TIM-3 Expression in Endometriosis.

PROBLEM: Endometriosis is a prevalent chronic gynecological disease linked to immune dysfunction. The protein T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) plays a crucial role in immune system balance. Malfunction of TIM-3 may result in excessive immune activation and inflammatory tissue damage. Given TIM-3's established role in the development of cancer and autoimmune diseases, we decided to study its role in women suffering from endometriosis. STUDY METHOD: We included a total of 62 female patients, all of whom had undergone laparoscopic surgery. Of these, 47 had endometriosis and 15 did not. During surgery, we collected peritoneal fluid (PF) and peripheral blood (PB) samples from every patient for analysis using flow cytometry. To mark the samples, we used a panel of monoclonal antibodies and examined TIM-3 expression in their immune cells. RESULTS: Endometriosis patients in PB demonstrated a significantly lower percentage of CD56+ T cells with TIM-3 expression. As endometriosis progressed through its stages, this expression lessened. This decrease was particularly notable in women with stage III/IV endometriosis. Additionally, both women diagnosed with intestinal endometriosis and those with recent endometriosis diagnoses showed a significantly reduced percentage of CD56+ T cells expressing TIM-3. CONCLUSIONS: Patients with endometriosis exhibit diminished TIM-3 expression within circulating T cells. This warrants further investigation to discern whether it contributes to the progression of endometriosis, potentially through the amplification of autoreactive T cells and inflammation.

Safety of Fibrinogen Concentrate in Non-Trauma and Non-Obstetric Adult Patients during Perioperative Care: Systematic Review and Meta-Analysis.

Background: Low fibrinogen levels are associated with an increased risk of perioperative bleeding. However, there is an ongoing debate over the ideal treatment threshold, the benefits of prophylactic supplementation with fibrinogen concentrate, and the best source of fibrinogen. While fibrinogen concentrate supplementation is being widely used to treat bleeding related to acquired haemostatic deficiencies, there is a lack of evidence regarding its dosage, effectiveness, and safety. This systematic review provides an up-to-date summary of the relationship between fibrinogen concentrate supplementation and safety measures in the perioperative care of non-trauma, non-obstetric adult patients. Methods: A comprehensive online search was conducted on PubMed/Medline, EMBASE, Scopus, Web of Science, the Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials. Results: This systematic review and meta-analysis encompasses ten studies involving 1391 patients. There was a decreased risk of total thromboembolic events in patients treated with fibrinogen compared to the control (OR 0.65, 95% CI 0.43 to 0.98, I2 = 0%). In addition, when fibrinogen was used prophylactically, it resulted in shorter ICU stays (MD -1.50, 95% CI -2.64 to -0.36), when set against its therapeutic use. A sensitivity analysis on cardiovascular surgery studies did not reveal any statistically significant difference. Conclusions: The use of fibrinogen concentrate in the perioperative care of non-trauma and non-obstetric adult patients may lead to potential benefits.

Chitosan-PLGA mucoadhesive nanoparticles for gemcitabine repurposing for glioblastoma therapy.

Glioblastoma (GBM) is a highly deadly brain tumor that does not respond satisfactorily to conventional treatment. The non-alkylating agent gemcitabine (GEM) has been proposed for treating GBM. It can overcome MGMT protein-mediated resistance, a major limitation of conventional therapy with the alkylating agent temozolomide (TMZ). However, GEM's high systemic toxicity and poor permeability across the blood-brain barrier (BBB) pose significant challenges for its delivery to the brain. Thus, mucoadhesive poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) coated with chitosan (CH), suitable for intranasal GEM delivery, were proposed in this work. A central composite design (CCD) was implemented for NPs optimization, and NPs with appropriate characteristics for intranasal administration were obtained. in vitro studies revealed that the NPs possess excellent mucoadhesive properties and the ability to selectively release GEM in the simulated tumor tissue environment. in vitro studies using two human GBM cell lines (U215 and T98G) revealed the NPs' ability to promote GEM's antiproliferative activity to sensitize cells to the effect of TMZ. The findings of this work demonstrate that the developed CH-GEM-NPs are suitable delivery systems for GEM, both as a single therapy and as a chemosensitizer to the GBM gold standard therapy.

Acute effect of ultramarathon on systolic and diastolic cardiac function: Systematic review and meta-analysis.

