De Novo Design of Inhibitors of DNA Methyltransferase 1: A Critical Comparison of Ligand- and Structure-Based Approaches.

Designing and developing inhibitors against the epigenetic target DNA methyltransferase (DNMT) is an attractive strategy in epigenetic drug discovery. DNMT1 is one of the epigenetic enzymes with significant clinical relevance. Structure-based de novo design is a drug discovery strategy that was used in combination with similarity searching to identify a novel DNMT inhibitor with a novel chemical scaffold and warrants further exploration. This study aimed to continue exploring the potential of de novo design to build epigenetic-focused libraries targeted toward DNMT1. Herein, we report the results of an in-depth and critical comparison of ligand- and structure-based de novo design of screening libraries focused on DNMT1. The newly designed chemical libraries focused on DNMT1 are freely available on GitHub.

Decoding the mechanism governing the structural stability of wheat germ agglutinin and its isolated domains: A combined calorimetric, NMR, and MD simulation study.

Wheat germ agglutinin (WGA) demonstrates potential as an oral delivery agent owing to its selective binding to carbohydrates and its capacity to traverse biological membranes. In this study, we employed differential scanning calorimetry and molecular dynamics simulations to comprehensively characterize the thermal unfolding process of both the complete lectin and its four isolated domains. Furthermore, we present the nuclear magnetic resonance structures of three domains that were previously lacking experimental structures in their isolated forms. Our results provide a collective understanding of the energetic and structural factors governing the intricate unfolding mechanism of the complete agglutinin, shedding light on the specific role played by each domain in this process. The analysis revealed negligible interdomain cooperativity, highlighting instead significant coupling between dimer dissociation and the unfolding of the more labile domains. By comparing the dominant interactions, we rationalized the stability differences among the domains. Understanding the structural stability of WGA opens avenues for enhanced drug delivery strategies, underscoring its potential as a promising carrier throughout the gastrointestinal environment.

Oral administration of a recombinant modified RBD antigen of SARS-CoV-2 as a possible immunostimulant for the care of COVID-19.

BACKGROUND: Developing effective vaccines against SARS-CoV-2 that consider manufacturing limitations, equitable access, and acceptance is necessary for developing platforms to produce antigens that can be efficiently presented for generating neutralizing antibodies and as a model for new vaccines. RESULTS: This work presents the development of an applicable technology through the oral administration of the SARS-CoV-2 RBD antigen fused with a peptide to improve its antigenic presentation. We focused on the development and production of the recombinant receptor binding domain (RBD) produced in E. coli modified with the addition of amino acids extension designed to improve antigen presentation. The production was carried out in shake flask and bioreactor cultures, obtaining around 200 mg/L of the antigen. The peptide-fused RBD and peptide-free RBD proteins were characterized and compared using SDS-PAGE gel, high-performance chromatography, and circular dichroism. The peptide-fused RBD was formulated in an oil-in-water emulsion for oral mice immunization. The peptide-fused RBD, compared to RBD, induced robust IgG production in mice, capable of recognizing the recombinant RBD in Enzyme-linked immunosorbent assays. In addition, the peptide-fused RBD generated neutralizing antibodies in the sera of the dosed mice. The formulation showed no reactive episodes and no changes in temperature or vomiting. CONCLUSIONS: Our study demonstrated the effectiveness of the designed peptide added to the RBD to improve antigen immunostimulation by oral administration.

Infarto agudo del miocardio secundario a trauma cerrado de tórax / Acute myocardial infarction secundary to blunt chest trauma

Se presenta el caso de un hombre de 44 años de edad sin factores de riesgo coronario; éste, después de un entrenamiento de artes marciales en el que recibió múltiples traumatismos con golpe a mano cerrada y puntapié en la cara anterior del tórax durante enfrentamiento corporal, presentó dolor opresivo intenso en región retroesternal y acudió con dos médicos, quienes le prescribieron analgésicos y antiinflamatorios. Por la persistencia de la sintomatología sin mejoría, acudió con un tercer facultativo quien realizó un electrocardiograma (ECG), el cual documentó lesión subepicárdica inferior; fue trasladado para realizar coronariografía, la cual mostró oclusión trombótica funcional del segmento proximal de la coronaria derecha, misma que fue tratada exitosamente con intervención coronaria percutánea primaria e implante de stent medicado. Este caso muestra que el infarto agudo del miocardio asociado con trauma cerrado de tórax es una patología de difícil diagnóstico.

