Varroa destructor shapes the unique viral landscapes of the honey bee populations of the Azores archipelago.

The worldwide dispersal of the ectoparasitic mite Varroa destructor from its Asian origins has fundamentally transformed the relationship of the honey bee (Apis mellifera) with several of its viruses, via changes in transmission and/or host immunosuppression. The extent to which honey bee-virus relationships change after Varroa invasion is poorly understood for most viruses, in part because there are few places in the world with several geographically close but completely isolated honey bee populations that either have, or have not, been exposed long-term to Varroa, allowing for separate ecological, epidemiological, and adaptive relationships to develop between honey bees and their viruses, in relation to the mite's presence or absence. The Azores is one such place, as it contains islands with and without the mite. Here, we combined qPCR with meta-amplicon deep sequencing to uncover the relationship between Varroa presence, and the prevalence, load, diversity, and phylogeographic structure of eight honey bee viruses screened across the archipelago. Four viruses were not detected on any island (ABPV-Acute bee paralysis virus, KBV-Kashmir bee virus, IAPV-Israeli acute bee paralysis virus, BeeMLV-Bee macula-like virus); one (SBV-Sacbrood virus) was detected only on mite-infested islands; one (CBPV-Chronic bee paralysis virus) occurred on some islands, and two (BQCV-Black queen cell virus, LSV-Lake Sinai virus,) were present on every single island. This multi-virus screening builds upon a parallel survey of Deformed wing virus (DWV) strains that uncovered a remarkably heterogeneous viral landscape featuring Varroa-infested islands dominated by DWV-A and -B, Varroa-free islands naïve to DWV, and a refuge of the rare DWV-C dominating the easternmost Varroa-free islands. While all four detected viruses investigated here were affected by Varroa for one or two parameters (usually prevalence and/or the Richness component of ASV diversity), the strongest effect was observed for the multi-strain LSV. Varroa unambiguously led to elevated prevalence, load, and diversity (Richness and Shannon Index) of LSV, with these results largely shaped by LSV-2, a major LSV strain. Unprecedented insights into the mite-virus relationship were further gained from implementing a phylogeographic approach. In addition to enabling the identification of a novel LSV strain that dominated the unique viral landscape of the easternmost islands, this approach, in combination with the recovered diversity patterns, strongly suggests that Varroa is driving the evolutionary change of LSV in the Azores. This study greatly advances the current understanding of the effect of Varroa on the epidemiology and adaptive evolution of these less-studied viruses, whose relationship with Varroa has thus far been poorly defined.

The value of axillary, facial, occipital, subclavian and common carotid arteries ultrasound in the diagnosis of giant cell arteritis.

OBJECTIVE: To assess the diagnostic value for GCA in adding the axillary arteries (AX) to the temporal artery (TA) ultrasound, particularly in patients with a cranial phenotype of the disease; and to investigate the utility of facial (FA), occipital (OC), subclavian (SC), and common carotid (CC) ultrasound in patients with suspected GCA. METHODS: Patients with new-onset GCA and a positive ultrasound of the TA, AX, FA, OC, SC or CC, followed at the rheumatology departments of two academic centres, were retrospectively included. RESULTS: 230 patients were assessed. TA halo sign was identified in 206/230 (89.6%) cases, FA in 40/82 (48.8%), OC in 17/69 (24.6%), AX in 56/230 (24.3%), SC in 31/57 (54.4%), and CC in 14/68 (20.6%). Negative TA ultrasound was found in 24/230 (10.4%) patients: 22 had AX involvement, 1 exclusive OC involvement and 1 exclusive SC involvement. Adding AX evaluation to the TA ultrasound increased the diagnostic yield for GCA in 9.6%, whereas adding OC or SCs to the TA and AX ultrasound increased it in 1.4% and 1.8%, respectively. No value was found in adding the FA or CCs. Notably, 13 patients with cranial symptoms and 4 with exclusively cranial symptoms showed negative TA ultrasound but positive AX ultrasound. CONCLUSION: Adding the evaluation of AXs to the TA ultrasound increased the number of patients diagnosed with GCA, even in cases of predominantly cranial symptoms. In the subset of patients where these arteries were assessed, no substantial benefit was found in adding the FA, OC, SC or CC arteries to the TA and AX ultrasonographic assessment.

