Impact of Genomic Mutation on Melanoma Immune Microenvironment and IFN-1 Pathway-Driven Therapeutic Responses.

The BRAFV600E mutation, found in approximately 50% of melanoma cases, plays a crucial role in the activation of the MAPK/ERK signaling pathway, which promotes tumor cell proliferation. This study aimed to evaluate its impact on the melanoma immune microenvironment and therapeutic responses, particularly focusing on immunogenic cell death (ICD), a pivotal cytotoxic process triggering anti-tumor immune responses. Through comprehensive in silico analysis of the Cancer Genome Atlas data, we explored the association between the BRAFV600E mutation, immune subtype dynamics, and tumor mutation burden (TMB). Our findings revealed that the mutation correlated with a lower TMB, indicating a reduced generation of immunogenic neoantigens. Investigation into immune subtypes reveals an exacerbation of immunosuppression mechanisms in BRAFV600E-mutated tumors. To assess the response to ICD inducers, including doxorubicin and Me-ALA-based photodynamic therapy (PDT), compared to the non-ICD inducer cisplatin, we used distinct melanoma cell lines with wild-type BRAF (SK-MEL-2) and BRAFV600E mutation (SK-MEL-28, A375). We demonstrated a differential response to PDT between the WT and BRAFV600E cell lines. Further transcriptomic analysis revealed upregulation of IFNAR1, IFNAR2, and CXCL10 genes associated with the BRAFV600E mutation, suggesting their involvement in ICD. Using a gene reporter assay, we showed that PDT robustly activated the IFN-1 pathway through cGAS-STING signaling. Collectively, our results underscore the complex interplay between the BRAFV600E mutation and immune responses, suggesting a putative correlation between tumors carrying the mutation and their responsiveness to therapies inducing the IFN-1 pathway, such as the ICD inducer PDT, possibly mediated by the elevated expression of IFNAR1/2 receptors.

Bacillus Calmette-Guérin immunotherapy induces an efficient antitumor response to control murine melanoma depending on MyD88 signaling.

Bacillus Calmette-Guérin (BCG) is the first line treatment for bladder cancer and it is also proposed for melanoma immunotherapy. BCG modulates the tumor microenvironment (TME) inducing an antitumor effective response, but the immune mechanisms involved still poorly understood. The immune profile of B16-F10 murine melanoma cells was assessed by infecting these cells with BCG or stimulating them with agonists for different innate immune pathways such as TLRs, inflammasome, cGAS-STING and type I IFN. B16-F10 did not respond to any of those stimuli, except for type I IFN agonists, contrasting with bone marrow-derived macrophages (BMDMs) that showed high production of proinflammatory cytokines. Additionally, we confirmed that BCG is able to infect B16-F10, which in turn can activate macrophages and spleen cells from mice in co-culture experiments. Furthermore, we established a subcutaneous B16-F10 melanoma model for intratumoral BCG treatment and compared wild type mice to TLR2-/-, TLR3-/-, TLR4-/-, TLR7-/-, TLR3/7/9-/-, caspase 1-/-, caspase 11-/-, IL-1R-/-, cGAS-/-, STING-/-, IFNAR-/-, MyD88-/-deficient animals. These results in vivo demonstrate that MyD88 signaling is important for BCG immunotherapy to control melanoma in mice. Also, BCG fails to induce cytokine production in the co-culture experiments using B16-F10 and BMDMs or spleen cells derived from MyD88-/- compared to wild-type (WT) animals. Immunotherapy with BCG was not able to induce the recruitment of inflammatory cells in the TME from MyD88-/- mice, impairing tumor control and IFN-γ production by T cells. In conclusion, MyD88 impacts on both innate and adaptive responses to BCG leading to an efficient antitumor response against melanoma.

Use of point-of-care ultrasound to assess the severity of scorpion stings in hospitalized patients.

