Personalizing Nutrition Strategies: Bridging Research and Public Health.

In recent years, although life expectancy has increased significantly, non-communicable diseases (NCDs) continue to pose a significant threat to the health of the global population. Therefore, eating habits have been recognized as key modifiable factors that influence people's health and well-being. For this reason, it is interesting to study dietary patterns, since the human diet is a complex mixture of macronutrients, micronutrients, and bioactive compounds, and can modulate multiple physiological processes, including immune function, the metabolism, and inflammation. To ensure that the data we acquired were current and relevant, we searched primary and secondary sources, including scientific journals, bibliographic indexes, and databases in the last 15 years with the most relevant articles. After this search, we observed that all the recent research on NCDs suggests that diet is a critical factor in shaping an individual's health outcomes. Thus, cardiovascular, metabolic, mental, dental, and visual health depends largely on the intake, habits and patterns, and nutritional behaviors. A diet high in processed and refined foods, added sugars, and saturated fats can increase the risk of developing chronic diseases. On the other hand, a diet rich in whole, nutrient-dense foods, such as vegetables, fruits, nuts, legumes, and a high adherence to Mediterranean diet can improve health's people.

Microbiota Implications in Endocrine-Related Diseases: From Development to Novel Therapeutic Approaches.

This comprehensive review article delves into the critical role of the human microbiota in the development and management of endocrine-related diseases. We explore the complex interactions between the microbiota and the endocrine system, emphasizing the implications of microbiota dysbiosis for the onset and progression of various endocrine disorders. The review aims to synthesize current knowledge, highlighting recent advancements and the potential of novel therapeutic approaches targeting microbiota-endocrine interactions. Key topics include the impact of microbiota on hormone regulation, its role in endocrine pathologies, and the promising avenues of microbiota modulation through diet, probiotics, prebiotics, and fecal microbiota transplantation. We underscore the importance of this research in advancing personalized medicine, offering insights for more tailored and effective treatments for endocrine-related diseases.

Dynamic prediction of malignant ventricular arrhythmias using neural networks in patients with an implantable cardioverter-defibrillator.

BACKGROUND: Risk stratification for ventricular arrhythmias currently relies on static measurements that fail to adequately capture dynamic interactions between arrhythmic substrate and triggers over time. We trained and internally validated a dynamic machine learning (ML) model and neural network that extracted features from longitudinally collected electrocardiograms (ECG), and used these to predict the risk of malignant ventricular arrhythmias. METHODS: A multicentre study in patients implanted with an implantable cardioverter-defibrillator (ICD) between 2007 and 2021 in two academic hospitals was performed. Variational autoencoders (VAEs), which combine neural networks with variational inference principles, and can learn patterns and structure in data without explicit labelling, were trained to encode the mean ECG waveforms from the limb leads into 16 variables. Supervised dynamic ML models using these latent ECG representations and clinical baseline information were trained to predict malignant ventricular arrhythmias treated by the ICD. Model performance was evaluated on a hold-out set, using time-dependent receiver operating characteristic (ROC) and calibration curves. FINDINGS: 2942 patients (61.7 ± 13.9 years, 25.5% female) were included, with a total of 32,129 ECG recordings during a mean follow-up of 43.9 ± 35.9 months. The mean time-varying area under the ROC curve for the dynamic model was 0.738 ± 0.07, compared to 0.639 ± 0.03 for a static (i.e. baseline-only model). Feature analyses indicated dynamic changes in latent ECG representations, particularly those affecting the T-wave morphology, were of highest importance for model predictions. INTERPRETATION: Dynamic ML models and neural networks effectively leverage routinely collected longitudinal ECG recordings for personalised and updated predictions of malignant ventricular arrhythmias, outperforming static models. FUNDING: This publication is part of the project DEEP RISK ICD (with project number 452019308) of the research programme Rubicon which is (partly) financed by the Dutch Research Council (NWO). This research is partly funded by the Amsterdam Cardiovascular Sciences (personal grant F.V.Y.T).

Epithelial Transport in Disease: An Overview of Pathophysiology and Treatment.

