AutoPepVax, a Novel Machine-Learning-Based Program for Vaccine Design: Application to a Pan-Cancer Vaccine Targeting EGFR Missense Mutations.

The current epitope selection methods for peptide vaccines often rely on epitope binding affinity predictions, prompting the need for the development of more sophisticated in silico methods to determine immunologically relevant epitopes. Here, we developed AutoPepVax to expedite and improve the in silico epitope selection for peptide vaccine design. AutoPepVax is a novel program that automatically identifies non-toxic and non-allergenic epitopes capable of inducing tumor-infiltrating lymphocytes by considering various epitope characteristics. AutoPepVax employs random forest classification and linear regression machine-learning-based models, which are trained with datasets derived from tumor samples. AutoPepVax, along with documentation on how to run the program, is freely available on GitHub. We used AutoPepVax to design a pan-cancer peptide vaccine targeting epidermal growth factor receptor (EGFR) missense mutations commonly found in lung adenocarcinoma (LUAD), colorectal adenocarcinoma (CRAD), glioblastoma multiforme (GBM), and head and neck squamous cell carcinoma (HNSCC). These mutations have been previously targeted in clinical trials for EGFR-specific peptide vaccines in GBM and LUAD, and they show promise but lack demonstrated clinical efficacy. Using AutoPepVax, our analysis of 96 EGFR mutations identified 368 potential MHC-I-restricted epitope-HLA pairs from 49,113 candidates and 430 potential MHC-II-restricted pairs from 168,669 candidates. Notably, 19 mutations presented viable epitopes for MHC I and II restrictions. To evaluate the potential impact of a pan-cancer vaccine composed of these epitopes, we used our program, PCOptim, to curate a minimal list of epitopes with optimal population coverage. The world population coverage of our list ranged from 81.8% to 98.5% for MHC Class II and Class I epitopes, respectively. From our list of epitopes, we constructed 3D epitope-MHC models for six MHC-I-restricted and four MHC-II-restricted epitopes, demonstrating their epitope binding potential and interaction with T-cell receptors. AutoPepVax's comprehensive approach to in silico epitope selection addresses vaccine safety, efficacy, and broad applicability. Future studies aim to validate the AutoPepVax-designed vaccines with murine tumor models that harbor the studied mutations.

Colangitis biliar primaria: caracterización de una cohorte retrospectiva / Primary biliary cholangitis: characterization of a retrospective cohort

Introducción. La colangitis biliar primaria (CBP) es una enfermedad hepática crónica de origen autoinmune, caracterizada por inflamación y destrucción progresiva de las células epiteliales de los conductos biliares intralobulillares, que causa de manera secundaria colestasis, fibrosis, cirrosis e insuficiencia hepática. La historia natural de la enfermedad ha cambiado en los últimos años debido a la mejoría en los métodos diagnósticos y terapéuticos. Metodología. Estudio observacional descriptivo de cohorte retrospectivo, en el cual se efectuó la revisión y análisis de las historias clínicas de los pacientes mayores de 16 años con diagnóstico de CBP, atendidos en la Unidad de Hepatología y Trasplante Hepático del Hospital Pablo Tobón Uribe, entre los años 2013 a 2021, con el fin de obtener información sobre las características de esta patología a nivel local. Resultados. Se evaluó un total de 239 pacientes, con un promedio de edad de 61,6±12,31 años, el 97,07% fue del sexo femenino, con criterios serológicos como anticuerpos antimitocondriales (AMA) positivos en un 76,89%, el 66,95% de los pacientes presentaban alguna enfermedad autoinmune concomitante y el 31,60% tuvieron sobreposición con hepatitis autoinmune. La manifestación clínica más frecuente fue el prurito en un 61,92% de los pacientes, seguido por la astenia en un 51,88%. La presencia de hipertensión portal al diagnóstico fue del 29,29%. La colangitis no supurativa y la ductopenia en la biopsia de hígado se documentó en un 43,79% de los casos. El ácido ursodesoxicólico (UDCA) fue la terapia de primera línea en el 100% de los pacientes, se identificó refractariedad del 16,36% según criterios de París II y del 31,79% con los criterios de Toronto. La no respuesta al UDCA, se asoció de manera significativa con mayor mortalidad (p=0,039) y presencia de hepatocarcinoma (p=0,042). Conclusión. Se caracterizó la CBP en nuestra población. El diagnóstico serológico por AMA fue bajo, con altos requerimientos de biopsia hepática en el contexto de síndromes de sobreposición. Los signos de hipertensión portal al momento del diagnóstico fueron prevalentes. La refractariedad bioquímica a la terapiafue descrita en relación con mayor progresión de fibrosis, aumento de mortalidad y presencia de hepatocarcinoma.

