Endoplasmic reticulum stress promotes hepatocellular carcinoma by modulating immunity: a study based on artificial neural networks and single-cell sequencing.

INTRODUCTION: Hepatocellular carcinoma (HCC) is characterized by the complex pathogenesis, limited therapeutic methods, and poor prognosis. Endoplasmic reticulum stress (ERS) plays an important role in the development of HCC, therefore, we still need further study of molecular mechanism of HCC and ERS for early diagnosis and promising treatment targets. METHOD: The GEO datasets (GSE25097, GSE62232, and GSE65372) were integrated to identify differentially expressed genes related to HCC (ERSRGs). Random Forest (RF) and Support Vector Machine (SVM) machine learning techniques were applied to screen ERSRGs associated with endoplasmic reticulum stress, and an artificial neural network (ANN) diagnostic prediction model was constructed. The ESTIMATE algorithm was utilized to analyze the correlation between ERSRGs and the immune microenvironment. The potential therapeutic agents for ERSRGs were explored using the Drug Signature Database (DSigDB). The immunological landscape of the ERSRGs central gene PPP1R16A was assessed through single-cell sequencing and cell communication, and its biological function was validated using cytological experiments. RESULTS: An ANN related to the ERS model was constructed based on SRPX, THBS4, CTH, PPP1R16A, CLGN, and THBS1. The area under the curve (AUC) of the model in the training set was 0.979, and the AUC values in three validation sets were 0.958, 0.936, and 0.970, respectively, indicating high reliability and effectiveness. Spearman correlation analysis suggests that the expression levels of ERSRGs are significantly correlated with immune cell infiltration and immune-related pathways, indicating their potential as important targets for immunotherapy. Mometasone was predicted to be the most promising treatment drug based on its highest binding score. Among the six ERSRGs, PPP1R16A had the highest mutation rate, predominantly copy number mutations, which may be the core gene of the ERSRGs model. Single-cell analysis and cell communication indicated that PPP1R16A is predominantly distributed in liver malignant parenchymal cells and may reshape the tumor microenvironment by enhancing macrophage migration inhibitory factor (MIF)/CD74 + CXCR4 signaling pathways. Functional experiments revealed that after siRNA knockdown, the expression of PPP1R16A was downregulated, which inhibited the proliferation, migration, and invasion capabilities of HCCLM3 and Hep3B cells in vitro. CONCLUSION: The consensus of various machine learning algorithms and artificial intelligence neural networks has established a novel predictive model for the diagnosis of liver cancer associated with ERS. This study offers a new direction for the diagnosis and treatment of HCC.

Analysis of preoperative nutrition, immunity and inflammation correlation index on the prognosis of upper tract urothelial carcinoma surgical patients: a retrospective single center study.

BACKGROUND: SII, PNI, SIRI, AAPR, and LIPI are prognostic scores based on inflammation, nutrition, and immunity. The purpose of this study was to examine the prognostic value of the SII, PNI, SIRI, AAPR, and LIPI in patients with UTUC who underwent radical nephroureterectomy with bladder cuff excision. MATERIALS AND METHODS: Data of UTUC patients in Sichuan Provincial People's Hospital from January 2017 to December 2021 were collected. The optimal critical values of SII, PNI, SIRI, and AAPR were determined by ROC curve, and LIPI was stratified according to the dNLR and LDH. The Kaplan-Meier method was used to draw the survival curve, and Cox proportional hazard model was used to analyze the factors affecting the prognosis of UTUC patients. RESULTS: A total of 81 patients with UTUC were included in this study. The optimal truncation value of PNI, SII, SIRI and AAPR were determined to be 48.15, 596.4, 1.45 and 0.50, respectively. Univariate Cox proportional hazard regression showed that low PNI, high SII, high SIRI, low AAPR and poor LIPI group were effective predictors of postoperative prognosis of UTUC patients. Multivariate Cox proportional hazard regression showed that high SII was an independent risk factor for postoperative prognosis of UTUC patients. According to ROC curve, the prediction efficiency of fitting indexes of PNI, SII, SIRI, AAPR and LIPI is better than that of using them alone. CONCLUSIONS: The SII, PNI, SIRI, AAPR, and LIPI was a potential prognostic predictor in UTUC patients who underwent radical nephroureterectomy with bladder cuff excision.

