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Hepatocellular carcinoma (HCC) is the prevalent form of liver cancer in adults and the fourth most common cause of cancer-related death worldwide. HCC predominantly arises in the context of cirrhosis as a result of chronic liver disease, injury and inflammation. Full-blown HCC has poor prognosis because it is highly aggressive and resistant to therapy. Consequently, interventions that can prevent or restrain HCC emergence from pre-cancerous diseased liver are a desirable strategy. Histone methylation is a dynamic, reversible epigenetic modification involving the addition or removal of methyl groups from lysine, arginine or glutamine residues. Aberrant activity of histone methylation writers, erases and readers has been implicated in several cancer types, including HCC. In this review, we provide an overview of research on the role of histone methylation in pre-cancerous and cancerous HCC published over the last 5 years. In particular, we present the evidence linking environmental factors such as diet, viral infections and carcinogenic agents with dysregulation of histone methylation during liver cancer progression with the aim to highlight future therapeutic possibilities.

Background and aims: Ductular reaction (DR) expands in chronic liver diseases and correlates with disease severity. Besides its potential role in liver regeneration, DR plays a role in the wound-healing response of the liver, promoting periductular fibrosis and inflammatory cell recruitment. However, there is no information regarding its role in intrahepatic angiogenesis. In the current study we investigated the potential contribution of DR cells to hepatic vascular remodeling during chronic liver disease. Approach and results: In mouse models of liver injury, DR cells express genes involved in angiogenesis. Among angiogenesis-related genes, the expression of Slit2 and its receptor Roundabout 1 (Robo1) was localized in DR cells and neoangiogenic vessels, respectively. The angiogenic role of the Slit2-Robo1 pathway in chronic liver disease was confirmed in ROBO1/2-/+ mice treated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine, which displayed reduced intrahepatic neovascular density compared to wild-type mice. However, ROBO1/2 deficiency did not affect angiogenesis in partial hepatectomy. In patients with advanced alcohol-associated disease, angiogenesis was associated with DR, and up-regulation of SLIT2-ROBO1 correlated with DR and disease severity. In vitro, human liver-derived organoids produced SLIT2 and induced tube formation of endothelial cells. Conclusions: Overall, our data indicate that DR expansion promotes angiogenesis through the Slit2-Robo1 pathway and recognize DR cells as key players in the liver wound-healing response., Supported by grants from Fondo de Investigación Sanitaria Carlos III (FIS), cofinanced by Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea, “Una manera de hacer Europa” (FIS PI20/00765, PI17/00673, to P.S.-B; FIS 18-PI18/00862, to I.G and M.C); from the National Institute on Alcohol Abuse and Alcoholism (1U01AA026972-01 and AGAUR 2017-SGR-01456, to P.S.-B.); and from the European Foundation for Alcohol Research (EA1653, to P.S.-B.). M.C. is funded by the Ramon y Cajal program from the Ministerio de Ciencia e Innovación RYC2019-026662-I. P.G. is funded by the Agencia de Gestió d'Ajuts Universitaris i de Recerca 2014 SGR 708, Centro de Investigaciónen Red Enfermedades Hepáticas y Digestivas (CIBERehd), and Institució Catalana de Recerca i Estudis Avançats. S.A. received a grant from the Ministerio de Educación, Cultura y Deporte (FPU17/04992). B.A.-B. is funded by the Instituto de Salud Carlos III (FI16/00203)

Hypercaloric diets overactivate the intestinal immune system and disrupt the microbiome and epithelial cell functions, impairing glucose metabolism. The origins of this inflammatory cascade are poorly characterized. We investigated the involvement of intestinal proinflammatory group 1 innate lymphoid cells (ILC1s) in obesity progression and metabolic disruption. In obese mice, we studied longitudinally the ILC1s response to the diet and ILC1s depletion to address its role in obesity. ILC1s are required for the expansion of pro-inflammatory macrophages and ILC2s. ILC1s depletion induced the ILC3-IL-22 pathway, increasing mucin production, antimicrobial peptides, and neuroendocrine cells. These changes were translated into higher gut hormones and reduced insulinemia and adiposity. ILC1s depletion was also associated with a bloom in Akkermansia muciniphila and decreases in Bilophila spp. Intestinal-ILC1s are upstream activators of inflammatory signals, connecting immunity with the microbiome, the enteroendocrine system, and the intestinal barrier in the control of glucose metabolism and adiposity., This study has been supported by the Spanish Ministry of Science and Innovation (MICINN) (grant PID2020-119536RB-I00). An PFU contract to RL-G from the Spanish Ministry of Universities (PFU 18/02026) and a Marie Sklodowska Curie Actions (MSCA-IF) ”MicroILCs” (GA: 8905454) contract to MO are acknowledged. The grant of Spanish Ministry of Science and Innovation (MCIN/AEI) of Center of Excellence Accreditation Severo Ochoa (CEX2021-001189-S/MCIN/AEI /10.13039/501100011033) is also acknowledged., With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2021-001189-S).

