Quality of Life of Hematological Neoplasm Survivors After Hematopoietic Stem Cell Transplantation.

PURPOSE: This study aimed to assess changes in the quality of life (QoL) of patients with hematological neoplasms who underwent hematopoietic stem cell transplantation (HSCT), identify factors influencing these changes, and quantify the associated monetary value. METHODS: A total of 122 hematopoietic stem cell transplantation (HSCT) recipients participated in the study completing a recall survey with questions about 3 different stages: (1) pre-HSCT (baseline), (2) 6 months post-transplantation, and (3) between the first and fifth post-transplantation years. The study first estimated the incremental variation in QoL between phases and conducted regression analyses to identify factors linked to QoL changes. Second, it explored the transition probabilities of QoL between phases and their monetary value. RESULTS: Baseline QoL predominantly determined future QoL changes, with disease type, transplantation type, and other sociodemographic factors proving insignificant. Notably, patients with the lowest baseline QoL experienced greater QoL improvement post-HSCT compared to others. Specifically, 90% of patients elevated their QoL quartile within the first post-transplantation year, with over 20% reaching the highest quartile and an average QoL increase of 0.619. The incremental economic benefit for patients with poor baseline QoL, compared to those with high baseline QoL, was 56,880€. CONCLUSION: This study provides new, useful, and relevant information on the evolution of the QoL of these patients. Our findings support that HSCT significantly enhances QoL for survivors with initially low QoL, while those with high pre-HSCT QoL maintain their levels. Furthermore, other factors were not significant contributors to this relationship. The study introduced a novel method to measure the economic benefit of incremental QoL.

Ccn2 Deletion Reduces Cardiac Dysfunction, Oxidative Markers, and Fibrosis Induced by Doxorubicin Administration in Mice.

Cellular Communication Network Factor 2 (CCN2) is a matricellular protein implicated in cell communication and microenvironmental signaling. Overexpression of CCN2 has been documented in various cardiovascular pathologies, wherein it may exert either deleterious or protective effects depending on the pathological context, thereby suggesting that its role in the cardiovascular system is not yet fully elucidated. In this study, we aimed to investigate the effects of Ccn2 gene deletion on the progression of acute cardiac injury induced by doxorubicin (DOX), a widely utilized chemotherapeutic agent. To this end, we employed conditional knockout (KO) mice for the Ccn2 gene (CCN2-KO), which were administered DOX and compared to DOX-treated wild-type (WT) control mice. Our findings demonstrated that the ablation of CCN2 ameliorated DOX-induced cardiac dysfunction, as evidenced by improvements in ejection fraction (EF) and fractional shortening (FS) of the left ventricle. Furthermore, DOX-treated CCN2-KO mice exhibited a significant reduction in the gene expression and activation of oxidative stress markers (Hmox1 and Nfe2l2/NRF2) relative to DOX-treated WT controls. Additionally, the deletion of Ccn2 markedly attenuated DOX-induced cardiac fibrosis. Collectively, these results suggest that CCN2 plays a pivotal role in the pathogenesis of DOX-mediated cardiotoxicity by modulating oxidative stress and fibrotic pathways. These findings provide a novel avenue for future investigations to explore the therapeutic potential of targeting CCN2 in the prevention of DOX-induced cardiac dysfunction.

Smooth muscle-specific deletion of Ccn2 causes severe aorta malformation and atherosclerosis.

AIMS: Cellular Communication Network Factor 2 (CCN2) is a matricellular protein implicated in fibrotic diseases, with ongoing clinical trials evaluating anti-CCN2-based therapies. By uncovering CCN2 as abundantly expressed in non-diseased artery tissue, this study aimed to investigate the hypothesis that CCN2 plays a pivotal role in maintaining smooth muscle cell (SMC) phenotype and protection against atherosclerosis. METHODS AND RESULTS: Global- and SMC-specific Ccn2 knockout mouse models were employed to demonstrate that Ccn2 deficiency leads to SMC de-differentiation, medial thickening, and aorta elongation under normolipidemic conditions. Inducing hyperlipidemia in both models resulted in severe aorta malformation and a 17-fold increase in atherosclerosis formation. Lipid-rich lesions developed at sites of the vasculature typically protected from atherosclerosis-development by laminar blood flow, covering 90% of aortas, and extending to other vessels, including coronary arteries. Evaluation at earlier time points revealed medial lipid accumulation as a lesion-initiating event. Fluorescently labelled LDL injection followed by confocal microscopy showed increased LDL retention in the medial layer of Ccn2 knockout aortas, likely attributed to marked proteoglycan enrichment of the medial extracellular matrix. Analyses leveraging data from the Athero-Express study cohort indicated relevance of CCN2 in established human lesions, as CCN2 correlated with SMC marker transcripts across 654 transcriptomically profiled carotid plaques. These findings were substantiated through in situ hybridization showing CCN2 expression predominantly in the fibrous cap. CONCLUSIONS: This study identifies CCN2 as a major constituent of the normal artery wall, critical in regulating SMC differentiation and aorta integrity, and possessing a protective role against atherosclerosis development. These findings underscore the need for further investigation into the potential effects of anti-CCN2-based therapies on the vasculature.

