bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of SMooth muscle cell minerAlocorticoid Receptor in inTestinal fibrosis (SMART)
Authors: Marion-Letellier R , Jaisser F , Ghosh S , Jaisser F 
Published: January 2025

Abstract

Background and aims
Intestinal fibrosis is a common complication in inflammatory bowel diseases (IBD) with no specific therapy1. Because mineralocorticoid receptor (MR) antagonism prevented inflammation and fibrosis in extra-intestinal organs but also in intestine and since we showed that smooth muscle cell (SMC)-MR deletion prevented colon fibrosis development in mice, we now aim to understand the underlying mechanisms of these benefits.

Methods
Fibrosis will be assessed in male and female mice with conditioned smooth muscle MR overexpression. We previously demonstrated that NGAL (Lipocalin-2) is a MR target in murine SMC and is involved in MR-mediated fibrosis and inflammation. We therefore will study the impact of MR or NGAL agonism/antagonism in murine SMC upon TGF-beta stimulation. To understand the potential inducers of MR or NGAL in murine SMC, we will screen the ability of microbial factors to induce fibrosis or MR signalling in intestinal fibroblasts or SMC. To assess the role of MR/NGAL signaling in macrophages/SMC interaction, we will also investigate the impact of myeloid MR or NGAL invalidation on SMC activation in co-culture experiments of murine macrophages and SMC. For translational approaches, conditioned medium of intestinal biopsies from Crohn’s disease (CD) patients or isolated monocytes derived macrophages from CD patients will be incubated with SMC to study their impact of MR/NGAL signalling and/or fibrosis development.

Anticipated impact
SMART may open new therapeutic avenues in IBD by the repositioning of MR antagonists already available in other medical applications. As SMC represent the main cell component of the increased wall thickness in intestinal fibrosis, a better understanding of the crosstalk between SMC, macrophages and gut microbiota will provide novel insights to develop potentially more effective therapies targeting stromal cells.
Inhibition of the gut sulfidogenic bacteria targeting the production of toxic and inflammatory sulfide
Authors: Pímenta A 
Published: January 2025

Abstract

Background and aims
This project seeks to develop novel strategies to modulate the human gut microbiota and mitigate the production of pathogenic sulphide strongly associated with inflammatory bowel diseases (IBD). Our focus lies in inhibiting a key respiratory complex present in majority of the gut sulfidogenic bacteria to curb excessive sulphide production.

Methods
We will use an array of genetic, microbiological, and biochemical techniques to perform both in vitro and in vivo experiments. Our primary target is the membrane complex DsrMKJOP, involved in the essential Dsr pathway in sulfidogenic bacteria, which is pivotal for sulphur respiration. To achieve this, we will evaluate the efficacy of inhibitors, specifically quinone analogues, which compete for binding sites in the DsrMKJOP complex. Our comprehensive work plan comprises two main components:
(1) expression and production of the DsrMKJOP complex from a major sulfidogenic bacterium and investigation of its inhibition profile through in vitro enzymatic assays; and
(2) assessment of the efficacy and toxicity of DsrMKJOP inhibitors in vivo. This includes determining minimal inhibitory and bactericidal concentrations for the two bacteria, evaluating cytotoxicity in human colonic cells, assessing toxicity in a non-vertebrate animal model, and determining the antimicrobial properties of the inhibitory drugs to modulate bacterial growth during infection and colonization.

Anticipated impact
The outcomes of this research will contribute to identifying new therapeutic agents against sulfidogenic bacteria, acting as metabolic modulators to inhibit the production of pathogenic inflammatory sulphide. We aim to not only identify novel DsrMKJOP inhibitors but also to characterize their in vivo efficacy and toxicity profiles. Successful outcomes hold the potential to significantly advance human health, offering promising avenues for preventing IBD, enhancing the quality of life for IBD patients, and alleviating the burden on healthcare systems.
Diagnostic Markers of Primary Sclerosing Cholangitis in Newly Diagnosed Patients with Inflammatory Bowel Disease - a Copenhagen IBD Inception Cohort Sub-study
Authors: Honoré T V , Attauabi M , Madsen G , Bendtsen F , Ytting H , Seidelin J B , Burisch J 
Published: January 2025

Abstract

Background and aims
Between 5-10% of patients with inflammatory bowel disease (IBD) will eventually be diagnosed with primary sclerosing cholangitis (PSC) [1,2]. Studies suggest that a significant number of IBD patients may have PSC despite lacking biochemical or clinical signs, leading to delayed diagnosis. Sometimes, the liver disease is identified only after severe liver complications or malignancy have developed. This highlights the need for improved diagnostic markers to identify individuals at a high risk of developing PSC [3]. The primary objective of this study is to identify new biomarkers that can detect patients at risk of developing PSC among newly diagnosed IBD patients, enabling early diagnosis of PSC.

