Intraoperative Transient Central Diabetes Insipidus Status Post-Cerebellopontine Meningioma Resection: A Case Report.

Central diabetes insipidus (CDI) is a neurological pathological condition in which vasopressin synthesis has been compromised. A 52-year-old male presented with a cerebellopontine angle mass not involving the hypothalamic-pituitary axis. Despite vasopressin therapy, the patient produced a total of 8650 mL of urine, with the urine-specific gravity measured at 1.002 near hour 8. A literature review found associations with certain anesthetic drugs that have an increased incidence of CDI, including alpha-2 agonists and sevoflurane. Reports have recommended administering desmopressin over vasopressin, especially for neurosurgery cases that warrant a more extended operative period, given that desmopressin has a longer context-sensitive half-life.

Metabolism and epigenetics: drivers of tumor cell plasticity and treatment outcomes.

Emerging evidence indicates that metabolism not only is a source of energy and biomaterials for cell division but also acts as a driver of cancer cell plasticity and treatment resistance. This is because metabolic changes lead to remodeling of chromatin and reprogramming of gene expression patterns, furthering tumor cell phenotypic transitions. Therefore, the crosstalk between metabolism and epigenetics seems to hold immense potential for the discovery of novel therapeutic targets for various aggressive tumors. Here, we highlight recent discoveries supporting the concept that the cooperation between metabolism and epigenetics enables cancer to overcome mounting treatment-induced pressures. We discuss how specific metabolites contribute to cancer cell resilience and provide perspective on how simultaneously targeting these key forces could produce synergistic therapeutic effects to improve treatment outcomes.

Transcriptional programming of translation by BCL6 controls skeletal muscle proteostasis.

Skeletal muscle is dynamically controlled by the balance of protein synthesis and degradation. Here we discover an unexpected function for the transcriptional repressor B cell lymphoma 6 (BCL6) in muscle proteostasis and strength in mice. Skeletal muscle-specific Bcl6 ablation in utero or in adult mice results in over 30% decreased muscle mass and force production due to reduced protein synthesis and increased autophagy, while it promotes a shift to a slower myosin heavy chain fibre profile. Ribosome profiling reveals reduced overall translation efficiency in Bcl6-ablated muscles. Mechanistically, tandem chromatin immunoprecipitation, transcriptomic and translational analyses identify direct BCL6 repression of eukaryotic translation initiation factor 4E-binding protein 1 (Eif4ebp1) and activation of insulin-like growth factor 1 (Igf1) and androgen receptor (Ar). Together, these results uncover a bifunctional role for BCL6 in the transcriptional and translational control of muscle proteostasis.

Dissecting the oncogenic properties of essential RNA-modifying enzymes: a focus on NAT10.

Chemical modifications of ribonucleotides significantly alter the physicochemical properties and functions of RNA. Initially perceived as static and essential marks in ribosomal RNA (rRNA) and transfer RNA (tRNA), recent discoveries unveiled a dynamic landscape of RNA modifications in messenger RNA (mRNA) and other regulatory RNAs. These findings spurred extensive efforts to map the distribution and function of RNA modifications, aiming to elucidate their distribution and functional significance in normal cellular homeostasis and pathological states. Significant dysregulation of RNA modifications is extensively documented in cancers, accentuating the potential of RNA-modifying enzymes as therapeutic targets. However, the essential role of several RNA-modifying enzymes in normal physiological functions raises concerns about potential side effects. A notable example is N-acetyltransferase 10 (NAT10), which is responsible for acetylating cytidines in RNA. While emerging evidence positions NAT10 as an oncogenic factor and a potential target in various cancer types, its essential role in normal cellular processes complicates the development of targeted therapies. This review aims to comprehensively analyze the essential and oncogenic properties of NAT10. We discuss its crucial role in normal cell biology and aging alongside its contribution to cancer development and progression. We advocate for agnostic approaches to disentangling the intertwined essential and oncogenic functions of RNA-modifying enzymes. Such approaches are crucial for understanding the full spectrum of RNA-modifying enzymes and imperative for designing effective and safe therapeutic strategies.