This is a case of the 44 year old male patient without history or risk factors for coronary disease, with blunt chest trauma in the anterior region after training of an Israeli martial art, right after he had typical retroesternal chest pain, he went to different doctors who prescribed different antiinflamatory drugs, because the persistence of the pain he decided to check with a third doctor who took an EKG and found an inferior epicardial lesion. Coronary angiography showed functional thrombotic occlusion of proximal segment of the right coronary. Successful primary angioplasty and stenting was done. The case shows that myocardial infarction after blunt chest trauma is challenging in terms of diagnosis and treatment.

Tratamiento endovascular exitoso del síndrome de cascanueces con stent autoexpandible / Successful endovascular treatment of nutcracker's syndrome with self-expanding stent

El síndrome de cascanueces (nutcracker's syndrome) se produce por compresión de la vena renal izquierda a su paso por la horquilla vascular, formada por la aorta y la arteria mesentérica superior, causando una compresión extrínseca que genera estenosis funcional de la misma. Esto produce congestión e hipertensión de la vena renal izquierda que se traduce en insuficiencia y várices de la vena gonadal izquierda, hematuria unilateral y dolor lumbar izquierdo, el diagnóstico pocas veces se realiza, por su baja frecuencia y por la falta de sospecha clínica. El tratamiento del síndrome de cascanueces incluye el autotransplante renal, trasposición de arteria mesentérica superior, revascularización y más recientemente, la colocación de stent en la vena renal. Presentamos el caso de un paciente que fue sometido a tratamiento endovascular exitoso con un stent autoexpandible en la vena renal izquierda, con criterios inmediatos de éxito por angiografía, reducción de la congestión venosa y por desaparición del gradiente cavo/renal.

Nutcracker's syndrome is caused by compression of the left renal vein between aorta and superior mesenteric artery, causing extrinsic compression generated functional stenosis. This causes congestion and hypertension of the left renal vein resulting in insufficiency and left gonadal vein varicose, unilateral hematuria and left flank pain, diagnosis is rarely identified by their low frequency and difficulty of suspecting, treatment of nutcracker's syndrome include renal autotransplantation, transposition of superior mesenteric artery revascularization and recently stenting in renal vein, we present the case of a patient, who showed this pathology by diagnostic support by image studies, was performed successfully implant a self-expanding stent with immediate success criteria by angiography, collateral reduction and by disappearance of cava/renal gradient.

Diagnóstico de Linfoma no Hodgkin con infiltración intra-auricular / No Hodgkin Linfoma diagnosis with intra-atrial infiltration

Los tumores cardíacos, son entidades raras en la práctica médica, tienen una incidencia del 0,05%, aproximadamente el 75% es benigno y un 25% maligno. De estos el linfoma es infrecuente representando alrededor del 0,25%. Los linfomas no Hodgkin pueden ser extranodales en el 20% de los casos, así mismo el 80% de los linfomas no Hodgkin son de células B difusos, que es la forma más frecuente de presentación en adultos jóvenes; corresponden a alto grado de malignidad y crecimiento rápido, pueden presentarse con infiltración primaria a diferentes órganos, con afectación cardiaca en 20 a 28% de los casos y suelen localizarse en las cavidades derechas. Los síntomas son inespecíficos, dependientes de la localización y extensión del tumor y la prueba diagnóstica en estos casos es indudablemente la biopsia ya sea del ganglio linfático o del tejido afectado. Se presenta un caso de linfoma no Hodgkin difuso, de células grandes con afectación intra-auricular derecha, en una paciente de 23 años que debutó con disnea progresiva. Se realizó un ecocardiograma transesofágico que detectó una masa tumoral intra-auricular derecha, por lo que se realizó biopsia por cateterismo venoso por vía femoral, que permitió hacer el diagnóstico histopatológico y establecer el tratamiento, con lo cual se encuentra en primera remisión completa a un año del evento.

