Increased hepatic putrescine levels as a new potential factor related to the progression of metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver condition that often progresses to more advanced stages, such as metabolic dysfunction-associated steatohepatitis (MASH). MASH is characterized by inflammation and hepatocellular ballooning, in addition to hepatic steatosis. Despite the relatively high incidence of MASH in the population and its potential detrimental effects on human health, this liver disease is still not fully understood from a pathophysiological perspective. Deregulation of polyamine levels has been detected in various pathological conditions, including neurodegenerative diseases, inflammation, and cancer. However, the role of the polyamine pathway in chronic liver disorders such as MASLD has not been explored. In this study, we measured the expression of liver ornithine decarboxylase (ODC1), the rate-limiting enzyme responsible for the production of putrescine, and the hepatic levels of putrescine, in a preclinical model of MASH as well as in liver biopsies of patients with obesity undergoing bariatric surgery. Our findings reveal that expression of ODC1 and the levels of putrescine, but not spermidine nor spermine, are elevated in hepatic tissue of both diet-induced MASH mice and patients with biopsy-proven MASH compared with control mice and patients without MASH, respectively. Furthermore, we found that the levels of putrescine were positively associated with higher aspartate aminotransferase concentrations in serum and an increased SAF score (steatosis, activity, fibrosis). Additionally, in in vitro assays using human HepG2 cells, we demonstrate that elevated levels of putrescine exacerbate the cellular response to palmitic acid, leading to decreased cell viability and increased release of CK-18. Our results support an association between the expression of ODC1 and the progression of MASLD, which could have translational relevance in understanding the onset of this disease. © 2024 The Pathological Society of Great Britain and Ireland.

Structural mechanisms of autoinhibition and substrate recognition by the ubiquitin ligase HACE1.

Ubiquitin ligases (E3s) are pivotal specificity determinants in the ubiquitin system by selecting substrates and decorating them with distinct ubiquitin signals. However, structure determination of the underlying, specific E3-substrate complexes has proven challenging owing to their transient nature. In particular, it is incompletely understood how members of the catalytic cysteine-driven class of HECT-type ligases (HECTs) position substrate proteins for modification. Here, we report a cryogenic electron microscopy (cryo-EM) structure of the full-length human HECT HACE1, along with solution-based conformational analyses by small-angle X-ray scattering and hydrogen-deuterium exchange mass spectrometry. Structure-based functional analyses in vitro and in cells reveal that the activity of HACE1 is stringently regulated by dimerization-induced autoinhibition. The inhibition occurs at the first step of the catalytic cycle and is thus substrate-independent. We use mechanism-based chemical crosslinking to reconstitute a complex of activated, monomeric HACE1 with its major substrate, RAC1, determine its structure by cryo-EM and validate the binding mode by solution-based analyses. Our findings explain how HACE1 achieves selectivity in ubiquitinating the active, GTP-loaded state of RAC1 and establish a framework for interpreting mutational alterations of the HACE1-RAC1 interplay in disease. More broadly, this work illuminates central unexplored aspects in the architecture, conformational dynamics, regulation and specificity of full-length HECTs.

Non-alcoholic fatty liver disease and diabetes mellitus as growing aetiologies of hepatocellular carcinoma.

Obesity-related complications such as non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) are well-established risk factors for the development of hepatocellular carcinoma (HCC). This review provides insights into the molecular mechanisms that underlie the role of steatosis, hyperinsulinemia and hepatic inflammation in HCC development and progression. We focus on recent findings linking intracellular pathways and transcription factors that can trigger the reprogramming of hepatic cells. In addition, we highlight the role of enzymes in dysregulated metabolic activity and consequent dysfunctional signalling. Finally, we discuss the potential uses and challenges of novel therapeutic strategies to prevent and treat NAFLD/T2D-associated HCC.

New challenges in cholangiocarcinoma candidates for elective surgery: harnessing the microbiome dysbiosis.

