0·99, 1·05) or CHD (OR 0·99; 95 % CI 0·95, 1·03). Current Mendelian randomisation analysis does not provide evidence for a causal inverse relationship between milk consumption and stroke or CHD risk. PublicationIntroduction to computational causal inference using reproducible Stata, R, and Python code: A tutorial.(2021-10-28) Smith, Matthew J; Mansournia, Mohammad A; Maringe, Camille; Zivich, Paul N; Cole, Stephen R; Leyrat, Clémence; Belot, Aurélien; Rachet, Bernard; Luque-Fernandez, Miguel AThe main purpose of many medical studies is to estimate the effects of a treatment or exposure on an outcome. However, it is not always possible to randomize the study participants to a particular treatment, therefore observational study designs may be used. There are major challenges with observational studies; one of which is confounding. Controlling for confounding is commonly performed by direct adjustment of measured confounders; although, sometimes this approach is suboptimal due to modeling assumptions and misspecification. Recent advances in the field of causal inference have dealt with confounding by building on classical standardization methods. However, these recent advances have progressed quickly with a relative paucity of computational-oriented applied tutorials contributing to some confusion in the use of these methods among applied researchers. In this tutorial, we show the computational implementation of different causal inference estimators from a historical perspective where new estimators were developed to overcome the limitations of the previous estimators (ie, nonparametric and parametric g-formula, inverse probability weighting, double-robust, and data-adaptive estimators). We illustrate the implementation of different methods using an empirical example from the Connors study based on intensive care medicine, and most importantly, we provide reproducible and commented code in Stata, R, and Python for researchers to adapt in their own observational study. The code can be accessed at https://github.com/migariane/Tutorial_Computational_Causal_Inference_Estimators. PublicationLysozyme crystallization in hydrogel media under ultrasound irradiation.(2022-07-18) Savchenko, Mariia; Hurtado, Manuel; Lopez-Lopez, Modesto T; Rus, Guillermo; Álvarez de Cienfuegos, Luis; Melchor, Juan; Gavira, José ASonocrystallization implies the application of ultrasound radiation to control the nucleation and crystal growth depending on the actuation time and intensity. Its application allows to induce nucleation at lower supersaturations than required under standard conditions. Although extended in inorganic and organic crystallization, it has been scarcely explored in protein crystallization. Now, that industrial protein crystallization is gaining momentum, the interest on new ways to control protein nucleation and crystal growth is advancing. In this work we present the development of a novel ultrasound bioreactor to study its influence on protein crystallization in agarose gel. Gel media minimize convention currents and sedimentation, favoring a more homogeneous and stable conditions to study the effect of an externally generated low energy ultrasonic irradiation on protein crystallization avoiding other undesired effects such as temperature increase, introduction of surfaces which induce nucleation, destructive cavitation phenomena, etc. In-depth statistical analysis of the results has shown that the impact of ultrasound in gel media on crystal size populations are statistically significant and reproducible. PublicationCommon model of stress, anxiety, and depressive symptoms in pregnant women from seven high-income Western countries at the COVID-19 pandemic onset.(2022-11-01) Lobel, Marci; Preis, Heidi; Mahaffey, Brittain; Schaal, Nora K; Yirmiya, Karen; Atzil, Shir; Reuveni, Inbal; Balestrieri, Matteo; Penengo, Chiara; Colli, Chiara; Garzitto, Marco; Driul, Lorenza; Ilska, Michalina; Brandt-Salmeri, Anna; Kołodziej-Zaleska, Anna; Caparros-Gonzalez, Rafael A; Castro, Rita Amiel; La Marca-Ghaemmaghami, Pearl; Meyerhoff, HannahIncreases in stress, anxiety, and depression among women pregnant during the COVID-19 pandemic have been reported internationally. Yet rigorous comparison of the prevalence of maternal mental health problems across countries is lacking. Moreover, whether stress is a common predictor of maternal mental health during the pandemic across countries is unknown. 