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"O'Brien, James"
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ENVIRONMENTAL ENGEL CURVES
Environmental Engel curves (EECs) describe households’ incomes and the pollution necessary to produce the goods and services they consume. We calculate 29 annual EECs from 1984 to 2012 for point-source air pollutants in the United States, revealing three clear results: EECs slope upward, have income elasticities less than 1, and shift down over time. Even without changes to production techniques, pollution would have declined despite growing incomes. This improvement can be attributed about equally to two trends: household income growth represented by movement along inelastic EECs and economy-wide changes represented by downward shifts in EECs over time.
Journal Article
Targeting the EMT transcription factor TWIST1 overcomes resistance to EGFR inhibitors in EGFR-mutant non-small-cell lung cancer
Patients with
EGFR-
mutant non-small-cell lung cancer (NSCLC) have significantly benefited from the use of EGFR tyrosine kinase inhibitors (TKIs). However, long-term efficacy of these therapies is limited due to de novo resistance (~30%) as well as acquired resistance. Epithelial–mesenchymal transition transcription factors (EMT-TFs), have been identified as drivers of EMT-mediated resistance to EGFR TKIs, however, strategies to target EMT-TFs are lacking. As the third generation EGFR TKI, osimertinib, has now been adopted in the first-line setting, the frequency of
T790M
mutations will significantly decrease in the acquired resistance setting. Previously less common mechanisms of acquired resistance to first generation EGFR TKIs including EMT are now being observed at an increased frequency after osimertinib. Importantly, there are no other FDA approved targeted therapies after progression on osimertinib. Here, we investigated a novel strategy to overcome EGFR TKI resistance through targeting the EMT-TF, TWIST1, in
EGFR-
mutant NSCLC. We demonstrated that genetic silencing of
TWIST1
or treatment with the TWIST1 inhibitor, harmine, resulted in growth inhibition and apoptosis in
EGFR-
mutant NSCLC. TWIST1 overexpression resulted in erlotinib and osimertinib resistance in
EGFR
-mutant NSCLC cells. Conversely, genetic and pharmacological inhibition of TWIST1 in EGFR TKI-resistant
EGFR-
mutant cells increased sensitivity to EGFR TKIs. TWIST1-mediated EGFR TKI resistance was due in part to TWIST1 suppression of transcription of the pro-apoptotic BH3-only gene,
BCL2L11
(BIM), by directly binding to
BCL2L11
intronic regions and promoter. As such, pan-BCL2 inhibitor treatment overcame TWIST1-mediated EGFR TKI resistance and were more effective in the setting of TWIST1 overexpression. Finally, in a mouse model of autochthonous
EGFR
-mutant lung cancer, Twist1 overexpression resulted in erlotinib resistance and suppression of erlotinib-induced apoptosis. These studies establish TWIST1 as a driver of resistance to EGFR TKIs and provide rationale for use of TWIST1 inhibitors or BCL2 inhibitors as means to overcome EMT-mediated resistance to EGFR TKIs.
Journal Article
Age, autos, and the value of a statistical life
The value of a statistical life (VSL) is used to assign a dollar value to the benefits of health and safety regulations. Many of those regulations disproportionately benefit older people, but most estimates of the VSL come from hedonic wage regressions with few older workers and no retirees. Using automobile purchase decisions, I estimate a VSL for individuals from the age of 18 up to the age of 85. Combining information on vehicle holdings and use, household attributes, used vehicle prices, crash test results, and yearly fatal accidents for each make, model, and vintage automobile, I calculate a separate willingness to pay for reduced mortality for different age groups. I find a significant inverted-U shape to the age-VSL function that ranges from $1.5 to $19.2 million (in 2009 dollars). The shape and magnitude of the vehiclebased age-VSL relationship corroborate labor market estimates and extend the age range of revealed preference evidence on the relationship between age and the VSL.
