Enhanced radiosensitivity of pancreatic cancer achieved through inhibition of Cyclin-dependent kinase 1.

BACKGROUND AND PURPOSE: Overcoming radioresistance is a critical challenge in pancreatic ductal adenocarcinoma (PDAC). Our study investigates the targeting of Cyclin-dependent kinase-1 (CDK1) through genetic and pharmaceutical inhibition to radiosensitize PDAC cells. MATERIALS AND METHODS: Mass spectrometry and phosphoproteomics were used to analyze engineered radiation-resistant PDAC cell lines (MIA PaCa-2 and PANC-1) compared to parental controls. The TCGA PDAC database was queried for clinical outcomes and patients were dichotomized based on the median CDK1 mRNA expression. We generated a microRNA-based TET-on inducible shRNA to inhibit CDK1 expression in two PDAC cell lines. We used an orthotopic model of PDAC to test the radiation sensitivity of PDAC tumors with or without doxycycline treatment. We targeted CDK1 activation with a selective CDK1 inhibitor, RO-3306, followed by in vitro experiments employing immunoblotting, immunocytochemistry, and clonogenic assays. RESULTS: Phosphoproteomics analysis revealed that phospho-CDK1 (Tyr15) was significantly elevated in the resistant clones. We found that high CDK1 expression was associated with worse OS in PDAC patients. Radiation exposure increased CDK1 phosphorylation. In MIA PaCa-2 and PANC-1 cells, CDK1 inhibition synergized with radiation therapy to delay tumor growth in vivo. CDK1 inhibition via. RO-3306 resulted in a significant shift of cells into the G2/M phase and disrupted DNA repair after radiation exposure. In vitro, pre-treatment with RO-3306 led to enhanced radiosensitivity of PDAC cells. CONCLUSION: CDK1 plays a crucial role in PDAC radioresistance. Targeting CDK1 with radiotherapy holds promise for further investigation in PDAC treatment.

RAS-RAF-miR-296-3p signaling axis increases Rad18 expression to augment radioresistance in pancreatic and thyroid cancers.

Oncogenic RAS and RAF signaling has been implicated in contributing to radioresistance in pancreatic and thyroid cancers. In this study, we sought to better clarify molecular mechanisms contributing to this effect. We discovered that miRNA 296-3p (miR-296-3p) is significantly correlated with radiosensitivity in a panel of pancreatic cancer cells, and miR-296-3p is highly expressed in normal cells, but low in cancer cell lines. Elevated expression of miR-296-3p increases radiosensitization while decreasing the expression of the DNA repair enzyme RAD18 in both pancreatic and thyroid cancer cells. RAD18 is overexpressed in both pancreatic and thyroid tumors compared to matched normal controls, and high expression of RAD18 in tumors is associated with poor prognostic features. Modulating the expression of mutant KRAS in pancreatic cancer cells or mutant BRAF in thyroid cancer cells demonstrates a tight regulation of RAD18 expression in both cancer types. Depletion of RAD18 results in DNA damage and radiation-induced cell death. Importantly, RAD18 depletion in combination with radiotherapy results in marked and sustained tumor regression in KRAS mutant pancreatic cancer orthotopic tumors and BRAF mutant thyroid heterotopic tumors. Overall, our findings identify a novel coordinated RAS/RAF-miR-296-3p-RAD18 signaling network in pancreatic and thyroid cancer cells, which leads to enhanced radioresistance.

Discovery of the inhibitor of DNA binding 1 as a novel marker for radioresistance in pancreatic cancer using genome-wide RNA-seq.

