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  • There are some limitations and further experiments that are


    There are some limitations and further experiments that are required. First, to our surprise, measurement of the cardiomyocyte cross-sectional area in Akt1−/−/iAkt2 KO mice showed comparable areas to WT mouse despite of reduced heart weight. In addition to measuring cardiomyocyte cross-sectional area, measurement of long and short axis cell width of H&E-stained cardiomyocytes in the left ventricle would be useful to assess cardiomyocyte volume in the smaller Akt1−/−/iAkt2 KO hearts. Second, in the strict sense, the present study is not a cardiomyocyte-specific DKO mouse model because the Akt2 gene is deleted specifically in cardiomyocytes, but not the Akt1 gene. The Akt1 gene was removed in all cardiac tissues, including fibroblasts and cardiomyocytes. Moreover, because Akt1 deficiency occurred in the germline, it is possible that long-term adaptations to Akt1 deficiency could confound the cardiac response to inducible deletion of Akt2 in Akt1 null cardiomyocytes. Therefore, it will be necessary to compare the phenotype of cardiomyocyte-specific Akt1/2 DKO mice with that of Akt1−/−/iAkt2 KO mice described in this study. Thus, it is possible that inducible cardiomyocyte-specific Akt1/2 DKO mice could exhibit more striking phenotypes. Third, this study has not explored other potential mechanisms leading to cardiac dysfunction in Akt1−/−/iAkt2 KO mice such as potential changes in cytoskeletal proteins. Previous studies proposed that ZO-1 interacts with other cytoskeleton proteins in addition to Cx43 [[38], [39], [40]]. Barker et al. showed that ZO-1 stabilizes the gap junction through anchoring of Cytarabine filaments, an important major cytoskeleton protein associated with contractile function [38]. Another study revealed that permeability of Cx43-containing channels was regulated dynamically by F-actin and the small G-protein RhoA, which are major regulators of cellular junctions and the actin cytoskeleton [39]. In addition, although not a study using cardiomyocytes, it was reported that disruption of the Cx43/ZO-1 complex induced collapse of the organized F-actin cytoskeleton [40]. Therefore, future studies will further explore the contributions of changes in other cytoskeleton proteins in the Akt1−/−/iAkt2 KO mouse model that might contribute to the acute heart failure that develops in the absence of gross pathological changes as early as 4 days after deletion of Akt1 and Akt2. The following are the supplementary data related to this article.
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    Funding This work was supported by grants of the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning [2009-0077202 to JK, 2016R1A4A1009895 to YKK, HK, WJP, JK] and by grant U01 HL087947 from the National Institutes of Health to EDA.
    Introduction As the fourth leading cause of cancer death in females worldwide, cervical cancer has been reported to cause 266,000 deaths worldwide each year (Siegel et al., 2016). It is reported that about 99.7% of cervical cancers were induced by the high-risk (HR) human papillomavirus (HPV) (Forman et al., 2012). Although cervical cancer can be effectively treated with surgery or radiation at the early stage, the treatment of advanced stage of cervical cancer remains a great challenge (Schiffman et al., 2011). In addition, the overall therapy outcomes of cervical cancer are also very poor (Schiffman et al., 2011). Therefore, the identification of novel therapy targets and illustration of its related mechanisms will be great helpful for cervical cancer treatment. Both epidemiological and laboratory studies indicated that estrogenic signals can promote the tumorigenesis and progression of cervical cancer (Chung et al., 2010). It was reported that chronic low-dose E2 treatment will significantly increase the incidence of cervical cancer after HPV infection (den Boon et al., 2015). Estrogen receptor α (ERα), rather than ERβ, is necessary for the development of cervical cancer (Chung et al., 2013). Further studies indicated that environmental estrogenic chemicals such as phthalates and bisphenol A (BPA) can trigger the progression of cervical cancer. Recently, it has been shown that food contaminant BPA can act as agonist for ERα in breast cancer cells (Vivacqua et al., 2003). Nanomolar concentrations of BPA can promote the migration of cervical cancer cells via activation of IKK-β/NF-κB signals (Ma et al., 2015). Therefor there is great chance that other environmental estrogenic chemicals can also regulate the development cervical cancers.