8148 pregnant women from Germany, Israel, Italy, Poland, Spain, Switzerland, and the United States were enrolled in the International COVID-19 Pregnancy Experiences (I-COPE) Study between April 17 and May 31, 2020. Sociodemographic characteristics, pandemic-related stress, pregnancy-specific stress, anxiety, and depression were assessed with well-validated instruments. The magnitude of stress and mood disturbances was compared across countries. A path model predicting clinically significant levels of anxiety and depression from maternal characteristics and stress was tested for all study participants and then examined separately in each country with >200 participants. Countries differed significantly in magnitude of pandemic-related pregnancy stress and pandemic-unrelated pregnancy-specific stress, and in prevalence of clinically significant anxiety and depression levels. A well-fitting common path model for the entire sample indicated that mood and anxiety disturbances were strongly predicted by pandemic-related and pregnancy-specific stress after accounting for maternal characteristics. The model was replicated in individual countries. Although pregnant women in high-income Western countries experienced different levels of stress resulting from the COVID-19 pandemic, stress is a strong, common predictor of anxiety and depressive symptoms in these individuals. The common model can be used to inform research and clinical interventions to protect against adverse consequences of prenatal maternal stress, anxiety, and depression for mothers and infants. PublicationMaternal urinary concentrations of bisphenol A during pregnancy are associated with global DNA methylation in cord blood of newborns in the "NELA" birth cohort.(2022-06-07) Navarro-Lafuente, Fuensanta; Adoamnei, Evdochia; Arense-Gonzalo, Julián J; Prieto-Sánchez, María T; Sánchez-Ferrer, María L; Parrado, Antonio; Fernández, Mariana F; Suarez, Beatriz; López-Acosta, Antonia; Sánchez-Guillamón, Antonio; García-Marcos, Luis; Morales, Eva; Mendiola, Jaime; Torres-Cantero, Alberto M; NELA Study groupEndocrine disrupting chemicals (EDCs) set a public health risk through disruption of normal physiological processes. The toxicoepigenetic mechanisms of developmental exposure to common EDCs, such as bisphenol A (BPA), are poorly known. The present study aimed to evaluate associations between perinatal maternal urinary concentrations of BPA, bisphenol S (BPS) and bisphenol F (BPF) and LINE-1 (long interspersed nuclear elements) and Alu (short interspersed nuclear elements, SINEs) DNA methylation levels in newborns, as surrogate markers of global DNA methylation. Data come from 318 mother-child pairs of the `Nutrition in Early Life and Asthma´ (NELA) birth cohort. Urinary bisphenol concentration was measured by dispersive liquid-liquid microextraction and ultrahigh performance liquid chromatography with tandem mass spectrometry detection. DNA methylation was quantitatively assessed by bisulphite pyrosequencing on 3 LINEs and 5 SINEs. Unadjusted linear regression analyses showed that higher concentration of maternal urinary BPA in 24th week's pregnancy was associated with an increase in LINE-1 methylation in all newborns (p = 0.01) and, particularly, in male newborns (p = 0.03). These associations remained in full adjusted models [beta = 0.09 (95 % CI = 0.03; 0.14) for all newborns; and beta = 0.10 (95 % CI = 0.03; 0.17) for males], including a non-linear association for female newborns as well (p-trend = 0.003). No associations were found between maternal concentrations of bisphenol and Alu sequences. Our results suggest that exposure to environmental levels of BPA may be associated with a modest increase in LINE-1 methylation -as a relevant marker of epigenomic stability- during human fetal development. However, any effects on global DNA methylation are likely to be small, and of uncertain biological significance. PublicationBDNF as a potential mediator between childhood BPA exposure and behavioral function in adolescent boys from the INMA-Granada cohort.