Identification of PRMT5 as a therapeutic target in cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is a very difficult-to-treat cancer. Chemotherapies are little effective and response to immune checkpoint inhibitors is limited. Therefore, new therapeutic strategies need to be identified. OBJECTIVE: We characterised the enzyme protein arginine-methyltransferase 5 (PRMT5) as a novel therapeutic target in CCA. DESIGN: We evaluated the expression of PRMT5, its functional partner MEP50 and methylthioadenosine phosphorylase (MTAP)-an enzyme that modulates the sensitivity of PRMT5 to pharmacological inhibitors-in human CCA tissues. PRMT5-targeting drugs, currently tested in clinical trials for other malignancies, were assessed in human CCA cell lines and organoids, as well as in two immunocompetent CCA mouse models. Transcriptomic, proteomic and functional analyses were performed to explore the underlying antitumoural mechanisms. RESULTS: PRMT5 and MEP50 proteins were correlatively overexpressed in most CCA tissues. MTAP was absent in 25% of intrahepatic CCA. PRMT5-targeting drugs markedly inhibited CCA cell proliferation, synergising with cisplatin and gemcitabine and hindered the growth of cholangiocarcinoma organoids. PRMT5 inhibition blunted the expression of oncogenic genes involved in chromatin remodelling and DNA repair, consistently inducing the formation of RNA loops and promoting DNA damage. Treatment with PRMT5-targeting drugs significantly restrained the growth of experimental CCA without adverse effects and concomitantly induced the recruitment of CD4 and CD8 T cells to shrinking tumourous lesions. CONCLUSION: PRMT5 and MEP50 are frequently upregulated in human CCA, and PRMT5-targeting drugs have significant antitumoural efficacy in clinically relevant CCA models. Our findings support the evaluation of PRMT5 inhibitors in clinical trials, including their combination with cytotoxic and immune therapies.

Conocimiento de la Comprensión de los Estudiantes sobre la Anatomía Macroscópica Humana / Knowledge of Students' Understanding of Human Gross Anatomy

El propósito de esta investigación fue comprender las dificultades y necesidades para el aprendizaje de las ideas principales de la Anatomía Macroscópica Humana AMH. Se investigó un grupo de 90 estudiantes de segundo semestre del programa académico de Medicina y Cirugía de una Universidad pública, quienes se encontraban cursando la asignatura de Anatomía Macroscópica Humana I, para ello se tuvo en cuenta el modelo del conocimiento pedagógico del contenido PCK que incluye el conocimiento de los estudiantes, de su comprensión de la AMH, se realizó una observación participante de las clases teóricas y prácticas durante 16 semanas, llevando a cabo los registros de la observación en diario de campo y se obtuvo material audiovisual. Posteriormente se elaboró un índice analítico, se transcribió la información, todos los documentos fueron analizados por medio del software para análisis ATLAS.ti. Se encontraron aspectos de la enseñanza que dificultan el aprendizaje, como son la metodología de enseñanza, la gran cantidad de contenido abordado en la asignatura, la dificultad en la comprensión de las descripciones y complejidad de la ubicación espacial de las piezas anatómicas, la dificultad para encontrar una metodología de estudio apropiada y la falta de concentración durante las clases. El comprender la complejidad del proceso de aprendizaje puede favorecer la planeación y desarrollo de la enseñanza y la evaluación.

SUMMARY: The purpose of this research was to understand the difficulties and needs for learning the main ideas of Human Macroscopic Anatomy AMH. A group of 90 students from the second semester of the academic program of Medicine and Surgery of a public University were investigated, who were studying the subject of Human Macroscopic Anatomy I, for this the model of pedagogical knowledge of the PCK content that includes the knowledge of the students, their understanding of the AMH, a participant observation of the theoretical and practical classes was carried out for 16 weeks, keeping records of the observation in a field diary, and audiovisual material was obtained. Subsequently, an analytical index was prepared, the information was transcribed, all documents were analyzed using the ATLAS.ti analysis software. Aspects of teaching that hinder learning were found, such as the teaching methodology, the great amount of content addressed in the subject, the difficulty in understanding the descriptions and complexity of the spatial location of the anatomical pieces, the difficulty in finding an appropriate study methodology and the lack of concentration during classes. Understanding the complexity of the learning process can favor the planning and development of teaching and assessment.

High and very high risk of osteoporotic fracture in Colombia, 2003-2022: identifying diagnostic and treatment gaps.

