Melanoma antigens in pediatric medulloblastoma contribute to tumor heterogeneity and species-specificity of group 3 tumors.

Background: Medulloblastoma (MB) is the most malignant childhood brain cancer. Group 3 MB subtype accounts for about 25% of MB diagnoses and is associated with the most unfavorable outcomes. Herein, we report that more than half of group 3 MB tumors express melanoma antigens (MAGEs), which are potential prognostic and therapeutic markers. MAGEs are tumor antigens, expressed in several types of adult cancers and associated with poorer prognosis and therapy resistance; however, their expression in pediatric cancers is mostly unknown. The aim of this study was to determine whether MAGEs are activated in pediatric MB. Methods: To determine MAGE frequency in pediatric MB, we obtained formalin-fixed paraffin-embedded tissue (FFPE) samples of 34 patients, collected between 2008 - 2015, from the Children's Medical Center Dallas pathology archives and applied our validated reverse transcription quantitative PCR (RT-qPCR) assay to measure the relative expression of 23 MAGE cancer-testis antigen genes. To validate our data, we analyzed several published datasets from pediatric MB patients and patient-derived orthotopic xenografts, totaling 860 patients. We then examined how MAGE expression affects the growth and oncogenic potential of medulloblastoma cells by CRISPR-Cas9- and siRNA-mediated gene depletion. Results: Our RT-qPCR analysis suggested that MAGEs were expressed in group 3/4 medulloblastoma. Further mining of bulk and single-cell RNA-sequencing datasets confirmed that 50-75% of group 3 tumors activate a subset of MAGE genes. Depletion of MAGEAs, B2, and Cs alter MB cell survival, viability, and clonogenic growth due to decreased proliferation and increased apoptosis. Conclusions: These results indicate that targeting MAGEs in medulloblastoma may be a potential therapeutic option for group 3 medulloblastomas. Key Points: Several Type I MAGE CTAs are expressed in >60% of group 3 MBs. Type I MAGEs affect MB cell proliferation and apoptosis. MAGEs are potential biomarkers and therapeutic targets for group 3 MBs. Importance of the Study: This study is the first comprehensive analysis of all Type I MAGE CTAs ( MAGEA , -B , and -C subfamily members) in pediatric MBs. Our results show that more than 60% of group 3 MBs express MAGE genes, which are required for the viability and growth of cells in which they are expressed. Collectively, these data provide novel insights into the antigen landscape of pediatric MBs. The activation of MAGE genes in group 3 MBs presents potential stratifying and therapeutic options.

Cell-specific secretory granule sorting mechanisms: the role of MAGEL2 and retromer in hypothalamic regulated secretion.

Intracellular protein trafficking and sorting are extremely arduous in endocrine and neuroendocrine cells, which synthesize and secrete on-demand substantial quantities of proteins. To ensure that neuroendocrine secretion operates correctly, each step in the secretion pathways is tightly regulated and coordinated both spatially and temporally. At the trans-Golgi network (TGN), intrinsic structural features of proteins and several sorting mechanisms and distinct signals direct newly synthesized proteins into proper membrane vesicles that enter either constitutive or regulated secretion pathways. Furthermore, this anterograde transport is counterbalanced by retrograde transport, which not only maintains membrane homeostasis but also recycles various proteins that function in the sorting of secretory cargo, formation of transport intermediates, or retrieval of resident proteins of secretory organelles. The retromer complex recycles proteins from the endocytic pathway back to the plasma membrane or TGN and was recently identified as a critical player in regulated secretion in the hypothalamus. Furthermore, melanoma antigen protein L2 (MAGEL2) was discovered to act as a tissue-specific regulator of the retromer-dependent endosomal protein recycling pathway and, by doing so, ensures proper secretory granule formation and maturation. MAGEL2 is a mammalian-specific and maternally imprinted gene implicated in Prader-Willi and Schaaf-Yang neurodevelopmental syndromes. In this review, we will briefly discuss the current understanding of the regulated secretion pathway, encompassing anterograde and retrograde traffic. Although our understanding of the retrograde trafficking and sorting in regulated secretion is not yet complete, we will review recent insights into the molecular role of MAGEL2 in hypothalamic neuroendocrine secretion and how its dysregulation contributes to the symptoms of Prader-Willi and Schaaf-Yang patients. Given that the activation of many secreted proteins occurs after they enter secretory granules, modulation of the sorting efficiency in a tissue-specific manner may represent an evolutionary adaptation to environmental cues.