(2021-09-01) Mustieles, Vicente; Rodríguez-Carrillo, Andrea; Vela-Soria, Fernando; D'Cruz, Shereen Cynthia; David, Arthur; Smagulova, Fatima; Mundo-López, Antonio; Olivas-Martínez, Alicia; Reina-Pérez, Iris; Olea, Nicolás; Freire, Carmen; Arrebola, Juan P; Fernández, Mariana FBisphenol A (BPA) exposure has been linked to altered behavior in children. Within the European Human Biomonitoring Initiative (HBM4EU), an adverse outcome pathway (AOP) network was constructed supporting the mechanistic link between BPA exposure and brain-derived neurotrophic factor (BDNF). To test this toxicologically-based hypothesis in the prospective INMA-Granada birth cohort (Spain). BPA concentrations were quantified by LC-MS/MS in spot urine samples from boys aged 9-11 years, normalized by creatinine and log-2 transformed. At adolescence (15-17 years), blood and urine specimens were collected, and serum and urinary BDNF protein levels were measured using immunoassays. DNA methylation levels at 6 CpGs in Exon IV of the BDNF gene were also assessed in peripheral blood using bisulfite-pyrosequencing. Adolescent's behavior was parent-rated using the Child Behavior Checklist (CBCL/6-18) in 148 boys. Adjusted linear regression and mediation models were fit. Childhood urinary BPA concentrations were longitudinally and positively associated with thought problems (β = 0.76; 95% CI: 0.02, 1.49) and somatic complaints (β = 0.80; 95% CI: -0.16, 1.75) at adolescence. BPA concentrations were positively associated with BDNF DNA methylation at CpG6 (β = 0.21; 95% CI: 0.06, 0.36) and mean CpG methylation (β = 0.10; 95% CI: 0.01, 0.18), but not with total serum or urinary BDNF protein levels. When independent variables were categorized in tertiles, positive dose-response associations were observed between BPA-thought problems (p-trend = 0.08), BPA-CpG6 (p-trend ≤ 0.01), and CpG6-thought problems (p-trend ≤ 0.01). A significant mediated effect by CpG6 DNA methylation was observed (β = 0.23; 95% CI: 0.01, 0.57), accounting for up to 34% of the BPA-thought problems association. In line with toxicological studies, BPA exposure was longitudinally associated with increased BDNF DNA methylation, supporting the biological plausibility of BPA-behavior relationships previously described in the epidemiological literature. Given its novelty and preliminary nature, this effect biomarker approach should be replicated in larger birth cohorts. PublicationThe Q-junction and the inflammatory response are critical pathological and therapeutic factors in CoQ deficiency.(2022-07-15) González-García, Pilar; Díaz-Casado, María Elena; Hidalgo-Gutiérrez, Agustín; Jiménez-Sánchez, Laura; Bakkali, Mohammed; Barriocanal-Casado, Eliana; Escames, Germaine; Chiozzi, Riccardo Zenezini; Völlmy, Franziska; Zaal, Esther A; Berkers, Celia R; Heck, Albert J R; López, Luis CDefects in Coenzyme Q (CoQ) metabolism have been associated with primary mitochondrial disorders, neurodegenerative diseases and metabolic conditions. The consequences of CoQ deficiency have not been fully addressed, and effective treatment remains challenging. Here, we use mice with primary CoQ deficiency (Coq9R239X), and we demonstrate that CoQ deficiency profoundly alters the Q-junction, leading to extensive changes in the mitochondrial proteome and metabolism in the kidneys and, to a lesser extent, in the brain. CoQ deficiency also induces reactive gliosis, which mediates a neuroinflammatory response, both of which lead to an encephalopathic phenotype. Importantly, treatment with either vanillic acid (VA) or β-resorcylic acid (β-RA), two analogs of the natural precursor for CoQ biosynthesis, partially restores CoQ metabolism, particularly in the kidneys, and induces profound normalization of the mitochondrial proteome and metabolism, ultimately leading to reductions in gliosis, neuroinflammation and spongiosis and, consequently, reversing the phenotype. Together, these results provide key mechanistic insights into defects in CoQ metabolism and identify potential disease biomarkers. Furthermore, our findings clearly indicate that the use of analogs of the CoQ biosynthetic precursor is a promising alternative therapy for primary CoQ deficiency and has potential for use in the treatment of more common neurodegenerative and metabolic diseases that are associated with secondary CoQ deficiency. PublicationDuration of the patient interval in breast cancer and factors associated with longer delays in low-and middle-income countries: A systematic review with meta-analysis.