BACKGROUND: Ultramarathon running poses physiological challenges, impacting cardiac function. This systematic review and meta-analysis explore the acute effects of single-stage ultramarathon running on cardiac function. METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations were followed. Searches covered Medline, Embase, CINAHL, SPORTDiscus, Web of Science, Central Cochrane, and Scopus. Random effects meta-analyses assessed left ventricular (LV) and right ventricular (RV) variables, expressed as mean differences (MD) with 95% confidence intervals (CI). RESULTS: Among 6972 studies, 17 were included. Post-ultramarathon reductions were found in LV end-diastolic diameter (LVEDD) (-1.24; 95% CI = -1.77, -0.71 mm), LV end-diastolic volume (LVEDV) (-9.92; 95% CI = -15.25, -4.60 ml), LV stroke volume (LVSV) (-8.96 ml, 95% CI -13.20, -4.72 ml), LV ejection fraction (LVEF) (-3.71; 95% CI = -5.21, -2.22%), LV global longitudinal strain (LVGLS) (-1.48; 95% CI = -2.21, -0.76%), E/A (-0.30; 95% CI = -0.38, -0.22 cm/s), .E' (-1.35 cm/s, 95% CI -1.91, -0.79 cm/s), RV fractional area change (RVFAC) (-3.34, 95% CI = -5.84, -0.84%), tricuspid annular plane systolic excursion (TAPSE) (-0.12, 95% CI = -0.22, -0.02 cm), RV global longitudinal strain (RVGLS) (-1.73, 95% CI = -2.87, -0.59%), with increases in RV end-diastolic area (RVEDA) (1.89, 95% CI = 0.63, 3.14 cm2), RV Peak A' (1.32 cm/s, 95% CI 0.20, 2.44), and heart rate (18.24, 95% CI = 15.16, 21.32). No significant differences were observed in LV end-systolic diameter (LVESD), LV end-systolic volume (LVESV), RV end-diastolic diameter (RVEDD), RV Peak E', and RV Peak S'. CONCLUSIONS: Evidence suggests immediate impairment of systolic and diastolic cardiac function post-ultramarathon running.

Prognosis of polymerase epsilon (POLE) mutation in high-grade endometrioid endometrial cancer: Systematic review and meta-analysis.

BACKGROUND: POLE mutated endometrial carcinomas may represent a subspecific type of tumors harboring a more favorable prognosis. Grade 3 (G3 or high-grade) endometrioid endometrial carcinomas remain a clinical dilemma, with some tumors behaving as the low-grade counterparts and others presenting a more aggressive behavior. OBJECTIVES: To determine the association between POLE mutational status and the overall-survival (OS) and progression-free-survival (PFS) of patients with G3 endometrioid endometrial cancer (EC). We also aimed to determine the prevalence of POLE mutations in G3 endometrioid EC. METHODS: We conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (PROSPERO No: CRD4202340008). We searched the following electronic databases: PubMed/Medline, EMBASE, Cochrane Library, Scopus, and Web of Science. For time-to-event data, the effect of POLE mutation in G3 EC was described using hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). Individual patient data for each study was investigated if available from the study authors. If individual patient data were not available, information regarding time-to-event outcomes was extracted using an appropriate methodology. OS and PFS were analyzed using both one-stage and two-stage approaches, the Kaplan-Meier method, and Cox-proportional hazards models. RESULTS: This systematic review and meta-analysis included 19 studies with 3092 patients who had high-grade endometrioid EC. Patients with POLE mutations had lower risks of death (HR = 0.36, 95% CI 0.26 to 0.50, I2 = 0%, 10 trials) and disease progression (HR = 0.31, 95% CI 0.17 to 0.57, I2 = 33%, 10 trials). The pooled prevalence of POLE mutation was 11% (95% CI 9 to 13, I2 = 68%, 18 studies). CONCLUSION: POLE mutations in high-grade endometrioid EC are associated with a more favorable prognosis with increased OS and PFS.

Clinical Presentation and Outcomes of Patients With Cancer-Associated Isolated Distal Deep Vein Thrombosis.

