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Oxidative stress elicited by reactive oxygen species (ROS) and chronic inflammation are involved both in deterring and the generation/progression of human cancers. Exogenous ROS can injure mitochondria and induce them to generate more endogenous mitochondrial ROS to further perpetuate the deteriorating condition in the affected cells. Dysfunction of these cancer mitochondria may possibly be offset by the Warburg effect, which is characterized by amplified glycolysis and metabolic reprogramming. ROS from neutrophil extracellular traps (NETs) are an essential element for neutrophils to defend against invading pathogens or to kill cancer cells. A chronic inflammation typically includes consecutive NET activation and tissue damage, as well as tissue repair, and together with NETs, ROS would participate in both the destruction and progression of cancers. This review discusses human mitochondrial plasticity and the glucose metabolic reprogramming of cancer cells confronting oxidative stress by the means of chronic inflammation and neutrophil extracellular traps (NETs).

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The inducers of neutrophil extracellular trap (NET) formation are heterogeneous and consequently, there is no specific pathway or signature molecule indispensable for NET formation. But certain events such as histone modification, chromatin decondensation, nuclear envelope breakdown, and NET release are ubiquitous. During NET formation, neutrophils drastically rearrange their cytoplasmic, granular and nuclear content. Yet, the exact mechanism for decoding each step during NET formation still remains elusive. Here, we investigated the mechanism of nuclear envelope breakdown during NET formation. Immunofluorescence microscopic evaluation revealed a gradual disintegration of outer nuclear membrane protein nesprin-1 and alterations in nuclear morphology during NET formation. MALDI-TOF analysis of NETs that had been generated by various inducers detected the accumulation of nesprin-1 fragments. This suggests that nesprin-1 degradation occurs before NET release. In the presence of a calpain-1, inhibitor nesprin-1 degradation was decreased in calcium driven NET formation. Microscopic evaluation confirmed that the disintegration of the lamin B receptor (LBR) and the collapse of the actin cytoskeleton occurs in early and later phases of NET release, respectively. We conclude that the calpain-1 degrades nesprin-1, orchestrates the weakening of the nuclear membrane, contributes to LBR disintegration, and promoting DNA release and finally, NETs formation.

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BACKGROUND: A quasi-experimental comparative trial will be designed in Burkina Faso. The study will compare the use and preferences for two groups types of insecticide-treated nets textile: polyester-based and polyethylene-based, according to their use and preferences in selected health districts. These health districts will be selected in three eco-climate zones (Sahelian, dry savannah and wet savannah) in the country. These findings will inform decisions on future net procurements for national malaria control programme in 2025. METHODS: Quantitative surveys and qualitative data collection will be carried out to gather information on the type of net textile most commonly used and preferred by the community. They will be performed between the end of the dry season and the early rainy season. The quantitative surveys involved household interviews with households and individuals' questionnaires, while the qualitative data collection involved in-depth individual interviews and focus group discussions to explore and clarify some key evaluation criteria. A total of 9450 insecticide-treated nets were surveyed for quantitative survey purposes. For the qualitative study, 48 in-depth individual interviews and 12 focus group discussions were carried out. A mixed model approach combining the results from quantitative surveys and qualitative studies will be used for decision-making on the type of insecticide-treated net preference. CONCLUSION: This methodological approach will be used by the National Malaria Control Programme to conduct this study on determinants of net use in Burkina Faso in order to provide robust evidence across diverse settings. This mixed-methods approach for data collection and analysis could be used in other countries to provide evidence that would help to increase the uptake of insecticide-treated nets, the main vector control tool in Africa.

