Interacción del tratamiento y el control de la presión en el deterioro de la memoria incidental visuoespacial en pacientes con hipertensión arterial sistémica / Pressure control and treatment interact in the deterioration of incidental visuospatial memory in hypertensive patients

Resumen Antecedentes: La hipertensión arterial sistémica (HAS) es el principal factor de riesgo para el deterioro cognitivo; por otro lado, la memoria visuoespacial es más vulnerable al envejecimiento. Algunos fármacos antihipertensivos tienen un efecto neuroprotector, pero tal efecto puede enmascararse o bien no manifestarse por comorbilidad o por falta de control efectivo de la presión arterial. Objetivo: Evaluar las alteraciones en la memoria visuoespacial incidental de pacientes con HAS en relación con su tratamiento antihipertensivo y su control de la presión. Método: Se incluyeron 80 pacientes con HAS (46 mujeres), agrupados por su medicación en bloqueadores de los receptores de la angiotensina II (BRA) o inhibidores de la enzima convertidora de angiotensina (IECA). Se realizó un análisis de correlaciones múltiples para los puntajes obtenidos en la prueba de memoria visuoespacial incidental/intencional y un análisis de modelos mixtos (factores fijos: tratamiento, control de la presión y comorbilidad con diabetes; factores aleatorios: edad, escolaridad, meses desde el diagnóstico de HAS y coeficiente intelectual). Resultados: De los pacientes controlados, la mayoría de los que recibían BRA fueron eficientes y los que recibían IECA fueron deficientes. De los que recibían IECA, los descontrolados hipertensos fueron más eficientes que los normotensos. La memoria visuoespacial se correlacionó negativamente con la presión sistólica a pesar de no haber diferencias en MoCA y Raven. Conclusiones: La eficiencia en la memoria visuoespacial dependió de la interacción del tratamiento y el control de la presión. Ambos factores, tratamiento y control efectivo de la presión, deben considerarse en la evaluación del deterioro cognitivo asociado a la HAS.

Abstract Background: Systemic hypertension (SH) is the main risk factor to cognitive deterioration, whereas visuospatial memory is more vulnerable to ageing. Some antihypertensive agents have a neuroprotector effect, however, such effects could be masked by comorbidities and/or the lack of effective control on the arterial pressure of patients. Objective: To assess this, the evaluation of incidental visuospatial memory of SH patients and the relation to the treatment received and the effective control of pressure were made. Method: 80 patients (46 woman) were included grouped by the received medication: angiotensin 2 receptor blockers (ARB) or angiotensin converting enzyme inhibitors (ACEI). A multiple correlation analysis between visuospatial scores and clinical variables was made; also, a mixed model analysis (fixed factors: treatment, pressure control, diabetes comorbidity; aleatory factors: age, schooling, months from SH diagnoses). Results: Half of the patients had a controlled pressure, from them the higher proportion received ARB, and a minor number of patients received ACEI. The normotensive patients receiving ACEI were inefficient whereas the hypertensive patients were more efficient. The systolic pressure was negatively related with the visuospatial scores in spite of no correlations occurred with MoCA and Raven tests. Conclusions: The visuospatial incidental/intentional scores were negatively correlated with systolic pressure. The efficiency in the visuospatial ability depends on the interaction of treatment and effective control of blood pressure. The interaction between treatment and effective pressure control must be taken in count when cognitive deterioration is studied.

Virus-like particle-mediated delivery of structure-selected neoantigens demonstrates immunogenicity and antitumoral activity in mice.