Minimal hepatic encephalopathy (MHE) is associated with changes in the immune system including an increased pro-inflammatory environment and altered differentiation of CD4+ T lymphocytes. The mechanisms remain unknown. Changes in extracellular vesicle (EV) cargo including proteins and miRNAs could play a main role as mediators of immune system changes associated with MHE. The aim was to assess whether plasma EVs from MHE patients played a role in inducing the pro-inflammatory environment and altered differentiation of CD4+ T lymphocyte subtypes in MHE patients. We characterized the miRNA and protein cargo of plasma EVs from 50 cirrhotic patients (27 without and 23 with MHE) and 24 controls. CD4+ T cells from the controls were cultured with plasma EVs from the three groups of study, and the cytokine release and differentiation to CD4+ T-cell subtypes were assessed. Plasma EVs from MHE patients had altered miRNA and protein contents, and were enriched in inflammatory factors compared to the controls and patients without MHE. EVs from MHE patients modulated the expression of pro-inflammatory IL-17, IL-21, and TNF-α and anti-inflammatory TGF-β in cultured CD4+ T lymphocytes, and increased the proportion of Th follicular and Treg cells and the activation of Th17 cells. In conclusion, plasma EVs could play an important role in the induction of immune changes observed in MHE.

Introducción: La neumonía adquirida en la comunidad (NAC) es una enfermedad frecuente que puede serabordada en hospitalización a domicilio (HAD). En el presente trabajo evaluamos el margen de mejoracon el uso de antibióticos en la NAC en HAD. Métodos: Se reclutaron retrospectivamente todos los pacientes con NAC en dos hospitales españolesdesde el 01 de enero de 2018 al 30 de octubre de 2019. Se registraron variables demográficas, clínicas y sobre calidad de prescripción antibiótica. Posteriormente se construyó una variable que recogía seis indi-cadores de calidad asistencial, categorizando y comparando a los pacientes en dos grupos: buena calidadasistencial (cuatro o más indicadores realizados) o mala calidad asistencial (tres o menos indicadoresrealizados). Resultados: Obtuvimos una muestra de 260 pacientes. La solicitud de pruebas diagnósticas y la adecuacióna las guías de práctica clínica fue del 85, 4 y 85, 8%, respectivamente. Los porcentajes de realización dedesescalada (53, 7%) y terapia secuencial (57, 7%) cuando estaban indicadas fueron bajos. La duraciónmedia del tratamiento fue de 7, 3 días para el intravenoso y 9, 5 días para el total. La calidad de prescripciónfue buena en 134 (63, 2%) pacientes, siendo más frecuente en aquellos que ingresaron directamente enHAD desde urgencias. También se asoció a menor reingreso a 30 días. Conclusión: Existe un amplio margen de mejora en algunos aspectos con el uso de antimicrobianos enHAD, que podría motivar la implementación de programas de optimización del uso de antibióticos. Introduction: Community Acquired Pneumonia (CAP) is common disease that can be treated in Hospital At Home (HAH). In this paper we evaluate the room of improvement in the use of antibiotics in CAP in HH. Methods: Patients with CAP were retrospectively recruited in two Spanish hospitals from 1/1/18 to 10/30/19. Demographic, clinical and quality of antibiotic prescription variables were recorded. Subsequently, we created a new variable that collected six quality of care indicator, categorizing and comparing patients into two groups: good quality of care (4 or more indicators performed) or poor quality of care (3 or less indicators performed). Results: We recruited 260 patients. The request for diagnostic tests and the adequacy to Clinical Practice Guidelines were 85.4% and 85.8% respectively. Percentages of de-escalation (53.7%) and sequential therapy (57.7%) when indicated were low. The average length of treatment was 7.3 days for intravenous and 9.5 days for total. Quality of prescription was good in 134 (63.2%) patients, being more frequent in those who were admitted directly to HAD from the emergency room. It was also associated with less readmission at 30 days. Conclusion: There is a wide room for improvement in some fields of antimicrobials use in HAH that could stimulate the implementation of Antimicrobial Stewardship Programs.