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Non-alcoholic Fatty Liver Disease (NAFLD), noted for its widespread prevalence among adults, has become the leading chronic liver condition globally. Simultaneously, the annual disease burden, particularly liver cirrhosis caused by NAFLD, has increased significantly. Neutrophil Extracellular Traps (NETs) play a crucial role in the progression of this disease and are key to the pathogenesis of NAFLD. However, research into the specific roles of NETs-related genes in NAFLD is still a field requiring thorough investigation. Utilizing techniques like AddModuleScore, ssGSEA, and WGCNA, our team conducted gene screening to identify the genes linked to NETs in both single-cell and bulk transcriptomics. Using algorithms including Random Forest, Support Vector Machine, Least Absolute Shrinkage, and Selection Operator, we identified ZFP36L2 and PHLDA1 as key hub genes. The pivotal role of these genes in NAFLD diagnosis was confirmed using the training dataset GSE164760. This study identified 116 genes linked to NETs across single-cell and bulk transcriptomic analyses. These genes demonstrated enrichment in immune and metabolic pathways. Additionally, two NETs-related hub genes, PHLDA1 and ZFP36L2, were selected through machine learning for integration into a prognostic model. These hub genes play roles in inflammatory and metabolic processes. scRNA-seq results showed variations in cellular communication among cells with different expression patterns of these key genes. In conclusion, this study explored the molecular characteristics of NETs-associated genes in NAFLD. It identified two potential biomarkers and analyzed their roles in the hepatic microenvironment. These discoveries could aid in NAFLD diagnosis and management, with the ultimate goal of enhancing patient outcomes.

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Advancements in somatostatin receptor (SSTR) targeted imaging and treatment of well-differentiated neuroendocrine tumors (NETs) have revolutionized the management of these tumors. This comprehensive review delves into the current practice, discussing the use of the various FDA-approved SSTR-agonist PET tracers and the predictive imaging biomarkers, and elaborating on Lu177-DOTATATE peptide receptor radionuclide therapy (PRRT) including the evolving areas of post-therapy imaging practices, PRRT retreatment, and the potential role of dosimetry in optimizing patient treatments. The future directions sections highlight ongoing research on investigational PET imaging radiotracers, future prospects in alpha particle therapy, and combination therapy strategies.

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Background: There is accumulating evidence regarding the benefits of the 5-HT3 receptor antagonist ondansetron for the treatment of critical illness due to its potential anti-inflammatory effect. This study attempted to determine the potential targets and molecular mechanisms of ondansetron's action against critical illnesses. Methods: A bioinformatics analysis of network pharmacology was conducted to demonstrate screening targets and the signaling pathways of ondansetron action against the most common critical illnesses such as acute kidney injury (AKI), sepsis, and acute respiratory distress syndrome (ARDS). Experiments of LPS-stimulated rat neutrophils with ondansetron treatment were conducted to further validate the relevant hypothesis. Results: A total of 198, 111, and 26 primary causal targets were identified from the data for the action of ondansetron against AKI, sepsis, and ARDS respectively. We found that the pathway of neutrophil extracellular traps (NETs) formation is statistically significantly involved in the action of ondansetron against these three critical illnesses. In the pathway of NETs formation, the common drug-disease intersection targets in these three critical illnesses were toll-like receptor 8 (TLR8), mitogen-activated protein kinase-14 (MAPK14), nuclear factor kappa-B1 (NFKB1), neutrophil elastase (NE), and myeloperoxidase (MPO). Considering these bioinformatics findings, we concluded that ondansetron anti-critical illness effects are mechanistically and pharmacologically implicated with suppression of neutrophils-associated inflammatory processes. It was also showed that after treatment of LPS-stimulated rat neutrophils with ondansetron, the key proteins NE, MPO, and Peptide Arginine Deaminase 4 (PAD4) in the NETs formation were significantly reduced, and the inflammatory factors IL-6, IL-1ß, TNF-α, and chemokine receptor (CXCR4) were also significantly decreased. Conclusion: The excessive formation of NETs may have important research value in the development and progression of critical illness. Ondansetron may reduce excessive inflammatory injury in critical diseases by reducing the formation of NETs via influencing the five targets: TLR8, NFKB1, MAPK14, NE, and MPO. Ondansetron and these primary predictive biotargets may potentially be used to treat critical illness in future clinical practice.

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Neutrophils interact with Leishmania when the sandfly vector inoculates these parasites in the host with saliva and promastigotes-derived extracellular vesicles (EVs). It has been shown that this co-injection induces inflammation and exacerbates leishmaniasis lesions. EVs are a heterogeneous group of vesicles released by cells that play a crucial role in intercellular communication. Neutrophils are among the first cells to interact with the parasites and release neutrophil extracellular traps (NETs) that ensnare and kill the promastigotes. Here, we show that Leishmania amazonensis EVs induce NET formation and identify molecular mechanisms involved. We showed the requirement of neutrophils' Toll-like receptors (TLRs) for EVs-induced NET. EVs carrying the virulence factors lipophosphoglycan (LPG) and the zinc metalloproteases were endocytosed by some neutrophils and snared by NETs. EVs-induced NET formation required reactive oxygen species, myeloperoxidase, elastase, peptidyl arginine deiminase (PAD), and Ca++. The proteomic analysis of the EVs cargo revealed 1,189 proteins; the 100 most abundant identified comprised some known Leishmania virulent factors. Importantly, L. amazonensis EVs-induced NETs lead to the killing of promastigotes and could participate in the exacerbated inflammatory response induced by the EVs, which may play a role in the pathogenesis process.