BACKGROUND: Neoantigens are patient- and tumor-specific peptides that arise from somatic mutations. They stand as promising targets for personalized therapeutic cancer vaccines. The identification process for neoantigens has evolved with the use of next-generation sequencing technologies and bioinformatic tools in tumor genomics. However, in-silico strategies for selecting immunogenic neoantigens still have very low accuracy rates, since they mainly focus on predicting peptide binding to Major Histocompatibility Complex (MHC) molecules, which is key but not the sole determinant for immunogenicity. Moreover, the therapeutic potential of neoantigen-based vaccines may be enhanced using an optimal delivery platform that elicits robust de novo immune responses. METHODS: We developed a novel neoantigen selection pipeline based on existing software combined with a novel prediction method, the Neoantigen Optimization Algorithm (NOAH), which takes into account structural features of the peptide/MHC-I interaction, as well as the interaction between the peptide/MHC-I complex and the TCR, in its prediction strategy. Moreover, to maximize neoantigens' therapeutic potential, neoantigen-based vaccines should be manufactured in an optimal delivery platform that elicits robust de novo immune responses and bypasses central and peripheral tolerance. RESULTS: We generated a highly immunogenic vaccine platform based on engineered HIV-1 Gag-based Virus-Like Particles (VLPs) expressing a high copy number of each in silico selected neoantigen. We tested different neoantigen-loaded VLPs (neoVLPs) in a B16-F10 melanoma mouse model to evaluate their capability to generate new immunogenic specificities. NeoVLPs were used in in vivo immunogenicity and tumor challenge experiments. CONCLUSIONS: Our results indicate the relevance of incorporating other immunogenic determinants beyond the binding of neoantigens to MHC-I. Thus, neoVLPs loaded with neoantigens enhancing the interaction with the TCR can promote the generation of de novo antitumor-specific immune responses, resulting in a delay in tumor growth. Vaccination with the neoVLP platform is a robust alternative to current therapeutic vaccine approaches and a promising candidate for future personalized immunotherapy.

Expanding the coverage of regulons from high-confidence prior knowledge for accurate estimation of transcription factor activities.

Gene regulation plays a critical role in the cellular processes that underlie human health and disease. The regulatory relationship between transcription factors (TFs), key regulators of gene expression, and their target genes, the so called TF regulons, can be coupled with computational algorithms to estimate the activity of TFs. However, to interpret these findings accurately, regulons of high reliability and coverage are needed. In this study, we present and evaluate a collection of regulons created using the CollecTRI meta-resource containing signed TF-gene interactions for 1186 TFs. In this context, we introduce a workflow to integrate information from multiple resources and assign the sign of regulation to TF-gene interactions that could be applied to other comprehensive knowledge bases. We find that the signed CollecTRI-derived regulons outperform other public collections of regulatory interactions in accurately inferring changes in TF activities in perturbation experiments. Furthermore, we showcase the value of the regulons by examining TF activity profiles in three different cancer types and exploring TF activities at the level of single-cells. Overall, the CollecTRI-derived TF regulons enable the accurate and comprehensive estimation of TF activities and thereby help to interpret transcriptomics data.

Extended BODIPYs as Red-NIR Laser Radiation Sources with Emission from 610 nm to 750 nm.

Herein, we report the synthetic access to a set of π-extended BODIPYs featuring a penta-arylated (phenyl and/or thiophene) dipyrrin framework. We take advantage of the full chemoselective control of 8-methylthio-2,3,5,6-tetrabromoBODIPY when we conduct the Liebeskind-Srogl cross-coupling (LSCC) to functionalize exclusively the meso-position, followed by the tetra-Suzuki reaction to arylate the halogenated sites. All these laser dyes display absorption and emission bands in the red edge of the visible spectrum reaching the near-infrared with thiophene functionalization. The emission efficiency, both fluorescence and laser, of the polyphenylBODIPYs can be enhanced upon decoration of the peripheral phenyls with electron donor/acceptor groups at para positions. Alternatively, the polythiopheneBODIPYs show an astonishing laser performance despite the charge transfer character of the emitting state. Therefore, these BODIPYs are suitable as a palette of stable and bright laser sources covering the spectral region from 610 nm to 750 nm.

Multinational Prospective Cohort Study of Mortality Risk Factors in 198 ICUs of 12 Latin American Countries over 24 Years: The Effects of Healthcare-Associated Infections.