Comment on Shah et al. Genetic Characteristics and Phylogeographic Dynamics of Lagoviruses, 1988-2021. Viruses 2023, 15, 815.

Shah and colleagues [...].

Integrated behavioural and physiological responses of sand smelt larvae to the effects of warming and hypoxia as combined stressors.

Forecasts indicate that rising temperatures towards the future and the expansion of dead zones will change environmental suitability for fish early stages. Therefore, we assessed the chronic effects of warming (26 °C), hypoxia (<2-2.5 mg L-1) or their combination on mortality rate, growth, behaviour, energy metabolism and oxidative stress using Atherina presbyter larvae as a model species. There were no differences between the treatments in terms of mortality rate. The combination of warming and hypoxia induced faster loss of body mass (+22.7%). Warming, hypoxia or their combination enhanced boldness (+14.7-25.4%), but decreased exploration (-95%-121%), increased the time in frozen state (+60.6-80.5%) and depleted swimming speed (-45.6-50.5%). Moreover, routine metabolic rate was depleted under hypoxia or under the combination of warming and hypoxia (-56.6 and 57.2%, respectively). Under hypoxia, increased catalase activity (+56.3%) indicates some level of antioxidant defence capacity, although increased DNA damage (+25.2%) has also been observed. Larvae also exhibited a great capacity to maintain the anaerobic metabolism stable in all situations, but the aerobic metabolism is enhanced (+19.3%) when exposed to the combination of both stressors. The integrative approach showed that changes in most target responses can be explained physiologically by oxidative stress responses. Increased oxidative damages (lipid peroxidation and DNA damage) and increased interaction between antioxidant enzymes (superoxide dismutase and catalase) are associated to increased time in frozen state and decreased swimming activity, growth rates and boldness. Under all stressful situations, larvae reduced energy-consuming behaviours (e.g. depleted exploration and swimming activity) likely to stabilize or compensate for the aerobic and anaerobic metabolisms. Despite being an active small pelagic fish, we concluded that the sensitive larval phase exhibited complex coping strategies to physiologically acclimate under thermal and hypoxic stress via behavioural responses.

Transdiaphragmatic intercostal hernia induced by sternutation: A case report.

INTRODUCTION AND IMPORTANCE: Sternutation is, by definition, a situation that increases abdominal pressure. However, it has not been clearly linked to protrusion of abdominal content through weaknesses in the abdominal boundaries. CASE PRESENTATION: Here we present a case report in which the only trigger factor found for an abdominal content protrusion was a sternutation episode. The patient arrived in our institution with the diagnosis of a transdiaphragmatic intercostal hernia, proven in CT-scan. He was, then, submitted to emergent surgery, where through thoracotomy and subcostal laparotomy, hernia content was reduced. The patient had a favorable evolution. CLINICAL DISCUSSION: TDIH is a rare entity, for which there are still no consensus regarding its management. This makes clinical practice more challenging, leaving to the surgeon the therapeutic decision tailored to each patient. CONCLUSION: This entity should be further studied, and consensus reached regarding its management.

Genetic profile and characterization of antimicrobial resistance in Acinetobacter baumannii post-COVID-19 pandemic: a study in a tertiary hospital in Recife, Brazil.

AIMS: To investigate the genetic profile and characterize antimicrobial resistance, including the main ß-lactam antibiotic resistance genes, in Acinetobacterbaumannii isolates from a tertiary hospital in Recife-PE, Brazil, in the post-COVID-19 pandemic period. METHODS AND RESULTS: Acinetobacter baumannii isolates were collected between 2023 and 2024 from diverse clinical samples. Antimicrobial resistance testing followed standardized protocols, with ß-lactamase-encoding genes detected via PCR and sequencing. Investigation into ISAba1 upstream of blaOXA-carbapenemase and blaADC genes was also conducted. Genetic diversity was assessed through ERIC-PCR. Among the 78 A. baumannii, widespread resistance to multiple antimicrobials was evident. Various acquired ß-lactamase-encoding genes (blaOXA-23,-24,-58,-143, blaVIM, and blaNDM) were detected. Furthermore, this is the first report of blaVIM-2 in A. baumannii isolates harboring either the blaOXA-23-like or the blaOXA-143 gene in Brazil. Molecular typing revealed a high genetic heterogeneity among the isolates, and multi-clonal dissemination. CONCLUSION: The accumulation of genetic resistance determinants underscores the necessity for stringent infection control measures and robust antimicrobial stewardship programs to curb multidrug-resistant strains.

