Mobile App/Web Platform for Monitoring Food Oral Immunotherapy in Children: Longitudinal Clinical Validation Study.

BACKGROUND: Milk and egg allergies significantly impact the quality of life, particularly in children. In this regard, food oral immunotherapy (OIT) has emerged as an effective treatment option; however, the occurrence of frequent adverse reactions poses a challenge, necessitating close monitoring during treatment. OBJECTIVE: This study aims to evaluate the ability of a new mobile/web app called OITcontrol to monitor milk and egg OIT. METHODS: Patients undergoing milk or egg OIT were recruited and divided into 2 groups: the active group used the OITcontrol app in conjunction with standard written monitoring methods, whereas the control group relied solely on written diaries. Investigators documented hospital doses, hospital reactions, and administered treatments on the website. Patients recorded their daily allergen home-dose intake, home reactions, and administered treatments using the app. The following variables were compared between both groups: number and severity of hospital and reported home reactions, patient's adhesion to the OITcontrol app or written diary or both in terms of daily home-dose intake and home reactions recording, and treatment and dose adjustment compliance at home in case of reaction. RESULTS: Sixteen patients were assigned to be monitored using the OITcontrol app along with additional written methods (active group), while 14 patients relied solely on a written paper diary (control group). A similar distribution was observed in terms of sex, age, basal characteristics, allergen treated in OIT, premedication, and sensitization profile. Active patients reported a comparable number of hospital and home reactions compared with the control group. In terms of recording system usage, 13/16 (81%) active patients used the OITcontrol app, while 10/14 (71%) control patients relied on the written diary. Among active patients, 6/16 (38%) used both methods, and 1 active patient used only written methods. However, control patients recorded home reactions more frequently than active patients (P=.009). Among active patients, the app was the preferred method for recording reactions (59/86, 69%), compared with the written diary (15/86, 17%) or both methods (12/86, 14%; P<.001). Treatment compliance in home-recorded reactions was similar between both groups (P=.15). However, treatment indications after an adverse reaction were more frequently followed (P=.04) in reactions recorded solely in the app (36/59, 61%) than in the written diary (29/71, 41%) or both systems (4/12, 33%). Moreover, compliance with dose adjustments after a moderate-severe reaction in home-recorded reactions was higher in the active group than in the control group (P<.001). Home reactions recorded only in the app (16/19, 84%) were more likely to follow dose adjustments (P<.001) than those recorded in the written diary (3/20, 15%) or using both methods (2/3, 67%). CONCLUSIONS: The OITcontrol app appears to be a valuable tool for monitoring OIT treatment in children with food allergies. It proves to be a suitable method for recording daily home dose intakes and reactions, and it seems to enhance adherence to treatment indications following an adverse reaction as well as compliance with dose adjustments in home reactions. However, additional studies are necessary to comprehensively grasp the benefits and limitations of using the OITcontrol app in the management of OIT.

International Nosocomial Infection Control Consortium (INICC) report of health care associated infections, data summary of 45 countries for 2015 to 2020, adult and pediatric units, device-associated module.

BACKGROUND: Reporting on the International Nosocomial Infection Control Consortium study results from 2015 to 2020, conducted in 630 intensive care units across 123 cities in 45 countries spanning Africa, Asia, Eastern Europe, Latin America, and the Middle East. METHODS: Prospective intensive care unit patient data collected via International Nosocomial Infection Control Consortium Surveillance Online System. Centers for Disease Control and Prevention/National Health Care Safety Network definitions applied for device-associated health care-associated infections (DA-HAI). RESULTS: We gathered data from 204,770 patients, 1,480,620 patient days, 936,976 central line (CL)-days, 637,850 mechanical ventilators (MV)-days, and 1,005,589 urinary catheter (UC)-days. Our results showed 4,270 CL-associated bloodstream infections, 7,635 ventilator-associated pneumonia, and 3,005 UC-associated urinary tract infections. The combined rates of DA-HAIs were 7.28%, and 10.07 DA-HAIs per 1,000 patient days. CL-associated bloodstream infections occurred at 4.55 per 1,000 CL-days, ventilator-associated pneumonias at 11.96 per 1,000 MV-days, and UC-associated urinary tract infections at 2.91 per 1,000 UC days. In terms of resistance, Pseudomonas aeruginosa showed 50.73% resistance to imipenem, 44.99% to ceftazidime, 37.95% to ciprofloxacin, and 34.05% to amikacin. Meanwhile, Klebsiella spp had resistance rates of 48.29% to imipenem, 72.03% to ceftazidime, 61.78% to ciprofloxacin, and 40.32% to amikacin. Coagulase-negative Staphylococci and Staphylococcus aureus displayed oxacillin resistance in 81.33% and 53.83% of cases, respectively. CONCLUSIONS: The high rates of DA-HAI and bacterial resistance emphasize the ongoing need for continued efforts to control them.

White blood cell subtypes and neutrophil extracellular traps content as biomarkers for stroke etiology in acute ischemic stroke clots retrieved by mechanical thrombectomy.