BACKGROUND: The International Nosocomial Infection Control Consortium (INICC) has found a high ICU mortality rate in Latin America. METHODS: A prospective cohort study in 198 ICUs of 96 hospitals in 46 cities in 12 Latin American countries to identify mortality risk factors (RF), and data were analyzed using multiple logistic regression. RESULTS: Between 07/01/1998 and 02/12/2022, 71,685 patients, followed during 652,167 patient-days, acquired 4700 HAIs, and 10,890 died. We prospectively collected data of 16 variables. Following 11 independent mortality RFs were identified in multiple logistic regression: ventilator-associated pneumonia (VAP) acquisition (adjusted odds ratio [aOR] = 1.17; 95% CI: 1.06-1.30; p < 0.0001); catheter-associated urinary tract infection (CAUTI) acquisition (aOR = 1.34; 95% CI: 1.15-1.56; p < 0.0001); older age, rising risk 2% yearly (aOR = 1.02; 95% CI: 1.01-1.02; p < 0.0001); longer indwelling central line(CL)-days, rising risk 3% daily (aOR = 1.03; 95% CI: 1.02-1.03; p < 0.0001); longer indwelling urinary catheter(UC)-days, rising risk 1% daily (aOR = 1.01; 95% CI: 1.01-1.26; p < 0.0001); higher mechanical ventilation (MV) (aOR = 6.47; 95% CI: 5.96-7.03; p < 0.0001) and urinary catheter-utilization ratio (aOR = 1.19; 95% CI: 1.11-1.27; p < 0.0001); lower-middle level income country (aOR = 2.94; 95% CI: 2.10-4.12; p < 0.0001); private (aOR = 1.50; 95% CI: 1.27-1.77; p < 0.0001) or public hospital (aOR = 1.47; 95% CI: 1.24-1.74; p < 0.0001) compared with university hospitals; medical hospitalization instead of surgical (aOR = 1.67; 95% CI: 1.59-1.75; p < 0.0001); neurologic ICU (aOR = 4.48; 95% CI: 2.68-7.50; p < 0.0001); adult oncology ICU (aOR = 3.48; 95% CI: 2.14-5.65; p < 0.0001); and others. CONCLUSION: Some of the identified mortality RFs are unlikely to change, such as the income level of the country, facility ownership, hospitalization type, ICU type, and age. But some of the mortality RFs we found can be changed, and efforts should be made to reduce CL-days, UC-days, MV-utilization ratio, UC-utilization ratio, and lower VAPs and CAUTI rates.

Favipiravir and/or nitazoxanide: a randomized, double-blind, 2×2 design, placebo-controlled trial of early therapy in COVID-19 in health workers, their household members, and patients treated at IMSS (FANTAZE).

BACKGROUND: The 2020 pandemic of SARS-CoV-2 causing COVID-19 disease is an unprecedented global emergency. COVID-19 appears to be a disease with an early phase where the virus replicates, coinciding with the first presentation of symptoms, followed by a later 'inflammatory' phase which results in severe disease in some individuals. It is known from other rapidly progressive infections such as sepsis and influenza that early treatment with antimicrobials is associated with a better outcome. The hypothesis is that this holds for COVID-19 and that early antiviral treatment may prevent progression to the later phase of the disease. METHODS: Trial design: Phase IIA randomised, double-blind, 2 × 2 design, placebo-controlled, interventional trial. RANDOMISATION: Participants will be randomised 1:1 by stratification, with the following factors: gender, obesity, symptomatic or asymptomatic, current smoking status presence or absence of comorbidity, and if the participant has or has not been vaccinated. BLINDING: Participants and investigators will both be blinded to treatment allocation (double-blind). DISCUSSION: We propose to conduct a proof-of-principle placebo-controlled clinical trial of favipiravir plus or minus nitazoxanide in health workers, their household members and patients treated at the Mexican Social Security Institute (IMSS) facilities. Participants with or without symptomatic COVID-19 or who tested positive will be assigned to receive favipiravir plus nitazoxanide or favipiravir plus nitazoxanide placebo. The primary outcome will be the difference in the amount of virus ('viral load') in the upper respiratory tract after 5 days of therapy. Secondary outcomes will include hospitalization, major morbidity and mortality, pharmacokinetics, and impact of antiviral therapy on viral genetic mutation rate. If favipiravir with nitazoxanide demonstrates important antiviral effects without significant toxicity, there will be a strong case for a larger trial in people at high risk of hospitalization or intensive care admission, for example older patients and/or those with comorbidities and with early disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT04918927 . Registered on June 9, 2021.

Annotating Cancer-Related Variants at Protein-Protein Interface with Structure-PPi.