Methods
Since May 2021, a prospective population-based inception cohort study (Copenhagen IBD Inception Cohort) has been conducted, including newly diagnosed IBD patients within the uptake area of Hvidovre and Herlev University Hospital, Denmark (approx. 1.1 million inhabitants) [4]. Blood samples have been collected from the cohort at the time of diagnosis. These samples, now stored in a biobank at our disposal, will be utilized for this study.
In this study, we will investigate diagnostic markers in blood samples by comparing proteomic and genetic profiles between data from newly diagnosed PSC-IBD patients (n=15) and IBD patients without PSC (n=30). Plasma will be analysed using the Olink Explore 3072 panel (Olink Proteomics, Uppsala, Sweden). RNA will be extracted from the blood samples and analysed by bulk RNA sequencing.

Anticipated impact
To our knowledge, no studies have yet investigated biomarkers in newly diagnosed PSC-IBD patients who are naive to any prior treatment for both IBD and PSC. This study presents a unique opportunity to discover biological markers in PSC-IBD patients at early stages of the disease.

References
1.Karlsen TH, Folseraas T, Thorburn D, Vesterhus M. Primary sclerosing cholangitis – a comprehensive review. Vol. 67, Journal of Hepatology. Elsevier B.V.; 2017. p. 1298–323.
2.Dyson JK, Beuers U, Jones DEJ, Lohse AW, Hudson M. Primary sclerosing cholangitis. Vol. 391, The Lancet. Lancet Publishing Group; 2018. p. 2547–59.
3.Lunder AK, Hov JR, Borthne A, Gleditsch J, Johannesen G, Tveit K, et al. Prevalence of Sclerosing Cholangitis Detected by Magnetic Resonance Cholangiography in Patients With Long-term Inflammatory Bowel Disease. Gastroenterology. 2016 Oct 1;151(4):660-669.e4.
4.Attauabi M, Madsen GR, Bendtsen F, Wewer AV, Wilkens R, Ilvemark J, et al. Influence of Genetics, Immunity and the Microbiome on the Prognosis of Inflammatory Bowel Disease (IBD Prognosis Study): The protocol for a Copenhagen IBD Inception Cohort Study. BMJ Open. 2022 Jun 1;12(6).
Role of indole derivatives in neutrophil functions in homeostasis and inflammation
Authors: Danne C 
Published: January 2025

Abstract

Background and aims
Inflammatory Bowel Disease (IBD) are chronic inflammatory conditions of the gastrointestinal tract with increasing prevalence. Current therapies are only partially efficient and associated with potentially severe side effects. New therapeutic strategies with innovative targets are thus urgently needed. Neutrophils are key players of innate immunity in IBD, but their roles in disease development are neglected compared to those of other immune cells. Essential to host defence, their overactivation can cause chronic inflammation and tissue damage. Converging evidence has highlighted interactions between neutrophils, gut inflammation and microbiota. Notably, numerous IBD susceptibility genes are involved in neutrophil functions related to defence against microbes; and IBD is associated with alterations of the intestinal microbiota. However, the influence of microbiota on neutrophil functions, and the consequences in terms of disease development remain largely unknown. Microbiota metabolites, including short-chain fatty acids, bile acids, and tryptophan (Trp)-derived metabolites, have shown regulatory effects on immune cell types, such as T cells and macrophages. However, their impact on neutrophils is underexplored, especially concerning indole derivatives, molecules derived from Trp degradation by the microbiota. Based on preliminary data, our objectives are to (i) explore the influence of two indole derivatives, indole and indoxyl-3-sulfate (I3S), on neutrophil functions in homeostasis, and (ii) decipher the effect of these microbiota metabolites on neutrophils in the context of intestinal inflammation.

