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Abstract The genetic landscape underlying the transformation of splenic diffuse red pulp small B‐cell lymphoma (SDRPL) is not well understood. The present study aimed to unravel the genomic alterations involved in the progression and transformation of SDRPL. We performed genetic studies on both SDRPL and subsequent or synchronous diffuse large B cell lymphoma (DLBCL) samples in three SDRPL patients who eventually developed DLBCL. Our findings revealed that SDRPL cases progressing to DLBCL acquired genomic alterations in genes related to the cell cycle (CDKN2A/B, TP53, MYC and CCND3) and B cell development (BCL6).

Abstract Novel chimeric antigen receptor (CAR) T-cell approaches are needed to improve therapeutic efficacy in solid tumors. High-risk neuroblastoma is an aggressive pediatric solid tumor that expresses cell-surface GPC2 and GD2 with a tumor microenvironment infiltrated by CD16a-expressing innate immune cells. Here we engineer T-cells to express a GPC2-directed CAR and simultaneously secrete a bispecific innate immune cell engager (BiCE) targeting both GD2 and CD16a. In vitro, GPC2.CAR-GD2.BiCE T-cells induce GPC2-dependent cytotoxicity and secrete GD2.BiCE that promotes GD2-dependent activation of antitumor innate immunity. In vivo, GPC2.CAR-GD2.BiCE T-cells locally deliver GD2.BiCE and increase intratumor retention of NK-cells. In mice bearing neuroblastoma patient-derived xenografts and reconstituted with human CD16a-expressing immune cells, GD2.BiCEs enhance GPC2.CAR antitumor efficacy. A CAR.BiCE strategy should be considered for tumor histologies where antigen escape limits CAR efficacy, especially for solid tumors like neuroblastoma that are infiltrated by innate immune cells.

Abstract Neurotensin-polyplex nanoparticles provide efficient gene transfection of nigral dopaminergic neurons when intracerebrally injected in preclinical trials of Parkinson’s disease because they do not cross the blood–brain barrier (BBB). Therefore, this study aimed to open BBB with focused ultrasound (FUS) on the substantia nigra to attain systemic and intranasal transfections and evaluate its detrimental effect in rats. Systemically injected Evans Blue showed that a two-pulse FUS opened the nigral BBB. Accordingly, 35 μL of neurotensin-polyplex nanoparticles encompassing the green fluorescent protein plasmid (79.6 nm mean size and + 1.3 mV Zeta-potential) caused its expression in tyrosine hydroxylase(+) cells (dopaminergic neurons) of both substantiae nigrae upon delivery via internal carotid artery, retro-orbital venous sinus, or nasal mucosa 30 min after FUS. The intracarotid delivery yielded the highest transgene expression, followed by intranasal and venous administration. However, FUS caused neuroinflammation displayed by infiltrated lymphocytes (positive to cluster of differentiation 45), activated microglia (positive to ionized calcium-binding adaptor molecule 1), neurotoxic A1 astrocytes (positive to glial fibrillary acidic protein and complement component 3), and neurotrophic A2 astrocytes (positive to glial fibrillary acidic protein and S100 calcium-binding protein A10), that ended 15 days after FUS. Dopaminergic neurons and axonal projections decreased but recuperated basal values on day 15 after transfection, correlating with a decrease and recovery of locomotor behavior. In conclusion, FUS caused transient neuroinflammation and reversible neuronal affection but allowed systemic and intranasal transfection of dopaminergic neurons in both substantiae nigrae. Therefore, FUS could advance neurotensin-polyplex nanotechnology to clinical trials for Parkinson’s disease.

[INLINE:1] Parkinsonism by unilateral, intranigral β-sitosterol β-D-glucoside administration in rats is distinguished in that the α-synuclein insult begins unilaterally but spreads bilaterally and increases in severity over time, thus replicating several clinical features of Parkinson's disease, a typical α-synucleinopathy. As Nurr1 represses α-synuclein, we evaluated whether unilateral transfected of rNurr1-V5 transgene via neurotensin-polyplex to the substantia nigra on day 30 after unilateral β-sitosterol β-D-glucoside lesion could affect bilateral neuropathology and sensorimotor deficits on day 30 post-transfection. This study found that rNurr1-V5 expression but not that of the green fluorescent protein (the negative control) reduced β-sitosterol β-D-glucoside-induced neuropathology. Accordingly, a bilateral increase in tyrosine hydroxylase-positive cells and arborization occurred in the substantia nigra and increased tyrosine hydroxylase-positive ramifications in the striatum. In addition, tyrosine hydroxylase-positive cells displayed less senescence marker β-galactosidase and more neuron-cytoskeleton marker βIII-tubulin and brain-derived neurotrophic factor. A significant decrease in activated microglia (positive to ionized calcium-binding adaptor molecule 1) and neurotoxic astrocytes (positive to glial fibrillary acidic protein and complement component 3) and increased neurotrophic astrocytes (positive to glial fibrillary acidic protein and S100 calcium-binding protein A10) also occurred in the substantia nigra. These effects followed the bilateral reduction in α-synuclein aggregates in the nigrostriatal system, improving sensorimotor behavior. Our results show that unilateral rNurr1-V5 transgene expression in nigral dopaminergic neurons mitigates bilateral neurodegeneration (senescence and loss of neuron-cytoskeleton and tyrosine hydroxylase-positive cells), neuroinflammation (activated microglia, neurotoxic astrocytes), α-synuclein aggregation, and sensorimotor deficits. Increased neurotrophic astrocytes and brain-derived neurotrophic factor can mediate the rNurr1-V5 effect, supporting its potential clinical use in the treatment of Parkinson's disease.

