Aspirin 15cH has Different Effects on Morphology and Function of Lipopolysaccharide-Challenged RAW 264.7 Macrophages In Vitro Compared to a Pharmacological Dose of Aspirin.

INTRODUCTION: Aspirin is one of the most commonly used drugs worldwide. It is known to present antipyretic, anti-inflammatory and anti-thrombotic actions, making it extremely useful in a wide range of clinical contexts. Interestingly, homeopathically prepared Aspirin 15cH has been found to have a pro-thrombotic effect in rats, raising the hypothesis that Aspirin 15cH could also modulate the activity of inflammatory cells in different pathological processes. OBJECTIVE: Our objective was to assess what effect Aspirin 15cH has on RAW 264.7 macrophages in vitro. METHODS: The effects of Aspirin 15cH on biochemical and morphological activities of lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages were evaluated. These effects were compared with unchallenged macrophages (negative control), untreated LPS-stimulated macrophages, macrophages treated with succussed water (vehicle control), or aspirin 200 µg/mL (pharmacological inhibitor of LPS activity). Cell morphology (adhered cell area and cytoskeleton arrangements), cell viability, toll-like receptor-4 (TLR-4) expression, and the production of nitric oxide, cytokines and intracellular reactive oxygen species were assessed. RESULTS: Aspirin 15cH reduced the number of cells expressing TLR-4 on the surface (p = 0.03) and induced a "columnar" morphology of macrophage pseudopods, indicating changes in cytoskeleton arrangement. When cells were treated with both Aspirin 15cH and LPS, cell morphology became heterogeneous, suggesting that sub-populations of cells had differing sensitivities to LPS or Aspirin 15cH. Exposure of the cells to LPS alone, succussed water or aspirin 200 µg/mL produced effects consistent with the literature. CONCLUSION: Aspirin 15cH, aspirin 200 µg/mL, LPS and succussed water appear to act as independent stimuli able to induce different patterns of macrophage response. Aspirin 15cH induced changes suggestive of M2 polarization of the macrophages (i.e., toward a wound healing or tissue repair, rather than inflammatory, phenotype). These preliminary findings need to be confirmed in further specific studies.

An encyclopedia of enhancer-gene regulatory interactions in the human genome.

Identifying transcriptional enhancers and their target genes is essential for understanding gene regulation and the impact of human genetic variation on disease1-6. Here we create and evaluate a resource of >13 million enhancer-gene regulatory interactions across 352 cell types and tissues, by integrating predictive models, measurements of chromatin state and 3D contacts, and largescale genetic perturbations generated by the ENCODE Consortium7. We first create a systematic benchmarking pipeline to compare predictive models, assembling a dataset of 10,411 elementgene pairs measured in CRISPR perturbation experiments, >30,000 fine-mapped eQTLs, and 569 fine-mapped GWAS variants linked to a likely causal gene. Using this framework, we develop a new predictive model, ENCODE-rE2G, that achieves state-of-the-art performance across multiple prediction tasks, demonstrating a strategy involving iterative perturbations and supervised machine learning to build increasingly accurate predictive models of enhancer regulation. Using the ENCODE-rE2G model, we build an encyclopedia of enhancer-gene regulatory interactions in the human genome, which reveals global properties of enhancer networks, identifies differences in the functions of genes that have more or less complex regulatory landscapes, and improves analyses to link noncoding variants to target genes and cell types for common, complex diseases. By interpreting the model, we find evidence that, beyond enhancer activity and 3D enhancer-promoter contacts, additional features guide enhancerpromoter communication including promoter class and enhancer-enhancer synergy. Altogether, these genome-wide maps of enhancer-gene regulatory interactions, benchmarking software, predictive models, and insights about enhancer function provide a valuable resource for future studies of gene regulation and human genetics.

Increased susceptibility to encephalitozoonosis associated with mixed Th1/Th2 profile and M1/M2 profile in mice immunosuppressed with cyclophosphamide.

