Particle-induced pulmonary acute phase response may be the causal link between particle inhalation and cardiovascular disease

Inhalation of ambient and workplace particulate air pollution is associated with increased risk of cardiovascular disease. One proposed mechanism for this association is that pulmonary inflammation induces a hepatic acute phase response, which increases risk of cardiovascular disease. Induction of the acute phase response is intimately linked to risk of cardiovascular disease as shown in both epidemiological and animal studies. Indeed, blood levels of acute phase proteins, such as C-reactive protein and serum amyloid A, are independent predictors of risk of cardiovascular disease in prospective epidemiological studies. In this review, we present and review emerging evidence that inhalation of particles (e.g., air diesel exhaust particles and nanoparticles) induces a pulmonary acute phase response, and propose that this induction constitutes the causal link between particle inhalation and risk of cardiovascular disease. Increased levels of acute phase mRNA and proteins in lung tissues, bronchoalveolar lavage fluid and plasma clearly indicate pulmonary acute phase response following pulmonary deposition of different kinds of particles including diesel exhaust particles, nanoparticles, and carbon nanotubes. The pulmonary acute phase response is dose-dependent and long lasting. Conversely, the hepatic acute phase response is reduced relative to lung or entirely absent. We also provide evidence that pulmonary inflammation, as measured by neutrophil influx, is a predictor of the acute phase response and that the total surface area of deposited particles correlates with the pulmonary acute phase response. We discuss the implications of these findings in relation to occupational exposure to nanoparticles. How to cite this article: WIREs Nanomed Nanobiotechnol 2014, 6:517–531. doi: 10.1002/wnan.127

Surface modification does not influence the genotoxic and inflammatory effects of TiO₂ nanoparticles after pulmonary exposure by instillation in mice

The influence of surface charge of nanomaterials on toxicological effects is not yet fully understood. We investigated the inflammatory response, the acute phase response and the genotoxic effect of two different titanium dioxide nanoparticles (TiO(2) NPs) following a single intratracheal instillation. NRCWE-001 was unmodified rutile TiO(2) with endogenous negative surface charge, whereas NRCWE-002 was surface modified to be positively charged. C57BL/6J BomTac mice received 18, 54 and 162 µg/mouse and were humanely killed 1, 3 and 28 days post-exposure. Vehicle controls were tested alongside for comparison. The cellular composition and protein concentration were determined in bronchoalveolar lavage (BAL) fluid as markers for an inflammatory response. Pulmonary and systemic genotoxicity was analysed by the alkaline comet assay as DNA strand breaks in BAL cells, lung and liver tissue. The pulmonary and hepatic acute phase response was analysed by Saa3 mRNA levels in lung tissue or Saa1 mRNA levels in liver tissue by real-time quantitative polymerase chain reaction. Instillation of NRCWE-001 and -002 both induced a dose-dependent neutrophil influx into the lung lining fluid and Saa3 mRNA levels in lung tissue at all assessed time points. There was no statistically significant difference between NRCWE-001 and NRCWE-002. Exposure to both TiO(2) NPs induced increased levels of DNA strand breaks in lung tissue at all doses 1 and 28 days post-exposure and NRCWE-002 at the low and middle dose 3 days post-exposure. The DNA strand break levels were statistically significantly different for NRCWE-001 and -002 for liver and for BAL cells, but no consistent pattern was observed. In conclusion, functionalisation of reactive negatively charged rutile TiO(2) to positively charged did not consistently influence pulmonary toxicity of the studied TiO(2) NPs

Remote data collection speech analysis and prediction of the identification of Alzheimer’s disease biomarkers in people at risk for Alzheimer’s disease dementia: the Speech on the Phone Assessment (SPeAk) prospective observational study protocol

International audienceIntroduction Identifying cost-effective, non-invasive biomarkers of Alzheimer's disease (AD) is a clinical and research priority. Speech data are easy to collect, and studies suggest it can identify those with AD. We do not know if speech features can predict AD biomarkers in a preclinical population. Methods and analysis The Speech on the Phone Assessment (SPeAk) study is a prospective observational study. SPeAk recruits participants aged 50 years and over who have previously completed studies with AD biomarker collection. Participants complete a baseline telephone assessment, including spontaneous speech and cognitive tests. A 3-month visit will repeat the cognitive tests with a conversational artificial intelligence bot. Participants complete acceptability questionnaires after each visit. Participants are randomised to receive their cognitive test results either after each visit or only after they have completed the study. We will combine SPeAK data with AD biomarker data collected in a previous study and analyse for correlations between extracted speech features and AD biomarkers. The outcome of this analysis will inform the development of an algorithm for prediction of AD risk based on speech features. Ethics and dissemination This study has been approved by the Edinburgh Medical School Research Ethics Committee (REC reference 20-EMREC-007). All participants will provide informed consent before completing any study-related procedures, participants must have capacity to consent to participate in this study. Participants may find the tests, or receiving their scores, causes anxiety or stress. Previous exposure to similar tests may make this more familiar and reduce this anxiety. The study information will include signposting in case of distress. Study results will be disseminated to study participants, presented at conferences and published in a peer reviewed journal. No study participants will be identifiable in the study results