Current evidence for hypopressive exercises in healthy women: A systematic review.

BACKGROUND: Hypopressive exercises have been mainly used in the treatment of pelvic floor dysfunctions. Recently it has started to spread among healthy women. However, no comprehensive review is available in this population. PURPOSE: Assess the current evidence of the effects of hypopressive exercises on healthy women. METHODS: This study was registered on PROSPERO (CRD42020203103). The search was performed in Scielo, Pubmed, Lilacs, Embase, Scopus, Pedro, Trip Database, Web of Science, and Google Scholar. The last search was performed on November 1st, 2021. Inclusion criteria were randomized controlled trials and single-arm trials, healthy women, acute or late effects of hypopressive exercises, and pre and post-training analysis. Exclusion criteria included non-original research, conference proceedings, dissertations and theses. Downs and Black checklist were used to assess the methodological quality. Study design, participants characteristics, description of the intervention, follow-up period, variables, instruments, and outcomes were extracted and recorded. RESULTS: From the 410 studies, five were selected. The variable of major interest was waist circumference, which showed a decrease with exercise. It also seemed to have plausible positive effects on height, lower back mobility, abdominal and pelvic floor muscle contraction, respiratory flow and apnea, and hemodynamic responses. CONCLUSION: This study suggests that the current literature on the effects of hypopressive exercise on healthy women is very limited. Despite the plausible positive effects identified, we cannot recommend its practice due to the serious methodological problems. Therefore, more studies are needed to elucidate the benefits and adverse effects of hypopressive exercises.

Economic and Accessible Portable Homemade Magnetic Hyperthermia System: Influence of the Shape, Characteristics and Type of Nanoparticles in Its Effectiveness.

Currently, one of the main causes of death in the world is cancer; therefore, it is urgent to obtain a precocious diagnosis, as well as boost research and development of new potential treatments, which should be more efficient and much less invasive for the patient. Magnetic hyperthermia (MH) is an emerging cancer therapy using nanoparticles, which has proved to be effective when combined with chemotherapy, radiotherapy and/or surgery, or even by itself, depending on the type and location of the tumor's cells. This article presents the results obtained by using a previously developed economic homemade hyperthermia device with different types of magnetite nanoparticles, with sizes ranging between 12 ± 5 and 36 ± 11 nm and presenting different shapes (spherical and cubic particles). These magnetic nanoparticles (MNPs) were synthesized by three different methods (co-precipitation, solvothermal and hydrothermal processes), with their final form being naked, or possessing different kinds of covering layers (polyethylene glycol (PEG) or citric acid (CA)). The parameters used to characterize the heating by magnetic hyperthermia, namely the Specific Absorption Rate (SAR) and the intrinsic loss power (ILP), have been obtained by two different methods. Among other results, these experiments allowed for the determination of which synthesized MNPs showed the best performance concerning hyperthermia. From the results, it may be concluded that, as expected, the shape of MNPs is an important factor, as well as the time that the MNPs can remain suspended in solution (which is directly related to the concentration and covering layer of the MNPs). The MNPs that gave the best results in terms of the SAR were the cubic particles covered with PEG, while in terms of total heating the spherical particles covered with citric acid proved to be better.

Comparison among Different Green Extraction Methods of Polyphenolic Compounds from Exhausted Olive Oil Pomace and the Bioactivity of the Extracts.