This study examined the clinical characteristics and refracture rates of Colombian patients with high- and very high-risk osteoporosis. This reveals osteoporosis diagnoses and treatment gaps. Only 5.3% of the patients were diagnosed with osteoporosis at discharge and 70.5% had refractures. This finding underscores the need for national policies to enhance osteoporosis prevention and treatment. PURPOSE: This study aimed to assess the clinical features and refracture rates among patients with high- and very-high-risk osteoporosis in Colombia, highlighting diagnostic and treatment gaps. METHODS: A retrospective observational study was conducted using the medical records of patients aged ≥ 50 years who experienced fragility fractures between 2003 and 2022. Clinical and demographic characteristics at the time of the initial fracture were analyzed, as well as the subsequent imminent risk (refracture rate) and the diagnosis and treatment gap. RESULTS: 303.982 fragility fractures occurred, and only 5.3% of patients were diagnosed with osteoporosis upon discharge. The most prevalent index fractures were forearm, vertebral, rib, and hip. Only 17.8% of the cohort had a matched osteoporosis diagnosis, indicating a low healthcare capture. Among the diagnosed patients, 10.08% were classified as high- and very high-risk of fracture, predominantly women with a mean age of 73 years. Comorbidities included diabetes, Sjögren's syndrome, and heart failure. The prevalence of osteoporosis has increased significantly from 2004 to 2022, possibly due to improved detection methods, an aging population, or a combination of both. Despite this increase, treatment delay was evident. Refractures affected 70.5% of the patients, with forearm, hip, humerus, and vertebral fractures being the most common, with a mean time of refracture of 7 months. CONCLUSION: Significant delays were observed in the diagnosis and treatment of fragility fractures. Colombia's government and health system must address osteoporosis by implementing national policies that prioritize osteoporosis and fragility fracture prevention and reduce delays in diagnosis and treatment.

Habilidades sociales en estudiantes, adquiridas mediante indagación científica y gestión por procesos para la salud, con evaluación en línea

Fundamento: el desarrollo de habilidades sociales adquiridas mediante indagación científica en procesos de gestión para la salud por parte de los estudiantes que se desempeñan como docentes de Educación Física, así como su evaluación en línea son aspectos fundamentales, en la formación integral del personal, la mejora de la gestión por procesos y en la imagen corporativa de la institución. Objetivo: evaluar el estado de las actividades físicas para la formación de docentes de la entidad educativa. Métodos: se realizó una investigación no experimental con un diseño transeccional. Se efectuó un diagnóstico basado en la observación y la recogida de datos mediante la encuesta. La muestra estuvo constituida por el grupo de alumnos que se desempeñan como docentes. Se evaluaron dos variables en una de las cuatro dimensiones de la imagen corporativa. Resultados: la institución educativa carece de una imagen corporativa sólida, sin promoción de competencias digitales y habilidades sociales de los docentes. El 76 % de los encuestados calificó las habilidades sociales para el aprendizaje en la dimensión servicios ofrecidos al usuario con un nivel medio, el 14 % bajo y el 10 % alto. El 55 % calificó la gestión por procesos para la salud del usuario en un nivel medio, el 8 % bajo y el 10 % alto. La mayoría no percibió que la institución ofreciera variedad de servicios. Conclusiones: existe la necesidad de desarrollar las habilidades sociales adquiridas como una herramienta poderosa para ayudar a los estudiantes a gestionar sus necesidades y el cuidado de la salud.

Foundation: the development of social skills acquired through scientific inquiry in health management processes by students who work as physical education teachers, as well as their online evaluation are fundamental aspects, both in the comprehensive training of staff, the improvement of process management, and the corporate image of the institution. Objective: evaluate the state of physical activities for the training of teachers of the educational entity. Methods: the research was non-experimental with a transectional design. A diagnosis was made based on observation and data collection through the survey. The sample was the group of students who work as teachers. Two variables were evaluated in one of the four dimensions of corporate image. Results: the educational institution lacks a solid corporate image, without promoting digital competencies and social skills of teachers. 76 % of those surveyed rated the social skills for learning in the services offered to the user dimension with a medium level, 14 % low and 10 % high. 55 % rated process management for user health at a medium level, 8 % low and 10 % high. The majority did not perceive that the institution offered a variety of services. Conclusions: it's necessary to develop acquired social skills as a powerful tool to help students manage their needs and health care.

