NG2 is a target gene of MLL-AF4 and underlies glucocorticoid resistance in MLL-r B-ALL by regulating NR3C1 expression.

B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric cancer, with long-term overall survival rates of ~85%. However, B-ALL harboring rearrangements of the MLL gene (also known as KMT2A), referred to as MLLr B-ALL, is common in infants and is associated with poor 5-year survival (<30%), frequent relapses, and refractoriness to glucocorticoids (GCs). GCs are an essential part of the treatment backbone for B-ALL and GC resistance is a major clinical predictor of poor outcome. Elucidating the mechanisms of GC resistance in MLLr B-ALL is, therefore, critical to guide therapeutic strategies that deepen the response after induction therapy. Neuron-glial antigen-2 (NG2) expression is a hallmark of MLLr B-ALL and is minimally expressed in healthy hematopoietic cells. We recently reported that NG2 expression is associated with poor prognosis and that anti-NG2 immunotherapy strongly reduces/delays relapse in MLLr B-ALL xenograft models. Despite its contribution to MLLr B-ALL pathogenesis and its diagnostic utility, the role of NG2 in MLLr-mediated leukemogenesis/chemoresistance remains elusive. Here we show that NG2 is an epigenetically regulated direct target gene of the leukemic MLL-AF4 fusion protein. NG2 negatively regulates the expression of the GC receptor NR3C1 and confers GC resistance to MLLr B-ALL cells in vitro and in vivo. Mechanistically, NG2 interacts with FLT3 to render ligand-independent activation of FLT3 signaling (a hallmark of MLLr B-ALL) and downregulation of NR3C1 via AP-1-mediated trans-repression. Collectively, our study elucidates the role of NG2 in GC resistance in MLLr B-ALL through FLT3/AP-1-mediated downregulation of NR3C1, providing novel therapeutic avenues for MLLr B-ALL.

PCDHGC3 hypermethylation as a potential biomarker of intestinal neuroendocrine carcinomas.

Neuroendocrine neoplasms (NENs) encompass tumors arising from neuroendocrine cells in various organs, including the gastrointestinal tract, pancreas, adrenal gland, and paraganglia. Despite advancements, accurately predicting the aggressiveness of gastroenteropancreatic (GEP) NENs based solely on pathological data remains challenging, thereby limiting optimal clinical management. Our previous research unveiled a crucial link between hypermethylation of the protocadherin PCDHGC3 gene and neuroendocrine tumors originating from the paraganglia and adrenal medulla. This epigenetic alteration was associated with increased metastatic potential and succinate dehydrogenase complex (SDH) dysfunction. Expanding upon this discovery, the current study explored PCDHGC3 gene methylation within the context of GEP-NENs in a cohort comprising 34 cases. We uncovered promoter hypermethylation of PCDHGC3 in 29% of GEP-NENs, with a significantly higher prevalence in gastrointestinal (GI) neuroendocrine carcinomas (NECs) compared with both pancreatic (Pan) NECs and neuroendocrine tumors (NETs) of GI and Pan origin. Importantly, these findings were validated in one of the largest multi-center GEP-NEN cohorts. Mechanistic analysis revealed that PCDHGC3 hypermethylation was not associated with SDH mutations or protein loss, indicating an SDH-independent epigenetic mechanism. Clinically, PCDHGC3 hypermethylation emerged as a significant prognostic factor, correlating with reduced overall survival rates in both patient cohorts. Significantly, whereas PCDHGC3 hypermethylation exhibited a strong correlation with TP53 somatic mutations, a hallmark of NEC, its predictive value surpassed that of TP53 mutations, with an area under the curve (AUC) of 0.95 (95% CI 0.83-1.0) for discriminating GI-NECs from GI-NETs, highlighting its superior predictive performance. In conclusion, our findings position PCDHGC3 methylation status as a promising molecular biomarker for effectively stratifying patients with GI-NENs. This discovery has the potential to advance patient care by enabling more precise risk assessments and tailored treatment strategies. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Metformin and Glucose Concentration as Limiting Factors in Retinal Pigment Epithelial Cell Viability and Proliferation.

