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Inflammation and immune responses are intricately intertwined processes crucial for maintaining homeostasis and combating against pathogens. These processes involve complex signaling pathways, notably the Nuclear Factor kappa-light-chain-enhancer of activated B-cells (NF-κB) and Mitogen-Activated Protein Kinase (MAPK) pathways, which play crucial roles. Sulforaphane (SFN), a nutraceutic, has emerged as a potential regulator of NF-κB and MAPK signaling pathways, exhibiting anti-inflammatory properties. However, limited knowledge exists regarding SFN’s effects on immune cell modulation. This study aimed to assess the immunomodulatory capacity of SFN pretreatment in human dendritic cells (DCs), followed by exposure to a chronic inflammatory environment induced by lipopolysaccharide. SFN pretreatment was found to inhibit the NF-κB and MAPK signaling pathways, resulting in phenotypic changes in DCs characterized by a slight reduction in the expression of surface markers, as well as a decrease of TNF-α/IL-10 ratio. Additionally, SFN pretreatment enhanced the proliferation of Treg-cells and promoted the production of IL-10 by B-cells before exposure to the chronic inflammatory environment. Furthermore, these changes in DCs were found to be influenced by the inhibition of NF-κB and MAPK pathways (specifically p38 MAPK and JNK), suggesting that these pathways may play a role in the regulation of the differentiation of adaptive immune responses (proliferation of T- and IL-10-producing regulatory-cells), prior to SFN pretreatment. Our findings suggest that SFN pretreatment may induce a regulatory response by inhibiting NF-κB and MAPK signaling pathways in an inflammatory environment. SFN could be considered a promising strategy for utilizing functional foods to protect against inflammation and develop immunoregulatory interventions.

BackgroundImmunopathology in food allergy is characterized by an uncontrolled type 2 immune response and specific-IgE production. Recent studies have determined that group 2 innate lymphoid cells (ILC2) participate in the food allergy pathogenic mechanism and their severity. Our objective was to investigate the role of ILC2 in peach-allergic patients due to non-specific lipid transfer protein (Pru p 3) sensitization.MethodsThe immune response in peripheral blood mononuclear cells was characterized in lipid transfer protein-allergic patients and healthy controls. We have analyzed the Pru p 3 uptake on ILC2, the expression of costimulatory molecules, and their involvement on the T-cell proliferative response and cytokine production under different experimental conditions: cytokines involved in group 2 innate lymphoid cell activation (IL-33 and IL-25), Pru p 3 as main food allergen, and the combination of both components (IL-33/IL-25+Pru p 3) using cell sorting, EliSpot, flow cytometry, and confocal microscopy.ResultsOur results show that Pru p 3 allergen is taken up by group 2 innate lymphoid cells, regulating their costimulatory molecule expression (CD83 and HLA-DR) depending on the presence of Pru p 3 and its combination with IL-33/IL-25. The Pru p 3-stimulated ILC2 induced specific GATA3+Th2 proliferation and cytokine (IL-4, IL-5, and IL-13) production in lipid transfer protein-allergic patients in a cell contact-dependent manner with no changes in Tbet+Th1- and FOXP3+Treg cell differentiation.ConclusionsThe results indicate that in lipid transfer protein-allergic patients, the responsible allergen, Pru p 3, interacts with group 2 innate lymphoid cells, promoting a Th2 cell response. Our results might be of interest in vivo, as they show a role of group 2 innate lymphoid cells as antigen-presenting cells, contributing to the development of food allergy. Consequently, group 2 innate lymphoid cells may be considered as potential therapeutic targets.

Dendritic cells (DCs) are antigen presenting cells that link innate and adaptive immunity. DCs have been historically considered as the most effective and potent cell population to capture, process and present antigens to activate naïve T cells and originate favorable immune responses in many diseases, such as cancer. However, in the last decades, it has been observed that DCs not only promote beneficial responses, but also drive the initiation and progression of some pathologies, including inflammatory bowel disease (IBD). In line with those notions, different therapeutic approaches have been tested to enhance or impair the concentration and role of the different DC subsets. The blockade of inhibitory pathways to promote DCs or DC-based vaccines have been successfully assessed in cancer, whereas the targeting of DCs to inhibit their functionality has proved to be favorable in IBD. In this review, we (a) described the general role of DCs, (b) explained the DC subsets and their role in immunogenicity, (c) analyzed the role of DCs in cancer and therapeutic approaches to promote immunogenic DCs and (d) analyzed the role of DCs in IBD and therapeutic approaches to reduced DC-induced inflammation. Therefore, we aimed to highlight the “yin-yang” role of DCs to improve the understand of this type of cells in disease progression.

