Blockage of aquaporin-3 peroxiporin activity by organogold compounds affects melanoma cell adhesion, proliferation and migration.

Aquaporin-3 (AQP3) is a membrane channel with dual aquaglyceroporin/peroxiporin activity, facilitating the diffusion of water, glycerol and H2O2 across cell membranes. AQP3 shows aberrant expression in melanoma and its role in cell adhesion, migration and proliferation is well described. Gold compounds were shown to modulate AQP3 activity with reduced associated toxicity, making them promising molecules for cancer therapy. In this study, we validated the phenotype resulting from AQP3-silencing of two melanoma cell lines, MNT-1 and A375, which resulted in decreased H2O2 permeability. Subsequently, the AQP3 inhibitory effect of a new series of organogold compounds derived from Auphen, a potent AQP3 inhibitor, was first evaluated in red blood cells (RBCs) that highly express AQP3, and then in HEK-293T cells with AQP3 overexpression to ascertain the compounds' specificity. The first screening in RBCs unveiled two organogold compounds as promising blockers of AQP3 permeability. Moderate reduction of glycerol permeability but drastic inhibition of H2O2 permeability was detected for some of the gold derivatives in both AQP3-overexpressing cells and human melanoma cell lines. Additionally, all compounds were effective in impairing cell adhesion, proliferation and migration, although in a cell type-dependent manner. In conclusion, our data show that AQP3 peroxiporin activity is crucial for melanoma progression and highlight organogold compounds as promising AQP3 inhibitors with implications in melanoma cell adhesion, proliferation and migration, unveiling their potential as anticancer drugs against AQP3-overexpressing tumours. KEY POINTS: AQP3 affects cellular redox balance. Gold compounds inhibit AQP3 permeability in melanoma cells. AQP3 is involved in cell adhesion, proliferation and migration of melanoma. Blockage of AQP3 peroxiporin activity impairs melanoma cell migration. Gold compounds are potential anticancer drug leads for AQP3-overexpressing cancers.

Neutralizing Anti-Granulocyte Macrophage-Colony Stimulating Factor Autoantibodies Recognize Post-Translational Glycosylations on Granulocyte Macrophage-Colony Stimulating Factor Years Before Diagnosis and Predict Complicated Crohn's Disease.

BACKGROUND & AIMS: Anti-granulocyte macrophage-colony stimulating factor autoantibodies (aGMAbs) are detected in patients with ileal Crohn's disease (CD). Their induction and mode of action during or before disease are not well understood. We aimed to investigate the underlying mechanisms associated with aGMAb induction, from functional orientation to recognized epitopes, for their impact on intestinal immune homeostasis and use as a predictive biomarker for complicated CD. METHODS: We characterized using enzyme-linked immunosorbent assay naturally occurring aGMAbs in longitudinal serum samples from patients archived before the diagnosis of CD (n = 220) as well as from 400 healthy individuals (matched controls) as part of the US Defense Medical Surveillance System. We used biochemical, cellular, and transcriptional analysis to uncover a mechanism that governs the impaired immune balance in CD mucosa after diagnosis. RESULTS: Neutralizing aGMAbs were found to be specific for post-translational glycosylation on granulocyte macrophage-colony stimulating factor (GM-CSF), detectable years before diagnosis, and associated with complicated CD at presentation. Glycosylation of GM-CSF was altered in patients with CD, and aGMAb affected myeloid homeostasis and promoted group 1 innate lymphoid cells. Perturbations in immune homeostasis preceded the diagnosis in the serum of patients with CD presenting with aGMAb and were detectable in the noninflamed CD mucosa. CONCLUSIONS: Anti-GMAbs predict the diagnosis of complicated CD long before the diagnosis of disease, recognize uniquely glycosylated epitopes, and impair myeloid cell and innate lymphoid cell balance associated with altered intestinal immune homeostasis.

Altered IgG glycosylation at COVID-19 diagnosis predicts disease severity.