ntroduction. Primary biliary cholangitis (PBC) is a chronic liver disease of autoimmune origin, characterized by inflammation and progressive destruction of the epithelial cells of the intralobular bile ducts, causing secondary cholestasis, fibrosis, cirrhosis, and liver failure. The natural history of the disease has changed in recent years due to the improvement in diagnostic and therapeutic methods. Methodology. Cross-sectional descriptive observational study, where the medical records of patients older than 16 years with a diagnosis of PBC, treated at the Hepatology and Liver Transplant Unit of the Pablo Tobón Uribe Hospital, between the years 2013 to 2021, were reviewed and analyzed in order to obtain information on the characteristics of this pathology at a local level. Results. A total of 239 patients were evaluated, with a mean age of 61.6±12.31 years, 97.07% were females, with serological criteria such as positive antimitochondrial antibodies (AMA) in 76.89%. Of all included patients, 66.95% had some concomitant autoimmune disease and 31.60% had an overlap with autoimmune hepatitis. The most frequent clinical manifestation was pruritus in 61.92% of the patients, followed by asthenia in 51.88%. The presence of portal hypertension at diagnosis was 29.29%. Non-suppurative cholangitis and ductopenia on liver biopsy were documented in 43.79% of the cases. Ursodeoxycholic acid (UDCA) was the first line therapy in 100% of patients, 16.36% were refractory to treatment according to the Paris II criteria and 31.79% according to the Toronto criteria. Non-response to UDCA was significantly associated with higher mortality (p=0.039) and presence of hepatocarcinoma (p=0.042). Conclusion. PBC was characterized in our population. Serological diagnosis by AMA was low, with high requirements for liver biopsy in the context of overlap syndromes. Signs of portal hypertension at diagnosis were prevalent. Biochemical refractoriness to therapy was described in relation to greater progression of fibrosis, increased mortality, and the presence of hepatocarcinoma.

Associations between weight-based teasing and disordered eating behaviors among youth.

Weight-based teasing (WBT) is commonly reported among youth and is associated with disinhibited and disordered eating. Specifically, youth who experience WBT may engage in disordered eating behaviors to cope with the resultant negative affect. Therefore, we examined associations between WBT and disordered eating behaviors among youth and assessed whether negative affect mediated these relationships. Two hundred one non-treatment seeking youth (8-17y) completed questionnaires assessing WBT, disinhibited eating, depression, and anxiety. Disordered eating and loss-of-control (LOC) eating were assessed via semi-structured interview. Analyses of covariance were conducted to examine relationships between WBT and eating-related variables, and bootstrapping mediation models were used to evaluate negative affect (a composite of depressive and anxiety symptoms) as a mediator of these associations. All models were adjusted for sex, race, age, and adiposity. Among 201 participants (13.1 ± 2.8y; 54.2% female; 30.3% Black; 32.8% with overweight/obesity), WBT was associated with emotional eating, eating in the absence of hunger, and disordered eating attitudes and behaviors (ps ≤ 0.02). These associations were all mediated by negative affect. WBT was also associated with a threefold greater likelihood of reporting a recent LOC eating episode (p = .049). Among boys and girls across weight strata, WBT was associated with multiple aspects of disordered eating and these relationships were mediated by negative affect. Longitudinal studies are needed to clarify the directionality of these associations and to identify subgroups of youth that may be particularly vulnerable to WBT and its sequelae.

EGFR and HER2 small molecules inhibitors as potential therapeutics in veterinary oncology / Inhibidores EGFR y HER2 como tratamientos potenciales en oncología veterinaria

SUMMARY EGFR and HER2 receptors are crucial signaling molecules tyrosine kinase involved in human cancer. Aberrant signaling is associated with a variety of cancers, frequently with poor prognosis. Currently, EGFR and HER2 receptors are being targeted by small molecules, which offer a huge benefit to those patients afflicted by aggressive forms of cancer, improving their prognosis. Both human and canine cancers share molecular, biological, histopathological, and clinical similarities, including EGFR and HER2 expression in some forms of cancer. However, despite the use of one tyrosine kinase inhibitor approved to treat canine mastocytoma, canine cancers overexpressed EGFR and HER2 do not yet have targeted therapy, leading to high morbidity and mortality. Targeting EGFR and HER2 receptors in canine cancers using comparative approaches in human cancer could lead to better outcomes.