Determining the Best Noninvasive Test for Peripheral Arterial Disease Diagnosis to Predict Diabetic Foot Ulcer Healing in Patients Following Endovascular Revascularization.

BACKGROUND/OBJECTIVES: To analyze the best noninvasive tests prognosis marker in patients with diabetic foot ulcer (DFU) who underwent endovascular revascularization based on clinical outcomes, such as healing rate, time to heal, and free amputation survival after at least a six-month follow-up. METHODS: A multicentric prospective observational study was performed with 28 participants with ischemic or neuroischemic DFU who came to the participant centers and underwent endovascular revascularization between January 2022 and March 2023. Toe systolic pressure (TP), ankle systolic pressure (AP), the ankle brachial pressure index (ABPI), the toe brachial pressure index (TBPI), transcutaneous pressure of oxygen (TcPO2), and skin perfusion pressure (SPP) were evaluated using PeriFlux 6000 System, Perimed, Sweden, before (Visit 0) and four weeks after revascularization (Visit 1). The primary clinical outcome was an evaluation of the clinical evolution of noninvasive tests comparing Visit 0 and Visit 1, estimating the sensitivity for predicting wound healing of noninvasive tests at six months following initial recruitment. RESULTS: After six months, 71.43% (n = 20) of DFU healed, four patients (14.3%) received major amputations, and one (3.5%) died. The two tests that best predicted wound healing after revascularization according to the ROC curve were TcPO2 and TP with sensitivities of 0.89 and 0.70 for the cut-off points of 24 mmHg and 46 mmHg, respectively. CONCLUSIONS: TcPO2 and TP were the two tests that best predicted wound healing in patients who underwent endovascular revascularization. Clinicians should consider the importance of the evaluation of microcirculation in the healing prognosis of patients with diabetic foot ulcers.

Pharmacodynamic monitoring by residual gene expression of the nuclear factor of activated T cell-regulated genes in lung transplant recipients and its correlation with tacrolimus blood levels.

Introduction: Trough blood levels (C0) of tacrolimus are used to adjust drug dosage, but they do not consistently correlate with clinical outcomes. Measurement of residual gene expression of nuclear factor of activated T cell (NFAT)-regulated genes (NFAT-RGE) has been proposed as a pharmacodynamic biomarker to assess the degree of immunosuppression in certain solid organ transplantations, but little is known regarding lung transplant recipients (LTR). Our primary objective is to correlate tacrolimus blood levels with NFAT-RGE. Methods: NFAT-RGE and tacrolimus C0 and peak (C1.5) levels were determined in 42 patients at three, six and 12 months post-transplantation. Results: Tacrolimus C0 did not exhibit a correlation with NFAT-RGE, whereas C1.5 did. Besides, over 20% of measurements indicated high levels of immunosuppression based on the below 30% NFAT-RGE threshold observed in many studies. Among those measurements within the therapeutic range, 19% had an NFAT-RGE<30%. Conclusion: Consequently, a subset of patients within the tacrolimus therapeutic range may be more susceptible to infection or cancer, potentially benefiting from NFAT-RGE and tacrolimus peak level monitoring to tailor their dosage. Further quantitative risk assessment studies are needed to elucidate the relationship between NFAT-RGE and the risk of infection, cancer, or rejection.

