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Diarrhoea is one of the most burdensome and common adverse events of chemotherapeutics, and has no standardised therapy to date. Increasing evidence suggests that the gut microbiome can influence the development of chemotherapy-induced diarrhoea. Here we report findings from a randomised clinical trial of faecal microbiota transplantation (FMT) to treat diarrhoea induced by tyrosine kinase inhibitors (TKI) in patients with metastatic renal cell carcinoma (ClinicalTrials.gov number: NCT04040712). The primary outcome is the resolution of diarrhoea four weeks after the end of treatments. Twenty patients are randomised to receive FMT from healthy donors or placebo FMT (vehicle only). Donor FMT is more effective than placebo FMT in treating TKI-induced diarrhoea, and a successful engraftment is observed in subjects receiving donor faeces. No serious adverse events are observed in both treatment arms. The trial meets pre-specified endpoints. Our findings suggest that the therapeutic manipulation of gut microbiota may become a promising treatment option to manage TKI-dependent diarrhoea. Tyrosine kinase inhibitors (TKIs) have improved the clinical outcomes of patients with metastatic renal cell carcinoma (mRCC), however TKI-related diarrhoea is a common and serious adverse effect. Here the authors show in a randomized clinical trial that faecal microbiota transplantation from healthy donors can improve TKI-induced diarrhoea in patients with mRCC.

The link between the oral microbiome and neurodevelopmental disorders remains a compelling hypothesis, still requiring confirmation in large-scale datasets. Leveraging over 7000 whole-genome sequenced salivary samples from 2025 US families with children diagnosed with autism spectrum disorders (ASD), our cross-sectional study shows that the oral microbiome composition can discriminate ASD subjects from neurotypical siblings (NTs, AUC = 0.66), with 108 differentiating species ( q  < 0.005). The relative abundance of these species is highly correlated with cognitive impairment as measured by Full-Scale Intelligence Quotient (IQ). ASD children with IQ < 70 also exhibit lower microbiome strain sharing with parents ( p  < 10 −6 ) with respect to NTs. A two-pronged functional enrichment analysis suggests the contribution of enzymes from the serotonin, GABA, and dopamine degradation pathways to the distinct microbial community compositions observed between ASD and NT samples. Although measures of restrictive eating diet and proxies of oral hygiene show relatively minor effects on the microbiome composition, the observed associations with ASD and IQ may still represent unaccounted-for underlying differences in lifestyle among groups. While causal relationships could not be established, our study provides substantial support to the investigation of oral microbiome biomarkers in ASD. Here, Manghi et al. identify potential salivary microbial biomarkers for autism through a large-scale metagenomic analysis of 2,000 families, revealing shifts in neurotransmitter-related pathways

Sporadic and inflammatory forms of colorectal cancer (CRC) account for more than 80% of cases. Recent publications have shown mechanistic evidence for the involvement of gut bacteria in the development of both CRC-forms. Whereas, colon and rectal cancer have been routinely studied together as CRC, increasing evidence show these to be distinct diseases. Also, the common use of fecal samples to study microbial communities may reflect disease state but possibly not the tumor microenvironment. We performed this study to evaluate differences in bacterial communities found in tissue samples of 18 rectal-cancer subjects when compared to 18 non-cancer controls. Samples were collected during exploratory colonoscopy (non-cancer group) or during surgery for tumor excision (rectal-cancer group). High throughput 16S rRNA amplicon sequencing of the V4-V5 region was conducted on the Ion PGM platform, reads were filtered using and clustered using . We observed significant increases in species richness and diversity in rectal cancer samples, evidenced by the total number of OTUs and the Shannon and Simpson indexes. Enterotyping analysis divided our cohort into two groups, with the majority of rectal cancer samples clustering into one enterotype, characterized by a greater abundance of and . At the phylum level, rectal-cancer samples had increased abundance of candidate phylum (also known as ) whilst non-cancer samples had increased abundance of . At the genera level, rectal-cancer samples had higher abundances of , and whereas non-cancer samples had higher abundances of , and . Two OTUs were more abundant among rectal-cancer patients seen through 16S rRNA amplicon sequencing, whose presence was confirmed by immunohistochemistry and enrichment verified by digital droplet PCR. Our findings point to increased bacterial richness and diversity in rectal cancer, along with several differences in microbial community composition. Our work is the first to present evidence for a possible role of bacteria such as and the phylum in rectal cancer, emphasizing the need to study tissue-associated bacteria and specific regions of the gastrointestinal tract in order to better understand the possible links between the microbiota and rectal cancer.

