Interstitial Lung Disease and Progressive Pulmonary Fibrosis: a World Trade Center Cohort 20-Year Longitudinal Study.

PURPOSE: World Trade Center (WTC) exposure is associated with obstructive airway diseases and sarcoidosis. There is limited research regarding the incidence and progression of non-sarcoidosis interstitial lung diseases (ILD) after WTC-exposure. ILD encompasses parenchymal diseases which may lead to progressive pulmonary fibrosis (PPF). We used the Fire Department of the City of New York's (FDNY's) WTC Health Program cohort to estimate ILD incidence and progression. METHODS: This longitudinal study included 14,525 responders without ILD prior to 9/11/2001. ILD incidence and prevalence were estimated and standardized to the US 2014 population. Poisson regression modeled risk factors, including WTC-exposure and forced vital capacity (FVC), associated with ILD. Follow-up time ended at the earliest of incident diagnosis, end of study period/case ascertainment, transplant or death. RESULTS: ILD developed in 80/14,525 FDNY WTC responders. Age, smoking, and gastroesophageal reflux disease (GERD) prior to diagnosis were associated with incident ILD, though FVC was not. PPF developed in 40/80 ILD cases. Among the 80 cases, the average follow-up time after ILD diagnosis was 8.5 years with the majority of deaths occurring among those with PPF (PPF: n = 13; ILD without PPF: n = 6). CONCLUSIONS: The prevalence of post-9/11 ILD was more than two-fold greater than the general population. An exposure-response gradient could not be demonstrated. Half the ILD cases developed PPF, higher than previously reported. Age, smoking, and GERD were risk factors for ILD and PPF, while lung function was not. This may indicate that lung function measured after respirable exposures would not identify those at risk for ILD or PPF.

Lung function decline before and after treatment of World Trade Center associated obstructive airways disease with inhaled corticosteroids and long-acting beta agonists.

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.

Pre-COVID-19 lung function and other risk factors for severe COVID-19 in first responders.

Risk factors for #COVID19 infection and severe disease (hospitalisation or death) in NYC first responders: greater pre-pandemic rate of FEV1 decline is associated with severe COVID-19, as is emergency medical service work versus firefighting https://bit.ly/3nZPuZY.

Performance of Risk Factor-Based Guidelines and Model-Based Chest CT Lung Cancer Screening in World Trade Center-Exposed Fire Department Rescue/Recovery Workers.

BACKGROUND: Lung cancer is a leading cause of cancer incidence and death in the United States. Risk factor-based guidelines and risk model-based strategies are used to identify patients who could benefit from low-dose chest CT (LDCT) screening. Few studies compare guidelines or models within the same cohort. We evaluate lung cancer screening performance of two risk factor-based guidelines (US Preventive Services Task Force 2014 recommendations [USPSTF-2014] and National Comprehensive Cancer Network Group 2 [NCCN-2]) and two risk model-based strategies, Prostate Lung Colorectal and Ovarian Cancer Screening (PLCOm2012) and the Bach model) in the same occupational cohort. RESEARCH QUESTION: Which risk factor-based guideline or model-based strategy is most accurate in detecting lung cancers in a highly exposed occupational cohort? STUDY DESIGN AND METHODS: Fire Department of City of New York (FDNY) rescue/recovery workers exposed to the September 11, 2001 attacks underwent LDCT lung cancer screening based on smoking history and age. The USPSTF-2014, NCCN-2, PLCOm2012 model, and Bach model were retrospectively applied to determine how many lung cancers were diagnosed using each approach. RESULTS: Among the study population (N = 3,953), 930 underwent a baseline scan that met at least one risk factor or model-based LDCT screening strategy; 73% received annual follow-up scans. Among the 3,953, 63 lung cancers were diagnosed, of which 50 were detected by at least one LDCT screening strategy. The NCCN-2 guideline was the most sensitive (79.4%; 50/63). When compared with NCCN-2, stricter age and smoking criteria reduced sensitivity of the other guidelines/models (USPSTF-2014 [44%], PLCOm2012 [51%], and Bach[46%]). The 13 missed lung cancers were mainly attributable to smoking less and quitting longer than guideline/model eligibility criteria. False-positive rates were similar across all four guidelines/models. INTERPRETATION: In this cohort, our findings support expanding eligibility for LDCT lung cancer screening by lowering smoking history from ≥30 to ≥20 pack-years and age from 55 years to 50 years old. Additional studies are needed to determine its generalizability to other occupational/environmental exposed cohorts.

Factors Predicting Treatment of World Trade Center-Related Lung Injury: A Longitudinal Cohort Study.

The factors that predict treatment of lung injury in occupational cohorts are poorly defined. We aimed to identify patient characteristics associated with initiation of treatment with inhaled corticosteroid/long-acting beta-agonist (ICS/LABA) >2 years among World Trade Center (WTC)-exposed firefighters. The study population included 8530 WTC-exposed firefighters. Multivariable logistic regression assessed the association of patient characteristics with ICS/LABA treatment for >2 years over two-year intervals from 11 September 2001-10 September 2017. Cox proportional hazards models measured the association of high probability of ICS/LABA initiation with actual ICS/LABA initiation in subsequent intervals. Between 11 September 2001-1 July 2018, 1629/8530 (19.1%) firefighters initiated ICS/LABA treatment for >2 years. Forced Expiratory Volume in 1 s (FEV1), wheeze, and dyspnea were consistently and independently associated with ICS/LABA treatment. High-intensity WTC exposure was associated with ICS/LABA between 11 September 2001-10 September 2003. The 10th percentile of risk for ICS/LABA between 11 September 2005-10 Septmeber 2007 was associated with a 3.32-fold increased hazard of actual ICS/LABA initiation in the subsequent 4 years. In firefighters with WTC exposure, FEV1, wheeze, and dyspnea were independently associated with prolonged ICS/LABA treatment. A high risk for treatment was identifiable from routine monitoring exam results years before treatment initiation.

Hearing Loss Among World Trade Center Firefighters and Emergency Medical Service Workers.

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.

A novel tricarbonylmethane agent (CMC2.24) reduces human pancreatic tumor growth in mice by targeting Ras.

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.

Phospho-Aspirin (MDC-22) Prevents Pancreatic Carcinogenesis in Mice.

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.

The novel agent phospho-glycerol-ibuprofen-amide (MDC-330) inhibits glioblastoma growth in mice: an effect mediated by cyclin D1.

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.

Gestational marginal zinc deficiency impaired fetal neural progenitor cell proliferation by disrupting the ERK1/2 signaling pathway.

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.