(2022-11-15) Petrova, Dafina; Garrido, Dunia; Špacírová, Zuzana; Fernández-Martínez, Nicolás Francisco; Ivanova, Ganka; Rodríguez-Barranco, Miguel; Pollán, Marina; Barrios-Rodríguez, Rocío; Sánchez, Maria JoséBreast cancer survival is lower in low- and middle-income countries (LMICs) partially due to many women being diagnosed with late-stage disease. The patient interval refers to the time elapsed between the detection of symptoms and the first consultation with a healthcare provider and is considered one of the core indicators for early diagnosis and treatment. The goal of the current research was to conduct a meta-analysis of the duration of the patient interval in LMICs and investigate the socio-demographic and socio-cultural factors related to longer delays in presentation. We conducted a systematic review with meta-analysis (pre-registered protocol CRD42020200752). We searched seven information sources (2009-2022) and included 50 articles reporting the duration of patient intervals for 18,014 breast cancer patients residing in LMICs. The longest patient intervals were reported in studies from the Middle East (3-4 months), followed by South-East Asia (2 months), Africa (1-2 months), Latin America (1 month), and Eastern Europe (1 month). Older age, not being married, lower socio-economic status, illiteracy, low knowledge about cancer, disregarding symptoms or not attributing them to cancer, fear, negative beliefs about cancer, and low social support were related to longer delays across most regions. Longer delays were also related to use of alternative medicine in the Middle East, South-East Asia, and Africa and distrust in the healthcare system in Eastern Europe. There is large variation in the duration of patient intervals across LMICs in different geographical regions. Patient intervals should be reduced and, for this purpose, it is important to explore their determinants taking into account the social, cultural, and economic context. PublicationModulation of intestinal barrier function by glucocorticoids: Lessons from preclinical models.(2022-01-04) Tena-Garitaonaindia, Mireia; Arredondo-Amador, María; Mascaraque, Cristina; Asensio, Maitane; Marin, Jose J G; Martínez-Augustin, Olga; Sánchez de Medina, FermínGlucocorticoids (GCs) are widely used drugs for their anti-inflammatory and immunosuppressant effects, but they are associated with multiple adverse effects. Despite their frequent oral administration, relatively little attention has been paid to the effects of GCs on intestinal barrier function. In this review, we present a summary of the published studies on this matter carried out in animal models and cultured cells. In cultured intestinal epithelial cells, GCs have variable effects in basal conditions and generally enhance barrier function in the presence of inflammatory cytokines such as tumor necrosis factor (TNF). In turn, in rodents and other animals, GCs have been shown to weaken barrier function, with increased permeability and lower production of IgA, which may account for some features observed in stress models. When given to animals with experimental colitis, barrier function may be debilitated or strengthened, despite a positive anti-inflammatory activity. In sepsis models, GCs have a barrier-enhancing effect. These effects are probably related to the inhibition of epithelial cell proliferation and wound healing, modulation of the microbiota and mucus production, and interference with the mucosal immune system. The available information on underlying mechanisms is described and discussed. PublicationInfluence of Gestational Diabetes and Pregestational Maternal BMI on the Brain of Six-Year-Old Offspring.