The use of by-products as a source of bioactive compounds with economic added value is one of the objectives of a circular economy. The olive oil industry is a source of olive pomace as a by-product. The olive pomace used in the present study was the exhausted olive pomace, which is the by-product generated from the air drying and subsequent hexane extraction of residual oil from the olive pomace. The objective was to extract bioactive compounds remaining in this by-product. Various types of green extraction were used in the present study: solvent extraction (water and hydroalcoholic); ultrasound-assisted extraction; Ultra-Turrax-assisted extraction; and enzyme-assisted extraction (cellulase; viscoenzyme). The phenolic profile of each extract was determined using HPLC-DAD and the total phenolic content (TPC) and antioxidant activity (ABTS, DPPH, and ORAC) were determined as well. The results showed significant differences in the yield of extraction among the different methods used, with the enzyme-assisted, with or without ultrasound, extraction presenting the highest values. The ultrasound-assisted hydroethanolic extraction (USAHE) was the method that resulted in the highest content of the identified phenolic compounds: 2.021 ± 0.29 mg hydroxytyrosol/100 mg extract, 0.987 ± 0.09 mg tyrosol/100 mg extract, and 0.121 ± 0.005 mg catechol/100 mg extract. The conventional extraction with water at 50 °C produced the best results for TPC and antioxidant activity of the extracts. The extracts from the USAHE were able to inhibit Gram-positive bacteria, especially Bacillus cereus, showing 67.2% inhibition at 3% extract concentration.

High-Pressure Processing Effects on Microbiological Stability, Physicochemical Properties, and Volatile Profile of a Fruit Salad.

Nowadays, consumers are more aware of the effects of their diet on their health, and thus demand natural or minimally processed food products. Therefore, research has focused on processes that assure safe products without jeopardizing their nutritional properties. In this context, this work aimed to evaluate the effects of high-pressure processing (550 MPa/3 min/15 °C, HPP) on a fruit salad (composed of melon juice and pieces of Golden apple and Rocha pear) throughout 35 days of storage at 4 °C. For the physicochemical properties analysed (browning degree, polyphenol oxidase activity, antioxidant activity (ABTS assay), and volatile profile), a freshly made fruit salad was used, while for the microbiological tests (total aerobic mesophiles, and yeast and moulds) spoiled melon juice was added to the fruit salad to increase the microbial load and mimic a challenge test with a high initial microbial load. It was determined that processed samples were more microbiologically stable than raw samples, as HPP enabled a reduction of almost 4-log units of both total aerobic mesophiles and yeasts and moulds, as well as an almost 1.5-fold increase in titratable acidity of the unprocessed samples compared to HPP samples. Regarding browning degree, a significant increase (p < 0.05) was observed in processed versus unprocessed samples (roughly/maximum 68%), while the addition of ascorbic acid decreased the browning of the samples by 29%. For antioxidant activity, there were no significant differences between raw and processed samples during the 35 days of storage. An increase in the activity of polyphenol oxidase immediately after processing (about 150%) was confirmed, which was generally similar or higher during storage compared with the raw samples. Regarding the volatile profile of the product, it was seen that the compounds associated with melon represented the biggest relative percentage and processed samples revealed a decrease in the relative quantity of these compounds compared to unprocessed. Broadly speaking, HPP was shown to be efficient in maintaining the stability and overall quality of the product while assuring microbial safety (by inactivating purposely inoculated microorganisms), which allows for longer shelf life (7 versus 28 days for unprocessed and processed fruit salad, respectively).

Early and late-onset preeclampsia: effects of DDAH2 polymorphisms on ADMA levels and association with DDAH2 haplotypes.

Objective: To examine whether the DDAH2 promoter polymorphisms -1415G/A (rs2272592), -1151A/C (rs805304) and -449G/C (rs805305), and their haplotypes, are associated with PE compared with normotensive pregnant women, and whether they affect ADMA levels in these groups. Methods: A total of 208 pregnant women were included in the study and classified as early-onset (N=57) or late-onset PE (N =49), and as normotensive pregnant women (N = 102). Results: Pregnant with early-onset PE carrying the GC and GG genotypes for the DDAH2 -449G/C polymorphism had increased ADMA levels (P=0.01). No association of DDAH2 polymorphisms with PE in single-locus analysis was found. However, the G-C-G haplotype was associated with the risk for late-onset PE. Conclusion: It is suggested that DDAH2 polymorphisms could affect ADMA levels in PE, and that DDAH2 haplotypes may affect the risk for PE.

Influence of different presentation forms of chlorhexidine on contaminated root canals during agitation.