The transient hypoxic-ischemic attack, also known as a minor stroke, can result in long-term neurological issues such as memory loss, depression, and anxiety due to an increase in nitrosative stress. The individual or combined administration of chronic prophylactic zinc and therapeutic selenium is known to reduce nitrosative stress in the first seven days post-reperfusion and, due to an antioxidant effect, prevent cell death. Besides, zinc or selenium, individually administered, also causes antidepressant and anxiolytic effects. Therefore, this work evaluated whether combining zinc and selenium could prevent stroke-elicited cognition and behavior deficits after 30 days post-reperfusion. Accordingly, we assessed the expression of growth factors at 7 days post-reperfusion, a four-time course of memory (from 7 to 28 days post-learning test), and cell proliferation, depression, and anxiety-like behavior at 30 days post-reperfusion. Male Wistar rats with a weight between 190 and 240 g) were treated with chronic prophylactic zinc administration with a concentration of 0.2 mg/kg for 15 days before common carotid artery occlusion (10 min) and then with therapeutic selenium (6 μg/kg) for 7 days post-reperfusion. Compared with individual administrations, the administration combined of prophylactic zinc and therapeutic selenium decreased astrogliosis, increased growth factor expression, and improved cell proliferation and survival in two regions, the hippocampus, and cerebral cortex. These effects prevented memory loss, depression, and anxiety-like behaviors. In conclusion, these results demonstrate that the prophylactic zinc administration combined with therapeutic selenium can reduce the long-term sequelae caused by the transient ischemic attack.Significance statement.A minor stroke caused by a transient ischemic attack can result in psychomotor sequelae that affect not only the living conditions of patients and their families but also the economy. The incidence of these micro-events among young people has increased in the world. Nonetheless, there is no deep understanding of how this population group responds to regular treatments (Ekker and et al., 2018) [1]. On the basis that zinc and selenium have antioxidant, anti-inflammatory, and regenerative properties in stroke animal models, our work explored whether the chronic combined administration of prophylactic zinc and therapeutic selenium could prevent neurological sequelae in the long term in a stroke rat model of unilateral common carotid artery occlusion (CCAO) by 10-min. Our results showed that this combined treatment provided a long-term neuroprotective effect by decreasing astrogliosis, memory loss, anxiety, and depression-like behavior.

Abstract Background Animal models of acute respiratory distress syndrome (ARDS) do not completely resemble human ARDS, struggling translational research. We aimed to characterize a porcine model of ARDS induced by pneumonia—the most common risk factor in humans—and analyze the additional effect of ventilator-induced lung injury (VILI). Methods Bronchoscopy-guided instillation of a multidrug-resistant Pseudomonas aeruginosa strain was performed in ten healthy pigs. In six animals (pneumonia-with-VILI group), pulmonary damage was further increased by VILI applied 3 h before instillation and until ARDS was diagnosed by PaO2/FiO2

Achieving reproducible perovskite solar cell fabrication is crucial for making it a scalable technology. We demonstrate an automated gas quenching system to improve perovskite solar cell reproducibility at the lab-scale. We use in situ photoluminescence to monitor the perovskite film formation as a function of the atmosphere in the glove box and find that antisolvent quenching is more sensitive to lingering precursor solvents than the gas quenching method. We observe a better reproducibility with gas quenching than with antisolvent quenching because it maintains a more consistent atmosphere in the glove box. The automated gas quenching process leads to high performing devices that are reproducible both batch to batch and researcher to researcher. The insights into gas quenching film formation as a function of solvent atmosphere and quench velocity will help inform future studies on large scale fabrication systems.

Abstract Isometric handgrip or (wall) squat exercise performed three times per week produces reductions in systolic blood pressure (SBP) in adults with hypertension. We aimed to compare these interventions and the potential to retain benefits with one exercise session per week. We compared blood pressure changes following handgrip and squat isometric training interventions with controls in a randomized controlled multicentre trial in 77 unmedicated hypertensive (SBP ≥ 130 mmHg) adults. Exercise sessions were performed in the workplace and consisted of four repetitions—three sessions per week for the first 12 weeks (phase 1), and one session per week for the subsequent 12 weeks (phase 2). Office blood pressure (BP) was measured at baseline, post‐phase 1 and post‐phase 2. Post‐phase 1, mean reductions in SBP were significantly greater in handgrip (–11.2 mmHg, n = 28) and squat (–12.9 mmHg, n = 27) groups than in controls (–.4 mmHg; n = 22) but changes in DBP were not. There were no significant within‐group changes during phase 2 but SBP was 3.8 mmHg lower in the wall squat than the handgrip group—a small magnitude but clinically important difference. While both interventions produced significant SBP reductions, the wall squat appears to be more effective in maintaining benefits with a minimal training dose. The low time investment to achieve and retain clinically significant SBP reductions—42 and 12 min, respectively—and minimal cost, particularly of the wall squat, make it a promising intervention for delivery in public health settings.

Subgrid scale models for unresolved turbulent fluxes are investigated, with a focus on combustion for space propulsion applications. An extension to the gradient model is proposed, introducing a dependency on the local burning regimen. The dynamic behaviors of the model’s coefficients are investigated, and scaling laws are studied. The discussed models are validated using a DNS database of a high-pressure, turbulent, fuel-rich methane–oxygen diffusion flame. The operating point and turbulence characteristics are selected to resemble those of modern combustors for space propulsion applications to support the future usage of the devised model in this context.