BACKGROUND: Lymphocytes, macrophages, neutrophils, and neutrophil extracellular traps (NETs) associate with stroke risk factors and form a thrombus through different mechanisms. We investigated the total WBCs, WBC subtypes and NETs composition in acute ischemic stroke (AIS) clots to identify possible etiological differences that could help us further understand the process of thrombosis that leads to AIS. METHODS: AIS clots from 100 cases each of atherothrombotic (AT), cardioembolic (CE) and cryptogenic stroke etiology were collected per-pass as part of the CÚRAM RESTORE registry of AIS clots. Martius Scarlet Blue stain was used to identify the main histological components of the clots. Immunohistochemical staining was used to identify neutrophils, lymphocytes, macrophages, and NETs patterns. The cellular and histological components were quantified using Orbit Image Analysis software. RESULTS: AT clots were larger, with more red blood cells and fewer WBCs than CE clots. AT clots had more lymphocytes and cryptogenic clots had fewer macrophages than other etiologies. Most significantly, CE clots showed higher expression of neutrophils and extracellular web-like NETs compared to AT and cryptogenic clots. There was also a significantly higher distribution of web-like NETs around the periphery of the CE clots while a mixed distribution was observed in AT clots. CONCLUSION: The difference in neutrophil and NETs expression in clots from different etiologies may provide insight into the mechanism of clot formation.

Nanoscale Operando Characterization of Electrolyte-Gated Organic Field-Effect Transistors Reveals Charge Transport Bottlenecks.

Charge transport in electrolyte-gated organic field-effect transistors (EGOFETs) is governed by the microstructural property of the semiconducting thin film that is in direct contact with the electrolyte. Therefore, a comprehensive nanoscale operando characterization of the active channel is crucial to pinpoint various charge transport bottlenecks for rational and targeted optimization of the devices. Here, the local electrical properties of EGOFETs are systematically probed by in-liquid scanning dielectric microscopy (in-liquid SDM) and a direct picture of their functional mechanism at the nanoscale is provided across all operational regimes, starting from subthreshold, linear to saturation, until the onset of pinch-off. To this end, a robust interpretation framework of in-liquid SDM is introduced that enables quantitative local electric potential mapping directly from raw experimental data without requiring calibration or numerical simulations. Based on this development, a straightforward nanoscale assessment of various charge transport bottlenecks is performed, like contact access resistances, inter- and intradomain charge transport, microstructural inhomogeneities, and conduction anisotropy, which have been inaccessible earlier. Present results contribute to the fundamental understanding of charge transport in electrolyte-gated transistors and promote the development of direct structure-property-function relationships to guide future design rules.

JAK2, CALR, and MPL Mutation Profiles in Colombian patients with BCR-ABL Negative Myeloproliferative Neoplasms.

Background: Among the chronic myeloproliferative neoplasms (MPNs) not associated with BCR-ABL mutations are polycythemia vera, primary myelofibrosis, and essential thrombocythemia. These diseases are caused by mutations in genes, such as the JAK2, MPL, and CALR genes, which participate in regulating the JAK-STAT signaling pathway. Objective: This study aimed to establish the frequencies of mutations in the JAK2, MPL, and CALR genes in a group of Colombian patients with a negative clinical diagnosis of BCR-ABL chronic myeloproliferative neoplasms. Methods: The JAK2 V617F and MPL W515K mutations and deletions or insertions in exon 9 of the CALR gene were analyzed in 52 Colombian patients with polycythemia vera, primary myelofibrosis, and essential thrombocythemia. Results: The JAK2V617F mutation was carried by 51.9% of the patients, the CALR mutation by 23%, and the MPL mutation by 3.8%; 23% were triple-negative for the mutations analyzed. In these neoplasms, 6 mutation types in CALR were identified, one of which has not been previously reported. Additionally, one patient presented a double mutation in both the CALR and JAK2 genes. Regarding the hematological results for the mutations, significant differences were found in the hemoglobin level, hematocrit level, and platelet count among the three neoplasms. Conclusion: Thus, this study demonstrates the importance of the molecular characterization of the JAK2, CALR and MPL mutations in Colombian patients (the genetic context of which remains unclear in the abovementioned neoplasms) to achieve an accurate diagnosis, a good prognosis, adequate management, and patient survival.

Antecedentes: Entre las neoplasias mieloproliferativas crónicas no asociadas con mutaciones BCR-ABL se encuentran la policitemia vera, la mielofibrosis primaria y la trombocitemia esencial. Estas enfermedades están causadas por mutaciones en genes, como los genes JAK2, MPL y CALR, que participan en la regulación de la vía de señalización JAK-STAT. Objetivo: Establecer las frecuencias de mutaciones en los genes JAK2, MPL y CALR en un grupo de pacientes colombianos con diagnóstico clínico negativo de NMP BCR-ABL. Metodos: Se analizaron las mutaciones y deleciones o inserciones JAK2 V617F y MPL W515K en el exón 9 del gen CALR en 52 pacientes colombianos con policitemia vera, mielofibrosis primaria y trombocitemia esencial. Resultados: La mutación JAK2V617F la portaban el 51.9% de los pacientes, la mutación CALR el 23.0% y la mutación MPL el 3.8%; El 23.0% fueron triple negativos para las mutaciones analizadas. En estas neoplasias se identificaron seis tipos de mutación en CALR, uno de los cuales no ha sido reportado previamente. Además, un paciente presentó una doble mutación tanto en el gen CALR como en el JAK2. En cuanto a los resultados hematológicos para las mutaciones, se encontraron diferencias significativas en el nivel de hemoglobina, el nivel de hematocrito y el recuento de plaquetas entre las tres neoplasias. Conclusiones: Así, este estudio demuestra la importancia de la caracterización molecular de las mutaciones JAK2, CALR y MPL en pacientes colombianos (cuyo contexto genético aún no está claro en las neoplasias antes mencionadas) para lograr un diagnóstico certero, un buen pronóstico, un manejo adecuado y una mejoría del paciente. supervivencia.