This in vitro study aimed to verify the influence of chlorhexidine (CHX) (gel and solution) in association with different activation protocols on disinfection of root canals contaminated with Enterococcus faecalis. In total, 120 lower premolar roots were selected, contaminated and divided into 12 groups according to irrigation technique and substance. Samples were collected before and after each irrigation technique and analysed for colony-forming units (CFU). Three dentin discs were obtained for quantification of viable intratubular cells by using confocal laser scanning microscopy (CLSM). CFU results showed that sonic and ultrasonic were more effective than conventional irrigation. Ultrasonic activation was more effective than sonic for CHX gel (p < 0.05). CLSM showed that either activation was better than conventional in all groups and root canal thirds (p < 0.05). It was concluded that ultrasonic/sonic activation was more effective than conventional techniques and CHX enhanced intratubular dentin decontamination across all irrigation methods.

Molecular evidence of sporadic Coxiella burnetii excretion in sheep milk, central Portugal.

Coxiella burnetii is the etiologic agent of Q fever, a worldwide zoonosis. Cattle, sheep and goats are considered the main reservoirs of the disease. Transmission to humans occurs mainly through the inhalation of infectious aerosols from milk, faeces, urine, and birth products from infected ruminants. In this study, a 2-year longitudinal approach was performed to ascertain the excretion of C. burnetii in bulk tank milk samples of sheep from a mountain plateau in central Portugal, with sampling conducted during the years 2015 and 2016. From a total of 156 bulk tank milk samples tested by qPCR, only one showed to be positive for C. burnetii (1.28% [95%CI: 0.03-6.94]), from 2015, the first year of collection. Bidirectional sequencing and phylogenetic analysis of IS1111 transposase partial region confirmed the presence of C. burnetii DNA. The presence of C. burnetii in raw milk samples highlights the necessity for additional research to determine if raw milk is a potential source for human infection. Animal health surveillance and prevention measures against this zoonotic disease should be considered.

Satisfacción de los estudiantes de Odontología con el aprendizaje blended-learning en la Universidad San Sebastián, Chile / Student satisfaction with blended-learning in dentistry education in San Sebastian University, Chile

Introducción: La asignatura de Preclínico y Rehabilitación de la licenciatura de Odontología de la Universidad San Sebastián (Chile) prepara a los estudiantes para el desarrollo de habilidades prácticas que permiten el trabajo clínico con pacientes. En el año académico 2020-2021, posterior a la cuarentena por COVID-19, se mantuvo el curso en un entorno de aprendizaje en línea y con carácter semipresencial, apoyándose en un enfoque de aula invertida incorporando la estrategia blended-learning (B-learning). Objetivo: Evaluar la satisfacción del estudiantado con respecto a las actividades prácticas en modalidad B-learning.Materiales y métodos. Se realizó un estudio descriptivo-observacional. Se analizó el programa de la asignatura para desarrollar diversos recursos que se alojaron en una plataforma learning management system para efectuar una metodología de aula invertida. En 2022 se aplicó un instrumento en línea a 143 estudiantes con 18 ítems, en los que se usó una escala de tipo Likert para valorar su satisfacción en relación con la modalidad B-learning utilizada en la asignatura de Preclínico y Rehabilitación. Resultados: De 143 estudiantes inscritos en el curso 2021, contestaron 77. Se evidenció una buena consistencia internadel instrumento a través de un análisis del alfa de Cronbach (0,9). Para la subdimensión satisfacción con el aprendizaje se obtuvo una alta satisfacción, un 82,56%; un 86,75% en el ámbito de las metodologías y recursos; y un 94,38% para elproceso docente. Conclusiones: La modalidad B-learning se consideró satisfactoria para el estudiantado. El instrumento utilizado mostróuna buena consistencia interna, lo que permite retroalimentar procesos educativos.(AU)