OBJECTIVES: Alcoholic hepatitis (AH) is a severe condition characterized by a marked inflammatory response and high short-term mortality. Endothelial dysfunction (ED) is an early event in vascular and inflammatory disorders. The aim of this study is to evaluate ED in AH patients. METHODS: Prognostic value of ED biomarkers was evaluated in patients with severe AH (n = 67), compensated alcoholic cirrhosis (n = 15), heavy drinkers without liver disease (n = 15) and controls (n = 9), and in a validation cohort of 50 patients with AH. Gene expression of ED markers was analyzed in liver tissue. RESULTS: Plasma levels of ED markers such as vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), E-selectin and von Willebrand factor (vWF) increased along alcohol-related liver disease (ALD) progression. Intergroup analysis showed a significant increase of these markers in AH patients. In addition, VCAM-1 showed a positive correlation with Maddrey, MELD and ABIC scores and inflammation parameters (i.e. C-reactive protein and LPS levels). Importantly, levels of VCAM-1 were higher in patients with increased mortality and were independently associated with short-term survival (90-day) when adjusted by ABIC score. These results were confirmed in an independent cohort of AH patients. In addition, severe AH patients showed altered hepatic expression of ED markers. CONCLUSIONS: In this study we show that advanced ALD and particularly severe AH is associated with an increase of ED biomarkers, which correlate with patient outcomes. These results suggest that ED may be a pathogenic event in AH and highlight endothelial factors as potential biomarkers in AH.

La Retinopatía del Prematuro (ROP por sus siglas en inglés) es una causa importante de ceguera infantil en países totalmente industrializados desde 1942. Poco a poco en la medida que los servicios de atención en las unidades de neonatología en países en vías de desarrollo ha mejorado, esta patología es más frecuente. Se ha demostrado que las variaciones de las concentraciones de oxígeno durante las primeras semanas postnatales es perjudicial y favorece el desarrollo de ROP. Esto contribuye a las dos fases del desarrollo de la Retinopatía.

Aims: We analysed the impact of the SARS-CoV-2 pandemic (COVID-19) on the quality of breast cancer care in certified EUSOMA (European Society of Breast Cancer Specialists) breast centres.Materials and methods: The results of the EUSOMA quality indicators were compared, based on pseudonymised individual records, for the periods 1 March 2020 till 30 June 2020 (first COVID-19 peak in most countries in Europe) and 1 March 2019 till 30 June 2019. In addition, a questionnaire was sent to the participating Centres for investigating the impact of the COVID-19 pandemic on the organisation and the quality of breast cancer care.Results: Forty-five centres provided data and 31 (67%) responded to the questionnaire. The total number of new cases dropped by 19% and there was a small significant higher tumour (p = 0.003) and lymph node (p = 0.011) stage at presentation. Comparing quality indicators (12,736 patients) by multivariable analysis showed mostly non-significant differences. Surgery could be performed in a COVID-free zone in 94% of the centres, COVID testing was performed before surgery in 96% of the centres, and surgical case load was reduced in 55% of the centres. Modifications of the indications for neoadjuvant endocrine therapy, chemotherapy, and targeted therapy were necessary in 23%, 23%, and 10% of the centres; changes in indications for adjuvant endocrine, chemo-, targeted, immune, and radiotherapy in 3%, 19%, 3%, 6%, and 10%, respectively.Conclusion: Quality of breast cancer care was well maintained in EUSOMA breast centres during the first wave of the COVID-19 pandemic. A small but significantly higher tumour and lymph node stage at presentation was observed.