Transcriptome reprogramming through alternative splicing triggered by apigenin drives cell death in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is characterized by its aggressiveness and resistance to cancer-specific transcriptome alterations. Alternative splicing (AS) is a major contributor to the diversification of cancer-specific transcriptomes. The TNBC transcriptome landscape is characterized by aberrantly spliced isoforms that promote tumor growth and resistance, underscoring the need to identify approaches that reprogram AS circuitry towards transcriptomes, favoring a delay in tumorigenesis or responsiveness to therapy. We have previously shown that flavonoid apigenin is associated with splicing factors, including heterogeneous nuclear ribonucleoprotein A2 (hnRNPA2). Here, we showed that apigenin reprograms TNBC-associated AS transcriptome-wide. The AS events affected by apigenin were statistically enriched in hnRNPA2 substrates. Comparative transcriptomic analyses of human TNBC tumors and non-tumor tissues showed that apigenin can switch cancer-associated alternative spliced isoforms (ASI) to those found in non-tumor tissues. Apigenin preferentially affects the splicing of anti-apoptotic and proliferation factors, which are uniquely observed in cancer cells, but not in non-tumor cells. Apigenin switches cancer-associated aberrant ASI in vivo in TNBC xenograft mice by diminishing proliferation and increasing pro-apoptotic ASI. In accordance with these findings, apigenin increased apoptosis and reduced tumor proliferation, thereby halting TNBC growth in vivo. Our results revealed that apigenin reprograms transcriptome-wide TNBC-specific AS, thereby inducing apoptosis and hindering tumor growth. These findings underscore the impactful effects of nutraceuticals in altering cancer transcriptomes, offering new options to influence outcomes in TNBC treatments.

Splicing reprogramming of TRAIL/DISC-components sensitizes lung cancer cells to TRAIL-mediated apoptosis.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selective killing of cancer cells underlines its anticancer potential. However, poor tolerability and resistance underscores the need to identify cancer-selective TRAIL-sensitizing agents. Apigenin, a dietary flavonoid, sensitizes lung cancer cell lines to TRAIL. It remains unknown, however, whether apigenin sensitizes primary lung cancer cells to TRAIL and its underlying mechanisms. Here we show that apigenin reprograms alternative splicing of key TRAIL/death-inducing-signaling-complex (DISC) components: TRAIL Death Receptor 5 (DR5) and cellular-FLICE-inhibitory-protein (c-FLIP) by interacting with the RNA-binding proteins hnRNPA2 and MSI2, resulting in increased DR5 and decreased c-FLIPS protein levels, enhancing TRAIL-induced apoptosis of primary lung cancer cells. In addition, apigenin directly bound heat shock protein 70 (Hsp70), promoting TRAIL/DISC assembly and triggering apoptosis. Our findings reveal that apigenin directs alternative splicing and inhibits Hsp70 enhancing TRAIL anticancer activity. These findings underscore impactful synergies between diet and cancer treatments opening new avenues for improved cancer treatments.

Microbiological characteristics of infections in a group of colombian patients with oncological diagnosis, 2014 - 2016 / Características microbiológicas de infecciones en un grupo de colombianos con diagnóstico oncológico, 2014 - 2016

Objective: We aimed to describe the microbiological characteristics of infections in patients from an oncological center during 2.014-2.016. Methods: In this cross-sectional descriptive study, a total of 7.837 cultures corresponding to 1.216 patients were included. Microbiological and sociodemographic data were taken from cancer diagnosed patients admitted to Oncólogos de Occidente S.A. in Pereira, Armenia, Manizales and Cartago from January 2.014 to December 2.016. The bacterial resistance profiles were defined according to the CLSI guideline. Culture foci were blood, urine, tissue biopsies, skin and soft tissues, mucous membranes and feces. Results: The culture-positive rate was 27,94%. Amongst 2.190 isolates, Escherichia coli (22,42%) was the most frequent, followed by Klebsiella pneumonia (21,27%), Pseudomona aeruginosa (13,83%) and Staphylococcus aureus (5,11%). The most common mechanisms of antimicrobial resistance in Gram-negatives were Extended-Spectrum β-Lactamase (45,45%) and AmpC-type β-lactamases (37,71%). Discussion: Up to nearly one-third of our participants' cultures were positive and a vast majority were gram-negatives, provided with ESBLs or AmpCs which in oncological patients it is a catastrophic outcome. We recommend to establish antibiotic dispensing policies thus achieving a microbiological risk control and improve the epidemiological surveillance. Empirical use of beta-lactams with extended spectrum or cephalosporins of 1 to 3 generation is not recommended due to the high resistance found.

