Ablation of liver Fxr results in an increased colonic mucus barrier in mice

Background & Aims: The interorgan crosstalk between the liver and the intestine has been the focus of intense research. Key in this crosstalk are bile acids, which are secreted from the liver into the intestine, interact with the microbiome, and upon absorption reach back to the liver. The bile acid-activated farnesoid X receptor (Fxr) is involved in the gut-to-liver axis. However, liver-to-gut communication and the roles of bile acids and Fxr remain elusive. Herein, we aim to get a better understanding of Fxr-mediated liver-to-gut communication, particularly in colon functioning. Methods: Fxr floxed/floxed mice were crossed with cre-expressing mice to yield Fxr ablation in the intestine (Fxr-intKO), liver (Fxr-livKO), or total body (Fxr-totKO). The effects on colonic gene expression (RNA sequencing), the microbiome (16S sequencing), and mucus barrier function by ex vivo imaging were analysed. Results: Despite relatively small changes in biliary bile acid concentration and composition, more genes were differentially expressed in the colons of Fxr-livKO mice than in those of Fxr-intKO and Fxr-totKO mice (3272, 731, and 1824, respectively). The colons of Fxr-livKO showed increased expression of antimicrobial genes, Toll-like receptors, inflammasome-related genes and genes belonging to the ‘Mucin-type O-glycan biosynthesis’ pathway. Fxr-livKO mice have a microbiome profile favourable for the protective capacity of the mucus barrier. The thickness of the inner sterile mucus layer was increased and colitis symptoms reduced in Fxr-livKO mice. Conclusions: Targeting of FXR is at the forefront in the battle against metabolic diseases. We show that ablation of Fxr in the liver greatly impacts colonic gene expression and increased the colonic mucus barrier. Increasing the mucus barrier is of utmost importance to battle intestinal diseases such as inflammatory bowel disease, and we show that this might be done by antagonising FXR in the liver. Lay summary: This study shows that the communication of the liver to the intestine is crucial for intestinal health. Bile acids are key players in this liver-to-gut communication, and when Fxr, the master regulator of bile acid homoeostasis, is ablated in the liver, colonic gene expression is largely affected, and the protective capacity of the mucus barrier is increased

Feasibility and effectiveness of trifluridine/tipiracil in metastatic colorectal cancer: real-life data from The Netherlands

Background: The RECOURSE trial showed clinical efficacy for trifluridine/tipiracil for refractory metastatic colorectal cancer patients. We assessed the feasibility and effectiveness of trifluridine/tipiracil in daily clinical practice in The Netherlands. Methods: Medical records of patients from 17 centers treated in the trifluridine/tipiracil compassionate use program were reviewed and checked for RECOURSE eligibility criteria. Baseline characteristics, safety, and survival times were compared, and prespecified baseline characteristics were tested in multivariate analyses for prognostic significance on overall survival (OS). Results: A total of 136 patients with a median age of 62 years were analyzed. Forty-three patients (32%) did not meet the RECOURSE eligibility criteria for not having received all prior standard treatments (n = 35, 26%) and/or ECOG performance status (PS) 2 (n = 12, 9%). The most common grade ≥3 toxicities were neutropenia (n = 44, 32%), leukopenia (n = 8, 6%), anemia (n = 7, 5%), and fatigue (n = 7, 5%). Median progression-free survival (PFS) and median OS were 2.1 (95% CI, 1.8–2.3) and 5.4 months (95% CI, 4.0–6.9), respectively. Patients with ECOG PS 2 had a worse median OS (3.2 months) compared to patients with ECOG PS 0–1 (5.9 months). ECOG PS, KRAS-mutation status, white blood cell count, serum lactate dehydrogenase, and alkaline phosphatase were prognostic factors for OS. Conclusions: Our data show that treatment with trifluridine/tipiracil in daily clinical practice is feasible and safe. Differences in patient characteristics between our population and the RECOURSE study population should be taken into account in the interpretation of survival data. Our results argue against the use of trifluridine/tipiracil in patients with ECOG PS 2. Funding: Johannes J.M. Kwakman received an unrestricted research grant from Servier

Stress from Nucleotide Depletion Activates the Transcriptional Regulator HEXIM1 to Suppress Melanoma

Studying cancer metabolism gives insight into tumorigenic survival mechanisms and susceptibilities. In melanoma, we identify HEXIM1, a transcription elongation regulator, as a melanoma tumor suppressor that responds to nucleotide stress. HEXIM1 expression is low in melanoma. Its overexpression in a zebrafish melanoma model suppresses cancer formation, while its inactivation accelerates tumor onset in vivo. Knockdown of HEXIM1 rescues zebrafish neural crest defects and human melanoma proliferation defects that arise from nucleotide depletion. Under nucleotide stress, HEXIM1 is induced to form an inhibitory complex with P-TEFb, the kinase that initiates transcription elongation, to inhibit elongation at tumorigenic genes. The resulting alteration in gene expression also causes anti-tumorigenic RNAs to bind to and be stabilized by HEXIM1. HEXIM1 plays an important role in inhibiting cancer cell-specific gene transcription while also facilitating anti-cancer gene expression. Our study reveals an important role for HEXIM1 in coupling nucleotide metabolism with transcriptional regulation in melanoma

Play, Learn, and Teach Outdoors—Network (PLaTO-Net): terminology, taxonomy, and ontology

Background: A recent dialogue in the feld of play, learn, and teach outdoors (referred to as “PLaTO” hereafter) demonstrated the need for developing harmonized and consensus-based terminology, taxonomy, and ontology for PLaTO. This is important as the feld evolves and diversifes in its approaches, contents, and contexts over time and in diferent countries, cultures, and settings. Within this paper, we report the systematic and iterative processes under‑taken to achieve this objective, which has built on the creation of the global PLaTO-Network (PLaTO-Net). Methods: This project comprised of four major methodological phases. First, a systematic scoping review was conducted to identify common terms and defnitions used pertaining to PLaTO. Second, based on the results of the scoping review, a draft set of key terms, taxonomy, and ontology were developed, and shared with PLaTO members, who provided feedback via four rounds of consultation. Third, PLaTO terminology, taxonomy, and ontology were then fnalized based on the feedback received from 50 international PLaTO member participants who responded to≥3 rounds of the consultation survey and dialogue. Finally, eforts to share and disseminate project outcomes were made through diferent online platforms. Results: This paper presents the fnal defnitions and taxonomy of 31 PLaTO terms along with the PLaTO-Net ontol‑ogy model. The model incorporates other relevant concepts in recognition that all the aspects of the model are interrelated and interconnected. The fnal terminology, taxonomy, and ontology are intended to be applicable to, and relevant for, all people encompassing various identities (e.g., age, gender, culture, ethnicity, ability). Conclusions: This project contributes to advancing PLaTO-based research and facilitating intersectoral and inter‑disciplinary collaboration, with the long-term goal of fostering and strengthening PLaTO’s synergistic linkages with healthy living, environmental stewardship, climate action, and planetary health agendas. Notably, PLaTO terminology, taxonomy and ontology will continue to evolve, and PLaTO-Net is committed to advancing and periodically updating harmonized knowledge and understanding in the vast and interrelated areas of PLaTO