Prioritization of control factors for heavy metals in groundwater based on a source-oriented health risk assessment model

Heavy metals (HMs) in groundwater seriously threaten ecological safety and human health. To facilitate the effective management of groundwater contamination, priority control factors of HMs in groundwater need to be categorized. A total of 86 groundwater samples were collected from the Huangpi district of Wuhan city, China, during the dry and wet seasons. To determine priority control factors, a source-oriented health risk assessment model was applied to compare the pollution sources and health risks of seven HMs (Cu, Pb, Zn, Cr, Ni, As, and Fe). The results showed that the groundwater had higher As and Fe contents. The sources of HM pollution during the wet period were mainly industrial and agricultural activities and natural sources. During the dry period, origins were more complex due to the addition of domestic discharges, such as sewage wastewater. Industrial activities (74.10% during the wet period), agricultural activities (53.84% during the dry period), and As were identified as the priority control factors for groundwater HMs. The results provide valuable insights for policymakers to coordinate targeted management of HM pollution in groundwater and reduce the cost of HM pollution mitigation

The Effect of Human Factor H on Immunogenicity of Meningococcal Native Outer Membrane Vesicle Vaccines with Over-Expressed Factor H Binding Protein

The binding of human complement inhibitors to vaccine antigens in vivo could diminish their immunogenicity. A meningococcal ligand for the complement down-regulator, factor H (fH), is fH-binding protein (fHbp), which is specific for human fH. Vaccines containing recombinant fHbp or native outer membrane vesicles (NOMV) from mutant strains with over-expressed fHbp are in clinical development. In a previous study in transgenic mice, the presence of human fH impaired the immunogenicity of a recombinant fHbp vaccine. In the present study, we prepared two NOMV vaccines from mutant group B strains with over-expressed wild-type fHbp or an R41S mutant fHbp with no detectable fH binding. In wild-type mice in which mouse fH did not bind to fHbp in either vaccine, the NOMV vaccine with wild-type fHbp elicited 2-fold higher serum IgG anti-fHbp titers (P = 0.001) and 4-fold higher complement-mediated bactericidal titers against a PorA-heterologous strain than the NOMV with the mutant fHbp (P = 0.003). By adsorption, the bactericidal antibodies were shown to be directed at fHbp. In transgenic mice in which human fH bound to the wild-type fHbp but not to the R41S fHbp, the NOMV vaccine with the mutant fHbp elicited 5-fold higher serum IgG anti-fHbp titers (P = 0.002), and 19-fold higher bactericidal titers than the NOMV vaccine with wild-type fHbp (P = 0.001). Thus, in mice that differed only by the presence of human fH, the respective results with the two vaccines were opposite. The enhanced bactericidal activity elicited by the mutant fHbp vaccine in the presence of human fH far outweighed the loss of immunogenicity of the mutant protein in wild-type animals. Engineering fHbp not to bind to its cognate complement inhibitor, therefore, may increase vaccine immunogenicity in humans

Real-time genomic characterization of advanced pancreatic cancer to enable precision medicine

Clinically relevant subtypes exist for pancreatic ductal adenocarcinoma (PDAC), but molecular characterization is not yet standard in clinical care. We implemented a biopsy protocol to perform time-sensitive whole-exome sequencing and RNA sequencing for patients with advanced PDAC. Therapeutically relevant genomic alterations were identified in 48% (34/71) and pathogenic/likely pathogenic germline alterations in 18% (13/71) of patients. Overall, 30% (21/71) of enrolled patients experienced a change in clinical management as a result of genomic data. Twenty-six patients had germline and/or somatic alterations in DNA-damage repair genes, and 5 additional patients had mutational signatures of homologous recombination deficiency but no identified causal genomic alteration. Two patients had oncogenic in-frame BRAF deletions, and we report the first clinical evidence that this alteration confers sensitivity to MAPK pathway inhibition. Moreover, we identified tumor/stroma gene expression signatures with clinical relevance. Collectively, these data demonstrate the feasibility and value of real-time genomic characterization of advanced PDAC.Significance: Molecular analyses of metastatic PDAC tumors are challenging due to the heterogeneous cellular composition of biopsy specimens and rapid progression of the disease. Using an integrated multidisciplinary biopsy program, we demonstrate that real-time genomic characterization of advanced PDAC can identify clinically relevant alterations that inform management of this difficult disease. Cancer Discov; 8(9); 1096-111. ©2018 AACR.See related commentary by Collisson, p. 1062This article is highlighted in the In This Issue feature, p. 1047