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Background: The rapid spread of pyrethroid resistance has led to a change in strategy, going from pyrethroid-based nets to PBO + pyrethroid-treated nets. Although these new nets may significantly improve the control of pyrethroid-resistant mosquitoes, their durability in the field remain not yet well documented. This study investigates the durability and washing resistance of Olyset-Plus nets in the city centre and rural areas of Bertoua, Cameroon. In each site, a semi-structured questionnaire was administered to at least 190 households with an Olyset-Plus net. Factors such as net use, physical integrity and bioefficacy were recorded. Bioassays were conducted on the collected nets to assess their bioefficacy and resistance to washing. They were tested against wild Anopheles gambiae sensus lato (s.l.). Unused nets and the Kisumu strain were used as controls. Washing and cone testing of the nets was carried out according to standard WHO protocols. Results: A high rate of net use by children was recorded in the urban area (89.1% (106/119)) compared to the rural area (39.7% (118/297)). The majority of Olyset-Plus nets inspected 82.2% (162/197) in the rural area and 88% (206/234) in the urban centre were in good condition (Hole Index<64). Only 5.6% and 6.8% of nets were badly torn in rural and urban sites respectively. Nets were washed more regularly in the urban centre. 88.1% of urban dwellers reported having washed their nets at least once compared to only 62% of rural dwellers. Bioefficacy tests with nets indicated a mortality rate ranging from 66% for unwashed nets to 86.7% for nets washed at least once. Bioefficacy varied significantly in the city of Bertoua according to net washing frequency, soaking time, soap type and drying location, whereas in the rural village, only washing(washed or unwashed) and soaking status (soaked or unsoaked) significantly influenced the bioefficacy of Olyset-Plus nets. Conclusions: This study revealed different handling practices of bed nets in rural and urban settings which could significantly affect Olyset-Plus nets bio-efficacy and durability. Routine monitoring and sensitization of communities to best practices concerning bed nets usage and handling during mass distribution might enhance the net durability in the community.

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BACKGROUND: Understanding antibody responses to SARS-CoV-2 vaccination is crucial for refining COVID-19 immunization strategies. Generation of mucosal immune responses, including mucosal IgA, could be of potential benefit to vaccine efficacy, yet limited evidence exists regarding the production of mucosal antibodies following the administration of current mRNA vaccines to young children. METHODS: We measured the levels of antibodies against SARS-CoV-2 from a cohort of children under 5 years of age (N=24) undergoing SARS-CoV-2 mRNA vaccination (serially collected, matched serum and saliva samples) or in a convenience sample of children under 5 years of age presenting to pediatric emergency department (nasal swabs, N=103). Further, we assessed salivary and nasal samples for the ability to induce SARS-CoV-2 spike-mediated neutrophil extracellular traps (NET) formation. RESULTS: Longitudinal analysis of post-vaccine responses in saliva revealed the induction of SARS-CoV-2 specific IgG but not IgA. Similarly, SARS-CoV-2 specific IgA was only observed in nasal samples obtained from previously infected children with or without vaccination, but not in vaccinated children without a history of infection. In addition, oronasopharyngeal samples obtained from children with prior infection were able to trigger enhanced spike-mediated NET formation, and IgA played a key role in driving this process. CONCLUSIONS: Despite the induction of specific IgG in the oronasal mucosa, current intramuscular vaccines have limited ability to generate mucosal IgA in young children. These results confirm the independence of mucosal IgA responses from systemic humoral responses following mRNA vaccination and suggest potential future vaccination strategies for enhancing mucosal protection in this young age group.

