Simultaneous down-regulation of tumor suppressor genes RBSP3/CTDSPL, NPRL2/G21 and RASSF1A in primary non-small cell lung cancer

<p>Abstract</p> <p>Background</p> <p>The short arm of human chromosome 3 is involved in the development of many cancers including lung cancer. Three bona fide lung cancer tumor suppressor genes namely <it>RBSP3 </it>(AP20 region),<it>NPRL2 </it>and <it>RASSF1A </it>(LUCA region) were identified in the 3p21.3 region. We have shown previously that homozygous deletions in AP20 and LUCA sub-regions often occurred in the same tumor (P < 10^-6).</p> <p>Methods</p> <p>We estimated the quantity of <it>RBSP3, NPRL2, RASSF1A, GAPDH, RPN1 </it>mRNA and <it>RBSP3 </it>DNA copy number in 59 primary non-small cell lung cancers, including 41 squamous cell and 18 adenocarcinomas by real-time reverse transcription-polymerase chain reaction based on TaqMan technology and relative quantification.</p> <p>Results</p> <p>We evaluated the relationship between mRNA level and clinicopathologic characteristics in non-small cell lung cancer. A significant expression decrease (≥2) was found for all three genes early in tumor development: in 85% of cases for <it>RBSP3</it>; 73% for <it>NPRL2 </it>and 67% for <it>RASSF1A </it>(P < 0.001), more strongly pronounced in squamous cell than in adenocarcinomas. Strong suppression of both, <it>NPRL2 </it>and <it>RBSP3 </it>was seen in 100% of cases already at Stage I of squamous cell carcinomas. Deregulation of <it>RASSF1A </it>correlated with tumor progression of squamous cell (P = 0.196) and adenocarcinomas (P < 0.05). Most likely, genetic and epigenetic mechanisms might be responsible for transcriptional inactivation of <it>RBSP3 </it>in non-small cell lung cancers as promoter methylation of <it>RBSP3 </it>according to NotI microarrays data was detected in 80% of squamous cell and in 38% of adenocarcinomas. With NotI microarrays we tested how often LUCA (<it>NPRL2, RASSF1A</it>) and AP20 (<it>RBSP3</it>) regions were deleted or methylated in the same tumor sample and found that this occured in 39% of all studied samples (P < 0.05).</p> <p>Conclusion</p> <p>Our data support the hypothesis that these TSG are involved in tumorigenesis of NSCLC. Both genetic and epigenetic mechanisms contribute to down-regulation of these three genes representing two tumor suppressor clusters in 3p21.3. Most importantly expression of <it>RBSP3, NPRL2 </it>and <it>RASSF1A </it>was simultaneously decreased in the same sample of primary NSCLC: in 39% of cases all these three genes showed reduced expression (P < 0.05).</p

COVID-19 Incidence Proportion as a Function of Regional Testing Strategy, Vaccination Coverage, and Vaccine Type

Introduction: The COVID-19 pandemic has become a serious challenge for humanity almost everywhere globally. Despite active vaccination around the world, the incidence proportion in different countries varies significantly as of May 2022. The reason may be a combination of demographic, immunological, and epidemiological factors. The purpose of this study was to analyze possible relationships between COVID-19 incidence proportion in the population and the types of SARS-CoV-2 vaccines used in different countries globally, taking into account demographic and epidemiological factors. Materials and methods: An initial database was created of demographic and immunoepidemiological information about the COVID-19 situation in 104 countries collected from published official sources and repository data. The baseline included, for each country, population size and density; SARS-CoV-2 testing coverage; vaccination coverage; incidence proportion; and a list of vaccines that were used, including their relative share among all vaccinations. Subsequently, the initial data set was stratified by population and vaccination coverage. The final data set was subjected to statistical processing both in general and taking into account population testing coverage. Results: After formation of the final data set (including 53 countries), it turned out that reported COVID-19 case numbers correlated most strongly with testing coverage and the proportions of vaccine types used, specifically, mRNA (V1); vector (V2); peptide/protein (V3); and whole-virion/inactivated (V4). Due to the fact that an inverse correlation was found between ‘reported COVID-19 case numbers’ with V2, V3, and V4, these three vaccine types were also combined into one analytic group, ‘non-mRNA group’ vaccines (Vnmg). When the relationship between vaccine type and incidence proportion was examined, minimum incidence proportion was noted at V1:Vnmg ratios (%:%) from 0:100 to 30:70. Maximum incidence proportion was seen with V1:Vnmg from 80:20 to 100:0. On the other hand, we have shown that the number of reported COVID-19 cases in different countries largely depends on testing coverage. To offset this factor, countries with low and extremely high levels of testing were excluded from the data set; it was then confirmed that the largest number of reported COVID-19 cases occurred in countries with a dominance of V1 vaccines. The fewest reported cases were seen in countries with a dominance of Vnmg vaccines. Conclusion: In this paper, we have shown for the first time that the level of reported COVID-19 incidence proportion depends not only on SARS-CoV-2 testing and vaccination coverage, which is quite logical, but probably also on the vaccine types used. With the same vaccination level and testing coverage, those countries that predominantly use vector and whole-virion vaccines feature incidence proportion that is significantly lower than countries that predominantly use mRNA vaccines