Antibiotic treatment targeting gram negative bacteria prevents neratinib-induced diarrhea in rats

Background: Neratinib is a pan-ErbB tyrosine kinase inhibitor used for extended adjuvant treatment of HER2-positive breast cancer. Diarrhea is the main adverse event associated with neratinib treatment. We aimed here to determine whether antibiotic-induced gut microbial shifts altered development of neratinib-induced diarrhea. Methods: Female Albino Wistar rats (total n = 44) were given antibiotics (vancomycin, neomycin, or a cocktail of vancomycin, neomycin and ampicillin) in drinking water for four weeks, and then treated daily with neratinib (50 mg/kg) for 28 days. Diarrhea, along with markers of gastrointestinal damage and microbial alterations were measured by histopathology and 16S sequencing, respectively. Results: Rats treated with vancomycin or neomycin had significantly lower levels of diarrhea than rats treated with neratinib alone. In the distal ileum, neratinib was associated with a statistically significant increase in histological damage in all treatment groups expect the antibiotic cocktail. Key features included villous blunting and fusion and some inflammatory infiltrate. Differences in microbial composition at necropsy in vehicle control, neratinib and neratinib + neomycin groups, were characterized by a neratinib-induced increase in gram-negative bacteria that was reversed by neomycin. Neomycin shifted bacterial composition so that Blautia become the dominant genus. Conclusions: Narrow spectrum antibiotics reduced neratinib-induced diarrhea. This suggests that the microbiome may play a key role in the development and prolongation of diarrhea following neratinib treatment, although further research is required to understand the key bacteria and mechanisms by which they reduce diarrhea, as well as how this may impact presentation of diarrhea in clinical cohorts.Kate R. Secombe, Imogen A. Ball, Anthony D. Wignall, Emma Bateman, Dorothy M. Keefe, Joanne M. Bowe

Facies and evolution of the carbonate factory during the Permian–Triassic crisis in South Tibet, China

The nature of Phanerozoic carbonate factories is strongly controlled by the composition of carbonate-producing faunas. During the Permian–Triassic mass extinction interval there was a major change in tropical shallow platform facies: Upper Permian bioclastic limestones are characterized by benthic communities with significant richness, for example, calcareous algae, fusulinids, brachiopods, corals, molluscs and sponges, while lowermost Triassic carbonates shift to dolomicrite-dominated and bacteria-dominated microbialites in the immediate aftermath of the Permian–Triassic mass extinction. However, the spatial–temporal pattern of carbonates distribution in high latitude regions in response to the Permian–Triassic mass extinction has received little attention. Facies and evolutionary patterns of a carbonate factory from the northern margin of peri-Gondwana (palaeolatitude ca 40°S) are presented here based on four Permian–Triassic boundary sections that span proximal, inner to distal, and outer ramp settings from South Tibet. The results show that a cool-water bryozoan-dominated and echinoderm-dominated carbonate ramp developed in the Late Permian in South Tibet. This was replaced abruptly, immediately after the Permian–Triassic mass extinction, by a benthic automicrite factory with minor amounts of calcifying metazoans developed in an inner/middle ramp setting, accompanied by transient subaerial exposure. Subsequently, an extensive homoclinal carbonate ramp developed in South Tibet in the Early Triassic, which mainly consists of homogenous dolomitic lime mudstone/wackestone that lacks evidence of metazoan frame-builders. The sudden transition from a cool-water, heterozoan dominated carbonate ramp to a warm-water, metazoan-free, homoclinal carbonate ramp following the Permian–Triassic mass extinction was the result of the combination of the loss of metazoan reef/mound builders, rapid sea-level changes across Permian–Triassic mass extinction and profound global warming during the Early Triassic

Combined SANS and SAXS study of the action of ultrasound on the structure of amorphous zirconia gels

In the present work, we have studied for the first time the combined effect of both sonication and precipitation pH on the structure of amorphous zirconia gels synthesized from zirconium(IV) propoxide. The techniques of small-angle neutron and X-ray scattering (SANS and SAXS) and low temperature nitrogen adsorption provided the integral data on the changes in the microstructure and mesostructure of these materials caused by ultrasonic (US) treatment. Amorphous ZrO2·xH2O synthesized under ultrasonic treatment was found to possess a very structured surface, characterized by the surface fractal dimension 2.9–3.0, compared to 2.3–2.5 for the non US-assisted synthesis, and it was also found to possess a higher specific surface area, while the sizes of the primary particles remain unchanged