PURPOSE: Patients with isolated distal deep vein thrombosis (DVT) have lower rates of adverse outcomes (death, venous thromboembolism [VTE] recurrence or major bleeding) than those with proximal DVT. It is uncertain if such findings are also observed in patients with cancer. METHODS: Using data from the international Registro Informatizado de la Enfermedad TromboEmbolica venosa registry, we compared the risks of adverse outcomes at 90 days (adjusted odds ratio [aOR]; 95% CI) and 1 year (adjusted hazard ratio [aHR; 95% CI]) in 886 patients with cancer-associated distal DVT versus 5,196 patients with cancer-associated proximal DVT and 5,974 patients with non-cancer-associated distal DVT. RESULTS: More than 90% of patients in each group were treated with anticoagulants for at least 90 days. At 90 days, the adjusted risks of death, VTE recurrence, or major bleeding were lower in patients with non-cancer-associated distal DVT than in patients with cancer-associated distal DVT (reference): aOR = 0.16 (0.11-0.22), aOR = 0.34 (0.22-0.54), and aOR = 0.47 (0.27-0.80), respectively. The results were similar at 1-year follow-up: aHR = 0.12 (0.09-0.15), aHR = 0.39 (0.28-0.55), and aHR = 0.51 (0.32-0.82), respectively. Risks of death, VTE recurrence, and major bleeding were not statistically different between patients with cancer-associated proximal versus distal DVT, both at 90 days: aOR = 1.11 (0.91-1.36), aOR = 1.10 (0.76-1.62), and aOR = 1.18 (0.76-1.83), respectively, and 1 year: aHR = 1.01 (0.89-1.15), aHR = 1.02 (0.76-1.35), and aHR = 1.10 (0.76-1.61), respectively. However, more patients with cancer-associated proximal DVT, compared with cancer-associated distal DVT, developed fatal pulmonary embolism (PE) during follow-up: The risk difference was 0.40% (95% CI, 0.23 to 0.58). CONCLUSION: Cancer-associated distal DVT has serious and relatively comparable outcomes compared with cancer-associated proximal DVT. The lower risk of fatal PE from cancer-associated distal DVT needs further investigation.

Exome Sequencing Identifies Multiple Genetic Diagnoses in Children with Syndromic Growth Disorders.

OBJECTIVE: To evaluate the presence of multiple genetic diagnoses in syndromic growth disorders. STUDY DESIGN: We carried out a cross-sectional study to evaluate 115 patients with syndromic tall (n = 24) or short stature (n = 91) of unknown cause from a tertiary referral center for growth disorders. Exome sequencing was performed to assess germline single nucleotide, InDel, and copy number variants. All variants were classified according to ACMG/AMP guidelines. The main outcome measured was the frequency of multiple genetic diagnoses in a cohort of children with syndromic growth disorders. RESULTS: The total diagnostic yield of the cohort was 54.8% (63/115). Six patients had multiple genetic diagnoses (tall stature group = 2; short stature group = 4). The proportion of multiple diagnoses within total cases was 5.2% (6/115), and within solved cases was 9.5% (6/63). No characteristics were significantly more frequent when compared with patients with single or multiple genetic findings. Among patients with multiple diagnoses, 3 had syndromes with overlapping clinical features, and the others had syndromes with distinct phenotypes. CONCLUSION: Recognition of multiple genetic diagnoses as a possibility in complex cases of syndromic growth disorders opens a new perspective on treatment and genetic counseling for affected patients, defying the medical common sense of trying to fit all findings into one diagnosis.

Gold score athletics: talent detection model for track and field / Gold score athletics: modelo de detección de talentos para el atletismo / Gold score athletics: modelo de detecção de talentos para o atletismo

ABSTRACT Introduction: Talent detection is a dynamic and multifactorial process that must start at school. Objective: Create a mathematical model for evaluating the sporting potential of schoolchildren for athletics in speed, throwing, and endurance events and to test its psychometric properties. Methods: 2871 schoolchildren of both sexes, from 11 to 17 years old, from a military school participated. Between 2015 and 2019, students were submitted to a multidimensional battery of tests containing anthropometric, physical-motor, psychological, socio-environmental, maturational, and performance indicators. In addition, ten teachers evaluated the students regarding the intangibles aspects of their sporting potential and the expectation of future success during this period. Adopting analytical and heuristic procedures, the Gold Score Athletics was created - linear, hybrid (tests + coaches´ eye), and weighted index, according to each indicator's importance, depending on the event type. Results: In the model validation sample (n = 1384), 13.9%, 16.6%, and 11.7% of boys and 10.9%, 10.1%, and 9.1% of girls were classified as high potential (Gold Score ≥ 60) for speed, throwing and endurance events, respectively. Internal consistency (r = 0.76 to 0.82) and diagnostic stability were high (r = 0.72 to 0.81). The Gold Score Athletics for sprinters, throwers, and long-distance runners, both for boys and girls, was higher in students selected for a national competition when compared to those not selected (p < 0.001; d: 0.95 a 1.44) - construct validity - and higher in medalists in an athletics competition, held two years after diagnosis, when compared to non-medalists (p < 0.05; d: 0.62 a 1.87) - predictive validity. Conclusion: The Gold Score Athletics is a valid and reliable scientific model for evaluating the sport's potential of schoolchildren, being useful in the talents detection for Athletics. Level of Evidence II; Diagnostic study.