Epithelial transport is a multifaceted process crucial for maintaining normal physiological functions in the human body. This comprehensive review delves into the pathophysiological mechanisms underlying epithelial transport and its significance in disease pathogenesis. Beginning with an introduction to epithelial transport, it covers various forms, including ion, water, and nutrient transfer, followed by an exploration of the processes governing ion transport and hormonal regulation. The review then addresses genetic disorders, like cystic fibrosis and Bartter syndrome, that affect epithelial transport. Furthermore, it investigates the involvement of epithelial transport in the pathophysiology of conditions such as diarrhea, hypertension, and edema. Finally, the review analyzes the impact of renal disease on epithelial transport and highlights the potential for future research to uncover novel therapeutic interventions for conditions like cystic fibrosis, hypertension, and renal failure.

Global Impacts of Western Diet and Its Effects on Metabolism and Health: A Narrative Review.

The Western diet is a modern dietary pattern characterized by high intakes of pre-packaged foods, refined grains, red meat, processed meat, high-sugar drinks, candy, sweets, fried foods, conventionally raised animal products, high-fat dairy products, and high-fructose products. The present review aims to describe the effect of the Western pattern diet on the metabolism, inflammation, and antioxidant status; the impact on gut microbiota and mitochondrial fitness; the effect of on cardiovascular health, mental health, and cancer; and the sanitary cost of the Western diet. To achieve this goal, a consensus critical review was conducted using primary sources, such as scientific articles, and secondary sources, including bibliographic indexes, databases, and web pages. Scopus, Embase, Science Direct, Sports Discuss, ResearchGate, and the Web of Science were used to complete the assignment. MeSH-compliant keywords such "Western diet", "inflammation", "metabolic health", "metabolic fitness", "heart disease", "cancer", "oxidative stress", "mental health", and "metabolism" were used. The following exclusion criteria were applied: (i) studies with inappropriate or irrelevant topics, not germane to the review's primary focus; (ii) Ph.D. dissertations, proceedings of conferences, and unpublished studies. This information will allow for a better comprehension of this nutritional behavior and its effect on an individual's metabolism and health, as well as the impact on national sanitary systems. Finally, practical applications derived from this information are made.

The Role of Adipokines in Health and Disease.

Adipokines are cell-signaling proteins secreted by adipose tissue that has been related to a low-grade state of inflammation and different pathologies. The present review aims to analyze the role of adipokines in health and disease in order to understand the important functions and effects of these cytokines. For this aim, the present review delves into the type of adipocytes and the cytokines produced, as well as their functions; the relations of adipokines in inflammation and different diseases such as cardiovascular, atherosclerosis, mental diseases, metabolic disorders, cancer, and eating behaviors; and finally, the role of microbiota, nutrition, and physical activity in adipokines is discussed. This information would allow for a better understanding of these important cytokines and their effects on body organisms.

Metabolic Health, Mitochondrial Fitness, Physical Activity, and Cancer.

Cancer continues to be a significant global health issue. Traditional genetic-based approaches to understanding and treating cancer have had limited success. Researchers are increasingly exploring the impact of the environment, specifically inflammation and metabolism, on cancer development. Examining the role of mitochondria in this context is crucial for understanding the connections between metabolic health, physical activity, and cancer. This study aimed to review the literature on this topic through a comprehensive narrative review of various databases including MedLine (PubMed), Cochrane (Wiley), Embase, PsychINFO, and CinAhl. The review highlighted the importance of mitochondrial function in overall health and in regulating key events in cancer development, such as apoptosis. The concept of "mitochondrial fitness" emphasizes the crucial role of mitochondria in cell metabolism, particularly their oxidative functions, and how proper function can prevent replication errors and regulate apoptosis. Engaging in high-energy-demanding movement, such as exercise, is a powerful intervention for improving mitochondrial function and increasing resistance to environmental stressors. These findings support the significance of considering the role of the environment, specifically inflammation and metabolism, in cancer development and treatment. Further research is required to fully understand the mechanisms by which physical activity improves mitochondrial function and potentially reduces the risk of cancer.