Introduction: The Preclinical and Rehabilitation course in the Dentistry Degree at the University San Sebastian in Chile, prepares students for the development of practical skills essential for clinical work with patients. In the academic year 2020-2021, following the COVID-19 quarantine, the course was conducted in a blended learning environment, combining online and semi-presential aspects, employing a flipped classroom approach with the integration of blended learning (B-learning) strategy. Objective: To assess student satisfaction regarding practical activities in the B-learning mode.Materials and methods. A descriptive-observational study was conducted. The course program was analyzed to develop various resources hosted on a learning management system platform to implement a flipped classroom methodology. In 2022, an online instrument with 18 items, using a Likert scale, was administered to 143 students to assess their satisfaction with the B-learning mode in the Preclinical and Rehabilitation course. Results: Out of 143 enrolled students in the 2021 academic year, 77 responded. The instrument showed good internal consistency through Cronbach’s alpha analysis (0.9). For the satisfaction with learning sub-dimension, high satisfaction rates were obtained (82.56%), 86.75% for methodologies and resources, and 94.38% for the teaching process. Conclusions: The B-learning mode was considered satisfactory for the students. The instrument used demonstrated good internal consistency, providing feedback for educational processes.(AU)

Virulent Klebsiella pneumoniae ST11 clone carrying blaKPC and blaNDM from patients with and without COVID-19 in Brazil.

AIMS: Investigated and compared the occurrence of virulence genes fimH, mrkD, irp2, entB, cps, rmpA, and wabG, resistance genes blaKPC and blaNDM, and the genetic variability and clonal relationship of 29 Klebsiella pneumoniae clinical isolates of patients with and without COVID-19, from a hospital in Brazil. METHODS AND RESULTS: All isolates were resistant to beta-lactams. The genes were investigated by PCR, and for molecular typing, enterobacterial repetitive intergenic consensus-polymerase chain reaction (ERIC-PCR) and MLST were used. The detection of blaNDM was greater (n = 23) when compared to that of blaKPC (n = 14). The virulence genes that most occurred were fimH, entB, cps, and wabG, which are responsible for adhesins, siderophore enterobactin, capsule, and lipopolysaccharides, respectively. Among the isolates, 21 distinct genetic profiles were found by ERIC-PCR, with multiclonal dissemination. Four isolates belonged to the ST11 clone. CONCLUSIONS: The occurrence of the ST11 is worrying as it is a high-risk clone involved in the dissemination of virulent strains throughout the world.

Plant-Based Films and Hydrogels for Wound Healing.

Skin is constantly exposed to injury and infectious agents that can compromise its structural integrity and cause wounds. When this occurs, microorganisms from the skin microbiota and external bacteria and fungi can penetrate the wound and cause an infection, which complicates the healing process. Nowadays, there are several types of wound dressings available to treat wounds, some of which are incorporated with antimicrobial agents. However, the number of microorganisms resistant to these substances is rising. Therefore, the search for new, natural alternatives such as essential oils (EOs) and plant extracts (PEs) is on the rise. However, these substances present some limitations (poor bioavailability and poor target capacity), which limits their efficiency. Their incorporation in formulations in the form of films and hydrogels (HGs) can help to overcome these issues and may be a potential alternative to the current treatments. HGs and films incorporated with PEs and EOs have antimicrobial activity, promote the viability of skin cells and fibroblast migration, and are non-toxic and biocompatible. This review discusses the use of films and HGs for the topical delivery of EOs and PEs for wound treatment and their formulations as effective wound dressings, while debating some mechanisms and biological properties to elucidate their presumptive clinical relevance and possible applications.

Hunting for Answers: Assessing Brucella spp. Seroprevalence and Risks in Red Deer and Wild Boar in Central Portugal.

Between 2016 and 2023, a cross-sectional study was conducted in the central region of Portugal in order to better understand the epidemiology and public health risks resulting from the handling and consumption of game animals infected with Brucella spp. The seroprevalence and risk factors for Brucella spp. seropositivity were evaluated. Antibodies against Brucella spp. were determined using a commercial enzyme-linked immunosorbent assay (ELISA) according to the manufacturer's instructions. Results showed that in the 650 serum samples collected from red deer (n = 298) and wild boars (n = 352) in Portugal, 21.7% (n = 141; 95% CI: 18.6-25.1%) tested positive. Wild boar had a significantly higher prevalence (35.5%; 95% CI: 30.5-40.8%) than red deer (5.4%, 95% CI: 3.1-8.6%; p ≤ 0.001). Risk factors for seropositivity were investigated using multivariable logistic regression models. The odds of being seropositive was 8.39 (95% CI: 4.75-14.84; p ≤ 0.001) times higher in wild boar than in red deer. Correlations between sex, age, body condition, and seropositivity could not be observed. The higher seroprevalence in wild boar suggests that this species may primarily contribute to the Brucella spp. ecology in central Portugal.