RESUMEN Introducción: La detección de talentos es un proceso dinámico y multifactorial que debe iniciarse en la escuela. Objetivo: Crear un modelo matemático para evaluar el potencial deportivo de escolares para pruebas de velocidad, lanzamiento y resistencia en atletismo, y probar sus propiedades psicométricas. Métodos: Participaron 2871 escolares de ambos sexos de 11 a 17 años de una escuela militar. Los estudiantes fueron sometidos a una batería de pruebas multidimensionales, que contenían indicadores antropométricos, físico-motores, psicológicos, socioambientales, madurativos y de desempeño. 10 docentes evaluaron a los alumnos sobre los aspectos intangibles del potencial deportivo y la expectativa de éxito futuro. Adoptando procedimientos analíticos y heurísticos, se creó el Gold Score Athletics, índice lineal, híbrido (pruebas + mirada del profesor) y ponderado, según la importancia de cada indicador según el tipo de prueba. Resultados: En la muestra de validación del modelo (n = 1384), el 13,9%, 16,6% y 11,7% de los niños y el 10,9%, 10,1% y 9,1% de las niñas fueron clasificados como de alto potencial (Gold Score ≥ 60) en velocidad, lanzamiento y eventos de resistencia. La consistencia interna (r = 0,76 a 0,82) y la estabilidad diagnóstica fueron altas (r = 0,72 a 0,81). El Gold Score Athletics para velocistas, lanzadores y corredores de fondo, para ambos sexos, fue mayor en los estudiantes seleccionados para una competición nacional en comparación con los no seleccionados (p < 0.001; d: 0,95 a 1,44) - validez del constructo - y mayor en medallistas en una competición de atletismo, realizada dos años después del diagnóstico, en comparación con los no medallistas (p < 0,05; d: 0,62 a 1,87) - validez predictiva. Conclusión: El Gold Score Athletics es un modelo científico válido y fiable para evaluar el potencial deportivo de los escolares, siendo útil en la detección de talentos para el Atletismo. Nivel de Evidencia II; Estudio diagnóstico.

RESUMO Introdução: A detecção de talentos é um processo dinâmico e multifatorial que deve começar pela escola. Objetivo: Criar um modelo matemático de avaliação do potencial esportivo de escolares para as provas de velocidade, lançamentos e resistência no atletismo, e testar as suas propriedades psicométricas. Métodos: Participaram 2871 escolares de ambos os sexos de 11 a 17 anos de um colégio militar. Os alunos foram submetidos a uma bateria de testes multidimensionais, contendo indicadores antropométricos, físico-motores, psicológicos, socioambientais, maturacionais e de desempenho. 10 professores avaliaram os alunos quanto aos aspectos intangíveis do potencial esportivo e a expectativa de sucesso futuro. Adotando procedimentos analíticos e heurísticos, criou-se o Gold Score Athletics - índice linear, híbrido (testes + olho do treinador) e ponderado, de acordo com a importância de cada indicador em função do tipo de prova. Resultados: Na amostra de validação do modelo (n = 1384), 13,9%, 16,6% e 11,7% dos meninos e 10,9%, 10,1% e 9,1% das meninas foram classificados como elevado potencial (Gold Score ≥ 60) para provas de velocidade, lançamentos e resistência respectivamente. A consistência interna (r = 0,76 a 0,82) e estabilidade do diagnóstico foram elevadas (r = 0,72 a 0,81). O Gold Score Athletics para velocistas, lançadores e corredores de longa distância, para ambos os sexos, foi maior nos estudantes selecionados para uma competição nacional quando comparados aos não selecionados (p < 0,001; d: 0,95 a 1,44) - validade de construto - e maior nos medalhistas em uma competição de Atletismo, realizada dois anos após o diagnóstico, quando comparados aos não medalhistas (p < 0,05; d: 0,62 a 1,87) - validade preditiva. Conclusão: O Gold Score Athletics é um modelo científico válido e fidedigno de avaliação do potencial esportivo de escolares, sendo útil na detecção de talentos para o Atletismo. Nível de Evidência II; Estudo diagnóstico.

