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Despite the introduction of serological neoplastic biomarkers and typical radiological characteristics in clinical practice, liver biopsy (LB) is often still necessary to establish a histological diagnosis, especially in ambiguous cases. Nowadays, LB via the percutaneous approach (PC-LB), under computed tomography (CT) scan or ultrasonography (US) guidance, is the route of choice. However, certain focal liver lesions can be challenging to access percutaneously. In such cases, endoscopic ultrasound (EUS)-guided fine needle biopsy (FNB) may represent an attractive, minimally invasive alternative. This retrospective observational study aimed to evaluate the efficacy, diagnostic performance, and safety of EUS-FNB conducted on 58 focal liver lesions located in both liver lobes. The adequacy of FNB samples for focal liver lesions located in the left and right lobes was 100% and 81.2%, respectively, and the difference was statistically significant (p = 0.001). Technical success was 100% for both liver lobes. The overall sensitivity and specificity were 95% and 100%, respectively. EUS-FNB is effective in making an accurate diagnosis with an excellent safety profile for focal liver lesions located in both liver lobes.

Vascular dysfunction is associated with ageing and chronic diseases, but its role in lung repair and fibrosis is unclear. Here, the authors show that the endothelial transcription factor ERG is a mediator of vascular repair whose function declines in aged lungs resulting in sustained fibrosis

Over the past two decades, our understanding of the endocannabinoid system has greatly improved due to the wealth of results obtained from exploratory studies. Currently, two cannabinoid receptor subtypes have been well-characterized. The cannabinoid receptor type 1 (CB1) is widely expressed in the central nervous system, while the levels of the cannabinoid receptor type 2 (CB2) in the brain and spinal cord of healthy individuals are relatively low. However, recent studies demonstrated a CB2 upregulation on activated microglia upon neuroinflammation, an indicator of neurodegeneration. Our research group aims to develop a suitable positron emission tomography (PET) tracer to visualize the CB2 receptor in patients suffering from neurodegenerative diseases. Herein we report two novel thiophene-based 11C-labeled PET ligands designated [11C]AAT-015 and [11C]AAT-778. The reference compounds were synthesized using Gewald reaction conditions to obtain the aminothiophene intermediates, followed by amide formation. Saponification of the esters provided their corresponding precursors. Binding affinity studies revealed Ki-values of 3.3 ± 0.5 nM (CB2) and 1.0 ± 0.2 μM (CB1) for AAT-015. AAT-778 showed similar Ki-values of 4.3 ± 0.7 nM (CB2) and 1.1 ± 0.1 μM (CB1). Radiosynthesis was carried out under basic conditions using [11C]iodomethane as methylating agent. After semi-preparative HPLC purification both radiolabeled compounds were obtained in 99% radiochemical purity and the radiochemical yields ranged from 12 to 37%. Specific activity was between 96 and 449 GBq/μmol for both tracers. In order to demonstrate CB2 specificity of [11C]AAT-015 and [11C]AAT-778, we carried out autoradiography studies using CB2-positive mouse/rat spleen tissues. The obtained results revealed unspecific binding in spleen tissue that was not blocked by an excess of CB2-specific ligand GW402833. For in vivo analysis, [11C]AAT-015 was administered to healthy rats via tail-vein injection. Evaluation of the CB2-positive spleen, however, showed no accumulation of the radiotracer. Despite the promising in vitro binding affinities, specific binding of [11C]AAT-015, and [11C]AAT-778 could not be demonstrated. [ABSTRACT FROM AUTHOR]

Stenotrophomonas maltophilia (SM) is a multidrug-resistant, Gram-negative (GN) bacillus that is an increasingly recognized nosocomial and environment pathogen. It is intrinsically resistant to carbapenems, a drug commonly utilized in the management of necrotizing pancreatitis (NP). We report a 21-year-old immunocompetent female with NP complicated by pancreatic fluid collection (PFC) infected with SM. One-third of patients with NP will develop infections by GN bacteria, while broad-spectrum antibiotics, including carbapenems, cover most infections, trimethoprim-sulfamethoxazole (TMP-SMX) is the first-line treatment antibiotic for SM. This case is critical because it highlights a rare pathogen that should be considered a causal pathogen in patients who do not respond to their care plan.

Summary Therapies halting the progression of fibrosis are ineffective and limited. Activated myofibroblasts are emerging as important targets in the progression of fibrotic diseases. Previously, we performed a high-throughput screen on lung fibroblasts and subsequently demonstrated that the inhibition of myofibroblast activation is able to prevent lung fibrosis in bleomycin-treated mice. High-throughput screens are an ideal method of repurposing drugs, yet they contain an intrinsic limitation, which is the size of the library itself. Here, we exploited the data from our “wet” screen and used “dry” machine learning analysis to virtually screen millions of compounds, identifying novel anti-fibrotic hits which target myofibroblast differentiation, many of which were structurally related to dopamine. We synthesized and validated several compounds ex vivo (“wet”) and confirmed that both dopamine and its derivative TS1 are powerful inhibitors of myofibroblast activation. We further used RNAi-mediated knock-down and demonstrated that both molecules act through the dopamine receptor 3 and exert their anti-fibrotic effect by inhibiting the canonical transforming growth factor β pathway. Furthermore, molecular modelling confirmed the capability of TS1 to bind both human and mouse dopamine receptor 3. The anti-fibrotic effect on human cells was confirmed using primary fibroblasts from idiopathic pulmonary fibrosis patients. Finally, TS1 prevented and reversed disease progression in a murine model of lung fibrosis. Both our interdisciplinary approach and our novel compound TS1 are promising tools for understanding and combating lung fibrosis.