Characterization of potential spermatogonia biomarker genes in the European eel (Anguilla anguilla).

Identification of specific molecular markers for spermatogonial stem cells in teleost is crucial for enhancing the efficacy of reproductive biotechnologies in aquaculture, such as transplantation and surrogate production in fishes. Since it is not yet possible to distinguish spermatogonial stem cells of European eel (Anguilla anguilla) using specific molecular markers, we isolated spermatogonial cells from immature European eels to find these potential markers. We attempted this by studying three candidate genes: vasa, nanos2, and dnd1. Two vasa (vasa1 and vasa2) genes, nanos2, and dnd1 were identified, characterized, and studied in the muscle, testis, and isolated spermatogonia. Our results showed that vasa1 and vasa2 had the highest levels of expression when measured by qPCR. In situ hybridization and immunochemistry assays showed that the four genes were localized explicitly in type A spermatogonia. However, vasa1 and vasa2 exhibited stronger signals in the immature testicular tissue than the other two potential markers. According to this, vasa1 and vasa2 were found to be the most effective markers for spermatogonial cells in the European eel.

ACE inhibitors and their interaction with systems and molecules involved in metabolism.

The main function of the renin-angiotensin-aldosterone system (RAAS) is the regulation of blood pressure; therefore, researchers have focused on its study to treat cardiovascular and renal diseases. One of the most widely used treatments derived from the study of RAAS, is the use of angiotensin-converting enzyme inhibitors (ACEi). Since it was discovered, the main target of ACEi has been the cardiovascular and renal systems. However, being the RAAS expressed locally in several specialized tissues and cells such as pneumocytes, hepatocytes, spleenocytes, enterocytes, adipocytes, and neurons the effect of inhibitors has expanded, because it is expected that RAAS has a role in the specific function of those cells. Many chronic degenerative diseases compromise the correct function of those organs, and in most of them, the RAAS is overactivated. Therefore, the use of ACEi must exert a benefit on an impaired system. Accordingly, the objective of this review is to present a brief overview of the cardiovascular and renal actions of ACEi and its effects in organs that are not the classic targets of ACEi that carry on glucose and lipid metabolism.

Discovery and Preclinical Pharmacology of NX-2127, an Orally Bioavailable Degrader of Bruton's Tyrosine Kinase with Immunomodulatory Activity for the Treatment of Patients with B Cell Malignancies.

Bruton's tyrosine kinase (BTK), a member of the TEC family of kinases, is an essential effector of B-cell receptor (BCR) signaling. Chronic activation of BTK-mediated BCR signaling is a hallmark of many hematological malignancies, which makes it an attractive therapeutic target. Pharmacological inhibition of BTK enzymatic function is now a well-proven strategy for the treatment of patients with these malignancies. We report the discovery and characterization of NX-2127, a BTK degrader with concomitant immunomodulatory activity. By design, NX-2127 mediates the degradation of transcription factors IKZF1 and IKZF3 through molecular glue interactions with the cereblon E3 ubiquitin ligase complex. NX-2127 degrades common BTK resistance mutants, including BTKC481S. NX-2127 is orally bioavailable, exhibits in vivo degradation across species, and demonstrates efficacy in preclinical oncology models. NX-2127 has advanced into first-in-human clinical trials and achieves deep and sustained degradation of BTK following daily oral dosing at 100 mg.

Effect of seawater temperature and pH on the sperm motility of the European eel.

The current climate change situation could bring critical effects for marine species, especially those already considered endangered. Although some species can adapt fast to the environmental changes, it is necessary to get into the worst scenario and develop tools to anticipatedly assess the physiological effects of such environmental change. With this purpose, our study aims to determine the effect of a range of seawater temperatures and pHs on sperm motility in the European eel (Anguilla anguilla). Low seawater pH (6.5-7.4) decreased the eel sperm motility in comparison to the control (pH = 8.2). We also studied the combined effect of the pH of the artificial seminal plasma (the plasma where the sperm cells are suspended) with the pH of Artificial Sea Water (ASW, pH 7.8 or and 8.2). We did not find statistical differences in sperm motility and kinetic parameters caused by the artificial seminal plasma pH. However, seawater pH induced significantly higher values of total sperm motility, and the percentage of fast spermatozoa with a pH of 8.2 in comparison with a pH of 7.8. In contrast, the seawater temperature did not affect sperm motility parameters or sperm longevity. To study the effect of the interaction between seawater temperature and pH on sperm motility, two temperatures: 4 and 24 °C, and two pHs 7.8 and 8.2, were tested. There were significant differences between temperature and pH in several kinetic parameters and, in general, the lowest values were observed in the samples activated at low temperature and low pH (4 °C, pH 7.8). This work suggest that eel sperm motility and kinetics will not be affected by the expected changes in pH or temperature due to the climate change.

