RESUMO
BACKGROUND: Chronic rhinosinusitis (CRS) is a common upper airways inflammatory disease requiring multidisciplinary care. OBJECTIVE: To evaluate if African Americans (AA), Latinxs, and nonLatinx White (White) patients have different chronic rhinosinusitis outcomes and to identify associated factors impacting these outcomes. METHODS: We conducted a large prospective cohort study of CRS patients who were evaluated and followed for several clinical variables at the initial encounter and after continuous management of CRS for a mean of 40 months. The Sinonasal Outcome Test (SNOT-22) and Lund-MacKay scores were measured on initial visits, and SNOT-22 was repeated at the end of follow-up. Logistic regression was used to compare outcomes between the different groups adjusted for comorbidities and demographics. RESULTS: Among the 977 enrolled CRS cases, 615 (63.0%), 235 (24.1%) and 138 (13.0%) were White, AA and Latinx respectively. There was no difference in severity of CRS based on Lund-MacKay scores and SNOT-22 scores, and frequency of other comorbidities at presentation among the 3 groups. During the follow-up period, compared with Whites, AA and Latinx were less frequently evaluated by an allergist. AAs had less frequent CRS related visits and lower final SNOT-22 score compared with Whites. CONCLUSION: Although our enrolled patients from the 3 ethnic groups had similar clinical characteristics and disease burden at baseline, AAs had less frequent follow-up visits and worse final SNOT-22 after 40 months of follow-up. The observed poorer outcomes in AAs are likely owing to inequity in healthcare access evidenced by differences in insurance and suboptimal management of CRS.
Assuntos
Rinite , Sinusite , Humanos , Rinite/epidemiologia , Etnicidade , Estudos Prospectivos , Sinusite/epidemiologia , Doença Crônica , Qualidade de VidaAssuntos
Doença Hepática Terminal , Transplante de Fígado , Estado Terminal , Doença Hepática Terminal/diagnóstico , Doença Hepática Terminal/cirurgia , Humanos , Pacientes Internados , Unidades de Terapia Intensiva , Ácido Láctico , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
Poly (ADP-ribose) polymerases (PARPs) are a family of related enzymes that share the ability to catalyze the transfer of ADP-ribose to target proteins. PARPs play an important role in various cellular processes, including modulation of chromatin structure, transcription, replication, recombination, and DNA repair. The role of PARP proteins in DNA repair is of particular interest, in view of the finding that certain tumors defective in homologous recombination mechanisms, may rely on PARP-mediated DNA repair for survival, and are sensitive to its inhibition. PARP inhibitors may also increase tumor sensitivity to DNA-damaging agents. Clinical trials of PARP inhibitors are investigating the utility of these approaches in cancer. The hyperactivation of PARP has also been shown to result in a specific programmed cell death pathway involving NAD+/ATP depletion, mu-calpain activation, loss of mitochondrial membrane potential, and the release of apoptosis inducing factor. Hyperactivation of the PARP pathway may be exploited to selectively kill cancer cells. Other PARP forms, including tankyrase 1 (PARP 5a), which plays an important role in enhancing telomere elongation by telomerase, have been found to be potential targets in cancer therapy. The PARP pathway and its inhibition thus offers a number of opportunities for therapeutic intervention in both cancer and other disease states.