The astrocyte population, around 50% of human brain cells, plays a crucial role in maintaining the overall health and functionality of the central nervous system (CNS). Astrocytes are vital in orchestrating neuronal development by releasing synaptogenic molecules and eliminating excessive synapses. They also modulate neuronal excitability and contribute to CNS homeostasis, promoting neuronal survival by clearance of neurotransmitters, transporting metabolites, and secreting trophic factors. Astrocytes are highly heterogeneous and respond to CNS injuries and diseases through a process known as reactive astrogliosis, which can contribute to both inflammation and its resolution. Recent evidence has revealed remarkable alterations in astrocyte transcriptomes in response to several diseases, identifying at least two distinct phenotypes called A1 or neurotoxic and A2 or neuroprotective astrocytes. However, due to the vast heterogeneity of these cells, it is limited to classify them into only two phenotypes. This review explores the various physiological and pathophysiological roles, potential markers, and pathways that might be activated in different astrocytic phenotypes. Furthermore, we discuss the astrocyte heterogeneity in the main neurodegenerative diseases and identify potential therapeutic strategies. Understanding the underlying mechanisms in the differentiation and imbalance of the astrocytic population will allow the identification of specific biomarkers and timely therapeutic approaches in various neurodegenerative diseases.

Environmental air pollution poses a significant threat to human health, with nitrogen oxides (NOx) identified as contributors to respiratory and cardiovascular diseases. This study evaluates NOx levels in an underground car park of a hospital complex, where vulnerable patients frequently visit. NOx levels were assessed using direct-reading devices with high-resolution electrochemical sensors measuring NO and NO2 concentrations. Measurements consistently remained below the legal occupational exposure limit values for car park employees, averaging around 10% of the limit. However, approximately 75% of days recorded NO2 concentrations exceeding 70% of the World Health Organization’s (WHO) recommendations, with about 20% surpassing the 0.1 ppm limit set by the WHO. The highest recorded one-hour NO2 level reached 0.165 ppm, typically around 11:00 h. The study recommends that vulnerable patients, especially asthmatics, utilize outdoor parking, while all users should avoid using the car park as a waiting area. Employees are advised to spend more time in enclosed spaces with fresh air. Although occupational levels are generally within limits, environmental levels during peak hours could pose risks to vulnerable populations. Mitigation measures, such as increased ventilation during peak hours and restricted access based on emission levels, are suggested to minimize exposure and protect public health.

Os termos médicos utilizados na morfologia eram provenientes de um nome próprio, com o intuito de homenagear os que descobriram ou apresentaram a estrutura anatômica, conhecidos como epônimos. Buscando unificar a linguagem anatômica e facilitar o processo de ensino, em 1989 foi criado o Comitê Federativo Internacional de Terminologia Anatômica (FICAT), cujo propósito era revisar os epônimos e atualizar a terminologia anatômica. Com o objetivo de apresentar os fundamentos e conhecimentos sobre a origem das terminologias anatômicas nas mídias sociais, a Liga Acadêmica de Anatomia da Universidade Federal de Alfenas (LAANAT/UNIFAL-MG), por meio do projeto de extensão “Anatomia de A a Z”, divulgou conhecimentos científicos acerca da etimologia anatômica. Foram feitas postagens semanais no Instagram e no Facebook, a partir de publicações elaboradas pelos ligantes, supervisionadas pelos professores coordenadores e desenvolvidas no aplicativo Canva. Cada postagem seguiu sequencialmente as letras do alfabeto (de A a Z) e eram compostas da etimologia de duas estruturas anatômicas. Frente a uma análise de dados, observamos que em 23 publicações, alcançamos 712 curtidas, 194 compartilhamentos, 44 publicações salvas, 4739 contas alcançadas e 6608 impressões. A LAANAT promoveu, de forma clara e objetiva, a divulgação de conhecimentos das terminologias anatômicas ao público geral.

BackgroundAbdominal obesity (AO) indirectly represents visceral adiposity and can be assessed by waist circumference (WC) measurement. In Latin America, cut-off points for the diagnosis of AO are based on Asian population data. We aim to establish the WC cut-off points to predict major cardiovascular events (MACE) and incident diabetes.MethodsWe analyzed data from the cohort PURE study in Colombia. WC cut-off points were defined according to the maximum Youden index. Multivariate logistic regression was used to obtain associations between WC and MACE, diabetes, and cumulative incidence of outcomes visualized using Kaplan-Meier curves.ResultsAfter a mean follow-up of 12 years, 6,580 individuals with a mean age of 50.7 ± 9.7 years were included; 64.2% were women, and 53.5% were from rural areas. The mean WC was 85.2 ± 11.6 cm and 88.3 ± 11.1 cm in women and men, respectively. There were 635 cases of the MACE composite plus incident diabetes (5.25 events per 1,000 person-years). Using a cut-off value of 88.85 cm in men (sensitivity = 0.565) and 85.65 cm in women (sensitivity = 0.558) resulted in the highest value for the prediction of the main outcome. These values were associated with a 1.76 and 1.41-fold increased risk of presenting the composite outcome in men and women, respectively.ConclusionsWe defined WC cut-off points of 89 cm in men and 86 cm in women to identify the elevated risk of MACE and incident diabetes. Therefore, we suggest using these values in cardiovascular risk assessment in Latin America.