Cardiac tumors are rare entities in clinical practice, with an incidence of 0.05%. Approximately 75% are benign and 25% malignant. Among these, Lymphomas are uncommon, representing about 0.25%. The non-Hodgkin lymphomas can occur in extranodal tissues in 20% of the cases and 80% of these non-Hodgkin lymphomas are composed of diffuse B cells. The extranodal presentation is most frequent in young adults, with a high degree of malignancy and rapid growth. It can present with primary infiltration of various organs; cardiac involvement occurs in 20 to 28% of cases, usually located in the right chambers and with nonspecific symptoms, depending on the location and extent of the tumor. The diagnostic test in these cases is undoubtedly the biopsy of the lymph node or the affected tissue. We present the case of non-Hodgkin disease of diffuse large cells, with right intra-atrial involvement in a 23-year-old-female patient, who presented with progressive dyspnea. A transesophageal echocardiography was performed and an intra-atrial tumor mass was detected. A biopsy was performed, by femoral venous catheterization, allowing the establishment of the histopathological diagnosis and treatment. At a one year follow up, the patient shows complete remission.

Aplicaciones del stent cubierto con membrana de politetrafluoroetileno en el intervencionismo coronario (Experiencia del Instituto Nacional de Cardiología "Ignacio Chávez") / Synthetic membrane coronary stent graft in coronary disease

El stent cubierto con membrana se ha reportado como un dispositivo útil para corregir lesiones angiográficas específicas, así como complicaciones potenciales secundarias a procedimientos de intervencionismo coronario. El stent cubierto con membrana de (Jostent-Jomed) está compuesto por una fina capa de politetrafluoroetileno (PTFE) que se localiza entre dos stents metálicos. En esta revisión retrospectiva el stent de PTFE se utilizó en varias lesiones y situaciones angiográficas tanto en arterias coronarias como en injertos venosos. Nuestra experiencia consistió de 17 pacientes que fueron tratados por diferentes indicaciones clínicas y angiográficas: perforación coronaria en dos pacientes (pts), injertos venosos con trombo y cambios degenerativos en ocho (pts), aneurismas coronarios en 4 (pts) y trombo grande refractario a tratamiento habitual en otros 3 casos. Nuestros resultados con el stent de PTFE mostraron una tasa de éxito clínico del 100% sin complicaciones durante la fase hospitalaria y en el seguimiento clínico a 10 ± 3 meses sólo tres pacientes tuvieron algún evento cardíaco adverso mayor. La indicación potencial para el implante del stent de PTFE en injertos venosos todavía no se ha puntualizado; sin embargo a la luz de varios estudios pareciera haber poco beneficio en esta circunstancia. Por otro lado la perforación y el aneurisma coronario parecen ser las indicaciones más recomendables para la aplicación de este dispositivo.

Summary The use of a synthetic membrane-covered stent has been suggested to overcome some specific lesions in coronary arteries and to solve some potential complications that could arise in any procedure of coronary intervention. A synthetic membrane coronary stent graft (JOSTENT-JOMED) is constituted by a membrane of polytetrafluoroethylene (PTFE), fixed between two thin metallic stents. In this clinical review of our laboratory's experience, the Jostent graft was used in several angiographic circumstances in coronary arteries or in vein grafts. Our clinical experience consists of 17 patients that were treated with placement of PTFE stents for different indications: coronary rupture in two patients; thrombus and degenerative vein grafts in eight patients, coronary aneurysms in four patients, and thrombus in coronary arteries in three more. Our clinical results with this device suggest that its implant is feasible and safe with a clinical success of 100% without complications during in-hospital stay; during the clinical 11 ± 3 months follow-up, only three patients exhibited major cardiac events. The indication for PTFE stent in vein grafts with degenerative and thrombus lesions has not been determined yet; however, recently, some randomized trials have shown little benefit in this circumstance. On the other side, coronary vessel rupture and coronary aneurysms are currently the most definitive indications.