JAK2, CALR, and MPL Mutation Profiles in Colombian patients with BCR-ABL Negative Myeloproliferative Neoplasms

Background: Among the chronic myeloproliferative neoplasms (MPNs) not associated with BCR-ABL mutations are polycythemia vera, primary myelofibrosis, and essential thrombocythemia. These diseases are caused by mutations in genes, such as the JAK2, MPL, and CALR genes, which participate in regulating the JAK-STAT signaling pathway. Objective: This study aimed to establish the frequencies of mutations in the JAK2, MPL, and CALR genes in a group of Colombian patients with a negative clinical diagnosis of BCR-ABL chronic myeloproliferative neoplasms. Methods: The JAK2 V617F and MPL W515K mutations and deletions or insertions in exon 9 of the CALR gene were analyzed in 52 Colombian patients with polycythemia vera, primary myelofibrosis, and essential thrombocythemia. Results: The JAK2V617F mutation was carried by 51.9% of the patients, the CALR mutation by 23%, and the MPL mutation by 3.8%; 23% were triple-negative for the mutations analyzed. In these neoplasms, 6 mutation types in CALR were identified, one of which has not been previously reported. Additionally, one patient presented a double mutation in both the CALR and JAK2 genes. Regarding the hematological results for the mutations, significant differences were found in the hemoglobin level, hematocrit level, and platelet count among the three neoplasms. Conclusion: Thus, this study demonstrates the importance of the molecular characterization of the JAK2, CALR and MPL mutations in Colombian patients (the genetic context of which remains unclear in the abovementioned neoplasms) to achieve an accurate diagnosis, a good prognosis, adequate management, and patient survival.

Antecedentes: Entre las neoplasias mieloproliferativas crónicas no asociadas con mutaciones BCR-ABL se encuentran la policitemia vera, la mielofibrosis primaria y la trombocitemia esencial. Estas enfermedades están causadas por mutaciones en genes, como los genes JAK2, MPL y CALR, que participan en la regulación de la vía de señalización JAK-STAT. Objetivo: Establecer las frecuencias de mutaciones en los genes JAK2, MPL y CALR en un grupo de pacientes colombianos con diagnóstico clínico negativo de NMP BCR-ABL. Metodos: Se analizaron las mutaciones y deleciones o inserciones JAK2 V617F y MPL W515K en el exón 9 del gen CALR en 52 pacientes colombianos con policitemia vera, mielofibrosis primaria y trombocitemia esencial. Resultados: La mutación JAK2V617F la portaban el 51.9% de los pacientes, la mutación CALR el 23.0% y la mutación MPL el 3.8%; El 23.0% fueron triple negativos para las mutaciones analizadas. En estas neoplasias se identificaron seis tipos de mutación en CALR, uno de los cuales no ha sido reportado previamente. Además, un paciente presentó una doble mutación tanto en el gen CALR como en el JAK2. En cuanto a los resultados hematológicos para las mutaciones, se encontraron diferencias significativas en el nivel de hemoglobina, el nivel de hematocrito y el recuento de plaquetas entre las tres neoplasias. Conclusiones: Así, este estudio demuestra la importancia de la caracterización molecular de las mutaciones JAK2, CALR y MPL en pacientes colombianos (cuyo contexto genético aún no está claro en las neoplasias antes mencionadas) para lograr un diagnóstico certero, un buen pronóstico, un manejo adecuado y una mejoría del paciente. supervivencia.

Association between Variables of Eating Habits and Gastric Trophic Changes in a Gastroenterology Institution in Medellín, Colombia

Aim: To establish the relationship between consuming foods considered risk factors for gastric cancer and trophic changes in gastric mucosa. Materials and methods: Cross-sectional study. We included patients older than 18 admitted for upper GI endoscopy with biopsies who adequately answered a survey of personal history and eating habits. Those with a history of gastric cancer or gastric surgical resection for any reason were excluded. The association between feeding variables and trophic changes in the gastric mucosa was estimated. Results: In a population of 1,096 patients, the average age was 51 years (standard deviation [SD]: 15.5), and 59% were women. Trophic changes in the gastric mucosa were identified in 173 patients (15.8%). No statistical association was found between the independent variables of eating habits, obesity, and positive Helicobacter pylori versus the variable "trophic changes," unlike the variable "family history of gastric cancer" (odds ratio [OR]: 1.49 95% confidence interval [CI]: 1.03-2.17, p = 0.036). One case of high-grade dysplasia was detected in the study population (0.91 cases in 1,000 patients). Conclusions: No association was established between eating habits and trophic changes in the gastric mucosa in the studied population. A family history of gastric cancer is a statistically significant risk factor for developing atrophy, metaplasia, or dysplasia changes.