Dendritic cells (DCs) serve as professional antigen-presenting cells (APC) bridging innate and adaptive immunity, playing an essential role in triggering specific cellular and humoral responses against tumor and infectious antigens. Consequently, various DC-based antitumor therapeutic strategies have been developed, particularly vaccines, and have been intensively investigated specifically in the context of acute myeloid leukemia (AML). This hematological malignancy mainly affects the elderly population (those aged over 65), which usually presents a high rate of therapeutic failure and an unfavorable prognosis. In this review, we examine the current state of development and progress of vaccines in AML. The findings evidence the possible administration of DC-based vaccines as an adjuvant treatment in AML following initial therapy. Furthermore, the therapy demonstrates promising outcomes in preventing or delaying tumor relapse and exhibits synergistic effects when combined with other treatments during relapses or disease progression. On the other hand, the remarkable success observed with RNA vaccines for COVID-19, delivered in lipid nanoparticles, has revealed the efficacy and effectiveness of these types of vectors, prompting further exploration and their potential application in AML, as well as other neoplasms, loading them with tumor RNA.

Modulation of the allergic immune response through alternative therapies is a field of study that aims to address allergic reactions differently from traditional approaches. These therapies encompass the utilization of natural functional foods, which have been observed to exert an influence on the immune response, thus mitigating the severity of allergies. Indeed, some studies suggest that the incorporation of these nutraceuticals can regulate immune function, leading to a reduction in histamine release and subsequent alleviation of allergic symptoms. Moreover, certain herbs and dietary supplements, such as curcumin, are believed to possess anti-inflammatory properties, which may serve to moderate allergic responses. Although the results remain somewhat mixed and require further research, these alternative therapies exhibit the potential to impact the allergic immune response, thereby providing complementary options to conventional treatments. Therefore, in this review, we aim to provide an updated account of functional foods capable of modulating the immune response to allergies. In that sense, the review delves into functional foods sourced from plants (phytochemicals), animals, and marine algae. Emphasis is placed on their potential application in the treatment of allergic disorders. It also provides an overview of how these foods can be effectively utilized as functional foods. Additionally, it explores the molecular mechanisms and scientific validity of various bioactive natural compounds in the management of allergies.

Abstract To investigate food allergy-tolerance mechanisms induced through allergen-specific immunotherapy we used RNA-Sequencing to measure gene expression in lymph-node-derived dendritic cells from Pru p 3-anaphylactic mice after immunotherapy with glycodendropeptides at 2 nM and 5 nM, leading to permanent tolerance and short-term desensitization, respectively. Gene expression was also measured in mice receiving no immunotherapy (anaphylaxis); and in which anaphylaxis could never occur (antigen-only). Compared to anaphylaxis, the antigen-only group showed the greatest number of expression-changes (411), followed by tolerant (186) and desensitized (119). Only 29 genes changed in all groups, including Il12b, Cebpb and Ifngr1. The desensitized group showed enrichment for genes related to chronic inflammatory response, secretory granule, and regulation of interleukin-12 production; the tolerant group showed genes related to cytokine receptor activity and glucocorticoid receptor binding, suggesting distinct pathways for similar outcomes. We identified genes and processes potentially involved in the restoration of long-term tolerance via allergen-specific immunotherapy, representing potential prognostic biomarkers.

Food allergy (FA) is an adverse immunological reaction to a specific food that can trigger a wide range of symptoms from mild to life-threatening. This adverse reaction is caused by different immunological mechanisms, such as IgE-mediated, non-IgE-mediated and mixed IgE-mediated reactions. Its epidemiology has had a significant increase in the last decade, more so in developed countries. It is estimated that approximately 2 to 10% of the world’s population has FA and this number appears to be increasing and also affecting more children. The diagnosis can be complex and requires the combination of different tests to establish an accurate diagnosis. However, the treatment of FA is based on avoiding the intake of the specific allergenic food, thus being very difficult at times and also controlling the symptoms in case of accidental exposure. Currently, there are other immunomodulatory treatments such as specific allergen immunotherapy or more innovative treatments that can induce a tolerance response. It is important to mention that research in this field is ongoing and clinical trials are underway to assess the safety and efficacy of these different immunotherapy approaches, new treatment pathways are being used to target and promote the tolerance response. In this review, we describe the new in vitro diagnostic tools and therapeutic treatments to show the latest advances in FA management. We conclude that although significant advances have been made to improve therapies and diagnostic tools for FA, there is an urgent need to standardize both so that, in their totality, they help to improve the management of FA.