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BACKGROUND: Hidradenitis suppurativa (HS) is an inflammatory chronic skin disorder of unknown etiology characterized by inflamed abscess-like nodules and boils resulting in sinus tract formation, tissue scarring and massive infiltration of neutrophils. Multiple lines of evidence have highlighted the potential association between alterations in the Notch pathway and HS pathogenesis, but the mechanisms remain incompletely characterized. OBJECTIVE: Herein, we aim to elucidate the role of neutrophil extracellular traps in Notch-γ-secretase, signaling. METHODS: Twenty-six HS lesional tissues, primary HS macrophages and skin fibroblasts were interrogated by quantitative PCR, western blot, and Elisa analyses. γ-Secretase, and TACE activities were measured in HS skin lesions, macrophages and skin fibroblasts. Immunofluorescence and RNAscope analyzes were performed in HS and control skin. RESULTS: A prominent presence of Notch ligands, DLL4 and JAG2 were detected at the protein and mRNA levels in HS skin lesion when compared to control. Levels of DLL4, JAG1, cit-H3-DNA and γ-secretase activity correlated with HS disease severity. Additionally, significantly elevated levels of Notch ligands and γ-secretase activity were found in dissected sinus tracts when compared to the rest of HS tissue. Immunofluorescence microscopy in HS skin lesions showed activation of Notch 1 signaling in macrophages and skin fibroblasts. Neutrophil extracellular traps (NETs) purified from HS patients displayed elevated levels of DLL4. HS-NETs activated the Notch pathway in macrophages and dermal fibroblasts isolated from HS patients. HS skin fibroblasts displayed elevated levels of CD90 and DPP4 in association with increased migratory capacity and Notch activation. Inhibition of Notch decreased migratory capacity and pro-fibrotic markers in HS fibroblasts. CONCLUSION: These data support a pathogenic connection between NETs, Notch- γ-secretase activation and the release of pro-fibrotic molecules that promote dysregulation of macrophages and skin fibroblasts in HS. Unveiling the relevance of these molecular events not only expands our understanding of HS but also opens new venues for the development of targeted therapies to address the fibrotic complications of advanced stages of HS.

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Our purpose was to prospectively assess the distribution of NETPET scores in well-differentiated (WD) grade 2 and 3 gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) and to determine the impact of the NETPET score on clinical management. Methods: This single-arm, institutional ethics review board-approved prospective study included 40 patients with histologically proven WD GEP NETs. 68Ga-DOTATATE PET and 18F-FDG PET were performed within 21 d of each other. NETPET scores were evaluated qualitatively by 2 reviewers, with up to 10 marker lesions selected for each patient. The quantitative parameters that were evaluated included marker lesion SUVmax for each tracer; 18F-FDG/68Ga-DOTATATE SUVmax ratios; functional tumor volume (FTV) and metabolic tumor volume (MTV) on 68Ga-DOTATATE and 18F-FDG PET, respectively; and FTV/MTV ratios. The treatment plan before and after 18F-FDG PET was recorded. Results: There were 22 men and 18 women (mean age, 60.8 y) with grade 2 (n = 24) or grade 3 (n = 16) tumors and a mean Ki-67 index of 16.1%. NETPET scores of P0, P1, P2A, P2B, P3B, P4B, and P5 were documented in 2 (5%), 5 (12.5%), 5 (12.5%) 20 (50%), 2 (5%), 4 (10%), and 2 (5%) patients, respectively. No association was found between the SUVmax of target lesions on 68Ga-DOTATATE and the SUVmax of target lesions on 18F-FDG PET (P = 0.505). 18F-FDG/68Ga-DOTATATE SUVmax ratios were significantly lower for patients with low (P1-P2) primary NETPET scores than for those with high (P3-P5) primary NETPET scores (mean ± SD, 0.20 ± 0.13 and 1.68 ± 1.44, respectively; P < 0.001). MTV on 18F-FDG PET was significantly lower for low primary NETPET scores than for high ones (mean ± SD, 464 ± 601 cm3 and 66 ± 114 cm3, respectively; P = 0.005). A change in the type of management was observed in 42.5% of patients after 18F-FDG PET, with the most common being a change from systemic therapy to peptide receptor radionuclide therapy and from debulking surgery to systemic therapy. Conclusion: There was a heterogeneous distribution of NETPET scores in patients with WD grade 2 and 3 GEP NETs, with more than 1 in 5 patients having a high NETPET score and a frequent change in management after 18F-FDG PET. Quantitative parameters including 18F-FDG/68Ga-DOTATATE SUVmax ratios in target lesions and FTV/MTV ratios can discriminate between patients with high and low NETPET scores.