Serological Evidence of Hepatitis E Virus Infection in Brazilian Equines.

Hepatitis E virus (HEV) infection has been demonstrated in various animal species; those recognized as potential zoonotic reservoirs pose a considerable risk to public health. In Brazil, HEV-3 is the only genotype identified in humans and swine nationwide, in a colony-breeding cynomolgus monkey and, recently, in bovines and capybara. There is no information regarding HEV exposure in the equine population in Brazil. This study aimed to investigate anti-HEV antibodies and viral RNA in serum samples from horses slaughtered for meat export and those bred for sport/reproduction purposes. We used a commercially available ELISA kit modified to detect species-specific anti-HEV, using an anti-horse IgG-peroxidase conjugate and evaluating different cutoff formulas and assay precision. Serum samples (n = 257) were tested for anti-HEV IgG and HEV RNA by nested RT-PCR and RT-qPCR. The overall anti-HEV seroprevalence was 26.5% (68/257) without the detection of HEV RNA. Most municipalities (53.3%) and farms (58.8%) had positive horses. Animals slaughtered for human consumption had higher risk of HEV exposure (45.5%) than those bred for sports or reproduction (6.4%) (p < 0.0001). The statistical analysis revealed sex and breeding system as possible risk-associated factors. The first serological evidence of HEV circulation in Brazilian equines reinforces the need for the surveillance of HEV host expansion in a one-health approach.

Essential Trace Elements Status in Portuguese Pregnant Women and Their Association with Maternal and Neonatal Outcomes: A Prospective Study from the IoMum Cohort.

Cobalt (Co), copper (Cu), manganese (Mn), molybdenum (Mo), and zinc (Zn) are essential trace elements (ETEs) and important cofactors for intermediary metabolism or redox balance. These ETEs are crucial during pregnancy, their role on specific pregnancy outcomes is largely unknown. This prospective study (#NCT04010708) aimed to assess urinary levels of these ETEs in pregnancy and to evaluate their association with pregnancy outcomes. First trimester pregnant women of Porto and Lisbon provided a random spot urine sample, and sociodemographic and lifestyle data. Clinical data were obtained from clinical records. Urinary ETEs were quantified by inductively coupled plasma mass spectrometry (ICP-MS). A total of 635 mother:child pairs were included. Having urinary Zn levels above the 50th percentile (P50) was an independent risk factor for pre-eclampsia (PE) (aOR [95% CI]: 5.350 [1.044-27.423], p = 0.044). Urinary Zn levels above the P50 decreased the risk of small for gestational age (SGA) birth head circumference (aOR [95% CI]: 0.315 [0.113-0.883], p = 0.028), but it increased the risk SGA length (aOR [95% CI]: 2.531 [1.057-6.062], p = 0.037). This study may provide valuable information for public health policies related to prenatal nutrition, while informing future efforts to de-fine urinary reference intervals for ETEs in pregnant women.

Two new patients with acromesomelic dysplasia, PRKG2 type-identification and characterization of the first missense variant.

Acromesomelic dysplasia, PRKG2 type (AMDP, MIM 619636), is an extremely rare autosomal recessive skeletal dysplasia characterized by severe disproportionate short stature presenting with acromesomelia, mild metaphyseal widening of the long bones and mild spondylar dysplasia. To date, only four variants have been reported; one nonsense, one splice-site, and two frameshifts in five AMDP families. Here, we report the first missense variant and a second splice-site variant in PRKG2 in two patients with clinical and radiological features of acromesomelic dysplasia. Furthermore, functional studies of the novel missense variant, p.Val470Gly, revealed that it was unable to down-regulate FGF2-induced MAPK signaling and, thus, would be predicted to cause growth delay. Hence, this report expands the mutational spectrum in skeletal dysplasias associated with PRKG2 variants. In addition, we propose recognizable facial features with acromesomelic dysplasia, PRKG2 type.

TERTmonitor-qPCR Detection of TERTp Mutations in Glioma.