Objetivo: Describir las características microbiológicas de las infecciones en pacientes de un centro oncológico durante 2.014-2.016 Métodos: Estudio descriptivo, transversal. Incluyó 7.837 cultivos de 1.216 pacientes. Se recolectaron variables microbiológicas y sociodemográficas de pacientes diagnosticados con cáncer en las sedes de Pereira, Armenia, Manizales y Cartago de Oncólogos de Occidente S.A. durante 2.014 hasta 2.016. Los perfiles de resistencia bacteriana se definieron de acuerdo con la guía CLSI. Los focos de cultivo fueron sangre, orina, biopsias de tejidos, piel y tejidos blandos, membranas mucosas y heces. Resultados: La tasa de cultivo positivo fue del 27,94%. De 2.190 aislamientos, E. coli (22,42%) fue el más frecuente, seguido de K. pneumoniae (21,27%), P. aeruginosa (13,83%) y S. aureus (5,11%). Los principales mecanismos de resistencia identificados en Gram negativos fueron β-lactamasas de espectro extendido (45,45%) y β-lactamasa de tipo AmpC (37,71%). Discusión: Cerca de un tercio de los cultivos de los participantes fueron positivos y una vasta mayoría fueron gram negativos, provistos con ESBL o AmpC, lo que en pacientes oncológicos es un desenlace catastrófico. Recomendamos establecer políticas de dispensación de antibióticos, logrando así un control de riesgo microbiológico y mejorar la vigilancia epidemiológica. No se recomienda el uso empírico de betalactámicos con espectro extendido o cefalosporinas de 1 a 3 generación debido a la alta tasa de resistencia encontrada.

Serosurveillance for vaccine-preventable diseases: A look inside the pertussis experience / Serovigilancia de enfermedades prevenibles por vacunación: una mirada desde la experiencia con la tosferina

Abstract Introduction: Serological surveillance (serosurveillance) provides the most direct measure of herd immunity of vaccine-preventable diseases. Little is known about the opportunities and challenges of serosurveillance experiences, particularly pertussis. Objective: To describe the process of serosurveillance for vaccine-preventable diseases with an emphasis on the experience of pertussis in the metropolitan area of Antioquia (Valle de Aburrá) in 2015 and 2016 and analyze the contributions and challenges for its sustainability. Materials and methods: We described the planning and conduction of serosurveillance of pertussis antibodies of mothers and in the umbilical cord at the time of delivery in eight hospitals based on random sampling and their capacity to advance the serosurveillance periodically. We compared the contributions and the challenges of this experience with other probabilistic and non-probabilistic programs. Results: We achieved the participation of hospitals and mothers respecting the delivery care process. We established a serum bank following ethical and technical guidelines. This program based on the random selection of hospitals and mothers has enabled the estimation of antibodies prevalence in mothers and in the umbilical cord, which has been possible given the high coverage of hospital care during childbirth at a lower cost and fewer risks than a population-based survey in conflictive areas. The main challenges for the sustainability of this program are the creation of stable jobs and access to funding and legal and methodological long-term frameworks. Conclusions: Hospital serosurveillance as described is an option to monitor the impact of vaccination on the population. Our experience could be reproduced in other regions under similar conditions if the above-mentioned challenges are solved.

Resumen Introducción. La vigilancia serológica es la forma más directa de medir la inmunidad de rebaño frente a las enfermedades prevenibles por vacunación. Poco se sabe acerca de las oportunidades y los desafíos de las experiencias de serovigilancia, en general y, específicamente, la de la tosferina. Objetivo. Describir el proceso de serovigilancia de enfermedades prevenibles por vacunación con énfasis en la experiencia en el caso de la tosferina en el área metropolitana de Antioquia (Valle de Aburrá) en el 2015 y el 2016 y analizar lo que dicha experiencia ha aportado y los desafíos que persisten para su sostenibilidad. Materiales y métodos. Se describió el proceso de planeación y el desarrollo de la serovigilancia de tosferina en el momento del parto en ocho hospitales seleccionados al azar, así como la capacidad para adelantar el programa de manera periódica. Se compararon los aportes y los desafíos en el curso de esta experiencia con los de otros programas poblacionales probabilistas e institucionales no probabilistas. Resultados. Se logró la participación de los hospitales y de las madres con pleno respeto del proceso de atención del parto, y se conformó un banco de sueros siguiendo lineamientos éticos y técnicos. El programa permitió estimar la prevalencia de anticuerpos en la madre y en el cordón umbilical, lo que se facilitó por la alta cobertura de atención hospitalaria del parto, a un menor costo y menos riesgos que los programas poblacionales en zonas conflictivas. Los principales desafíos para la sostenibilidad del programa son la estabilidad laboral del personal de salud, así como normas y una financiación de largo plazo. Conclusiones. La serovigilancia hospitalaria es una opción para monitorizar el impacto poblacional de la vacunación. Esta experiencia se podría extender a otras regiones en condiciones similares si se resuelven los retos mencionados.