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Our objective is to explore quantitative imaging markers for early prediction of treatment response in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) undergoing [177Lu]Lu-DOTATATE therapy. By doing so, we aim to enable timely switching to more effective therapies in order to prevent time-resource waste and minimize toxicities. Methods: Patients diagnosed with unresectable or metastatic, progressive, well-differentiated, receptor-positive GEP-NETs who received 4 sessions of [177Lu]Lu-DOTATATE were retrospectively selected. Using SPECT/CT images taken at the end of treatment sessions, we counted all visible tumors and measured their largest diameters to calculate the tumor burden score (TBS). Up to 4 target lesions were selected and semiautomatically segmented. Target lesion peak counts and spleen peak counts were measured, and normalized peak counts were calculated. Changes in TBS (ΔTBS) and changes in normalized peak count (ΔnPC) throughout treatment sessions in relation to the first treatment session were calculated. Treatment responses were evaluated using third-month CT and were binarized as progressive disease (PD) or non-PD. Results: Twenty-seven patients were included (7 PD, 20 non-PD). Significant differences were observed in ΔTBSsecond-first, ΔTBSthird-first, and ΔTBSfourth-first (where second-first, third-first, and fourth-first denote scan number between the second and first, third and first, and fourth and first [177Lu]Lu-DOTATATE treatment cycles), respectively) between the PD and non-PD groups (median, 0.043 vs. -0.049, 0.08 vs. -0.116, and 0.109 vs. -0.123 [P = 0.023, P = 0.002, and P < 0.001], respectively). ΔnPCsecond-first showed significant group differences (mean, -0.107 vs. -0.282; P = 0.033); ΔnPCthird-first and ΔnPCfourth-first did not reach statistical significance (mean, -0.122 vs. -0.312 and -0.183 vs. -0.405 [P = 0.117 and 0.067], respectively). At the optimal threshold, ΔTBSfourth-first exhibited an area under the curve (AUC) of 0.957, achieving 100% sensitivity and 80% specificity. ΔTBSsecond-first and ΔTBSthird-first reached AUCs of 0.793 and 0.893, sensitivities of 71.4%, and specificities of 85% and 95%, respectively. ΔnPCsecond-first, ΔnPCthird-first, and ΔnPCfourth-first showed AUCs of 0.764, 0.693, and 0.679; sensitivities of 71.4%, 71.4%, and 100%; and specificities of 75%, 70%, and 35%, respectively. Conclusion: ΔTBS and ΔnPC can predict [177Lu]Lu-DOTATATE response by the second treatment session.

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Paragangliomas are rare tumors of neuroendocrine origin. Within the head and neck, these tumors are slow-growing and locally destructive, with a small malignant potential. Vagal paragangliomas (VPs) originate from paraganglia around the vagus nerve, typically at the level of the skull base. Cranial nerve deficits are common at presentation, with the vagus nerve and hypoglossal nerves being most affected. Similarly, hypoglossal paragangliomas (HPs) originate from around the hypoglossal nerve but are extremely rare and less documented. We describe the case of a patient presenting with an isolated hypoglossal nerve palsy in the setting of a tumor that radiologically represents a VP. A descriptive literature review was conducted to highlight presentation, management, and outcomes related to this pathology. A 65-year-old male presented to the clinic with tongue fasciculations and several years of dysarthria. Physical examination showed intermittent right tongue fasciculations in addition to ipsilateral hemi-atrophy. A computed tomography scan with contrast revealed an enhancing skull base mass inferior to the right carotid space. Subsequently, magnetic resonance imaging with contrast further delineated its anatomic involvement and site of origin, allowing for the diagnosis of a VP. After further discussion with the patient about his clinical findings, the decision was made to proceed with observation and serial imaging. Skull base paragangliomas are a rare pathologic entity that may pose a challenging multidisciplinary approach to optimize management strategies. Treatment may vary on a case-by-case basis and is dependent on patient and tumor characteristics.