Methods
Our project follows systematic approaches and takes advantage of up-to-date technologies (flow cytometry and Seahorse) and access to unique mouse and human samples (blood and intestinal tissue from the Saint-Antoine Hospital).

Anticipated impact
Based on both basic and translational research, it is essential to better understand the roles played by neutrophils in host-microbiota interactions in homeostasis and intestinal inflammation and to identify new therapeutic targets for IBD patients.
Deciphering the role of the intestinal microbiota in mediating the protective effect of Exclusive Enteral Nutrition on patients with Crohn’s disease
Authors: Stallbaum Bertram F , Huber S , Gerasimidis K 
Published: January 2025

Abstract

Background and aims
The intestinal microbiota, influenced by the host's diet, regulates the immune system. Exclusive enteral nutrition (EEN) effectively treats Crohn’s Disease (CD). Though likely involving the microbiome and its metabolites, the mechanism of action remains unclear. We aim to unravel the direct and indirect effects of microbiota from EEN-responsive patients (EENr) on the immune system and, by extension, CD.

Methods
We will generate patient-specific gnotobiotic mice of individuals with CD before and after EEN and assess IBD susceptibility using in vivo models. Supervised and unsupervised approaches will be combined to elucidate mechanism(s) underlying the effect of EEN on the immune system and the intestinal barrier. To identify active metabolites of the microbiota of EENr, we will stimulate intestinal organoids using cell-free filtrates from faecal samples, and single metabolites. We will describe the effect of total and single metabolites generated by the microbiota of EENr on the immune system

Anticipated impact
We propose a collaborative project establishing a long-lasting collaboration between the University of Glasgow, Scotland, and the University Medical Centre Hamburg. We anticipate deciphering the effects of EENr-microbiota and its metabolites. Our results will pave the way for the development of dietary and pharmaceutical approaches that emulate these effects and form a basis for the development of targeted microbiome-modifying treatments for patients with IBD.
Targeting hypoxia-induced signaling via HIF-2 inhibition, a promising treatment strategy for intestinal fibrosis?
Authors: Van Welden S 
Published: January 2025

Abstract

Background and aims
With this project, we aim to evaluate if targeting hypoxia-induced signalling via hypoxia inducible factor (HIF)-2 inhibition impacts experimental intestinal fibrosis and validate our findings in stenotic fibroblasts from CD patients.

Methods
Colonic fibroblasts will be sorted from mice with a fibroblast-specific deletion of the oxygen sensitive enzyme prolyl hydroxylase (PHD2) (i.e. PHD2ff- Col1a2-ERT2:Cre) and their wildtype littermate controls, followed by RNA sequencing and pathway analysis. Validation of key fibrotic mediators will be performed via qPCR or immunostainings. Intestinal fibrosis will be induced in PHD2ff Col1a2-ERT2:Cre mice wildtype littermate controls by chronic administration of dextran sodium sulphate in their drinking water, followed by treatment with the oral HIF-2 inhibitor, belzutifan. Translatability of preclinical findings will be confirmed in bio-banked fibrostenotic fibroblasts from CD patients.

Anticipated impact
Intestinal fibrosis is a debilitating complication of IBD which cannot be fully prevented by current anti-inflammatory therapies, highlighting the unmet clinical need for anti-fibrotic treatment strategies. Our preliminary data demonstrated that genetic deletion of Phd2 in fibroblasts aggravates experimental intestinal fibrosis without affecting inflammation and is most likely mediated via HIF-2. This suggests that signaling induced by this transcriptional modulator plays a crucial role in the fibrotic process. This proposal will identify the molecular mediators driving this fibrosis-promoting effect and validate if HIF-2 targeting could represent a promising novel anti-fibrotic treatment strategy. Data resulting from this project will therefore represent a final preclinical step and provide proof-of-concept data with the perspective to initiate a clinical trial in fibrostenotic IBD with belzutifan (awaiting EMA approval, but recently FDA-approved for advanced renal cell carcinoma).
Klebsiella pneumoniae T6SS impact in IBDs
Authors: Aschtgen M S 
Published: January 2025

Abstract

Background and aims
Our hypothesis is that Klebsiella pneumoniae (Kp) Type VI Secretion System (T6SS), normally used for bacteria competition during host colonization have a collateral impact on the host inflammatory pathway (Fig1). Our specific aims are to: (i) Characterize the impact of bacterial type VI Secretion System (T6SS) on host gut inflammation (ii) Develop a screen to identify T6SS inhibitors.