Not all respiratory infections were SARS-CoV-2 during the pandemic, analysis in a clinic on the Colombian Caribbean coast.

INTRODUCTION: Acute Respiratory Infections (ARIs) are considered one of the leading causes of morbidity and mortality worldwide. Children under five and older adults are most likely to die from this cause. OBJECTIVE: To describe the behavior of infection by respiratory viruses other than SARS-CoV-2 during the pandemic in a clinic in the Colombian Caribbean. METHODS: This descriptive and retrospective study evaluates the characteristics, associated comorbidities, and requirements of hospitalization or Intensive Care Unit in patients diagnosed with respiratory viral infections treated at IMAT Oncomedica clinic from July 2020 to August 2022. RESULTS: This study evaluated 351 patients with respiratory symptoms, observing an exponential increase in cases of respiratory infection as of April 2022, with a high proportion of syncytial virus infections mainly in children under 18 years of age (22.1%) and Human Rhinovirus/Enterovirus in patients with solid tumors and hematological disorders (48.8%), the latter was associated with a higher rate of hospitalization and ICU requirement in the individuals evaluated. CONCLUSIONS: Respiratory viruses other than SARS-CoV-2, such as Rhino/Enterovirus, RSV, and adenovirus, are circulating in the population at a clinic on the Colombian Caribbean coast. The findings should motivate public health authorities to conduct more thorough surveillance in the rest of the state.

Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study.

BACKGROUND AND AIMS: Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers, and real-world data are lacking. This study aimed to elucidate the natural history of liver disease in a contemporary, international cohort of children with ALGS. APPROACH AND RESULTS: This was a multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born between January 1997 and August 2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS. In total, 1433 children (57% male) from 67 centers in 29 countries were included. The 10 and 18-year NLS rates were 54.4% and 40.3%. By 10 and 18 years, 51.5% and 66.0% of children with ALGS experienced ≥1 adverse liver-related event (CEPH, transplant, or death). Children (>6 and ≤12 months) with median total bilirubin (TB) levels between ≥5.0 and <10.0 mg/dl had a 4.1-fold (95% confidence interval [CI], 1.6-10.8), and those ≥10.0 mg/dl had an 8.0-fold (95% CI, 3.4-18.4) increased risk of developing CEPH compared with those <5.0 mg/dl. Median TB levels between ≥5.0 and <10.0 mg/dl and >10.0 mg/dl were associated with a 4.8 (95% CI, 2.4-9.7) and 15.6 (95% CI, 8.7-28.2) increased risk of transplantation relative to <5.0 mg/dl. Median TB <5.0 mg/dl were associated with higher NLS rates relative to ≥5.0 mg/dl, with 79% reaching adulthood with native liver ( p < 0.001). CONCLUSIONS: In this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB <5.0 mg/dl between 6 and 12 months of age is associated with better hepatic outcomes. These thresholds provide clinicians with an objective tool to assist with clinical decision-making and in the evaluation of therapies.

