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Supplemental material, sj-docx-1-hpx-10.1177_00185787231159578 for Impact of a Multifaceted Intervention on Antibiotic Prescribing for Cystitis and Asymptomatic Bacteriuria in 23 Community Hospital Emergency Departments by Emily M. Ingalls, John J. Veillette, Jared Olson, Stephanie S. May, C. Dustin Waters, Stephanie S. Gelman, George Vargyas, Mary Hutton, Nick Tinker, Gabriel V. Fontaine, Rachel A. Foster, Jena Stallsmith, Ali Earl, Whitney R. Buckel and Todd J. Vento in Hospital Pharmacy

Hepatocellular carcinoma (HCC) is the most predominant primary malignancy in the liver. Genotoxic and genetic models have revealed that HCC cells are derived from hepatocytes, but where the critical region for tumor foci emergence is and how this transformation occurs are still unclear. Here, hyperpolyploidization of hepatocytes around the centrilobular (CL) region is demonstrated to be closely linked with the development of HCC cells after diethylnitrosamine treatment. We identify the CL region as a dominant lobule for accumulation of hyperpolyploid hepatocytes and preneoplastic tumor foci formation. We also demonstrate that upregulation of Aurkb plays a critical role in promoting hyperpolyploidization. Increase of AURKB phosphorylation is detected on the midbody during cytokinesis, causing abscission failure and hyperpolyploidization. Pharmacological inhibition of AURKB dramatically reduces nucleus size and tumor foci number surrounding the CL region in diethylnitrosamine-treated liver. Our work reveals an intimate molecular link between pathological hyperpolyploidy of CL hepatocytes and transformation into HCC cells., Polyploidy is a common feature in normal hepatocytes, however, the pathophysiological function of hepatic hyperpolyploidy is unclear. Here, the authors show that genotoxic stress induces accumulation of hyperpolyploid hepatocytes around the centrilobular region of the liver, which may indicate the origin of preneoplastic formation.

BACKGROUND:\ud In animals and humans black raspberries (BRBs) have chemo-preventative effects against Wnt driven colorectal cancer (CRC). While BRBs have made it into clinical trials, the exact mechanisms of BRB action remain unclear. Potentially the chemo-preventative properties are linked to their impact on the gut microbiome, as diet is known to influence the microbial diversity of the gut and plays a key role in regulating intestinal homeostasis and the aetiology of CRC.\ud \ud OBJECTIVE:\ud To determine the impact of a BRB diet on themicrobial biodiversityof thewild-type and malignant mouse intestine.\ud \ud METHODS:\ud Adult mice in which Wnt driven tumourigenesis could be initiated by conditional deletion of Apc in the intestinal stem cell (Lgr5CreERT2) were administered a 10% BRB diet. Total DNA from faecal pellets pre- and post-BRB exposure was used for longitudinal metataxonomic analysis of the V1 to V3 regions of the 16S rRNA gene.\ud \ud RESULTS:\ud Individually BRB intervention and Apc loss alter the microbial community of the gut. In combination, the microbiome changes observed in the Apc deficient intestine are attenuated upon administration of a BRB diet.\ud \ud CONCLUSIONS:\ud Our results suggest that BRB intervention may protectively regulate the gut microbiota in the healthy and malignant intestine.