Fontan surgery failure: risk factors and experience in a Colombian reference centre.

BACKGROUND: The Fontan procedure is considered one of the most remarkable achievements in paediatric cardiology and cardiac surgery. Its final anatomical objective is a venous return through the superior and inferior vena cava. The complications inherent to this procedure and subsequent failure are its limitations. OBJECTIVE: To describe the clinical and haemodynamic characteristics of patients with Fontan failure and define the risk factors associated with it, with its short- and long-term outcomes during a 21-year observation period. METHODS: This is a retrospective follow-up study in which 15 patients diagnosed with Fontan failure in the single-ventricle programme of a high-complexity hospital in Medellín, Colombia, between 2001 and 2022 were included. RESULTS: One hundred and eight patients were identified in whom the Fontan procedure was performed, and 17 met the failure criteria. 82.4% were men, with a median age of 4.3 years. Ebstein's anomaly was the most common diagnosis, 29.4%. All patients underwent Fontan with an extracardiac tube following the procedure. According to the type of failure, 58.8% of patients presented protein-losing enteropathy and 17.6% plastic bronchitis. During follow-up, 5.9% of patients died. CONCLUSION: Fontan surgery in our centre is an option for patients with univentricular physiology. The correct selection of the patient is essential to mitigate failure risks.

Presence of human papillomavirus in the buccal mucosa of blood donors / Presencia del virus del papiloma humano en la mucosa oral de donantes de sangre

Objective To determine the presence of human papillomavirus (HPV) in the oral mucosa of blood donors (BD) and risk factors associated with HPV and oral cancer. Materials and methods Prospective cross-sectional study, population matched to BD from the National Cancer Institute, Mexico for HPV identification in oral cytological samples using the CLART® Human Papillomavirus 2 Kit (35 genotypes) and risk factors. Results Of 352 BD with signed informed consent, 285 were selected by simple randomization. The prevalence of oral HPV was 17.5% (95% CI 13–21.9%), the genotype was identified in 13 cases, with a total of 16 genotypes (10 high-risk), the most common being 16 and 84. Five cases had multiple infections, three with at least one high-risk type. Associations were found for marital status (OR 3.3) and educational level (OR-1.9). Conclusions The percentage of HPV-positive cases in blood donors with no risk practices was similar to that found in Spanish-speaking population studies in which at least one risk practice was described. The presence of other genotypes with high oncogenic risk and multitype infection, described as a marker of persistence of HPV infection, is highlighted (AU)

Objetivo Identificar la presencia del virus del papiloma humano (VPH) en la mucosa oral de donantes de sangre (DS), así como los factores de riesgo relacionados con el VPH y el cáncer oral. Materiales y métodos Estudio transversal prospectivo. La población correspondió a los DS del Instituto Nacional de Cancerología, México, para la identificación de VPH en muestras citológicas orales con el kit CLART® Human Papillomavirus 2 (35 genotipos) y factores de riesgo. Resultados De 352 DS con firma de consentimiento informado, se seleccionaron 285 por aleatorización simple. La prevalencia de VPH oral fue del 17,5% (IC 95%: 13-21,9%); en 13 casos se identificó el genotipo, con un total de 16 genotipos (10 de alto riesgo), los más frecuentes el 16 y el 84. Cinco casos presentaron infección multitipo, 3 con al menos un tipo de alto riesgo. Las asociaciones encontradas fueron para el estado civil (OR 3,3) y el nivel de estudios (OR 1,9). Conclusiones El porcentaje de casos positivos para VPH en DS sin prácticas de riesgo fue similar a los hallazgos en estudios de población hispanohablante en los que se ha descrito al menos una práctica de riesgo. Se destaca la presencia de otros genotipos con alto riesgo oncogénico y la infección multitipo descrita como marcador de persistencia de la infección por VPH (AU)

Acid Sphingomyelinase Deficiency Type B Patient-Derived Liver Organoids Reveals Altered Lysosomal Gene Expression and Lipid Homeostasis.