Abstract Background Pseudomonas aeruginosa pneumonia is commonly treated with systemic antibiotics to ensure adequate treatment of multidrug resistant (MDR) bacteria. However, intravenous (IV) antibiotics often achieve suboptimal pulmonary concentrations. We therefore aimed to evaluate the effect of inhaled amikacin (AMK) plus IV meropenem (MEM) on bactericidal efficacy in a swine model of monolateral MDR P. aeruginosa pneumonia. Methods We ventilated 18 pigs with monolateral MDR P. aeruginosa pneumonia for up to 102 h. At 24 h after the bacterial challenge, the animals were randomized to receive 72 h of treatment with either inhaled saline (control), IV MEM only, or IV-MEM plus inhaled AMK (MEM + AMK). We dosed IV MEM at 25 mg/kg every 8 h and inhaled AMK at 400 mg every 12 h. The primary outcomes were the P. aeruginosa burden and histopathological injury in lung tissue. Secondary outcomes included the P. aeruginosa burden in tracheal secretions and bronchoalveolar lavage fluid, the development of antibiotic resistance, the antibiotic distribution, and the levels of inflammatory markers. Results The median (25–75th percentile) P. aeruginosa lung burden for animals in the control, MEM only, and MEM + AMK groups was 2.91 (1.75–5.69), 0.72 (0.12–3.35), and 0.90 (0–4.55) log10 CFU/g (p = 0.009). Inhaled therapy had no effect on preventing dissemination compared to systemic monotherapy, but it did have significantly higher bactericidal efficacy in tracheal secretions only. Remarkably, the minimum inhibitory concentration of MEM increased to > 32 mg/L after 72-h exposure to monotherapy in 83% of animals, while the addition of AMK prevented this increase (p = 0.037). Adjunctive therapy also slightly affected interleukin-1β downregulation. Despite finding high AMK concentrations in pulmonary samples, we found no paired differences in the epithelial lining fluid concentration between infected and non-infected lungs. Finally, a non-significant trend was observed for higher amikacin penetration in low-affected lung areas. Conclusions In a swine model of monolateral MDR P. aeruginosa pneumonia, resistant to the inhaled AMK and susceptible to the IV antibiotic, the use of AMK as an adjuvant treatment offered no benefits for either the colonization of pulmonary tissue or the prevention of pathogen dissemination. However, inhaled AMK improved bacterial eradication in the proximal airways and hindered antibiotic resistance.

The efficacy and toxicity of the PARP inhibitor parthanatine, radiolabeled with the alpha particle emitter astatine-211, in 11 patient derived neuroblastoma murine xenografts is investigated.

Background: Controversies exist on whether the presence of cardiovascular risk factors and their association with major cardiovascular events (MACE) is different between men and women. Most of the evidence comes from high-income countries, hindering extrapolation of sociocultural and demographic factors of other regions. Objective: To evaluate sex differences in the prevalence of cardiovascular risk factors and the incidence of MACE and diabetes in Colombian adults. Methods: We performed a survival analysis from women and men aged 35–70 belonging to the Prospective Urban Rural Epidemiology-Colombia prospective study. Incidence rates for MACE composite (myocardial infarction, stroke, heart failure, death) and each outcome and diabetes were calculated. Kaplan-Meier curves and log-rank tests were performed. The association between demographic, behavioral, and metabolic variables with MACE and diabetes were evaluated with Cox proportional hazards models. Results: 7,552 participants (50±9.7 years) were included; 64% were women. Women had higher hypertension prevalence, body mass index, levels of total cholesterol, LDL-c, and HDL-c but lower triglycerides levels. Women were more sedentary but fewer smokers or active alcohol consumers and had higher educational levels. After 12-year mean follow-up (SD 2.3), the incidence rate of MACE composite was higher in men [4.2 (3.6–4.9) vs. 3.2 (2.8–3.7) cases per 1000 person-years]. Diabetes had the greatest association with MACE (HR = 2.63 95%CI:1.85;3.76), followed by hypertension (HR = 1.75 95%CI:1.30;2.35), low relative grip strength (HR = 1.53 95%CI:1.15;2.02), smoking (HR = 1.47 95%CI: 1.11;1.93), low physical activity (HR = 1.42 95%CI: 1.03;1.96). When evaluating risk factors by sex, only an increased waist-to-hip ratio was more strongly associated with MACE in men (p-interaction

Overexpression of neurotrophic factors in nigral dopamine neurons is a promising approach to reverse neurodegeneration of the nigrostriatal dopamine system, a hallmark in Parkinson’s disease. The human cerebral dopamine neurotrophic factor (hCDNF) has recently emerged as a strong candidate for Parkinson’s disease therapy. This study shows that hCDNF expression in dopamine neurons using the neurotensin-polyplex nanoparticle system reverses 6-hydroxydopamine-induced morphological, biochemical, and behavioral alterations. Three independent electron microscopy techniques showed that the neurotensin-polyplex nanoparticles containing the hCDNF gene, ranging in size from 20 to 150 nm, enabled the expression of a secretable hCDNF in vitro. Their injection in the substantia nigra compacta on day 21 after the 6-hydroxydopamine lesion resulted in detectable hCDNF in dopamine neurons, whose levels remained constant throughout the study in the substantia nigra compacta and striatum. Compared with the lesioned group, tyrosine hydroxylase-positive (TH+) nigral cell population and TH+ fiber density rose in the substantia nigra compacta and striatum after hCDNF transfection. An increase in βIII-tubulin and growth-associated protein 43 phospho-S41 (GAP43p) followed TH+ cell recovery, as well as dopamine and its catabolite levels. Partial reversal (80%) of drug-activated circling behavior and full recovery of spontaneous motor and non-motor behavior were achieved. Brain-derived neurotrophic factor recovery in dopamine neurons that also occurred suggests its participation in the neurotrophic effects. These findings support the potential of nanoparticle-mediated hCDNF gene delivery to develop a disease-modifying treatment against Parkinson’s disease. The Institutional Animal Care and Use Committee of Centro de Investigación y de Estudios Avanzados approved our experimental procedures for animal use (authorization No. 162-15) on June 9, 2019.