BACKGROUND: The gut microbiota, composed by several species of microorganisms, works to preserve the liver-gut homeostasis and plays an important role during digestion and absorption of nutrients, and in the immune response of the host. In this review, we analyzed the influence of microbiota in patients with cholangiocarcinoma (CCA) who were candidates for elective surgery. METHODS: A literature review was conducted to identify papers that provided empiric evidence to support that the altered microbiota composition (dysbiosis) is related also to CCA development. RESULTS: Bacteria such as Helicobacter pylori, Helicobacter hepaticus, and Opisthorchis viverrini increase the risk of CCA. The most abundant genera were Enterococcus, Streptococcus, Bacteroides, Klebsiella, and Pyramidobacter in CCA's biliary microbiota. Additionally, levels of Bacteroides, Geobacillus, Meiothermus, and Anoxybacillus genera were significantly higher. An enrichment of Bifidobacteriaceae, Enterobacteriaceae, and Enterococcaceae families has also been observed in CCA tumor tissue. Microbiota is related to postoperative outcomes in abdominal surgery. The combination of caloric restriction diets in liver cancer or CCA increases the effect of the chemotherapy treatment. CONCLUSION: The correct use of nutrition for microbiota modulation according to each patient's needs could be a therapeutic tool in combination with elective surgery and chemotherapy to diminish side effects and improve prognosis. Further investigations are needed to fully understand the mechanisms by which they are related.

Physics-based tissue simulator to model multicellular systems: A study of liver regeneration and hepatocellular carcinoma recurrence.

We present a multiagent-based model that captures the interactions between different types of cells with their microenvironment, and enables the analysis of the emergent global behavior during tissue regeneration and tumor development. Using this model, we are able to reproduce the temporal dynamics of regular healthy cells and cancer cells, as well as the evolution of their three-dimensional spatial distributions. By tuning the system with the characteristics of the individual patients, our model reproduces a variety of spatial patterns of tissue regeneration and tumor growth, resembling those found in clinical imaging or biopsies. In order to calibrate and validate our model we study the process of liver regeneration after surgical hepatectomy in different degrees. In the clinical context, our model is able to predict the recurrence of a hepatocellular carcinoma after a 70% partial hepatectomy. The outcomes of our simulations are in agreement with experimental and clinical observations. By fitting the model parameters to specific patient factors, it might well become a useful platform for hypotheses testing in treatments protocols.

A Computational Investigation of In Vivo Cytosolic Protein Delivery for Cancer Therapy.

The ability to specifically block or degrade cytosolic targets using therapeutic proteins would bring tremendous therapeutic opportunities in cancer therapy. Over the last few years, significant progress has been made with respect to tissue targeting, cytosolic delivery, and catalytic inactivation of targets, placing this aim within reach. Here, we developed a mathematical model specifically built for the evaluation of approaches towards cytosolic protein delivery, involving all steps from systemic administration to translocation into the cytosol and target engagement. Focusing on solid cancer tissues, we utilized the model to investigate the effects of microvascular permeability, receptor affinity, the cellular density of targeted receptors, as well as the mode of activity (blocking/degradation) on therapeutic potential. Our analyses provide guidance for the rational optimization of protein design for enhanced activity and highlight the importance of tuning the receptor affinity as a function of receptor density as well as the receptor internalization rate. Furthermore, we provide quantitative insights into how enzymatic cargoes can enhance the distribution, extent, and duration of therapeutic activity, already at very low catalytic rates. Our results illustrate that with current protein engineering approaches, the goal of delivery of cytosolic delivery of proteins for therapeutic effects is well within reach.

Vitamin D and other environmental risk factors in Colombian patients with multiple sclerosis.