Encephalitozoon cuniculi is a unicellular, spore-forming, obligate intracellular eukaryote belonging to the phylum Microsporidia. It is known to infect mainly immunocompromised and immunocompetent mammals, including humans. The parasite-host relationship has been evaluated using both in vitro cell culturing and animal models. For example, Balb/c and C57BL/6 mouse strains have been used interchangeably, although the latter has been considered more susceptible due to the higher fungal load observed after infection. In the present study, we identified the characteristics of the immune response of C57BL/6 mice treated or not with the immunosuppressant cyclophosphamide (Cy) and challenged with E. cuniculi by intraperitoneal route. After 14 days of infection, serum was collected to analyze Th1, Th2, and Th17 cytokine levels. In addition, peritoneal washes were performed, and the spleen sample was collected for immune cell phenotyping, whereas liver, spleen, kidney, lung, intestine, and central nervous system (CNS) samples were collected for histopathological analysis. Although infected mice displayed a reduced absolute number of macrophages, they showed an M1 profile, an elevated number of CD4+T, CD8+T, B-1, and B-2 lymphocytes, with a predominance of Th1 inflammatory cytokines (interferon [IFN]-γ, tumor necrosis factor [TNF]-α, and interleukin [IL]-2) and Th17. Furthermore, Cy-Infected mice showed a reduced absolute number of macrophages with an M1 profile but a reduced number of CD4+T, CD8+T, B-1, and B-2 lymphocytes, with a predominance of Th1 inflammatory cytokines (IFN-γ, TNF-α, and IL-2) and Th2 (IL-4). This group displayed a higher fungal burden as well and developed more severe encephalitozoonosis, which was associated with a reduced number of T and B lymphocytes and a mixed profile of Th1 and Th2 cytokines.

Garnering effective telehealth to help optimize multidisciplinary team engagement (GET2HOME) for children with medical complexity: Protocol for a pragmatic randomized control trial.

BACKGROUND: Children and young adults with medical complexity (CMC) experience high rates of healthcare reutilization following hospital discharge. Prior studies have identified common hospital-to-home transition failures that may increase the risk for reutilization, including medication, technology and equipment issues, financial concerns, and confusion about which providers can help with posthospitalization needs. Few interventions have been developed and evaluated for CMC during this transition period. OBJECTIVE: We will compare the effectiveness of the garnering effective telehealth 2 help optimize multidisciplinary team engagement (GET2HOME) transition bundle intervention to the standard hospital-based care coordination discharge process by assessing healthcare reutilization and patient- and family-centered outcomes. DESIGNS, SETTINGS, AND PARTICIPANTS: We will conduct a pragmatic 2-arm randomized controlled trial (RCT) comparing the GET2HOME bundle intervention to the standard hospital-based care discharge process on CMC hospitalized and discharged from hospital medicine at two sites of our pediatric medical center between November 2022 and February 2025. CMC of any age will be identified as having complex chronic disease using the Pediatric Medical Complexity Algorithm tool. We will exclude CMC who live independently, live in skilled nursing facilities, are in custody of the county, or are hospitalized for suicidal ideation or end-of-life care. INTERVENTION: We will randomize participants to the bundle intervention or standard hospital-based care coordination discharge process. The bundle intervention includes (1) predischarge telehealth huddle with inpatient providers, outpatient providers, patients, and their families; (2) care management discharge task tracker; and (3) postdischarge telehealth huddle with similar participants within 7 days of discharge. As part of the pragmatic design, families will choose if they want to complete the postdischarge huddle. The standard hospital-based discharge process includes a pharmacist, social worker, and care management support when consulted by the inpatient team but does not include huddles between providers and families. MAIN OUTCOME AND MEASURES: Primary outcome will be 30-day urgent healthcare reutilization (unplanned readmission, emergency department, and urgent care visits). Secondary outcomes include 7-day urgent healthcare reutilization, patient- and family-reported transition quality, quality of life, and time to return to baseline using electronic health record and surveys at 7, 30, 60, and 90 days following discharge. We will also evaluate heterogeneity of treatment effect for the intervention across levels of financial strain and for CMC with high-intensity neurologic impairment. The primary analysis will follow the intention-to-treat principle with logistic regression used to study reutilization outcomes and generalized linear mixed modeling to study repeated measures of patient- and family-reported outcomes over time. RESULTS: This pragmatic RCT is designed to evaluate the effectiveness of enhanced discharge transition support, including telehealth huddles and a care management discharge tool, for CMC and their families. Enrollment began in November 2022 and is projected to complete in February 2025. Primary analysis completion is anticipated in July 2025 with reporting of results following.

