Combined epidemiology and genetic sequencing surveillance in the era of COVID-19 pandemic; Abu Dhabi experience, United Arab Emirates.

BACKGROUND: United Arab Emirates, has reported the first case of COVID-19 in January 2020 and by October 2022, a total of 1 Million cases and 2348 deaths due to COVID-19 have been reported. The Abu Dhabi Public Health Center, has led a novel initiative to conduct a large scale genomic surveillance project. The aim of this surveillance project is to generate data to guide public health pandemic response decision making. METHODS: Samples mainly from the community, points of entry to the emirate and healthcare facilities were collected for surveillance using both targeted PCR and/or Genome sequence analysis. Sample criteria were defined and specific metadata were collected in parallel. Using the unique identifiers and through the available datasets, epidemiological and clinical data were integrated. RESULTS: A total of 385,191 sample undertake analysis (from January 2021 to October 2022) either genotyping and/or sequence analysis. The most frequently encountered lineages in the community and among severe cases were reported. CONCLUSIONS: Genomic surveillance is a major tool essential for guiding public health measures throughout the pandemic.

p53 reactivating small molecule PRIMA­1MET/APR­246 regulates genomic instability in MDA­MB­231 cells.

Pharmacological reactivation of tumor­suppressor protein p53 has acted as a promising strategy for more than 50% of human cancers that carry a non­functional mutant p53 (mutp53). p53 plays a critical role in preserving genomic integrity and DNA fidelity through numerous biological processes, including cell cycle arrest, DNA repair, senescence and apoptosis. By contrast, non­functional mutp53 compromises the aforementioned genome stabilizing mechanisms through gain of function, thereby increasing genomic instability in human cancers. Restoring the functional activity of p53 using both genetic and pharmacological approaches has gained prominence in targeting p53­mutated tumors. Thus, the present study aimed to investigate the reactivation of p53 in DNA repair mechanisms and the maintenance of genomic stability using PRIMA­1MET/APR­246 small molecules, in both MDA­MB­231 and MCF­7 breast cancer cell lines, which carry mutp53 and wild­type p53, respectively. Results of the present study revealed that reactivation of p53 through APR­246 led to an increase in the functional activity of DNA repair. Prolonged treatment of MDA­MB­231 cells with APR­246 in the presence of cisplatin led to a reduction in mutational accumulation, compared with cells treated with cisplatin alone. These findings demonstrated that APR­246 may act as a promising small molecule to control the genomic instability in p53­mutated tumors.

Waterpipe smoke condensate influences epithelial to mesenchymal transition and interferes with the cytotoxic immune response in non-small cell lung cancer cell lines.

Waterpipe tobacco smoking (WPS) continues to spread globally and presents serious health hazards. The aim of the present study was to investigate the effects of treatment with WPS condensate (WPSC) on lung cell proliferation and plasticity as well as tumor cell recognition and killing by natural killer (NK) cells using cytotoxicity assays. The results indicated that exposure of normal and cancer lung cell lines to WPSC resulted in a decrease in their in vitro growth in a dose-dependent manner and it induced tumor senescence. In addition, WPSC selectively caused DNA damage as revealed by an increase in γH2AX and 53BP1 in tumor lung cells. To gain further insight into the molecular mechanisms altered by WPSC, we conducted a global comprehensive transcriptome analysis of WPSC-treated tumor cells. Data analysis identified an expression profile of genes that best distinguished treated and non-treated cells involving several pathways. Of these pathways, we focused on those involved in epithelial to mesenchymal transition (EMT) and stemness. Results showed that WPSC induced an increase in SNAI2 expression associated with EMT, ACTA2 and SERPINE2 were involved in invasion and CD44 was associated with stemness. Furthermore, WPSC exposure increased the expression of inflammatory response genes including CASP1, IL1B, IL6 and CCL2. While immune synapse formation between NK and WPSC-treated lung cancer target cells was not affected, the capacity of NK cells to kill these target cells was reduced. The data reported in the present study are, to the best of our knowledge, the first in vitro demonstration of WPSC effects on lung cellular parameters providing evidence of its potential involvement in tumor physiology and development.

Hypoxia increases mutational load of breast cancer cells through frameshift mutations.

Tumor hypoxia-induced downregulation of DNA repair pathways and enhanced replication stress are potential sources of genomic instability. A plethora of genetic changes such as point mutations, large deletions and duplications, microsatellite and chromosomal instability have been discovered in cells under hypoxic stress. However, the influence of hypoxia on the mutational burden of the genome is not fully understood. Here, we attempted to elucidate the DNA damage response and repair patterns under different types of hypoxic stress. In addition, we examined the pattern of mutations exclusively induced under chronic and intermittent hypoxic conditions in two breast cancer cell lines using exome sequencing. Our data indicated that hypoxic stress resulted in transcriptional downregulation of DNA repair genes which can impact the DNA repair induced during anoxic as well as reoxygenated conditions. In addition, our findings demonstrate that hypoxic conditions increased the mutational burden, characterized by an increase in frameshift insertions and deletions. The somatic mutations were random and non-recurring, as huge variations within the technical duplicates were recognized. Hypoxia also resulted in an increase in the formation of potential neoantigens in both cell lines. More importantly, these data indicate that hypoxic stress mitigates DNA damage repair pathways and causes an increase in the mutational burden of tumor cells, thereby interfering with hypoxic cancer cell immunogenicity.