Purpose/Objective(s): Discovery of genetic drivers of radioresistance is critical for developing novel therapeutic strategies to combine with radiotherapy of radioresistant PDAC. In this study, we used genome-wide RNA-seq to identify genes upregulated in generated radioresistant PDAC cell lines and discovered the Inhibitor of DNA Binding 1 (ID1) gene as a potential regulator of radioresistance in PDAC. Materials/Methods: Radioresistant clones of the PDAC cell lines MIA PaCa-2 and PANC-1 were generated by delivering daily ionizing irradiation (IR) (2 Gy/day) in vitro over two weeks (total 20 Gy) followed by standard clonogenic assays following one week from the end of IR. The generated RR and parental cell lines were submitted for RNA-seq analysis to identify differentially expressed genes. The Limma R package was used to calculate differential expression among genes. Log2 fold change values were calculated for each sample compared to the control. Genes with an absolute fold change > 1 were considered significant. RNA sequencing expression data from the Cancer Genome Atlas (TCGA) database was analyzed through the online databases GEPIA, cBioPortal, and the Human Protein Atlas. Results: Following exposure to two weeks of 2 Gy daily IR in vitro, the two PDAC cell lines showed significantly greater clonogenic cell survival than their parental cell lines, indicating enhanced RR in these cells. RNA-seq analysis comparing parental and RR cell lines found upregulated seven genes (TNS4, ZDHHC8P1, APLNR, AQP3, SPP1, ID1, ID2) and seven genes downregulated (PTX3, ITGB2, EPS8L1, ALDH1L2, KCNT2, ARHGAP9, IFI16) in both RR cell lines. Western blotting confirmed increased expression of the ID1 protein in the RR cell lines compared to their parental cell lines. We found that ID1 mRNA was significantly higher in PDAC tumors compared to matched normal and high ID1 expression correlated with significantly worse disease-free survival (DFS) in PDAC patients (HR = 2.2, log rank P = 0.009). ID1 mRNA expression was also strongly correlated in tumors with TP53 mutation, a known driver of radioresistance. Conclusion: Our analysis indicates a novel role of ID1 in PDAC radioresistance. ID1 expression is higher in tumor tissue compared to normal, and high expression correlates with both worse DFS and association with the TP53 mutation, suggesting that targeting ID1 prior to IR is an attractive strategy for overcoming radioresistance in PDAC.

Caracterización clínico epidemiológica de la diabetes mellitus tipo 1 en pediatría, Hospital Mario Catarino Rivas / Epidemiological Clinical characterization of diabetes mellitus type 1 in pediatrics, Mario Catarino Rivas Hospital

Antecedentes: Diabetes Mellitus (DM) se consi- dera una enfermedad metabólica con hiperglu- cemia de forma crónica, causada por un déficit parcial o total en la secreción o acción de la in- sulina. El 70-90% de DM1 tienen base autoin- mune. Objetivo: Describir las características clí- nico- epidemiológicas de Diabetes Mellitus I en Pediatría del Hospital Mario Catarino Rivas, San Pedro Sula, Cortés, en el período comprendido entre junio de 2017 - junio de 2019. Pacientes y métodos: Estudio cuantitativo, descriptivo, observacional, realizado en pacientes menores de 18 años que reunieron criterios de inclusión. Los datos se recolectaron mediante encuesta. Re- sultados: El grupo de edad más frecuente fue el escolar de 6-12 años en 49%. Mas frecuente en mujeres en 51%, 29% de los pacientes estudiados presentaron sedentarismo, 17% dislipidemias y sobrepeso, diagnosticadas en el debut de la enfer- medad. Los síntomas más frecuentes fueron po- lifagia en 44%, poliuria en 21%. Conclusiones: Las características socio-demográficas del grupo poblacional estudiado fueron las siguientes, el sexo más afectado fue el femenino y el grupo de edad más frecuente los escolares que se encuen- tran cursando la primaria, la mayoría de los pa- cientes estudiados no presentaban enfermedades asociadas, mientras que solo unos pocos presen- taban sobrepeso y dislipidemias asociado a Dia- betes Mellitus tipo I, se observó un predominio del debut sintomático asociado con la triada de polifagia, polidipsia y poliuria, además visión borrosa y pérdida de peso...(AU)

