RESUMEN
BACKGROUND: Greater than average loss of one-second forced expiratory volume (FEV1 ) is a risk factor for asthma, chronic obstructive pulmonary disease (COPD), and asthma/COPD overlap syndrome in World Trade Center (WTC)-exposed firefighters. Inhaled corticosteroids and long-acting beta agonists (ICS/LABA) are used to treat obstructive airways disease but their impact on FEV1 -trajectory in this population is unknown. METHODS: The study population included WTC-exposed male firefighters who were treated with ICS/LABA for 2 years or longer (with initiation before 2015), had at least two FEV1 measurements before ICS/LABA initiation and two FEV1 measurements posttreatment between September 11, 2001 and September 10, 2019. Linear mixed-effects models were used to estimate FEV1 -slope pre- and post-treatment. RESULTS: During follow-up, 1023 WTC-exposed firefighters were treated with ICS/LABA for 2 years or longer. When comparing intervals 6 years before and 6 years after treatment, participants had an 18.7 ml/year (95% confidence interval [CI]: 11.3-26.1) improvement in FEV1 -slope after adjustment for baseline FEV1 , race, height, WTC exposure, weight change, blood eosinophil concentration, and smoking status. After stratification by median date of ICS/LABA initiation (January 14, 2010), earlier ICS/LABA-initiators had a 32.5 ml/year (95% CI: 19.5-45.5) improvement in slope but later ICS/LABA-initiators had a nonsignificant FEV1 -slope improvement (7.9 ml/year, 95% CI: -0.5 to 17.2). CONCLUSIONS: WTC-exposed firefighters treated with ICS/LABA had improved FEV1 slope after initiation, particularly among those who started earlier. Treatment was, however, not associated with FEV1 -slope improvement if started after the median initiation date (1/14/2010), likely because onset of disease began before treatment initiation. Research on alternative treatments is needed for patients with greater than average FEV1 -decline who have not responded to ICS/LABA.
Asunto(s)
Corticoesteroides , Enfermedad Pulmonar Obstructiva Crónica , Administración por Inhalación , Corticoesteroides/uso terapéutico , Quimioterapia Combinada , Volumen Espiratorio Forzado , Humanos , Pulmón , Masculino , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/epidemiologíaRESUMEN
Pancreatic Cancer (PC) is a deadly disease in need of new therapeutic options. We recently developed a novel tricarbonylmethane agent (CMC2.24) as a therapeutic agent for PC, and evaluated its efficacy in preclinical models of PC. CMC2.24 inhibited the growth of various human PC cell lines in a concentration and time-dependent manner. Normal human pancreatic epithelial cells were resistant to CMC2.24, indicating selectivity. CMC2.24 reduced the growth of subcutaneous and orthotopic PC xenografts in mice by up to 65% (P < 0.02), and the growth of a human patient-derived tumor xenograft by 47.5% (P < 0.03 vs vehicle control). Mechanistically, CMC2.24 inhibited the Ras-RAF-MEK-ERK pathway. Based on Ras Pull-Down Assays, CMC2.24 inhibited Ras-GTP, the active form of Ras, in MIA PaCa-2 cells and in pancreatic acinar explants isolated from Kras mutant mice, by 90.3% and 89.1%, respectively (P < 0.01, for both). The inhibition of active Ras led to an inhibition of c-RAF, MEK, and ERK phosphorylation by 93%, 91%, and 87%, respectively (P < 0.02, for all) in PC xenografts. Furthermore, c-RAF overexpression partially rescued MIA PaCa-2 cells from the cell growth inhibition by CMC2.24. In addition, downstream of ERK, CMC2.24 inhibited STAT3 phosphorylation levels at the serine 727 residue, enhanced the levels of superoxide anion in mitochondria, and induced intrinsic apoptosis as shown by the release of cytochrome c from the mitochondria to the cytosol and the further cleavage of caspase 9 in PC cells. In conclusion, CMC2.24, a potential Ras inhibitor, is an efficacious agent for PC treatment in preclinical models, deserving further evaluation.