Objetivo: establecer la relación entre el consumo de alimentos considerados como factores de riesgo para cáncer gástrico y la presencia de cambios tróficos de la mucosa gástrica. Materiales y métodos: estudio de corte transversal. Se incluyeron los pacientes mayores de 18 años admitidos para realización de endoscopia digestiva superior con toma de biopsias que respondieron adecuadamente una encuesta de antecedentes personales y hábitos de alimentación. Se excluyeron aquellos con antecedente de cáncer gástrico o resección quirúrgica gástrica por cualquier motivo. Se estimó la asociación entre las variables de alimentación y la presencia de cambios tróficos de la mucosa gástrica. Resultados: en una población de 1096 pacientes, el promedio de la edad fue 51 años (desviación estándar [DE]: 15,5), y correspondió en un 59% a mujeres. Se identificaron cambios tróficos de la mucosa gástrica en 173 pacientes (15,8%). No se obtuvo asociación estadística entre las variables independientes de hábitos de alimentación, obesidad y Helicobacter pylori positivo frente a la variable "cambios tróficos", a diferencia de la variable "antecedente familiar de cáncer gástrico" (odds ratio [OR]: 1,49; intervalo de confianza [IC] 95%: 1,03-2,17; p = 0,036). Se obtuvo 1 caso de displasia de alto grado en la población estudiada (0,91 casos en 1000 pacientes). Conclusiones: no se estableció una asociación entre los hábitos de alimentación y la presencia de cambios tróficos de la mucosa gástrica en la población estudiada. El antecedente familiar de cáncer gástrico se muestra como un factor de riesgo estadísticamente significativo para el desarrollo de cambios de atrofia, metaplasia o displasia.

NEURONORMA Cognitive Battery Associations with Cerebrospinal Fluid Amyloid-ß and Tau Levels in the Continuum of Alzheimer's Disease.

BACKGROUND: Neuropsychological assessments are essential to define the cognitive profile and contribute to the diagnosis of Alzheimer's disease (AD). The progress in knowledge about the pathophysiological process of the disease has allowed conceptualizing AD through biomarkers as a biological continuum that encompasses different clinical stages. OBJECTIVE: To explore the association between cerebrospinal fluid (CSF) biomarkers of AD and cognition using the NEURONORMA battery, in a sample of cognitively unimpaired (CU), mild cognitive impaired (MCI), and mild dementia of the Alzheimer type (DAT) subjects, and to characterize the cognitive profiles in MCI subjects classified by A/T/N system. METHODS: 42 CU, 35 MCI, and 35 mild DAT were assessed using the NEURONORMA battery. Core AD biomarkers [amyloid-ß42 (Aß42) peptide, total tau (t-tau), and phosphorylated tau 181 (p-tau181)] proteins were measured in CSF. Correlation coefficients, multivariate regression, and effect sizes were calculated. We explored the age- and education-adjusted cognitive profiles by A/T/N variants within the MCI group. RESULTS: Cognitive outcomes were directly associated with CSF Aß42 and inversely with CSF tau measures. We found differences in both biomarkers and cognitive outcomes comparing all pairs except for CSF measures between cognitively impaired groups. The highest effect size was in memory tasks and biomarkers ratios. Lower performances were in memory and executive domains in MCI subjects with AD pathology (A+T+N±) compared to those with normal levels of AD biomarkers (A- T- N). CONCLUSION: This study provides further evidence of the validity of Spanish NEURONORMA cognitive battery to characterize cognitive impairment in the AD pathological continuum.

Epigenetic mechanisms of Strip2 in differentiation of pluripotent stem cells.

Significant evidence points to Strip2 being a key regulator of the differentiation processes of pluripotent embryonic stem cells. However, Strip2 mediated epigenetic regulation of embryonic differentiation and development is quite unknown. Here, we identified several interaction partners of Strip2, importantly the co-repressor molecular protein complex nucleosome remodeling deacetylase/Tripartite motif-containing 28/Histone deacetylases/Histone-lysine N-methyltransferase SETDB1 (NuRD/TRIM28/HDACs/SETDB1) histone methyltransferase, which is primarily involved in regulation of the pluripotency of embryonic stem cells and its differentiation. The complex is normally activated by binding of Krueppel-associated box zinc-finger proteins (KRAB-ZFPs) to specific DNA motifs, causing methylation of H3 to Lysin-9 residues (H3K9). Our data showed that Strip2 binds to a DNA motif (20 base pairs), like the KRAB-ZFPs. We establish that Strip2 is an epigenetic regulator of pluripotency and differentiation by modulating DNA KRAB-ZFPs as well as the NuRD/TRIM28/HDACs/SETDB1 histone methyltransferase complex.