INCIDENCIA DEL RÍO BOGOTÁ EN LA CALIDAD MICROBIOLÓGICA DEL AGUA DEL RÍO MAGDALENA, MUNICIPIO DE FLANDES (TOLIMA) / IMPACT OF THE BOGOTÁ RIVER ON THE MICROBIOLOGICAL QUALITY OF THE WATER OF THE MAGDALENA RIVER, MUNICIPALITY OF FLANDES (TOLIMA)

La cuenca del río Bogotá está considerada como la más contaminada de Colombia, producto de la descarga de aguas residuales de una población superior a 7 millones de habitantes; aguas que al desembocar en la margen derecha del río Magdalena ­principal arteria fluvial nacional­ deterioran su calidad y ponen en potencial riesgo la salud de una vasta población de la región central del país que se abastece de esta fuente hídrica para consumo humano, riego y contacto primario. En esta investigación se evaluó la incidencia del río Bogotá en la contaminación microbiológica del río Magdalena que sirve de fuente de abastecimiento del acueducto urbano del municipio de Flandes, departamento del Tolima, durante la ocurrencia del fenómeno de El Niño entre 2015-2016. Se realizaron muestreos en 4 puntos estratégicos a partir de ensayos microbiológicos efectuados en el tramo del río Magdalena, comprendido desde antes de la desembocadura del río Bogotá hasta la captación del acueducto urbano de Flandes, durante dos temporadas diferentes: la seca en el mes de febrero de 2016 y de lluvia en abril de 2016. Se concluyó que es una fuente de abastecimiento muy deficiente para consumo humano a partir de la contaminación microbiológica que le incorpora el río Bogotá, en especial en temporada seca, incidiendo en la calidad del agua captada por el acueducto de Flandes que puede llegar a implicar riesgo a la salud, requiriéndose a corto plazo la incorporación de nuevos procesos en su sistema de tratamiento para garantizar la remoción de la carga microbiológica.

The basin of the Bogotá River is considered the most polluted basin in Colombia due to the discharge of wastewater from a population of over 7 million inhabitants. These waters that flow into the right bank of the Magdalena River -the main national fluvial artery- deteriorate their quality and potential putting at risk the health of a vast population of the central region of the country that is supplied with this water source for human consumption, irrigation and primary contact. This research evaluated the impact of the Bogotá River in the microbiological contamination of the Magdalena River that serves as a source of supply for the urban aqueduct in the municipality of Flandes, Department of Tolima, during the occurrence of El Niño phenomenon between 2015 and 2016. Samplings were completed at 4 strategic points from microbiological tests carried out in the Magdalena River section containing the area before the mouth of the Bogota River to the catchment of the urban aqueduct of Flandes during two different seasons, the dry season in the month of February 2016, and the rainy season in April 2016. It was concluded that it is a very poor source of supply for human consumption based on the microbiological contamination that the Bogota River adds especially in the dry season, affecting the quality of the water collected by the aqueduct of Flandes that may imply a health risk, requiring the incorporation of new processes in its treatment system in a short-term to guarantee the removal of the microbiological load.

Talla alta, sindrome XYY: presentación de un caso / High -Class, XYY Syndrome: case report

Los niños y hombres con el síndrome 47 XYY tienen dos cromosomas Y en vez de uno. Esto significa que tienen 47 cromoso- mas en lugar de 46. El cromosoma adicional se obtuvo durante la formación del esperma que se juntó con el óvulo al formar el feto o durante el desarrollo temprano del feto, justo después de la concepción. El cromo - soma extra no puede ser removido nunca. El síndrome 47 XYY ocurre al azar. (1). Algunos médicos genetistas cuestionan si el uso del término «síndrome¼ es apropiado para ésta anomalía, porque el fenotipo es normal. (2). Las personas 47 XYY , presentan un aspecto físico normal, y se caracterizan por una estatura alta, que se hace más evidente en la adolescencia. (1, 2, 3)...(AU)