Diffuse overexpression of p16INK4a in basal and parabasal cells of cervical epithelium is a hallmark of human papillomavirus‐mediated transformation. Focal p16INK4a expression is occasionally observed in nondysplastic epithelium. In normal cells, expression of p16INK4a triggers cell cycle arrest. However, cells undergoing transformation in intraepithelial lesions actively proliferate. To prove that the different expression patterns of p16INK4a, i.e., focal versus diffuse, reflect biologically different entities, we hypothesized that p16INK4a‐positive cells in epithelia displaying focal p16INK4a expression pattern do not coexpress proliferation‐associated Ki‐67 protein, while p16INK4a‐positive cells in lesions with diffuse p16INK4a expression may do. A total of 138 cervical cone biopsies were stained for the expression of p16INK4a and Ki‐67 using a primary antibody cocktail. All metaplastic lesions (n = 21) displayed focal staining for p16INK4a, and in all of these lesions p16INK4a‐positive cells were found to be negative for Ki‐67 expression. Diffuse expression of p16INK4a was observed in 12/21 (57.1%) cervical intraepithelial neoplasia (CIN) 1 lesions, all of them simultaneously showed Ki‐67 immunoreactivity in a large proportion of p16INK4a‐positive cells. Seventeen of 23 (73.9%) CIN2 lesions and all 27 (100%) CIN3/carcinoma in situ (CIS) as well as all 46 (100%) carcinoma cases displayed diffuse and combined expression of p16INK4a and Ki‐67. Coexpression of Ki‐67 and p16INK4a in the same cell is entirely restricted to cervical lesions displaying diffuse p16INK4a expression, whereas in lesions with focal p16INK4a expression, p16INK4a‐expressing cells are negative for Ki‐67. Thus, diffuse expression of p16INK4a reflects lesions with proliferation‐competent cells, while p16INK4a‐expressing cells associated with focal expression patterns are cell cycle arrested.
Different types of vulvar cancers can be found in squamous cell tumors of the anterior fourchette, similar to the finding in vulvar cancers from other locations and to what has previously been reported for vulvar squamous cell carcinomas in general.
Comparative effectiveness of loop diuretics on mortality in the treatment of patients with chronic heart failure-a multicenter propensity score matched analysis.
Backround:
mTOR (mammalian target of rapamycin) is an essential multiprotein complex in cells. It consists in two different complexes, mTORC1 and mTORC2, each with distinct cellular functions. mTORC1 is important for protein synthesis, whereas mTORC2 influences cell survival. Both are important for maintaining cell homeostasis. A negative feedback mechanism between the mTORC1/mTORC2 is indispensable for controlled activity of the protein complex. Adrenergic overstimulation of mTORC1 contributes to severity of myocardial damage, including cardiac hypertrophy and heart failure. Thus the regulatory influence of mTORC2 seems to be important for physiological mTORC1 activation.
Hypothesis:
The activation of mTORC2 affects the pathogenesis of cardiac dysfunction. Therefore XPLN, a new found mTORC2 Inhibitor, could prove as a pivotal regulator protein for the mTOR complex and cardiac function.
Methods:
Combined pharmacological and molecular biological methods were used for disruption of the mTORC1/mTORC2 equilibrium. The experiments were performed in cultured cardiac myocytes as well as in human samples. Gain and loss of function of XPLN was used for demonstrating it′s relevance on mTORC2 regulation and the functionally consequence of mTORC1/mTORC2 interconnection. The importance of the mTORC equilibrium was demonstrated by application of pathological growth factors (Phenylephrine). mTORC2 inhibition after XPLN overexpression resulted in mTORC1 activation, hypertrophic cell formation and cardiac stress. Conversely, knockdown of XPLN results in shifting toward mTORC2 activation with significant reduction in BNP expression.
Conclusion:
The regulatory influence of mTORC2 is essential for physiological mTORC1/mTORC2 activation. Disruption of this equilibrium results in myocardial stress. We demonstrate XPLN as a potent mTORC2 inhibitor with significant influence on the mTORC2 regulation. Furthermore we could show it′s relevant consequences in cell survival and the extensive effects on mTORC1 activation. Therefore XPLN is an essential regulator protein in the pathogenesis of cardiac dysfunction and could prove as a new target protein for medical treatment.
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