Ewing Sarcoma Meets Epigenetics, Immunology and Nanomedicine: Moving Forward into Novel Therapeutic Strategies.

Ewing Sarcoma (EWS) is an aggressive bone and soft tissue tumor that mainly affects children, adolescents, and young adults. The standard therapy, including chemotherapy, surgery, and radiotherapy, has substantially improved the survival of EWS patients with localized disease. Unfortunately, this multimodal treatment remains elusive in clinics for those patients with recurrent or metastatic disease who have an unfavorable prognosis. Consistently, there is an urgent need to find new strategies for patients that fail to respond to standard therapies. In this regard, in the last decade, treatments targeting epigenetic dependencies in tumor cells and the immune system have emerged into the clinical scenario. Additionally, recent advances in nanomedicine provide novel delivery drug systems, which may address challenges such as side effects and toxicity. Therefore, therapeutic strategies stemming from epigenetics, immunology, and nanomedicine yield promising alternatives for treating these patients. In this review, we highlight the most relevant EWS preclinical and clinical studies in epigenetics, immunotherapy, and nanotherapy conducted in the last five years.

JMJD3 intrinsically disordered region links the 3D-genome structure to TGFß-dependent transcription activation.

Enhancers are key regulatory elements that govern gene expression programs in response to developmental signals. However, how multiple enhancers arrange in the 3D-space to control the activation of a specific promoter remains unclear. To address this question, we exploited our previously characterized TGFß-response model, the neural stem cells, focusing on a ~374 kb locus where enhancers abound. Our 4C-seq experiments reveal that the TGFß pathway drives the assembly of an enhancer-cluster and precise gene activation. We discover that the TGFß pathway coactivator JMJD3 is essential to maintain these structures. Using live-cell imaging techniques, we demonstrate that an intrinsically disordered region contained in JMJD3 is involved in the formation of phase-separated biomolecular condensates, which are found in the enhancer-cluster. Overall, in this work we uncover novel functions for the coactivator JMJD3, and we shed light on the relationships between the 3D-conformation of the chromatin and the TGFß-driven response during mammalian neurogenesis.

Incidence and characterization of colorectal adenomas in the area of influence of a specialized institution / Incidencia y caracterización de adenomas colorrectales en el área de influencia de una institución especializada

Abstract Aim: To locate and characterize colorectal adenomas endoscopically and histologically in a cohort of patients undergoing colonoscopy in Medellín, Colombia. Materials and methods: Descriptive cross-sectional study. We included patients older than 18 years who underwent colonoscopy between February and July 2020 at a specialized center in Medellín, Colombia. We determined the incidence of adenomas, their location in different segments of the colon, their endoscopic and histological characteristics, and cases of colorectal cancer (CRC) and high-grade dysplasia (HGD). Results: 992 colonoscopies were performed, finding colorectal polyps in 266 patients, of which 208 had adenomas. We resected 461 polyps, of which 336 were adenomas (72 %). The histological type with the highest representation was tubular (78 %). The location of adenomas was 37 % in the right colon, 25 % in the transverse colon, and 38 % in the left colon. CRC cases were nine per 1,000 patients, including advanced carcinoma and carcinoma in situ (HGD). Conclusions: Given the incidence of adenomas in the right and transverse colon, rectosigmoidoscopy is discouraged as a screening study for CRC. Tubular adenomas, sessile in appearance and tiny, predominated in the population studied. We recommend screening in the population over 40 years of age and the search for precursor lesions as strategies to reduce morbidity and mortality rates due to CRC.

Resumen Objetivo: localización y caracterización endoscópica e histológica de los adenomas colorrectales en una cohorte de pacientes sometidos a colonoscopia en Medellín, Colombia. Materiales y métodos: estudio descriptivo de corte transversal. Se incluyeron pacientes mayores de 18 años sometidos a colonoscopia entre febrero y julio de 2020 en un centro especializado de Medellín, Colombia. Se determinó la incidencia de adenomas, su localización en los diferentes segmentos del colon, sus características endoscópicas e histológicas, así como también los casos de cáncer colorrectal (CCR) y displasia de alto grado. Resultados: se realizaron 992 colonoscopias y se encontraron pólipos colorrectales en 266 pacientes, de los cuales 208 tenían adenomas. En total se resecaron 461 pólipos, de los cuales 336 fueron adenomas (72 %). El tipo histológico con mayor representación fue el tubular (78 %). La localización de adenomas fue del 37 % en el colon derecho, 25 % en el transverso y 38 % en el colon izquierdo. La cantidad de casos de CCR fue de 9 por 1000 pacientes, que incluyen carcinoma avanzado y carcinoma in situ (DAG). Conclusiones: dada la incidencia de adenomas en el colon derecho y transverso, no se recomienda la rectosigmoidoscopia como estudio de tamizaje para CCR. En la población estudiada fueron predominantes los adenomas tubulares, de aspecto sésil y tamaño diminuto. Se recomienda el tamizaje en la población mayor de 40 años y la búsqueda de lesiones precursoras como estrategias para disminuir las tasas de morbimortalidad por CCR.

Selective histone methyltransferase G9a inhibition reduces metastatic development of Ewing sarcoma through the epigenetic regulation of NEU1.