Validación clínica de la prueba RT-LAMP para el diagnóstico rápido del SARS-CoV-2 / Clinical validation of the isothermal RT-LAMP test for rapid diagnosis of SARS-CoV-2

Introducción. Desde el primer reporte en la provincia de Wuhan (China) en el año 2019, el SARS-CoV-2 se ha diseminado por todo el mundo, provocando un enorme impacto en la salud pública. Para su diagnóstico, la Organización Mundial de la Salud ha incentivado el desarrollo de pruebas rápidas, de simple ejecución, sensibles y específicas, que complementan la RT-qPCR como prueba de referencia. La prueba RT-LAMP ha mostrado ser una excelente alternativa para la detección del SARS-CoV-2 en diferentes biofluidos. Objetivo. Validar la técnica RT-LAMP colorimétrica en muestras de hisopado nasofaríngeo previamente confirmadas por RT-qPCR, usando el protocolo Charité, Berlín, Alemania. Materiales y métodos. Un total de 153 muestras de hisopado nasofaríngeo de individuos con sospecha de COVID-19 se sometieron a RT-qPCR y RT-LAMP, usando un estuche comercial colorimétrico (NEB, Germany). La RT-LAMP se practicó con las muestras de ARN extraídas del hisopado nasofaríngeo y con muestras crudas sin previa extracción de ARN. El resultado fue evaluado por un simple cambio de color en la reacción. Resultados. La sensibilidad y especificidad de la técnica RT-LAMP para detectar el gen N del SARS-CoV-2 mediante un set de cebadores previamente reportados (set de Broughton), arrojó valores de 0,97 (0,85-1,00) y 0,81 (0,65-0,92), respectivamente, con un intervalo de confianza del 95%. Otro set de cebadores dirigidos contra otra región del mismo gen (set de Lalli) arrojó valores de sensibilidad y especificidad de 0,96 (0,78-1,00) y 0,77 (0,55-0,92), respectivamente. Sin previa extracción de ARN, se encontró que la sensibilidad fue del 0,95 (0,74-1,00) y la especificidad del 0,88 (0,64-0,99). Conclusiones. Estos resultados evidencian que la técnica RT-LAMP podría considerarse una prueba diagnóstica rápida, de fácil ejecución, libre de equipos sofisticados, sensible y específica, para el diagnóstico del SARS-CoV-2 en muestras de hisopados nasofaríngeos.

Introduction: Since the first report in Wuhan (China) in 2019, the SARS-CoV-2 virus has spread throughout the world, with a significant impact in public health. To contain its transmission, the WHO has encouraged the development of rapid, simple, sensitive and specific tests that complement qRT-PCR, as the gold standard. RT-LAMP has shown to be a good alternative to detect SARS-CoV-2 in different fluid samples. Objective: To validate the colorimetric RT-LAMP technique using two sets of primers targeting N gene of SARS-CoV-2 in 117 nasopharyngeal swab samples previously confirmed by RT-qPCR, using the Charité/Berlin protocol. Material and methods: A total of 153 nasopharyngeal swab samples from individuals with suspected COVID-19 were subjected to qRT-PCR and RT-LAMP using a commercial colorimetric kit (NEB, Germany). RT-LAMP was performed using both extracted RNA samples and raw samples without prior RNA extraction, and the result was assessed by a simple color change in the reaction. Results: Sensitivity and specificity for the previously reported RT-LAMP primers (Broughton set) targeting N gene of SARS-CoV-2 were 0.97 (0.85-1.00) and 0.81 (0.65-0.92) respectively, with CI95%. The Lalli primers targeting another region of the N gene used showed a sensitivity value of 0.96 (0.78-1.00) and a specificity of 0.77 (0.55-0.92). Without RNA extraction we found a sensitivity value of 0.95 (0.74, 1.00) and a specificity of 0.88 (0.64, 0.99). A sensitivity value of 0.95 (0.74-1.00) and a specificity 0.88 (0.64-0.99) were found without prior RNA extraction. Conclusion: Taking together, the results showed that RT-LAMP technique could be considered as a rapid diagnostic test, easy to perform, free of sophisticated equipment, sensitive and specific to diagnose SARS-CoV-2 in nasopharyngeal swabs with and without prior RNA extraction, allowing its implementation in places with scarce resources.