BID expression determines the apoptotic fate of cancer cells after abrogation of the spindle assembly checkpoint by AURKB or TTK inhibitors.

BACKGROUND: Drugs targeting the spindle assembly checkpoint (SAC), such as inhibitors of Aurora kinase B (AURKB) and dual specific protein kinase TTK, are in different stages of clinical development. However, cell response to SAC abrogation is poorly understood and there are no markers for patient selection. METHODS: A panel of 53 tumor cell lines of different origins was used. The effects of drugs were analyzed by MTT and flow cytometry. Copy number status was determined by FISH and Q-PCR; mRNA expression by nCounter and RT-Q-PCR and protein expression by Western blotting. CRISPR-Cas9 technology was used for gene knock-out (KO) and a doxycycline-inducible pTRIPZ vector for ectopic expression. Finally, in vivo experiments were performed by implanting cultured cells or fragments of tumors into immunodeficient mice. RESULTS: Tumor cells and patient-derived xenografts (PDXs) sensitive to AURKB and TTK inhibitors consistently showed high expression levels of BH3-interacting domain death agonist (BID), while cell lines and PDXs with low BID were uniformly resistant. Gene silencing rendered BID-overexpressing cells insensitive to SAC abrogation while ectopic BID expression in BID-low cells significantly increased sensitivity. SAC abrogation induced activation of CASP-2, leading to cleavage of CASP-3 and extensive cell death only in presence of high levels of BID. Finally, a prevalence study revealed high BID mRNA in 6% of human solid tumors. CONCLUSIONS: The fate of tumor cells after SAC abrogation is driven by an AURKB/ CASP-2 signaling mechanism, regulated by BID levels. Our results pave the way to clinically explore SAC-targeting drugs in tumors with high BID expression.

DEHP exposure impairs human skeletal muscle cell proliferation in primary culture conditions: preliminary study.

The plasticizer di (2-ethylhexyl) phthalate (DEHP) inhibits differentiation, impairs glucose metabolism, and decreases mitochondrial function in murine muscle satellite cells; however, if these effects are translated to human cells is unknown. The goal of this study was to evaluate changes in morphology and proliferation of primary human skeletal muscle cells exposed to DEHP. Rectus abdominis muscle samples were obtained from healthy women undergoing programed cesarean surgery. Skeletal muscle cells were isolated and grown under standard primary culture conditions, generating two independent sample groups of 25 subcultures each. Cells from the first group were exposed to 1 mM DEHP for 13 days and monitored for changes in cell morphology, satellite cell frequency and total cell abundance, while the second group remained untreated (control). Differences between treated and untreated groups were compared using generalized linear mixed models (GLMM). Cell membrane and nuclear envelope boundary alterations, loss of cell volume and presence of stress bodies were observed in DEHP-treated cultures. DEHP-treated cultures also showed a significant reduction in satellite cell frequency compared to controls. Exposure to DEHP reduced human skeletal muscle cell abundance. Statistical differences were found between the GLMM slopes, suggesting that exposure to DEHP reduced growth rate. These results suggest that exposure to DEHP inhibits human skeletal muscle cell proliferation, as evidenced by reduced cell abundance, potentially compromising long-term culture viability. Therefore, DEHP induces human skeletal muscle cell deterioration potentially inducing an inhibitory effect of myogenesis by depleting satellite cells.

Pipeline for transferring annotations between proteins beyond globular domains.