Ewing sarcoma (EWS) is an aggressive bone and soft tissue tumor with high susceptibility to metastasize. The underlying molecular mechanisms leading to EWS metastases remain poorly understood. Epigenetic changes have been implicated in EWS tumor growth and progression. Linking epigenetics and metastases may provide insight into novel molecular targets in EWS and improve its treatment. Here, we evaluated the effects of a selective G9a histone methyltransferase inhibitor (BIX01294) on EWS metastatic process. Our results showed that overexpression of G9a in tumors from EWS patients correlates with poor prognosis. Moreover, we observe a significantly higher expression of G9a in metastatic EWS tumor as compared to either primary or recurrent tumor. Using functional assays, we demonstrate that pharmacological G9a inhibition using BIX01294 disrupts several metastatic steps in vitro, such as migration, invasion, adhesion, colony formation and vasculogenic mimicry. Moreover, BIX01294 reduces tumor growth and metastases in two spontaneous metastases mouse models. We further identified the sialidase NEU1 as a direct target and effector of G9a in the metastatic process in EWS. NEU1 overexpression impairs migration, invasion and clonogenic capacity of EWS cell lines. Overall, G9a inhibition impairs metastases in vitro and in vivo through the overexpression of NEU1. G9a has strong potential as a prognostic marker and may be a promising therapeutic target for EWS patients.

Can We Use the Indication for a Colonoscopy as a Predictor of the Adenoma Detection Rate? / ¿Podemos utilizar la indicación de colonoscopia como predictor de la tasa de detección de adenomas?

Abstract Aim: To determine the adenoma detection rate (ADR) and identify the indications for a colonoscopy that predict adenomas. Materials and methods: Cross-sectional study. We included patients older than 18 years who underwent colonoscopy between February and July 2020 at a specialized center in Medellín, Colombia. We estimated the ADR and identified the indications for a colonoscopy, considered predictors for finding adenomas. Results: The overall adenoma detection was 21 % (n = 992) and ADR in the screening population was 25 %. The range of 40-49 years contributed 12 % of the total number of adenomas detected, and the male population had a higher incidence (OR 1.73; 95 % CI 1.25-2.38; p < 0.001). Personal history of polyps (OR 1.86; 95 % CI 1.25-2.78; p = 0.002) and fecal occult blood (OR 2.67; 95 % CI 1.12-6.35; p 0.026) are deemed predictors for finding adenomas. LCI filters showed better results in detecting lesions (OR 1.43; 95 % CI 1.02-2.0). Conclusions: The indications for a colonoscopy can predict the probability of detecting adenomas. Male gender, a personal history of polyps, fecal occult blood, and the search for adenomas after the age of 40 are the variables that increase the probability of finding adenomas. The use of LCI filters increases lesion detection. The suggested age to start CRC screening is 40 years.

Resumen Objetivo: determinar la tasa de detección de los adenomas (TDA) e identificar las indicaciones de colonoscopia que predicen su hallazgo. Materiales y métodos: estudio de corte transversal. Se incluyeron pacientes mayores de 18 años sometidos a colonoscopia entre febrero y julio de 2020 en un centro especializado de Medellín, Colombia. Se estimó la TDA y se identificaron las indicaciones de colonoscopia, que se consideran predictores para el hallazgo de adenomas. Resultados: la detección general de adenomas fue del 21 % (n = 992) y la TDA en la población de tamizaje fue del 25 %. El rango de 40 a 49 años aportó el 12 % del total de adenomas detectados y la población masculina tuvo mayor incidencia (OR 1,73; IC 95 % 1,25-2,38; p < 0,001). El antecedente personal de pólipos (OR 1,86; IC 95 % 1,25-2,78; p = 0,002) y la presencia de sangre oculta en heces (OR 2,67; IC 95 % 1,12-6,35; p 0,026) se consideran predictores para el hallazgo de adenomas. El uso de filtros LCI mostró mejores resultados en la detección de las lesiones (OR 1,43; IC 95 % 1,02-2,0). Conclusiones: las indicaciones de la colonoscopia pueden predecir la probabilidad de detección de adenomas. El género masculino, el antecedente personal de pólipos, la presencia de sangre oculta en heces y la búsqueda de adenomas a partir de los 40 años son las variables que aumentan la probabilidad de encontrar adenomas. El uso de filtros LCI aumenta la detección de lesiones. La edad sugerida para el inicio del tamizaje de CCR es a partir de los 40 años.

Does prior administration of rtPA influence acute ischemic stroke clot composition? Findings from the analysis of clots retrieved with mechanical thrombectomy from the RESTORE registry.