IntroductionAllergen-specific immunotherapy (AIT) is applied as treatment to rise tolerance in patients with food allergies. Although AIT is thoroughly used, the underlying epigenetic events related to tolerant induction are still unknown. Thus, we aim to investigate epigenetic changes that could be related to tolerance in dendritic cells (DCs) from anaphylactic mice to lipid transfer proteins, Pru p 3, in the context of a sublingual immunotherapy (SLIT) with a glycodendropeptide (D1ManPrup3) that has demonstrated tolerant or desensitization responses depending on the treatment dose.MethodsChanges in DNA methylation in CpG context were determined comparing Sensitized (Antigen-only) animals and two groups receiving SLIT with the D1ManPrup3 nanostructure (D1ManPrup3-SLIT): Tolerant (2nM D1ManPrup3) and Desensitized (5nM D1ManPrup3), against anaphylactic animals. DNA from lymph nodes-DCs were isolated and then, Whole Genome Bisulphite Sequencing was performed to analyze methylation.ResultsMost differentially methylated regions were found on the area of influence of gene promoters (DMPRs). Compared to the Anaphylactic group, the highest value was found in Desensitized mice (n = 7,713 DMPRs), followed by Tolerant (n = 4,091 DMPRs) and Sensitized (n = 3,931 DMPRs) mice. Moreover, many of these epigenetic changes were found in genes involved in immune and tolerance responses (Il1b, Il12b, Il1a, Ifng, and Tnf) as shown by functional enrichment (DCs regulation, B cell-mediated immunity, and effector mechanisms).DiscussionIn conclusion, different doses of D1ManPrup3-SLIT induce different DNA methylation changes, which are reflected in the induction of distinct responses, tolerance, or desensitization.

Background: Sulforaphane (SFN) is an isothiocyanate of vegetable origin with potent antioxidant and immunomodulatory properties. The characterization of its pleiotropic activity in human dendritic cells (DCs) is poorly summarized. The aim of this work was to study the immunomodulatory power of SFN in response to an inflammatory microenvironment on human monocyte-derived DCs (moDCs). Methods: We studied the immunological response induced by SFN. Apoptosis and autophagy assays were performed using flow cytometry on moDCs and a cancer cell line (THP-1). These included moDC maturation, lymphocyte proliferation and cytokine production under different experimental conditions. We investigated whether these results were associated with an inflammatory microenvironment induced by lipopolysaccharides (LPSs). Results: Our results demonstrated that SFN could interact with moDCs, significantly reducing the autophagy process and enhancing apoptosis similarly to cancer cell line THP-1 cells in a chronic inflammatory microenvironment. Under chronic inflammation, SFN modulated the phenotypical characteristics of moDCs, reducing the expression of all markers (CD80, CD83, CD86, HLA-DR and PD-L1). SFN significantly reduced the Th2 proliferative response, with a decrease in the IL-9 and IL-13 levels. Although we did not observe any changes in the regulatory proliferative response, we noted an increase in the IL-10 levels. Conclusions: These findings demonstrate that SFN exerts protective effects against LPS-induced inflammation via the modulation of moDCs/T cells towards a regulatory profile. SFN may be a potential candidate for the treatment of pathologies with an inflammatory profile.