INTRODUCTION: Scorpionism is a public health problem, especially in tropical regions. In Brazil, the prevalence of envenomation by scorpions is high, and the average national lethality is around 0.16 percent. The Tityus serrulatus scorpion is the primary species of medical importance. However, objective tools to predict and define the severity of these envenomations are lacking. MATERIALS AND METHODS: This was an observational study conducted among patients aged 0-19 years with scorpionism. Patients were admitted to a reference hospital between December 2020 and May 2022. Point-of-care ultrasound was performed within 24 hours of the scorpion sting. RESULTS: Forty-nine patients were included, with a median age of 3.6 (interquartile range 2.3-5.3) years and a predominance of females (51 percent). Fifteen patients (30.6 percent) presented major life-threatening signs, 32 (65.3 percent) minor systemic manifestations, and two (4.1 percent) only local manifestations. Left ventricular dysfunction was identified in 13 patients (26.5 percent). Ten patients (20.4 percent) presented pattern B (visualization of three or more B lines in the evaluated quadrant) in at least one lung window. The sensitivity and specificity of cardiac and pulmonary ultrasound to identify the most severely ill patients were 86 percent and 94 percent, respectively. DISCUSSION: The changes found on point-of-care ultrasound were associated with life-threatening signs. All patients with class III envenomation were referred to the intensive care unit, showing the importance of early identification of this subgroup. The main limitations were the small sample size and the fact that admission to intensive care was not based on systematic criteria. CONCLUSIONS: Point-of-care ultrasound is able to identify early signs of pulmonary congestion and heart failure in scorpionism. It can be useful for the objective selection of patients who are at a higher risk of complications and death and who require intensive support; it may also be valuable for periodic reassessments. Point-of-care ultrasound is a valuable tool for identifying and monitoring severe cases of scorpionism.

STINGing Defenses: Unmasking the Mechanisms of DNA Oncovirus-Mediated Immune Escape.

DNA oncoviruses represent an intriguing subject due to their involvement in oncogenesis. These viruses have evolved mechanisms to manipulate the host immune response, facilitating their persistence and actively contributing to carcinogenic processes. This paper describes the complex interactions between DNA oncoviruses and the innate immune system, with a particular emphasis on the cGAS-STING pathway. Exploring these interactions highlights that DNA oncoviruses strategically target and subvert this pathway, exploiting its vulnerabilities for their own survival and proliferation within the host. Understanding these interactions lays the foundation for identifying potential therapeutic interventions. Herein, we sought to contribute to the ongoing efforts in advancing our understanding of the innate immune system in oncoviral pathogenesis.

Role of the STING pathway in myeloid neoplasms: a prospero-registered systematic review of principal hurdles of STING on the road to the clinical practice.

Myeloid neoplasms are a group of bone marrow diseases distinguished by disruptions in the molecular pathways that regulate the balance between hematopoietic stem cell (HSC) self-renewal and the generation of specialized cells. Cytokines and chemokines, two important components of the inflammatory process, also influence hematological differentiation. In this scenario, immunological dysregulation plays a pivotal role in the pathogenesis of bone marrow neoplasms. The STING pathway recognizes DNA fragments in the cell cytoplasm and triggers an immune response by type I interferons. The role of STING in cancer has not yet been established; however, both actions, as an oncogene or tumor suppressor, have been documented in other types of cancer. Therefore, we performed a systematic review (registered in PROSPERO database #CRD42023407512) to discuss the role of STING pathway in the advancement of pathogenesis and/or prognosis for different myeloid neoplasms. In brief, scientific evidence supports investigations that primarily use cell lines from myeloid neoplasms, such as leukemia. More high-quality research and clinical trials are needed to understand the role of the STING pathway in the pathology of hematological malignancies. Finally, the STING pathway suggests being a promising therapeutic molecular target, particularly when combined with current drug therapies.

Scorpion envenomation in Brazil and its relationship with the social determinants of health: A population-based ecological study.