The nature of the immune responses associated with COVID-19 pathogenesis and disease severity, as well as the breadth of vaccine coverage and duration of immunity, is still unclear. Given the unpredictability for developing a severe/complicated disease, there is an urgent need in the field for predictive biomarkers of COVID-19. We have analyzed IgG Fc N-glycan traits of 82 SARS-CoV-2+ unvaccinated patients, at diagnosis, by nano-LC-ESI-MS. We determined the impact of IgG Fc glyco-variations in the induction of NK cells activation, further evaluating the association between IgG Fc N-glycans and disease severity/prognosis. We found that SARS-CoV-2+ individuals display, at diagnosis, variations in the glycans composition of circulating IgGs. Importantly, levels of galactose and sialic acid structures on IgGs are able to predict the development of a poor COVID-19 disease. Mechanistically, we demonstrated that a deficiency on galactose structures on IgG Fc in COVID-19 patients appears to induce NK cells activation associated with increased release of IFN-γ and TNF-α, which indicates the presence of pro-inflammatory immunoglobulins and higher immune activation, associated with a poor disease course. This study brings to light a novel blood biomarker based on IgG Fc glycome composition with capacity to stratify patients at diagnosis.

Cardiovascular risk factors during pregnancy impact the postpartum cardiac and vascular reverse remodeling.

Pregnant women with cardiovascular risk (CVR) factors are highly prone to develop cardiovascular disease later in life. Thus, recent guidelines suggest extending the follow-up period to 1 yr after delivery. We aimed to evaluate cardiovascular remodeling during pregnancy and determine which CVR factors and potential biomarkers predict postpartum cardiac and vascular reverse remodeling (RR). Our study included a prospective cohort of 76 healthy and 54 obese and/or hypertensive and/or with gestational diabetes pregnant women who underwent transthoracic echocardiography, pulse-wave velocity (PWV), and blood collection at the 1st trimester (1T) and 3rd trimester (3T) of pregnancy as well as at the 1st/6th/12th mo after delivery. Generalized linear mixed-effects models was used to evaluate the extent of RR and its potential predictors. Pregnant women develop cardiac hypertrophy, as confirmed by a significant increase in left ventricular mass (LVM). Moreover, ventricular filling pressure (E/e') and atrial volume increased significantly during gestation. Significant regression of left ventricular (LV) volume, LVM, and filling pressures was observed as soon as 1 mo postpartum. The LV global longitudinal strain worsened slightly and recovered at 6 mo postpartum. PWV decreased significantly from 1T to 3T and normalized at 1 mo postpartum. We found that arterial hypertension, smoking habits, and obesity were independent predictors of increased LVM during pregnancy and postpartum. High C-reactive protein (CRP) and low ST2/IL33-receptor levels are potential circulatory biomarkers of worse LVM regression. Arterial hypertension, age, and gestational diabetes positively correlated with PWV. Altogether, our findings pinpoint arterial hypertension as a critical risk factor for worse RR and CRP, and ST2/IL33 receptors as potential biomarkers of postpartum hypertrophy reversal.NEW & NOTEWORTHY This study describes the impact of cardiovascular risk factors (CVR) in pregnancy-induced remodeling and postpartum reverse remodeling (up to 1 yr) by applying advanced statistic methods (multivariate generalized linear mixed-effects models) to a prospective cohort of pregnant women. Aiming to extrapolate to pathological conditions, this invaluable "human model" allowed us to demonstrate that arterial hypertension is a critical CVR for worse RR and that ST2/IL33-receptors and CRP are potential biomarkers of postpartum hypertrophy reversal.

Improving care pathways for people living with rare bone diseases (RBDs): outcomes from the first RBD Summit.

INTRODUCTION: Rare bone diseases (RBDs) are a heterogenous group of disorders that are poorly understood and challenging to treat. This creates a plethora of unmet needs for people with RBDs as well as their families and care providers, including diagnostic delays, limited access to expert care, and a lack of specialized treatments. The RBD Summit, which took place across 2 days in November 2021, was a virtual meeting of 65 RBD experts from clinical, academic, and patient communities as well as the pharmaceutical industry. The first meeting of its kind, the RBD Summit aimed to facilitate dialog and information exchange between delegates to advance knowledge and awareness of RBDs and improve patient outcomes. METHODS: Key challenges were discussed, and actions for overcoming them were proposed, including how obstacles to diagnosis can be overcome by (a) improving awareness of RBDs, (b) the implementation of a person-centered care pathway, and (c) how to narrow the communication gap between patients and healthcare professionals. RESULTS: Agreed actions were categorized as short term and long term, and priorities determined. CONCLUSION: In this position paper, we provide an overview of key discussions from the RBD Summit, summarize the subsequent action plan, and discuss the next steps in this continued collaboration.