The Burden of Carbohydrates in Health and Disease.

Foods high in carbohydrates are an important part of a healthy diet, since they provide the body with glucose to support bodily functions and physical activity. However, the abusive consumption of refined, simple, and low-quality carbohydrates has a direct implication on the physical and mental pathophysiology. Then, carbohydrate consumption is postulated as a crucial factor in the development of the main Western diseases of the 21st century. We conducted this narrative critical review using MedLine (Pubmed), Cochrane (Wiley), Embase, and CinAhl databases with the MeSH-compliant keywords: carbohydrates and evolution, development, phylogenetic, GUT, microbiota, stress, metabolic health, consumption behaviors, metabolic disease, cardiovascular disease, mental disease, anxiety, depression, cancer, chronic kidney failure, allergies, and asthma in order to analyze the impact of carbohydrates on health. Evidence suggests that carbohydrates, especially fiber, are beneficial for the well-being and growth of gut microorganisms and consequently for the host in this symbiotic relationship, producing microbial alterations a negative effect on mental health and different organic systems. In addition, evidence suggests a negative impact of simple carbohydrates and refined carbohydrates on mood categories, including alertness and tiredness, reinforcing a vicious circle. Regarding physical health, sugar intake can affect the development and prognosis of metabolic disease, as an uncontrolled intake of refined carbohydrates puts individuals at risk of developing metabolic syndrome and subsequently developing metabolic disease.

Nutritional and Exercise Interventions in Cancer-Related Cachexia: An Extensive Narrative Review.

One of the common traits found in cancer patients is malnutrition and cachexia, which affects between 25% to 60% of the patients, depending on the type of cancer, diagnosis, and treatment. Given the lack of current effective pharmacological solutions for low muscle mass and sarcopenia, holistic interventions are essential to patient care, as well as exercise and nutrition. Thus, the present narrative review aimed to analyze the nutritional, pharmacological, ergonutritional, and physical exercise strategies in cancer-related cachexia. The integration of multidisciplinary interventions could help to improve the final intervention in patients, improving their prognosis, quality of life, and life expectancy. To reach these aims, an extensive narrative review was conducted. The databases used were MedLine (PubMed), Cochrane (Wiley), Embase, PsychINFO, and CinAhl. Cancer-related cachexia is a complex multifactorial phenomenon in which systemic inflammation plays a key role in the development and maintenance of the symptomatology. Pharmacological interventions seem to produce a positive effect on inflammatory state and cachexia. Nutritional interventions are focused on a high-energy diet with high-density foods and the supplementation with antioxidants, while physical activity is focused on strength-based training. The implementation of multidisciplinary non-pharmacological interventions in cancer-related cachexia could be an important tool to improve traditional treatments and improve patients' quality of life.

Reflexión sobre la incidencia de la desigualdad social en la salud mental de los jóvenes del barrio El Recreo del municipio de San Andrés de Cuerquia ­ Antioquia (2019-2020): una adicción o un patrón de relación inadecuado / Reflection on the incidence of social inequality in the mental health of young people in the El Recreo neighborhood of the municipality of San Andrés de Cuerquia-Antioquia (2019-2020)

Este artículo presenta una reflexión alrededor de un ejercicio de corte investigativo, desarrollado por el semillero de investigación: Trabajo Social, Calidad de Vida y Bienestar, perteneciente al programa de Trabajo Social de la Universidad Católica Luis Amigó. El tema central es explorar la incidencia de la desigualdad social en la salud mental de los jóvenes del municipio de San Andrés de Cuerquia, Antioquia, durante el primer semestre de 2020.

This article presents a reflection on an academic exercise, developed by the research lab: Social Work, Quality of Life and Well-being, belonging to the Social Work program of the Universidad Católica Luis Amigó. The central theme of this academic exercise consisted of exploring the incidence of social inequality in the mental health of young people in the municipality of San Andrés de Cuerquia, Antioquia, during the first semester of 2020

Cultural Differences in Stress-Related Psychological, Nutrition, Physical Activity and Oral Health Factors of Professors.