A comprehensive analysis of germline and somatic variants requires complex computational approaches that combine next-generation sequencing (NGS)-based omics data with curated annotations from public repositories. Here, we describe Structure-PPi, which facilitates the analysis of cancer-related variants onto protein 3D structures, interaction interfaces, and other important functional sites (i.e., catalytic, ligand-binding, posttranslational modification). Our approach relies on features extracted from Interactome3D, UniProtKB, InterPro, APPRIS, dbNSFP, and COSMIC databases and provides complementary information to pathogenicity prediction methods. Thus, Structure-PPi helps in the discrimination of false-positive predictions and adds both mechanistic and biological insights into the role of variants in a given cancer. An online version of the tools is available at https://rbbt.bsc.es/StructurePPI/ .

Three-Component Synthesis of 2-Amino-3-cyano-4H-chromenes, In Silico Analysis of Their Pharmacological Profile, and In Vitro Anticancer and Antifungal Testing.

Chromenes are compounds that may be useful for inhibiting topoisomerase and cytochrome, enzymes involved in the growth of cancer and fungal cells, respectively. The aim of this study was to synthesize a series of some novel 2-amino-3-cyano-4-aryl-6,7-methylendioxy-4H-chromenes 4a-o and 2-amino-3-cyano-5,7-dimethoxy-4-aryl-4H-chromenes 6a-h by a three-component reaction, and test these derivatives for anticancer and antifungal activity. Compounds 4a and 4b were more active than cisplatin (9) and topotecan (7) in SK-LU-1 cells, and more active than 9 in PC-3 cells. An evaluation was also made of the series of compounds 4 and 6 as potential antifungal agents against six Candida strains, finding their MIC50 to be less than or equal to that of fluconazole (8). Molecular docking studies are herein reported, for the interaction of 4 and 6 with topoisomerase IB and the active site of CYP51 of Candida spp. Compounds 4a-o and 6a-h interacted in a similar way as 7 with key amino acids of the active site of topoisomerase IB and showed better binding energy than 8 at the active site of CYP51. Hence, 4a-o and 6a-h are good candidates for further research, having demonstrated their dual inhibition of enzymes that participate in the growth of cancer and fungal cells.

Arteriovenous Fistula Maturation, Functional Patency, and Intervention Rates.

Importance: National initiatives have emphasized the use of autogenous arteriovenous fistulas (AVFs) for hemodialysis, but their purported benefits have been questioned. Objective: To examine AVF usability, longer-term functional patency, and remedial procedures to facilitate maturation, manage complications, or maintain patency in the Hemodialysis Fistula Maturation (HFM) Study. Design, Setting, and Participants: The HFM Study was a multicenter (n = 7) prospective National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases cohort study performed to identify factors associated with AVF maturation. A total of 602 participants were enrolled (dialysis, kidney failure: 380; predialysis, chronic kidney disease [CKD]: 222) with AVF maturation ascertained for 535 (kidney failure, 353; CKD, 182) participants. Interventions: All clinical decisions regarding AVF management were deferred to the individual centers, but remedial interventions were discouraged within 6 weeks of creation. Main Outcomes and Measures: In this case series analysis, the primary outcome was unassisted maturation. Functional patency, freedom from intervention, and participant survival were summarized using Kaplan-Meier analysis. Results: Most participants evaluated (n = 535) were men (372 [69.5%]) and had diabetes (311 [58.1%]); mean (SD) age was 54.6 (13.6) years. Almost two-thirds of the AVFs created (342 of 535 [64%]) were in the upper arm. The AVF maturation rates for the kidney failure vs CKD participants were 29% vs 10% at 3 months, 67% vs 38% at 6 months, and 76% vs 58% at 12 months. Several participants with kidney failure (133 [37.7%]) and CKD (63 [34.6%]) underwent interventions to facilitate maturation or manage complications before maturation. The median time from access creation to maturation was 115 days (interquartile range [IQR], 86-171 days) but differed by initial indication (CKD, 170 days; IQR, 113-269 days; kidney failure, 105 days; IQR, 81-137 days). The functional patency for the AVFs that matured at 1 year was 87% (95% CI, 83.2%-90.2%) and at 2 years, 75% (95% CI, 69.7%-79.7%), and there was no significant difference for those receiving interventions before maturation. Almost half (188 [47.5%]) of the AVFs that matured had further intervention to maintain patency or treat complications. Conclusions and Relevance: The findings of this study suggest that AVF remains an accepted hemodialysis access option, although both its maturation and continued use require a moderate number of interventions to maintain patency and treat the associated complications.