SARS-CoV-2 Infection Drives a Glycan Switch of Peripheral T Cells at Diagnosis.

COVID-19 is a highly selective disease in which SARS-CoV-2 infection can result in different clinical manifestations ranging from asymptomatic/mild to severe disease that requires hospitalization. In this study, we demonstrated that SARS-CoV-2 infection results in a glycosylation reprogramming of circulating lymphocytes at diagnosis. We identified a specific glycosignature of T cells, defined upon SARS-CoV-2 infection and apparently triggered by a serological factor. This specific glycan switch of T cells is detected at diagnosis being more pronounced in asymptomatic patients. We further demonstrated that asymptomatic patients display an increased expression of a viral-sensing receptor through the upregulation of DC-SIGN in monocytes. We showed that higher levels of DC-SIGN in monocytes at diagnosis correlates with better COVID-19 prognosis. This new evidence pave the way to the identification of a novel glycan-based response in T cells that may confer protection against SARS-CoV-2 infection in asymptomatic patients, highlighting a novel prognostic biomarker and potential therapeutic target.

Multifocal Infantile Hepatic Hemangiomas Complicated by Consumptive Hypothyroidism: The Benefits of Early Diagnosis and Treatment.

Infantile hepatic hemangiomas (IHH) account for 12% of all childhood hepatic tumors. Most IHH are diagnosed within the first 6 months of life and involute spontaneously; however, some require medical treatment. The present report describes a case of multifocal IHH associated with subcutaneous and lingual hemangiomas, complicated by consumptive hypothyroidism and successfully managed with oral propranolol and thyroid replacement therapy, without documented adverse effects. Consumptive hypothyroidism is a rare complication of IHH, but suggestive of multifocal/diffuse subtypes. The authors intend to reinforce the importance of early referral to a Vascular Anomalies Center and treatment with propranolol in selected patients.

Unraveling the Aquaporin-3 Inhibitory Effect of Rottlerin by Experimental and Computational Approaches.

The natural polyphenolic compound Rottlerin (RoT) showed anticancer properties in a variety of human cancers through the inhibition of several target molecules implicated in tumorigenesis, revealing its potential as an anticancer agent. Aquaporins (AQPs) are found overexpressed in different types of cancers and have recently emerged as promising pharmacological targets. Increasing evidence suggests that the water/glycerol channel aquaporin-3 (AQP3) plays a key role in cancer and metastasis. Here, we report the ability of RoT to inhibit human AQP3 activity with an IC50 in the micromolar range (22.8 ± 5.82 µM for water and 6.7 ± 2.97 µM for glycerol permeability inhibition). Moreover, we have used molecular docking and molecular dynamics simulations to understand the structural determinants of RoT that explain its ability to inhibit AQP3. Our results show that RoT blocks AQP3-glycerol permeation by establishing strong and stable interactions at the extracellular region of AQP3 pores interacting with residues essential for glycerol permeation. Altogether, our multidisciplinary approach unveiled RoT as an anticancer drug against tumors where AQP3 is highly expressed providing new information to aquaporin research that may boost future drug design.

A systematic review of prevalence and incidence of pressure ulcers/injuries in hospital emergency services.