Propiedades psicométricas del Eating Attitudes Test-26 en escolares españoles / Psychometric properties of the Eating Attitudes Test-26 in Spanish schoolchildren

Introducción: Las Actitudes y los Comportamientos Alimentarios Desordenados (DEAB, por sus siglas en inglés) pueden afectar tanto a la salud mental como física en los niños/as. Su detección temprana es crucial para prevenir complicaciones y mejorar las posibilidades de recuperación. El Eating Attitudes Test-26 (EAT-26) es una herramienta ampliamente utilizada para evaluar las DEAB debido a su costo/efectividad.ObjetivoEvaluar las propiedades psicométricas del EAT-26, analizando la estructura factorial, la consistencia interna, la validez convergente e invarianza de medida entre ambos sexos en escolares españoles.MétodoEstudio instrumental con una muestra de 718 escolares. La muestra se dividió aleatoriamente en 2 grupos, cada uno con 359 participantes, realizando un análisis factorial exploratorio (AFE) y un análisis factorial confirmatorio (AFC). Posteriormente, se estimó la consistencia interna con el alfa ordinal, la validez convergente con el cuestionario SCOFF y la invarianza de medida entre ambos sexos.ResultadosLos hallazgos del AFE y AFC respaldaron una estructura multidimensional del EAT, compuesta por 6 factores y 21 ítems. Estos factores subyacen en un modelo de segundo orden de las DEAB. La consistencia interna fue suficiente para la mayoría de los factores. Se mostró una validez convergente moderada con el cuestionario SCOFF para la mayoría de los factores. Se alcanzó una invarianza estricta entre ambos sexos. (AU)

Introduction: Disordered Eating Attitudes and Behaviours (DEABs) can impact both the mental and physical health of children. Early detection is crucial to prevent complications and improve outcomes. The Eating Attitudes Test-26 (EAT-26) is a widely used, cost-effective tool for assessing DEABs.ObjectiveTo evaluate the psychometric properties of the EAT-26 by analysing its factor structure, internal consistency, convergent validity, and measurement invariance across sexes in Spanish schoolchildren.MethodValidation study in a sample of 718 schoolchildren. The sample was randomly divided into two groups, each with 359 participants, and we carried out an exploratory factor analysis (EFA) and a confirmatory factor analysis (CFA) of the instrument. Subsequently, for the total sample, we assessed the internal consistency by means of the ordinal alpha, the convergent validity with the SCOFF questionnaire and the measurement invariance between the sexes.ResultsThe results of the EFA and CFA supported a multidimensional structure of the EAT comprising six factors and 21 items. These factors underlie a second-order model of DEABs. The internal consistency was adequate for most factors. The SCOFF questionnaire showed a moderate convergent validity for most factors. We found strict invariance across the sexes. (AU)

Psychometric properties of the Eating Attitudes Test-26 in Spanish schoolchildren.

INTRODUCTION: Disordered Eating Attitudes and Behaviours (DEABs) can impact both the mental and physical health of children. Early detection is crucial to prevent complications and improve outcomes. The Eating Attitudes Test-26 (EAT-26) is a widely used, cost-effective tool for assessing DEABs. OBJECTIVE: To evaluate the psychometric properties of the EAT-26 by analysing its factor structure, internal consistency, convergent validity, and measurement invariance across sexes in Spanish schoolchildren. METHOD: Validation study in a sample of 718 schoolchildren. The sample was randomly divided into 2 groups, each with 359 participants, and we carried out an exploratory factor analysis (EFA) and a confirmatory factor analysis (CFA) of the instrument. Subsequently, we assessed the internal consistency by means of the ordinal alpha, the convergent validity with the SCOFF questionnaire and the measurement invariance across the sexes. RESULTS: The results of the EFA and CFA supported a multidimensional structure of the EAT comprising 6 factors and 21 items. These factors underlie a second-order model of DEABs. The internal consistency was adequate for most factors. The SCOFF questionnaire showed a moderate convergent validity for most of the EAT-21 factors. We found measurement invariance across the sexes. CONCLUSIONS: The abbreviated EAT-21 scale exhibited modest and promising psychometric properties, making it a suitable instrument for assessing DEABs in both sexes in educational settings.

Colony stimulating factor-1 receptor drives glomerular parietal epithelial cell activation in focal segmental glomerulosclerosis.