Dietary Apigenin Exerts Immune-Regulatory Activity in Vivo by Reducing NF-κB Activity, Halting Leukocyte Infiltration and Restoring Normal Metabolic Function.

The increasing prevalence of inflammatory diseases and the adverse effects associated with the long-term use of current anti-inflammatory therapies prompt the identification of alternative approaches to reestablish immune balance. Apigenin, an abundant dietary flavonoid, is emerging as a potential regulator of inflammation. Here, we show that apigenin has immune-regulatory activity in vivo. Apigenin conferred survival to mice treated with a lethal dose of Lipopolysaccharide (LPS) restoring normal cardiac function and heart mitochondrial Complex I activity. Despite the adverse effects associated with high levels of splenocyte apoptosis in septic models, apigenin had no effect on reducing cell death. However, we found that apigenin decreased LPS-induced apoptosis in lungs, infiltration of inflammatory cells and chemotactic factors' accumulation, re-establishing normal lung architecture. Using NF-κB luciferase transgenic mice, we found that apigenin effectively modulated NF-κB activity in the lungs, suggesting the ability of dietary compounds to exert immune-regulatory activity in an organ-specific manner. Collectively, these findings provide novel insights into the underlying immune-regulatory mechanisms of dietary nutraceuticals in vivo.

Dietary apigenin reduces LPS-induced expression of miR-155 restoring immune balance during inflammation.

SCOPE: High incidence of inflammatory diseases afflicts the increasing aging-population infringing a great health burden. Dietary flavonoids, including the flavone apigenin, are emerging as important anti-inflammatory nutraceuticals due to their health benefits, lack of adverse effects and reduced costs. MicroRNAs (miRs) play a central role in inflammation by regulating gene expression, yet how dietary ingredients affect miRs is poorly understood. The aim of this study was to identify miRs involved in the anti-inflammatory activity of apigenin and apigenin-rich diets and determine their immune regulatory mechanisms in macrophages and in vivo. METHODS AND RESULTS: A high-throughput quantitative reverse transcriptase PCR screen of 312 miRs in macrophages revealed that apigenin reduced LPS-induced miR-155 expression. Analyses of miR-155 precursor and primary transcript indicated that apigenin regulated miR-155 transcriptionally. Apigenin-reduced expression of miR-155 led to the increase of anti-inflammatory regulators forkhead box O3a and smooth-muscle-actin and MAD-related protein 2 in LPS-treated macrophages. In vivo, apigenin or a celery-based apigenin-rich diet reduced LPS-induced expression of miR-155 and decreased tumor necrosis factor α in lungs from LPS-treated mice. CONCLUSION: These results demonstrate that apigenin and apigenin-rich diets exert effective anti-inflammatory activity in vivo by reducing LPS-induced expression of miR-155, thereby restoring immune balance.

Molecular basis for the action of a dietary flavonoid revealed by the comprehensive identification of apigenin human targets.

Flavonoids constitute the largest class of dietary phytochemicals, adding essential health value to our diet, and are emerging as key nutraceuticals. Cellular targets for dietary phytochemicals remain largely unknown, posing significant challenges for the regulation of dietary supplements and the understanding of how nutraceuticals provide health value. Here, we describe the identification of human cellular targets of apigenin, a flavonoid abundantly present in fruits and vegetables, using an innovative high-throughput approach that combines phage display with second generation sequencing. The 160 identified high-confidence candidate apigenin targets are significantly enriched in three main functional categories: GTPase activation, membrane transport, and mRNA metabolism/alternative splicing. This last category includes the heterogeneous nuclear ribonucleoprotein A2 (hnRNPA2), a factor involved in splicing regulation, mRNA stability, and mRNA transport. Apigenin binds to the C-terminal glycine-rich domain of hnRNPA2, preventing hnRNPA2 from forming homodimers, and therefore, it perturbs the alternative splicing of several human hnRNPA2 targets. Our results provide a framework to understand how dietary phytochemicals exert their actions by binding to many functionally diverse cellular targets. In turn, some of them may modulate the activity of a large number of downstream genes, which is exemplified here by the effects of apigenin on the alternative splicing activity of hnRNPA2. Hence, in contrast to small-molecule pharmaceuticals designed for defined target specificity, dietary phytochemicals affect a large number of cellular targets with varied affinities that, combined, result in their recognized health benefits.