Acid sphingomyelinase deficiency (ASMD) or Niemann-Pick disease type A (NPA), type B (NPB) and type A/B (NPA/B), is a rare lysosomal storage disease characterized by progressive accumulation of sphingomyelin (SM) in the liver, lungs, bone marrow and, in severe cases, neurons. A disease model was established by generating liver organoids from a NPB patient carrying the p.Arg610del variant in the SMPD1 gene. Liver organoids were characterized by transcriptomic and lipidomic analysis. We observed altered lipid homeostasis in the patient-derived organoids showing the predictable increase in sphingomyelin (SM), together with cholesterol esters (CE) and triacylglycerides (TAG), and a reduction in phosphatidylcholine (PC) and cardiolipins (CL). Analysis of lysosomal gene expression pointed to 24 downregulated genes, including SMPD1, and 26 upregulated genes that reflect the lysosomal stress typical of the disease. Altered genes revealed reduced expression of enzymes that could be involved in the accumulation in the hepatocytes of sphyngoglycolipids and glycoproteins, as well as upregulated genes coding for different glycosidases and cathepsins. Lipidic and transcriptome changes support the use of hepatic organoids as ideal models for ASMD investigation.

Quantitative Lipid Profiling Reveals Major Differences between Liver Organoids with Normal Pi*M and Deficient Pi*Z Variants of Alpha-1-antitrypsin.

Different mutations in the SERPINA1 gene result in alpha-1 antitrypsin (AAT) deficiency and in an increased risk for the development of liver diseases. More than 90% of severe deficiency patients are homozygous for Z (Glu342Lys) mutation. This mutation causes Z-AAT polymerization and intrahepatic accumulation which can result in hepatic alterations leading to steatosis, fibrosis, cirrhosis, and/or hepatocarcinoma. We aimed to investigate lipid status in hepatocytes carrying Z and normal M alleles of the SERPINA1 gene. Hepatic organoids were developed to investigate lipid alterations. Lipid accumulation in HepG2 cells overexpressing Z-AAT, as well as in patient-derived hepatic organoids from Pi*MZ and Pi*ZZ individuals, was evaluated by Oil-Red staining in comparison to HepG2 cells expressing M-AAT and liver organoids from Pi*MM controls. Furthermore, mass spectrometry-based lipidomics analysis and transcriptomic profiling were assessed in Pi*MZ and Pi*ZZ organoids. HepG2 cells expressing Z-AAT and liver organoids from Pi*MZ and Pi*ZZ patients showed intracellular accumulation of AAT and high numbers of lipid droplets. These latter paralleled with augmented intrahepatic lipids, and in particular altered proportion of triglycerides, cholesterol esters, and cardiolipins. According to transcriptomic analysis, Pi*ZZ organoids possess many alterations in genes and cellular processes of lipid metabolism with a specific impact on the endoplasmic reticulum, mitochondria, and peroxisome dysfunction. Our data reveal a relationship between intrahepatic accumulation of Z-AAT and alterations in lipid homeostasis, which implies that liver organoids provide an excellent model to study liver diseases related to the mutation of the SERPINA1 gene.

Cell wall-related genes and lignin accumulation contribute to the root resistance in different maize (Zea mays L.) genotypes to Fusarium verticillioides (Sacc.) Nirenberg infection.