Exploring novel capping framework: high substituent pyridine-hydroxamic acid derivatives as potential antiproliferative agents.

PURPOSE: Histone deacetylases (HDACs) play a vital role in the epigenetic regulation of gene expression due to their overexpression in several cancer forms. Therefore, these enzymes are considered as a potential anticancer drug target. Different synthetic and natural structures have been studied as HDACs inhibitors; based on available structural design information, the capping group is important for the biological activity due to the different interactions in the active site entrance. The present study aimed to analyze high substituted pyridine as a capping group, which included carrying out the synthesis, antiproliferative activity analysis, and docking studies of these novel compounds. METHODS: To achieve the synthesis of these derivatives, four reaction steps were performed, generating desired products 15a-k. Their effects on cell proliferation and gene expression of p21, cyclin D1, and p53 were determined using the sulphorhodamine B (SRB) method and quantitative real-time polymerase chain reaction. The HDAC1, HDAC6, and HDAC8 isoforms were used for performing docking experiments with our 15a-k products. RESULT: The products 15a-k were obtained in overall yields of 40-71%. Compounds 15j and 15k showed the highest antiproliferative activity in the breast (BT-474 and MDA-MB-231) and prostate (PC3) cancer cell lines at a concentration of 10 µM. These compounds increased p21 mRNA levels and decreased cyclin D1 and p53 gene expression. The docking study showed an increment in the strength, and in the number of interactions performed by the capping moiety of the tested molecules compared with SAHA; interactions displayed are mainly van der Waals, π-stacking, and hydrogen bond. CONCLUSION: The synthesized compounds 2-thiophene (15j) and 2-furan (15k) pyridine displayed cell growth inhibition, regulation of genes related to cell cycle progression in highly metastatic cancer cell lines. The molecular coupling analysis performed with HDAC1, HDAC6 and HDAC8 showed an increment in the number of interactions performed by the capping moiety and consequently in the strength of the capping group interaction.

Immune analysis of lymph nodes in relation to the presence or absence of tumor infiltrating lymphocytes in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with unmet medical needs. Several studies have proved that high levels of tumor infiltrating lymphocytes (TILs) at diagnosis of TNBC confer better prognosis and patients respond better to specific chemotherapies. Nonetheless, current evidence suggests that only 15% of TNBC patients have very high levels of TILs, and another 15% lacks TILs. One possible reason to explain why patients have low TILs at diagnosis is that lymphocytes might be deactivated by an immune checkpoint in local lymph nodes, provoking their retention in there as they are unresponsive to other immune stimuli. We have identified 15 high TILs (≥50%) and 20 low TILs (≤5%) TNBC patients with localised tumour (T1c-T2N0M0) and compared the protein expression of five immune checkpoints in lymph nodes. We have also performed a customised 50-immune gene NanoString expression panel, the NanoString 360 Breast Cancer panel, and whole exome sequencing for mutation and neoantigen load analyses. In low TILs, we observed higher expression of CTLA-4 in local lymph nodes, which could explain why lymphocytes get retained in there and do not migrate to tumour. These patients have also higher neoantigen load and higher expression of B7.H3 and B7.H4 in the tumour. In high TILs, we observed more PD-L1+ tumour cells and more expanded humoral response. These results could provide a strategy to revert low tumour immune infiltration at diagnosis of TNBC, improving their prognosis.

Rationale and design of the Kidney Precision Medicine Project.