Targeting pediatric cancers via T-cell recognition of the monomorphic MHC class I-related protein MR1.

Human leukocyte antigen (HLA) restriction of conventional T-cell targeting introduces complexity in generating T-cell therapy strategies for patients with cancer with diverse HLA-backgrounds. A subpopulation of atypical, major histocompatibility complex-I related protein 1 (MR1)-restricted T-cells, distinctive from mucosal-associated invariant T-cells (MAITs), was recently identified recognizing currently unidentified MR1-presented cancer-specific metabolites. It is hypothesized that the MC.7.G5 MR1T-clone has potential as a pan-cancer, pan-population T-cell immunotherapy approach. These cells are irresponsive to healthy tissue while conferring T-cell receptor(TCR) dependent, HLA-independent cytotoxicity to a wide range of adult cancers. Studies so far are limited to adult malignancies. Here, we investigated the potential of MR1-targeting cellular therapy strategies in pediatric cancer. Bulk RNA sequencing data of primary pediatric tumors were analyzed to assess MR1 expression. In vitro pediatric tumor models were subsequently screened to evaluate their susceptibility to engineered MC.7.G5 TCR-expressing T-cells. Targeting capacity was correlated with qPCR-based MR1 mRNA and protein overexpression. RNA expression of MR1 in primary pediatric tumors varied widely within and between tumor entities. Notably, embryonal tumors exhibited significantly lower MR1 expression than other pediatric tumors. In line with this, most screened embryonal tumors displayed resistance to MR1T-targeting in vitro MR1T susceptibility was observed particularly in pediatric leukemia and diffuse midline glioma models. This study demonstrates potential of MC.7.G5 MR1T-cell immunotherapy in pediatric leukemias and diffuse midline glioma, while activity against embryonal tumors was limited. The dismal prognosis associated with relapsed/refractory leukemias and high-grade brain tumors highlights the promise to improve survival rates of children with these cancers.

Single nucleotide polymorphism (SNP) rs4291 of the angiotensin-converting enzyme (ACE) gene is associated with the response to losartan treatment in hypertensive patients.

Arterial hypertension is characterized by systolic pressure ≥ 140 mmHg and/or diastolic pressure ≥ 90 mmHg and its treatment consists of the use of antihypertensive drugs, as losartan and hydrochlorothiazide. Blood pressure is regulated by angiotensin-converting enzyme (ACE) and polymorphisms in the ACE gene are associated to a greater predisposition to hypertension and response to treatment. The aim of this study was to evaluate the association of genetic polymorphisms of ACE rs4363, rs4291 and rs4335 and the response to antihypertensive drugs in hypertensive patients from Ouro Preto/MG, Brazil. A case-control study was carried out with 87 hypertensive patients being treated with losartan and 75 with hydrochlorothiazide, who answered a questionnaire and had blood samples collected. Biochemical analyzes were performed on serum using UV/Vis spectrophotometry and identification of ACE variants rs4363, rs4291 and rs4335 was performed by real-time PCR using the TaqMan® system. Univariate logistic regression test was performed to compare categorical data in STATA 13.0 software. The results showed that there was an influence of ACE polymorphisms on the response to losartan, demonstrating that AT or TT genotypes of rs4291 were more frequent in the group of controlled AH (54.9%), indicating that these individuals are 2.8 times more likely to of being controlled AH (95% CI 1.12-6.80, p. =0.026) compared to those with AA genotype. In contrast, no influence of ACE polymorphisms on the response to hydrochlorothiazide was observed. In conclusion, the presence of the T allele of the rs4291 variant was associated to controled blood pressure when losartan was used as an antihypertensive agent. These results show the importance of pharmacogenetic studies to detect genetic characteristics, enabling therapeutic individuality and reducing costs for the healthcare system.