DisProt is the primary repository of Intrinsically Disordered Proteins (IDPs). This database is manually curated and the annotations there have strong experimental support. Currently, DisProt contains a relatively small number of proteins highlighting the importance of transferring annotations regarding verified disorder state and corresponding functions to homologous proteins in other species. In such a way, providing them with highly valuable information to better understand their biological roles. While the principles and practicalities of homology transfer are well-established for globular proteins, these are largely lacking for disordered proteins. We used DisProt to evaluate the transferability of the annotation terms to orthologous proteins. For each protein, we looked for their orthologs, with the assumption that they will have a similar function. Then, for each protein and their orthologs, we made multiple sequence alignments (MSAs). Disordered sequences are fast evolving and can be hard to align, therefore, we implemented alignment quality control steps ensuring robust alignments before mapping the annotations. We have designed a pipeline to obtain good-quality MSAs and to transfer annotations from any protein to their orthologs. Applying the pipeline to DisProt proteins, from the 1731 entries with 5623 annotations, we can reach 97,555 orthologs and transfer a total of 301,190 terms by homology. We also provide a web server for consulting the results of DisProt proteins and execute the pipeline for any other protein. The server Homology Transfer IDP (HoTIDP) is accessible at http://hotidp.leloir.org.ar.

MRGPRX2 signaling involves the Lysyl-tRNA synthetase and MITF pathway.

MRGPRX2, a G-protein-coupled-seven transmembrane domain receptor, is mainly expressed in mast cells and neurons and is involved in skin immunity and pain. It is implicated in the pathophysiology of non-IgE-mediated immediate hypersensitivity and has been related to adverse drug reactions. Moreover, a role has been proposed in asthma, atopic dermatitis, contact dermatitis, and chronic spontaneous urticaria. Although it has a prominent role in disease, its signaling transduction is poorly understood. This study shows that MRGPRX2 activation with substance P increased Lysyl t-RNA synthetase (LysRS) translocation to the nucleus. LysRS is a moonlighting protein with a dual role in protein translation and IgE signaling in mast cells. Upon allergen- IgE-FcεRI crosslinking, LysRS is translocated to the nucleus and activates microphthalmia-associated transcription factor (MITF) activity. In this study, we found that MRGPRX2 triggering led to MITF phosphorylation and increased MITF activity. Therefore, overexpression of LysRS increased MITF activity after MRGPRX2 activation. MITF silencing reduced MRGPRX2-dependent calcium influx and mast cell degranulation. Furthermore, a MITF pathway inhibitor, ML329, impaired MITF expression, calcium influx, and mast cell degranulation. Moreover, drugs such as atracurium, vancomycin, and morphine, reported to induce MRGPRX2-dependent degranulation, increased MITF activity. Altogether, our data show that MRGPRX2 signaling enhances MITF activity, and its abrogation by silencing or inhibition resulted in defective MRGPRX2 degranulation. We conclude that MRGPRX2 signaling involves the LysRS and MITF pathway. Thus, MITF and MITF-dependent targets may be considered therapeutic approaches to treat pathologies where MRGPRX2 is implicated.

Reconsidering the lives of the earliest Puerto Ricans: Mortuary Archaeology and bioarchaeology of the Ortiz site.

We possess rather little detailed information on the lives of the first inhabitants of Puerto Rico-the so-called "Archaic" or "Pre-Arawak" people-despite more than a century of archeological research. This is particularly true bioarchaeologically, as fewer than twenty burials of the several millennia of the Archaic Age have been recovered, let alone analyzed in any detail. Here, we present the results of archeological, osteological, radiometric, and isotopic analysis of five individuals from the Ortiz site in Cabo Rojo, southwestern Puerto Rico. Study of these previously unpublished remains, which represent a 20-25% increase in the sample size of remains attributed to the period, provides many critical insights into earliest Puerto Rican lifeways, including aspects of mortuary practice, paleodiet, and possibly even social organization. A review of their burial treatment finds a mostly standardized set of mortuary practices, a noteworthy finding given the site's potential millennium-long use as a mortuary space and the possibly distinct place(s) of origin of the individuals interred there. Although osteological analysis was limited by poor preservation, we were able to reconstruct aspects of the demography that indicate the presence of both male and female adults. Stable isotope analysis revealed dietary differences from later Ceramic Age individuals, while dental pathology indicated heavy masticatory wear attributable to diet and/or non-masticatory function. Perhaps most crucially, direct AMS dating of the remains confirms these as the oldest burials yet recovered from the island, providing us both with a glimpse into the lives of some of the island's first inhabitants, and with tantalizing clues to the existence of a different degree of cultural "complexity" than is often ascribed to these earliest peoples. The existence of what radiocarbon dates suggest may be a persistent formal cemetery space at the Ortiz site has potentially significant implications concerning the territoriality, mobility, and social organization of the earliest peoples of southwestern Puerto Rico.