Chronic kidney disease (CKD) and acute kidney injury (AKI) are common, heterogeneous, and morbid diseases. Mechanistic characterization of CKD and AKI in patients may facilitate a precision-medicine approach to prevention, diagnosis, and treatment. The Kidney Precision Medicine Project aims to ethically and safely obtain kidney biopsies from participants with CKD or AKI, create a reference kidney atlas, and characterize disease subgroups to stratify patients based on molecular features of disease, clinical characteristics, and associated outcomes. An additional aim is to identify critical cells, pathways, and targets for novel therapies and preventive strategies. This project is a multicenter prospective cohort study of adults with CKD or AKI who undergo a protocol kidney biopsy for research purposes. This investigation focuses on kidney diseases that are most prevalent and therefore substantially burden the public health, including CKD attributed to diabetes or hypertension and AKI attributed to ischemic and toxic injuries. Reference kidney tissues (for example, living-donor kidney biopsies) will also be evaluated. Traditional and digital pathology will be combined with transcriptomic, proteomic, and metabolomic analysis of the kidney tissue as well as deep clinical phenotyping for supervised and unsupervised subgroup analysis and systems biology analysis. Participants will be followed prospectively for 10 years to ascertain clinical outcomes. Cell types, locations, and functions will be characterized in health and disease in an open, searchable, online kidney tissue atlas. All data from the Kidney Precision Medicine Project will be made readily available for broad use by scientists, clinicians, and patients.

Reiterative infusions of MSCs improve pediatric osteogenesis imperfecta eliciting a pro-osteogenic paracrine response: TERCELOI clinical trial.

BACKGROUND: Osteogenesis imperfecta (OI) is a rare genetic disease characterized by bone fragility, with a wide range in the severity of clinical manifestations. The majority of cases are due to mutations in the COL1A1 or COL1A2 genes, which encode type I collagen. Mesenchymal stem cells (MSCs), as the progenitors of the osteoblasts, the main type I collagen secreting cell type in the bone, have been proposed and tested as an innovative therapy for OI with promising but transient outcomes. METHODS: To overcome the short-term effect of MSCs therapy, we performed a phase I clinical trial based on reiterative infusions of histocompatible MSCs, administered in a 2.5-year period, in two pediatric patients affected by severe and moderate OI. The aim of this study was to assess the safety and effectiveness of this cell therapy in nonimmunosuppressed OI patients. The host response to MSCs was studied by analyzing the sera from OI patients, collected before, during, and after the cell therapy. RESULTS: We first demonstrated that the sequential administration of MSCs was safe and improved the bone parameters and quality of life of OI patients along the cell treatment plus 2-year follow-up period. Moreover, the study of the mechanism of action indicated that MSCs therapy elicited a pro-osteogenic paracrine response in patients, especially noticeable in the patient affected by severe OI. CONCLUSIONS: Our results demonstrate the feasibility and potential of reiterative MSCs infusion for two pediatric OI and highlight the paracrine response shown by patients as a consequence of MSCs treatment.

Secondary hypereosinophilic syndrome: an unusual manifestation in a patient with syringotropic mycosis fungoides and human immunodeficiency virus infection.

Syringotropic mycosis fungoides is a very rare variant of cutaneous T-cell lymphomas characterised by prominent involvement of the eccrine glands. Hypereosinophilic syndrome refers to a rare group of conditions that are associated with persistent eosinophilia with organ involvement. It is classified into idiopathic, primary and secondary (reactive). We report herein an unusual case of hypereosinophilic syndrome with great impact on morbidity, which developed in a patient with human immunodeficiency virus infection and long-time misdiagnosed syringotropic mycosis fungoides.

Autonomic Nervous System and Recall Modeling in Audiovisual Emotion-Mediated Advertising Using Partial Least Squares-Path Modeling.

Interest in improving advertisement impact on potential consumers has increased recently. One well-known strategy is to use emotion-based advertisement. In this approach, an emotional link with consumers is created, aiming to enhance the memorization process. In recent years, Neuromarketing techniques have allowed us to obtain more objective information on this process. However, the role of the autonomic nervous system (ANS) in the memorization process using emotional advertisement still needs further research. In this work, we propose the use of two physiological signals, namely, an electrocardiogram (heart rate variability, HRV) and electrodermal activity (EDA), to obtain indices assessing the ANS. We measured these signals in 43 subjects during the observation of six different spots, each conveying a different emotion (rational, disgust, anger, surprise, and sadness). After observing the spots, subjects were asked to answer a questionnaire to measure the spontaneous and induced recall. We propose the use of a statistical data-driven model based on Partial Least Squares-Path Modeling (PSL-PM), which allows us to incorporate contextual knowledge by defining a relational graph of unobservable variables (latent variables, LV), which are, in turn, estimated by measured variables (indices of the ANS). We defined four LVs, namely, sympathetic, vagal, ANS, and recall. Sympathetic and vagal are connected to the ANS, the latter being a measure of recall, estimated from a questionnaire. The model is then fitted to the data. Results showed that vagal activity (described by HRV indices) is the most critical factor to describe ANS activity; they are inversely related except for the spot, which is mainly rational. The model captured a moderate-to-high variability of ANS behavior, ranging from 38% up to 64% of the explained variance of the ANS. However, it can explain at most 11% of the recall score of the subjects. The proposed approach allows for the easy inclusion of more physiological measurements and provides an easy-to-interpret model of the ANS response to emotional advertisement.