Parietal epithelial cells (PECs) are kidney progenitor cells with similarities to a bone marrow stem cell niche. In focal segmental glomerulosclerosis (FSGS) PECs become activated and contribute to extracellular matrix deposition. Colony stimulating factor-1 (CSF-1), a hematopoietic growth factor, acts via its specific receptor, CSF-1R, and has been implicated in several glomerular diseases, although its role on PEC activation is unknown. Here, we found that CSF-1R was upregulated in PECs and podocytes in biopsies from patients with FSGS. Through in vitro studies, PECs were found to constitutively express CSF-1R. Incubation with CSF-1 induced CSF-1R upregulation and significant transcriptional regulation of genes involved in pathways associated with PEC activation. Specifically, CSF-1/CSF-1R activated the ERK1/2 signaling pathway and upregulated CD44 in PECs, while both ERK and CSF-1R inhibitors reduced CD44 expression. Functional studies showed that CSF-1 induced PEC proliferation and migration, while reducing the differentiation of PECs into podocytes. These results were validated in the Adriamycin-induced FSGS experimental mouse model. Importantly, treatment with either the CSF-1R-specific inhibitor GW2580 or Ki20227 provided a robust therapeutic effect. Thus, we provide evidence of the role of the CSF-1/CSF-1R pathway in PEC activation in FSGS, paving the way for future clinical studies investigating the therapeutic effect of CSF-1R inhibitors on patients with FSGS.

Inhibition of BRD4 Attenuates ER Stress-induced Renal Ischemic-Reperfusion Injury.

Renal ischemia-reperfusion injury (IRI) leads to endoplasmic reticulum (ER) stress, thereby initiating the unfolded protein response (UPR). When sustained, this response may trigger the inflammation and tubular cell death that acts to aggravate the damage. Here, we show that knockdown of the BET epigenetic reader BRD4 reduces the expression of ATF4 and XBP1 transcription factors under ER stress activation. BRD4 is recruited to the promoter of these highly acetylated genes, initiating gene transcription. Administration of the BET protein inhibitor, JQ1, one hour after renal damage induced by bilateral IRI, reveals reduced expression of ATF4 and XBP1 genes, low KIM-1 and NGAL levels and recovery of the serum creatinine and blood urea nitrogen levels. To determine the molecular pathways regulated by ATF4 and XBP1, we performed stable knockout of both transcription factors using CRISPR-Cas9 and RNA sequencing. The pathways triggered under ER stress were mainly XBP1-dependent, associated with an adaptive UPR, and partially regulated by JQ1. Meanwhile, treatment with JQ1 downmodulated most of the pathways regulated by ATF4 and related to the pathological processes during exacerbated UPR activation. Thus, BRD4 inhibition could be useful for curbing the maladaptive UPR activation mechanisms, thereby ameliorating the progression of renal disease.

Mechanisms of mesothelial cell response to viral infections: HDAC1-3 inhibition blocks poly(I:C)-induced type I interferon response and modulates the mesenchymal/inflammatory phenotype.

Infectious peritonitis is a leading cause of peritoneal functional impairment and a primary factor for therapy discontinuation in peritoneal dialysis (PD) patients. Although bacterial infections are a common cause of peritonitis episodes, emerging evidence suggests a role for viral pathogens. Toll-like receptors (TLRs) specifically recognize conserved pathogen-associated molecular patterns (PAMPs) from bacteria, viruses, and fungi, thereby orchestrating the ensuing inflammatory/immune responses. Among TLRs, TLR3 recognizes viral dsRNA and triggers antiviral response cascades upon activation. Epigenetic regulation, mediated by histone deacetylase (HDAC), has been demonstrated to control several cellular functions in response to various extracellular stimuli. Employing epigenetic target modulators, such as epidrugs, is a current therapeutic option in several cancers and holds promise in treating viral diseases. This study aims to elucidate the impact of TLR3 stimulation on the plasticity of human mesothelial cells (MCs) in PD patients and to investigate the effects of HDAC1-3 inhibition. Treatment of MCs from PD patients with the TLR3 agonist polyinosinic:polycytidylic acid (Poly(I:C)), led to the acquisition of a bona fide mesothelial-to-mesenchymal transition (MMT) characterized by the upregulation of mesenchymal genes and loss of epithelial-like features. Moreover, Poly(I:C) modulated the expression of several inflammatory cytokines and chemokines. A quantitative proteomic analysis of MCs treated with MS-275, an HDAC1-3 inhibitor, unveiled altered expression of several proteins, including inflammatory cytokines/chemokines and interferon-stimulated genes (ISGs). Treatment with MS-275 facilitated MMT reversal and inhibited the interferon signature, which was associated with reduced STAT1 phosphorylation. However, the modulation of inflammatory cytokine/chemokine production was not univocal, as IL-6 and CXCL8 were augmented while TNF-α and CXCL10 were decreased. Collectively, our findings underline the significance of viral infections in acquiring a mesenchymal-like phenotype by MCs and the potential consequences of virus-associated peritonitis episodes for PD patients. The observed promotion of MMT reversal and interferon response inhibition by an HDAC1-3 inhibitor, albeit without a general impact on inflammatory cytokine production, has translational implications deserving further analysis.