(2022-05-23) Manuello, Jordi; Verdejo-Román, Juan; Torres Espínola, Francisco; Escudero-Marín, Mireia; Catena, Andrés; Cauda, Franco; Campoy, CristinaGestational diabetes (GD) and maternal excess weight are common pregnancy conditions that increase the risk of future complications for both the mother and her offspring. Their consequences on neurodevelopment are widely described in the literature, but less is known concerning the potential transgenerational influence on the brain structure. We used a combination of support vectors machine and hierarchical clustering to investigate the potential presence of anatomical brain differences in a sample of 109 children aged six years, born to mothers with overweight or obesity, or to mothers diagnosed with GD during pregnancy. Significant effects are visible in the brain of children born to mothers with GD associated with pregestational excess weight, especially overweight instead of obesity. No differences in children's brain were observed when considering those born to normal-weight mothers. Our study highlights the need for clinical attention of pregnant women at risk to develop GD, and especially those with pregestational excess weight, since this status was found to be associated with detectable transgenerational brain changes. These effects may be due to the absence of specific and individualized intervention in these mothers during pregnancy. PublicationPhysiological lentiviral vectors for the generation of improved CAR-T cells.(2022-05-18) Tristán-Manzano, María; Maldonado-Pérez, Noelia; Justicia-Lirio, Pedro; Muñoz, Pilar; Cortijo-Gutiérrez, Marina; Pavlovic, Kristina; Jiménez-Moreno, Rosario; Nogueras, Sonia; Carmona, M Dolores; Sánchez-Hernández, Sabina; Aguilar-González, Araceli; Castella, María; Juan, Manel; Marañón, Concepción; Marchal, Juan Antonio; Benabdellah, Karim; Herrera, Concha; Martin, FranciscoAnti-CD19 chimeric antigen receptor (CAR)-T cells have achieved impressive outcomes for the treatment of relapsed and refractory B-lineage neoplasms. However, important limitations still remain due to severe adverse events (i.e., cytokine release syndrome and neuroinflammation) and relapse of 40%-50% of the treated patients. Most CAR-T cells are generated using retroviral vectors with strong promoters that lead to high CAR expression levels, tonic signaling, premature exhaustion, and overstimulation, reducing efficacy and increasing side effects. Here, we show that lentiviral vectors (LVs) expressing the transgene through a WAS gene promoter (AW-LVs) closely mimic the T cell receptor (TCR)/CD3 expression kinetic upon stimulation. These AW-LVs can generate improved CAR-T cells as a consequence of their moderate and TCR-like expression profile. Compared with CAR-T cells generated with human elongation factor α (EF1α)-driven-LVs, AW-CAR-T cells exhibited lower tonic signaling, higher proportion of naive and stem cell memory T cells, less exhausted phenotype, and milder secretion of tumor necrosis factor alpha (TNF-α) and interferon (IFN)-ɣ after efficient destruction of CD19+ lymphoma cells, both in vitro and in vivo. Moreover, we also showed their improved efficiency using an in vitro CD19+ pancreatic tumor model. We finally demonstrated the feasibility of large-scale manufacturing of AW-CAR-T cells in guanosine monophosphate (GMP)-like conditions. Based on these data, we propose the use of AW-LVs for the generation of improved CAR-T products. PublicationA hypothesis-driven method based on machine learning for neuroimaging data analysis(Elsevier, 2022-09-13) Gorriz, J. M.; Martin-Clemente, R.; Puntonet, C. G.; Ortiz, A.; Ramirez, J.; Suckling, J.; SiPBA Grp; [Gorriz, J. M.] Univ Granada, DaSCI Inst, Granada, Spain; [Ramirez, J.] Univ Granada, DaSCI Inst, Granada, Spain; [SiPBA Grp] Univ Granada, DaSCI Inst, Granada, Spain; [Gorriz, J. M.] Univ Cambridge, Dept Psychiat, Cambridge, England; [Suckling, J.] Univ Cambridge, Dept Psychiat, Cambridge, England; [Gorriz, J. M.] IbsGranada, Granada, Spain; [Puntonet, C. G.] Univ Granada, Dept Comp Architecture & Technol, Granada, Spain; [Martin-Clemente, R.] Univ Seville, Dept Signal Theory & Commun, Seville, Spain; [Ortiz, A.] Univ Malaga, Dept Commun Engn, Malaga, Spain; MCIN/AEI; FEDER ``Una manera de hacer Europa"; Consejeria de Economia, Innovacion, Ciencia y Empleo (Junta de Andalucia); FEDER; research project ACACIA; FEDER; Junta de Andalucia (Consejeria de Economia, Conocimiento, Empresas y Universidad)There remains an open question about the usefulness and the interpretation of machine learning (ML) approaches for discrimination of spatial patterns of brain images between samples or activation states. In the last few decades, these approaches have limited their operation to feature extraction and linear classification tasks for between-group inference. In this context, statistical inference is assessed by ran-domly permuting image labels or by the use of random effect models that consider between-subject vari-ability. These multivariate ML-based statistical pipelines, whilst potentially more effective for detecting activations than hypotheses-driven methods, have lost their mathematical elegance, ease of interpreta-tion, and spatial localization of the ubiquitous General linear Model (GLM). Recently, the estimation of the conventional GLM parameters has been demonstrated to be connected to an univariate classification task when the design matrix in the GLM is expressed as a binary indicator matrix. In this paper we explore the complete connection between the univariate GLM and ML-based regressions. To this purpose we derive a refined statistical test with the GLM based on the parameters obtained by a linear Support Vector Regression (SVR) in the inverse problem (SVR-iGLM). Subsequently, random field theory (RFT) is employed for assessing statistical significance following a conventional GLM benchmark. Experimental results demonstrate how parameter estimations derived from each model (mainly GLM and SVR) result in different experimental design estimates that are significantly related to the predefined functional task. Moreover, using real data from a multisite initiative the proposed ML-based inference demonstrates sta-tistical power and the control of false positives, outperforming the regular GLM. (c) 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). PublicationStory of two sisters with kidney disease: genetics command.(2020-12-19) Barral-Juez, Mikel; García-Rabaneda, Carmen; Poyatos-Andújar, Antonio Miguel; Martínez-Atienza, Margarita; Morales-García, Ana Isabel; Morales-Santana, Sonia; Bellido-Díaz, María Luz; Bravo-Soto, Juan Antonio; Esteban-de la Rosa, Rafael José PublicationAn m-Health telerehabilitation and health education program on physical performance in patients with hip fracture and their family caregivers: Study protocol for the ActiveHip+ randomized controlled trial.(2022-02-11) Mora-Traverso, Marta; Molina-Garcia, Pablo; Prieto-Moreno, Rafael; Borges-Cosic, Milkana; Cruz Guisado, Victor; Del Pino Algarrada, Rogelio; Moreno-Ramírez, Paz; Gomez-Jurado, Gema; Gomez Tarrias, Consuelo; Hidalgo Isla, Margarita; Jimenez Andrés, Patricia; Linares Gago, Marta; Lirola-Liebanas, Ana; Mesa-Ruiz, Antonio; Muñoz-Garach, Araceli; Salazar-Graván, Susana; Estevez-Lopez, Fernando; Martín-Matillas, Miguel; Ariza-Vega, PatrocinioTelerehabilitation interventions administered via a smartphone may provide new feasible and effective rehabilitation options at home for patients with hip fracture. However, to date, no such interventions have been shown to be effective in the recovery key health outcomes of these patients. The present multicentre randomized controlled trial (RCT) aims to test the effect of the ActiveHip+ m-Health system in the recovery of physical performance, functional level, quality of life, and other health-related outcomes in both patients with hip fracture and their family caregivers. A total of 104 patients older than 65 years, with hip fracture, and their family caregivers will be randomized into the ActiveHip+ rehabilitation (N = 52) or the control group (N = 52). ActiveHip+ is a 12-week smartphone-based rehabilitation program conducted in Granada and Cádiz (Spain) that includes: (1) 24 sessions of physical exercise and 12 sessions of occupational therapy; (2) seven educational modules for patients and for caregivers; and (3) general recommendations in activities of daily living. The control group will receive the usual rehabilitation protocol offered by the Andalusian Public Healthcare System. The primary outcome is the patient's physical performance, while the secondary outcomes are the patient's functional level, quality of life, pain, fear of falling, fitness perception, pre-fracture functional level, emotional status, and caregiver burden. The present project will