OBJECTIVE: The aim of this study was to explore the association between MS and vitamin D levels, as well as Epstein-Barr virus (EBV) seropositivity and smoking history in a Colombian population. METHODS: We conducted a cross-sectional study between 2017 and 2018. We measured vitamin D levels and EBV antibody titers and administered a questionnaire to assess dietary habits, smoking, second-hand smoking and duration of smoking, sunlight exposure, physical activity, and personal and family history in individuals with and without multiple sclerosis during adolescence. A multivariable logistic regression model was then performed to explore the association between vitamin D status and MS. RESULTS: A total of 87 individuals with MS (mean age 40.9 years; 65.52% females) and 87 without MS (mean age 55 years; 65.52% females) were included in the analysis. In the multivariable analysis, after controlling for supplementation vitamin D levels did not differ between both groups and no difference was found regarding tobacco smoke exposure. The proportion of individuals who tested positive for anti-EBV nuclear antigen was significantly higher in individuals with MS (95.4% vs 82.76%, p = 0.028) CONCLUSION: : We did not find a statistically significant association between MS and vitamin D levels while anti-EBV nuclear antigen titers behaved as previously described in the literature. This study provides new evidence of the association between MS and different risk factors in our country, reinforcing the hypothesis that the pathogenesis of MS is multifactorial. Further studies are needed to better define the association between environmental factors and the development of MS in low prevalence areas.

Entrustable Professional Activities: Una propuesta innovadora para la evaluación de competencias médicas / Entrustable professional activities: a new proposal for the evaluation of the medical competencies

Medical education migrated from a practice-based to a knowledge-based discipline after the publication of the Flexner Report. The emergence of competence-based medical education led to a greater standardization of teaching, allowing students to integrate knowledge, skills and attitudes for the execution of a given task. A challenge is the evaluation of learning. Complex evaluation systems and a consequent atomization that independently assesses different competence components. However, the evaluation carried out at the clinical practice sites allows assessing the overall level of learning. Supervisors observe students' performance and decide if the apprentice can execute a specific task independently. This decision is based upon the trust that the tutor places on the student. Consequently, Ten Cate (2005) proposed the term Entrustable Professional Activities (EPAs), as a framework for professional practice tasks or responsibilities that can be fully entrusted to students, when they demonstrate the competences that are necessary to execute such activity with an increasing level of autonomy.

Hemangioma gástrico neonatal. Reporte de un caso y revisión de la literatura / Neonatal gastric hemangioma. Literature review and a case report

Resumen Los hemangiomas son las neoplasias más comunes en la infancia; incluyen diferentes tipos según su histología, expresión proteica y curso clínico. Por lo general, aparecen en piel y tejidos blandos. Son lesiones raras a nivel intestinal, y más aún en un recién nacido; por ello, decidimos publicar un caso que ocurrió en nuestro hospital y el manejo que se le dio; revisamos la literatura.

Abstract The most common neoplastic lesions in the infancy are hemangiomas; they are classified according to their histology, proteic expression, and clinical presentation. They normally appear in the skin and soft tissue. They are very rare in the viscera, in the stomach, and in neonates they are even more unusual; this is the reason why we decided to review the literature and present this case.

Calidad de vida en pacientes chilenas sobrevivientes de cáncer de mama / Quality of life in Chilean breast cancer survivors

Background: Quality of Life (QOL) assessment may evaluate the impact of diseases and their treatment on the overall well-being of patients. Aim: To assess QOL in Chilean breast cancer survivors. Patients and Methods: Ninety one female breast cancer patients aged 60 ± 10 years, who finished their oncologic treatment at least a year prior to the assessment, who were disease free and in medical follow-up were included in the study. They completed the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 core questionnaire and the breast cancer module QLQ-BR23. Results: Forty eight percent of respondents were long term survivors (more than five years). Global QOL scores were high (73.6 ± 18.2), emotional scale had the lowest scores in QLQ-C30 functional scales (72.1). Symptoms with the highest scores were: Insomnia (= 21.2), pain (= 20.8), and fatigue (= 19.1). Body image, sexual function, and concern about the future were the most relevant problems. Body image was superior in patients with breast-conserving surgery (p = 0.008), and cognitive function was better in patients in early disease stage (p = 0.03) and in those with more than five years of survival (p = 0.04). Conclusions: Even when global QOL scores were high, some symptoms were prevalent. Awareness about these problems and symptoms should improve their diagnosis and treatment.

Usefulness of percutaneous elastography by acoustic radiation force impulse for the non-invasive diagnosis of chronic pancreatitis.