The Endosomal Sorting Complex, ESCRT, has diverse roles in blood progenitor maintenance, lineage choice and immune response.

Most hematological malignancies are associated with reduced expression of one or more components of the Endosomal Sorting Complex Required for Transport (ESCRT). However, the roles of ESCRT in stem cell and progenitor maintenance are not resolved. Parsing signaling pathways in relation to the canonical role of ESCRT poses a challenge. The Drosophila hematopoietic organ, the larval lymph gland, provides a path to dissect the roles of cellular trafficking pathways such as ESCRT in blood development and maintenance. Drosophila has 13 core ESCRT components. Knockdown of individual ESCRTs showed that only Vps28 and Vp36 were required in all lymph gland progenitors. Using the well-conserved ESCRT-II complex as an example of the range of phenotypes seen upon ESCRT depletion, we show that ESCRTs have cell-autonomous as well as non-autonomous roles in progenitor maintenance and differentiation. ESCRT depletion also sensitized posterior lobe progenitors to respond to immunogenic wasp infestation. We also identify key heterotypic roles for ESCRT in position-dependent control of Notch activation to suppress crystal cell differentiation. Our study shows that the cargo sorting machinery determines the identity of progenitors and their adaptability to the dynamic microenvironment. These mechanisms for control of cell fate may tailor developmental diversity in multiple contexts.

Association between systemic immunity-inflammation index and sex hormones in children and adolescents aged 6-19.

Objectives: This study aimed to evaluate the relationship between systemic immune-inflammation index (SII) and sex hormones in children and adolescents aged 6-19 years. Methods: Data were obtained from the National Health and Nutrition Examination Survey (NHANES) conducted between 2013 and 2016. Inclusion criteria comprised subjects aged 6-19 years with complete data on both SII and sex hormones. We employed weighted multiple regression analysis and subgroup analytical methods to independently estimate the relationship between SII and sex hormones. Results: In this study, a total of 3767 participants were included, with an average age of 12.32 ± 3.95 years. Males constituted 50.54%, and females 49.46%. Among males, a statistically significant negative correlation emerged between SII and sex hormone-binding globulin (SHBG). Similarly, in the female population, SII exhibited a statistically significant negative correlation with total testosterone (TT), SHBG, and the Ratio of TT to estradiol, while maintaining a positive correlation with free androgen index (FAI). Subgroup analysis underscored variances in the association between sex hormones and SII within cohorts distinguished by pubertal status or different body mass index (BMI). In addition, the relationship between SII and estradiol exhibited nonlinearity. Employing a two-segment linear regression model, we identified an inverted U-shaped association between SII and estradiol, with an inflection point of 748.09 (1000cell/ml). Conclusion: Our findings suggest that SII may be an independent risk factor for changes in sex hormones in both male and female children and adolescents. More prospective and experimental studies should be conducted to validate our results and elucidate the underlying molecular pathways.

Mitochondrial Reactive Oxygen Species in Infection and Immunity.

Reactive oxygen species (ROS) contain at least one oxygen atom and one or more unpaired electrons and include singlet oxygen, superoxide anion radical, hydroxyl radical, hydroperoxyl radical, and free nitrogen radicals. Intracellular ROS can be formed as a consequence of several factors, including ultra-violet (UV) radiation, electron leakage during aerobic respiration, inflammatory responses mediated by macrophages, and other external stimuli or stress. The enhanced production of ROS is termed oxidative stress and this leads to cellular damage, such as protein carbonylation, lipid peroxidation, deoxyribonucleic acid (DNA) damage, and base modifications. This damage may manifest in various pathological states, including ageing, cancer, neurological diseases, and metabolic disorders like diabetes. On the other hand, the optimum levels of ROS have been implicated in the regulation of many important physiological processes. For example, the ROS generated in the mitochondria (mitochondrial ROS or mt-ROS), as a byproduct of the electron transport chain (ETC), participate in a plethora of physiological functions, which include ageing, cell growth, cell proliferation, and immune response and regulation. In this current review, we will focus on the mechanisms by which mt-ROS regulate different pathways of host immune responses in the context of infection by bacteria, protozoan parasites, viruses, and fungi. We will also discuss how these pathogens, in turn, modulate mt-ROS to evade host immunity. We will conclude by briefly giving an overview of the potential therapeutic approaches involving mt-ROS in infectious diseases.