Metformin is a well-established drug for the treatment of type 2 diabetes; however, the mechanism of action has not been well described and many aspects of how it truly acts are still unknown. Moreover, regarding in vitro experiments, the glycaemic status when metformin is used is generally not considered, which, added to the suprapharmacological drug concentrations that are commonly employed in research, has resulted in gaps of its mechanism of action. The aim of this study was to determine how glucose and metformin concentrations influence cell culture. Considering that diabetic retinopathy is one of the most common complications of diabetes, a retinal pigment epithelial cell line was selected, and cell viability and proliferation rates were measured at different glucose and metformin concentrations. As expected, glucose concentration by itself positively influenced cell proliferation rates. When the metformin was considered, results were conditioned, as well, by metformin concentration. This conditioning resulted in cell death when high concentrations of metformin were used under physiological concentrations of glucose, while this did not happen when clinically relevant concentrations of metformin were used independently of glucose status. Our study shows the importance of in vitro cell growth conditions when drug effects such as metformin's are being analysed.

Novel 14q32.2 paternal deletion encompassing the whole DLK1 gene associated with Temple syndrome.

BACKGROUND: Temple syndrome (TS14) is a rare imprinting disorder caused by maternal UPD14, imprinting defects or paternal microdeletions which lead to an increase in the maternal expressed genes and a silencing the paternally expressed genes in the 14q32 imprinted domain. Classical TS14 phenotypic features include pre- and postnatal short stature, small hands and feet, muscular hypotonia, motor delay, feeding difficulties, weight gain, premature puberty along and precocious puberty. METHODS: An exon array comparative genomic hybridization was performed on a patient affected by psychomotor and language delay, muscular hypotonia, relative macrocephaly, and small hand and feet at two years old. At 6 years of age, the proband presented with precocious thelarche. Genes dosage and methylation within the 14q32 region were analyzed by MS-MLPA. Bisulfite PCR and pyrosequencing were employed to quantification methylation at the four known imprinted differentially methylated regions (DMR) within the 14q32 domain: DLK1 DMR, IG-DMR, MEG3 DMR and MEG8 DMR. RESULTS: The patient had inherited a 69 Kb deletion, encompassing the entire DLK1 gene, on the paternal allele. Relative hypermethylation of the two maternally methylated intervals, DLK1 and MEG8 DMRs, was observed along with normal methylation level at IG-DMR and MEG3 DMR, resulting in a phenotype consistent with TS14. Additional family members with the deletion showed modest methylation changes at both the DLK1 and MEG8 DMRs consistent with parental transmission. CONCLUSION: We describe a girl with clinical presentation suggestive of Temple syndrome resulting from a small paternal 14q32 deletion that led to DLK1 whole-gene deletion, as well as hypermethylation of the maternally methylated DLK1-DMR.

A personalized medicine approach identifies enasidenib as an efficient treatment for IDH2 mutant chondrosarcoma.