A descriptive cross-sectional study on eating disorders, suicidal thoughts, and behaviors among adolescents in the Valencian community (Spain). The pivotal role of school nurses.

PURPOSE: The aims of this study were: 1) to describe the rates of risk of having an Eating Disorder (ED) and the rates of suicidal thoughts and behaviors, and 2) to examine the relationship between the risk of having an ED with suicidal thoughts and behaviors in adolescents enrolled in educational centers in the Community of Valencia (Spain). DESIGN AND METHODS: A cross-sectional study was conducted with 718 adolescents between September 2019 and July 2020 in five schools in the Community of Valencia (Spain). RESULTS: The adolescents studied, mostly females, are at risk of having an ED (18.6% to 30.8%) and experiencing suicidal thoughts (23% to 30.7%) and behaviors (2.2% to 6.2%). A strong association was found between EDs and suicidal thoughts and behaviors in both sexes. This association was higher in females with positive EAT-26 scores (OR: 2.09; 95% CI: 1.35-3.24) and in males with positive SCOFF scores (OR: 4.66; 95% CI: 2.40-9.02). Suicidal behaviors were positively associated with both EAT-26 (OR: 2.58; 95% CI: 1.17-5.67) and SCOFF (OR: 1.89; 95% CI: 1.21-2.26) scores in females. CONCLUSIONS: A considerable number of adolescents, females in particular, are at risk of having an ED and of experiencing suicidal thoughts and behaviors, establishing a strong link between EDs and suicidal tendencies. PRACTICAL IMPLICATIONS: The study highlights the importance of establishing national and regional regulations to ensure the availability of school nurses in the Community of Valencia (Spain). Collaboration between school nurses, educators, and policy makers is critical to the early detection of problems and the provision of support to both adolescents and families.

Regulated necrosis role in inflammation and repair in acute kidney injury.

Acute kidney injury (AKI) frequently occurs in patients with chronic kidney disease (CKD) and in turn, may cause or accelerate CKD. Therapeutic options in AKI are limited and mostly relate to replacement of kidney function until the kidneys recover spontaneously. Furthermore, there is no treatment that prevents the AKI-to-CKD transition. Regulated necrosis has recently emerged as key player in kidney injury. Specifically, there is functional evidence for a role of necroptosis, ferroptosis or pyroptosis in AKI and the AKI-to-CKD progression. Regulated necrosis may be proinflammatory and immunogenic, triggering subsequent waves of regulated necrosis. In a paradigmatic murine nephrotoxic AKI model, a first wave of ferroptosis was followed by recruitment of inflammatory cytokines such as TWEAK that, in turn, triggered a secondary wave of necroptosis which led to persistent kidney injury and decreased kidney function. A correct understanding of the specific forms of regulated necrosis, their timing and intracellular molecular pathways may help design novel therapeutic strategies to prevent or treat AKI at different stages of the condition, thus improving patient survival and the AKI-to-CKD transition. We now review key regulated necrosis pathways and their role in AKI and the AKI-to-CKD transition both at the time of the initial insult and during the repair phase following AKI.

BET Protein Inhibitor JQ1 Ameliorates Experimental Peritoneal Damage by Inhibition of Inflammation and Oxidative Stress.