Opposing tumor-cell-intrinsic and -extrinsic roles of the IRF1 transcription factor in antitumor immunity.

Type I interferon (IFN-I) and IFN-γ foster antitumor immunity by facilitating T cell responses. Paradoxically, IFNs may promote T cell exhaustion by activating immune checkpoints. The downstream regulators of these disparate responses are incompletely understood. Here, we describe how interferon regulatory factor 1 (IRF1) orchestrates these opposing effects of IFNs. IRF1 expression in tumor cells blocks Toll-like receptor- and IFN-I-dependent host antitumor immunity by preventing interferon-stimulated gene (ISG) and effector programs in immune cells. In contrast, expression of IRF1 in the host is required for antitumor immunity. Mechanistically, IRF1 binds distinctly or together with STAT1 at promoters of immunosuppressive but not immunostimulatory ISGs in tumor cells. Overexpression of programmed cell death ligand 1 (PD-L1) in Irf1-/- tumors only partially restores tumor growth, suggesting multifactorial effects of IRF1 on antitumor immunity. Thus, we identify that IRF1 expression in tumor cells opposes host IFN-I- and IRF1-dependent antitumor immunity to facilitate immune escape and tumor growth.

HIF-1α and MIF enhance neutrophil-driven type 3 immunity and chondrogenesis in a murine spondyloarthritis model.

The hallmarks of spondyloarthritis (SpA) are type 3 immunity-driven inflammation and new bone formation (NBF). Macrophage migration inhibitory factor (MIF) was found to be a key driver of the pathogenesis of SpA by amplifying type 3 immunity, yet MIF-interacting molecules and networks remain elusive. Herein, we identified hypoxia-inducible factor-1 alpha (HIF1A) as an interacting partner molecule of MIF that drives SpA pathologies, including inflammation and NBF. HIF1A expression was increased in the joint tissues and synovial fluid of SpA patients and curdlan-injected SKG (curdlan-SKG) mice compared to the respective controls. Under hypoxic conditions in which HIF1A was stabilized, human and mouse neutrophils exhibited substantially increased expression of MIF and IL-23, an upstream type 3 immunity-related cytokine. Similar to MIF, systemic overexpression of IL-23 induced SpA pathology in SKG mice, while the injection of a HIF1A-selective inhibitor (PX-478) into curdlan-SKG mice prevented or attenuated SpA pathology, as indicated by a marked reduction in the expression of MIF and IL-23. Furthermore, genetic deletion of MIF or HIF1A inhibition with PX-478 in IL-23-overexpressing SKG mice did not induce evident arthritis or NBF, despite the presence of psoriasis-like dermatitis and blepharitis. We also found that MIF- and IL-23-expressing neutrophils infiltrated areas of the NBF in curdlan-SKG mice. These neutrophils potentially increased chondrogenesis and cell proliferation via the upregulation of STAT3 in periosteal cells and ligamental cells during endochondral ossification. Together, these results provide supporting evidence for an MIF/HIF1A regulatory network, and inhibition of HIF1A may be a novel therapeutic approach for SpA by suppressing type 3 immunity-mediated inflammation and NBF.

The global role of G6PD in infection and immunity.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy in humans. G6PD is an essential enzyme in the pentose phosphate pathway (PPP), generating NADPH needed for cellular biosynthesis and reactive oxygen species (ROS) homeostasis, the latter especially key in red blood cells (RBCs). Beyond the RBC, there is emerging evidence that G6PD exerts an immunologic role by virtue of its functions in leukocyte oxidative metabolism and anabolic synthesis necessary for immune effector function. We review these here, and consider the global immunometabolic role of G6PD activity and G6PD deficiency in modulating inflammation and immunopathology.