This study comprehensively analyzed cases of scorpion envenomation in Brazil, exploring the temporal trends and geographic patterns of such incidents between January 1, 2012, and December 31, 2022. Simultaneously, we assessed the correlation between scorpion envenomation and social determinants of health and social vulnerability. We conducted a population-based ecological study, gathering information on the number of scorpion envenomation cases in Brazil, as well as socioeconomic data and social vulnerability indicators across the 5,570 Brazilian municipalities. The season-trend model, based on the classical additive decomposition method, informed estimations of scorpion envenomation variations over time. The spatial correlation of scorpion envenomation with socioeconomic and vulnerability indicators was assessed using the Bivariate Moran's I. A total of 1,343,224 cases of scorpion envenomation were recorded in Brazil from Jan 2012 to Dec 2022. A single increasing time trend was observed for the entire country for this period (APC 8.94, P < 0.001). The seasonal analysis was significant for Brazil as a whole and all regions (p < 0.001), with peaks evident between October and November. The spatial distribution of cases was heterogeneous, with spatial clusters concentrated in the high-risk Southeast and Northeast regions. There was a high incidence of scorpion envenomation in municipalities facing social vulnerability, and, paradoxically, in those with better sanitation and waste collection. Our study revealed a heterogeneous geographical distribution of scorpion accidents in Brazil. Municipalities with higher social vulnerability exhibited a high incidence of scorpion envenomation.

P26 enhances baculovirus gene delivery by modulating the mammalian antiviral response.

Poxins are poxviral proteins that act by degrading 2´3´-cGAMP, a key molecule of cGAS-STING axis that drives and amplifies the antiviral response. Previous works have described some poxin homologous among lepidopteran and baculoviral genes. In particular, P26, a poxin homologous from AcMNPV retains the 2´3´-cGAMP degradation activity in vitro. In this work, we demonstrated that the antiviral activity triggered by baculovirus was disrupted by the transient expression of P26 in murine and human cell lines, and the effect of this action is not only on IFN-ß production but also on the induction of IFN-λ. Besides, we proved P26 functionality in a stable-transformed cell line where the protein was constitutively expressed, preventing the production of IFN-ß induced by baculovirus and resulting in an improvement in the transduction efficiency by the attenuation of the antiviral activity. Finally, we incorporated P26 into budded virions by capsid display or passive incorporation, and the results showed that both strategies resulted in an improvement of 3-17 times in the efficiency of transgene expression in murine fibroblasts. Our results suggest that the incorporation of P26 to budded baculoviral vectors is a very promising tool to modulate negatively the innate antiviral cellular response and to improve the efficiency of gene delivery in mammalian cells. KEY POINTS: • P26 affects baculovirus-induced IFN-ß and IFN-λ production in mammalian cells. • Murine fibroblasts expressing P26 are more susceptible to transduction by baculovirus. • Incorporation of P26 into the virion improves gene delivery efficiency of baculovirus.

Role of the cGAS/STING pathway in the control of Brucella abortus infection acquired through the respiratory route.

Despite the importance of the respiratory route for Brucella transmission, the lung immune response to this pathogen is scarcely characterized. We investigated the role of the cGAS/STING pathway of microbial DNA recognition in the control of respiratory Brucella infection. After in vitro B. abortus infection, CFU numbers were significantly higher in alveolar macrophages (AM) and lung explants from STING KO mice than in samples from wild type (WT) mice, but no difference was observed for cGAS KO samples. CFU were also increased in WT AM and lung epithelial cells preincubated with the STING inhibitor H151. Several proinflammatory cytokines (TNF-α, IL-1ß, IL-6, IP-10/CXCL10) were diminished in Brucella-infected lung explants and/or AM from STING KO mice and cGAS KO mice. These cytokines were also reduced in infected AM and lung epithelial cells pretreated with H151. After intratracheal infection with B. abortus, STING KO mice exhibited increased CFU in lungs, spleen and liver, a reduced expression of IFN-ß mRNA in lungs and spleen, and reduced levels of proinflammatory cytokines and chemokines in bronchoalveolar lavage fluid (BALF) and lung homogenates. Increased lung CFU and reduced BALF cytokines were also observed in cGAS KO mice. In summary, the cGAS/STING pathway induces the production of proinflammatory cytokines after respiratory Brucella infection, which may contribute to the STING-dependent control of airborne brucellosis.

Prospective insight into the role of benzyl propylene glycoside as a modulator of the cGAS-STING signaling pathway in the management of nonalcoholic fatty pancreas animal model.