Weight Loss and Mortality in Overweight and Obese Cancer Survivors: A Systematic Review

Background Excess adiposity is a risk factor for poorer cancer survival, but there is uncertainty over whether losing weight reduces the risk. We conducted a critical review of the literature examining weight loss and mortality in overweight or obese cancer survivors. Methods We systematically searched PubMed and EMBASE for articles reporting associations between weight loss and mortality (cancer-specific or all-cause) in overweight/obese patients with obesity-related cancers. Where available, data from the same studies on non-overweight patients were compared. Results Five articles describing observational studies in breast cancer survivors were included. Four studies reported a positive association between weight loss and mortality in overweight/obese survivors, and the remaining study observed no significant association. Results were similar for non-overweight survivors. Quality assessment indicated high risk of bias across studies. Conclusions There is currently a lack of observational evidence that weight loss improves survival for overweight and obese cancer survivors. However, the potential for bias in these studies is considerable and the results likely reflect the consequences of disease-related rather than intentional weight loss. There is a need for stronger study designs, incorporating measures of intentionality of weight loss, and extended to other cancers

Risks to human and animal health related to the presence of deoxynivalenol and its acetylated and modified forms in food and feed

Peer reviewedPublisher PD

Transcriptomic Analysis Reveals Novel Mechanistic Insight into Murine Biological Responses to Multi-Walled Carbon Nanotubes in Lungs and Cultured Lung Epithelial Cells

There is great interest in substituting animal work with in vitro experimentation in human health risk assessment; however, there are only few comparisons of in vitro and in vivo biological responses to engineered nanomaterials. We used high-content genomics tools to compare in vivo pulmonary responses of multiwalled carbon nanotubes (MWCNT) to those in vitro in cultured lung epithelial cells (FE1) at the global transcriptomic level. Primary size, surface area and other properties of MWCNT- XNRI -7 (Mitsui7) were characterized using DLS, SEM and TEM. Mice were exposed via a single intratracheal instillation to 18, 54, or 162 μg of Mitsui7/mouse. FE1 cells were incubated with 12.5, 25 and 100 μg/ml of Mitsui7. Tissue and cell samples were collected at 24 hours post-exposure. DNA microarrays were employed to establish mechanistic differences and similarities between the two models. Microarray results were confirmed using gene-specific RT-qPCR. Bronchoalveolar lavage (BAL) fluid was assessed for indications of inflammation in vivo. A strong dose-dependent activation of acute phase and inflammation response was observed in mouse lungs reflective mainly of an inflammatory response as observed in BAL. In vitro, a wide variety of core cellular functions were affected including transcription, cell cycle, and cellular growth and proliferation. Oxidative stress, fibrosis and inflammation processes were altered in both models. Although there were similarities observed between the two models at the pathway-level, the specific genes altered under these pathways were different, suggesting that the underlying mechanisms of responses are different in cells in culture and the lung tissue. Our results suggest that careful consideration should be given in selecting relevant endpoints when substituting animal with in vitro testing

Understanding the yeast host cell response to recombinant membrane protein production

Membrane proteins are drug targets for a wide range of diseases. Having access to appropriate samples for further research underpins the pharmaceutical industry's strategy for developing new drugs. This is typically achieved by synthesizing a protein of interest in host cells that can be cultured on a large scale, allowing the isolation of the pure protein in quantities much higher than those found in the protein's native source. Yeast is a popular host as it is a eukaryote with similar synthetic machinery to that of the native human source cells of many proteins of interest, while also being quick, easy and cheap to grow and process. Even in these cells, the production of human membrane proteins can be plagued by low functional yields; we wish to understand why. We have identified molecular mechanisms and culture parameters underpinning high yields and have consolidated our findings to engineer improved yeast host strains. By relieving the bottlenecks to recombinant membrane protein production in yeast, we aim to contribute to the drug discovery pipeline, while providing insight into translational processes

Effects of physicochemical properties of TiO2 nanomaterials for pulmonary inflammation, acute phase response and alveolar proteinosis in intratracheally exposed mice