AIM: To develop a systematic review on the prevalence and the incidence of pressure ulcers/injuries in adult patients in hospital emergency services. MATERIALS AND METHODS: Systematic review of prevalence and incidence studies developed according to the Preferred Reporting Items Form Systematic Review and Meta-Analysis Protocols and the Joanna Briggs Institute methodology. The inclusion criteria were based on the CoCoPop mnemonic. The main variables of interest were the "prevalence" and/or the "incidence" of "pressure ulcers/injuries" (Condition) reported in studies developed in hospital emergency services (Context) with adult participants (Population). The Systematic Review Protocol was registered in PROSPERO (CDR42021252906). RESULTS: The pressure ulcer/injury (point) prevalence ranged from 5.2% (at admission) to 12.3% (at discharge) and the pressure ulcer/injury incidence ranged from 4.5% to 78.4%. Most of the pressure ulcers/injuries documented were category/stage I. The most problematic anatomical locations were the sacrococcygeal region and the heels. The preventive measures should be implemented as soon as possible and are important in patients older than 75 years, with multiple comorbidities, high C-Reative Protein levels, cervical spine immobilization, presented to hospital emergency service by ambulance or with hypotension at the time of admission. CONCLUSIONS: The prevalence and incidence of pressure ulcers/injuries in hospital emergency services remains an understudied topic which could limit the generalization of our data. This systematic review highlighted that the management of pressure ulcers/injuries is a real and current challenge in hospital emergency services. It is important to identify the patients at (higher) risk to establish an (earlier) preventive care plan according to patients and emergency services' characteristics.

Prevalence and incidence of pressure ulcers/injuries in emergency services: A systematic review protocol.

AIM: To develop a systematic review protocol on the prevalence and/or the incidence of pressure ulcers/injuries in adult patients in emergency services. MATERIALS AND METHODS: This protocol was developed according to the Preferred Reporting Items Form Systematic Review and Meta-Analysis Protocols (PRISMA-P) and the Joanna Briggs Institute (JBI) methodology for systematic reviews of prevalence and incidence studies. The inclusion criteria will be based on the CoCoPop mnemonic. The main variables of interest will be the "prevalence" and/or the "incidence" of "pressure ulcers/injuries" (Condition) reported in studies developed in emergency services (Context), with participants aged 18 or more (Population). This Systematic Review Protocol was registered in PROSPERO (CDR42021252906). RESULTS: If meta-analysis is not possible, the syntheses of quantitative data will be presented in a narrative form to address the scope and objectives of this systematic review. Tables, graphs and/or figures will be designed to present the results of the prevalence and the incidence of pressure ulcers/injuries, their body locations and the respective categories/stages. The Systematic Review is currently ongoing. CONCLUSIONS: Prevalence and incidence systematic reviews are an emerging methodology in the field of evidence synthesis. We believe that the systematic review on prevalence and incidence of pressure ulcers/injuries in emergency services can provide useful information for healthcare professionals and policy makers about the dimension of this problem in a specific context. The standardized approach outlined in this systematic review protocol offers a rigorous and transparent method to conduct the review.

Composition of the immunoglobulin G glycome associates with the severity of COVID-19.

A large variation in the severity of disease symptoms is one of the key open questions in coronavirus disease 2019 (COVID-19) pandemics. The fact that only a small subset of people infected with severe acute respiratory syndrome coronavirus 2 develops severe disease suggests that there have to be some predisposing factors, but biomarkers that reliably predict disease severity have not been found so far. Since overactivation of the immune system is implicated in a severe form of COVID-19 and the immunoglobulin G (IgG) glycosylation is known to be involved in the regulation of different immune processes, we evaluated the association of interindividual variation in IgG N-glycome composition with the severity of COVID-19. The analysis of 166 severe and 167 mild cases from hospitals in Spain, Italy and Portugal revealed statistically significant differences in the composition of the IgG N-glycome. The most notable difference was the decrease in bisecting N-acetylglucosamine in severe patients from all three cohorts. IgG galactosylation was also lower in severe cases in all cohorts, but the difference in galactosylation was not statistically significant after correction for multiple testing.

The Role of Glycosylation in Inflammatory Diseases.

The diversity of glycan presentation in a cell, tissue and organism is enormous, which reflects the huge amount of important biological information encoded by the glycome which has not been fully understood. A compelling body of evidence has been highlighting the fundamental role of glycans in immunity, such as in development, and in major inflammatory processes such as inflammatory bowel disease, systemic lupus erythematosus and other autoimmune disorders. Glycans play an instrumental role in the immune response, integrating the canonical circuits that regulate innate and adaptive immune responses. The relevance of glycosylation in immunity is demonstrated by the role of glycans as important danger-associated molecular patterns and pathogen-associated molecular patterns associated with the discrimination between self and non-self; also as important regulators of the threshold of T cell activation, modulating receptors signalling and the activity of both T and other immune cells. In addition, glycans are important determinants that regulate the dynamic crosstalk between the microbiome and immune response. In this chapter, the essential role of glycans in the immunopathogenesis of inflammatory disorders will be presented and its potential clinical applications (diagnosis, prognosis and therapeutics) will be highlighted.