Glioblastoma is the most aggressive and lethal brain tumor in adults, presenting diffuse brain infiltration, necrosis, and drug resistance. Although new drugs have been approved for recurrent patients, the median survival rate is two years; therefore, new alternatives to treat these patients are required. Previous studies have reported the anticancer activity of albendazole, its active metabolite albendazole sulfoxide, and melatonin; therefore, the present study was performed to evaluate if the combination of melatonin with albendazole or with albendazole sulfoxide induces an additive or synergistic cytotoxic effect on C6 and RG2 rat glioma cells, as well as on U87 human glioblastoma cells. Drug interaction was determined by the Chou–Talalay method. We evaluated the mechanism of cell death by flow cytometry, immunofluorescence, and crystal violet staining. The cytotoxicity of the combinations was mainly synergistic. The combined treatments induced significantly more apoptotic and autophagic cell death on the glioma cell lines. Additionally, albendazole and albendazole sulfoxide inhibited proliferation independently of melatonin. Our data justify continuing with the evaluation of this proposal since the combinations could be a potential strategy to aid in the treatment of glioblastoma.

Nutraceuticals act as cellular and functional modulators, contributing to the homeostasis of physiological processes. In an inflammatory microenvironment, these functional foods can interact with the immune system by modulating or balancing the exacerbated proinflammatory response. In this process, immune cells, such as antigen-presenting cells (APCs), identify danger signals and, after interacting with T lymphocytes, induce a specific effector response. Moreover, this conditions their change of state with phenotypical and functional modifications from the resting state to the activated and effector state, supposing an increase in their energy requirements that affect their intracellular metabolism, with each immune cell showing a unique metabolic signature. Thus, nutraceuticals, such as polyphenols, vitamins, fatty acids, and sulforaphane, represent an active option to use therapeutically for health or the prevention of different pathologies, including obesity, metabolic syndrome, and diabetes. To regulate the inflammation associated with these pathologies, intervention in metabolic pathways through the modulation of metabolic energy with nutraceuticals is an attractive strategy that allows inducing important changes in cellular properties. Thus, we provide an overview of the link between metabolism, immune function, and nutraceuticals in chronic inflammatory processes associated with obesity and diabetes, paying particular attention to nutritional effects on APC and T cell immunometabolism, as well as the mechanisms required in the change in energetic pathways involved after their activation.

In 2010, the Mediterranean diet was recognized by UNESCO as an Intangible Cultural Heritage of Humanity. Olive oil is the most characteristic food of this diet due to its high nutraceutical value. The positive effects of olive oil have often been attributed to its minor components; however, its oleic acid (OA) content (70–80%) is responsible for its many health properties. OA is an effective biomolecule, although the mechanism by which OA mediates beneficial physiological effects is not fully understood. OA influences cell membrane fluidity, receptors, intracellular signaling pathways, and gene expression. OA may directly regulate both the synthesis and activities of antioxidant enzymes. The anti-inflammatory effect may be related to the inhibition of proinflammatory cytokines and the activation of anti-inflammatory ones. The best-characterized mechanism highlights OA as a natural activator of sirtuin 1 (SIRT1). Oleoylethanolamide (OEA), derived from OA, is an endogenous ligand of the peroxisome proliferator-activated receptor alpha (PPARα) nuclear receptor. OEA regulates dietary fat intake and energy homeostasis and has therefore been suggested to be a potential therapeutic agent for the treatment of obesity. OEA has anti-inflammatory and antioxidant effects. The beneficial effects of olive oil may be related to the actions of OEA. New evidence suggests that oleic acid may influence epigenetic mechanisms, opening a new avenue in the exploration of therapies based on these mechanisms. OA can exert beneficial anti-inflammatory effects by regulating microRNA expression. In this review, we examine the cellular reactions and intracellular processes triggered by OA in T cells, macrophages, and neutrophils in order to better understand the immune modulation exerted by OA.

Local respiratory allergy (LRA) is defined by the negativity of atopy tests, a clinical history suggestive of airway allergy and a positive response to the nasal and/or bronchial allergen challenge. The clinical spectrum of LRA is comprised of three conditions: local allergic rhinitis (LAR) and local allergic asthma in non-atopic patients, and dual allergic rhinitis (coexistence of allergic rhinitis and LAR) in atopic individuals. LRA is an independent disease phenotype not progressing to atopy over time, but naturally evolving to the clinical worsening and the onset of comorbidities. Published data suggests that LRA is mediated through the mucosal synthesis of allergen-specific (s)IgE, which binds to FcϵRI on resident mast cells, and in >50% of cases traffics to the blood stream to sensitize circulating basophils. To date, 4 clinical trials have demonstrated the capacity of allergen immunotherapy (AIT) to decrease nasal, conjunctival and bronchial symptoms, to improve quality of life, to increase the threshold dose of allergen eliciting respiratory symptoms, and to induce serum sIgG4 in LRA individuals. Collectively, these data indicate that local allergy is a relevant disease mechanisms in both atopic and non-atopic patients with airway diseases.