With the aim to explore cultural differences in stress-related psychological, nutrition, physical activity, and oral health factors between Spanish and Latin American professors, we analysed stress-related factors in 598 professors (39.9% male, 60.1% female, 41.3 ± 9.8 years) by a collection of questionnaires, which involved psychological, nutritional, physical activity and oral health items. Results showed how Spanish professors presented significantly (p ≤ 0.05) higher scores than Latin American professors in perceived stress (Spanish: 21.40 ± 4.32 vs. Latin American: 20.36 ± 4.31), teaching stress (Spanish: 6.59 ± 2.28 vs. Latin American: 6.00 ± 2.99) and neuroticism (Spanish: 5.40 ± 2.10 vs. Latin American: 4.58 ± 1.72). Spanish professors also showed healthier nutritional and physical activity habits than their Latin American counterparts, presenting higher consumption of milk products and a higher numbers of meals per day, greater weekly meat and fish consumption and higher weekly resistance training, as well as less eating between hours and snacking consumption. Nevertheless, Spanish professors brushed their teeth less and showed a higher smoking habit than Latin American professors. We concluded that there were cultural differences between Spanish and Latin American professors. In the present research, Spanish professors showed significantly higher burnout levels, teaching stress, perceived stress, and neuroticism than Latin American professors, and several differences were also found around health behaviours. These differences in perceived stress, teaching stress and burnout syndrome may be due to the habituation process of Latin American professors, and probably are associated with a higher stressful and demanding socio-cultural context.

Tumor penetrating peptides inhibiting MYC as a potent targeted therapeutic strategy for triple-negative breast cancers.

Overexpression of MYC oncogene is highly prevalent in many malignancies such as aggressive triple-negative breast cancers (TNBCs) and it is associated with very poor outcome. Despite decades of research, attempts to effectively inhibit MYC, particularly with small molecules, still remain challenging due to the featureless nature of its protein structure. Herein, we describe the engineering of the dominant-negative MYC peptide (OmoMYC) linked to a functional penetrating 'Phylomer' peptide (FPPa) as a therapeutic strategy to inhibit MYC in TNBC. We found FPPa-OmoMYC to be a potent inducer of apoptosis (with IC50 from 1-2 µM) in TNBC cells with negligible effects in non-tumorigenic cells. Transcriptome analysis of FPPa-OmoMYC-treated cells indicated that the fusion protein inhibited MYC-dependent networks, inducing dynamic changes in transcriptional, metabolic, and apoptotic processes. We demonstrated the efficacy of FPPa-OmoMYC in inhibiting breast cancer growth when injected orthotopically in TNBC allografts. Lastly, we identified strong pharmacological synergisms between FPPa-OmoMYC and chemotherapeutic agents. This study highlights a novel therapeutic approach to target highly aggressive and chemoresistant MYC-activated cancers.

Outer-membrane protein LptD (PA0595) plays a role in the regulation of alginate synthesis in Pseudomonas aeruginosa.

PURPOSE: The presence of alginate-overproducing (Alg+) strains of Pseudomonas aeruginosa in cystic fibrosis patients is indicative of chronic infection. The Alg+ phenotype is generally due to a mutation in the mucA gene, encoding an innermembrane protein that sequesters AlgT/U, the alginate-specific sigma factor. AlgT/U release from the anti-sigma factor MucA is orchestrated via a complex cascade called regulated intramembrane proteolysis. The goal of this study is to identify new players involved in the regulation of alginate production. METHODOLOGY: Previously, a mutant with a second-site suppressor of alginate production (sap), sap27, was isolated from the constitutively Alg+ PDO300 that harbours the mucA22 allele. A cosmid from a P. aeruginosa minimum tiling path library was identified via en masse complementation of sap27. The cosmid was transposon mutagenized to map the contributing gene involved in the alginate production. The identified gene was sequenced in sap27 along with algT/U, mucA, algO and mucP. The role of the novel gene was explored using precise in-frame algO and algW deletion mutants of PAO1 and PDO300.Results/Key findings. The gene responsible for restoring the mucoid phenotype was mapped to lptD encoding an outer-membrane protein. However, the sequencing of sap27 revealed a mutation in algO, but not in lptD. In addition, we demonstrate that lipopolysaccharide transport protein D (LptD)-dependent alginate production requires AlgW in PAO1 and AlgO in PDO300. CONCLUSION: LptD plays a specific role in alginate production. Our findings suggest that there are two pathways for the production of alginate in P. aeruginosa, one involving AlgW in the wild-type, and one involving AlgO in the mucA22 mutant.