Introduction: The fungal pathogen Fusarium verticillioides (Sacc.) Nirenberg (Fv) causes considerable agricultural and economic losses and is harmful to animal and human health. Fv can infect maize throughout its long agricultural cycle, and root infection drastically affects maize growth and yield. Methods: The root cell wall is the first physical and defensive barrier against soilborne pathogens such as Fv. This study compares two contrasting genotypes of maize (Zea mays L.) roots that are resistant (RES) or susceptible (SUS) to Fv infection by using transcriptomics, fluorescence, scanning electron microscopy analyses, and ddPCR. Results: Seeds were infected with a highly virulent local Fv isolate. Although Fv infected both the RES and SUS genotypes, infection occurred faster in SUS, notably showing a difference of three to four days. In addition, root infections in RES were less severe in comparison to SUS infections. Comparative transcriptomics (rate +Fv/control) were performed seven days after inoculation (DAI). The analysis of differentially expressed genes (DEGs) in each rate revealed 733 and 559 unique transcripts that were significantly (P ≤0.05) up and downregulated in RES (+Fv/C) and SUS (+Fv/C), respectively. KEGG pathway enrichment analysis identified coumarin and furanocoumarin biosynthesis, phenylpropanoid biosynthesis, and plant-pathogen interaction pathways as being highly enriched with specific genes involved in cell wall modifications in the RES genotype, whereas the SUS genotype mainly displayed a repressed plant-pathogen interaction pathway and did not show any enriched cell wall genes. In particular, cell wall-related gene expression showed a higher level in RES than in SUS under Fv infection. Analysis of DEG abundance made it possible to identify transcripts involved in response to abiotic and biotic stresses, biosynthetic and catabolic processes, pectin biosynthesis, phenylpropanoid metabolism, and cell wall biosynthesis and organization. Root histological analysis in RES showed an increase in lignified cells in the sclerenchymatous hypodermis zone during Fv infection. Discussion: These differences in the cell wall and lignification could be related to an enhanced degradation of the root hairs and the epidermis cell wall in SUS, as was visualized by SEM. These findings reveal that components of the root cell wall are important against Fv infection and possibly other soilborne phytopathogens.

NAFLD and AATD Are Two Diseases with Unbalanced Lipid Metabolism: Similarities and Differences.

Non-alcoholic fatty liver disease (NAFLD) is a type of steatosis commonly associated with obesity, dyslipidemia, hypertension, and diabetes. Other diseases such as inherited alpha-1 antitrypsin deficiency (AATD) have also been related to the development of liver steatosis. The primary reasons leading to hepatic lipid deposits can be genetic and epigenetic, and the outcomes range from benign steatosis to liver failure, as well as to extrahepatic diseases. Progressive hepatocellular damage and dysregulated systemic immune responses can affect extrahepatic organs, specifically the heart and lungs. In this review, we discuss the similarities and differences between the molecular pathways of NAFLD and AATD, and the putative value of hepatic organoids as novel models to investigate the physio pathological mechanisms of liver steatosis.

Presence of human papillomavirus in the buccal mucosa of blood donors.

OBJECTIVE: To determine the presence of human papillomavirus (HPV) in the oral mucosa of blood donors (BD) and risk factors associated with HPV and oral cancer. MATERIALS AND METHODS: Prospective cross-sectional study, population matched to BD from the National Cancer Institute, Mexico for HPV identification in oral cytological samples using the CLART® Human Papillomavirus 2 Kit (35 genotypes) and risk factors. RESULTS: Of 352 BD with signed informed consent, 285 were selected by simple randomization. The prevalence of oral HPV was 17.5% (95% CI 13-21.9%), the genotype was identified in 13 cases, with a total of 16 genotypes (10 high-risk), the most common being 16 and 84. Five cases had multiple infections, three with at least one high-risk type. Associations were found for marital status (OR 3.3) and educational level (OR-1.9). CONCLUSIONS: The percentage of HPV-positive cases in blood donors with no risk practices was similar to that found in Spanish-speaking population studies in which at least one risk practice was described. The presence of other genotypes with high oncogenic risk and multitype infection, described as a marker of persistence of HPV infection, is highlighted.

Viscosity Factor (VF) Complementary to the Statistical Indicators Associated with the Rheological Behavior of Aqueous Solutions of Polyvinyl Alcohol.

The rheological behavior of aqueous solutions of polyvinyl alcohol at 4, 6, 8 and 10% by weight has been studied and evaluated at temperatures of 20, 25, 30 and 35 °C, using five non-Newtonian fluid models independent of time: Ferrys, Robertson-Stiff, Williamson, Sisko, and Ellis de Haven. The classical method consists in carrying out regression analysis. Using a comparative procedure of determination coefficients and variances, the model that most appropriately adjusts the experimental data to said model is selected. From the statistical point of view, the Sisko and Robertson-Stiff models present better regression parameters; to better specify the choice of the respective rheological model, a new factor has been proposed in the literature, the viscosity factor (VF), which expresses the relationship between apparent and dynamic viscosity. The analysis of this factor for the five models confirms the greater stability of the Ellis de Haven model in terms of the coefficient of variation of the VF. The value of VF fluctuates between 1 and 2 for all ranges of temperature and concentration experienced for vinyl alcohol solutions. As a consequence of the above, for the choice of the non-Newtonian fluid model associated with the rheology of the aqueous solution of polyvinyl alcohol, it is necessary to analyze the statistical parameters and the VF factor simultaneously.

