Molecular origins of mutational spectra produced by the environmental carcinogen N-nitrosodimethylamine and SN1 chemotherapeutic agents.

DNA-methylating environmental carcinogens such as N-nitrosodimethylamine (NDMA) and certain alkylators used in chemotherapy form O 6-methylguanine (m6G) as a functionally critical intermediate. NDMA is a multi-organ carcinogen found in contaminated water, polluted air, preserved foods, tobacco products, and many pharmaceuticals. Only ten weeks after exposure to NDMA, neonatally-treated mice experienced elevated mutation frequencies in liver, lung and kidney of ∼35-fold, 4-fold and 2-fold, respectively. High-resolution mutational spectra (HRMS) of liver and lung revealed distinctive patterns dominated by GC→AT mutations in 5'-Pu-G-3' contexts, very similar to human COSMIC mutational signature SBS11. Commonly associated with alkylation damage, SBS11 appears in cancers treated with the DNA alkylator temozolomide (TMZ). When cells derived from the mice were treated with TMZ, N-methyl-N-nitrosourea, and streptozotocin (two other therapeutic methylating agents), all displayed NDMA-like HRMS, indicating mechanistically convergent mutational processes. The role of m6G in shaping the mutational spectrum of NDMA was probed by removing MGMT, the main cellular defense against m6G. MGMT-deficient mice displayed a strikingly enhanced mutant frequency, but identical HRMS, indicating that the mutational properties of these alkylators is likely owed to sequence-specific DNA binding. In sum, the HRMS of m6G-forming agents constitute an early-onset biomarker of exposure to DNA methylating carcinogens and drugs.

Cutaneous Manifestations of SARS-CoV-2 Infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the coronavirus disease 2019 (COVID-19) pandemic, affecting people worldwide. SARS-CoV-2 infection is a multisystem disease with potential for detrimental effects on various systemic organs. It affects people of all ages with varying degrees of disease severity. Patients with SARS-CoV-2 infection commonly present with dry cough, fever, and fatigue. A clinical spectrum of skin findings secondary to SARS-CoV-2 has also been reported. The most common cutaneous patterns associated with COVID-19 are chilblain-like lesions (CBLL), maculopapular lesions, urticarial lesions, vesicular lesions, and livedoid lesions. Other skin findings secondary to SARS-COV-2 infection are erythema multiforme (EM)-like lesions and skin findings associated with multisystem inflammatory syndrome in children (MIS-C) and rarely multisystem inflammatory syndrome in adults (MIS-A). Physician awareness of skin manifestations of SARS-CoV-2 infection can help with early identification and treatment. This narrative review provides an update of various skin manifestations reported with SARS-CoV-2 infection, including clinical presentation, proposed pathogenesis, histopathology, prognosis, and treatment options.