Malestar psicológico y preocupaciones psicosociales durante la tercera ola de la pandemia en pacientes oncológicos y familiares: Un análisis exploratorio / Distress and pychosocial concers during the third wave of the pandemic among oncological patients and family caregivers: an exploratory análisis

Objetivo: Describir el malestar psicológico y las preocupaciones psicosociales durante la tercera ola de la pandemia de los pacientes oncológicos y sus familiares y analizar la evolución de estas variables teniendo como referencia los meses de abril y diciembre de 2020. Método. Se utilizó un cuestionario autoadministrado que estaba compuesto por ítems elaborados ad hoc para evaluar las características sociodemográficas y las preocupaciones psicosociales y la escala Kessler K-6 para evaluar el malestar psicológico. Resultados. La proporción de pacientes y familiares que presentaban niveles clínicos de malestar era mayor que la de la población general. El porcentaje de personas con cáncer que mostraba malestar psicológico en niveles clínicos se incrementó significativamente durante el mes de diciembre de 2020, en comparación con el mes de abril. Este aumento fue especialmente significativo entre las mujeres y los pacientes más jóvenes, siendo también estas poblaciones las más afectadas en el primer momento de medida. Las preocupaciones más frecuentes en la población oncológica (pacientes y familiares) durante el mes de diciembre de 2020 fueron: el miedo a contraer la COVID-19, la inquietud y el miedo al futuro, la suspensión de los contactos y la ausencia del contacto cara a cara y la inactividad en las calles y comercios. Conclusiones. Los resultados de este estudio destacan la necesidad de desarrollar intervenciones específicas que permitan cubrir las secuelas psicológicas y las preocupaciones psicosociales derivadas de la COVID-19 en los pacientes oncológicos y sus familiares (AU)

Aim: Describe the psychological distress and the psychosocial concerns during the third wave of the pandemic in oncological patients and family caregivers and analyze the evolution of these variables in cancer patients taking as references April and December of 2020. Method. The researchers developed a self-administered questionnaire. It was composed by items developed ad hoc to assess sociodemographic characteristics and social concerns and the Kessler K-6 scale to measure psychological distress. Results.The proportion of oncological patients and family caregivers who showed clinical levels of distress was higher than that the ones of non-oncological population during December 2020. Clinical distress was higher in oncological patients during the December 2020, compared to April levels. This increase was especially significant among women and younger patients in both assessment moments. The main social concerns at the third wave for oncological patients and family caregivers were: the fear of contracting COVID-19, restlessness and fear of the future, suspension of the social contacts, the absence of face-to-face contact and inactivity in the streets and shops. Conclusions.The results of this study highlight the need to provide the proper care to oncological patients and family caregivers due to the presence of socio-emotional needs, and to develop strategies that allow them to be covered from psychological impact of COVID-19 (AU)

Predicción de diabetes mellitus basada en el índice triglicéridos y glucosa / Diabetes mellitus prediction based on the triglyceride and glucose index

Introducción: En México la diabetes mellitus tipo 2 (DM2) presenta niveles epidemiológicos, con una tasa de prevalencia del 9,12% y con los índices de sobrepeso y obesidad más altos del mundo. Para superar esta situación se deben crear estrategias enfocadas en la identificación de sujetos en riesgo. El índice triglicéridos y glucosa (TyG) fue creado para la detección de la resistencia a la insulina, y recientemente se ha empleado en la predicción de diabetes mellitus. El objetivo del presente estudio fue determinar el poder predictivo del índice TyG en una cohorte de la Ciudad de México.MétodosSe seleccionaron 3.195 pacientes de una cohorte de pacientes del área de crónico degenerativos de los Centros de Salud de los Servicios de Salud Pública de la Ciudad de México. Se evaluó la capacidad del índice TyG en la predicción de diabetes calculado como: ln (triglicéridos en ayunas [mg/dl]×glucosa en ayunas [mg/dl]/2) después de un seguimiento de al menos 4,5 años. Se determinó una prueba Chi-squared automated interaction detector analysis, que fue corroborada por una prueba ROC.ResultadosEl valor del índice de TyG fue significativamente mayor para los pacientes que desarrollar DM2. Los valores de área bajo la curva=0,934, intervalo de confianza (IC) 95%=0,924-0,924. Obteniendo un punto de corte de 9,45 en mujeres; en hombres: DM AUC=0.824, IC 95%=0,824-0,873 punto de corte 9.12.ConclusionesEl índice TyG es un buen marcador en la predicción de DM2 respaldado por la aplicación del algoritmo CHAID como herramienta útil para la predicción de DM2. (AU)