Bulletin d'immunisation, v.46, n.1, Mar. 2024

L'Organisation panaméricaine de la santé (OPS) publie quatre fois par an le Bulletin d'Immunisation en anglais, français, portugais et espagnol. Son objectif est de faciliter l'échange d'idées et d'informations sur les programmes de vaccination dans la région des Amériques et au-delà. Il est publié depuis 1979 en anglais et en espagnol, les versions française et portugaise ayant débuté en 2001 et 2019, respectivement. Le numéro de mars 2024 du bulletin trimestriel Bulletin d'Immunisation traite des sujets suivants : Troisième réunion annuelle de la Commission régionale de suivi et de revérification de l'élimination de la rougeole, de la rubéole et du syndrome de rubéole ; Le Groupe consultatif technique de l’OPS sur les maladies évitables par la vaccination fournit des recommandations régionales sur les vaccins contre la dengue et le virus respiratoire syncytial, et publie une déclaration sur les efforts de vaccination en cours contre la COVID-19 ; Tracer la voie à suivre : réflexions sur l’initiative d’élimination des maladies transmissibles de l’OPS et les orientations futures; Vers l’élimination des maladies associées aux infections à papillomavirus humains dans la Caraïbe française : mise en œuvre d’une campagne généralisée de vaccination en milieu scolaire depuis octobre 2023; Méthodologie et outil de suivi de la performance du Programme élargi de vaccination pour la Région des Amériques; Surveillance sentinelle du rotavirus chez les enfants de moins de 5 ans dans la Région des Amériques; Surveillance sentinelle des pneumonies et méningites bactériennes chez les enfants de moins de 5 ans dans la Région des Amériques ; Atelier sur la préparation de textes et d'articles scientifiques dans le domaine de la santé à Bogota (Colombie) ; Classement final des cas, Région des Amériques, 2023 ; Le système d'information sur la vaccination et la qualité des données; Cours d'auto-apprentissage en ligne : Outils de suivi des interventions intégrées de santé publique. Vaccination et vermifugation pour la géohelminthiase ; et Renforcer la gestion des données de vaccination.

Boletim de Imunização, v.46, n.1, Mar. 2024

A Organização Pan-Americana da Saúde (OPAS) publica o Boletim de Imunização quatro vezes por ano em inglês, francês, português e espanhol. Seu objetivo é facilitar o intercâmbio de ideias e informações sobre programas de imunização na Região das Américas e fora dela. Ele é publicado desde 1979 em inglês e espanhol, com versões em francês e português iniciadas em 2001 e 2019, respectivamente. A edição de marzo de 2024 do Boletim de Imunização aborda os seguintes tópicos: Terceira Reunião Anual da Comissão Regional de Monitoramento e Reverificação da Eliminação do Sarampo, Rubéola e Síndrome da Rubéola Congênita; O Grupo Técnico Assessor da OPAS sobre Doenças Imunopreveníveis fornece recomendações regionais sobre as vacinas contra a dengue e o vírus sincicial respiratório e publica uma declaração sobre os esforços atuais de vacinação contra a COVID-19; Definição do caminho a seguir: reflexões sobre a Iniciativa da OPAS de Eliminação de Doenças Transmissíveis e orientações para o futuro; Rumo à eliminação de doenças associadas à infecção pelo papilomavírus humano no Caribe francês: implementação de uma campanha geral de vacinação nas escolas a partir de outubro de 2023; Metodologia e ferramenta de monitoramento do desempenho do Programa Ampliado de Imunização para a Região das Américas; Vigilância sentinela de rotavírus em menores de 5 anos na Região das Américas; Vigilância sentinela de casos de pneumonia e meningite bacteriana em menores de 5 anos na Região das Américas; Oficina de elaboração de textos e artigos científicos na área de saúde em Bogotá, Colômbia; Classificação final dos casos na Região das Américas, 2022; Sistema de informação de imunização e qualidade dos dados; Curso virtual de autoaprendizagem Ferramentas de monitoramento de intervenções integradas em saúde pública. Vacinação e desparasitação de geo-helmintíases; e Fortalecimento da gestão dos dados de imunização.