Background Antibody–drug conjugates (ADCs) that deliver cytotoxic drugs to tumor cells have emerged as an effective and safe anticancer therapy. ADCs may induce immunogenic cell death (ICD) to promote additional endogenous antitumor immune responses. Here, we characterized the immunomodulatory properties of D3-GPC2-PBD, a pyrrolobenzodiazepine (PBD) dimer-bearing ADC that targets glypican 2 (GPC2), a cell surface oncoprotein highly differentially expressed in neuroblastoma.Methods ADC-mediated induction of ICD was studied in GPC2-expressing murine neuroblastomas in vitro and in vivo. ADC reprogramming of the neuroblastoma tumor microenvironment was profiled by RNA sequencing, cytokine arrays, cytometry by time of flight and flow cytometry. ADC efficacy was tested in combination with macrophage-driven immunoregulators in neuroblastoma syngeneic allografts and human patient-derived xenografts.Results The D3-GPC2-PBD ADC induced biomarkers of ICD, including neuroblastoma cell membrane translocation of calreticulin and heat shock proteins (HSP70/90) and release of high-mobility group box 1 and ATP. Vaccination of immunocompetent mice with ADC-treated murine neuroblastoma cells promoted T cell-mediated immune responses that protected animals against tumor rechallenge. ADC treatment also reprogrammed the tumor immune microenvironment to a proinflammatory state in these syngeneic neuroblastoma models, with increased tumor trafficking of activated macrophages and T cells. In turn, macrophage or T-cell inhibition impaired ADC efficacy in vivo, which was alternatively enhanced by both CD40 agonist and CD47 antagonist antibodies. In human neuroblastomas, the D3-GPC2-PBD ADC also induced ICD and promoted tumor phagocytosis by macrophages, which was further enhanced when blocking CD47 signaling in vitro and in vivo.Conclusions We elucidated the immunoregulatory properties of a GPC2-targeted ADC and showed robust efficacy of combination immunotherapies in diverse neuroblastoma preclinical models.

Circular RNAs (circRNAs) are widely expressed in eukaryotes. However, only a subset has been functionally characterized. We identify and validate a collection of circRNAs in Drosophila, and show that depletion of the brain-enriched circRNA Edis (circ_Ect4) causes hyperactivation of antibacterial innate immunity both in cultured cells and in vivo. Notably, Edis depleted flies display heightened resistance to bacterial infection and enhanced pathogen clearance. Conversely, ectopic Edis expression blocks innate immunity signaling. In addition, inactivation of Edis in vivo leads to impaired locomotor activity and shortened lifespan. Remarkably, these phenotypes can be recapitulated with neuron-specific depletion of Edis, accompanied by defective neurodevelopment. Furthermore, inactivation of Relish suppresses the innate immunity hyperactivation phenotype in the fly brain. Moreover, we provide evidence that Edis encodes a functional protein that associates with and compromises the processing and activation of the immune transcription factor Relish. Importantly, restoring Edis expression or ectopic expression of Edis-encoded protein suppresses both innate immunity and neurodevelopment phenotypes elicited by Edis depletion. Thus, our study establishes Edis as a key regulator of neurodevelopment and innate immunity.

Background Pediatric brain tumors are the leading cause of cancer death in children with an urgent need for innovative therapies. Glypican 2 (GPC2) is a cell surface oncoprotein expressed in neuroblastoma for which targeted immunotherapies have been developed. This work aimed to characterize GPC2 expression in pediatric brain tumors and develop an mRNA CAR T cell approach against this target.Methods We investigated GPC2 expression across a cohort of primary pediatric brain tumor samples and cell lines using RNA sequencing, immunohistochemistry, and flow cytometry. To target GPC2 in the brain with adoptive cellular therapies and mitigate potential inflammatory neurotoxicity, we used optimized mRNA to create transient chimeric antigen receptor (CAR) T cells. We developed four mRNA CAR T cell constructs using the highly GPC2-specific fully human D3 single chain variable fragment for preclinical testing.Results We identified high GPC2 expression across multiple pediatric brain tumor types including medulloblastomas, embryonal tumors with multilayered rosettes, other central nervous system embryonal tumors, as well as definable subsets of highly malignant gliomas. We next validated and prioritized CAR configurations using in vitro cytotoxicity assays with GPC2-expressing neuroblastoma cells, where the light-to-heavy single chain variable fragment configurations proved to be superior. We expanded the testing of the two most potent GPC2-directed CAR constructs to GPC2-expressing medulloblastoma and high-grade glioma cell lines, showing significant GPC2-specific cell death in multiple models. Finally, biweekly locoregional delivery of 2–4 million GPC2-directed mRNA CAR T cells induced significant tumor regression in an orthotopic medulloblastoma model and significantly prolonged survival in an aggressive orthotopic thalamic diffuse midline glioma xenograft model. No GPC2-directed CAR T cell related neurologic or systemic toxicity was observed.Conclusion Taken together, these data show that GPC2 is a highly differentially expressed cell surface protein on multiple malignant pediatric brain tumors that can be targeted safely with local delivery of mRNA CAR T cells, laying the framework for the clinical translation of GPC2-directed immunotherapies for pediatric brain tumors.