Introduction: In Mexico, type 2 Diabetes mellitus (DM2) presents epidemiological levels with a prevalence rate of 9.12% and with the highest overweight and obesity rates worldwide. To overcome this situation, strategies must be created focused on the identification of subjects at risk. The Triglyceride and Glucose (TyG) index, was created for the detection of insulin resistance, has recently been used in the prediction of DM. The objective of the present study was to determine the predictive power of the TyG index in a cohort from Mexico City.Methods3195 patients were selected from a cohort of patients from the chronic degenerative area of the Health Centers of the Public Health Services of Mexico City. The ability of the TyG index in predicting diabetes was evaluated as: ln [Fasting triglycerides (mg/dl) x fasting glucose (mg/dl)/2]. after a follow-up of at least 4.5 years. A CHAID test was determined that was corroborated by a ROC test.Resultsthe value of the TyG index was significantly higher for patients who develop DM2. Values of AUC=0.934, 95% CI: 0.924-0.924. Obtaining a cut-off point of 9.45 in women; in men: DM2 AUC=0.824, 95% CI: 0.824-0.873, and cut-off point 9.12.ConclusionsThe TyG index is a good marker in the prediction of DM2. The CHAID determination is a useful tool in the prediction of DM2. (AU)

Losartan controls immune checkpoint blocker-induced edema and improves survival in glioblastoma mouse models.

Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma trials. Here, we found that ICBs induce cerebral edema in some patients and mice with glioblastoma. Through single-cell RNA sequencing, intravital imaging, and CD8+ T cell blocking studies in mice, we demonstrated that this edema results from an inflammatory response following antiprogrammed death 1 (PD1) antibody treatment that disrupts the blood-tumor barrier. Used in lieu of immunosuppressive corticosteroids, the angiotensin receptor blocker losartan prevented this ICB-induced edema and reprogrammed the tumor microenvironment, curing 20% of mice which increased to 40% in combination with standard of care treatment. Using a bihemispheric tumor model, we identified a "hot" tumor immune signature prior to losartan+anti-PD1 therapy that predicted long-term survival. Our findings provide the rationale and associated biomarkers to test losartan with ICBs in glioblastoma patients.

MITF Downregulation Induces Death in Human Mast Cell Leukemia Cells and Impairs IgE-Dependent Degranulation.

Activating mutations in KIT (CD117) have been associated with several diseases, including gastrointestinal stromal tumors and mastocytosis. Rapidly progressing pathologies or drug resistance highlight the need for alternative treatment strategies. Previously, we reported that the adaptor molecule SH3 binding protein 2 (SH3BP2 or 3BP2) regulates KIT expression at the transcriptional level and microphthalmia-associated transcription factor (MITF) expression at the post-transcriptional level in human mast cells and gastrointestinal stromal tumor (GIST) cell lines. Lately, we have found that the SH3BP2 pathway regulates MITF through miR-1246 and miR-5100 in GIST. In this study, miR-1246 and miR-5100 were validated by qPCR in the SH3BP2-silenced human mast cell leukemia cell line (HMC-1). MiRNA overexpression reduces MITF and MITF-dependent target expression in HMC-1. The same pattern was observed after MITF silencing. In addition, MITF inhibitor ML329 treatment reduces MITF expression and affects the viability and cell cycle progression in HMC-1. We also examine whether MITF downregulation affected IgE-dependent mast cell degranulation. MiRNA overexpression, MITF silencing, and ML329 treatment reduced IgE-dependent degranulation in LAD2- and CD34+-derived mast cells. These findings suggest MITF may be a potential therapeutic target for allergic reactions and deregulated KIT mast-cell-mediated disorders.