This study presents functional limit theorems for the Euler characteristic of Vietoris–Rips complexes. The points are drawn from a nonhomogeneous Poisson process on $\\mathbb{R}^d$ , and the connectivity radius governing the formation of simplices is taken as a function of the time parameter t, which allows us to treat the Euler characteristic as a stochastic process. The setting in which this takes place is that of the critical regime, in which the simplicial complexes are highly connected and have nontrivial topology. We establish two ‘functional-level’ limit theorems, a strong law of large numbers and a central limit theorem, for the appropriately normalized Euler characteristic process.

Association studies have linked microbiome alterations with many human diseases. However, they have not always reported consistent results, thereby necessitating cross-study comparisons. Here, a meta-analysis of eight geographically and technically diverse fecal shotgun metagenomic studies of colorectal cancer (CRC, n = 768), which was controlled for several confounders, identified a core set of 29 species significantly enriched in CRC metagenomes (false discovery rate (FDR) < 1 × 10−5). CRC signatures derived from single studies maintained their accuracy in other studies. By training on multiple studies, we improved detection accuracy and disease specificity for CRC. Functional analysis of CRC metagenomes revealed enriched protein and mucin catabolism genes and depleted carbohydrate degradation genes. Moreover, we inferred elevated production of secondary bile acids from CRC metagenomes, suggesting a metabolic link between cancer-associated gut microbes and a fat- and meat-rich diet. Through extensive validations, this meta-analysis firmly establishes globally generalizable, predictive taxonomic and functional microbiome CRC signatures as a basis for future diagnostics.Cross-study analysis defines fecal microbial species associated with colorectal cancer.

The phenotypes of allergic airway diseases are influenced by the interplay between host genetics and the gut microbiota, which may be modulated by probiotics. We investigated the probiotic effects on allergic inflammation in A/J and C57BL/6 mice. C57BL/6 mice had increased gut microbiota diversity compared to A/J mice at baseline . Acetate producer probiotics differentially modulated and altered the genus abundance of specific bacteria, such as Akkermansia and Allistipes , in mouse strains. We induced airway inflammation followed by probiotic treatment and found that only A/J mice exhibited decreased inflammation, and the beneficial effects of probiotics in A/J mice were partially due to acetate production. To understand the relevance of microbial composition colonization in the development of allergic diseases, we implanted female C57BL/6 mice with A/J embryos to naturally modulate the microbial composition of A/J mice, which increased gut microbiota diversity and reduced eosinophilic inflammation in A/J. These data demonstrate the central importance of microbiota to allergic phenotype severity. 3HgJewfMcf3oVqbgvbkYNZ Video Abstract

Synovial fibroblasts in persistent inflammatory arthritis have been suggested to have parallels with cancer growth and wound healing, both of which involve a stereotypical serum response programme. We tested the hypothesis that a serum response programme can be used to classify diseased tissues, and investigated the serum response programme in fibroblasts from multiple anatomical sites and two diseases. To test our hypothesis we utilized a bioinformatics approach to explore a publicly available microarray dataset including rheumatoid arthritis (RA), osteoarthritis (OA) and normal synovial tissue, then extended those findings in a new microarray dataset representing matched synovial, bone marrow and skin fibroblasts cultured from RA and OA patients undergoing arthroplasty. The classical fibroblast serum response programme discretely classified RA, OA and normal synovial tissues. Analysis of low and high serum treated fibroblast microarray data revealed a hierarchy of control, with anatomical site the most powerful classifier followed by response to serum and then disease. In contrast to skin and bone marrow fibroblasts, exposure of synovial fibroblasts to serum led to convergence of RA and OA expression profiles. Pathway analysis revealed three inter-linked gene networks characterising OA synovial fibroblasts: Cell remodelling through insulin-like growth factors, differentiation and angiogenesis through _3 integrin, and regulation of apoptosis through CD44. We have demonstrated that Fibroblast serum response signatures define disease at the tissue level, and that an OA specific, serum dependent repression of genes involved in cell adhesion, extracellular matrix remodelling and apoptosis is a critical discriminator between cultured OA and RA synovial fibroblasts.