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Background: Interleukin-6-receptor inhibition with tocilizumab improves myocardial salvage in patients with ST-segment elevation myocardial infarction (STEMI). Reduced levels of neutrophil extracellular traps (NETs), which consist of nuclear material studded with proteins released upon neutrophil activation, might contribute to this effect. Objectives: The purpose of this study was to evaluate the effect of tocilizumab on NETs and investigate the association between NETs and myocardial injury in patients with STEMI. Methods: In the ASSAIL-MI study, 199 patients with STEMI were randomized to tocilizumab or placebo during percutaneous coronary intervention. In this substudy, we analyzed blood levels of the NET markers double-stranded deoxyribonucleic acid (dsDNA), myeloperoxidase-DNA, and citrullinated histone 3 (H3Cit) at admission and after 24 hours and 3 to 7 days. In a subgroup of patients, we assessed regulation of transcripts related to the formation of NETs. We also investigated associations between NET markers and the myocardial salvage index (MSI). Results: All NET markers were lower in the tocilizumab group than in the placebo group at 3 to 7 days (all P < 0.04). Several NET-related pathways were downregulated in the tocilizumab group. The beneficial effect of tocilizumab on the MSI seemed to be partly dependent on reduction of NETs (structural equation modeling: 0.05, P = 0.001 [dsDNA] and 0.02, P = 0.055 [H3Cit]). Patients with NETs in the 3 lowest quartiles had higher MSI than patients in quartile 4 (10.9 [95% CI: 4.0-15.0] [dsDNA] and 8.9 [95% CI: 2.0-15.9] [H3Cit], both P = 0.01). Conclusions: NETs were reduced by tocilizumab and associated with myocardial injury. The effect of tocilizumab on MSI might be mediated through reduced NETs. (ASSessing the Effect of Anti-IL-6 Treatment in Myocardial Infarction: The ASSAIL-MI Trial [ASSAIL-MI]; NCT03004703).

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Background: Psychiatric disorders often emerge during late adolescence/early adulthood, a period with increased susceptibility to socioenvironmental factors that coincides with incomplete parvalbumin interneuron (PVI) development. Stress during this period causes functional loss of PVIs in the ventral hippocampus (vHip), which has been associated with dopamine system overdrive. This vulnerability persists until the appearance of perineuronal nets (PNNs) around PVIs. We assessed the long-lasting effects of adolescent or adult stress on behavior, ventral tegmental area dopamine neuron activity, and the number of PVIs and their associated PNNs in the vHip. Additionally, we tested whether PNN removal in the vHip of adult rats, proposed to reset PVIs to a juvenile-like state, would recreate an adolescent-like phenotype of stress susceptibility. Methods: Male rats underwent a 10-day stress protocol during adolescence or adulthood. Three to 4 weeks poststress, we evaluated behaviors related to anxiety, sociability, and cognition, ventral tegmental area dopamine neuron activity, and the number of PV+ and PNN+ cells in the vHip. Furthermore, adult animals received intra-vHip infusion of ChABC (chondroitinase ABC) to degrade PNNs before undergoing stress. Results: Unlike adult stress, adolescent stress induced anxiety responses, reduced sociability, cognitive deficits, ventral tegmental area dopamine system overdrive, and decreased PV+ and PNN+ cells in the vHip. However, intra-vHip ChABC infusion caused the adult stress to produce changes similar to the ones observed after adolescent stress. Conclusions: Our findings underscore adolescence as a period of heightened vulnerability to the long-lasting impact of stress and highlight the protective role of PNNs against stress-induced damage in PVIs.

In this work, we aimed to go deeper into understanding perineuronal nets (PNNs), a specialized extracellular matrix that evolves and protects inhibitory neurons in the brain, specifically parvalbumin-positive interneurons (PVIs). PVIs are essential in regulating brain activity. PNNs only reach maturity in adulthood, which leaves these interneurons unprotected during early life. To investigate this vulnerability, we conducted experiments in which we exposed adolescent and adult animals to a stress protocol. We observed that adolescent animals exhibited a higher susceptibility to developing changes associated with psychiatric disorders later in life. This susceptibility may stem from the absence of PNN protection around their PVIs. To explore this possibility further, we administered an enzyme into a specific brain region, the ventral hippocampus, of adult animals to selectively remove PNNs and induce an adolescent-like state. When subjected to stress, these animals displayed abnormalities similar to those observed in animals stressed during adolescence. Our findings have significant implications, suggesting that the presence of PNN protection around PVIs may be critical for mitigating stress-related psychiatric disorders.