BACKGROUND: Sarcomas represent an extensive group of malignant diseases affecting mesodermal tissues. Among sarcomas, the clinical management of chondrosarcomas remains a complex challenge, as high-grade tumours do not respond to current therapies. Mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes are among the most common mutations detected in chondrosarcomas and may represent a therapeutic opportunity. The presence of mutated IDH (mIDH) enzymes results in the accumulation of the oncometabolite 2-HG leading to molecular alterations that contribute to drive tumour growth. METHODS: We developed a personalized medicine strategy based on the targeted NGS/Sanger sequencing of sarcoma samples (n = 6) and the use of matched patient-derived cell lines as a drug-testing platform. The anti-tumour potential of IDH mutations found in two chondrosarcoma cases was analysed in vitro, in vivo and molecularly (transcriptomic and DNA methylation analyses). FINDINGS: We treated several chondrosarcoma models with specific mIDH1/2 inhibitors. Among these treatments, only the mIDH2 inhibitor enasidenib was able to decrease 2-HG levels and efficiently reduce the viability of mIDH2 chondrosarcoma cells. Importantly, oral administration of enasidenib in xenografted mice resulted in a complete abrogation of tumour growth. Enasidenib induced a profound remodelling of the transcriptomic landscape not associated to changes in the 5 mC methylation levels and its anti-tumour effects were associated with the repression of proliferative pathways such as those controlled by E2F factors. INTERPRETATION: Overall, this work provides preclinical evidence for the use of enasidenib to treat mIDH2 chondrosarcomas. FUNDING: Supported by the Spanish Research Agency/FEDER (grants PID2022-142020OB-I00; PID2019-106666RB-I00), the ISC III/FEDER (PI20CIII/00020; DTS18CIII/00005; CB16/12/00390; CB06/07/1009; CB19/07/00057); the GEIS group (GEIS-62); and the PCTI (Asturias)/FEDER (IDI/2021/000027).

The lipopolysaccharide-TLR4 axis regulates hepatic glutaminase 1 expression promoting liver ammonia build-up as steatotic liver disease progresses to steatohepatitis.

INTRODUCTION: Ammonia is a pathogenic factor implicated in the progression of metabolic-associated steatotic liver disease (MASLD). The contribution of the glutaminase 1 (GLS) isoform, an enzyme converting glutamine to glutamate and ammonia, to hepatic ammonia build-up and the mechanisms underlying its upregulation in metabolic-associated steatohepatitis (MASH) remain elusive. METHODS: Multiplex transcriptomics and targeted metabolomics analysis of liver biopsies in dietary mouse models representing the whole spectra of MASLD were carried out to characterize the relevance of hepatic GLS during disease pathological progression. In addition, the acute effect of liver-specific GLS inhibition in hepatic ammonia content was evaluated in cultured hepatocytes and in in vivo mouse models of diet-induced MASLD. Finally, the regulatory mechanisms of hepatic GLS overexpression related to the lipopolysaccharide (LPS)/Toll-like receptor 4 (TLR4) axis were explored in the context of MASH. RESULTS: In mouse models of diet-induced MASLD, we found that augmented liver GLS expression is closely associated with the build-up of hepatic ammonia as the disease progresses from steatosis to steatohepatitis. Importantly, the acute silencing/pharmacological inhibition of GLS diminishes the ammonia burden in cultured primary mouse hepatocytes undergoing dedifferentiation, in steatotic hepatocytes, and in a mouse model of diet-induced steatohepatitis, irrespective of changes in ureagenesis and gut permeability. Under these conditions, GLS upregulation in the liver correlates positively with the hepatic expression of TLR4 that recognizes LPS. In agreement, the pharmacological inhibition of TLR4 reduces GLS and hepatic ammonia content in LPS-stimulated mouse hepatocytes and hyperammonemia animal models of endotoxemia. CONCLUSIONS: Overall, our results suggest that the LPS/TLR4 axis regulates hepatic GLS expression promoting liver ammonia build-up as steatotic liver disease progresses to steatohepatitis.

A multiomic atlas of the aging hippocampus reveals molecular changes in response to environmental enrichment.

Aging involves the deterioration of organismal function, leading to the emergence of multiple pathologies. Environmental stimuli, including lifestyle, can influence the trajectory of this process and may be used as tools in the pursuit of healthy aging. To evaluate the role of epigenetic mechanisms in this context, we have generated bulk tissue and single cell multi-omic maps of the male mouse dorsal hippocampus in young and old animals exposed to environmental stimulation in the form of enriched environments. We present a molecular atlas of the aging process, highlighting two distinct axes, related to inflammation and to the dysregulation of mRNA metabolism, at the functional RNA and protein level. Additionally, we report the alteration of heterochromatin domains, including the loss of bivalent chromatin and the uncovering of a heterochromatin-switch phenomenon whereby constitutive heterochromatin loss is partially mitigated through gains in facultative heterochromatin. Notably, we observed the multi-omic reversal of a great number of aging-associated alterations in the context of environmental enrichment, which was particularly linked to glial and oligodendrocyte pathways. In conclusion, our work describes the epigenomic landscape of environmental stimulation in the context of aging and reveals how lifestyle intervention can lead to the multi-layered reversal of aging-associated decline.