BACKGROUND: Nonalcoholic fatty pancreatitis (NAFP) is one of the metabolic syndrome manifestations that need further studies to determine its molecular determinants and find effective medications. We aimed to investigate the potential effect of benzyl propylene glycoside on NAFP management via targeting the pancreatic cGAS-STING pathway-related genes (DDX58, NFκB1 & CHUK) and their upstream regulator miRNA (miR-1976) that were retrieved from bioinformatics analysis. METHODS: The rats were fed either normal chow or a high-fat high-sucrose diet (HFHS), as a nutritional model for NAFP. After 8 weeks, the HFHS-fed rats were subdivided randomly into 4 groups; untreated HFHS group (NAFP model group) and three treated groups which received 3 doses of benzyl propylene glycoside (10, 20, and 30 mg/kg) daily for 4 weeks, parallel with HFHS feeding. RESULTS: The molecular analysis revealed that benzyl propylene glycoside could modulate the expression of the pancreatic cGAS-STING pathway-related through the downregulation of the expression of DDX58, NFκB1, and CHUK mRNAs and upregulation of miR-1976 expression. Moreover, the applied treatment reversed insulin resistance, inflammation, and fibrosis observed in the untreated NAFP group, as evidenced by improved lipid panel, decreased body weight and the serum level of lipase and amylase, reduced protein levels of NFκB1 and caspase-3 with a significant reduction in area % of collagen fibers in the pancreatic sections of treated animals. CONCLUSION: benzyl propylene glycoside showed a potential ability to attenuate NAFP development, inhibit pancreatic inflammation and fibrosis and reduce the pathological and metabolic disturbances monitored in the applied NAFP animal model. The detected effect was correlated with modulation of the expression of pancreatic (DDX58, NFκB1, and CHUK mRNAs and miR-1976) panel.

The ubiquitin E3 ligase TRIM10 promotes STING aggregation and activation in the Golgi apparatus.

STING is an endoplasmic reticulum-resident protein regulating innate immunity. After binding with cyclic guanosine monophosphate-AMP (cGAMP), STING translocates from the endoplasmic reticulum (ER) to the Golgi apparatus to stimulate TBK1 and IRF3 activation, leading to expression of type I interferon. However, the exact mechanism concerning STING activation remains largely enigmatic. Here, we identify tripartite motif 10 (TRIM10) as a positive regulator of STING signaling. TRIM10-deficient macrophages exhibit reduced type I interferon production upon double-stranded DNA (dsDNA) or cGAMP stimulation and decreased resistance to herpes simplex virus 1 (HSV-1) infection. Additionally, TRIM10-deficient mice are more susceptible to HSV-1 infection and exhibit faster melanoma growth. Mechanistically, TRIM10 associates with STING and catalyzes K27- and K29-linked polyubiquitination of STING at K289 and K370, which promotes STING trafficking from the ER to the Golgi apparatus, formation of STING aggregates, and recruitment of TBK1 to STING, ultimately enhancing the STING-dependent type I interferon response. Our study defines TRIM10 as a critical activator in cGAS-STING-mediated antiviral and antitumor immunity.

The stimulator of interferon genes (STING) agonists for treating acute myeloid leukemia (AML): current knowledge and future outlook.

Acute myeloid leukemia (AML) is an aggressive hematologic cancer in adults. Some patients exhibit restricted T cell infiltration and do not respond to routine treatments. This may be prevented by enhancing adaptive immunity by stimulating innate immune cells inside the tumor microenvironment (TME). To activate the adaptive immunological reaction against tumors, type I interferons (IFNs) can promote the presentation of tumor-specific cytotoxic T lymphocyte (CTL) cell recruitment. During the activation of innate immunity, cyclic di-nucleotides (CDNs) bind to and stimulate the stimulator of interferon genes (STING), a protein localized inside the endoplasmic reticulum (ER) membrane, resulting in the expression of type I IFNs. The efficacy of STING agonists as effective stimulators of the anti-tumor response in AML is being investigated in numerous clinical studies. Therefore, the purpose of this investigation was to thoroughly review existing knowledge in this field and provide perspective into the clinical potential of STING agonists in AML.