Plant-food allergy is an increasing problem, with nonspecific lipid transfer proteins (nsLTPs) triggering mild/severe reactions. Pru p 3 is the major sensitizer in LTP food allergy (FA). However, in vivo and in vitro diagnosis is hampered by the need for differentiating between asymptomatic sensitization and allergy with clinical relevance. The basophil activation test (BAT) is an ex vivo method able to identify specific IgE related to the allergic response. Thus, we aimed to establish the value of BAT in a precise diagnosis of LTP-allergic patients. Ninety-two individuals with peach allergy sensitized to LTP, Pru p 3, were finally included, and 40.2% of them had symptoms to peanut (n = 37). In addition, 16 healthy subjects were recruited. BAT was performed with Pru p 3 and Ara h 9 (peanut LTP) at seven ten-fold concentrations, and was evaluated by flow cytometry, measuring the percentage of CD63 (%CD63+) and CD203c (%CD203chigh) cells, basophil allergen threshold sensitivity (CD-Sens), and area under the dose–response curve (AUC). Significant changes in BAT parameters (%CD63+ and %CD203chigh) were found between the controls and patients. However, comparisons for %CD63+, %CD203chigh, AUC, and CD-Sens showed similar levels among patients with different symptoms. An optimal cut-off was established from ROC curves, showing a significant positive percentage of BAT in patients compared to controls and great values of sensitivity (>87.5%) and specificity (>85%). In addition, BAT showed differences in LTP-allergic patients tolerant to peanut using its corresponding LTP, Ara h 9. BAT can be used as a potential diagnostic tool for identifying LTP allergy and for differentiating peanut tolerance, although neither reactivity nor sensitivity can distinguish the severity of the clinical symptoms.

Food allergy (FA) is an increasing problem worldwide and, over recent years, its prevalence is rising in developed countries. Nowadays, the immunological and cellular processes that occur in the allergic reactions are not fully understood, which hampers the development of in vitro diagnostic tools and further treatment options. Moreover, allergic diseases could be reinforced by environmental exposure and genetic modifications. Gene expression can be controlled by different epigenetic mechanisms like DNA methylation, histone modifications, and microRNAs. In addition, several environmental factors such as dietary components (vitamin D, butyrate, folic acid) are able to regulate this epigenetic mechanism. All these factors produce modifications in immune genes that could alter the development and function of immune cells, and therefore the etiology of the disease. Furthermore, these epigenetic mechanisms have also an influence on immunomodulation, which could explain sustained responsiveness or unresponsiveness during immunotherapy due to epigenetic modifications in key genes that induce tolerance in several FA. Thus, in this review we focus on the different epigenetic mechanisms that occur in FA and on the influence of several dietary components in these gene modifications.

Food allergy is an increasing problem worldwide, with strict avoidance being classically the only available reliable treatment. The main objective of this review is to cover the latest information about the tools available for the diagnosis and treatment of food allergies. In recent years, many efforts have been made to better understand the humoral and cellular mechanisms involved in food allergy and to improve the strategies for diagnosis and treatment. This review illustrates IgE-mediated food hypersensitivity and provides a current description of the diagnostic strategies and advances in different treatments. Specific immunotherapy, including different routes of administration and new therapeutic approaches, such as hypoallergens and nanoparticles, are discussed in detail. Other treatments, such as biologics and microbiota, are also described. Therefore, we conclude that although important efforts have been made in improving therapies for food allergies, including innovative approaches mainly focusing on efficacy and safety, there is an urgent need to develop a set of basic and clinical results to help in the diagnosis and treatment of food allergies.