Telomerase promoter (TERTp) mutations are frequently observed in various types of tumours and commonly characterised by two specific hotspots located at positions -124 and -146 upstream of the start codon. They enhance TERTp activity, resulting in increased TERT expression. In central nervous system (CNS) tumours, they are integrated as biomarkers, aiding in the diagnosis and with a role in prognosis, where, in some settings, they are associated with aggressive behaviour. In this study, we evaluated the performance of TERTmonitor for TERTp genotyping in a series of 185 gliomas in comparison to the traditional method, Sanger sequencing. Against the gold-standard Sanger method, TERTmonitor performed with a 97.8% accuracy. Inaccuracy was mainly due to the over-detection of variants in negative cases (by Sanger) and the presence of variants that can modify the chemistry of the probe detection. The distribution of the mutations was comparable to other series, with the -124 being the most represented (38.92% for Sanger and TERTmonitor) and more prevalent in the higher-grade tumours, gliosarcoma (50.00%) and glioblastoma (52.6%). The non-matched cases are debatable, as we may be dealing with the reduced sensitivity of Sanger in detecting rare alleles, which strengthens the use of the TERTmonitor. With this study, we present a reliable and rapid potential tool for TERTp genotyping in gliomas.

Transferrin-Conjugated PLGA Nanoparticles for Co-Delivery of Temozolomide and Bortezomib to Glioblastoma Cells.

Glioblastoma (GBM) represents almost half of primary brain tumors, and its standard treatment with the alkylating agent temozolomide (TMZ) is not curative. Treatment failure is partially related to intrinsic resistance mechanisms mediated by the O6-methylguanine-DNA methyltransferase (MGMT) protein, frequently overexpressed in GBM patients. Clinical trials have shown that the anticancer agent bortezomib (BTZ) can increase TMZ's therapeutic efficacy in GBM patients by downregulating MGMT expression. However, the clinical application of this therapeutic strategy has been stalled due to the high toxicity of the combined therapy. The co-delivery of TMZ and BTZ through nanoparticles (NPs) of poly(lactic-co-glycolic acid) (PLGA) is proposed in this work, aiming to explore their synergistic effect while decreasing the drug's toxicity. The developed NPs were optimized by central composite design (CCD), then further conjugated with transferrin (Tf) to enhance their GBM targeting ability by targeting the blood-brain barrier (BBB) and the cancer cells. The obtained NPs exhibited suitable GBM cell delivery features (sizes lower than 200 nm, low polydispersity, and negative surface charge) and a controlled and sustained release for 20 days. The uptake and antiproliferative effect of the developed NPs were evaluated in in vitro human GBM models. The obtained results disclosed that the NPs are rapidly taken up by the GBM cells, promoting synergistic drug effects in inhibiting tumor cell survival and proliferation. This cytotoxicity was associated with significant cellular morphological changes. Additionally, the biocompatibility of unloaded NPs was evaluated in healthy brain cells, demonstrating the safety of the nanocarrier. These findings prove that co-delivery of BTZ and TMZ in Tf-conjugated PLGA NPs is a promising approach to treat GBM, overcoming the limitations of current therapeutic strategies, such as drug resistance and increased side effects.

High VEGFA Expression Is Associated with Improved Progression-Free Survival after Bevacizumab Treatment in Recurrent Glioblastoma.

Glioblastoma (GB) is one of the deadliest human cancers. Many GB patients do not respond to treatment, and inevitably die within a median of 15-18 months post-diagnosis, highlighting the need for reliable biomarkers to aid clinical management and treatment evaluation. The GB microenvironment holds tremendous potential as a source of biomarkers; several proteins such as MMP-2, MMP-9, YKL40, and VEGFA have been identified as being differentially expressed in GB patient samples. Still to date, none of these proteins have been translated into relevant clinical biomarkers. This study evaluated the expression of MMP-2, MMP-9, YKL40, and VEGFA in a series of GBs and their impact on patient outcome. High levels of VEGFA expression were significantly associated with improved progression-free survival after bevacizumab treatment, thus having potential as a tissue biomarker for predicting patients' response to bevacizumab. Noteworthily, VEGFA expression was not associated with patient outcome after temozolomide treatment. To a lesser extent, YKL40 also provided significant information regarding the extent of bevacizumab treatment. This study highlights the importance of studying secretome-associated proteins as GB biomarkers and identifies VEGFA as a promising marker for predicting response to bevacizumab.

Kaposiform Lymphangiomatosis in a Male Adolescent: A Clinical Challenge and the Role of Genetics.