Assuntos
Neoplasias/terapia , Poli(ADP-Ribose) Polimerases/metabolismo , Animais , Reparo do DNA , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Epigênese Genética , Humanos , Terapia de Alvo Molecular , Nanomedicina , Naftoquinonas/farmacologia , Necrose/enzimologia , Necrose/patologia , Inibidores de Poli(ADP-Ribose) Polimerases , Fatores de Transcrição/metabolismoRESUMO
Improving patient outcome by personalized therapy involves a thorough understanding of an agent's mechanism of action. ß-Lapachone (clinical forms, Arq501/Arq761) has been developed to exploit dramatic cancer-specific elevations in the phase II detoxifying enzyme NAD(P)H:quinone oxidoreductase (NQO1). NQO1 is dramatically elevated in solid cancers, including primary and metastatic [e.g., triple-negative (ER-, PR-, Her2/Neu-)] breast cancers. To define cellular factors that influence the efficacy of ß-lapachone using knowledge of its mechanism of action, we confirmed that NQO1 was required for lethality and mediated a futile redox cycle where â¼120 moles of superoxide were formed per mole of ß-lapachone in 2 minutes. ß-Lapachone induced reactive oxygen species (ROS), stimulated DNA single-strand break-dependent poly(ADP-ribose) polymerase-1 (PARP1) hyperactivation, caused dramatic loss of essential nucleotides (NAD(+)/ATP), and elicited programmed necrosis in breast cancer cells. Although PARP1 hyperactivation and NQO1 expression were major determinants of ß-lapachone-induced lethality, alterations in catalase expression, including treatment with exogenous enzyme, caused marked cytoprotection. Thus, catalase is an important resistance factor and highlights H2O2 as an obligate ROS for cell death from this agent. Exogenous superoxide dismutase enhanced catalase-induced cytoprotection. ß-Lapachone-induced cell death included apoptosis-inducing factor (AIF) translocation from mitochondria to nuclei, TUNEL+ staining, atypical PARP1 cleavage, and glyceraldehyde 3-phosphate dehydrogenase S-nitrosylation, which were abrogated by catalase. We predict that the ratio of NQO1:catalase activities in breast cancer versus associated normal tissue are likely to be the major determinants affecting the therapeutic window of ß-lapachone and other NQO1 bioactivatable drugs.
Assuntos
Neoplasias da Mama/tratamento farmacológico , NAD(P)H Desidrogenase (Quinona)/metabolismo , Naftoquinonas/administração & dosagem , Poli(ADP-Ribose) Polimerases/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Catalase/genética , Catalase/metabolismo , Quebras de DNA de Cadeia Simples/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/metabolismo , NAD(P)H Desidrogenase (Quinona)/genética , Necrose/genética , Necrose/patologia , Poli(ADP-Ribose) Polimerase-1 , Espécies Reativas de Oxigênio/metabolismoRESUMO
Agents, such as ß-lapachone, that target the redox enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1), to induce programmed necrosis in solid tumors have shown great promise, but more potent tumor-selective compounds are needed. Here, we report that deoxynyboquinone kills a wide spectrum of cancer cells in an NQO1-dependent manner with greater potency than ß-lapachone. Deoxynyboquinone lethality relies on NQO1-dependent futile redox cycling that consumes oxygen and generates extensive reactive oxygen species (ROS). Elevated ROS levels cause extensive DNA lesions, PARP1 hyperactivation, and severe NAD+ /ATP depletion that stimulate Ca2+ -dependent programmed necrosis, unique to this new class of NQO1 "bioactivated" drugs. Short-term exposure of NQO1+ cells to deoxynyboquinone was sufficient to trigger cell death, although genetically matched NQO1- cells were unaffected. Moreover, siRNA-mediated NQO1 or PARP1 knockdown spared NQO1+ cells from short-term lethality. Pretreatment of cells with BAPTA-AM (a cytosolic Ca2+ chelator) or catalase (enzymatic H2O2 scavenger) was sufficient to rescue deoxynyboquinone-induced lethality, as noted with ß-lapachone. Investigations in vivo showed equivalent antitumor efficacy of deoxynyboquinone to ß-lapachone, but at a 6-fold greater potency. PARP1 hyperactivation and dramatic ATP loss were noted in the tumor, but not in the associated normal lung tissue. Our findings offer preclinical proof-of-concept for deoxynyboquinone as a potent chemotherapeutic agent for treatment of a wide spectrum of therapeutically challenging solid tumors, such as pancreatic and lung cancers.