Prospective insight into the role of benzyl propylene glycoside as a modulator of the cGAS-STING signaling pathway in the management of nonalcoholic fatty pancreas animal model

BACKGROUND: Nonalcoholic fatty pancreatitis (NAFP) is one of the metabolic syndrome manifestations that need further studies to determine its molecular determinants and find effective medications. We aimed to investigate the potential effect of benzyl propylene glycoside on NAFP management via targeting the pancreatic cGAS-STING pathway-related genes (DDX58, NFκB1 & CHUK) and their upstream regulator miRNA (miR-1976) that were retrieved from bioinformatics analysis. METHODS: The rats were fed either normal chow or a high-fat high-sucrose diet (HFHS), as a nutritional model for NAFP. After 8 weeks, the HFHS-fed rats were subdivided randomly into 4 groups; untreated HFHS group (NAFP model group) and three treated groups which received 3 doses of benzyl propylene glycoside (10, 20, and 30 mg/kg) daily for 4 weeks, parallel with HFHS feeding. RESULTS: The molecular analysis revealed that benzyl propylene glycoside could modulate the expression of the pancreatic cGAS-STING pathway-related through the downregulation of the expression of DDX58, NFκB1, and CHUK mRNAs and upregulation of miR-1976 expression. Moreover, the applied treatment reversed insulin resistance, inflammation, and fibrosis observed in the untreated NAFP group, as evidenced by improved lipid panel, decreased body weight and the serum level of lipase and amylase, reduced protein levels of NFκB1 and caspase-3 with a significant reduction in area % of collagen fibers in the pancreatic sections of treated animals. CONCLUSION: benzyl propylene glycoside showed a potential ability to attenuate NAFP development, inhibit pancreatic inflammation and fibrosis and reduce the pathological and metabolic disturbances monitored in the applied NAFP animal model. The detected effect was correlated with modulation of the expression of pancreatic (DDX58, NFκB1, and CHUK mRNAs and miR-1976) panel.

The Relationship between Reactive Oxygen Species and the cGAS/STING Signaling Pathway in the Inflammaging Process.

During Inflammaging, a dysregulation of the immune cell functions is generated, and these cells acquire a senescent phenotype with an increase in pro-inflammatory cytokines and ROS. This increase in pro-inflammatory molecules contributes to the chronic inflammation and oxidative damage of biomolecules, classically observed in the Inflammaging process. One of the most critical oxidative damages is generated to the host DNA. Damaged DNA is located out of the natural compartments, such as the nucleus and mitochondria, and is present in the cell's cytoplasm. This DNA localization activates some DNA sensors, such as the cGAS/STING signaling pathway, that induce transcriptional factors involved in increasing inflammatory molecules. Some of the targets of this signaling pathway are the SASPs. SASPs are secreted pro-inflammatory molecules characteristic of the senescent cells and inducers of ROS production. It has been suggested that oxidative damage to nuclear and mitochondrial DNA generates activation of the cGAS/STING pathway, increasing ROS levels induced by SASPs. These additional ROS increase oxidative DNA damage, causing a loop during the Inflammaging. However, the relationship between the cGAS/STING pathway and the increase in ROS during Inflammaging has not been clarified. This review attempt to describe the potential connection between the cGAS/STING pathway and ROS during the Inflammaging process, based on the current literature, as a contribution to the knowledge of the molecular mechanisms that occur and contribute to the development of the considered adaptative Inflammaging process during aging.

Escorpionismo en pediatría: estudio descriptivo, transversal y retrospectivo de factores predictores de gravedad / Pediatric scorpionism: a descriptive, cross-sectional, and retrospective study of predictors of severity