The thyroid hormone enhances mouse embryonic fibroblasts reprogramming to pluripotent stem cells: role of the nuclear receptor corepressor 1.

Introduction: Pluripotent stem cells can be generated from somatic cells by the Yamanaka factors Oct4, Sox2, Klf4 and c-Myc. Methods: Mouse embryonic fibroblasts (MEFs) were transduced with the Yamanaka factors and generation of induced pluripotent stem cells (iPSCs) was assessed by formation of alkaline phosphatase positive colonies, pluripotency gene expression and embryod bodies formation. Results: The thyroid hormone triiodothyronine (T3) enhances MEFs reprogramming. T3-induced iPSCs resemble embryonic stem cells in terms of the expression profile and DNA methylation pattern of pluripotency genes, and of their potential for embryod body formation and differentiation into the three major germ layers. T3 induces reprogramming even though it increases expression of the cyclin kinase inhibitors p21 and p27, which are known to oppose acquisition of pluripotency. The actions of T3 on reprogramming are mainly mediated by the thyroid hormone receptor beta and T3 can enhance iPSC generation in the absence of c-Myc. The hormone cannot replace Oct4 on reprogramming, but in the presence of T3 is possible to obtain iPSCs, although with low efficiency, without exogenous Klf4. Furthermore, depletion of the corepressor NCoR (or Nuclear Receptor Corepressor 1) reduces MEFs reprogramming in the absence of the hormone and strongly decreases iPSC generation by T3 and also by 9cis-retinoic acid, a well-known inducer of reprogramming. NCoR depletion also markedly antagonizes induction of pluripotency gene expression by both ligands. Conclusions: Inclusion of T3 on reprogramming strategies has a potential use in enhancing the generation of functional iPSCs for studies of cell plasticity, disease and regenerative medicine.

Diseño y elaboración del libro electrónico de proceso de atención de enfermería: (software educativo) / Design and drawing up of electronic book on nursing care process

Motivado por el afán de primer orden de nuestro gobierno revolucionario en desarrollar la informatización progresiva de la sociedad cubana, y que la actualidad impone un nuevo enfoque a la enseñanza con el uso de las nuevas tecnologías de la información que favorecen el proceso educativo, y es una fuente de motivación la satisfacción de una de las propuestas del Plan Director de la Informática Médica para el Proceso de Enseñanza-Aprendizaje de la Licenciatura en Enfermería, se diseñó y elaboró un software educativo para apoyar la enseñanza del Proceso de Atención de Enfermería. Se tuvieron en cuenta las dificultades detectadas en el proceso de enseñanza aprendizaje. Este sistema educativo (libro electrónico), aborda los elementos teóricos del método científico de la enfermería. Para lograr este propósito se realizó un estudio exploratorio previo, cuyos resultados se muestran en este documento; también se realizó búsqueda y análisis de bibliografía actualizada sobre el tema, y se utilizaron técnicas grupales en el diseño del software. Se destacan los antecedentes y estado actual de la Enseñanza Asistida por Computadora (E.A.C), y se realizó la fundamentación pedagógica del sistema y el análisis de las influencias de las diferentes corrientes o tendencias pedagógicas actuales, cuyas contribuciones dotan de un nivel óptimo de eficacia y calidad a esta moderna modalidad de la enseñanza. Consideramos que este material es de gran utilidad para el profesional de enfermería, que con su uso dispondrá de una herramienta de apoyo a la enseñanza y el aprendizaje de un tema indispensable para su formación y desempeño profesional(AU)