Kaposiform lymphangiomatosis (KLA) is a rare and aggressive generalized lymphatic anomaly (GLA), with distinctive clinical, radiology, morphologic, and genetic features. It does not have a current standard treatment and presents poor overall prognosis. Somatic mutations in the RAS pathway were reported as the likely driver for the majority of patients. We report a case of a 17-year-old male adolescent who was referred to the emergency department due to a severe anemia. Laboratory workup confirmed the anemia and revealed coagulation factor consumption and fibrinolysis. Chest-abdomen-pelvis computed tomography revealed an extensive cervical, mediastinal, abdominal and retroperitoneal "hematoma." During admission, progressive pancytopenia, and disseminated intravascular coagulation were observed, and the hypothesis of a tumor/neoplastic etiology was considered. A thoracoscopy revealed a moderate hemorrhagic pleural effusion and a mediastinal mass resembling a "hemolymphangiomatosis" malformation, which was biopsied. Histology displayed a lymphatic-venous malformation. The patient was presented at the multidisciplinary Vascular Anomalies Center and, due to the complex vascular anomaly diagnosis, oral sirolimus monotherapy was initiated. Four years later, the patient remains clinically stable, with stability of the lesion's dimensions and characteristics. A p.Q61R variant in the NRAS gene [NM_002524.4: c.182A>G, p.(Gln61Arg)], with 5% allelic fraction and 1993x coverage was detected. In conjunction with clinical and pathological findings, it allowed KLA final diagnosis. This case reinforces the importance of a high index of clinical suspicion and highlights the need of referring these cases to referral to Vascular Anomalies Centers.

Congenital Infantile Myofibroma: The Importance of Molecular Diagnosis.

Infantile myofibromatosis is an uncommon soft tissue neoplasm that may present at birth or in early infancy. Although rare, this neoplasm is one of the most common benign fibrous tumors of infancy. Even though these tumors do not spread, they can compress or damage nearby organs. There is not an established management protocol, but it is advisable to maintain periodic clinical and imagological control until stability. Watchful waiting is an option to consider in the absence of problematic symptoms and visceral involvement. We report a case of solitary infantile myofibromatosis, without visceral involvement. It showed an initial rapid growth, raising concern among medical doctors and motivating soft tissue biopsy, always recommended as the clinical picture deviates from the classic presentation. Histology interpretation is often challenging, making genetics and clinical evaluation essential to exclude and prevent the misdiagnosing of more aggressive lesions.

Digging the intercellular crosstalk via extracellular vesicles: May exosomes be the drug delivery solution for target glioblastoma?

Glioblastoma (GBM) is an adult's most aggressive brain tumor. The advances in molecular pathology and cell signaling pathways have deepened researchers' understanding of intercellular communication mechanisms that can induce tumor progression, namely the release of extracellular vesicles. Exosomes are small extracellular vesicles in various biological fluids released by almost all cells, thus carrying various biomolecules specific to their parental cell. Several pieces of evidence indicate that exosomes mediate intercellular communication in the tumor microenvironment and cross the blood-brain barrier (BBB), valuable tools for diagnostic and therapeutic applications under the scope of brain diseases such as brain tumors. This review aims to resume the several biological characteristics and the interplay between glioblastoma and exosomes, describing highlight studies that demonstrate the role of exosomes in the tumor microenvironment of GBM and their potential for non-invasive diagnoses and therapeutic approaches, namely, as nanocarriers for drug or gene delivery and cancer vaccines.

Talent identification and development in Olympic triathlon: a perspective from Brazilian coaches / Identificação e desenvolvimento de talentos no triatlo olímpico: uma perspectiva de treinadores brasileiros

Abstract The knowledge of coaches has been used in research on talent identification and development. The objective was to investigate how Brazilian triathlon coaches identify talents and what is the importance of different factors and indicators for the development of young triathletes. 37 coaches (89% male; 36.2 ± 8.3 years; 43% international competitive level) answered an online questionnaire about anthropometric, physical-motor, technical, tactical, psychological and environmental characteristics. On a scale of 1 (not very important) to 5 (extremely important), coaches indicated to what extent a factor/indicator of sporting potential was important for talent development in triathlon. 45.9% of the coaches perform talent identification, mainly by physical-motor tests and triathlon simulations. In talent development, the physical-motor factor was the most important, followed by the technical, psychological and anthropometric factor, and finally the tactical and environmental factor. Most coaches considered as extremely important the following indicators: determination (70%), aerobic endurance (65%), specific swimming skills (62%), ability to withstand pressure (59%), and efficiency of the cyclic gesture of swimming, cycling, and running (57%). We conclude that Brazilian triathlon coaches identify talents mainly through batteries of tests and triathlon simulations and consider the physical-motor factor the most important for the development of young talented triathletes, but not the only one.