Immunization Newsletter, v.46, n.1, Mar. 2024

The Pan American Health Organization (PAHO) publishes the Immunization Newsletter four times a year in English, French, Portuguese, and Spanish. Its purpose is to facilitate the exchange of ideas and information on immunization programs in the Region of the Americas and beyond. It has been published since 1979 in English and Spanish, with French and Portuguese versions beginning in 2001 and 2019, respectively. The March 2024 issue of the quarterly Immunization Newsletter covers the following topics: Third annual meeting of the Regional Monitoring and Re-verification Commission for Measles, Rubella, and Congenital Rubella Syndrome Elimination; PAHO’s Technical Advisory Group (TAG) on Vaccine-preventable Diseases provides regional recommendations on dengue and respiratory syncytial virus vaccines and issues a statement on the ongoing COVID-19 vaccination efforts; Charting the path forward: reflections on PAHO's Communicable Diseases Elimination Initiative and future directions; Towards the Elimination of Diseases Associated with Human Papillomavirus Infection in the French Caribbean: Implementation of a Mass Vaccination Campaign in Schools Since October 2023; Expanded Immunization Program methodology and performance monitoring tool for the Region of the Americas; Sentinel surveillance of rotavirus in children under 5 years of age in the Region of the Americas; Sentinel surveillance of bacterial pneumonia and meningitis in children under 5 years of age in the Americas; Workshop on the preparation of scientific texts and articles on health in Bogotá, Colombia; Final Classification of Cases in the Region of the Americas, 2023; Immunization information systems and data quality; Virtual self-learning course: Tools for monitoring integrated public health interventions. Vaccination and deworming for soil-transmitted helminth infections; and Strengthening immunization data management.

Appendice. Pour une meilleure immunité : l’approche du parcours de vie pour une longévité en bonne santé

Cette publication est une annexe au document technique "Building better immunity : Une approche du parcours de vie pour une longévité en bonne santé", avec les contributions de plusieurs experts en la matière au sein et en dehors de l'Organisation panaméricaine de la santé (OPS). Cette annexe fournit des exemples d'activités au sein du programme national de vaccination qui peuvent améliorer les taux de couverture et réduire les occasions manquées pour quatre groupes de population : les femmes enceintes, les adolescents, les travailleurs de la santé et les personnes âgées. Ces exemples traduisent les principes et les concepts de l'approche fondée sur le parcours de vie en activités concrètes, qui peuvent être utilisées par les responsables des programmes nationaux de vaccination et par les vaccinateurs, respectivement, pour améliorer les taux de couverture vaccinale. Ces quatre groupes représentent des étapes de la vie pour lesquelles il existe des vaccins très efficaces et qui peuvent grandement influencer leurs capacités sanitaires. L'application des séries primaires, des rappels et des doses de vaccin de rattrapage dans ces groupes est essentielle pour combler les déficits d'immunité émergents. Les activités sont regroupées en huit composantes : (i) gestion et plaidoyer, (ii) équité, (iii) ressources humaines et financement, (iv) organisation et prestation de services, (v) génération de la demande et engagement communautaire, (vi) systèmes d'information, (vii) formation et (viii) évaluation et recherche. Les exemples doivent être évalués, adaptés, mis en œuvre et éventuellement élargis par les États membres pour s'aligner sur les contextes nationaux et locaux. Ce document s'inscrit dans le cadre des efforts déployés par l'OPS pour promouvoir l'application d'une approche de la vaccination fondée sur le parcours de vie dans les pays et territoires des Amériques et pour aider les ministères de la santé à mettre en place des stratégies de santé publique aux niveaux infranational et local afin de préserver la santé et le bien-être des personnes de tous âges.