Epigenetic regulation plays a key role in the link between inflammation and cancer. Here we examine Mbd2, which mediates epigenetic transcriptional silencing by binding to methylated DNA. In separate studies the Mbd2 −/− mouse has been shown (1) to be resistant to intestinal tumourigenesis and (2) to have an enhanced inflammatory/immune response, observations that are inconsistent with the links between inflammation and cancer. To clarify its role in tumourigenesis and inflammation, we used constitutive and conditional models of Mbd2 deletion to explore its epithelial and non‐epithelial roles in the intestine. Using a conditional model, we found that suppression of intestinal tumourigenesis is due primarily to the absence of Mbd2 within the epithelia. Next, we demonstrated, using the DSS colitis model, that non‐epithelial roles of Mbd2 are key in preventing the transition from acute to tumour‐promoting chronic inflammation. Combining models revealed that prior to inflammation the altered Mbd2 −/− immune response plays a role in intestinal tumour suppression. However, following inflammation the intestine converts from tumour suppressive to tumour promoting. To summarise, in the intestine the normal function of Mbd2 is exploited by cancer cells to enable tumourigenesis, while in the immune system it plays a key role in preventing tumour‐enabling inflammation. Which role is dominant depends on the inflammation status of the intestine. As environmental interactions within the intestine can alter DNA methylation patterns, we propose that Mbd2 plays a key role in determining whether these interactions are anti‐ or pro‐tumourigenic and this makes it a useful new epigenetic model for inflammation‐associated carcinogenesis. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Epigenetic regulation plays a key role in the link between inflammation and cancer. Here we examine Mbd2, which mediates epigenetic transcriptional silencing by binding to methylated DNA. In separate studies the Mbd2−/− mouse has been shown (1) to be resistant to intestinal tumourigenesis and (2) to have an enhanced inflammatory/immune response, observations that are inconsistent with the links between inflammation and cancer. To clarify its role in tumourigenesis and inflammation, we used constitutive and conditional models of Mbd2 deletion to explore its epithelial and non-epithelial roles in the intestine. Using a conditional model, we found that suppression of intestinal tumourigenesis is due primarily to the absence of Mbd2 within the epithelia. Next, we demonstrated, using the DSS colitis model, that non-epithelial roles of Mbd2 are key in preventing the transition from acute to tumour-promoting chronic inflammation. Combining models revealed that prior to inflammation the altered Mbd2−/− immune response plays a role in intestinal tumour suppression. However, following inflammation the intestine converts from tumour suppressive to tumour promoting. To summarise, in the intestine the normal function of Mbd2 is exploited by cancer cells to enable tumourigenesis, while in the immune system it plays a key role in preventing tumour-enabling inflammation. Which role is dominant depends on the inflammation status of the intestine. As environmental interactions within the intestine can alter DNA methylation patterns, we propose that Mbd2 plays a key role in determining whether these interactions are anti- or pro-tumourigenic and this makes it a useful new epigenetic model for inflammation-associated carcinogenesis.

A massive expansion of a GGGGCC repeat upstream of the C9orf72 coding region is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. Despite its intronic localization and lack of a canonical start codon, both strands are translated into aggregating dipeptide repeat (DPR) proteins: poly-GA, poly-GP, poly-GR, poly-PR and poly-PA. To address conflicting findings on the predominant toxicity of the different DPR species in model systems, we compared the expression pattern of the DPR proteins in rat primary neurons and postmortem brain and spinal cord of C9orf72 mutation patients. Only poly-GA overexpression closely mimicked the p62-positive neuronal cytoplasmic inclusions commonly observed for all DPR proteins in patients. In contrast, overexpressed poly-GR and poly-PR formed nucleolar p62-negative inclusions. In patients, most of the less common neuronal intranuclear DPR inclusions were para-nucleolar and p62 positive. Neuronal nucleoli in C9orf72 cases showed normal size and morphology regardless of the presence of poly-GR and poly-PR inclusions arguing against widespread nucleolar stress, reported in cellular models. Colocalization of para-nucleolar DPR inclusions with heterochromatin and a marker of transcriptional repression (H3K9me2) indicates a link to gene transcription. In contrast, we detected numerous intranuclear DPR inclusions not associated with nucleolar structures in ependymal and subependymal cells. In patients, neuronal inclusions of poly-GR, poly-GP and the poly-GA interacting protein Unc119 were less abundant than poly-GA inclusions, but showed similar regional and subcellular distribution. Regardless of neurodegeneration, all inclusions were most abundant in neocortex, hippocampus and thalamus, with few inclusions in brain stem and spinal cord. In the granular cell layer of the cerebellum, poly-GA and Unc119 inclusions were significantly more abundant in cases with FTLD than in cases with MND and FTLD/MND. Poly-PR inclusions were rare throughout the brain but significantly more abundant in the CA3/4 region of FTLD cases than in MND cases. Thus, although DPR distribution is not correlated with neurodegeneration spatially, it correlates with neuropathological subtypes. Electronic supplementary material The online version of this article (doi:10.1007/s00401-015-1450-z) contains supplementary material, which is available to authorized users.