Budding of filamentous and non-filamentous influenza A virus occurs via a VPS4 and VPS28-independent pathway

The mechanism of membrane scission during influenza A virus budding has been the subject of controversy. We confirm that influenza M1 binds VPS28, a subunit of the ESCRT-1 complex. However, confocal microscopy of infected cells showed no marked colocalisation between M1 and VPS28 or VPS4 ESCRT proteins, or relocalisation of the cellular proteins. Trafficking of HA and M1 appeared normal when endosomal sorting was impaired by expression of inactive VPS4. Overexpression of either isoform of VPS28 or wildtype or dominant negative VPS4 proteins did not alter production of filamentous virions. SiRNA depletion of endogenous VPS28 had no significant effect on influenza virus replication. Furthermore, cells expressing wildtype or dominant-negative VPS4 replicated filamentous and non-filamentous strains of influenza to similar titres, indicating that influenza release is VPS4-independent. Overall, we see no role for the ESCRT pathway in influenza virus budding and the significance of the M1-VPS28 interaction remains to be determined. (C) 2009 Elsevier Inc. All rights reserved

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Health equity and synergistic abatement strategies of carbon dioxide and air pollutant emissions reduction in China’s eastern coastal area

Quantifying regional health disparities linked to air pollution is essential for enhancing air quality and attaining carbon neutrality objectives. Nonetheless, the efficacy of proactive policies in ensuring equitable health protection in China’s Eastern Coastal Area (ECA) remains uncertain. Here, we employed an integrated assessment model to assess the combined reduction of carbon dioxide (CO2) and atmospheric pollutants and their health repercussions in the ECA of China. Our findings reveal that 273 000 premature deaths are attributable to air pollution in 2060 in the ECA in the absence of mitigation policies. Conversely, carbon reduction policies are poised to curtail 80% of CO2 emissions, alongside reductions of 76% for NOx, 79% for SO2, 80% for PM2.5, 72% for VOCs, and 66% for NH3 emissions. Air pollution control policies could mitigate premature deaths by 19 600, while carbon reduction policies could potentially lower them by 50 800. The health inequality coefficient among provinces stands at 0.19, primarily attributable to significantly higher mortality rates in Hebei and Shandong. These findings yield valuable insights for crafting synergistic abatement strategies in similarly imbalanced developmental regions grappling with comparable environmental challenges

Carbon neutrality and clean air acts can enable China to meet the Minamata Convention goals with substantial cost savings

China faces the concurrent challenges of carbon dioxide (CO2) and toxic mercury (Hg) emissions from coal combustion, with implications for environmental and human health. To address these problems, China has implemented carbon neutrality targets and air pollution controls and signed the Minamata Convention. However, how to best leverage these measures for optimal outcomes (i.e., effectively reduce emissions and pollution with the least cost) remains elusive. Here we examined the best-practice portfolio of climate, air pollution, and Hg reduction policies via an energy-environment-economic integrated assessment model. We found that the most cost-effective solution to simultaneously address these issues is coupling carbon neutrality strategies with clean air policies, which can further save 384 million Chinese yuan (CNY) in Hg abatement in 2060. Furthermore, carbon neutrality measures alone can achieve near-zero Hg emissions, whereas Hg policies will only achieve about one-third of the carbon neutrality target. These findings provide practical lessons to cost-effectively address multiple climate and pollution issues, especially for emerging economies that face similar challenges