RESUMO
People with HIV (PWH) are at elevated risk for cardiovascular diseases (CVDs), including myocardial infarction, heart failure, and sudden cardiac death, among other CVD manifestations. Chronic immune dysregulation resulting in persistent inflammation is common among PWH, particularly those with sustained viremia and impaired CD4+ T cell recovery. This inflammatory milieu is a major contributor to CVDs among PWH, in concert with common comorbidities (such as dyslipidemia and smoking) and, to a lesser extent, off-target effects of antiretroviral therapy. In this review, we discuss the clinical and mechanistic evidence surrounding heightened CVD risks among PWH, implications for specific CVD manifestations, and practical guidance for management in the setting of evolving data.
Assuntos
Doenças Cardiovasculares , Infecções por HIV , Humanos , Doenças Cardiovasculares/epidemiologia , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , ComorbidadeRESUMO
N-Nitrosodimethylamine (NDMA) is a DNA-methylating agent that has been discovered to contaminate water, food, and drugs. The alkyladenine DNA glycosylase (AAG) removes methylated bases to initiate the base excision repair (BER) pathway. To understand how gene-environment interactions impact disease susceptibility, we study Aag-knockout (Aag-/-) and Aag-overexpressing mice that harbor increased levels of either replication-blocking lesions (3-methyladenine [3MeA]) or strand breaks (BER intermediates), respectively. Remarkably, the disease outcome switches from cancer to lethality simply by changing AAG levels. To understand the underlying basis for this observation, we integrate a suite of molecular, cellular, and physiological analyses. We find that unrepaired 3MeA is somewhat toxic, but highly mutagenic (promoting cancer), whereas excess strand breaks are poorly mutagenic and highly toxic (suppressing cancer and promoting lethality). We demonstrate that the levels of a single DNA repair protein tip the balance between blocks and breaks and thus dictate the disease consequences of DNA damage.
Assuntos
Replicação do DNA/genética , Mutagênese/genética , Neoplasias/genética , Neoplasias/patologia , Animais , Biomarcadores Tumorais/metabolismo , Morte Celular , Instabilidade Cromossômica/genética , Dano ao DNA/genética , DNA Glicosilases/deficiência , DNA Glicosilases/metabolismo , Reparo do DNA/genética , Dietilnitrosamina , Suscetibilidade a Doenças , Histonas/metabolismo , Recombinação Homóloga/genética , Fígado/patologia , Neoplasias Hepáticas/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Micronúcleos com Defeito Cromossômico , Nitrosaminas , Fenótipo , Fosfoproteínas/metabolismo , FosforilaçãoRESUMO
The COVID-19 pandemic has led to delays in cancer diagnosis, in part due to postponement of cancer screening. We used Google Trends data to assess public attention to cancer screening during the first peak of the COVID-19 pandemic. Search volume for terms related to established cancer screening tests ("colonoscopy," "mammogram," "lung cancer screening," and "pap smear") showed a marked decrease of up to 76% compared to the pre-pandemic period, a significantly greater drop than for search volume for terms denoting common chronic diseases. Maintaining awareness of cancer screening during future public health crises may decrease delays in cancer diagnosis.