Motivated by the zeal of the first order of our revolutionary government in to develop the progressive computerization of our society, and knowing that the current importance imposes a new approach on the education, which unavoidably must be based on the use of the new technologies of the information, which are tools that used suitable favor the educational process; constituting also fountain of motivation, the satisfaction of one of the offers of " Director Plan of the Medical Informatics to the Process of Education - Learning of the Licentiate in Infirmary. We proposed the production of an educational software to lean the education of " Nursing Process ". It is an electronic book, that it approaches this subject matter with an essentially theoretical approach. To achieve this intention I realized an exploratory previous study, which results appear in this work; there was realized search of updated bibliography, and technologies groupers were used to elaborate the design of the software. Are outlined the precedents and current condition of the Learning Assisted for Computer , As well as it influences them of the different Currents or Pedagogic Trends, which contributions provide with an ideal level of efficiency and quality to this modern modality of the education. We thought that this material is of great usefulness for the professional of infirmary, which with its use will have a tool of support to the learning of an indispensable topic for his formation and professional performance, likewise it will be highly useful for the teachers of the Infirmary since we show them a route to give a step of advance to a superiors level in the educational process(AU)

Bioética y nuevas tecnologías: telemedicina / Bioethics and new technologies: telemedicine

En el marco de este nuevo milenio, que se distingue por el crecimiento constante de los volúmenes de información y el desarrollo vertiginoso de las tecnologías para el manejo de esta, se realizó una revisión bibliográfica con el propósito de describir el impacto bioético de la Telemedicina, la cual constituye una tecnología de reciente utilización que promete convertirse en una herramienta que apoyará la solución de algunas problemáticas de Salud existentes en el mundo actual. No obstante, su desarrollo debe estar vinculado estrechamente al uso de regulaciones nacionales e internacionales que tengan en cuenta los aspectos éticos que inciden en este novedoso Servicio de salud. La atención conciente y consecuente de los principios de la Bioética llevan, a todo aquel responsabilizado con las investigaciones y la asistencia médica, a una mayor capacidad y mejoramiento de la práctica en el ejercicio de sus actividades. El obligatorio e indetenible desarrollo de la tecnología médica, en su aplicación, puede conllevar a la vulnerabilidad de los principios bioéticos, sobre todo, los de justicia y de beneficencia, con deterioro de los favores que se procuran adquirir por las personas involucradas(AU)

In the framework of this new millenium, characterized by the constant growing of information volumes and the accelerated development of technologies for the information management, a bibliographic review was made to describe the bioethical impact of telemedicine, which is a newly used technology promising to become a tool that will support the solution of some health problems existing in the present world. Nevertheless, its development should be closely linked to the use of national and international regulations considering the ethical aspects that influence on this novel health service. The conscious and consequent attention to the principles of Bioethics leads those responsible for research and medical assistance to a greater ability and improvement of practice in the exercise of their activities. The compulsory and unstoppable development of medical technology, in its application, may cause the vulnerability of bioethical principles, mainly those of justice and well-being, with a deterioration of the favours the persons involved try to receive(AU)

El proceso de atención de enfermería en la retinosis pigmentaria / The nursing care process in retinosis pigmentosa