A Middle-Out Modeling Strategy to Extend a Colon Cancer Logical Model Improves Drug Synergy Predictions in Epithelial-Derived Cancer Cell Lines.

Cancer is a heterogeneous and complex disease and one of the leading causes of death worldwide. The high tumor heterogeneity between individuals affected by the same cancer type is accompanied by distinct molecular and phenotypic tumor profiles and variation in drug treatment response. In silico modeling of cancer as an aberrantly regulated system of interacting signaling molecules provides a basis to enhance our biological understanding of disease progression, and it offers the means to use computer simulations to test and optimize drug therapy designs on particular cancer types and subtypes. This sets the stage for precision medicine: the design of treatments tailored to individuals or groups of patients based on their tumor-specific molecular cancer profiles. Here, we show how a relatively large manually curated logical model can be efficiently enhanced further by including components highlighted by a multi-omics data analysis of data from Consensus Molecular Subtypes covering colorectal cancer. The model expansion was performed in a pathway-centric manner, following a partitioning of the model into functional subsystems, named modules. The resulting approach constitutes a middle-out modeling strategy enabling a data-driven expansion of a model from a generic and intermediate level of molecular detail to a model better covering relevant processes that are affected in specific cancer subtypes, comprising 183 biological entities and 603 interactions between them, partitioned in 25 functional modules of varying size and structure. We tested this model for its ability to correctly predict drug combination synergies, against a dataset of experimentally determined cell growth responses with 18 drugs in all combinations, on eight cancer cell lines. The results indicate that the extended model had an improved accuracy for drug synergy prediction for the majority of the experimentally tested cancer cell lines, although significant improvements of the model's predictive performance are still needed. Our study demonstrates how a tumor-data driven middle-out approach toward refining a logical model of a biological system can further customize a computer model to represent specific cancer cell lines and provide a basis for identifying synergistic effects of drugs targeting specific regulatory proteins. This approach bridges between preclinical cancer model data and clinical patient data and may thereby ultimately be of help to develop patient-specific in silico models that can steer treatment decisions in the clinic.

Design of Fluorescent Coumarin-Hydroxamic Acid Derivatives as Inhibitors of HDACs: Synthesis, Anti-Proliferative Evaluation and Docking Studies.

Coumarin-hydroxamic acid derivatives 7a-k were herein designed with a dual purpose: as antiproliferative agents and fluorescent probes. The compounds were synthesized in moderate yields (30-87%) through a simple methodology, biological evaluation was carried out on prostate (PC3) and breast cancer (BT-474 and MDA-MB-231) cell lines to determine the effects on cell proliferation and gene expression. For compounds 7c, 7e, 7f, 7i and 7j the inhibition of cancer cell proliferation was similar to that found with the reference compound at a comparable concentration (10 µM), in addition, their molecular docking studies performed on histone deacetylases 1, 6 and 8 showed strong binding to the respective active sites. In most cases, antiproliferative activity was accompanied by greater levels of cyclin-dependent kinase inhibitor p21, downregulation of the p53 tumor suppressor gene, and regulation of cyclin D1 gene expression. We conclude that compounds 7c, 7e, 7f, 7i and 7j may be considered as potential anticancer agents, considering their antiproliferative properties, their effect on the regulation of the genes, as well as their capacity to dock to the active sites. The fluorescent properties of compound 7j and 7k suggest that they can provide further insight into the mechanism of action.