Metabolic control of T cell immune response through glycans in inflammatory bowel disease.

Mucosal T lymphocytes from patients with ulcerative colitis (UC) were previously shown to display a deficiency in branched N-glycosylation associated with disease severity. However, whether this glycosylation pathway shapes the course of the T cell response constituting a targeted-specific mechanism in UC remains largely unknown. In this study, we demonstrated that metabolic supplementation of ex vivo mucosal T cells from patients with active UC with N-acetylglucosamine (GlcNAc) resulted in enhancement of branched N-glycosylation in the T cell receptor (TCR), leading to suppression of T cell growth, inhibition of the T helper 1 (Th1)/Th17 immune response, and controlled T cell activity. We further demonstrated that mouse models displaying a deficiency in the branched N-glycosylation pathway (MGAT5-/-, MGAT5+/-) exhibited increased susceptibility to severe forms of colitis and early-onset disease. Importantly, the treatment of these mice with GlcNAc reduced disease severity and suppressed disease progression due to a controlled T cell-mediated immune response at the intestinal mucosa. In conclusion, our human ex vivo and preclinical results demonstrate the targeted-specific immunomodulatory properties of this simple glycan, proposing a therapeutic approach for patients with UC.

Radiological pseudoprogression post-radiotherapy in a child with pineal germ cell tumour.

Little is known about pseudoprogression in brain tumours other than gliomas. A 9-year-old male child with a pineal teratoma/germinoma underwent surgical resection followed by adjuvant chemo-radiotherapy. The magnetic resonance imaging scan 4 months post-radiotherapy showed a contrast-enhancing lesion within the surgical cavity suspicious of recurrence. These radiological findings subsequently resolved without any specific intervention. The child continues in remission 2 years post-treatment. This case illustrates the occurrence of pseudoprogression post-radiotherapy in intracranial GCT and highlights an unmet need for greater implementation of functional imaging techniques in paediatric neuro-oncology to avoid undue discontinuation of effective treatments or inappropriate enrolment in clinical trials.

Liraglutide Protects Against Brain Amyloid-ß1-42 Accumulation in Female Mice with Early Alzheimer's Disease-Like Pathology by Partially Rescuing Oxidative/Nitrosative Stress and Inflammation.

Alzheimer's disease (AD) is the most common form of dementia worldwide, being characterized by the deposition of senile plaques, neurofibrillary tangles (enriched in the amyloid beta (Aß) peptide and hyperphosphorylated tau (p-tau), respectively) and memory loss. Aging, type 2 diabetes (T2D) and female sex (especially after menopause) are risk factors for AD, but their crosslinking mechanisms remain unclear. Most clinical trials targeting AD neuropathology failed and it remains incurable. However, evidence suggests that effective anti-T2D drugs, such as the GLP-1 mimetic and neuroprotector liraglutide, can be also efficient against AD. Thus, we aimed to study the benefits of a peripheral liraglutide treatment in AD female mice. We used blood and brain cortical lysates from 10-month-old 3xTg-AD female mice, treated for 28 days with liraglutide (0.2 mg/kg, once/day) to evaluate parameters affected in AD (e.g., Aß and p-tau, motor and cognitive function, glucose metabolism, inflammation and oxidative/nitrosative stress). Despite the limited signs of cognitive changes in mature female mice, liraglutide only reduced their cortical Aß1-42 levels. Liraglutide partially attenuated brain estradiol and GLP-1 and activated PKA levels, oxidative/nitrosative stress and inflammation in these AD female mice. Our results support the earlier use of liraglutide as a potential preventive/therapeutic agent against the accumulation of the first neuropathological features of AD in females.

Developing inclusive education in Portugal: Evidence and challenges.