Pseudomonas aeruginosa Regulated Intramembrane Proteolysis: Protease MucP Can Overcome Mutations in the AlgO Periplasmic Protease To Restore Alginate Production in Nonmucoid Revertants.

The progression of cystic fibrosis (CF) from an acute to a chronic disease is often associated with the conversion of the opportunistic pathogen Pseudomonas aeruginosa from a nonmucoid form to a mucoid form in the lung. This conversion involves the constitutive synthesis of the exopolysaccharide alginate, whose production is under the control of the AlgT/U sigma factor. This factor is regulated posttranslationally by an extremely unstable process and has been commonly attributed to mutations in the algT (algU) gene. By exploiting this unstable phenotype, we isolated 34 spontaneous nonmucoid variants arising from the mucoid strain PDO300, a PAO1 derivative containing the mucA22 allele commonly found in mucoid CF isolates. Complementation analysis using a minimal tiling path cosmid library revealed that most of these mutants mapped to two protease-encoding genes, algO, also known as prc or PA3257, and mucP Interestingly, our algO mutations were complemented by both mucP and algO, leading us to delete, clone, and overexpress mucP, algO, mucE, and mucD in both wild-type PAO1 and PDO300 backgrounds to better understand the regulation of this complex regulatory mechanism. Our findings suggest that the regulatory proteases follow two pathways for regulated intramembrane proteolysis (RIP), where both the AlgO/MucP pathway and MucE/AlgW pathway are required in the wild-type strain but where the AlgO/MucP pathway can bypass the MucE/AlgW pathway in mucoid strains with membrane-associated forms of MucA with shortened C termini, such as the MucA22 variant. This work gives us a better understanding of how alginate production is regulated in the clinically important mucoid variants of Pseudomonas aeruginosaIMPORTANCE Infection by the opportunistic pathogen Pseudomonas aeruginosa is the leading cause of morbidity and mortality seen in CF patients. Poor patient prognosis correlates with the genotypic and phenotypic change of the bacteria from a typical nonmucoid to a mucoid form in the CF lung, characterized by the overproduction of alginate. The expression of this exopolysaccharide is under the control an alternate sigma factor, AlgT/U, that is regulated posttranslationally by a series of proteases. A better understanding of this regulatory phenomenon will help in the development of therapies targeting alginate production, ultimately leading to an increase in the length and quality of life for those suffering from CF.

Tfr cells lack IL-2Rα but express decoy IL-1R2 and IL-1Ra and suppress the IL-1-dependent activation of Tfh cells.

Follicular regulatory T (Tfr) cells from lymph node germinal centers control follicular helper T (Tfh) cell-dependent B cell activation. These scarce cells, often described and purified as CD25+ cells, are thought to be derived from thymic regulatory T (Treg) cells. However, we observed that mouse Tfr cells do not respond to interleukin-2 (IL-2), unlike Treg cells. Stringent immunophenotyping based on B cell lymphoma 6 (Bcl6), programmed cell death protein 1 (PD-1), and CXCR5 expression revealed that Tfr cells are actually CD25-, in mice and humans. Moreover, Tfr cell characterization based only on CXCR5 and PD-1 high expression without excluding CD25+ cells resulted in contamination with Treg cells. Transcriptome studies of CD4+CXCR5+PD-1+Bcl6+Foxp3+CD25- Tfr cells revealed that they express the IL-1 decoy receptor IL-1R2 and the IL-1 receptor antagonist IL-1Ra, whereas Tfh cells express the IL-1R1 agonist receptor. IL-1 treatment expanded Tfh cells in vivo and activated their production of IL-4 and IL-21 in vitro. Tfr cells suppressed the IL-1-induced activation of Tfh cells as efficiently as the IL-1 receptor antagonist Anakinra. Altogether, these results reveal an IL-1 axis in the Tfh cell control of B cell responses and an IL-2/IL-1 dichotomy for Treg cell control of effector T cells versus Tfr cell control of Tfh cells.