Caracterización de la infección urinaria y resistencia antimicrobiana en receptores de trasplante renal de un centro colombiano / Characterization of Urinary Tract Infection and Antimicrobial Resistance in Kidney Transplant Recipients from a Colombian Tertiary Center

La infección del tracto urinario (ITU) es una de las principales complicaciones postrasplante renal, los datos a nivel nacional en ese grupo poblacional son limitados. Objetivos caracterizar la microbiología de las ITU presentadas en receptores de trasplante renal (TxR) en un centro colombiano durante el periodo 2017­2019, los factores relacionados con la resistencia antimicrobiana y el impacto de la ITU en la función del injerto renal. Métodos estudio de corte transversal ejecutado mediante el análisis de la base de datos de ingresos hospitalarios por urgencias de pacientes receptores de TxR con sospecha clínica de ITU en una institución de cuarto nivel en Bogotá, Colombia. El análisis de datos se ejecutó en STATA 13.0. Resultados La ITU causó 12,69% de visitas a urgencias en pacientes trasplantados. Los microorganismos aislados fueron: Escherichia coli 52,22%, Klebsiella pneumoniae 16,67%, Pseudomonas aeruginosa 4,44%, Salmonella spp 4,44%, Proteus mirabilis 3,33%, Serratia marcescens 2,22%, Klebsiella oxytoca 2,22%, Citrobacter koseri 1,11%, Enterobacter cloacae 1,11%, otros 2,22%; El urocultivo fue negativo en 10% de los casos. El 28,39% (n:23) de gérmenes aislados fue multisensible mientras que el 71,60% (n:58) expresó algún tipo de patrón de resistencia distribuido así: 68,96% productor de betalactamasa de espectro extendido (BLEE), 15,52% productor de carbapenemasas, 12,06% productor de betalactamasa tipo IRT, 3,45% fue catalogado como multirresistente. 17,78% de los pacientes presentó criterios de urosepsis, no se registró ningún caso de mortalidad asociada a la ITU. La creatinina sérica tuvo un incremento promedio de 0,46 mg/dl durante el episodio de ITU (p: <0,0001) y el antecedente de diabetes mellitus se relacionó con la ITU causada por gérmenes resistentes (p: 0,008). Conclusiones La ITU es una causa frecuente de atención en urgencias para pacientes receptores de TxR; la Escherichia coli es el microorganismo causal más frecuente y cerca del 70% de los gérmenes aislados presentó algún patrón de resistencia antimicrobiana.

Urinary tract infection (UTI) is one of the most common complications after kidney transplantation (KTx). This study aims to characterize the microbiology of UTIs presented in KTx recipients in a Colombian tertiary center during the period 2017­2019, factors related with antimicrobial resistance and the impact of UTI on kidney graft function. Methods A cross-sectional retrospective single center study were made through the institutional database analysis of hospital admissions to the emergency room of KTx recipients with clinical suspicion of UTI. Data analysis was run on STATA 13.0. Results UTI caused 12.69% of visits to the emergency room in transplant patients during the study period. The isolated microorganisms were Escherichia coli 52.22%, Klebsiella pneumoniae 16.67%, Pseudomonas aeruginosa 4.44%, Salmonella spp 4.44%, Proteus mirabilis 3.33%, Serratia marcescens 2.22%, Klebsiella oxytoca 2.22%, Citrobacter koseroi 1.11%, others 2.22%; Urine culture was negative in 10% of cases. 28.39% (n: 23) of isolated germs were multisensitive while 71.60% (n: 58) expressed some type of resistance pattern distributed as follows: 68.96% extended spectrum beta-lactamase (ESBL) producers, 15.52% carbapenemases producers, 12.06% IRT-type beta-lactamase producers, 3.45% was classified as multi-resistant. 17.78% of patients presented criteria for urosepsis, there was no cases of mortality due to UTI. Serum creatinine had an average increase of 0.46 mg/dl during the UTI episode (p: <0.0001) and a history of diabetes mellitus was related with UTI caused by resistant germs (p: 0.008). Conclusion UTI is a frequent cause of emergency care for KTx recipients. E. coli is the most common causative microorganism and about 70% of isolated germs showed some pattern of antimicrobial resistance.