BACKGROUND AND PURPOSE: There is still much debate whether bridging-therapy [intravenous thrombolysis (IVT) prior to mechanical thrombectomy (MT)] might be beneficial compared to MT alone. We investigated the effect of IVT on size and histological composition of the clots retrieved from patients undergoing bridging-therapy or MT alone. METHODS: We collected mechanically extracted thrombi from 1000 acute ischemic stroke (AIS) patients included in RESTORE registry. Patients were grouped according to the administration (or not) of IVT before thrombectomy. Gross photos of each clot were taken and Extracted Clot Area (ECA) was measured using ImageJ software. Martius Scarlett Blue stain was used to characterize the main histological clot components [red blood cells (RBCs), fibrin (FIB), platelets/other (PTL)] and Orbit Image Analysis was used for quantification. Additionally, we calculated the area of each main component by multiplying the component percent by ECA. Chi-squared and Kruskal-Wallis tests were used for statistical analysis. RESULTS: 451 patients (45%) were treated with bridging-therapy while 549 (55%) underwent MT alone. When considering only percent histological composition, we did not find any difference in RBC% (P = 0.895), FIB% (P = 0.458) and PTL% (P = 0.905). However, bridging-therapy clots were significantly smaller than MT-alone clots [32.7 (14.8-64.9) versus 36.8 (20.1-79.8) mm2, N = 1000, H1 = 7.679, P = 0.006*]. A further analysis expressing components per clot area showed that clots retrieved from bridging-therapy cases contained less RBCs [13.25 (4.29-32.06) versus 14.97 (4.93-39.80) mm2, H1 = 3.637, P = 0.056] and significantly less fibrin [9.10 (4.62-17.98) versus 10.54 (5.57-22.48) mm2, H1 = 7.920, P = 0.005*] and platelets/other [5.04 (2.26-11.32) versus 6.54 (2.94-13.79) mm2, H1 = 9.380, P = 0.002*] than MT-alone clots. CONCLUSIONS: Our results suggest that previous IVT administration significantly reduces thrombus size, proportionally releasing all the main histological components.

Preserved central nervous system functioning after use of romidepsin as a latency-reversing agent in an HIV cure strategy.

OBJECTIVE: To assess the central nervous system (CNS) impact of a kick&kill HIV cure strategy using therapeutic vaccine MVA.HIVconsv and the histone deacetylase inhibitor (HDACi) romidepsin (RMD) as latency-reversing agent. DESIGN: Neurological observational substudy of the BCN02 trial (NCT02616874), a proof-of-concept, open-label, single-arm, phase I clinical trial testing the safety and immunogenicity of the MVA.HIVconsv vaccine and RMD in early-treated HIV-1-infected individuals. A monitored antiretroviral pause (MAP) was performed, with cART resumption after 2 pVL more than 2000 copies/ml. Reinitiated participants were followed for 24 weeks. METHODS: Substudy participation was offered to all BCN02 participants (N = 15). Evaluations covered cognitive, functional, and brain imaging outcomes, performed before RMD administration (pre-RMD), after three RMD infusions (post-RMD), and at the end of the study (EoS). A group of early-treated HIV-1-infected individuals with matched clinical characteristics was additionally recruited (n = 10). Primary endpoint was change in a global cognitive score (NPZ-6). RESULTS: Eleven participants from BCN02 trial were enrolled. No significant changes were observed in cognitive, functional, or brain imaging outcomes from pre-RMD to post-RMD. No relevant alterations were detected from pre-RMD to EoS either. Scores at EoS were similar in participants off cART for 32 weeks (n = 3) and those who resumed therapy for 24 weeks (n = 7). Controls showed comparable punctuations in NPZ-6 across all timepoints. CONCLUSION: No detrimental effects on cognitive status, functional outcomes, or brain imaging parameters were observed after using the HDACi RMD as latency-reversing agent with the MVA.HIVconsv vaccine in early-treated HIV-1-infected individuals. CNS safety was also confirmed after completion of the MAP.

Human EWS-FLI protein recapitulates in Drosophila the neomorphic functions that induce Ewing sarcoma tumorigenesis.

Ewing sarcoma (EwS) is a human malignant tumor typically driven by the Ewing sarcoma-Friend leukemia integration (EWS-FLI) fusion protein. A paucity of genetically modified animal models, partially owed to the high toxicity of EWS-FLI, hinders research on EwS. Here, we report a spontaneous mutant variant, EWS-FLI1FS, that circumvents the toxicity issue in Drosophila. Through proteomic and genomic analyses, we show that human EWS-FLI1FS interacts with the Drosophila homologues of EWS-FLI human protein partners, including core subunits of chromatin remodeling complexes, the transcription machinery, and the spliceosome; brings about a massive dysregulation of transcription that affects a significant fraction of known targets of EWS-FLI in human cells; and modulates splicing. We also show that EWS-FLI1FS performs in Drosophila the two major neomorphic activities that it is known to have in human cells: activation of transcription from GGAA microsatellites and out competition of ETS transcription factors. We conclude that EWS-FLI1FS reproduces in Drosophila the known oncogenic activities of EWS-FLI that drive EwS tumorigenesis in humans. These results open up an unprecedented opportunity to investigate EWS-FLI's oncogenic pathways in vivo in a genetically tractable organism.