Introducción. El emponzoñamiento por Tityus carrilloi n. sp. representa una amenaza para la vida. Según las manifestaciones clínicas, se clasifica en leve, moderado y grave. Objetivo. Comparar las características epidemiológicas y bioquímicas en niños con escorpionismo leve, moderado y grave. Población y métodos. Estudio descriptivo, transversal y retrospectivo. Se analizaron las consultas de menores de 15 años picados por Tityus carrilloi n. sp. entre enero de 2017 y diciembre de 2018 en un hospital pediátrico de tercer nivel en Santa Fe (Argentina). Resultados. Se incluyeron 524 niños, el 81 % (421) con dolor local y el 19 % (103) con manifestaciones sistémicas. Los niños con síntomas sistémicos de escorpionismo fueron más pequeños en edad que los que presentaron manifestaciones locales (p <0,001). En el invierno los niños desarrollaron 8 veces más manifestaciones sistémicas de escorpionismo y durante la primavera, 2,4 veces más que durante el verano. De los 103 niños internados, 80 fueron casos moderados y 23, graves. No hubo diferencias entre grupos en edad (p = 0,29) ni en la demora en recibir suero antiescorpiónico (p = 0,81). El tiempo de internación fue mayor en los graves (p <0,001). Los valores de glóbulos blancos o glucemia mayores a 30 000 cel/ml y 300 mg/dl respectivamente estuvieron presentes casi exclusivamente en escorpionismos graves. Conclusión. En niños picados por el escorpión Tityus carrilloi n. sp., el riesgo de desarrollar manifestaciones sistémicas fue mayor cuanto menor fue la edad y durante el invierno y la primavera. Los valores de glóbulos blancos y de glucemia fueron mayores en niños con escorpionismo grave.

Introduction. Scorpion envenomation by Tityus carrilloi n. sp. represents a threat to life. Depending on its clinical manifestations, it is classified as mild, moderate or severe. Objective. To compare the epidemiological and biochemical characteristics among children with mild, moderate, and severe scorpionism. Population and methods. Descriptive, crosssectional, and retrospective study. The consultations at a tertiary care children's hospital in Santa Fe (Argentina) of children under 15 years of age stung by Tityus carrilloi n. sp. between January 2017 and December 2018 were analyzed. Results. In total, 524 children were included, 81% (421) with local pain and 19% (103) with systemic manifestations. Children with systemic symptoms of scorpionism were younger in age than those with local manifestations (p < 0.001). In the winter, children developed 8 times more systemic manifestations of scorpionism; during the spring, 2.4 times more than during the summer. Out of the 103 hospitalized children, 80 were moderate cases and 23 severe cases. There were no differences between age groups (p = 0.29) or in the delay in receiving the anti-scorpion serum (p = 0.81). The length of hospital stay was longer among severe cases (p < 0.001). WBC and blood glucose levels higher than 30 000 cell/mL and 300 mg/dL, respectively, were present almost exclusively in severe scorpionism cases. Conclusion. In children stung by the scorpion Tityus carrilloi n. sp., the younger the age and during winter and spring, the higher the risk for systemic manifestations. WBC and blood glucose levels were higher in children with severe scorpionism.

Pediatric scorpionism: a descriptive, cross-sectional, and retrospective study of predictors of severity. / Escorpionismo en pediatría: estudio descriptivo, transversal y retrospectivo de factores predictores de gravedad.

INTRODUCTION: Scorpion envenomation by Tityus carrilloi n. sp. represents a threat to life. Depending on its clinical manifestations, it is classified as mild, moderate or severe. OBJECTIVE: To compare the epidemiological and biochemical characteristics among children with mild, moderate, and severe scorpionism. POPULATION AND METHODS: Descriptive, crosssectional, and retrospective study. The consultations at a tertiary care children's hospital in Santa Fe (Argentina) of children under 15 years of age stung by Tityus carrilloi n. sp. between January 2017 and December 2018 were analyzed. RESULTS: In total, 524 children were included, 81% (421) with local pain and 19% (103) with systemic manifestations. Children with systemic symptoms of scorpionism were younger in age than those with local manifestations (p < 0.001). In the winter, children developed 8 times more systemic manifestations of scorpionism; during the spring, 2.4 times more than during the summer. Out of the 103 hospitalized children, 80 were moderate cases and 23 severe cases. There were no differences between age groups (p = 0.29) or in the delay in receiving the anti-scorpion serum (p = 0.81). The length of hospital stay was longer among severe cases (p < 0.001). WBC and blood glucose levels higher than 30 000 cell/mL and 300 mg/dL, respectively, were present almost exclusively in severe scorpionism cases. CONCLUSIONS: In children stung by the scorpion Tityus carrilloi n. sp., the younger the age and during winter and spring, the higher the risk for systemic manifestations. WBC and blood glucose levels were higher in children with severe scorpionism.