Asunto(s)
Antineoplásicos/uso terapéutico , Proliferación Celular/efectos de los fármacos , Curcumina/análogos & derivados , Neoplasias Pancreáticas/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Proteínas ras/metabolismo , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Curcumina/farmacología , Curcumina/uso terapéutico , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologíaRESUMEN
Given that glioblastoma multiforme (GBM) is associated with poor prognosis, new agents are urgently needed. We developed phospho-glycerol-ibuprofen-amide (PGIA), a novel ibuprofen derivative, and evaluated its safety and efficacy in preclinical models of GBM, and its mechanism of action using human GBM cells and animal tumor models. Furthermore, we explored whether formulating PGIA in polymeric nanoparticles could enhance its levels in the brain. PGIA was 3.7- to 5.1-fold more potent than ibuprofen in suppressing the growth of human GBM cell lines. PGIA 0.75× IC50 inhibited cell proliferation by 91 and 87% in human LN-229 and U87-MG GBM cells, respectively, and induced strong G1/S arrest.In vivo, compared with control, PGIA reduced U118-MG and U87-MG xenograft growth by 77 and 56%, respectively (P< 0.05), and was >2-fold more efficacious than ibuprofen. Normal human astrocytes were resistant to PGIA, indicating selectivity. Mechanistically, PGIA reduced cyclin D1 levels in a time- and concentration-dependent manner in GBM cells and in xenografts. PGIA induced cyclin D1 degradation via the proteasome pathway and induced dephosphorylation of GSK3ß, which was required for cyclin D1 turnover. Furthermore, cyclin D1 overexpression rescued GBM cells from the cell growth inhibition by PGIA. Moreover, the formulation of PGIA in poly-(L)-lactic acid poly(ethylene glycol) polymeric nanoparticles improved its pharmacokinetics in mice, delivering PGIA to the brain. PGIA displays strong efficacy against GBM, crosses the blood-brain barrier when properly formulated, reaching the target tissue, and establishes cyclin D1 as an important molecular target. Thus, PGIA merits further evaluation as a potential therapeutic option for GBM.
Asunto(s)
Neoplasias Encefálicas/patología , Ciclina D1/metabolismo , Glioblastoma/patología , Ibuprofeno/análogos & derivados , Animales , Línea Celular Tumoral , Ibuprofeno/química , RatonesRESUMEN
OBJECTIVE: To determine if World Trade Center (WTC) exposure is associated with hearing loss. METHODS: Logistic regression to evaluate the immediate impact of WTC exposure and parametric survival analysis to assess longitudinal outcomes. RESULTS: Those arriving on the morning of September 11, 2001 had elevated odds of low-frequency (odds ratio [OR]: 1.24; 95% confidence interval [CI]: 1.04 to 1.47) and high-frequency (OR: 1.16; 95% CI: 1.02 to 1.31) hearing loss at their first post-September 11, 2001 examination. Longitudinally, participants arriving before September 13, 2001 and spending more than or equal to 6 months at the WTC-site had greater risk of hearing loss in the low frequencies (risk ratio [RR]: 1.31; 95% CI: 1.05 to 1.60) and high frequencies (RR: 1.37; 95% CI: 1.22 to 1.54). By 2016, 3194 (37%) had abnormal hearing sensitivity in either ear and 1751 (20%) in both ears. CONCLUSIONS: More heavily WTC-exposed workers were at increased risk of hearing loss, and group differences persisted for at least 15 years. Those with abnormal hearing sensitivity may benefit from interventions such as hearing aids and other rehabilitation.