LincRNA-Cox2 Regulates Smoke-induced Inflammation in Murine Macrophages.

Cigarette smoke (CS) exposure is a risk factor for many chronic diseases, including chronic obstructive pulmonary disease, but the mechanism by which smoke exposure can alter homeostasis and bring about chronic inflammation is poorly understood. Here, we showcase a novel role for smoke in regulating long noncoding RNAs, showing that it activates lincRNA-Cox2, which we previously characterized as functional in inflammatory regulation. Exposing lincRNA-Cox2 murine models to smoke in vivo confirmed lincRNA-Cox2 as a regulator of inflammatory gene expression in response to smoke both systemically and within the lung. We also report that lincRNA-Cox2 negatively regulates genes in smoked bone marrow-derived macrophages exposed to LPS stimulation. In addition to the effects on long noncoding RNAs, we also report dysregulated transcription and splicing of inflammatory protein-coding genes in the bone marrow niche after CS exposure in vivo. Collectively, this work provides insights into how innate immune signaling from gene expression to splicing is altered after in vivo exposure to CS and highlights an important new role for lincRNA-Cox2 in regulating immune genes after smoke exposure.

The microphthalmia-associated transcription factor is involved in gastrointestinal stromal tumor growth.

Gastrointestinal stromal tumors (GISTs) are the most common neoplasms of mesenchymal origin, and most of them emerge due to the oncogenic activation of KIT or PDGFRA receptors. Despite their relevance in GIST oncogenesis, critical intermediates mediating the KIT/PDGFRA transforming program remain mostly unknown. Previously, we found that the adaptor molecule SH3BP2 was involved in GIST cell survival, likely due to the co-regulation of the expression of KIT and Microphthalmia-associated transcription factor (MITF). Remarkably, MITF reconstitution restored KIT expression levels in SH3BP2 silenced cells and restored cell viability. This study aimed to analyze MITF as a novel driver of KIT transforming program in GIST. Firstly, MITF isoforms were characterized in GIST cell lines and GIST patients' samples. MITF silencing decreases cell viability and increases apoptosis in GIST cell lines irrespective of the type of KIT primary or secondary mutation. Additionally, MITF silencing leads to cell cycle arrest and impaired tumor growth in vivo. Interestingly, MITF silencing also affects ETV1 expression, a linage survival factor in GIST that promotes tumorigenesis and is directly regulated by KIT signaling. Altogether, these results point to MITF as a key target of KIT/PDGFRA oncogenic signaling for GIST survival and tumor growth.

[Diabetes mellitus prediction based on the triglyceride and glucose index]. / Predicción de diabetes mellitus basada en el índice triglicéridos y glucosa.

INTRODUCTION: In Mexico, type 2 Diabetes mellitus (DM2) presents epidemiological levels with a prevalence rate of 9.12% and with the highest overweight and obesity rates worldwide. To overcome this situation, strategies must be created focused on the identification of subjects at risk. The Triglyceride and Glucose (TyG) index, was created for the detection of insulin resistance, has recently been used in the prediction of DM. The objective of the present study was to determine the predictive power of the TyG index in a cohort from Mexico City. METHODS: 3195 patients were selected from a cohort of patients from the chronic degenerative area of the Health Centers of the Public Health Services of Mexico City. The ability of the TyG index in predicting diabetes was evaluated as: ln [Fasting triglycerides (mg/dl) x fasting glucose (mg/dl)/2]. after a follow-up of at least 4.5 years. A CHAID test was determined that was corroborated by a ROC test. RESULTS: the value of the TyG index was significantly higher for patients who develop DM2. Values of AUC=0.934, 95% CI: 0.924-0.924. Obtaining a cut-off point of 9.45 in women; in men: DM2 AUC=0.824, 95% CI: 0.824-0.873, and cut-off point 9.12. CONCLUSIONS: The TyG index is a good marker in the prediction of DM2. The CHAID determination is a useful tool in the prediction of DM2.