Direct numerical simulations of non-premixed fuel-rich methane–oxygen flames at 20 bar are conducted to investigate the turbulent mixing burning of gaseous propellants in rocket engines. The reacting flow is simulated by using an EBI-DNS solver within an OpenFOAM frame. The transport of species is resolved with finite-rate chemistry by using a complex skeletal mechanism that entails 21 species. Two different flames at low and high Reynolds numbers are considered to study the sensitivity of the flame dynamics to turbulence. Regime markers are used to measure the probability of the flow to burn in premixed and non-premixed conditions at different regions. The local heat release statistics are studied in order to understand the drivers in the development of the turbulent diffusion flame. Despite the eminent non-premixed configuration, a significant amount of combustion takes place in premixed conditions. Premixed combustion is viable in both lean and fuel-rich regions, relatively far from the stoichiometric line. It has been found that a growing turbulent kinetic energy is detrimental to combustion in fuel-rich premixed conditions. This is motivated by the disruption of the local premixed flame front, which promotes fuel transport into the diffusion flame. In addition, at downstream positions, higher turbulence enables the advection of methane into the lean core of the flame, enhancing the burning rates in these regions. Therefore, the primary effect of turbulence is to increase the fraction of propellants burnt in oxygen-rich and near-stoichiometric conditions. Consequently, the mixture fraction of the products shifts towards lean conditions, influencing combustion completion at downstream positions.

Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma. There are two main subtypes of RMS, alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma. ARMS typically encompasses fusion‐positive rhabdomyosarcoma, which expresses either PAX3‐FOXO1 or PAX7‐FOXO1 fusion proteins. There are no targeted therapies for ARMS; however, recent studies have begun to illustrate the cooperation between epigenetic proteins and the PAX3‐FOXO1 fusion, indicating that epigenetic proteins may serve as targets in ARMS. Here, we investigate the contribution of BMI1, given the established role of this epigenetic regulator in sustaining aggression in cancer. We determined that BMI1 is expressed across ARMS tumors, patient‐derived xenografts, and cell lines. We depleted BMI1 using RNAi and inhibitors (PTC‐209 and PTC‐028) and found that this leads to a decrease in cell growth/increase in apoptosis in vitro, and delays tumor growth in vivo. Our data suggest that BMI1 inhibition activates the Hippo pathway via phosphorylation of LATS1/2 and subsequent reduction in YAP levels and YAP/TAZ target genes. These results identify BMI1 as a potential therapeutic vulnerability in ARMS and warrant further investigation of BMI1 in ARMS and other sarcomas.

Abstract Background Adiposity is a major component of the metabolic syndrome (MetS), low muscle strength has also been identified as a risk factor for MetS and for cardiovascular disease. We describe the prevalence of MetS and evaluate the relationship between muscle strength, anthropometric measures of adiposity, and associations with the cluster of the components of MetS, in a middle-income country. Methods MetS was defined by the International Diabetes Federation criteria. To assess the association between anthropometric variables (waist circumference (WC), waist-to-hip ratio (W/H), body mass index (BMI)), strength (handgrip/kg bodyweight (HGS/BW)) and the cluster of MetS, we created a MetS score. For each alteration (high triglycerides, low HDLc, dysglycemia, or high blood pressure) one point was conferred. To evaluate the association an index of fat:muscle and MetS score, participants were divided into 9 groups based on combinations of sex-specific tertiles of WC and HGS/BW. Results The overall prevalence of MetS in the 5,026 participants (64% women; mean age 51.2 years) was 42%. Lower HGS/BW, and higher WC, BMI, and W/H were associated with a higher MetS score. Amongst the 9 HGS/BW:WC groups, participants in the lowest tertile of HGS/BW and the highest tertile of WC had a higher MetS score (OR = 4.69 in women and OR = 8.25 in men;p

Abstract Background An estimated 70.8 million people are forcibly displaced worldwide, 75% of whom are women and children. Prioritizing a global research agenda to inform guidance, service delivery, access to and quality of services is essential to improve the survival and health of women, children and adolescents in humanitarian settings. Method A mixed-methods design was adapted from the Child Health and Nutrition Research Initiative (CHNRI) methodology to solicit priority research questions across the sexual, reproductive, maternal, newborn, child and adolescent health (SRMNCAH) domains in humanitarian settings. The first step (CHNRI) involved data collection and scoring of perceived priority questions, using a web-based survey over two rounds (first, to generate the questions and secondly, to score them). Over 1000 stakeholders from across the globe were approached; 177 took part in the first survey and 69 took part in the second. These research questions were prioritized by generating a research prioritization score (RPP) across four dimensions: answerability, program feasibility, public health relevance and equity. A Delphi process of 29 experts followed, where the 50 scored and prioritized CHRNI research questions were shortlisted. The top five questions from the CHNRI scored list for each SRMNCAH domain were voted on, rendering a final list per domain. Results A total of 280 questions were generated. Generated questions covered sexual and reproductive health (SRH) (n = 90, 32.1%), maternal health (n = 75, 26.8%), newborn health (n = 42, 15.0%), child health (n = 43, 15.4%), and non-SRH aspects of adolescent health (n = 31, 11.1%). A shortlist of the top ten prioritized questions for each domain were generated on the basis of the computed RPPs. During the Delphi process, the prioritized questions, based on the CHNRI process, were further refined. Five questions from the shortlist of each of the SRMNCAH domain were formulated, resulting in 25 priority questions across SRMNCAH. For example, one of the prioritized SRH shortlisted and prioritized research question included: “What are effective strategies to implement good quality comprehensive contraceptive services (long-acting, short-acting and EC) for women and girls in humanitarian settings?” Conclusion Data needs, effective intervention strategies and approaches, as well as greater efficiency and quality during delivery of care in humanitarian settings were prioritized. The findings from this research provide guidance for researchers, program implementers, as well as donor agencies on SRMNCAH research priorities in humanitarian settings. A global research agenda could save the lives of those who are at greatest risk and vulnerability as well as increase opportunities for translation and innovation for SRMNCAH in humanitarian settings.