Gastric cancer predominantly occurs in adenocarcinoma form and is characterized by uncontrolled growth and metastases of gastric epithelial cells. The growth of gastric cells is regulated by the action of several major cell cycle regulators including Cyclins and Cyclin-dependent kinases (CDKs), which act sequentially to modulate the life cycle of a living cell. It has been reported that inadequate or over-activity of these molecules leads to disturbances in cell cycle dynamics, which consequently results in gastric cancer development. Manny studies have reported the key roles of Cyclins and CDKs in the development and progression of the disease in either in vitro cell culture studies or in vivo models. We aimed to compile the evidence of molecules acting as regulators of both Cyclins and CDKs, i.e., upstream regulators either activating or inhibiting Cyclins and CDKs. The review entails an introduction to gastric cancer, along with an overview of the involvement of cell cycle regulation and focused on the regulation of various Cyclins and CDKs in gastric cancer. It can act as an extensive resource for developing new hypotheses for future studies.

Description, The mTOR-LARP1-5′TOP axis acts at the translational level as a primary guardian of the anabolic capacity of the cell., Ribosomes execute the transcriptional program in every cell. Critical to sustain nearly all cellular activities, ribosome biogenesis requires the translation of ~200 factors of which 80 are ribosomal proteins (RPs). As ribosome synthesis depends on RP mRNA translation, a priority within the translatome architecture should exist to ensure the preservation of ribosome biogenesis capacity, particularly under adverse growth conditions. Here, we show that under critical metabolic constraints characterized by mTOR inhibition, LARP1 complexed with the 40S subunit protects from ribophagy the mRNAs regulon for ribosome biogenesis and protein synthesis, acutely preparing the translatome to promptly resume ribosomes production after growth conditions return permissive. Characterizing the LARP1-protected translatome revealed a set of 5′TOP transcript isoforms other than RPs involved in energy production and in mitochondrial function, among other processes, indicating that the mTOR-LARP1-5′TOP axis acts at the translational level as a primary guardian of the cellular anabolic capacity.

The molecular mechanisms driving the progression from early-chronic liver disease (CLD) to cirrhosis and, finally, acute-on-chronic liver failure (ACLF) are largely unknown. Our aim was to develop a protein network-based approach to investigate molecular pathways driving progression from early-CLD to ACLF.Transcriptome analysis was performed on liver biopsies from patients at different liver disease stages, including fibrosis, compensated cirrhosis, decompensated cirrhosis and ACLF, and control healthy livers. We created 9 liver-specific disease-related protein-protein interaction networks capturing key pathophysiological processes potentially related to CLD. We used these networks as a framework and performed gene set-enrichment analysis (GSEA) to identify dynamic gene profiles of disease progression.Principal component analyses revealed that samples clustered according to the disease stage. GSEA of the defined processes showed an upregulation of inflammation, fibrosis and apoptosis networks throughout disease progression. Interestingly, we did not find significant gene expression differences between compensated and decompensated cirrhosis, while ACLF showed acute expression changes in all the defined liver disease-related networks. The analyses of disease progression patterns identified ascending and descending expression profiles associated with ACLF onset. Functional analyses showed that ascending profiles were associated with inflammation, fibrosis, apoptosis, senescence and carcinogenesis networks, while descending profiles were mainly related to oxidative stress and genetic factors. We confirmed by qPCR the upregulation of genes of the ascending profile and validated our findings in an independent patient cohort.ACLF is characterized by a specific hepatic gene expression pattern related to inflammation, fibrosis, apoptosis, senescence and carcinogenesis. Moreover, the observed profile is significantly different from that of compensated and decompensated cirrhosis, supporting the hypothesis that ACLF should be considered a distinct entity.By using transjugular biopsies obtained from patients at different stages of chronic liver disease, we unveil the molecular pathogenic mechanisms implicated in the progression of chronic liver disease to cirrhosis and acute-on-chronic liver failure. The most relevant finding in this study is that patients with acute-on-chronic liver failure present a specific hepatic gene expression pattern distinct from that of patients at earlier disease stages. This gene expression pattern is mostly related to inflammation, fibrosis, angiogenesis, and senescence and apoptosis pathways in the liver.