Background: Although albendazole is the drug-of-choice for the treatment of neurocysticercosis, its efficacy is limited due to its low bioavailability. An alternative for optimizing pharmacological treatment is through drug combinations. In vitro studies have shown that nitazoxanide and tizoxanide (the active metabolite of nitazoxanide) exhibit cysticidal activity and that the combination of tizoxanide with albendazole sulfoxide (the active metabolite of albendazole) produced an additive effect. Objectives: (1) To assess the concentration profile of tizoxanide in plasma and in cerebrospinal fluid; and (2) to evaluate the influence of nitazoxanide on the pharmacokinetics of albendazole in plasma and in cerebrospinal fluid. Methods: Two different studies were conducted. In study 1, 10 male Sprague-Dawley rats received a single oral dose of 7.5 mg/kg of nitazoxanide and serial blood and cerebrospinal fluid samples were collected over a period of 4 h. In study 2, 38 healthy male Sprague-Dawley rats were randomly divided into two groups: one of these received a single dose of albendazole (15 mg/kg) and, in the other group, albendazole (15 mg/kg) was co-administered with nitazoxanide (7.5 mg/kg). Plasma and cerebrospinal fluid samples were collected from 0 to 16 h after administration. Albendazole sulfoxide and tizoxanide levels were assayed by using HPLC or LC/MS techniques. Results: In study 1, tizoxanide reached a maximum plasma concentration of 244.42 ± 31.98 ng/mL at 0.25 h; however, in cerebrospinal fluid, this could be detected only at 0.5 h, and levels were below the quantification limit (10 ng/mL). These data indicate low permeation of tizoxanide into the blood brain barrier. In study 2, Cmax, the area under the curve, and the mean residence time of albendazole sulfoxide in plasma and cerebrospinal fluid were not affected by co-administration with nitazoxanide. Conclusion: The results of the present study indicate that in rats at the applied doses, tizoxanide does not permeate into the cerebrospinal fluid. Furthermore, nitazoxanide does not appear to alter significantly the pharmacokinetics of albendazole in plasma or in cerebrospinal fluid.

Objetivo: Determinar el efecto citotóxico in vitro de la combinación de Albendazol y Temozolomida en células C6 de glioma. Antecedentes: El Glioblastoma es el tumor cerebral más maligno y letal en el humano. La supervivencia de los pacientes diagnosticados es menor a 2 años. El tratamiento estándar incluye cirugía, radioterapia, quimioterapia con temozolomida (TMZ) o una combinación de estos. Sin embargo, la eficacia de estos tratamientos es limitada, por lo que es necesario encontrar alternativas terapéuticas más eficaces. Recientemente se ha encontrado que el albendazol (ALB) presenta potencial como agente anticancerígeno, por lo que en este trabajo se reporta el efecto de la combinación de ALB con TMZ sobre células C6 de glioma. Métodos: Para los experimentos se utilizaron placas de cultivo de 96 pozos y se sembraron 3,000 células en cada pozo, se le adicionaron medio de cultivo conteniendo ALB (0.08 a 0.8 µM), TMZ (30 a 2000 µM) o ALB+TMZ (0.08-0.2 µM para ALB y 30-128 µM para TMZ). Las células se incubaron por 72 horas a 37°C y 5% de CO2, posteriormente se evaluó la viabilidad celular con la técnica de MTT. Para cada tratamiento (fármacos solos o la combinación), se construyó la curva concentración-respuesta. La IC50 para cada fármaco se calculó usando regresión Profit. Se construyó la superficie de interacción sinérgica (SIS) para identificar las combinaciones que presentaron sinergismo. Los valores de citotoxicidad de las combinaciones se compararon con el valor de la suma teórica de obtenida con cada fármaco, usando una prueba de ANOVA seguida de una t-student (p<0.05). Protocolo No. 150/16. Resultados: Los valores de IC50 obtenidos fueron de 0.6 µM (0.55-.68) para ALB y de 1213 µM (1125-1315) para TMZ. ALB exhibió actividad citotóxica más potente que TMZ. La SIS característica de la combinación ALB+TMZ mostro un efecto de sinergismo en dos de las nueve combinaciones evaluadas. Las combinaciones con mayor sinergismo fueron ALB 0.13 µM + TMZ 30 µM la cual mostró un incremento del efecto teórico de suma de 2 veces y ALB 0.32 µM + TMZ 30 µM la cual mostro un incremento de 1.5 veces sobre el efecto aditivo. En ambas combinaciones el efecto fue estadísticamente significativo (p<0.001). Conclusiones: El albendazol podría ayudar a potenciar el efecto de temozolomida, además de reducir los efectos secundarios causados por TMZ al disminuir su dosis. Se requieren estudios en otras líneas celulares para comprobar la utilidad terapéutica de esta combinación. [ABSTRACT FROM AUTHOR]

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