Nanomaterial (NM) characteristics may affect the pulmonary toxicity and inflammatory response, including specific surface area, size, shape, crystal phase or other surface characteristics. Grouping of TiO2 in hazard assessment might be challenging because of variation in physicochemical properties. We exposed C57BL/6 J mice to a single dose of four anatase TiO2 NMs with various sizes and shapes by intratracheal instillation and assessed the pulmonary toxicity 1, 3, 28, 90 or 180 days post-exposure. The quartz DQ12 was included as benchmark particle. Pulmonary responses were evaluated by histopathology, electron microscopy, bronchoalveolar lavage (BAL) fluid cell composition and acute phase response. Genotoxicity was evaluated by DNA strand break levels in BAL cells, lung and liver in the comet assay. Multiple regression analyses were applied to identify specific TiO2 NMs properties important for the pulmonary inflammation and acute phase response. The TiO2 NMs induced similar inflammatory responses when surface area was used as dose metrics, although inflammatory and acute phase response was greatest and more persistent for the TiO2 tube. Similar histopathological changes were observed for the TiO2 tube and DQ12 including pulmonary alveolar proteinosis indicating profound effects related to the tube shape. Comparison with previously published data on rutile TiO2 NMs indicated that rutile TiO2 NMs were more inflammogenic in terms of neutrophil influx than anatase TiO2 NMs when normalized to total deposited surface area. Overall, the results suggest that specific surface area, crystal phase and shape of TiO2 NMs are important predictors for the observed pulmonary effects of TiO2 NMs.Peer reviewe

Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition over 10 months (COVID-OUT): a multicentre, randomised, quadruple-blind, parallel-group, phase 3 trial.

BACKGROUND: Post-COVID-19 condition (also known as long COVID) is an emerging chronic illness potentially affecting millions of people. We aimed to evaluate whether outpatient COVID-19 treatment with metformin, ivermectin, or fluvoxamine soon after SARS-CoV-2 infection could reduce the risk of long COVID. METHODS: We conducted a decentralised, randomised, quadruple-blind, parallel-group, phase 3 trial (COVID-OUT) at six sites in the USA. We included adults aged 30-85 years with overweight or obesity who had COVID-19 symptoms for fewer than 7 days and a documented SARS-CoV-2 positive PCR or antigen test within 3 days before enrolment. Participants were randomly assigned via 2 × 3 parallel factorial randomisation (1:1:1:1:1:1) to receive metformin plus ivermectin, metformin plus fluvoxamine, metformin plus placebo, ivermectin plus placebo, fluvoxamine plus placebo, or placebo plus placebo. Participants, investigators, care providers, and outcomes assessors were masked to study group assignment. The primary outcome was severe COVID-19 by day 14, and those data have been published previously. Because the trial was delivered remotely nationwide, the a priori primary sample was a modified intention-to-treat sample, meaning that participants who did not receive any dose of study treatment were excluded. Long COVID diagnosis by a medical provider was a prespecified, long-term secondary outcome. This trial is complete and is registered with ClinicalTrials.gov, NCT04510194. FINDINGS: Between Dec 30, 2020, and Jan 28, 2022, 6602 people were assessed for eligibility and 1431 were enrolled and randomly assigned. Of 1323 participants who received a dose of study treatment and were included in the modified intention-to-treat population, 1126 consented for long-term follow-up and completed at least one survey after the assessment for long COVID at day 180 (564 received metformin and 562 received matched placebo; a subset of participants in the metformin vs placebo trial were also randomly assigned to receive ivermectin or fluvoxamine). 1074 (95%) of 1126 participants completed at least 9 months of follow-up. 632 (56·1%) of 1126 participants were female and 494 (43·9%) were male; 44 (7·0%) of 632 women were pregnant. The median age was 45 years (IQR 37-54) and median BMI was 29·8 kg/m2 (IQR 27·0-34·2). Overall, 93 (8·3%) of 1126 participants reported receipt of a long COVID diagnosis by day 300. The cumulative incidence of long COVID by day 300 was 6·3% (95% CI 4·2-8·2) in participants who received metformin and 10·4% (7·8-12·9) in those who received identical metformin placebo (hazard ratio [HR] 0·59, 95% CI 0·39-0·89; p=0·012). The metformin beneficial effect was consistent across prespecified subgroups. When metformin was started within 3 days of symptom onset, the HR was 0·37 (95% CI 0·15-0·95). There was no effect on cumulative incidence of long COVID with ivermectin (HR 0·99, 95% CI 0·59-1·64) or fluvoxamine (1·36, 0·78-2·34) compared with placebo. INTERPRETATION: Outpatient treatment with metformin reduced long COVID incidence by about 41%, with an absolute reduction of 4·1%, compared with placebo. Metformin has clinical benefits when used as outpatient treatment for COVID-19 and is globally available, low-cost, and safe. FUNDING: Parsemus Foundation; Rainwater Charitable Foundation; Fast Grants; UnitedHealth Group Foundation; National Institute of Diabetes, Digestive and Kidney Diseases; National Institutes of Health; and National Center for Advancing Translational Sciences