Cyclin D1 and human papillomavirus implications in oropharyngeal cáncer

ABSTRACT : Oropharyngeal cancers (OPC) are subdivide in two different entities based on HPV infections, which are mainly by p16 subtype alone, due to better overall survival (OS) rates. However differences in the techniques used and the few cohorts looking for other HPV subtypes suggest the necessity to approach this further. Moreover, there is still a group of HPV+ patients that present a lethal and aggressive disease. Cyclin D1 overexpression has been proposed as a possible marker to better stratify these patients although results differed among studies. Due to that, this study aimed to assess HPV prevalence and subtypes in a cohort of 54 OPC patients from HUMV as well as Cyclin D1 expression among them to determine its effect on prognosis. Our results show a high HPV prevalence (38% of patients) and confirm HPV patients increased OS (p=0,035). p16 was the most common HPV-subtype (50%), followed by 59, 58 and 53. 38% of patients had multiple infections strongly contrasting with other cohorts (5%). Moreover, not significant differences were observed when looking at HPV+/cyclin D1 positive patients OS (p=0,933). However, due to low sample number and different cut-offs in other studies we can´t affirm this forcefully so further analysis should be done.RESUMEN : Los cánceres de orofaringe (CO) se pueden dividir en dos entidades diferentes en función de las infecciones por VPH, principalmente causadas por el subtipo 16, debido a una mejor supervivencia. Sin embargo, las diferencias en las técnicas usadas y las pocas cohortes mirando otros subtipos del VPH sugieren la necesidad profundizar más en este campo. Además, hay un grupo de pacientes VPH+ que presentan una enfermedad más letal y agresiva. La sobreexpresión de Ciclina D1 ha sido propuesta como un posible marcador para mejorar la estratificación de estos pacientes aunque los resultados difieren entre diferentes estudios. Debido a esto, este estudio tuvo el objetivo de determinar la prevalencia de VPH y sus subtipos en una cohorte de 54 pacientes de CO del HUMV así como la expresión de Ciclina D1 entre ellos para determinar los efectos en el pronóstico. Nuestros resultados muestran una prevalencia del 38% para el VPH y confirma el aumento de supervivencia entre estos pacientes (p=0,035). El subtipo 16 fue el más común (50%), seguido por 59, 58 y 53. El 38% de los pacientes están infectados por múltiples subtipos lo que contrasta con otras cohortes (5%). Además, no vimos diferencias significativas en la supervivencia cuando miramos a los pacientes positivos para VPH y Ciclina D1 (p=0,933). Sin embargo, debido al bajo número de muestras y diferencias en el corte en la expresión de Ciclina D1 no podemos afirmar esto por lo que nuevos análisis deben de hacerse.Grado en Medicin

Ras site-specific effects in thyroid cáncer

RESUMEN: El oncógeno RAS, frecuentemente mutado en cáncer de tiroides, está presente en diferentes localizaciones celulares, como en las balsas lipídicas (BL) o en membrana desordenada (MD), donde su distribución está modulada por la depalmitoilasa, APT-1, y en Retículo Endoplasmático (RE) y el Complejo de Golgi (CG). Sin embargo, poco se ha sabe de cómo la sublocalización de RAS afectan a su potencial oncogénico. Para analizar los efectos de las sublocalizaciones de RAS en el cáncer de tiroides utilizamos las células PCCL3 expresando H- o N-RASv12 en RE, BL, MD y CG. Al mirar el papel de RAS in vivo en el modelo de metástasis del embrión de pollo, vimos que los tumores más pequeños, generados por RAS en MD y CG, eran los más metastáticos lo que confirmamos en líneas de tiroides con H-RAS endógeno mutado localizado en BL, C643, ó MD, HTH83. Además, la modificación de APT-1 fue capaz de promover la translocación de H-RAS, modificando los efectos en crecimiento tumoral y metástasis de las dos líneas celulares. Además, hemos visto que las sublocalizaciones de RAS afectan la biogénesis, secreción y cargo de los exosomas demostrando que los exosomas secretados por células con RAS en MD y CG son capaces de transferir su potencial metastático a otras células lo que abre nuevas puertas para el diagnóstico y seguimiento de los pacientes con cáncer de tiroides.ABSTRACT: RAS, is frequently mutated in thyroid cancer, where it can be present at different subcellular locations, such as at lipids rafts (LR) or disordered membrane (DM), where acyl-protein thioesterase 1 (APT-1) control its distribution, and at Endoplasmic Reticulum (ER) and at Golgi Complex (GC). However, little is known about how RAS sublocalizations affect its oncogenic potential. To explore their effects in thyroid cancer we used PCCL3 cells expressing H- or N-RASv12 at ER, LR, DM or GC. When we looked at RAS effects using the chick embryo metastasis model, we saw that the smaller tumors, generated by RAS at DM or GC, were surprisingly the most metastatic ones. We confirmed the effects of these subcellular locations using cells with endogenous H-RAS mutated at DM, HTH83, or at LR, C643. Moreover, APT-1 modification was capable to translocate H-RAS between the different membrane microdomains affecting RAS oncogenic potential. Moreover, we have seen that RAS subcellular location affects exosome biogenesis, secretion and cargo demonstrating that exosomes secreted by cells with RAS at DM and GC are capable to transfer its metastatic potential to other cells. These results open a new front in the diagnosis and follow-up in thyroid cancer patients