OBJECTIVE: To determine the accuracy of the acoustic radiation force impulse (ARFI) technique for the diagnosis of chronic pancreatitis. MATERIALS AND METHODS: We present an observational, single-center study that included patients with suspected chronic pancreatitis in the period between October 2012 and September 2015 who underwent endoscopic ultrasound (EUS) and were classified according to the standard and Rosemont criteria. The same group of patients was assessed by the ARFI technology using ACUSON S2000™ equipment with Virtual Touch™ Quantification software for the assessment of pancreatic stiffness by obtaining the shear wave velocity (SWV) in the head, body and tail of the pancreas. Data were analyzed using ANOVA and nonparametric correlation methods. Diagnostic accuracy was obtained by analyzing receiver operating characteristic (ROC) curve. RESULTS: A total of thirty-three patients were studied (45.5% women); mean age was 58.3 ± 11.8 years. Seventeen with a diagnosis of chronic pancreatitis and sixteen classified as normal according to standard criteria. A significant difference was detected between the means of SWV in pancreatic body of patients without (SWV: 1.27 m/s) and with chronic pancreatitis (SWV 1.57 m/s), p = 0.037. The area under the ROC curve was 71.3% (95% CI 0.532-0.895) and the accuracy of ARFI for diagnosing chronic pancreatitis was 69.7% for a SWV of 1.4 m/s in the pancreatic body. The SWV means in head (r = 0.421, p < 0.05) and body (r = 0.455, p < 0.05) of the pancreas showed a significant correlation with the number of EUS criteria for chronic pancreatitis. CONCLUSION: Quantification of pancreatic stiffness with ARFI elastography technique has proven to be useful for the non-invasive diagnosis of chronic pancreatitis.

EFECTOS DEL ENTRENAMIENTO EN ESPACIOS REDUCIDOS A TRAVÉS DE MODELAMIENTO EN RUGBISTAS / EFFECTS OF TRAINING IN REDUCED SPACES THROUGH MODELING IN RUGBY PLAYERS / EFEITOS DO TREINAMENTO EM ESPAÇOS REDUZIDOS ATRAVÉS DE MODELAMIENTO EM RUGBISTAS

El estudio midió los efectos del entrenamiento a jugadores de rugby con espacios reducidos. Se realizó con 27 jugadores pertenecientes a dos equipos de la Liga Antioqueña de Rugby, con edad de 22,4 (±3,66) años, peso de 78,76 (±11,93) kg. y talla de 176,06 (±5,97) cm. Para medir los efectos de la planificación con espacios reducidos se utilizó una fase de un programa modelador (Agudelo, 2012), lo que constituyó la variable independiente. Para verificar los posibles efectos, como pre pruebas y pos pruebas, se utilizaron los 30 m para velocidad (aceleración), los 3000 m para resistencia, y la adaptación de un test de pase realizado en Australia, lo que permitió verificar, a través de estadísticos no paramétricos seleccionados, qué tan significativo fueron los cambios. Verificados los resultados, se puede afirmar que el juego con espacios reducidos, aparentemente propicia un excelente medio para entrenar de forma integrada, ya que facilita el incremento del componente condicional, especialmente en cuanto a la resistencia, y mantiene la velocidad, a la vez que permite el desarrollo del componente técnico.

The study measured the effects of training on rugby players with reduced spaces. It was made with 27 players belonging to two teams of the Antioquia Rugby League, with age of 22.4 (± 3.66) years, weight of 78.76 (± 11.93) kg. and size of 176.06 (± 5.97) cm. To measure the effects of planning with reduced spaces, a phase of a modeling program was used (Agudelo, 2012), which constituted the independent variable. To verify the possible effects, such as pre-tests and post-tests, were used the 30 m for speed (acceleration), the 3000 m for resistance, and the adaptation of a pass test carried out in Australia, which allowed us to verify, through selected nonparametric statistics, how significant the changes were. Once the results have been verified, it can be affirmed that the game in reduced spaces, apparently propitiates an excellent means to train in an integrated manner, since it facilitates the increase of the conditional component, especially in terms of resistance, and maintains speed, while at the same time allows the development of the technical component.