NaHS restores the vascular alterations in the renin-angiotensin system induced by hyperglycemia in rats.

Hyperglycemia (HG) impairs the renin-angiotensin system (RAS), which may contribute to vascular dysfunction. Besides, hydrogen sulfide (H2S) exerts beneficial cardiovascular effects in metabolic diseases. Therefore, our study aimed to determine the effects of chronic administration of sodium hydrosulfide (NaHS; inorganic H2S donor) and DL-Propargylglycine [DL-PAG; cystathionine-×¥-lyase (CSE) inhibitor] on the RAS-mediated vascular responses impairments observed in thoracic aortas from male diabetic Wistar rats. For that purpose, neonatal rats were divided into two groups that received: 1) citrate buffer (n = 12) or 2) streptozotocin (STZ, 70 mg/kg; n = 48) on the third postnatal day. After 12 weeks, diabetic animals were divided into 4 subgroups (n = 12 each) that received daily i.p. injections during 4 weeks of: 1) non-treatment; 2) vehicle (PBS, 1 mL/kg); 3) NaHS (5.6 mg/kg); and 4) DL-PAG (10 mg/kg). After treatments (16 weeks), blood glucose, angiotensin-(1-7) [Ang-(1-7)], and angiotensin II (Ang II) levels, vascular responses to Ang-(1-7) and Ang II, and the expression of angiotensin AT1, AT2, and Mas receptors, angiotensin converting enzyme (ACE) and ACE type 2 (ACE2) were determined. HG induced: 1) increased blood glucose levels and expression of angiotensin II AT1 receptor; 2) impaired Ang-(1-7) and Ang II mediated vascular responses; 3) decreased angiotensin levels and expression of angiotensin II AT2 and angiotensin-(1-7) Mas receptors, and ACE2; and 4) no changes in ACE expression. Interestingly, NaHS, but not DL-PAG, reversed HG-induced impairments, except for blood glucose level changes. These results suggest that NaHS restores vascular function in streptozotocin-induced HG through RAS modulation.

Silver nanoparticles induce a non-immunogenic tumor cell death.

Immunogenic cell death (ICD) is a form of cell death characterized by the release of danger signals required to trigger an adaptive immune response against tumor-associated antigens. Silver nanoparticles (AgNP) display anti-proliferative and cytotoxic effects in tumor cells, but it has not been previously studied whether AgNP act as an ICD inductor. The present study evaluated the in vitro release of calreticulin as a damage-associated molecular pattern (DAMP) associated with the cytotoxicity of AgNP and their in vivo anti-cancer effects. In vitro, mouse CT26 colon carcinoma and MCA205 fibrosarcoma cells were exposed to AgNP and then cell proliferation, adhesion, and release of calreticulin were determined. The results indicated there were time- and concentration-related anti-proliferative effects of AgNP in both the CT26 and MCA205 lines. Concurrently, changes in cell adhesion were detected mainly in the CT26 cells. Regarding DAMP detection, a significant increase in calreticulin was observed only in CT26 cells treated with doxorubicin and AgNP; however, no differences were found in the MCA205 cells. In vivo, the survival and growth of subcutaneous tumors were monitored after vaccination of mice with cell debris from tumor cells treated with AgNP or after intra-tumoral administration of AgNP to established tumors. Consequently, anti-tumoral prophylactic immunization with AgNP-dead cells failed to protect mice from tumor re-challenge; intra-tumor injection of AgNP did not induce a significant effect. In conclusion, there was a noticeable anti-tumoral effect of AgNP in vitro in both CT26 and MCA205 cell lines, accompanied by the release of calreticulin in CT26 cells. In vivo, immunization with cell debris derived from AgNP-treated tumor cells failed to induce a protective immune response in the cancer model mice. Clearly, further research is needed to determine if one could combine AgNP with other ICD inducers to improve the anti-tumor effect of these nanoparticles in vivo.

Mice inflammatory responses to inhaled aerosolized LPS: effects of various forms of human alpha1-antitrypsin.