Ras subcellular localization inversely regulates thyroid tumor growth and dissemination

RAS mutations are the second most common genetic alteration in thyroid tumors. However, the extent to which they are associated with the most aggressive phenotypes is still controversial. Regarding their malignancy, the majority of RAS mutant tumors are classified as undetermined, which complicates their clinical management and can lead to undesired under-or overtreatment. Using the chick embryo spontaneous metastasis model, we herein demonstrate that the aggressiveness of HRAS-transformed thyroid cells, as determined by the ability to extravasate and metastasize at distant organs, is orchestrated by HRAS subcellular localization. Remarkably, aggressiveness inversely correlates with tumor size. In this respect, we also show that RAS sitespecific capacity to regulate tumor growth and dissemination is dependent on VEGF-B secretion. Furthermore, we have identified the acyl protein thioesterase APT-1 as a determinant of thyroid tumor growth versus dissemination. We show that alterations in APT-1 expression levels can dramatically affect the behavior of thyroid tumors, based on its role as a regulator of HRAS sublocalization at distinct plasma membrane microdomains. In agreement, APT-1 emerges in thyroid cancer clinical samples as a prognostic factor. As such, APT-1 levels could serve as a biomarker that could help in the stratification of HRAS mutant thyroid tumors based on their aggressiveness.PC lab is supported by grant RTI2018-096658B-100 from the Spanish Ministry of Science (MICIU/AEI/FEDER, UE). Santisteban, Riesco and Crespo Laboratories are supported jointly by grants from Asociación Española Contra el Cancer (AECC; GCB141423113) and CIBERONC from the Instituto de Salud Carlos III (ISCIII). PS acknowledges support from: SAF2016-75531-R (MINECO/FEDER, UE); B2017/BMD-3724 Tironet2 (Comunidad de Madrid) and PID2019-105303RB-I00/AEI/10.13039/501100011033 from Ministerio de Ciencia e Innovación (MICIN). B.C is funded by Retos Jóvenes Investigadores grant SAF2015-73364-JIN (MICIU/AEI/FEDER, UE), a PIE grant from Consejo Superior de Investigaciones Científicas (CSIC)- MICIU and the Ramón y Cajal Research Program (MICIU, RYC2018-024004-I)

ALK1 loss results in vascular hyperplasia in mice and humans through PI3K activation

Objective: ALK1 (activin-receptor like kinase 1) is an endothelial cell-restricted receptor with high affinity for BMP (bone morphogenetic protein) 9 TGF-[beta] (transforming growth factor-[beta]) family member. Loss-of-function mutations in ALK1 cause a subtype of hereditary hemorrhagic telangiectasia-a rare disease characterized by vasculature malformations. Therapeutic strategies are aimed at reducing potential complications because of vascular malformations, but currently, there is no curative treatment for hereditary hemorrhagic telangiectasia. Approach and results: in this work, we report that a reduction in ALK1 gene dosage (heterozygous ALK1+/- mice) results in enhanced retinal endothelial cell proliferation and vascular hyperplasia at the sprouting front. We found that BMP9/ALK1 represses VEGF (vascular endothelial growth factor)-mediated PI3K (phosphatidylinositol 3-kinase) by promoting the activity of the PTEN (phosphatase and tensin homolog). Consequently, loss of ALK1 function in endothelial cells results in increased activity of the PI3K pathway. These results were confirmed in cutaneous telangiectasia biopsies of patients with hereditary hemorrhagic telangiectasia 2, in which we also detected an increase in endothelial cell proliferation linked to an increase on the PI3K pathway. In mice, genetic and pharmacological inhibition of PI3K is sufficient to abolish the vascular hyperplasia of ALK1+/- retinas and in turn normalize the vasculature. Conclusions: overall, our results indicate that the BMP9/ALK1 hub critically mediates vascular quiescence by limiting PI3K signaling and suggest that PI3K inhibitors could be used as novel therapeutic agents to treat hereditary hemorrhagic telangiectasia

ALK1 loss results in vascular hyperplasia in mice and humans through PI3K activation