Introducción. El emponzoñamiento por Tityus carrilloi n. sp. representa una amenaza para la vida. Según las manifestaciones clínicas, se clasifica en leve, moderado y grave. Objetivo. Comparar las características epidemiológicas y bioquímicas en niños con escorpionismo leve, moderado y grave. Población y métodos. Estudio descriptivo, transversal y retrospectivo. Se analizaron las consultas de menores de 15 años picados por Tityus carrilloi n. sp. entre enero de 2017 y diciembre de 2018 en un hospital pediátrico de tercer nivel en Santa Fe (Argentina). Resultados. Se incluyeron 524 niños, el 81 % (421) con dolor local y el 19 % (103) con manifestaciones sistémicas. Los niños con síntomas sistémicos de escorpionismo fueron más pequeños en edad que los que presentaron manifestaciones locales (p <0,001). En el invierno los niños desarrollaron 8 veces más manifestaciones sistémicas de escorpionismo y durante la primavera, 2,4 veces más que durante el verano. De los 103 niños internados, 80 fueron casos moderados y 23, graves. No hubo diferencias entre grupos en edad (p = 0,29) ni en la demora en recibir suero antiescorpiónico (p = 0,81). El tiempo de internación fue mayor en los graves (p <0,001). Los valores de glóbulos blancos o glucemia mayores a 30 000 cel/ml y 300 mg/dl respectivamente estuvieron presentes casi exclusivamente en escorpionismos graves. Conclusión. En niños picados por el escorpión Tityus carrilloi n. sp., el riesgo de desarrollar manifestaciones sistémicas fue mayor cuanto menor fue la edad y durante el invierno y la primavera. Los valores de glóbulos blancos y de glucemia fueron mayores en niños con escorpionismo grave.

Epidemiological analysis of accidents by scorpions in a municipality in the Triângulo Mineiro / Análise epidemiológica dos acidentes por escorpiões em um município do Triângulo Mineiro

Introduction: Minas Gerais is the Brazilian state with the highest rate of scorpionism, 223,033 cases were recorded between 2010-2017, so reflections on how to reduce this public health problem are necessary. Objective: to describe the epidemiological profile of accidents with scorpions that occurred in the municipality of Patos de Minas (MG), from 2013 to 2017, and to develop an intervention project based on it. Methods: First, the number of accidents by venomous animals in Patos de Minas (MG) was analyzed using the variables included in the SINAN notification and investigation form, available on DATASUS. Additionally, two databases, CAFE and Pubmed, were used for the theoretical framework, with the following descriptors: "escorpião", "Minas Gerais", "envenenamento", "prevenção", and their respective translations into English: "scorpion", "Minas Gerais", "envenomation" and "prevention". Results: Scorpion sting accidents were the most recorded among venomous animals, and were increased annually during the study period, reaching, in 2017, the number of 274 reported cases. In addition, the frequency of accidents was recorded in greater numbers in males (51.18%) and the most affected age group was between 20 and 39 years of age (32.64%). It is also observed that most of the victims were classified as mild cases and treated in the first hour of the sting (97.92%), with no deaths in the period. The results found are in agreement with the references used, being more common, in studies, the registration of mild cases, in male adults. For the basis of the intervention proposal, five articles were used, and based on them, preventive, corrective environmental and educational actions are proposed. Conclusion: The study allowed to identify the target audience of the intervention proposals and when they should be intensified, to try to contain, thus, the constant increase in cases of scorpionism in the analyzed municipality (AU)