Peritoneal dialysis (PD) is a current replacement therapy for end-stage kidney diseases (ESKDs). However, long-term exposure to PD fluids may lead to damage of the peritoneal membrane (PM) through mechanisms involving the activation of the inflammatory response and mesothelial-to-mesenchymal transition (MMT), leading to filtration failure. Peritoneal damage depends on a complex interaction among external stimuli, intrinsic properties of the PM, and subsequent activities of the local innate-adaptive immune system. Epigenetic drugs targeting bromodomain and extra-terminal domain (BET) proteins have shown beneficial effects on different experimental preclinical diseases, mainly by inhibiting proliferative and inflammatory responses. However the effect of BET inhibition on peritoneal damage has not been studied. To this aim, we have evaluated the effects of treatment with the BET inhibitor JQ1 in a mouse model of peritoneal damage induced by chlorhexidine gluconate (CHX). We found that JQ1 ameliorated the CHX-induced PM thickness and inflammatory cell infiltration. Moreover, JQ1 decreased gene overexpression of proinflammatory and profibrotic markers, together with an inhibition of the nuclear factor-κB (NF-κB) pathway. Additionally, JQ1 blocked the activation of nuclear factor erythroid 2-related factor 2 (NRF2) and restored changes in the mRNA expression levels of NADPH oxidases (NOX1 and NOX4) and NRF2/target antioxidant response genes. To corroborate the in vivo findings, we evaluated the effects of the BET inhibitor JQ1 on PD patients' effluent-derived primary mesothelial cells and on the MeT-5A cell line. JQ1 inhibited tumor necrosis factor-α (TNF-α)-induced proinflammatory gene upregulation and restored MMT phenotype changes, together with the downmodulation of oxidative stress. Taken together, these results suggest that BET inhibitors may be a potential therapeutic option to ameliorate peritoneal damage.

B- and T-lymphocyte attenuator could be a new player in accelerated atherosclerosis associated with chronic kidney disease.

BACKGROUND: In chronic kidney disease (CKD), cardiovascular morbi-mortality is higher than in general population. Atherosclerotic cardiovascular disease is accelerated in CKD, but specific CKD-related risk factors for atherosclerosis are unknown. METHODS: CKD patients from the NEFRONA study were used. We performed mRNA array from blood of patients free from atheroma plaque at baseline, with (n=10) and without (n=10) de novo atherosclerotic plaque development 2 years later. Selected mRNA candidates were validated in a bigger sample (n=148). Validated candidates were investigated in vivo in an experimental model of CKD-accelerated atherosclerosis, and in vitro in murine macrophages. RESULTS: mRNA array analysis showed 92 up-regulated and 67 down-regulated mRNAs in samples from CKD patients with de novo plaque development. The functional analysis pointed to a paramount role of the immune response. The validation in a bigger sample confirmed that B- and T-lymphocyte co-inhibitory molecule (BTLA) down-regulation was associated with de novo plaque presence after 2 years. However, BTLA down-regulation was not found to be associated with atherosclerotic progression in patients with plaque already present at baseline. In a model of CKD-accelerated atherosclerosis, mRNA and protein expression levels of BTLA were significantly decreased in blood samples and atheroma plaques. Plaques from animals with CKD were bigger, had more infiltration of inflammatory cells, higher expression of IL6 and IL17 and less presence of collagen than plaques from control animals. Incubation of macrophages with rat uremic serum decreased BTLA expression. CONCLUSIONS: BTLA could be a potential biomarker or therapeutic target for atherosclerosis incidence in CKD patients.

Extensive rewiring of the gene regulatory interactions between in vitro-produced conceptuses and endometrium during attachment.

Pregnancy loss is a significant problem when embryos produced in vitro are transferred to a synchronized uterus. Currently, mechanisms that underlie losses of in vitro-produced embryos during implantation are largely unknown. We investigated this problem using cattle as a model of conceptus attachment by analyzing transcriptome data of paired extraembryonic membrane and endometrial samples collected on gestation days 18 and 25, which spans the attachment window in cattle. We identified that the transfer of an in vitro-produced embryo caused a significant alteration in transcript abundance of hundreds of genes in extraembryonic and endometrial tissues on gestation days 18 and 25, when compared to pregnancies initiated by artificial insemination. Many of the genes with altered transcript abundance are associated with biological processes that are relevant to the establishment of pregnancy. An integrative analysis of transcriptome data from the conceptus and endometrium identified hundreds of putative ligand-receptor pairs. There was a limited variation of ligand-receptor pairs in pregnancies initiated by in vitro-produced embryos on gestation day 18, and no alteration was observed on gestation day 25. In parallel, we identified that in vitro production of embryos caused an extensive alteration in the coexpression of genes expressed in the extraembryonic membranes and the corresponding endometrium on both gestation days. Both the transcriptional dysregulation that exists in the conceptus or endometrium independently and the rewiring of gene transcription between the conceptus and endometrium are a potential component of the mechanisms that contribute to pregnancy losses caused by in vitro production of embryos.

CCN2 Activates RIPK3, NLRP3 Inflammasome, and NRF2/Oxidative Pathways Linked to Kidney Inflammation.