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Hyperspectral imaging has demonstrated its potential to provide correlated spatial and spectral information of a sample by a non-contact and non-invasive technology. In the medical field, especially in histopathology, HSI has been applied for the classification and identification of diseased tissue and for the characterization of its morphological properties. In this work, we propose a hybrid scheme to classify non-tumor and tumor histological brain samples by hyperspectral imaging. The proposed approach is based on the identification of characteristic components in a hyperspectral image by linear unmixing, as a features engineering step, and the subsequent classification by a deep learning approach. For this last step, an ensemble of deep neural networks is evaluated by a cross-validation scheme on an augmented dataset and a transfer learning scheme. The proposed method can classify histological brain samples with an average accuracy of 88%, and reduced variability, computational cost, and inference times, which presents an advantage over methods in the state-of-the-art. Hence, the work demonstrates the potential of hybrid classification methodologies to achieve robust and reliable results by combining linear unmixing for features extraction and deep learning for classification.

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A priority for machine learning in healthcare and other high stakes applications is to enable end-users to easily interpret individual predictions. This opinion piece outlines recent developments in interpretable classifiers and methods to open black box models.

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Autism spectrum disorder (ASD) is a complex psychological syndrome characterized by persistent difficulties in social interaction, restricted behaviours, speech, and nonverbal communication. The impacts of this disorder and the severity of symptoms vary from person to person. In most cases, symptoms of ASD appear at the age of 2 to 5 and continue throughout adolescence and into adulthood. While this disorder cannot be cured completely, studies have shown that early detection of this syndrome can assist in maintaining the behavioural and psychological development of children. Experts are currently studying various machine learning methods, particularly convolutional neural networks, to expedite the screening process. Convolutional neural networks are considered promising frameworks for the diagnosis of ASD. This study employs different pre-trained convolutional neural networks such as ResNet34, ResNet50, AlexNet, MobileNetV2, VGG16, and VGG19 to diagnose ASD and compared their performance. Transfer learning was applied to every model included in the study to achieve higher results than the initial models. The proposed ResNet50 model achieved the highest accuracy, 92%, compared to other transfer learning models. The proposed method also outperformed the state-of-the-art models in terms of accuracy and computational cost.

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The aim of this study is to investigate the inflammasome dysregulation in peripheral blood leukocytes of VEXAS patients. The constitutive and in vitro triggered activation of inflammasome in PBMC and neutrophils was analysed in two Brazilian patients with typical UBA1 mutations, and compared with heathy donors. Our findings highlight the constitutive activation of caspase-1 in VEXAS leukocytes, accompanied by increased plasma levels of IL-18. Furthermore, upon stimulation of isolated peripheral blood mononuclear cells (PBMC) and neutrophils, we observed not only the exhaustion of NLRP3 and NLRP1/CARD8 pathways in VEXAS PBMC but also a significant increase in NLRP3-mediated NETs release in VEXAS neutrophils. These findings support previous studies on the contribution of the inflammasome to VEXAS pathogenesis, identifying at least two profoundly affected pathways (NLRP3 and NLRP1/CARD8) in VEXAS peripheral blood.

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Background: Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant disorder marked by pathogenic variants in the MEN1 tumor suppressor gene, leading to tumors in the parathyroid glands, pancreas, and pituitary. The occurrence of ACTH-producing pancreatic neuroendocrine carcinoma is exceedingly rare in MEN1. Case presentation: This report details a Colombian family harboring a novel MEN1 variant identified through genetic screening initiated by the index case. Affected family members exhibited primary hyperparathyroidism (PHPT) symptoms from their 20s to 50s. Uniquely, the index case developed an ACTH-secreting pancreatic neuroendocrine carcinoma, a rarity in MEN1 syndromes. Proactive screening enabled the early detection of pituitary neuroendocrine tumors (PitNETs) as microadenomas in two carriers, with subsequent surgical or pharmacological intervention based on the clinical presentation. Conclusion: Our findings underscore the significance of cascade screening in facilitating the early diagnosis and individualized treatment of MEN1, contributing to better patient outcomes. Additionally, this study brings to light a novel presentation of ACTH-producing pancreatic neuroendocrine carcinoma within the MEN1 spectrum, expanding our understanding of the disease's manifestations.

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