Asunto(s)
Auxiliares de Urgencia , Bomberos , Pérdida Auditiva/epidemiología , Exposición Profesional/efectos adversos , Ataques Terroristas del 11 de Septiembre , Adulto , Audiometría , Pérdida Auditiva/diagnóstico , Humanos , Masculino , Ciudad de Nueva York/epidemiologíaRESUMEN
Pancreatic cancer is a deadly disease with a dismal 5-year survival rate of <6%. The currently limited treatment options for pancreatic cancer underscore the need for novel chemopreventive and therapeutic agents. Accumulating evidence indicates that aspirin use is associated with a decreased risk of pancreatic cancer. However, the anticancer properties of aspirin are restricted by its gastrointestinal toxicity and its limited efficacy. Therefore, we developed phospho-aspirin (MDC-22), a novel derivative of aspirin, and evaluated its chemopreventive efficacy in preclinical models of pancreatic cancer. Phospho-aspirin inhibited the growth of human pancreatic cancer cell lines 8- to 12-fold more potently than aspirin; based on the 24-hour IC50 values. In a Panc-1 xenograft model, phospho-aspirin, at a dose of 100 mg/kg/d 5 times per week for 30 days, reduced tumor growth by 78% (P < 0.01 vs. vehicle control). Furthermore, phospho-aspirin prevented pancreatitis-accelerated acinar-to-ductal metaplasia in mice with activated Kras. In p48-Cre;Kras(G12D) mice, cerulein treatment (6 hourly injections two times per week for 3 weeks) led to a significant increase in ductal metaplasia, replacing the majority of the exocrine compartment. Administration of phospho-aspirin 100 mg/kg/day five times per week for 21 days (starting on the first day of cerulein injection) inhibited the acinar-to-ductal metaplasia, reducing it by 87% (P < 0.01, vs. cerulein-treated control). Phospho-aspirin appeared to be safe, with the animals showing no signs of toxicity during treatment. Mechanistically, phospho-aspirin inhibited EGFR activation in pancreatic cancer, an effect consistently observed in pancreatic cancer cells, primary acinar explants and in vivo In conclusion, our findings indicate that phospho-aspirin has strong anticancer efficacy in preclinical models of pancreatic cancer, warranting its further evaluation. Cancer Prev Res; 9(7); 624-34. ©2016 AACR.
Asunto(s)
Antineoplásicos/farmacología , Aspirina/análogos & derivados , Aspirina/farmacología , Carcinogénesis/efectos de los fármacos , Neoplasias Pancreáticas/patología , Animales , Proliferación Celular/efectos de los fármacos , Quimioprevención/métodos , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Ratones Transgénicos , Neoplasias Pancreáticas/prevención & control , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
This study investigated if a marginal zinc deficiency during gestation in rats could affect fetal neural progenitor cell (NPC) proliferation through a down-regulation of the extracellular signal-regulated kinase (ERK1/2) signaling pathway. Rats were fed a marginally zinc-deficient or adequate diet from the beginning of gestation until embryonic day (E)19. The proportion of proliferating cells in the E19 fetal ventricular zone was decreased by marginal zinc deficiency. Immunostaining for phosphorylated ERK1/2 in the cerebral cortex was decreased in the marginal zinc fetuses, and this effect was strongest in the ventricular zone. Furthermore, phosphorylation of the upstream mitogen-activated ERK kinases (MEK1/2) was not affected, suggesting that marginal zinc deficiency could have increased ERK-directed phosphatase activity. Similar findings were observed in cultured rat embryonic cortical neurons and in IMR-32 neuroblastoma cells, in which zinc-deficiency decreased ERK1/2 phosphorylation without affecting MEK1/2 phosphorylation. Indeed, zinc deficiency increased the activity of the ERK-directed phosphatase protein phosphatase 2A (PP2A) in the fetal cortex and IMR-32 cells. Inhibition of PP2A with okadaic acid prevented the decrease in ERK phosphorylation and proliferation of zinc-deficient IMR-32 cells. Together these results demonstrated that decreased zinc availability reduces ERK1/2 signaling and decreased NPC proliferation as a consequence of PP2A activation. Disruption of fetal neurogenesis could underlie irreversible neurobehavioral impairments observed after even marginal zinc nutrition during a critical period of early brain development.