Objective: ALK1 (activin-receptor like kinase 1) is an endothelial cell-restricted receptor with high affinity for BMP (bone morphogenetic protein) 9 TGF-[beta] (transforming growth factor-[beta]) family member. Loss-of-function mutations in ALK1 cause a subtype of hereditary hemorrhagic telangiectasia-a rare disease characterized by vasculature malformations. Therapeutic strategies are aimed at reducing potential complications because of vascular malformations, but currently, there is no curative treatment for hereditary hemorrhagic telangiectasia. Approach and results: in this work, we report that a reduction in ALK1 gene dosage (heterozygous ALK1+/- mice) results in enhanced retinal endothelial cell proliferation and vascular hyperplasia at the sprouting front. We found that BMP9/ALK1 represses VEGF (vascular endothelial growth factor)-mediated PI3K (phosphatidylinositol 3-kinase) by promoting the activity of the PTEN (phosphatase and tensin homolog). Consequently, loss of ALK1 function in endothelial cells results in increased activity of the PI3K pathway. These results were confirmed in cutaneous telangiectasia biopsies of patients with hereditary hemorrhagic telangiectasia 2, in which we also detected an increase in endothelial cell proliferation linked to an increase on the PI3K pathway. In mice, genetic and pharmacological inhibition of PI3K is sufficient to abolish the vascular hyperplasia of ALK1+/- retinas and in turn normalize the vasculature. Conclusions: overall, our results indicate that the BMP9/ALK1 hub critically mediates vascular quiescence by limiting PI3K signaling and suggest that PI3K inhibitors could be used as novel therapeutic agents to treat hereditary hemorrhagic telangiectasia

ALK1 loss results in vascular hyperplasia in mice and humans through PI3K activation

Objective: ALK1 (activin-receptor like kinase 1) is an endothelial cell-restricted receptor with high affinity for BMP (bone morphogenetic protein) 9 TGF-[beta] (transforming growth factor-[beta]) family member. Loss-of-function mutations in ALK1 cause a subtype of hereditary hemorrhagic telangiectasia-a rare disease characterized by vasculature malformations. Therapeutic strategies are aimed at reducing potential complications because of vascular malformations, but currently, there is no curative treatment for hereditary hemorrhagic telangiectasia. Approach and results: in this work, we report that a reduction in ALK1 gene dosage (heterozygous ALK1+/- mice) results in enhanced retinal endothelial cell proliferation and vascular hyperplasia at the sprouting front. We found that BMP9/ALK1 represses VEGF (vascular endothelial growth factor)-mediated PI3K (phosphatidylinositol 3-kinase) by promoting the activity of the PTEN (phosphatase and tensin homolog). Consequently, loss of ALK1 function in endothelial cells results in increased activity of the PI3K pathway. These results were confirmed in cutaneous telangiectasia biopsies of patients with hereditary hemorrhagic telangiectasia 2, in which we also detected an increase in endothelial cell proliferation linked to an increase on the PI3K pathway. In mice, genetic and pharmacological inhibition of PI3K is sufficient to abolish the vascular hyperplasia of ALK1+/- retinas and in turn normalize the vasculature. Conclusions: overall, our results indicate that the BMP9/ALK1 hub critically mediates vascular quiescence by limiting PI3K signaling and suggest that PI3K inhibitors could be used as novel therapeutic agents to treat hereditary hemorrhagic telangiectasia

ALK1 loss results in vascular hyperplasia in mice and humans through PI3K activation

Objective: ALK1 (activin-receptor like kinase 1) is an endothelial cell-restricted receptor with high affinity for BMP (bone morphogenetic protein) 9 TGF-[beta] (transforming growth factor-[beta]) family member. Loss-of-function mutations in ALK1 cause a subtype of hereditary hemorrhagic telangiectasia-a rare disease characterized by vasculature malformations. Therapeutic strategies are aimed at reducing potential complications because of vascular malformations, but currently, there is no curative treatment for hereditary hemorrhagic telangiectasia. Approach and results: in this work, we report that a reduction in ALK1 gene dosage (heterozygous ALK1+/- mice) results in enhanced retinal endothelial cell proliferation and vascular hyperplasia at the sprouting front. We found that BMP9/ALK1 represses VEGF (vascular endothelial growth factor)-mediated PI3K (phosphatidylinositol 3-kinase) by promoting the activity of the PTEN (phosphatase and tensin homolog). Consequently, loss of ALK1 function in endothelial cells results in increased activity of the PI3K pathway. These results were confirmed in cutaneous telangiectasia biopsies of patients with hereditary hemorrhagic telangiectasia 2, in which we also detected an increase in endothelial cell proliferation linked to an increase on the PI3K pathway. In mice, genetic and pharmacological inhibition of PI3K is sufficient to abolish the vascular hyperplasia of ALK1+/- retinas and in turn normalize the vasculature. Conclusions: overall, our results indicate that the BMP9/ALK1 hub critically mediates vascular quiescence by limiting PI3K signaling and suggest that PI3K inhibitors could be used as novel therapeutic agents to treat hereditary hemorrhagic telangiectasia

Impact of late presentation of HIV infection on short-, mid- and long-term mortality and causes of death in a multicenter national cohort : 2004-2013

To analyze the impact of late presentation (LP) on overall mortality and causes of death and describe LP trends and risk factors (2004-2013). Cox models and logistic regression were used to analyze data from a nation-wide cohort in Spain. LP is defined as being diagnosed when CD4 < 350 cells/ml or AIDS. Of 7165 new HIV diagnoses, 46.9% (CI:45.7-48.0) were LP, 240 patients died.First-year mortality was the highest (aHR = 10.3[CI:5.5-19.3]); between 1 and 4 years post-diagnosis, aHR = 1.9(1.2-3.0); an