Inflammation is a key characteristic of both acute and chronic kidney diseases. Preclinical data suggest the involvement of the NLRP3/Inflammasome, receptor-interacting protein kinase-3 (RIPK3), and NRF2/oxidative pathways in the regulation of kidney inflammation. Cellular communication network factor 2 (CCN2, also called CTGF in the past) is an established fibrotic biomarker and a well-known mediator of kidney damage. CCN2 was shown to be involved in kidney damage through the regulation of proinflammatory and profibrotic responses. However, to date, the potential role of the NLRP3/RIPK3/NRF2 pathways in CCN2 actions has not been evaluated. In experimental acute kidney injury induced with folic acid in mice, CCN2 deficiency diminished renal inflammatory cell infiltration (monocytes/macrophages and T lymphocytes) as well as the upregulation of proinflammatory genes and the activation of NLRP3/Inflammasome-related components and specific cytokine products, such as IL-1ß. Moreover, the NRF2/oxidative pathway was deregulated. Systemic administration of CCN2 to C57BL/6 mice induced kidney immune cell infiltration and activated the NLRP3 pathway. RIPK3 deficiency diminished the CCN2-induced renal upregulation of proinflammatory mediators and prevented NLRP3 modulation. These data suggest that CCN2 plays a fundamental role in sterile inflammation and acute kidney injury by modulating the RIKP3/NLRP3/NRF2 inflammatory pathways.

STING1 deficiency ameliorates immune-mediated crescentic glomerulonephritis in mice.

Rapidly progressive/crescentic glomerulonephritis (RPGN/CGN) involves the formation of glomerular crescents by maladaptive differentiation of parietal epithelial cells that leads to rapid loss of renal function. The molecular mechanisms of crescent formation are poorly understood. Therefore, new insights into molecular mechanisms could identify alternative therapeutic targets for RPGN/CGN. Analysis of kidney biopsies from patients with RPGN revealed increased interstitial, glomerular, and tubular expression of STING1, an accessory protein of the c-GAS-dependent DNA-sensing pathway, which was also observed in murine nephrotoxic nephritis induced by an anti-GBM antibody. STING1 was expressed by key cell types involved in RPGN and crescent formation such as glomerular parietal epithelial cells, and tubular cells as well as by inflammation accessory cells. In functional in vivo studies, Sting1-/- mice with nephrotoxic nephritis had lower kidney cytokine expression, milder kidney infiltration by innate and adaptive immune cells, and decreased disease severity. Pharmacological STING1 inhibition mirrored these findings. Direct STING1 agonism in parietal and tubular cells activated the NF-κB-dependent cytokine response and the interferon-induced genes (ISGs) program. These responses were also triggered in a STING1-dependent manner by the pro-inflammatory cytokine TWEAK. These results identify STING1 activation as a pathological mechanism in RPGN/CGN and TWEAK as an activator of STING1. Pharmacological strategies targeting STING1, or upstream regulators may therefore be potential alternatives to treat RPGN. © 2023 The Pathological Society of Great Britain and Ireland.

Intravascular hemolysis triggers NAFLD characterized by a deregulation of lipid metabolism and lipophagy blockade.

Intravascular hemolysis is a common feature of different clinical entities, including sickle cell disease and malaria. Chronic hemolytic disorders are associated with hepatic damage; however, it is unknown whether heme disturbs lipid metabolism and promotes liver steatosis, thereby favoring the progression to nonalcoholic fatty liver disease (NAFLD). Using an experimental model of acute intravascular hemolysis, we report here the presence of liver injury in association with microvesicular lipid droplet deposition. Hemolysis promoted serum hyperlipidemia and altered intrahepatic triglyceride fatty acid composition, with increments in oleic, palmitoleic, and palmitic acids. These findings were related to augmented expression of transporters involved in fatty acid uptake (CD36 and MSR1) and deregulation of LDL transport, as demonstrated by decreased levels of LDL receptor and increased PCSK9 expression. Hemolysis also upregulated hepatic enzymes associated with cholesterol biosynthesis (SREBP2, HMGC1, LCAT, SOAT1) and transcription factors regulating lipid metabolism (SREBP1). Increased LC3II/LC3I ratio and p62/SQSTM1 protein levels were reported in mice with intravascular hemolysis and hepatocytes stimulated with heme, indicating a blockade of lipophagy. In cultured hepatocytes, cell pretreatment with the autophagy inductor rapamycin diminished heme-mediated toxicity and accumulation of lipid droplets. In conclusion, intravascular hemolysis enhances liver damage by exacerbating lipid accumulation and blocking the lipophagy pathway, thereby promoting NAFLD. These new findings have a high translational potential as a novel NAFLD-promoting mechanism in individuals suffering from severe hemolysis episodes. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Incidence and time trends of childhood hematological neoplasms: a 36-year population-based study in the southern European context, 1983-2018.