Apéndice. Lograr una mejor inmunidad: El enfoque del curso de vida para una longevidad saludable

Esta publicación es un apéndice del documento técnico "Lograr una mejor inmunidad: el enfoque de curso de vida para una longevidad saludable", con las contribuciones de varios expertos en la materia dentro y fuera de la Organización Panamericana de la Salud (OPS). Este apéndice proporciona ejemplos de actividades dentro del programa nacional de inmunización que pueden mejorar las tasas de cobertura y reducir las oportunidades perdidas para cuatro grupos de población: mujeres embarazadas, adolescentes, trabajadores sanitarios y adultos mayores. Estos ejemplos traducen los principios y conceptos del Enfoque del Ciclo Vital en actividades concretas, que pueden ser utilizadas por los gestores de los programas nacionales de inmunización y por los vacunadores, respectivamente, para reforzar las tasas de cobertura de vacunación. Estos cuatro grupos representan etapas de la vida para las que existen vacunas muy eficaces y que pueden influir enormemente en sus capacidades sanitarias. La aplicación de dosis de vacunas de la serie primaria, de refuerzo y de recuperación en estos grupos es fundamental para cerrar las brechas de inmunidad emergentes. Las actividades se agrupan en ocho componentes (i) administración y promoción, (ii) equidad, (iii) recursos humanos y financiación, (iv) organización y prestación de servicios, (v) generación de demanda y participación de la comunidad, (vi) sistemas de información, (vii) formación y (viii) evaluación e investigación. Los ejemplos deben ser evaluados, adaptados, implementados y posiblemente ampliados por los Estados Miembros para alinearlos con los contextos nacionales y locales. Este documento forma parte de los esfuerzos de la OPS para promover la aplicación de un enfoque de inmunización a lo largo de la vida por parte de los países y territorios de las Américas y para apoyar a los Ministerios de Salud a establecer estrategias de salud pública a nivel subnacional y local para salvaguardar la salud y el bienestar de las personas de todas las edades.

The impact of the Mediterranean diet on immune function in older adults.

Diet is one of the lifestyle factors that is most amenable to intervention, and has a substantial effect on the potential for successful aging and mitigation of the risk of disease. Good nutrition is a pillar of healthy aging, and a large body of evidence attests to the benefits of the Mediterranean diet on the quality of the aging process. The Mediterranean diet comprises a wide range of nutrients which, both individually and collectively, exert positive effects on immunity, in large part mediated by the gut microbiota. In this article, we review the effect of the Mediterranean diet on immunity, and how its beneficial effects are mediated by the gut microbiota. We review the effects of certain key components of the Mediterranean dietary pattern, including vitamins, zinc, selenium, and polyphenols. Overall, the existing body of evidence convincingly demonstrates that the Mediterreanean diet affects immune health by maintaining a healthy body weight and reducing the risk of metabolic and cardiovascular diseases; by reducing inflammation and by promoting a healthy gut microbiota profile.

Zinc metabolism and its role in immunity status in subjects with trisomy 21: chromosomal dosage effect.

Introduction: Trisomy 21 (T21), which causes Down syndrome (DS), is the most common chromosomal aneuploidy in humankind and includes different clinical comorbidities, among which the alteration of the immune system has a heavy impact on patient's lives. A molecule with an important role in immune response is zinc and it is known that its concentration is significantly lower in children with T21. Different hypotheses were made about this metabolic alteration and one of the reasons might be the overexpression of superoxide dismutase 1 (SOD1) gene, as zinc is part of the SOD1 active enzymatic center. Methods: The aim of our work is to explore if there is a linear correlation between zinc level and immune cell levels measured in a total of 217 blood samples from subjects with T21. Furthermore, transcriptome map analyses were performed using Transcriptome Mapper (TRAM) software to investigate whether a difference in gene expression is detectable between subjects with T21 and euploid control group in tissues and cells involved in the immune response such as lymphoblastoid cells, thymus and white blood cells. Results: Our results have confirmed the literature data stating that the blood zinc level in subjects with T21 is lower compared to the general population; in addition, we report that the T21/control zinc concentration ratio is 2:3, consistent with a chromosomal dosage effect due to the presence of three copies of chromosome 21. The transcriptome map analyses showed an alteration of some gene's expression which might explain low levels of zinc in the blood. Discussion: Our data suggest that zinc level is not associated with the levels of immunity cells or proteins analyzed themselves and rather the main role of this ion might be played in altering immune cell function.