Rodent models of lipopolysaccharide (LPS)-induced pulmonary inflammation are used for anti-inflammatory drug testing. We aimed to characterize mice responses to aerosolized LPS alone or with intraperitoneal (i.p.) delivery of alpha1-antitrypsin (AAT). Balb/c mice were exposed to clean air or aerosolized LPS (0.21 mg/mL) for 10 min per day, for 3 d. One hour after each challenge, animals were treated i.p. with saline or with (4 mg/kg body weight) one of the AAT preparations: native (AAT), oxidized (oxAAT), recombinant (recAAT), or peptide of AAT (C-36). Experiments were terminated 6 h after the last dose of AATs. Transcriptome data of mice lungs exposed to clean air versus LPS revealed 656 differentially expressed genes and 155 significant gene ontology terms, including neutrophil migration and toll-like receptor signaling pathways. Concordantly, mice inhaling LPS showed higher bronchoalveolar lavage fluid neutrophil counts and levels of myeloperoxidase, inducible nitric oxide synthase, IL-1ß, TNFα, KC, IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Plasma inflammatory markers did not increase. After i.p. application of AATs, about 1% to 2% of proteins reached the lungs but, except for GM-CSF, none of the proteins significantly influenced inflammatory markers. All AATs and C-36 significantly inhibited LPS-induced GM-CSF release. Surprisingly, only oxAAT decreased the expression of several LPS-induced inflammatory genes, such as Cxcl3, Cd14, Il1b, Nfkb1, and Nfkb2, in lung tissues. According to lung transcriptome data, oxAAT mostly affected genes related to transcriptional regulation while native AAT or recAAT affected genes of inflammatory pathways. Hence, we present a feasible mice model of local lung inflammation induced via aerosolized LPS that can be useful for systemic drug testing.

Patentes otorgadas a las universidades peruanas en el campo de la biomedicina. 2010 a 2020 / Patents granted to Peruvian universities in the biomedical field: 2010 to 2020

Introducción: La patente es un título de propiedad industrial otorgado por el Estado al inventor de un nuevo producto o tecnología, susceptible de ser comercializado para obtener ganancias de forma exclusiva a un plazo de tiempo determinado. Objetivo: Determinar el número de patentes otorgadas a las universidades peruanas en el campo biomédico de 2010 a 2020, en comparación con la producción de otros inventores. Material y método: Este estudio descriptivo, observacional, retrospectivo y transversal analizó 73 patentes provenientes de un universo de 759, obtenidas de la base de datos del Instituto Nacional de Defensa de la Competencia y de la Protección de la Propiedad Intelectual en el Perú, de 2010 a 2020. Para comparar el número de patentes otorgadas a las universidades respecto a otros inventores, se aplicó la prueba del Chi Cuadrado de Pearson con la corrección de continuidad de Yates. Resultados: En el Perú, durante 2010 a 2020 se han otorgado 759 patentes, de las cuales 73 pertenecen al campo biomédico (9,61 por ciento), de los cuales las universidades han generado 24,66 por ciento; es decir 2,47 por ciento del total. Además, las universidades presentaron diferencias significativas de producción de patentes (p = 0,019) en comparación a otros autores. Conclusiones: En el campo biomédico, la producción de patentes en las universidades peruanas ha sido muy limitadas desde 2010 a 2020. Además, las universidades presentaron significativamente menor producción de patentes en comparación a otros inventores, observándose que desde 2016, no se les ha otorgado ninguna patente de invención en el campo biomédico(AU)

Introduction: A patent is an industrial property title granted by the State to the inventor of a new product or technology, susceptible of being marketed for profit on an exclusive basis for a determined period of time. Objective: To determine the number of patents granted to Peruvian universities in the biomedical field from 2010 to 2020, in comparison with the production of other inventors. Material and Methods: This descriptive, observational, retrospective and cross-sectional study analyzed 73 patents from a universe of 759 patents obtained from the database of the National Institute for the Defense of Competition and Protection of Intellectual Property in Peru, from 2010 to 2020. To compare the number of patents granted to universities with respect to other inventors, Pearson's chi-square test with Yates' continuity correction was applied. Results: In Peru, during the years 2010 to 2020, 759 patents have been granted, of which 73 belong to the biomedical field (9.61 percent), of which universities have generated 24.66 percent, i.e. 2.47 percent of the total. Furthermore, universities showed significant differences in patent production (p = 0.019) compared to other authors. Conclusions: In the biomedical field, patent production in Peruvian universities has been very limited from 2010 to 2020. In addition, universities presented significantly lower patent production compared to other inventors, noting that since 2016, they have not been granted any invention patents in the biomedical field(AU)