Fonoaudiología en Educación: Experiencias docentes para la conformación de una Spin-off universitaria / Speech and language therapy in education: Teaching experiences for the conformation of a university Spin-off

Este artículo pretende demostrar la viabilidad que tiene la creación de una spin-off universitaria que ofrezca servicios fonoaudiológicos para darle solución a las dificultades comunicativas que se presentan en el ámbito escolar, tanto en estudiantes como en docentes y administrativos. Metodología: Este fue un estudio cualitativo con diseño de investigación mixto, en el cual se obtuvieron los resultados a partir de una revisión documental y la aplicación de dos instrumentos de recolección de datos a profesionales de algunas instituciones educativas públicas y privadas de Medellín. Resultados: Los resultados evidenciaron que los docentes no reconocen en su totalidad las funciones del fonoaudiólogo en el sector educativo, y así mismo, se demostró que la participación que se ha tenido en los procesos que lleva a cabo este profesional en las instituciones educativas no ha sido la esperada; los docentes refirieron identificar diversas dificultades en los estudiantes y en ellos mismos, relacionadas con la comunicación; además, reconocieron la importancia y necesidad de incluir al fonoaudiólogo en las instituciones educativas. Conclusión: Se concluye que en el sector educativo son evidentes las dificultades comunicativas que presentan los estudiantes, los docentes y administrativos, sin embargo, en estas instituciones aún no se ha integrado el servicio de fonoaudiología, por ende, no se logra dimensionar el alcance que tiene el fonoaudiólogo para beneficiar la población escolar. Las experiencias docentes permitieron confirmar el gran valor que tiene la conformación de una spin-off que ofrezca servicios fonoaudiológicos a la comunidad educativa, brinde solución a las necesidades y complemente la labor docente

To demonstrate the viability of creating a university spin-off that offers speech and language services to solve communication difficulties that appear in the school environment for students, teachers and administrators. Methodology: This was a qualitative study with a mixed research design in which the results were obtained from a documentary review and the application of two data collection instruments to professionals in some public and private educational institutions in Medellin. Results: The results showed that the teachers do not fully recognize the functions of the speech and language therapist in the educational sector and it was also demonstrated that the participation in the processes carried out by this professional in the educational institutions has not been as expected. The teachers referred to identify various difficulties in the students and in themselves related to communication. In addition, they recognized the importance and need to include the speech and language therapist in the educational institutions.Conclusion: It is concluded that in the educational sector the communication difficulties presented by students, teachers and administrators are evident; however, in these educational institutions the speech and language service has not yet been integrated. Therefore, it is not possible to dimension the scope that the speech and language therapist has to benefit the school population. The teaching experiences allowed confirming the great value of the conformation of a spin-off that offers speech and language services to the educational community, providing solutions to the needs and complementing the teaching work

Selective inhibition of HDAC6 regulates expression of the oncogenic driver EWSR1-FLI1 through the EWSR1 promoter in Ewing sarcoma.

Ewing sarcoma (EWS) is an aggressive bone and soft tissue tumor of children and young adults in which the principal driver is a fusion gene, EWSR1-FLI1. Although the essential role of EWSR1-FLI1 protein in the regulation of oncogenesis, survival, and tumor progression processes has been described in-depth, little is known about the regulation of chimeric fusion-gene expression. Here, we demonstrate that the active nuclear HDAC6 in EWS modulates the acetylation status of specificity protein 1 (SP1), consequently regulating the SP1/P300 activator complex binding to EWSR1 and EWSR1-FLI1 promoters. Selective inhibition of HDAC6 impairs binding of the activator complex SP1/P300, thereby inducing EWSR1-FLI1 downregulation and significantly reducing its oncogenic functions. In addition, sensitivity of EWS cell lines to HDAC6 inhibition is higher than other tumor or non-tumor cell lines. High expression of HDAC6 in primary EWS tumor samples from patients correlates with a poor prognosis in two independent series accounting 279 patients. Notably, a combination treatment of a selective HDAC6 and doxorubicin (a DNA damage agent used as a standard therapy of EWS patients) dramatically inhibits tumor growth in two EWS murine xenograft models. These results could lead to suitable and promising therapeutic alternatives for patients with EWS.

The chromatin, topological and regulatory properties of pluripotency-associated poised enhancers are conserved in vivo.

Poised enhancers (PEs) represent a genetically distinct set of distal regulatory elements that control the expression of major developmental genes. Before becoming activated in differentiating cells, PEs are already bookmarked in pluripotent cells with unique chromatin and topological features that could contribute to their privileged regulatory properties. However, since PEs were originally characterized in embryonic stem cells (ESC), it is currently unknown whether PEs are functionally conserved in vivo. Here, we show that the chromatin and 3D structural features of PEs are conserved among mouse pluripotent cells both in vitro and in vivo. We also uncovered that the interactions between PEs and their target genes are globally controlled by the combined action of Polycomb, Trithorax and architectural proteins. Moreover, distal regulatory sequences located close to developmental genes and displaying the typical genetic (i.e. CpG islands) and chromatin (i.e. high accessibility and H3K27me3 levels) features of PEs are commonly found across vertebrates. These putative PEs show high sequence conservation within specific vertebrate clades, with only a few being evolutionary conserved across all vertebrates. Lastly, by genetically disrupting PEs in mouse and chicken embryos, we demonstrate that these regulatory elements play essential roles during the induction of major developmental genes in vivo.