Background: Hematological neoplasms (HNs) are the first and most common childhood cancers globally. Currently, there is a lack of updated population-based data on the incidence of these cancers in the Spanish pediatric population. This study aimed to describe the incidence and incidence trends of HNs in children (0-14 years) in Spain using data from the Spanish Network of Cancer Registries and to compare the results with other southern European countries. Methods: Data were extracted from 15 Spanish population-based cancer registries between 1983 and 2018. Cases were coded according to the International Classification of Diseases for Oncology, third edition, first revision, and grouped according to the International Classification of Childhood Cancer, third edition. Crude rates (CRs), age-specific rates, and age-standardized incidence rates using the 2013 European population (ASRE) were calculated and expressed as cases per 1,000,000 child-years. Incidence trends and annual percentage changes (APCs) were estimated. Results: A total of 4,747 HNs were recorded (59.5% boys). Age distribution [n (%)] was as follows: <1 year, 266 (5.6%); 1-4 years, 1,726 (36.4%); 5-9 years, 1,442 (30.4%); and 10-14 years, 1,313 (27.6%). Leukemias were the most common group, with a CR and an ASRE of 44.0 (95%CI: 42.5; 45.5) and 44.1 (95%CI: 42.6; 45.7), respectively. The CR and ASRE of lymphomas were 20.1 (95%CI: 19.1; 21.1) and 20.0 (95%CI: 19.0; 21.1), respectively. The comparable incidence rates between our results and those of other southern European countries were similar for lymphomas, while some differences were observed for leukemias. From 1988 to 2016, the trend in leukemia incidence was stable for both sexes, with an APC of 0.0 (95%CI: -0.5; 0.7), whereas a constant overall increase was observed for lymphoma in both sexes, with an APC of 1.0 (95%CI: 0.4; 1.6). Conclusion: Leukemias are the most common HNs in children, and their incidence has remained stable since 1988, whereas the incidence of lymphomas has increased every year. Lymphoma incidence is like that of other southern European countries, while leukemia incidence is similar only to that of southwestern European countries. Collaborative cancer registry projects allow for assessing epidemiological indicators for cancers such as HNs, which helps health authorities and clinicians provide more knowledge about these malignancies.

Projected Impact on Labour Productivity Costs of Cancer-Related Premature Mortality in Europe 2018-2040.

AIM: To estimate the potential cost of lost labour productivity due to cancer-related premature mortality in Europe (EU-27 plus Norway, Switzerland, Iceland and United Kingdom) from 2018 to 2040. METHODS: Deaths and years of potential productive life lost due to 23 types of cancer were estimated for 2018-2040, for 31 European countries. The data were analysed by age groups, by sex and by year. Projected productivity costs were estimated by calculating gross earnings by country, gender and age group using the Human Capital Approach, adjusting for projected labour force participation and unemployment rates. Various data sources were used. Sensitivity analyses were conducted. RESULTS: Between 2018 and 2040, cancer is expected to cause around eight million premature deaths (58% male). The cumulative projected productivity costs in this respect are €1.3 trillion, representing an annual average of €58.7 billion, or 0.43% of the EU-27 gross domestic product. Labour productivity costs are projected to decrease by 6% from 2018 to 2040. The highest cost region is Western Europe, where Germany and France will experience the highest cumulative losses (€288 and €192 billion, respectively). The most costly cancers, in terms of total costs related to productivity losses, are of the lung and colorectum (€264.4 and €116.3 billion, respectively). In terms of average productivity cost per death, the most costly forms of cancer are Hodgkin lymphoma (€301,157) and melanoma (€260,522). CONCLUSION: The novel information presented could help national policymakers anticipate possible areas for cost savings. Action should be taken on disease prevention, on reducing mortality and on delaying the age of death due to Hodgkin lymphoma, brain cancer, leukaemia and melanoma. Furthermore, the study findings enhance our understanding of macroeconomic variables and could be useful in determining a re-allocation of health expenditures.