SH3BP2 Silencing Increases miRNAs Targeting ETV1 and Microphthalmia-Associated Transcription Factor, Decreasing the Proliferation of Gastrointestinal Stromal Tumors.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Gain of function in receptor tyrosine kinases type III, KIT, or PDGFRA drives the majority of GIST. Previously, our group reported that silencing of the adaptor molecule SH3 Binding Protein 2 (SH3BP2) downregulated KIT and PDGFRA and microphthalmia-associated transcription factor (MITF) levels and reduced tumor growth. This study shows that SH3BP2 silencing also decreases levels of ETV1, a required factor for GIST growth. To dissect the SH3BP2 pathway in GIST cells, we performed a miRNA array in SH3BP2-silenced GIST cell lines. Among the most up-regulated miRNAs, we found miR-1246 and miR-5100 to be predicted to target MITF and ETV1. Overexpression of these miRNAs led to a decrease in MITF and ETV1 levels. In this context, cell viability and cell cycle progression were affected, and a reduction in BCL2 and CDK2 was observed. Interestingly, overexpression of MITF enhanced cell proliferation and significantly rescued the viability of miRNA-transduced cells. Altogether, the KIT-SH3BP2-MITF/ETV1 pathway deserves to be considered in GIST cell survival and proliferation.

Periodontal Disease in Obese Patients; Interleukin-6 and C-Reactive Protein Study: A Systematic Review.

Periodontal disease (PD) and obesity are characterized by a dysregulated inflammatory state. Both conditions trigger inflammatory and immune responses with an increase in proinflammatory cytokines such as Interleukin 6 (IL-6) and the release of inflammatory mediators such as C-reactive protein (CRP). Individuals with a high body mass index (BMI) present a chronic inflammatory state. The aim of the present study was to perform a systematic review of inflammatory markers (IL-6 and CRP) in obese patients with PD and their possible relationship by analyzing the levels of these markers. A digital literature search was performed in three databases-PubMed, SciElo and Medigraphic-through an advanced search for original articles, employing IL-6 and CRP in obese patients with PD, within a publication period from 2010 to 2021. PRISMA guidelines, the JADAD scale and a qualitative analysis of scientific evidence were performed using the Cochrane collaboration method and the RoB 2 assessment tool. Ten articles were included in this analysis with the variables recorded and associated with subjects with obesity and PD. Of the ten articles included, three analyzed IL-6 and CRP, four analyzed IL-6 and three analyzed CRP. In conclusion, and based on the available evidence, the aforementioned markers of inflammation demonstrate that there is a relationship between PD and obesity.

Ergonomic Maturity Model: A tool for integrating ergonomics/human factors into organizations.

BACKGROUND: Currently, there is a need for models, methods, and tools that allow ergonomics/human factor (E/HF) practitioners to assess the level of E/HF integration into organizations from a macroergonomics perspective. OBJECTIVE: This paper aims to propose the Ergonomic Maturity Model (EMM) and the tools for its application as a framework for integrating E/HF in organizations. METHODS: The EMM is a macroergonomic tool that allows stakeholders to evaluate the degree of development and integration of E/HF in the organization based on a participatory and macroergonomic approach. The EMM classifies organizations into five gradual levels of maturity: Ignorance, Understanding, Experimentation, Regular use, and Innovation. RESULTS: In this paper, we provide a three-stage procedure for guiding the application of the EMM: preparation of the evaluation, evaluation, and improvement plan and implementation. We include four tools developed specifically for applying EMM in organizations: evaluation matrix, weighting questionnaire, quick questionnaire, and prioritization matrix. Also, we present a Colombian floriculture company's case study to exemplify the use of the EMM. CONCLUSIONS: The EMM provides a framework for integrating E/HF into organizations from the macroergonomics approach. E/HF practitioners can find in the EMM a tool to help them channel the actions taken by the different organizational actors to improve the safety, health, well-being, and performance of work systems. Finally, it should be noted that further studies on the reliability and validity of the EMM are needed, which would contribute to demonstrating that the EMM can effectively and successfully guide change in E/HF maturity levels in organizations.