Apigenin induces DNA damage through the PKCδ-dependent activation of ATM and H2AX causing down-regulation of genes involved in cell cycle control and DNA repair.

Apigenin, an abundant plant flavonoid, exhibits anti-proliferative and anti-carcinogenic activities through mechanisms yet not fully defined. In the present study, we show that the treatment of leukemia cells with apigenin resulted in the induction of DNA damage preceding the activation of the apoptotic program. Apigenin-induced DNA damage was mediated by p38 and protein kinase C-delta (PKCδ), yet was independent of reactive oxygen species or caspase activity. Treatment of monocytic leukemia cells with apigenin induced the phosphorylation of the ataxia-telangiectasia mutated (ATM) kinase and histone H2AX, two key regulators of the DNA damage response, without affecting the ataxia-telangiectasia mutated and Rad-3-related (ATR) kinase. Silencing and pharmacological inhibition of PKCδ abrogated ATM and H2AX phosphorylation, whereas inhibition of p38 reduced H2AX phosphorylation independently of ATM. We established that apigenin delayed cell cycle progression at G1/S and increased the number of apoptotic cells. In addition, genome-wide mRNA analyses showed that apigenin-induced DNA damage led to down-regulation of genes involved in cell-cycle control and DNA repair. Taken together, the present results show that the PKCδ-dependent activation of ATM and H2AX define the signaling networks responsible for the regulation of DNA damage promoting genome-wide mRNA alterations that result in cell cycle arrest, hence contributing to the anti-carcinogenic activities of this flavonoid.

Flavone deglycosylation increases their anti-inflammatory activity and absorption.

SCOPE: Flavones have reported anti-inflammatory activities, but the ability of flavone-rich foods to reduce inflammation is unclear. Here, we report the effect of flavone glycosylation in the regulation of inflammatory mediators in vitro and the absorption of dietary flavones in vivo. METHODS AND RESULTS: The anti-inflammatory activities of celery extracts, some rich in flavone aglycones and others rich in flavone glycosides, were tested on the inflammatory mediators tumor necrosis factor α (TNF-α) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in lipopolysaccharide-stimulated macrophages. Pure flavone aglycones and aglycone-rich extracts effectively reduced TNF-α production and inhibited the transcriptional activity of NF-κB, while glycoside-rich extracts showed no significant effects. Deglycosylation of flavones increased cellular uptake and cytoplasmic localization as shown by high-performance liquid chromatography (HPLC) and microscopy using the flavonoid fluorescent dye diphenylboric acid 2-aminoethyl ester (DPBA). Celery diets with different glycoside or aglycone contents were formulated and absorption was evaluated in mice fed with 5 or 10% celery diets. Relative absorption in vivo was significantly higher in mice fed with aglycone-rich diets as determined by HPLC-MS/MS (where MS/MS is tandem mass spectrometry). CONCLUSION: These results demonstrate that deglycosylation increases absorption of dietary flavones in vivo and modulates inflammation by reducing TNF-α and NF-κB, suggesting the potential use of functional foods rich in flavones for the treatment and prevention of inflammatory diseases.

Enfermedad de pompe: descripción de las características clínicas y de laboratorio de una familia colombiana / Pompe disease: clinical presentation in a colombian family

La enfermedad de Pompe (EP) es debida a la deficiencia de la enzima lisosomal maltasa ácida o alfa glucosidasa ácida (AGA) y se manifiesta clínicamente como una miopatía. La cantidad y calidad de la enzima determinan la variedad de presentación. A continuación se presentan las formas de debut, características clínicas, hallazgos de laboratorio y evolución de dos casos evaluados con EP.