In Spain, more than 10% of patients discharged with acute heart failure (AHF) are readmitted in the first 30 days. This study is designed to assess whether the treatment of AHF guided by clinical ultrasound (CU) in the setting of hospitalization at home (HAH) reduces the incidence of readmission and mortality compared to the standard care (SC).A randomized, open, parallel, single-center and controlled clinical trial (RCT) was designed (NT05042752). Patients18 years of age admitted for AHF to HAD from January 2021 to April 2021 at the Reina Sofía Hospital in Tudela were consecutively included. The patients were randomized to the UG-ultrasound group (SC and CU performed) and the CG-control group (SC). The diuretic treatment was tailored according to the findings of the SC together with the CU or according to the findings of the SC respectively. The main variables were the relative risk of readmission and mortality from AHF.A total of 79 patients were randomized, 39 to UG and 40 to CG. Of these, only 35 of the UG and 35 of the CG completed the intervention. The risk of readmission due to AHF was reduced by 60% in UG compared to CG (RR 0.4; 95% CI: 0.1-1) and mortality by 30% (RR 0.7; 95% CI: 0.2-2.2). Despite the relevant magnitude of the effect found, the results did not reach statistical significance due to lack of power.Our results suggest that in HAH, a CE guided strategy for AHF could reduce the risk of readmission and mortality compared to SC alone. However, studies with greater statistical power are needed to confirm these results.

Substance-related disorders are the most frequent comorbidity in schizophrenia. Concretely, alcohol is the most commonly consumed substance after tobacco. Patients with schizophrenia with this comorbidity have a worse clinical course and can develop serious neuropsychiatric complications. One of them, Marchiafava-Bignami disease (MBD) can be incorrectly diagnosed as a decompensation of their mental disorder.

El articulo plantea una propuesta pedagogica para los Este analisis de la obra Caudillo con bebe 2000-2007 del artista colombiano Rosemberg Sandoval parte de la consideracion de la repeticion de patrones poeticos que se dan en la obra de arte y el concepto de sacrif icio desde diversas lineas de pensamiento, que genera una conexion entre la violencia ritual ejercida en la infancia, por ejemplo en el ritual de Capacocha, con la violencia ejercida sobre la infancia en la actualidad.

Chronic liver diseases are characterized by the expansion of ductular reaction (DR) cells and the expression of liver progenitor cell (LPC) markers. In alcoholic hepatitis (AH), the degree of DR expansion correlates with disease progression and short-term survival. However, little is known about the biological properties of DR cells, their impact on the pathogenesis of human liver disease, and their contribution to tissue repair. In this study, we have evaluated the transcriptomic profile of DR cells by laser capture microdissection in patients with AH and assessed its association with disease progression. The transcriptome analysis of cytokeratin 7-positive (KRT7(+)) DR cells uncovered intrinsic gene pathways expressed in DR and genes associated with alcoholic liver disease progression. Importantly, DR presented a proinflammatory profile with expression of neutrophil recruiting C-X-C motif chemokine ligand (CXC) and C-C motif chemokine ligand chemokines. Moreover, LPC markers correlated with liver expression and circulating levels of inflammatory mediators such as CXCL5. Histologically, DR was associated with neutrophil infiltration at the periportal area. In order to model the DR and to assess its functional role, we generated LPC organoids derived from patients with cirrhosis. Liver organoids mimicked the transcriptomic and proinflammatory profile of DR cells. Conditioned medium from organoids induced neutrophil migration and enhanced cytokine expression in neutrophils. Likewise, neutrophils promoted the proinflammatory profile and the expression of chemokines of liver organoids. CONCLUSION: Transcriptomic and functional analysis of KRT7(+) cells indicate that DR has a proinflammatory profile and promote neutrophil recruitment. These results indicate that DR may be involved in the liver inflammatory response in AH, and suggest that therapeutic strategies targeting DR cells may be useful to mitigate the inflammatory cell recruitment in AH.

Background Epigenetic modifiers, such as methyltransferases, play crucial roles in the regulation of many biological processes, including development, cancer and multiple physiopathological conditions. Summary The Su(Var)3–9, Enhancer-of-zeste and Trithorax (SET) and Myeloid, Nervy, and DEAF-1 (MYND) domain-containing (SMYD) protein family consists of five members in humans and mice (i.e. SMYD1, SMYD2, SMYD3, SMYD4 and SMYD5), which are known or predicted to have methyltransferase activity on histone and non-histone substrates. The abundance of information concerning SMYD2 and SMYD3 is of note, whereas the other members of the SMYD family have not been so thoroughly studied Conclusion Here we review the literature regarding SMYD proteins published in the last five years, including basic molecular biology mechanistic studies using in vitro systems and animal models, as well as human studies with a more translational or clinical approach.