Introdução: Minas Gerais é o estado brasileiro com a maior taxa de escorpionismo, foram registrados 223.033 casos entre 2010-2017, dessa forma se faz necessária reflexões sobre como reduzir esse problema de saúde pública. Objetivo: O presente estudo visa descrever o perfil epidemiológico de acidentes oriundos do escorpionismo ocorridos no município de Patos de Minas (MG) no período de 2013 a 2017 e desenvolver um projeto de intervenção a partir do mesmo. Métodos: Primeiramente, o número de acidentes por animais peçonhentos em Patos de Minas (MG) foi analisado utilizando-se as variáveis que contemplam a ficha de notificação e investigação do SINAN, disponíveis no DATASUS. Além disso, foram utilizadas duas bases de dados, CAFE e PUBMED, para o referencial teórico, com os seguintes descritores: escorpião, Minas Gerais, envenenamento e prevenção e suas respectivas traduções para o inglês. Resultados: Acidentes por picada de escorpião foram os mais registrados dentre os animais peçonhentos, além de terem aumentado anualmente no período de estudo, atingindo, em 2017, o número de 274 casos notificados. Ademais, a frequência dos acidentes foi registrada em maior número no sexo masculino (51,18%) e a faixa etária mais atingida foi entre 20 a 39 anos (32,64%). Observa-se também que os acidentados foram classificados como casos leves e atendidos na primeira hora da picada (97,92%), com nenhum óbito no período. Os resultados encontrados estão em concordância com as referências utilizadas, sendo mais comum, em estudos, o registro de casos leves, em adultos, do sexo masculino. Para o embasamento da proposta de intervenção, foram utilizados cinco artigos e baseado neles propõem-se o desenvolvimento de ações preventivas, corretivas do ambiente e educacionais. Conclusão:Com o estudo, foi possível identificar o público-alvo das propostas de intervenção e quando elas deveriam ser intensificadas, para tentar conter, assim, o aumento constante dos casos de escorpionismo no município analisado (AU)

Intravitreal injection of mitochondrial DNA induces cell damage and retinal dysfunction in rats.

BACKGROUND: Retinal neurodegeneration is induced by a variety of environmental insults and stresses, but the exact mechanisms are unclear. In the present study, we explored the involvement of cytosolic mitochondrial DNA (mtDNA), resulting in the cGAS-STING dependent inflammatory response and apoptosis in retinal damage in vivo. METHODS: Retinal injury was induced with white light or intravitreal injection of lipopolysaccharide (LPS). After light- or LPS-induced injury, the amount of cytosolic mtDNA in the retina was detected by PCR. The mtDNA was isolated and used to transfect retinas in vivo. WB and real-time PCR were used to evaluate the activation of cGAS-STING pathway and the levels of apoptosis-associated protein at different times after mtDNA injection. Retinal cell apoptosis rate was detected by TUNEL staining. Full-field electroretinography (ERG) was used to assess the retinal function. RESULTS: Light injury and the intravitreal injection of LPS both caused the leakage of mtDNA into the cytoplasm in retinal tissue. After the transfection of mtDNA in vivo, the levels of cGAS, STING, and IFN-ß mRNAs and the protein levels of STING, phosph-TBK1, phospho-IRF3, and IFN-ß were upregulated. mtDNA injection also induced the activation of caspase 3 and caspase 9. BAX and BAK were increased at both the mRNA and protein levels. The release of cytochrome c from the mitochondria to the cytosol was increased after mtDNA injection. The wave amplitudes on ERG decreased and retinal cell apoptosis was detected after mtDNA injection. CONCLUSIONS: Cytosolic mtDNA triggers an inflammatory response. It also promotes apoptosis and the dysfunction of the retina.

STING is an intrinsic checkpoint inhibitor that restrains the TH17 cell pathogenic program.

External and intrinsic factors regulate the transcriptional profile of T helper 17 (TH17) cells, thereby affecting their pathogenic potential and revealing their context-dependent plasticity. The stimulator of interferon genes (STING), a component of the intracellular DNA-sensing pathway, triggers immune responses but remains largely unexplored in T cells. Here, we describe an intrinsic role of STING in limiting the TH17 cell pathogenic program. We demonstrate that non-pathogenic TH17 cells express higher levels of STING than those activated under pathogenic conditions. Activation of STING induces interleukin-10 (IL-10) production in TH17 cells, decreasing IL-17A and IL-23R expression in a type I interferon (IFN)-independent manner. Mechanistically, STING-induced IL-10 production partially requires aryl hydrocarbon receptor (AhR) signaling, while the decrease of IL-17A expression occurs due to a reduction of Rorγt transcriptional activity. Our findings reveal a regulatory function of STING in the TH17 cell activation program, proposing it as a valuable target to limit TH17-cell-mediated inflammation.