This article assesses evidence of and challenges to the development of inclusive education in Portugal, which is built on three pillars: access to, participation in, and achievement in education for all children and young people. It presents an overview of the present policy framework, followed by an analysis of available statistical data on Portuguese students with disabilities in mainstream schools. The article also discusses significant achievements at the policy and practice levels, namely the attempt to align curriculum and pedagogy and the presence of almost 100% of students with disabilities in mainstream schools. It also considers challenges, such as the issue of monitoring achievement (both at the student and system level) and investments in the system and in teacher education.

BN-Doped Graphene and Single-Walled Carbon Nanotubes for the Catalysis of SN2 Reactions: Insights from Density Functional Theory Modeling.

The inner space of carbon nanotubes has already been proven to provide a type of confinement, which can dramatically alter the energetics of chemical reactions when compared to the gas phase. Moreover, BN doping can be used to fine-tune electronic properties, which might influence the enthalpy and activation energy of chemical reactions that take place inside their inner space. The energy profile of the prototype Menshutkin SN2 reaction between ammonia and chloromethane has been analyzed in a variety of carbon-based materials at the DFT (density functional theory) level. Pristine zigzag (9,0) and (12,0) single-walled carbon nanotubes and graphene sheets have been doped with boron and nitrogen at different stoichiometries, namely, BN, BNC, BNC2, and BNC4, that resulted in remarkable variations of their catalytic effects. Graphene has revealed to be the support material, which depends less on doping in terms of enthalpy and energy barrier of the reaction. However, when graphene is rolled up into tubular forms, the influence of doping becomes increasingly stronger as the nanotube radius decreases. In the case of BNC4 doping of (9,0) nanotubes, the activation energy drops 10 kcal/mol when compared to the pristine case, and the reaction became even exothermic by more than 15 kcal/mol.

Glycans as critical regulators of gut immunity in homeostasis and disease.

The diversity of glycans expression within a cell or an organism is enormous and the amount of relevant biological information that each glycan structure encodes is far from being clarified. The importance of glycans in health and life sciences is highlighted by their multiple functional implications in different cellular and molecular biology processes with impact in homeostasis and diseases, such as cancer and inflammatory conditions. Glycans actively participate in the regulatory circuits that govern both innate and adaptive immune response. Changes in the glycans repertoire occur during the transition from normal to inflamed conditions and the aberrant expression of glycans dictates either pro-inflammatory or anti-inflammatory responses. This review summarizes how glycans integrate the regulatory networks of immune response with a focus on gut immunity.

iFUSE: integrated fusion gene explorer.

UNLABELLED: We present iFUSE (integrated fusion gene explorer), an online visualization tool that provides a fast and informative view of structural variation data and prioritizes those breaks likely representing fusion genes. This application uses calculated break points to determine fusion genes based on the latest annotation for genomic sequence information, and where relevant the structural variation (SV) events are annotated with predicted RNA and protein sequences. iFUSE takes as input a Complete Genomics (CG) junction file, a FusionMap fusion detection report file or a file already analysed and annotated by the iFUSE application on a previous occasion. RESULTS: We demonstrate the use of iFUSE with case studies from tumour-normal SV detection derived from Complete Genomics whole-genome sequencing results. AVAILABILITY: iFUSE is available as a web service at http://ifuse.erasmusmc.nl.

Assigned sex estimation with the clavicle and scapula: A study in a Portuguese reference sample.

The estimation of biological sex is a critical step in the assessment of the biological profile of an anonymous skeletonized individual. In certain recovery circumstances, the most dimorphic skeletal areas, such as the pelvis, are absent or fragmented; in that case, other bones of the skeleton, including the clavicle and scapula, can be used to predict sex. The purpose of this research is to generate new models for the estimation of sex with clavicular and scapular measurements using a study-sample of 129 individuals with clavicle (65 males and 64 females) and 112 individuals with scapula (50 males and 62 females) from the Lisbon Identified Skeletal Collection (Portugal). A decision tree classifier (C4.5) and logistic regression (LR) were employed to create univariable and multivariable sex prediction models. Accuracy under cross-validation of the classification models is high (up to 93.8%), with minimal bias (<5%), particularly in the multivariable models. The proposed LR models facilitate the probabilistic estimation of biological sex, accounting for the significant overlap in the expression of sexual dimorphism.