Evaluation of low dose exposure and immunogenicity of transgenic maize expressing the Escherichia coli heat-labile toxin B subunit when fed intermittently and daily

Transgenic maize expressing the non-toxic B subunit of the Escherichia coli heat-labile toxin (LT-B) in seed has proven to be an effective oral immunogen in mice. Currently, there is considerable concern over accidental consumption of transgenic maize expressing LT-B by humans and domestic animals. While consuming maize-expressed LT-B appears to have no toxic side effects, we have yet to define nonimmunogenic levels of transgenic LT-B when ingested. We also intend to determine if accidental exposure to LT-B could affect a later response to a vaccine containing LT-B as either an antigen or a carrier.;Our first goal was to determine the largest dose of LT-B orally administered in mice that does not result in a measurable immune response. Mice were fed low doses of LT-B intermittently (days 0, 7 and 21) resembling vaccine dose scheduling. To determine the effects of previous exposure on vaccine administration, we fed mice intermittently or daily for 28 days to resemble two distinct inadvertent exposure scenarios. We subsequently boosted all mice with vaccine-level doses of LT-B. To determine immune responses, serum and fecal pellets were collected weekly for measurement of LT-B-specific antibodies.;Mice fed 0.02 microg LT-B intermittently demonstrated immune priming in 62.5% of the animals. Mice that were fed ≤0.002 microg LT-B showed no increase in specific antibody nor did they demonstrate immune priming, thus indicating that 0.002 microg LT-B was the highest nonimmunogenic dose tested. Mice that were exposed to maize-derived LT-B, whether daily or intermittently, generate dose-dependent antibody responses to LT-B. All animals that had been previously exposed to LT-B by either intermittent or daily feeding responded strongly to the vaccine-like booster doses, indicating that mice orally exposed to LT-B do not develop oral tolerance to LT-B. Thus, inadvertent oral exposure to LT-B may not negatively impact future vaccinations containing LT-B as either an antigen or carrier

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

Evaluation of low dose exposure and immunogenicity of transgenic maize expressing the Escherichia coli heat-labile toxin B subunit when fed intermittently and daily

Transgenic maize expressing the non-toxic B subunit of the Escherichia coli heat-labile toxin (LT-B) in seed has proven to be an effective oral immunogen in mice. Currently, there is considerable concern over accidental consumption of transgenic maize expressing LT-B by humans and domestic animals. While consuming maize-expressed LT-B appears to have no toxic side effects, we have yet to define nonimmunogenic levels of transgenic LT-B when ingested. We also intend to determine if accidental exposure to LT-B could affect a later response to a vaccine containing LT-B as either an antigen or a carrier.;Our first goal was to determine the largest dose of LT-B orally administered in mice that does not result in a measurable immune response. Mice were fed low doses of LT-B intermittently (days 0, 7 and 21) resembling vaccine dose scheduling. To determine the effects of previous exposure on vaccine administration, we fed mice intermittently or daily for 28 days to resemble two distinct inadvertent exposure scenarios. We subsequently boosted all mice with vaccine-level doses of LT-B. To determine immune responses, serum and fecal pellets were collected weekly for measurement of LT-B-specific antibodies.;Mice fed 0.02 microg LT-B intermittently demonstrated immune priming in 62.5% of the animals. Mice that were fed ≤0.002 microg LT-B showed no increase in specific antibody nor did they demonstrate immune priming, thus indicating that 0.002 microg LT-B was the highest nonimmunogenic dose tested. Mice that were exposed to maize-derived LT-B, whether daily or intermittently, generate dose-dependent antibody responses to LT-B. All animals that had been previously exposed to LT-B by either intermittent or daily feeding responded strongly to the vaccine-like booster doses, indicating that mice orally exposed to LT-B do not develop oral tolerance to LT-B. Thus, inadvertent oral exposure to LT-B may not negatively impact future vaccinations containing LT-B as either an antigen or carrier.</p