Autoimmune inflammatory reactions triggered by the COVID-19 genetic vaccines in terminally differentiated tissues.

As a result of the spread of SARS-CoV-2, a global pandemic was declared. Indiscriminate COVID-19 vaccination has been extended to include age groups and naturally immune people with minimal danger of suffering serious complications due to COVID-19. Solid immuno-histopathological evidence demonstrates that the COVID-19 genetic vaccines can display a wide distribution within the body, affecting tissues that are terminally differentiated and far away from the injection site. These include the heart and brain, which may incur in situ production of spike protein eliciting a strong autoimmunological inflammatory response. Due to the fact that every human cell which synthesises non-self antigens, inevitably becomes the target of the immune system, and since the human body is not a strictly compartmentalised system, accurate pharmacokinetic and pharmacodynamic studies are needed in order to determine precisely which tissues can be harmed. Therefore, our article aims to draw the attention of the scientific and regulatory communities to the critical need for biodistribution studies for the genetic vaccines against COVID-19, as well as for rational harm-benefit assessments by age group.

A Case Report: Multifocal Necrotizing Encephalitis and Myocarditis after BNT162b2 mRNA Vaccination against COVID-19.

The current report presents the case of a 76-year-old man with Parkinson's disease (PD) who died three weeks after receiving his third COVID-19 vaccination. The patient was first vaccinated in May 2021 with the ChAdOx1 nCov-19 vector vaccine, followed by two doses of the BNT162b2 mRNA vaccine in July and December 2021. The family of the deceased requested an autopsy due to ambiguous clinical signs before death. PD was confirmed by post-mortem examinations. Furthermore, signs of aspiration pneumonia and systemic arteriosclerosis were evident. However, histopathological analyses of the brain uncovered previously unsuspected findings, including acute vasculitis (predominantly lymphocytic) as well as multifocal necrotizing encephalitis of unknown etiology with pronounced inflammation including glial and lymphocytic reaction. In the heart, signs of chronic cardiomyopathy as well as mild acute lympho-histiocytic myocarditis and vasculitis were present. Although there was no history of COVID-19 for this patient, immunohistochemistry for SARS-CoV-2 antigens (spike and nucleocapsid proteins) was performed. Surprisingly, only spike protein but no nucleocapsid protein could be detected within the foci of inflammation in both the brain and the heart, particularly in the endothelial cells of small blood vessels. Since no nucleocapsid protein could be detected, the presence of spike protein must be ascribed to vaccination rather than to viral infection. The findings corroborate previous reports of encephalitis and myocarditis caused by gene-based COVID-19 vaccines.

Frequent loss of the CDKN2C (p18INK4c) gene product in pituitary adenomas.

Genomic alterations of cyclin-dependent kinase inhibitors have been demonstrated in a variety of tumor types including brain tumors. Among them, the cyclin-dependent kinase inhibitor 2A (CDKN2A or p16(INK4a)) gene has been shown to be frequently deleted or inactivated in astrocytic tumors. The CDKN2C (p18(INK4c)) gene is functionally related to CDKN2A. Moreover, mice with targeted disruption of CDKN2C alone or combined CDKN2C and cyclin-dependent kinase inhibitor 1B (CDKN1B or p27(Kip1)), or CDKN2C and TP53 gene disruption develop pituitary adenomas (PA) at high frequencies. The purpose of our study was to investigate genetic alterations of the CDKN2C gene by analysis of loss of heterozygosity (LOH), screening for mutations, analysis of promoter methylation, and protein expression in 38 PAs. In addition, genomic alterations and protein expression of the cell cycle genes CDKN2A and its alternatively spliced form, p14(ARF), as well as the retinoblastoma RB1 gene were investigated. LOH at the CDKN2C gene locus was detected in 25% of pituitary adenomas, whereas the RB1 and CDKN2A loci were altered in only 10%. No mutations were detected within the coding regions of the CDKN2C gene. However, 39.5% of adenomas displayed CDKN2C promoter methylation. The absence of CDKN2C protein was correlated with LOH of the CDKN2C locus on chromosome 1 and with methylation of the CDKN2C promoter. This is the first report to describe that the tumor suppressor gene CDKN2C is frequently targeted by genomic alterations in pituitary adenoma. The most common genetic alteration was promoter methylation suggesting that inactivation of CDKN2C by this mechanism may play an important role in pituitary adenoma development. Additional Supporting Information may be found in the online version of this article.

[Exploration of tumor suppressors p16INK4a and p14ARF in oral leukoplakias]. / Untersuchung der Tumorsuppressoren p16INK4a und p14ARF in Mundschleimhautleukoplakien.

The inactivation of p16 and p14ARF is considered to be an important step in the carcinogenesis of oropharygeal carcinomas. This consideration is supported by the observation of multiple allelic losses in the coding loci of chromosome 9p21 in squamous cell carcinomas and in dysplastic premalignant lesions. The present study hypothesized that comparable alterations already occur in leukoplakia, which are seen as potential predecessors of oral squamous cell carcinomas and that it is possible to differ leukoplakia with from leukoplakia without further malignant transformation. Furthermore we evaluated, whether such leukoplakia show sequence alterations in the genes p16 and p14ARF, which are capable to cause a limitation in gene function. The results show that the LOH pattern in genes p16 and p14ARF occur as well in leuplakia with malignant transformation as in leukoplakia, that do not show clinical alterations. The rate of allelic loss did not differ significantly. Overall, the incidence of allelic loss was lower in leuplakia compared to succeeding squamous-cell carcinomas (p<0,05). The results further illustrated an increase in LOH patterns in dyplastic leukoplakia, without reaching statistical significance. Significant increases in allelic losses were found in heavy smokers, (p < 0,05). PCR analysis of the exons 1-alpha, exon 1-beta and exon 2 in leukoplakia, containing LOH patterns did not show genetic alterations. Thus we concluded, that gene deletion and gene mutation have a minor role in the inactivation process of p16 and p14ARF in oral leukoplakia. Representing an early process in carcinogenesis, gene deletion and mutation occur in leukoplakia with and without malignant transformation. Therefore, taken as a singular parameter they represent an uncertain criteria to assess the potential of malignant transformation. However they could provide information in combination with other genetic factors like chromosomal methylation patterns and histology.