RESUMO
Whole national screening of pre-cancer is done only in some few countries, dominated by The Netherlands, Denmark, UK, Norway and Finland. These national screenings are done combining national cancer registry, national public health and national medical bodies or hospitals. Until some few years ago national screening was only done using morphological or visual methods or technology. Today a number of molecular methods have been implemented to serve these national screening programs. Based on all the discussions within this review, it is clear that the main driving engine and the cause of cervical pre-cancer and the main cause of invasive cervical cancer is the expression of E6 and E7 oncoproteins from HPV 16, 18, 31, 33 and 45. However, the main challenge is the role of morphology or imaging-based diagnosis in the original definition of pre-cancer disease. This definition is not based on the cause of cervical precancer but based on a complex, subjective, morphological observations. The difference between these two definitions are discussed in this review. The unique discovery done while validating the first standardized detection technology used against mRNA, confirmed that the presence of both abnormal E6 and/or E7 mRNA and protein is the cause of cervical pre-cancer or severe neoplasia and the main cause of invasive cervical cancer. This confirmation was evident even though all these studies were disturbed by the above defined biases from morphology or imaging-based diagnosis. The use of the screening target that cause stable and high expression of the most carcinogenic compounds ever discovered, must cause a more accurate screening program. A number of studies have proved that the detection of E6/E7 mRNA followed-up by indirect or direct treatment in a well-organized national screening program, would reduce the incidence of cervical cancer. This review discusses the main studies involved in the scientific, clinical evaluation and how this unique technology could be used as a new medical gold standard for national screening of cervical pre-cancer.
RESUMO
OBJECTIVE: We have previously shown that overexpression of the Na-Ca exchanger (NCX1), a protein responsible for Ca(2+) extrusion from cells, increases ß-cell programmed cell death (apoptosis) and reduces ß-cell proliferation. To further characterize the role of NCX1 in ß-cells under in vivo conditions, we developed and characterized mice deficient for NCX1. RESEARCH DESIGN AND METHODS: Biologic and morphologic methods (Ca(2+) imaging, Ca(2+) uptake, glucose metabolism, insulin release, and point counting morphometry) were used to assess ß-cell function in vitro. Blood glucose and insulin levels were measured to assess glucose metabolism and insulin sensitivity in vivo. Islets were transplanted under the kidney capsule to assess their performance to revert diabetes in alloxan-diabetic mice. RESULTS: Heterozygous inactivation of Ncx1 in mice induced an increase in glucose-induced insulin release, with a major enhancement of its first and second phase. This was paralleled by an increase in ß-cell proliferation and mass. The mutation also increased ß-cell insulin content, proinsulin immunostaining, glucose-induced Ca(2+) uptake, and ß-cell resistance to hypoxia. In addition, Ncx1(+/-) islets showed a two- to four-times higher rate of diabetes cure than Ncx1(+/+) islets when transplanted into diabetic animals. CONCLUSIONS: Downregulation of the Na/Ca exchanger leads to an increase in ß-cell function, proliferation, mass, and resistance to physiologic stress, namely to various changes in ß-cell function that are opposite to the major abnormalities seen in type 2 diabetes. This provides a unique model for the prevention and treatment of ß-cell dysfunction in type 2 diabetes and after islet transplantation.
