Receptor-Mediated Oral Delivery of a Bioencapsulated Green Fluorescent Protein Expressed in Transgenic Chloroplasts Into the Mouse Circulatory System

Oral delivery of biopharmaceutical proteins expressed in plant cells should reduce their cost of production, purification, processing, cold storage, transportation, and delivery. However, poor intestinal absorption of intact proteins is a major challenge. To overcome this limitation, we investigate here the concept of receptor-mediated oral delivery of chloroplast-expressed foreign proteins. Therefore, the transmucosal carrier cholera toxin B-subunit and green fluorescent protein (CTB-GFP), separated by a furin cleavage site, was expressed via the tobacco chloroplast genome. Polymerase chain reaction (PCR) and Southern blot analyses confirmed site-specific transgene integration and homoplasmy. Immunoblot analysis and ELISA confirmed expression of monomeric and pentameric forms of CTB-GFP, up to 21.3% of total soluble proteins. An in vitro furin cleavage assay confirmed integrity of the engineered furin cleavage site, and a GM1 binding assay confirmed the functionality of CTB-GFP pentamers. Following oral administration of CTB-GFP expressing leaf material to mice, GFP was observed in the mice intestinal mucosa, liver, and spleen in fluorescence and immunohistochemical studies, while CTB remained in the intestinal cell. This report of receptor-mediated oral delivery of a foreign protein into the circulatory system opens the door for low-cost production and delivery of human therapeutic proteins

When It Rains, It Pours: Future Climate Extremes and Health

Background: The accelerating accumulation of greenhouse gases in the Earth’s atmosphere is changing global environmental conditions in unprecedented and potentially irreversible ways. Climate change poses a host of challenges to the health of populations through complex direct and indirect mechanisms. The direct effects include an increased frequency of heat waves, rising sea levels that threaten low-lying communities, anticipated extremes in the global hydrologic cycle (droughts, floods, and intense storms), and adverse effects on agricultural production and fisheries due to environmental stressors and changes in land use. Indirectly, climate change is anticipated to threaten health by worsening urban air pollution and increasing rates of infectious (particularly waterborne and vector-borne) disease transmission. Objective: To provide a state-of-the-science review on the health consequences of a changing climate. Findings: Environmental public health researchers have concluded that, on balance, adverse health outcomes will dominate under these changed climatic conditions. The number of pathways through which climate change can affect the health of populations makes this environmental health threat one of the largest and most formidable of the new century. Geographic location plays an influential role the potential for adverse health effects caused by climate change, and certain regions and populations are more vulnerable than others to expected health effects. Two kinds of strategies are available for responding to climate change: mitigation policies (which aim to reduce greenhouse gas emissions) and adaptation measures (relating to preparedness for anticipated impacts). Conclusions: To better understand and address the complex nature of health risks posed by climate change, interdisciplinary collaboration is critical. Efforts to move beyond our current reliance on fossil fuels to cleaner, more sustainable energy sources may offer some of the greatest health opportunities in more than a century and cobenefits beyond the health sector. Because the nations least responsible for climate change are most vulnerable to its effects, the challenge to reduce greenhouse gas emissions is not merely technical, but also moral

Integrated proteomics and phosphoproteomics revealed druggable kinases in neoadjuvant chemotherapy resistant tongue cancer

Tongue squamous cell carcinoma is an aggressive oral cancer with a high incidence of metastasis and poor prognosis. Most of the oral cavity cancer patients present in clinics with locally advanced unresectable tumors. Neoadjuvant treatment is beneficial for these individuals as it reduces the tumor size aiding complete resection. However, patients develop therapy resistance to the drug regimen. In this study, we explored the differential expression of proteins and altered phosphorylation in the neoadjuvant chemotherapy resistant tongue cancer patients. We integrated the proteomic and phosphoproteomic profiles of resistant (n = 4) and sensitive cohorts (n = 4) and demonstrated the differential expression and phosphorylation of proteins in the primary tissue of the respective subject groups. We observed differential and extensive phosphorylation of keratins such as KRT10 and KRT1 between the two cohorts. Furthermore, our study revealed a kinase signature associated with neoadjuvant chemotherapy resistance. Kinases such as MAPK1, AKT1, and MAPK3 are predicted to regulate the resistance in non-responders. Pathway analysis showed enrichment of Rho GTPase signaling and hyperphosphosphorylation of proteins involved in cell motility, invasion, and drug resistance. Targeting the kinases could help with the clinical management of neoadjuvant chemotherapy-resistant tongue cancer

Guidelines for Modeling and Reporting Health Effects of Climate Change Mitigation Actions.

BACKGROUND: Modeling suggests that climate change mitigation actions can have substantial human health benefits that accrue quickly and locally. Documenting the benefits can help drive more ambitious and health-protective climate change mitigation actions; however, documenting the adverse health effects can help to avoid them. Estimating the health effects of mitigation (HEM) actions can help policy makers prioritize investments based not only on mitigation potential but also on expected health benefits. To date, however, the wide range of incompatible approaches taken to developing and reporting HEM estimates has limited their comparability and usefulness to policymakers. OBJECTIVE: The objective of this effort was to generate guidance for modeling studies on scoping, estimating, and reporting population health effects from climate change mitigation actions. METHODS: An expert panel of HEM researchers was recruited to participate in developing guidance for conducting HEM studies. The primary literature and a synthesis of HEM studies were provided to the panel. Panel members then participated in a modified Delphi exercise to identify areas of consensus regarding HEM estimation. Finally, the panel met to review and discuss consensus findings, resolve remaining differences, and generate guidance regarding conducting HEM studies. RESULTS: The panel generated a checklist of recommendations regarding stakeholder engagement: HEM modeling, including model structure, scope and scale, demographics, time horizons, counterfactuals, health response functions, and metrics; parameterization and reporting; approaches to uncertainty and sensitivity analysis; accounting for policy uptake; and discounting. DISCUSSION: This checklist provides guidance for conducting and reporting HEM estimates to make them more comparable and useful for policymakers. Harmonization of HEM estimates has the potential to lead to advances in and improved synthesis of policy-relevant research that can inform evidence-based decision making and practice. https://doi.org/10.1289/EHP6745

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Collaborative approaches to account for the health costs of climate-sensitive events

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Evaluating responses to health-related messages about the financial costs of climate change

Introduction: Science communication research has increasingly explored what factors shape public opinion around climate change policies. The public health consequences of climate change are becoming an increasingly prominent focus of research and policy, and prior research has identified the importance of health messaging for effective risk communication efforts. While prior research on communication appeals that highlight the impact of climate change on public health has shown promise, evidence around the effectiveness of such appeals remains thin, especially around health-related financial costs related to climate hazards. Materials: We explore how social media messages that describe the ramifications of climate-related health problems may influence support for climate change policies. We fielded an experiment embedded in an online survey of 2,859 English-speaking U.S. adults to understand how health-cost climate messaging may have a differential impact on distinct segments of the public. Treatment groups read a hypothetical social media post about how a failure to invest in climate change mitigation and adaptation may result in financial burdens from either damaged property or healthcare costs due to worsening climate hazards quantified at either a national or household scale. Following exposure to treatment stimuli, respondents were asked to state to what extent they perceived climate change to be a threat to the US, supported policy responses, and supported federal investments in mitigation and adaptation. Results: While all messaging conditions were associated with significantly higher perceptions that climate change poses a threat, no differences were observed when comparing across the health- versus property-related economic damage messages. Conclusion: Communication of costs on a per household basis was associated with significantly higher perceptions that climate change is a threat compared to messages that emphasized costs at a national level