The scaffold protein synectin plays a critical role in the trafficking and regulation of membrane receptor pathways. As platelet-derived growth factor receptor (PDGFR) is essential for hepatic stellate cell (HSC) activation and liver fibrosis, we sought to determine the role of synectin on the PDGFR pathway and development of liver fibrosis. Mice with deletion of synectin from HSC were found to be protected from liver fibrosis. mRNA sequencing revealed that knockdown of synectin in HSC demonstrated reductions in the fibrosis pathway of genes, including PDGFR-β. Chromatin IP assay of the PDGFR-β promoter upon synectin knockdown revealed a pattern of histone marks associated with decreased transcription, dependent on p300 histone acetyltransferase. Synectin knockdown was found to downregulate PDGFR-α protein levels, as well, but through an alternative mechanism: protection from autophagic degradation. Site-directed mutagenesis revealed that ubiquitination of specific PDGFR-α lysine residues was responsible for its autophagic degradation. Furthermore, functional studies showed decreased PDGF-dependent migration and proliferation of HSC after synectin knockdown. Finally, human cirrhotic livers demonstrated increased synectin protein levels. This work provides insight into differential transcriptional and posttranslational mechanisms of synectin regulation of PDGFRs, which are critical to fibrogenesis.

Objective: Rarefaction of blood and lymphatic vessels in the skin has been reported in systemic sclerosis (SSc) (scleroderma). E26 transformation–specific–related factor (ERG) and Friend leukemia virus–induced erythroleukemia 1 (FLI‐1) are important regulators of angiogenesis, but their role in lymphatic vasculature is lesser known. The goal of this study was to determine the role of ERG and FLI‐1 in postnatal lymphangiogenesis and SSc lymphatic system defects. Methods: Immunofluorescence was used to detect ERG and FLI‐1 in skin biopsy samples from patients with SSc and healthy controls. Transcriptional analysis of ERG or FLI‐1–silenced human dermal lymphatic endothelial cells (LECs) was performed using microarrays. Effects of ERG and FLI‐1 deficiency on in vitro tubulogenesis in human dermal LECs were examined using a Matrigel assay. ERG and FLI‐1 endothelial–specific knockouts and ERG lymphatic–specific knockouts were generated to examine vessel regeneration in mice. Results: ERG and FLI‐1 protein levels were reduced in the blood and lymphatic vasculature in SSc skin biopsy samples. ERG levels were shown to regulate genes involved in lymphatic vessel specification, including vascular endothelial growth factor receptor 3/FLT‐4, lymphatic vessel endothelial hyaluronan receptor 1, SOX‐18, and prospero homeobox 1 (PROX‐1), whereas FLI‐1 enhanced the function of ERG. The ERG–FLT‐4 pathway regulated in vitro tubulogenesis in human LECs. Deficiency of ERG or FLI‐1 similarly impaired the function of blood vessels in mice. However, only ERG deficiency affected the regeneration of lymphatic vessels during wound healing. Conclusion: ERG and FLI‐1 are essential regulators of blood and lymphatic vessel regeneration. Deficiency of ERG and FLI‐1 in SSc endothelial cells may contribute to the impairment of blood and lymphatic vasculature in patients with SSc. [ABSTRACT FROM AUTHOR]

Simple Summary: Large language models (LLMs) are revolutionizing the field of medicine, particularly in Gastroenterology, by improving access to information, diagnostics, treatment customization, and medical education. They analyze extensive medical data to enhance decision-making, patient outcomes, and educational tasks. While LLMs face challenges such as incomplete data, varying response accuracy, and reliance on specific input wording, they have shown promising results. However, their full integration into medical practice requires further research and regulation. Moreover, the successful integration of LLMs into medical practice necessitates customization to specific medical contexts and adherence to guidelines. This review focuses on the current evidence supporting the use of LLMs in Gastroenterology, emphasizing their potential and limitations. Large language models (LLMs) are transforming the medical landscape by enhancing access to information, diagnostics, treatment customization, and medical education, especially in areas like Gastroenterology. LLMs utilize extensive medical data to improve decision-making, leading to better patient outcomes and personalized medicine. These models are instrumental in interpreting medical literature and synthesizing patient data, facilitating real-time knowledge for physicians and supporting educational pursuits in medicine. Despite their potential, the complete integration of LLMs in real-life remains ongoing, particularly requiring further study and regulation. This review highlights the existing evidence supporting LLMs' use in Gastroenterology, addressing both their potential and limitations. Recent studies demonstrate LLMs' ability to answer questions from physicians and patients accurately. Specific applications in this field, such as colonoscopy, screening for colorectal cancer, and hepatobiliary and inflammatory bowel diseases, underscore LLMs' promise in improving the communication and understanding of complex medical scenarios. Moreover, the review discusses LLMs' efficacy in clinical contexts, providing guideline-based recommendations and supporting decision-making processes. Despite these advancements, challenges such as data completeness, reference suitability, variability in response accuracy, dependency on input phrasing, and a lack of patient-generated questions underscore limitations in reproducibility and generalizability. The effective integration of LLMs into medical practice demands refinement tailored to specific medical contexts and guidelines. Overall, while LLMs hold significant potential in transforming medical practice, ongoing development and contextual training are essential to fully realize their benefits. [ABSTRACT FROM AUTHOR]