The human gut microbiome is considered an organ in its entirety and has been the subject of extensive research due to its role in physiology, metabolism, digestion, and immune regulation. Disequilibria of the normal microbiome have been associated with the development of several gastrointestinal diseases, but the exact underlying interactions are not well understood. Conventional in vivo and in vitro modelling systems fail to faithfully recapitulate the complexity of the human host–gut microbiome, emphasising the requirement for novel systems that provide a platform to study human host–gut microbiome interactions with a more holistic representation of the human in vivo microenvironment. In this review, we outline the progression and applications of new and old modelling systems with particular focus on their ability to model and to study host–microbiome cross-talk.

We could show that markers for the erURP and mtUPR alter during the course of differentiation. Furthermore, the cells activate an ER-associated degradation (ERAD). In vivo, we observed a compensatory adaptive response to counteract the critical requirement of Grp78 or Cpn60 via up-regulation of ERAD in the Grp78+/- mice and the Cpn60+/- mice. In conclusion, stress responses are somehow involved in the development of obesity. Wir konnten zeigen, dass die erUPR sowie die mtUPR während der adipogenen Differenzierung beeinflusst wird. Des Weiteren wird während der Adipogenese der ER-assoziierte Abbau (ERAD) aktiviert. In vivo konnten wir mit Hilfe der Grp78+/- Maus und der Cpn60+/- Maus eine Steigerung des ERAD erkennen. Zusammenfassend zeigt sich, dass Stressantworten bei der Entwicklung von Adipositas involviert sind. Das teilweise Fehlen von Grp78 oder Cpn60 wird durch die Aktivierung der ERAD kompensiert.

As a result of an error during digital processing of Figure 1a for publication, one of the immunofluorescence panels (GA175-GFP Nucleolin staining) was accidentally strongly altered in contrast and brightness. The corrected version of the figure is shown below. The authors apologize for any confusion caused by this error. In the published article, the collaborators from the two institutions, German Consortium for Frontotemporal Lobar Degeneration and Bavarian Brain Banking Alliance, were incorrectly listed in article note. These names have been relocated to the Appendix section in the article now.Figure 1a and the collaborators list have been amended in the published article.

It is estimated that over half of colorectal cancer (CRC) cases in the UK are preventable through lifestyle changes. Perhaps unsurprisingly, bowel cancer is strongly linked to dietary choices. Diets that are high in fat and low in fibre are associated with increased risk of cancer while diets rich in fruit, vegetables and fibre have a reduced risk. Several studies have investigated the effect of certain dietary components in CRC initiation and development. Previous work, in humans and animals, has demonstrated that the polyphenols found in black raspberries (BRBs) have chemopreventative and therapeutic effects. However, the exact mechanism for these effects remain unknown. As CRC can originate from an intestinal stem cell (ISC) it is possible that the chemopreventative role is due to the impact BRBs have on the normal and/or malignant ISCs. This thesis aimed to investigate the chemopreventative effect of BRBS on normal intestinal tissue and on the initial and later stages of intestinal tumourigenesis, in the context of ISC dynamics and activated Wnt signalling. This was achieved using a Cre-loxP based approach to conditionally delete Apc (the negative regulator of the Wnt signalling pathway) within different compartments of the adult murine intestinal epithelium and also utilised the 3D intestinal organoid system.\ud Exposure to a BRB enriched diet is reported here to be well tolerated in mice and have no major detrimental effects on normal intestinal homeostasis and health. Feeding of BRB diet 2 weeks prior to Apc gene ablation is shown to partially attenuate the ‘crypt-progenitor’ phenotype typical of acute Apc loss. In this context of activated Wnt signalling, BRBs altered ISC dynamics in vivo and reduced the self-renewal capacity of Apc deficient cells ex vivo. Additionally, long-term feeding of BRB diet was shown to significantly improve survival of mice which developed macroscopic stem-cell derived Wnt-driven adenomas.\ud Together, these data are the first evidence that BRBs play a role in CRC chemoprevention by protectively regulating the ISC compartment. These findings further support the use of BRB intervention in cancer prevention in the context of Wnt-driven tumourigenesis.