O estudo mede os efeitos de treinar com espaços reduzidos a jogadores de rugby, realizou-se em 27 jogadores pertencentes a duas equipes, de une-a Antioqueña de Rugby. Tinham uma idade de 22,4 (±3,66) anos, um peso de 78,76 (±11,93) Kg. e uma talha de 176,06 (±5,97) cm. Para medir os efeitos do planejamento com espaços reduzidos utilizou-se uma fase de um programa modelador (Agudelo, 2012) o que constituiu a variável independente, utilizaram-se como pré-teste e pós-testes para verificar "possíveis efeitos" 30 m. Para a velocidade (aceleração), os 3000 m. Para a resistência e uma adaptação de um teste de passe realizado em Austrália, o que permitiu verificar através de estatísticos não paramétricos selecionados que tão significativas são as mudanças. Verificados os resultados pode ser afirmado que o jogo em espaços reduzidos aparentemente propicia uma excelente maneira para treinar de forma integrada já que facilita o incremento da parte condicional, especialmente quanto à resistência e mantém a velocidade, enquanto permite o desenvolvimento do técnico.

[Quality of life in Chilean breast cancer survivors]. / Calidad de vida en pacientes chilenas sobrevivientes de cáncer de mama.

BACKGROUND: Quality of Life (QOL) assessment may evaluate the impact of diseases and their treatment on the overall well-being of patients. AIM: To assess QOL in Chilean breast cancer survivors. PATIENTS AND METHODS: Ninety one female breast cancer patients aged 60 ± 10 years, who finished their oncologic treatment at least a year prior to the assessment, who were disease free and in medical follow-up were included in the study. They completed the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 core questionnaire and the breast cancer module QLQ-BR23. RESULTS: Forty eight percent of respondents were long term survivors (more than five years). Global QOL scores were high (73.6 ± 18.2), emotional scale had the lowest scores in QLQ-C30 functional scales (72.1). Symptoms with the highest scores were: Insomnia (= 21.2), pain (= 20.8), and fatigue (= 19.1). Body image, sexual function, and concern about the future were the most relevant problems. Body image was superior in patients with breast-conserving surgery (p = 0.008), and cognitive function was better in patients in early disease stage (p = 0.03) and in those with more than five years of survival (p = 0.04). CONCLUSIONS: Even when global QOL scores were high, some symptoms were prevalent. Awareness about these problems and symptoms should improve their diagnosis and treatment.

[Validation of BR23 questionnaire for the assessment of quality of life of breast cancer patients in Chile]. / Calidad de vida en cáncer de mama: validación del cuestionario BR23 en Chile.

BACKGROUND: Quality of Life assessment in oncologic patients evaluates the impact and sequels of the disease ana the adverse effects of available treatments. AIM: To validate in Chile the breast cancer specific-questionnaire (BR23) developed by the European Organization for Research and Treatment of Cancer (EORTC). PATIENTS AND METHODS: After performing a linguistic validation of the BR23 according to EORTC instructions, its psychometric properties were tested in 103 patients with breast cancer whose ages ranged from 34 to 83 years. Internal consistency of the scales was assessed using the Cronbach's alpha coefficient. The test-retest correlations of each scale (n = 83) were evaluated. The correlation of BR23 scales with SF36 version 2 and C30 version 3.0 scales was also assessed. The sensitivity and specificity of the instrument were analyzed using receiver operating characteristic curves (ROC). RESULTS: Alpha values showed acceptable levels of internal consistency, ranging between 0.702 and 0.917 in all scales of BR23. The statistical analysis revealed significant test-retest correlations in most scales of BR23. The correlations between BR23 and similar domains of C30 and SF36 questionnaires were also significant. The BR23 questionnaire demonstrated satisfactory levels of sensitivity and specificity when compared with the SF-36 scale. CONCLUSIONS: The BR23 questionnaire adapted for use in Chile is linguistically appropriate and psychometrically valid.