Resumo O conhecimento dos treinadores tem sido utilizado na pesquisa sobre identificação e desenvolvimento de talentos. O objetivo foi investigar como os treinadores de triatlo brasileiros identificam os talentos e qual é a importância de diferentes fatores e indicadores para o desenvolvimento de jovens triatletas. 37 treinadores (89% homens; 36,2 ± 8,3 anos; 43% nível competitivo internacional) responderam um questionário online sobre características antropométricas, físico-motoras, técnicas, táticas, psicológicas e ambientais. Em uma escala de 1 (não muito importante) a 5 (extremamente importante), os treinadores indicaram em que medida um fator/indicador do potencial esportivo era importante para o desenvolvimento de talentos no triatlo. 45,9% dos treinadores realizam identificação de talentos, principalmente por testes físico-motores e simulados de triatlo. No desenvolvimento de talentos, o fator físico-motor foi o mais importante, seguido pelo fator técnico, psicológico e antropométrico, e por fim o fator tático e ambiental. A maioria dos treinadores considerou como extremamente importante os indicadores: determinação (70%), resistência aeróbica (65%), habilidades específicas de natação (62%), capacidade de suportar pressão (59%) e eficiência do gesto cíclico de nadar, pedalar e correr (57%). Conclui-se que os treinadores de triatlo brasileiros identificam talentos principalmente por meio de baterias de testes e simulados de triatlo e consideram o fator físico-motor o mais importante para o desenvolvimento de jovens triatletas talentosos, mas não o único.

Association of B Cells with Idiopathic Recurrent Pregnancy Loss: A Systematic Review and Meta-Analysis.

Recurrent pregnancy loss (RPL) affects 1-2% of women and is defined as having experienced two or more failed pregnancies. In almost 50% of cases, the causes are idiopathic (IRPL), but increasing evidence has suggested an immunological cause. B cells are known to provide crucial support for a successful pregnancy outcome. However, their involvement in the mechanisms underlying IRPL is still unclear. This systematic review and meta-analysis aimed to comprehensively summarise the existing evidence regarding the levels and profiles of B cells in IRPL. An extensive computerized search in PubMed/Medline, Embase, Scopus, and Web of Science databases was performed with no imposed limits. Two reviewers independently screened all retrieved studies, extracted all the data, and assessed the methodological quality. Disagreements were resolved by a third reviewer. From a total of 1125 retrieved studies, 19 studies were included in the systematic review, and 8 studies were quantitatively analysed. We highlight a potential association between women with IRPL and increased levels of endometrial B cells. In addition, the flow cytometry technique seems to be preferred over immunohistochemistry for identifying those differences, while further studies are necessary to clarify the role of B cells as an immunological risk factor for RPL.

Burden of Rare Copy Number Variants in Microcephaly: A Brazilian Cohort of 185 Microcephalic Patients and Review of the Literature.

Microcephaly presents heterogeneous genetic etiology linked to several neurodevelopmental disorders (NDD). Copy number variants (CNVs) are a causal mechanism of microcephaly whose investigation is a crucial step for unraveling its molecular basis. Our purpose was to investigate the burden of rare CNVs in microcephalic individuals and to review genes and CNV syndromes associated with microcephaly. We performed chromosomal microarray analysis (CMA) in 185 Brazilian patients with microcephaly and evaluated microcephalic patients carrying < 200 kb CNVs documented in the DECIPHER database. Additionally, we reviewed known genes and CNV syndromes causally linked to microcephaly through the PubMed, OMIM, DECIPHER, and ClinGen databases. Rare clinically relevant CNVs were detected in 39 out of the 185 Brazilian patients investigated by CMA (21%). In 31 among the 60 DECIPHER patients carrying < 200 kb CNVs, at least one known microcephaly gene was observed. Overall, four gene sets implicated in microcephaly were disclosed: known microcephaly genes; genes with supporting evidence of association with microcephaly; known macrocephaly genes; and novel candidates, including OTUD7A, BBC3, CNTN6, and NAA15. In the review, we compiled 957 known microcephaly genes and 58 genomic CNV loci, comprising 13 duplications and 50 deletions, which have already been associated with clinical findings including microcephaly. We reviewed genes and CNV syndromes previously associated with microcephaly, reinforced the high CMA diagnostic yield for this condition, pinpointed novel candidate loci linked to microcephaly deserving further evaluation, and provided a useful resource for future research on the field of neurodevelopment.