The objective of this study is to examine the asymptotic behavior of Betti numbers of Čech complexes treated as stochastic processes and formed from random points in the d-dimensional Euclidean space ℝ d . We consider the case where the points of the Čech complex are generated by a Poisson process with intensity nf for a probability density f. We look at the cases where the behavior of the connectivity radius of the Čech complex causes simplices of dimension greater than k + 1 to vanish in probability, the so-called sparse regime, as well when the connectivity radius is of the order of n -1/d , the critical regime. We establish limit theorems in the aforementioned regimes: central limit theorems for the sparse and critical regimes, and a Poisson limit theorem for the sparse regime. When the connectivity radius of the Čech complex is o(n -1/d ), i.e. the sparse regime, we can decompose the limiting processes into a time-changed Brownian motion or a time-changed homogeneous Poisson process respectively. In the critical regime, the limiting process is a centered Gaussian process but has a much more complicated representation, because the Čech complex becomes highly connected with many topological holes of any dimension.

Background It has been hypothesized that chronic inflammatory diseases such as rheumatoid arthritis (RA) may be caused by a failure of negative feedback mechanisms. This study sought to examine negative feedback mechanisms in fibroblast-like synoviocytes (FLS), one of the most abundant cell types in the joint. We hypothesized that prior exposure of healthy FLS to an inflammatory stimulus would attenuate their responses to a second inflammatory stimulus, in the same way that negative feedback mechanisms desensitize macrophages to repeated stimulation by lipopolysaccharide. We further hypothesized that such negative feedback mechanisms would be defective in FLS derived from the joints in RA. Methods Synovial fibroblasts and dermal fibroblasts from non-inflamed joints and joints affected by RA and a fibroblast cell line from neonatal foreskin were stimulated twice with tumour necrosis factor (TNF) α or interleukin (IL)-1α, with a 24-h rest period between the two 24-h stimulations. Differences between response to the first and second dose of cytokine were examined by assessing secretion of inflammatory factors and intracellular signalling activity. Results FLS from both non-inflamed joints and joints affected by RA mounted an augmented response to re-stimulation. This response was site-specific, as primary dermal fibroblasts did not alter their response between doses. The fibroblast priming was also gene-specific and transient. Assessment of signalling events and nuclear localization showed prolonged activation of nuclear factor (NF)-κB during the second stimulation. Conclusion This study aimed to examine mechanisms of negative regulation of inflammatory responses in FLS. Instead, we found a pro-inflammatory stromal memory in FLS obtained from both non-inflamed joints and joints affected by RA. This suggests the joint is an area at high risk of chronic inflammation, and may provide a piece in the puzzle of how chronic inflammation is established in RA.

Several millions of kilometres of pipes and cables are buried beneath our streets in the UK. As they are not visible and easily accessible, the monitoring of their integrity as well as the quality of their contents is a challenge. Any information of these properties aids the utility owners in their planning and management of their maintenance regime. Traditionally, expensive and very localised sensors are used to provide irregular measurements of these properties. In order to have a complete picture of the utility network, cheaper sensors need to be investigated which would allow large numbers of small sensors to be incorporated into (or near to) the pipe leading to so-called smart pipes. This paper focuses on a novel trial where a short section of a prototype smart pipe was buried using mainly off-the-shelf sensors and communication elements. The challenges of such a burial are presented together with the limitations of the sensor system. Results from the sensors were obtained during and after burial indicating that off-the-shelf sensors can be used in a smart pipes system although further refinements are necessary in order to miniaturise these sensors. The key challenges identified were the powering of these sensors and the communication of the data to the operator using a range of different methods.