HPV16 E6 Oncogene Contributes to Cancer Immune Evasion by Regulating PD-L1 Expression through a miR-143/HIF-1a Pathway.

Human Papillomaviruses have been associated with the occurrence of cervical cancer, the fourth most common cancer that affects women globally, while 70% of cases are caused by infection with the high-risk types HPV16 and HPV18. The integration of these viruses' oncogenes E6 and E7 into the host's genome affects a multitude of cellular functions and alters the expression of molecules. The aim of this study was to investigate how these oncogenes contribute to the expression of immune system control molecules, using cell lines with integrated HPV16 genome, before and after knocking out E6 viral gene using the CRISPR/Cas9 system, delivered with a lentiviral vector. The molecules studied are the T-cell inactivating protein PD-L1, its transcription factor HIF-1a and the latter's negative regulator, miR-143. According to our results, in the E6 knock out (E6KO) cell lines an increased expression of miR-143 was recorded, while a decrease in the expression of HIF-1a and PD-L1 was exhibited. These findings indicate that E6 protein probably plays a significant role in enabling cervical cancer cells to evade the immune system, while we propose a molecular pathway in cervical cancer, where PD-L1's expression is regulated by E6 protein through a miR-143/HIF-1a axis.

Sex-Related Effects on Cardiac Development and Disease.

Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality. Interestingly, male and female patients with CVD exhibit distinct epidemiological and pathophysiological characteristics, implying a potentially important role for primary and secondary sex determination factors in heart development, aging, disease and therapeutic responses. Here, we provide a concise review of the field and discuss current gaps in knowledge as a step towards elucidating the "sex determination-heart axis". We specifically focus on cardiovascular manifestations of abnormal sex determination in humans, such as in Turner and Klinefelter syndromes, as well as on the differences in cardiac regenerative potential between species with plastic and non-plastic sexual phenotypes. Sex-biased cardiac repair mechanisms are also discussed with a focus on the role of the steroid hormone 17ß-estradiol. Understanding the "sex determination-heart axis" may offer new therapeutic possibilities for enhanced cardiac regeneration and/or repair post-injury.

Developmental and regenerative biology of cardiomyocytes.

Current progress and challenges in understanding the molecular and cellular mechanisms of cardiomyocyte embryonic development and regeneration are reviewed in our present work. Three major topics are critically discussed: how do cardiomyocytes form in the embryo? What is the adult origin of the cells that regenerate cardiomyocytes in animal models with adult heart regeneration capabilities? Can the promise of therapeutic cardiomyocyte regeneration be realized in humans? In the first topic, we highlight current advances in understanding the developmental biology of cardiomyocytes, with emphasis on the regulative capabilities of the early embryo during specification and allocation of the cardiomyoblasts that produce the primordial heart. We place further emphasis on trabecular cardiomyocyte development from late cardiomyoblasts, neural crest cells and primordial cardiomyocytes, and their critical role in the clonal growth of the compact/septal and cortical cardiomyocyte layers in the mammalian embryo and adult zebrafish, respectively. In the second topic, we focus on the re-activation of the cortical or trabecular compaction programs as hallmarks of cardiomyocyte regenerative cells during adult zebrafish and neonatal mouse heart regeneration, respectively, and underscore the metabolic remodeling that commonly drives cardiomyocyte regeneration in these organisms. Finally, we discuss the status of preclinical and clinical-stage therapeutics for cardiomyocyte regeneration, with particular emphasis on gene therapy, as well as adult and pluripotent stem cell-based cellular cardiomyoplasty approaches. In summary, our article provides a bird's-eye view of current knowledge and potential pitfalls in the field of developmental biology-guided regenerative medicine strategies for the treatment of heart diseases.