Hyaluronic acid (HA) and proteoglycans (such as dermatan sulphate (DS) and chondroitin sulphate (CS)) are the main components of the extracellular matrix of the skin, along with collagen and elastin. These components decrease with age, which implies a loss of skin moisture causing wrinkles, sagging and aging. Currently, the external and internal administration of effective ingredients that can reach the epidermis and dermis is the main alternative for combating skin aging. The objective of this work was to extract, characterise and evaluate the potential of an HA matrix ingredient to support anti-aging. The HA matrix was isolated and purified from rooster comb and characterised physicochemically and molecularly. In addition, its regenerative, anti-aging and antioxidant potential and intestinal absorption were evaluated. The results show that the HA matrix is composed of 67% HA, with an average molecular weight of 1.3 MDa; 12% sulphated glycosaminoglycans, including DS and CS; 17% protein, including collagen (10.4%); and water. The in vitro evaluation of the HA matrix’s biological activity showed regenerative properties in both fibroblasts and keratinocytes, as well as moisturising, anti-aging and antioxidant effects. Furthermore, the results suggest that the HA matrix could be absorbed in the intestine, implying a potential oral as well as topical use for skin care, either as an ingredient in a nutraceutical or a cosmetic product.

We present the data for taurine (2-aminoethanesulfonic acid) treatment to healthy pregnant Sprague Dawley rats (SD). At embryonic day 15 (E15), healthy pregnant SD rats were given taurine treatment (50 mg/L drinking water) and then to their male offspring until they reached the age of eight months. We quantify, in the offspring, the concentration of nitric oxide (NO) through the Griess colorimetric reaction [1] and malondialdehyde + 4-hydroxyalkenals (MDA + 4-HDA) by the Gérard-Monnier technique [2]. The assessment ages for NO and MDA + 4-HDA were at postnatal day 15 (PND15), 1, 3, and 8 months of age.The body weight was measured along with the integral motor behavior in the perinatal stage through the surface righting reflex test at PND5, cliff aversion test at PND9, grip strength test at PND 11, and front limb and hindlimb suspension tests at PND13. The tests were performed accordingly with [3].The data obtained showed that SD rats with the taurine administration performed poorly in the motor tests compared with the untreated healthy rats. The taurine-treated rats also showed increased lipid peroxidation preferentially in cerebral regions involved in motor activity, such as the medulla oblongata, the subcortical nuclei, and the cerebral cortex. However, the taurine treatment only increased NO concentration in the evaluated cerebral regions at older ages.At E15, taurine plays a pivotal role in the excitatory/inhibitory neuromodulation, presumably by acting as an excitatory neurotransmitter during the GABA-switch [4]. The increase in the taurine concentration during the embryonic period might cause excitotoxicity in healthy brains, which might lead to impairments in the motor development of the offspring. Therefore, the present datasets can be valuable for researchers who attempt to use the taurine supplement on healthy animal models at gestational stages; and explore the relation with taurine intake during pregnancy in human patients. These datasets are related to the article “Long-term taurine administration improves motor skills in a tubulinopathy rat model by decreasing oxidative stress and promoting myelination” [5].

Resumo: Considerando a importância em compreender o Museu da Diversidade Sexual da cidade de São Paulo como ecologia informacional complexa, tendo em vista que é composto por seus ambientes informacionais analógico e digital, esta pesquisa objetiva avaliá-lo a partir dos atributos da Encontrabilidade da Informação e da Arquitetura da Informação Pervasiva por meio de um checklist e a partir da técnica de observação participativa. De um modo geral, o Museu da Diversidade Sexual apresentou em sua grande maioria uma parcialidade no que diz respeito aos atributos de Encontrabilidade da informação. Por se tratar de uma ecologia informacional complexa ele apresenta uma diversidade dos fatores envolvidos. Percebemos que os maiores problemas encontrados se referem à s descobertas de informação e a mediação dos sujeitos informacionais; e ausência de elementos de acessibilidade no website os quais possibilitariam ampliar o acesso à informação por pessoas com deficiência. Por meio deste estudo foi possível potencializar as divulgações de ideias considerando os sujeitos informacionais no processo de produção e organização da informação, tornando o ambiente informacional digital, especialmente, mais colaborativo e interativo.

La enfermería de salud mental se centra en el cuidado a partir de las relaciones interpersonales, es guiada por un marco teórico y metodológico propio que la convierten en una profesión autónoma. La pandemia por COVID-19 ha afectado la salud mental de muchas personas poniendo a prueba todos los niveles de atención de la salud. Por lo que en este artículo se busca describir las realidades, los avances y los desafíos para la enfermería de salud mental después de la pandemia por COVID-19. Se exponen algunos elementos que podrían mejorar la calidad de los servicios en esta área, dentro de los que se mencionan el desarrollo de: Investigación en e-salud, enfermería de salud mental en el hospital general, cuidado remoto, manejo del duelo, medios de comunicación y cooperación en equipo. La enfermería de salud mental debe aprovechar los desafíos que genera la pandemia por COVID-19 para innovar su ejercicio profesional basado en evidencia científica.