substantially contribute to the existing knowledge by testing for the first time the efficacy and feasibility of a multidisciplinary m-Health system in the rehabilitation of patients with hip fracture. PublicationCombined use of UV and MS data for ICH Stability-Indication Method: Quantification and isoforms identification of intact nivolumab(Elsevier, 2022-08-31) Torrente-Lopez, Anabel; Hermosilla, Jesus; Perez-Robles, Raquel; Salmeron-Garcia, Antonio; Cabeza, Jose; Navas, Natalia; [Torrente-Lopez, Anabel] Univ Granada, Biomed Res Inst Ibs Granada, Sci Fac, Dept Analyt Chem, E-18071 Granada, Spain; [Hermosilla, Jesus] Univ Granada, Biomed Res Inst Ibs Granada, Sci Fac, Dept Analyt Chem, E-18071 Granada, Spain; [Perez-Robles, Raquel] Univ Granada, Biomed Res Inst Ibs Granada, Sci Fac, Dept Analyt Chem, E-18071 Granada, Spain; [Navas, Natalia] Univ Granada, Biomed Res Inst Ibs Granada, Sci Fac, Dept Analyt Chem, E-18071 Granada, Spain; [Perez-Robles, Raquel] Junta Andalucia, Fdn Invest Biosanitaria Andalucia Oriental Alejan, Granada, Spain; [Salmeron-Garcia, Antonio] San Cecilio Univ Hosp Granada, Biomed Res Inst Ibs Granada, UGC Hosp Pharm, E-18012 Granada, Spain; [Cabeza, Jose] San Cecilio Univ Hosp Granada, Biomed Res Inst Ibs Granada, UGC Hosp Pharm, E-18012 Granada, Spain; Ministry of Universities, Spain; Junta de Andalucia (Spain); European Regional Develop-ment Funds; Junta de Andalucia, Spain; I + D + i-Junta de Andalucia, Spain; Universidad de Granada, Proyectos I +D +i del Programa Operativo FEDER Andalucia 2020; European Regional Development Funds; CBUA/Universidad de GranadaNivolumab (Opdivo (R)) is a fully human immunoglobulin G4 isotype approved for the treatment of many cancers. It acts as an immune checkpoint inhibitor by blocking the interaction between PD-1 (Programmed Cell Death Protein 1) - an inhibitory receptor expressed on activated T cells- and its ligands, PD-L1 and PD-L2. The quantification of therapeutic proteins in their medicines and pharmaceutical preparations remains challenging because the protein content, a critical quality attribute, must be rigorously calculated using a validated stabilityindicating method, such as that indicated by the International Conference on Harmonization (ICH) quality guidelines, and this requires the analysis of the drug in the presence of its degraded products. In this work, we present an strategy based on the combined use of the UV and MS data to full file the requirement of the ICH-Q2 (R1) to develop and validated as stability indicated a (RP)UHPLC/UV-(HESI/OrbitrapTM)MS method for the quantification of nivolumab in medicinal products. A comparative study of all figures of merit of the method using UV or MS data are shown and discussed. The results show that linearity was similar for the two detectors and was established over a range of 4-45 mu g/mL and 1-45 mu g/mL for the UV and (HESI/OrbitrapTM)MS signals, respectively. The sensitivity of the method was higher when using the (HESI/OrbitrapTM)MS signal (0.2 mu g/mL) than with the UV(2.0 mu g/mL). However, the UV signal provided better accuracy and precision than the (HESI/ OrbitrapTM)MS signal, which did not meet the criteria for method robustness and system suitability. In spite of this, the MS signal plays a crucial role in this methodology by obtaining the molecular weight profile of the nivolumab isoforms, so enabling us to propose the glycans profile and detect structural modification due to degradation. The specificity of the method was evaluated by conducting forced degradation tests on samples of nivolumab in medicine form. The aim was to find out whether nivolumab suffers structural modifications when subject to stress. Structural modifications were detected by analysing the MS isoform profile, as changes of this kind promote new isoforms that are not chromatographically separated or detected by the UV signal. In this way, we demonstrated that the (RP)UHPLC/UV-(HESI/OrbitrapTM)MS method was capable of detecting nivolumab degradation, and was suitable for use in nivolumab stability studies. Thus, the protein content in the daily surplus of the Opdivo (R) medicine, stored either at room temperature (20 degrees C) or refrigerated at 4 degrees C, could be tracked for 15 days.