Julio Plaza-Diaz is part of the "UGR Plan Propio de Investigacion 2016" and the "Excellence actions: Unit of Excellence on Exercise and Health (UCEES), University of Granada". He is likewise supported by a grant to postdoctoral researchers at foreign universities and research centers from the "Fundacion Ramon Areces", Madrid, Spain., Helicobacter pylori (H. pylori) is a Gram-negative bacterium that colonizes the stomach and can induce gastric disease and intra-gastric lesions, including chronic gastritis, peptic ulcers, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. This bacterium is responsible for long-term complications of gastric disease. The conjunction of host genetics, immune response, bacterial virulence expression, diet, micronutrient availability, and microbiome structure influence the disease outcomes related to chronic H. pylori infection. In this regard, the consumption of unhealthy and unbalanced diets can induce microbial dysbiosis, which infection with H. pylori may contribute to. However, to date, clinical trials have reported controversial results and current knowledge in this field is inconclusive. Here, we review preclinical studies concerning the changes produced in the microbiota that may be related to H. pylori infection, as well as the involvement of diet. We summarize and discuss the last approaches based on the modulation of the microbiota to improve the negative impact of H. pylori infection and their potential translation from bench to bedside., "Fundacion Ramon Areces", Madrid, Spain

Hepatic stellate cells (HSCs) are nonparenchymal liver cells responsible for extracellular matrix homeostasis and are the main cells involved in the development of liver fibrosis following injury. The lack of reliable sources of HSCs has hence limited the development of complex in vitro systems to model liver diseases and toxicity. Here we describe a protocol to differentiate human induced pluripotent stem cells (iPSCs) into hepatic stellate cells (iPSC-HSCs). The protocol is based on the addition of several growth factors important for liver development sequentially over 12 d. iPSC-HSCs present phenotypic and functional characteristics of primary HSCs and can be expanded or frozen and used to perform high-throughput in vitro studies. We also describe how to coculture iPSC-HSCs with hepatocytes, which self-assemble into three-dimensional (3D) hepatic spheroids. This protocol enables the generation of HSC-like cells for in vitro modeling and drug screening studies. Human iPSCs are differentiated into HSCs by culture with growth factors. They respond to fibrogenic stimuli, arising as a new source of HSC-like cells for in vitro modeling. Subsequent coculture with hepatocytes facilitates self-assembly into 3D hepatic spheroids.

The revelance of the epigenetic regulation of cancer led to the design and testing of many drugs targeting epigenetic modifiers. The Su(Var)3–9, Enhancer-of-zeste and Trithorax (SET) and myeloid, Nervy, and DEAF-1 (MYND) domain-containing protein 2 (SMYD2) and 3 (SMYD3) are methyltransferases which act on histone and non-histone proteins to promote tumorigenesis in many cancer types. In addition to their oncogenic roles, SMYD2 and SMYD3 are involved in many other physiopathological conditions. In this review we will focus on the advances made in the last five years in the field of pharmacology regarding drugs targeting SMYD2 (such as LLY-507 or AZ505) and SMYD3 (such as BCI-121 or EPZ031686) and their potential cellular and molecular mechanisms of action and application in anti-tumoural therapy and/or against other diseases.

Epigenetics is an emerging field, due to its relevance in the regulation of a wide range of biological processes. The Su(Var)3-9, Enhancer-of-zeste and Trithorax (SET) and Myeloid, Nervy, and DEAF-1 (MYND) domain-containing (SMYD) proteins, named SMYD1, SMYD2, SMYD3, SMYD4 and SMYD5, are enzymes that catalyse methylation of histone and non-histone substrates, thereby playing a key role in gene expression regulation in many biological contexts, such as muscle development and physiology, haematopoiesis and many types of cancer. This review focuses on a relatively unexplored aspect of SMYD family members - their relation with immunology. Here, immunology is defined in the broadest sense of the word, including basic research on macrophage function or host immunity against pathogen infection, as well as clinical studies, most of which are centred on blood cancers.