Abstract The spreading and accumulation of α-synuclein and dopaminergic neurodegeneration, two hallmarks of Parkinson’s disease (PD), have been faithfully reproduced in rodent brains by chronic, oral administration of β-sitosterol β-D-glucoside (BSSG). We investigated whether a single injection of BSSG (6 μg BSSG/μL DMSO) in the left substantia nigra of Wistar rats causes the same effects. Mock DMSO injections and untreated rats formed control groups. We performed immunostainings against the pathological α-synuclein, the dopaminergic marker tyrosine hydroxylase (TH), the neuroskeleton marker β-III tubulin, the neurotensin receptor type 1 (NTSR1) as non-dopaminergic phenotype marker and Fluro-Jade C (F-J C) label for neurodegeneration. Using β-galactosidase (β-Gal) assay and active caspase-3 immunostaining, we assessed cell death mechanisms. Golgi-Cox staining was used to measure the density and types of dendritic spines of striatal medium spiny neurons. Motor and non-motor alterations were also evaluated. The study period comprised 15 to 120 days after the lesion. In the injured substantia nigra, BSSG caused a progressive α-synuclein aggregation and dopaminergic neurodegeneration caused by senescence and apoptosis. The α-synuclein immunoreactivity was also present within microglia cells. Decreased density of dopaminergic fibers and dendritic spines also occurred in the striatum. Remarkably, all the histopathological changes also appeared on the contralateral nigrostriatal system, and α-synuclein aggregates were present in other brain regions. Motor and non-motor behavioral alterations were progressive. Our data show that the stereotaxic BSSG administration reproduces PD α-synucleinopathy phenotype in the rat. This approach will aid in identifying the spread mechanism of α-synuclein pathology and validate anti-synucleinopathy therapies.

The development of reliable measures of health in ageing organisms is a need in ageing research. Using atomic force microscopy, here, the authors assess whole body stiffness of worms and show that it reflects organismal fitness.

B7–H3 (CD276), a member of the B7 superfamily, is an important factor in downregulating immune responses against tumors. It is also aberrantly expressed in many human malignancies. Beyond immune regulatory roles, its overexpression has been linked to invasive metastatic potential and poor prognosis in patients with cancer. Antibody-dependent cell-mediated cytotoxicity strategies targeting B7–H3 are currently in development, and early-phase clinical trials have shown encouraging preliminary results.To understand the role of B7–H3 in pediatric central nervous system (CNS) malignancies, a comprehensive panel of primary CNS tumors of childhood was examined by immunohistochemistry for levels and extent of B7–H3 expression. In addition, B7–H3 m-RNA expression status and association with overall survival in various pediatric CNS tumor types was accessed by curating publicly available patient gene expression data sets derived from bioinformatics analysis and visualization platforms (GlioVis).We demonstrate that B7–H3 is broadly expressed in pediatric glial and nonglial CNS tumors, and its aberrant expression, as determined by immunohistochemical staining intensity, correlates with tumor grade. Moreover, high B7–H3 m-RNA expression is significantly associated with worse survival and could potentially improve prognostication in various brain tumor types of childhood. B7–H3 can be used as a therapeutic target, given its tumor selectivity and the availability of targeted therapeutic agents to this antigen.

Objective: The aim of this study was to assess the association between dopaminergic-induced complications and satisfaction with life in patients with Parkinson’s disease. Methods: A cross-sectional study was carried out. Subjects were recruited from two movement disorders clinics in Mexico, from May to October 2019. Dopaminergic drug-induced complications were assessed with the movement disorders society – unified Parkinson’s disease rating scale items 4.1-4.5 where satisfaction with life scale score was used as the outcome variable. Correlation coefficients were utilized. Results: Sixty-eight patients were included in the study. The mean satisfaction with life scale score was 25.7 (SD = 5.3), with 66.1% of them scoring higher than average scores. Age at diagnosis (rs = 0.256, p = 0.035), education (rs = 0.240, p = 0.048), geographic region (r2 = 0.180, p = 0.034), movement disorders society - unified Parkinson’s disease rating scale part I (rs = −0.378, p = 0.002) and II (rs = −0.280, p = 0.021), and Hoehn and Yahr stage (rs = −0.295, p = 0.015) were significantly correlated with satisfaction with life scale scores. Partial correlation coefficient analysis revealed a statistically significant but moderate correlation between motor fluctuations and satisfaction with life scale scores (rs = −0.408, p = 0.001). No significant correlation was observed with dyskinesias. Conclusions: Motor fluctuations but not dyskinesias have a detrimental effect on patients’ life satisfaction. Strategies to reduce motor fluctuations and better understanding the contribution of these to patients’ lives may help minimize the negative impact of these complications on patients with PD.

Background: Previous studies showed that proline-rich polypeptide (PRP-1) is a ligand for innate immunity toll-like receptors (TLR), and an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1) which induces the death of chondrosarcoma cancer stem cells (CSC). The aim of this study was to investigate the effect of PRP-1 on the regulation of unfolded protein response (UPR) in human chondrosarcoma cells. Materials and methods: Lysates were prepared from a monolayer (bulk or ALDHhigh population), or spheroids chondrosarcoma cell cultures and treated with PRP-1 or control, followed by protein levels quantification by western blotting and mRNA expression by RT-qPCR of protein-RNA-like endoplasmic reticulum kinase (PERK), eukaryotic translation initiation factor 2α (eIF2α), activating transcription factor 4 (ATF4), CCAAT-enhancer-binding protein homologous protein (CHOP), activating transcription factor 6 (ATF6), inositol-requiring enzyme 1 (IRE1α), and X-box binding protein (XBP1). Results: The PRP-1 has been shown to increase the expression of PERK, eIF2α, ATF4, CHOP, ATF6, IRE1α, and XBP1, on both protein and mRNA levels. Conclusion: PRP-1 activated UPR branches in monolayer, spheroid, and stem cell populations of human chondrosarcoma.