Calidad de vida en cáncer de mama: validación del cuestionario BR23 en Chile / Validation of BR23 questionnaire for the assessment of quality of life of breast cancer patients in Chile

Background: Quality of Life assessment in oncologic patients evaluates the impact ana sequels of the disease ana the adverse effects of available treatments. Aim: To validate in Chile the breast cáncer specific-questionnaire (BR23) developed by the European Organization for Research and Treatment of Cancer (EORTC). Patients and Methods: After performing a linguistic validation of the BR23 according to EORTC instructions, its psychometric properties were tested in 103 patients with breast cancer whose ages ranged from 34 to 83 years. Infernal consistency ofthe scales was assessed using the Cronbach's alpha coefficient. The test-retest correlations of each scale (n = 83) were evaluated. The correlation ofBR23 scales with SF36 version 2 and C30 version 3.0 scales was also assessed. The sensitivity and specificity of the instrument were analyzed using receiver operating characteristic curves (ROC). Results: Alpha values showed acceptable levels of internal consistency, ranging between 0.702 and 0.917 in all scales of BR23. The statistical analysis revealed significant test-retest correlations in most scales ofBR23. The correlations between BR23 and similar domains of C30 and SF36 questionnaires were also significant. The BR23 questionnaire demonstrated satisfactory levels of sensitivity and specificity when compared with the SF-36 scale. Conclusions: The BR23 questionnaire adapted for use in Chile is linguistically appropriate and psychometrically valid.

Cirugía de reducción mamaria en pacientes obesos masculinos / Surgical breast reduction in male obese patients

La intención de este trabajo es mostrar el protocolo que utilizamos en nuestra unidad para la selección de pacientes y elección de la técnica quirúrgica apropiada de reducción mamaria en hombres obesos masculinos, que ofrezca los mejores resultados postoperatorios. Para eso se estudian el Indice de Masa Corporal Total (Body Mass Index-BMI) (1), los grados de Obesidad Mórbida (2), la medición de la ptosis del complejo aréola-pezón (NAC) (3,4) y la revisión de las técnicas clásicas (5), así como de los criterios de inclusión o eclusión de las mismas (6)

The aim of the present report was to show the protocol used in our Unit for the selection of patients suitables for breast reduction and to choice the appropriate surgical technique in obese male patients that offers the best postoperative results. For that, we studied the Total. Corporal Mass Index (Body Mass Index-BMI) (1), the degrees of Morbid Obesity (2), measurement of ptosis, the complex areola-nipple (NAC) (3,4), with a revision of the classical techniques (5), the same as the criteria for inclusion or exclusion (6)

Reconstrucción auricular con expansión tisular / Auricular reconstruction with tissular expansion

Existe una multitud de técnicas quirúrgicas para la corrección de orejas micróticas. Sin embargo, uno de los factores que regula la calidad de los mismos son las condiciones iniciales en el área y la habilidad quirúrgica para tallar el marco cartilaginoso. En las técnicas convencionales, las primeras etapas de reconstrucción sólo brindan dos dimensiones lo que siempre implica un tiempo quirúrgico posterior para la proyección del marco, que conlleva mayor cantidad de cicatrices totales, de tiempo quirúrgico y de cirugías, con pérdida de sensibilidad en el área retroauricular. Se presenta la técnica clásica de Tanzer en 1959 posteriormente modificada por Brent en 1980, brinda características únicas, ya que el marco en sí tiene altura, profundidad y anchura determinados, así como cierto grado de movimiento y proyección de la oreja neoformada desde un inicio, dando una apariencia en tres dimensiones y recrea el surco aurículo-cefálico sin necesidad de otro tiempo quirúrgico, con un resultado estético adecuado.

There is a great number of surgical techniques for microtic ear correction. However, one factor that regulates the quality of these is the initial conditions in the area and surgical skill to carve the cartilage frame-work. In conventional techniques, the early stages of reconstruction only provide two dimensional which always involves a posterior surgical time of surgery, with loss of sensation in the retroauricular area. The technique presented is the classic technique of Tanzer in 1959 and subsequently amended by Brent in 1980, offers unique features such as the frame itself has height, depth and width determined and a degree of movement and projection of the newly formed ear from the beginning, giving a three dimensional appearance and recreates the atrium-ventricular groove head once without surgery, with an adequate cosmetic result.