La Retinosis Pigmentaria o también conocida como Retinis Pigmentosa es una enfermedad crónica degenerativa y progresiva, cuya afectación incide en la retina y el epitelio pigmentoso, que se caracteriza por pérdida progresiva de la visión, específicamente con reducción del campo visual. Su incidencia en la población mundial la coloca en el quinto lugar entre las enfermedades hereditarias, y es la cuarta causa de discapacidad visual severa. Motivados por la alta incidencia de esta patología, nos propusimos aplicar una revisión actualizada sobre la Retinosis Pigmentaria y la aplicación del Proceso de Atención de Enfermería a pacientes que padecen esta enfermedad; se efectuó una revisión de los Procesos de Atención de Enfermería aplicados a pacientes venezolanos, ingresados en el Centro Internacional de Retinosis Pigmentaria Camilo Cienfuegos en el período comprendido entre noviembre del 2001 a noviembre del 2005, y se realizó además búsqueda de bibliografía actualizada sobre el tema, específicamente de aspectos básicos, estadísticos y conceptos en el ámbito nacional e internacional. Como resultado de este estudio se describen elementos esenciales de esta enfermedad y se propone un esquema de aplicación del Proceso de Atención de Enfermería a los pacientes. La utilidad de este trabajo radica en que aporta nociones teóricas actualizadas de esta enfermedad, de gran beneficio para el profesional de enfermería, partiendo de la escasa existencia de literatura al respecto con la visión profesional de la enfermería(AU)

Pigmentary retinosis, also known as Retinitis Pigmentosa, is a progressive and degenerative chronic disease, which affects retina and the pigmentary epithelium, characterized by progressive loss of vision, specifically with reduction of the visual field. At a global level, its incidence is in the fifth place among hereditary diseases, and it is the fourth cause of severe visual disability. Because of the high incidence of this pathology, we proposed to apply an updated review on Retinitis Pigmentosa and the implementation of a Nursing Care Process in patients presenting with this condition, as well as a review of the application of this process to Venezuelan patients admitted in “Camilo Cienfuegos” International Center for Retinitis Pigmentosa from November 2001 to November 2005.It was made a search of the updated bibliography on this topic, specifically of the basic, statistical features, and of the concepts in the national and international spheres. As result of this study the essential elements of this conditions are described, and a scheme for the application of the Nursing Care Process to the patients is recommended. This paper is very useful, since it provides updated theoretical notions of this condition that are advantageous for the nursing professional, taking into account the scarce information existing on this regard from the nursing professional view(AU)

Presentación de 1 caso con neumonía varicelosa y distrés respiratorio / Presentation of a case with varicella pneumonia and respiratory distress

Se presentó un caso de 46 años, masculino, con antecedentes de salud, que mantuvo contacto con niños portadores de varicela y que llegó a nosotros con lesiones en la piel típicas de varicela, falla respiratoria aguda y alteraciones de la coagulación. Se trató con aciclovir, intacglobin, y ventilación mecánica, a pesar de lo cual falleció antes de las 24 h de su ingreso, aunque debemos destacar que el tratamiento comenzó tardíamente y no existían antecedentes de vacunación previa. Se decidió presentar este caso, por la poca frecuencia de la varicela complicada en adultos sanos

Evaluación del estrés en pacientes hipertensos mediante el sistema "Neuro-Omega" / Assessment of stree in hypertensive patients by the \"Neuro-Omega\"

Se realizó la evaluación de diferentes índices cuantitativos del sistema nervioso con el Sistema "Neuro-Omega" a un grupo de 30 pacientes con hipertensión arterial esencial y a un grupo de 77 sujetos supuestamente sanos (grupo control), ambos grupos bajo condiciones basales. Otro grupo de 35 sujetos supuestamente sanos de alta responsabilidad y nivel ejecutivo (grupo de referencia) fue evaluado después de transcurrir la mayor parte de su jornada laboral. Los resultados de la comparación de los diferentes índices de la actividad cronotrópica cardiaca, de la respuesta psicomotora y sensoromotora, del análisis espectral del electroencefalograma, de la intensidad de la respuesta de la sustancia activadora reticular ascendente y de los potenciales evocados visuales por patrón con estimulación rítmica y selectiva, demuestran que el grupo de pacientes hipertensos se diferencia significativamente del grupo de sujetos control y estos cambios guardan relación con los observados en el grupo de referencia sometidos a una situación de estrés: lo que evidencia la importancia del estrés en su vinculación con la hipertensión arterial esencial