RESUMEN El receptor de factor de crecimiento epidérmico (Epidermal growth factor receptor, EGFR) y el receptor 2 del factor de crecimiento epidérmico (HER2 epidermal growth factor receptor 2) son moléculas señalizadoras cruciales pertenecientes a la familia de proteínas tirosina quinasa involucradas en el cáncer en humanos. La señalización aberrante de dichos receptores se encuentra asociada con una variedad de tumores, frecuentemente asociados a mal pronóstico. Actualmente, EGFR y HER2 son tratados específicamente a través de pequeñas moléculas inhibidoras, las cuales ofrecen un gran beneficio a aquellos pacientes que padecen formas agresivas de cáncer, y de esta manera su pronóstico mejora. Tanto el cáncer en medicina humana como veterinaria comparte similitudes moleculares, biológicas, histopatológicas y clínicas, las cuales incluyen la expresión tanto de EGFR y HER2 en algunas formas de cáncer. Sin embrago, a pesar del uso de un inhibidor tirosina quinasa aprobado para el manejo del mastocitoma canino los tumores que se caracterizan por la sobre-expresión de EGFR y HER2 aún no cuentan con un inhibidor específico, lo cual conduce a alta morbilidad y mortalidad.

The association between alexithymia and eating behavior in children and adolescents.

OBJECTIVE: Alexithymia, or the difficulty identifying or describing one's own emotions, may be a risk factor for dysregulated eating and excess weight gain. However, the relationships between alexithymia and eating behaviors in community samples of non-clinical youth have not been well-characterized. We hypothesized that alexithymia would be positively associated with disordered and disinhibited eating in a community-based sample of boys and girls without an eating disorder. METHOD: Two hundred children (8-17 years old) across the weight spectrum completed an interview to assess loss of control (LOC) eating and eating-related psychopathology, a laboratory test meal designed to induce disinhibited eating, and questionnaires to assess alexithymia, eating in the absence of hunger, and emotional eating. Linear and logistic regressions were conducted to examine the relationship between alexithymia and eating variables, with age, sex, race, and fat mass as covariates. Test meal analyses also adjusted for lean mass. Given the overlap between alexithymia and depression, all models were repeated with depressive symptoms as an additional covariate. RESULTS: Alexithymia was associated with an increased likelihood of reporting LOC eating (p < .05). Moreover, alexithymia was positively associated with disordered eating attitudes, emotional eating, and eating in the absence of hunger (ps < .05). Greater alexithymia was associated with more carbohydrate and less fat intake at the test meal (ps < .05). After adjusting for depressive symptoms, alexithymia remained associated with eating in the absence of hunger and carbohydrate and fat intake (ps < .05). DISCUSSION: In healthy children, alexithymia is associated with some facets of eating behavior and food intake. If supported prospectively, these preliminary findings suggest alexithymia may be a modifiable risk factor to reduce disordered eating and excess weight gain in youth.

Associations of sleep patterns with metabolic syndrome indices, body composition, and energy intake in children and adolescents.

BACKGROUND: Self-reported short sleep duration is associated with greater risk for metabolic syndrome (MetS), obesity, and higher energy intake (EI). However, studies of these associations in children using objective methods are sparse. OBJECTIVES: The study aims to determine the associations for sleep patterns with MetS indices, body composition, and EI using objective measures in children. METHODS: Free-living sleep and physical activity were measured in 125 children (aged 8-17 years, BMI z = 0.57 ± 1.0, 55% female) using wrist-worn actigraphs for 14 nights. Blood pressure, fasting blood levels of lipids, insulin, glucose, waist circumference, and body composition (dual-energy X-ray absorptiometry [DXA]) were obtained during outpatient visits. EI was assessed during an ad libitum buffet meal. RESULTS: Later weekday and weekend bedtimes were associated with higher systolic blood pressure (Ps < 0.05). Sleep duration and bedtime were not significantly associated with other components of MetS, body composition, or EI. Short sleepers (duration less than 7 hours) consumed a greater percentage of carbohydrates than those with adequate (greater than or equal to 7 hours) sleep (P < 0.05). CONCLUSION: Indicators of sleep duration were variably associated with children's eating patterns and risk for chronic disease. Prospective data are needed to determine whether these indicators of sleep quality represent unique or shared risk factors for poor health outcomes.