Journal Article
scaRNA1 Expression Levels Affect Alternative Splicing of mRNA
Our previous research identified 12 small Cajal body-specific RNAs (scaRNAs) with reduced expression in the right ventricle in infant patients with tetralogy of Fallot. Likewise, we showed that there were significant changes in mRNA processing in the RV in these patients. ScaRNAs play a crucial role in the biochemical maturation of spliceosomal RNAs (pseudouridylation and 2′-O-methylation). We showed that variations in scaRNA1 levels resulted in changes in alternative splicing in human cells. To investigate further the role that scaRNAs play in mRNA processing, we examine here the impact of knocking down scaRNA1 in quail myoblast cells (Coturnix japonica, a well-established animal model for studying embryonic development). Following the knockdown of scaRNA1, transcriptome analysis revealed that the genes Tjp1, Map3k7, and Sppl2a were alternatively spliced. Growing evidence indicates that alternative splicing of mRNA plays an important role in regulating cell differentiation and tissue development. Our data presented here provide additional support for research to clarify the specific roles that individual scaRNAs play in regulating spliceosome function and mRNA splicing.
Journal Article
The violence of climate change : lessons of resistance from nonviolent activists
It is beyond debate that human beings are the primary cause of climate change. Many think of climate change as primarily a scientific, economic, or political problem, and those perspectives inform Kevin O'Brien's analysis. But O'Brien argues that we should respond to climate change first and foremost as a case of systematic and structural violence. As he points out, global warming is primarily caused by the carbon emissions of the affluent, emissions that harm the poor first and worst. Climate change divides human beings from one another and from the earth; in short, global warming and climate change is violence. In order to sustain a constructive and creative response to this violence, he contends, society needs practical examples of activism and nonviolent peacemaking. O'Brien identifies five such examples from US history, providing brief biographies of heroic individuals whose idealism and social commitment and political savvy can model the fight against climate change and for climate justice: Quaker abolitionist John Woolman; social reformer Jane Addams; Catholic worker advocate Dorothy Day; civil rights leader Martin Luther King, Jr.; and union organizer Cesar Chavez. These moral exemplars, all of whom were motivated by their Christian faith, serve as witnesses to those seeking to make peace in response to the violence of climate change.
Book
Acquired Weakness, Handgrip Strength, and Mortality in Critically Ill Patients
ICU-acquired paresis (ICUAP) is common in survivors of critical illness. There is significant associated morbidity, including prolonged time on the ventilator and longer hospital stay. However, it is unclear whether ICUAP is independently associated with mortality, as sicker patients are more prone and existing studies have not adjusted for this.
To test the hypothesis that ICUAP is independently associated with increased mortality. Secondarily, to determine if handgrip dynamometry is a concise measure of global strength and is independently associated with mortality.
A prospective multicenter cohort study was conducted in intensive care units (ICU) of five academic medical centers. Adults requiring at least 5 days of mechanical ventilation without evidence of preexisting neuromuscular disease were followed until awakening and were then examined for strength.
We measured global strength and handgrip dynamometry. The primary outcome was in-hospital mortality and secondary outcomes were hospital and ICU-free days, ICU readmission, and recurrent respiratory failure. Subjects with ICUAP (average MRC score of < 4) had longer hospital stays and required mechanical ventilation longer. Handgrip strength was lower in subjects with ICUAP and had good test performance for diagnosing ICUAP. After adjustment for severity of illness, ICUAP was independently associated with hospital mortality (odds ratio [OR], 7.8; 95% confidence interval [CI], 2.4-25.3; P = 0.001). Separately, handgrip strength was independently associated with hospital mortality (OR, 4.5; 95% CI, 1.5-13.6; P = 0.007).
ICUAP is independently associated with increased hospital mortality. Handgrip strength is also independently associated with poor hospital outcome and may serve as a simple test to identify ICUAP. Clinical trial registered with www.clinicaltrials.gov (NCT00106665).
Journal Article