Methods
In vivo experiments involve infecting mice with Kp wild type (WT) and T6SS mutants to evaluate gut inflammation and immune response. Metagenomic analysis of IBD and CRC patients' microbiota will be conducted to assess T6SS gene enrichment. The molecular mechanism of T6SS activity and LPS release will be explored using various imaging and biochemical techniques. High-throughput screening of small molecule inhibitors targeting T6SS assembly will be performed, followed by validation in cellular models. The role of bacteria in tumorigenesis is increasingly recognized, yet our understanding of the underlying mechanisms remains incomplete, hindering the identification of new therapeutic strategies. It is therefore critical to decipher the bacterial mechanisms and their impact on the host to identify pathways that can be targeted from both sides.

Anticipated impact
Our preliminary data have uncovered a novel role of Type VI Secretion System (T6SS) role in gut inflammation. Building on our extensive expertise of this specific system, we will employ a multidisciplinary approach to inhibit T6SS. Inhibiting the T6SS could prevent both gut inflammation and Enterobacteria competition advantage in the gut, therefore reducing dysbiosis. Moreover, inhibition of bacterial virulence factors is an attractive strategy to complement antibiotic and anti-inflammatory treatments already in use.
Self-care in patients affected with inflammatory bowel disease and Mutuality in nursing: A protocol for a longitudinal study
Authors: Napolitano D , Vellone E , Martella P , Monaci A , Radice S , Schiavoni E , Lusignani M , Cocchieri A , Ciluffo S 
Published: January 2025

Abstract

Background and aims
Inflammatory bowel diseases (IBD) pose a growing global health challenge, with prevalence expected to double in coming years. The chronic nature of IBD, marked by recurrent inflammatory episodes, significantly impacts patients' quality of life and increases healthcare costs. In this context, the IBD nurse plays a crucial role in building a supportive relationship with patients, promoting self-care, and encouraging active health management, ultimately reducing hospitalizations. This study examines self-care behaviours and nurse-patient mutuality among IBD patients in Italy. The aims are: describing levels of self-care, assessing mutuality between patients and nurses, and analysing the impact of these factors on clinical outcomes, quality of life, and resilience.

Methods
This multicentre, longitudinal study will enrol 400 IBD patients across 9 Italian centres. Guided by the Middle-Range Theory of Self-Care of Chronic Illness, which defines self-care as an active process for maintaining health in chronic conditions, data will be collected at baseline (T0), 6 months (T1), and 12 months (T2). Sociodemographic and clinical characteristics, disease severity, self-care practices, and mutuality levels will be gathered using standardized tools. Mutuality, based on the Nurse-Patient Mutuality conceptual framework, will be measured with the Nurse-Patient Mutuality in Chronic Illnesses Scale, assessing the quality of relationship, including shared understanding, collaboration, and emotional support. Clinical indicators include C-reactive protein levels, faecal calprotectin, endoscopic scores, QoL, and resilience.

Anticipated impact
The findings will provide valuable insights into self-care behaviours and nurse-patient mutuality in managing IBD, identifying predictors of effective self-care and the role of mutuality in enhancing clinical outcomes, QoL, and resilience. This project will further advance nursing research, fostering collaboration across centres and promoting a nationwide network of evidence-based, patient-centred care. These outcomes will lay a foundation for future research, strengthening the role of specialized IBD nurses and supporting an integrated, optimized approach to patient management.
Kissing balloon technique as rescue strategy to treat left ventricular outflow tract obstruction after transcatheter mitral valve replacement: a case report
Authors: Çatalkaya Sibel , Erkan Hakan 
Published: January 2025

Abstract

Background
Transcatheter mitral valve replacement (TMVR) has become a viable, minimally invasive treatment for inoperable patients with severe mitral valve disease, particularly among elderly individuals with significant comorbidities. A key complication of TMVR is left ventricular outflow tract (LVOT) obstruction, necessitating various preventive and therapeutic strategies. This report presents a case of severe LVOT obstruction following TMVR and highlights the effective application of the kissing balloon technique as a therapeutic intervention.