TGF-ß and VEGF cooperatively control the immunotolerant tumor environment and the efficacy of cancer immunotherapies.

Tregs imprint an early immunotolerant tumor environment that prevents effective antitumor immune responses. Using transcriptomics of tumor tissues, we identified early upregulation of VEGF and TGF-ß pathways compatible with tolerance imprinting. Silencing of VEGF or TGF-ß in tumor cells induced early and pleiotropic modulation of immune-related transcriptome signatures in tumor tissues. These were surprisingly similar for both silenced tumors and related to common downstream effects on Tregs. Silencing of VEGF or TGF-ß resulted in dramatically delayed tumor growth, associated with decreased Tregs and myeloid-derived suppressor cells and increased effector T cell activation in tumor infiltrates. Strikingly, co-silencing of TGF-ß and VEGF led to a substantial spontaneous tumor eradication rate and the combination of their respective inhibitory drugs was synergistic. VEGF and/or TGF-ß silencing also restored tumor sensitivity to tumor-specific cell therapies and markedly improved the efficacy of anti-PD-1/anti-CTLA-4 treatment. Thus, TGF-ß and VEGF cooperatively control the tolerant environment of tumors and are targets for improved cancer immunotherapies.

Regulatory T Cells Orchestrate Similar Immune Evasion of Fetuses and Tumors in Mice.

Embryos and tumors are both masses of dividing cells expressing foreign Ags, but they are not rejected by the immune system. We hypothesized that similar tolerogenic mechanisms prevent their rejection. Global comparison of fetal and tumor microenvironments through transcriptomics in mice revealed strikingly similar and dramatic decreases in expression of numerous immune-related pathways, including Ag presentation and T cell signaling. Unsupervised analyses highlighted the parallel kinetics and similarities of immune signature downregulation, from the very first days after tumor or embryo implantation. Besides upregulated signatures related to cell proliferation, the only significant signatures shared by the two conditions across all biological processes and all time points studied were downmodulated immune response signatures. Regulatory T cell depletion completely reverses this immune downmodulation to an immune upregulation that leads to fetal or tumor immune rejection. We propose that evolutionarily selected mechanisms that protect mammalian fetuses from immune attack are hijacked to license tumor development.

Regulatory T-cells in pregnancy: historical perspective, state of the art, and burning questions.

In this review, we first revisit the original concept of "suppressor T-cells" in pregnancy, put it in a historical perspective, and then highlight the main data that licensed its resurrection and revision into the concept of "regulatory T-cells" (Tregs) in pregnancy. We review the evidence for a major role of Tregs in murine and human pregnancy and discuss Treg interactions with dendritic and uterine natural killer cells, other players of maternal-fetal tolerance. Finally, we highlight what we consider as the most important questions in the field.

How shape influences uptake: interactions of anisotropic polymer nanoparticles and human mesenchymal stem cells.

Among several nanoparticle properties, shape is important for their interaction with cells and, therefore, relevant for uptake studies and applications. In order to further investigate such characteristics, fluorescently labeled spherical polymer nanoparticles are synthesized by free-radical polymerization via the miniemulsion process. The spherical nanoparticles are subsequently submitted to controlled mechanical deformation to yield quasi-ellipsoidal polymeric nanoparticles with different aspect ratios. The uptake behaviors of spherical and non-spherical particles with equal volume are investigated qualitatively and quantitatively by electron microscopy, confocal laser scanning microscopy, and flow cytometry measurements. Non-spherical particles show fewer uptake by cells than their spherical counterparts with a negative correlation between aspect ratio and uptake rate. This is attributed to the larger average curvature radius of adsorbed non-spherical particles experienced by the cells.