Case summary
A 79-year-old female with New York Heart Association Class IV dyspnoea due to severe mitral stenosis and a high operative risk, with a Society of Thoracic Surgeons Risk of Mortality (STS-PROM) score of 6.2%, underwent TMVR. Pre-procedural evaluations indicated significant mitral valve calcification and a mitral valve area of 0.9 cm². After successful TMVR deployment, post-implantation echocardiography revealed an LVOT pressure gradient of 53/85 mmHg, prompting the use of the kissing balloon technique, which reduced the gradient to 28 mmHg. Follow-up assessments showed normal mitral valve function and stable LVOT gradients during short-term follow-up throughout the patient’s hospital stay.

Discussion
Left ventricular outflow tract obstruction is a potentially life-threatening complication of TMVR, often associated with high mortality rates due to haemodynamic impairment. This complication can arise from various anatomical factors and valve positioning issues. Several strategies have been developed to address LVOT obstruction, including the laceration of the anterior mitral leaflet and alcohol septal ablation. The successful implementation of the kissing balloon technique in this case underscores its potential to improve outcomes in LVOT obstruction.
Evaluation of right ventricular pacing-induced coronary microvascular dysfunction using guide wire-based sensor technology: a case report
Authors: Mishina Takashi , Inoue Naoya , Morikawa Shuji 
Published: January 2025

Abstract

Background
The diagnosis of ischaemic non-obstructive coronary artery disease is crucial for the differential diagnosis of chest pain. However, the pathophysiology of chest pain and evaluation of coronary microcirculation in patients with right ventricular pacing (RVP) have not been sufficiently reported.

Case summary
The patient was a 53-year-old woman who underwent dual-chamber pacemaker implantation because of sinus node dysfunction. She experienced chest pain before pacemaker implantation; however, the frequency and severity of her chest pain increased after the implantation. She was referred for the evaluation of coronary microvascular dysfunction (CMD). Coronary angiography revealed no significant stenosis of the epicardial vessels. Subsequent evaluation of CMD showed that while the index of microcirculatory resistance [normalized index of microcirculatory resistance (IMR)] in the left anterior descending artery (LAD) was 19 U during the native rhythm, an increase in IMR (normalized IMR: 27 U) was observed during RVP.

Discussion
Right ventricular pacing may not only induce left ventricular dyssynchrony due to non-physiological excitation propagation but may also provoke CMD in the LAD territory, particularly in the septal branches, which could contribute to pacing-induced structural CMD and chest pain. However, RVP may well be a contributing but not exclusively a factor of CMD.
Thrombotic prosthetic valve dysfunction requiring valve re-replacement after mitral valve replacement for caseous calcification with hypereosinophilic syndrome: a case report
Authors: Miyazawa Keishi , Imai Eriya , Kodaira Ami , Ota Toshiki , Yokozuka Motoi 
Published: January 2025

Abstract

Background
Caseous calcification of the mitral annulus (CCMA) and hypereosinophilic syndrome (HES) are both associated with thrombotic tendencies. Caseous calcification of the mitral annulus may cause mitral valve regurgitation (MR), which may necessitate surgical intervention, depending on its severity. Given the absence of reported cases combining CCMA and HES, the optimal target range for anticoagulation therapy after mitral valve replacement remains to be established.

Case summary
A 64-year-old man with CCMA complicated by HES was admitted due to heart failure and severe MR. The patient underwent mitral valve replacement with a mechanical valve. Despite standard anticoagulation therapy, prosthetic valve dysfunction had developed because of thrombosis. Intraoperative transoesophageal echocardiography revealed a closed stuck valve, necessitating valve re-replacement. A bioprosthetic valve was selected.

Discussion
In cases of CCMA complicated by HES, the target of anticoagulation therapy is unclear. This case demonstrated that more intensive anticoagulation is required because of the thrombogenic risk of CCMA and HES. The mechanism of calcification due to eosinophilia has been suggested, and the relationship between eosinophilia and CCMA remains a subject for future research.