[Posted 29/May/2023]

AUDIENCE: Gastroenterology, Oncology, Internal Medicine

KEY FINDINGS: The findings identify an important role for a subgroup of highly connected enhancers (iHUBs) in regulating chemotherapy response and demonstrate targetability in sensitisation to chemotherapy.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) displays a remarkable propensity towards therapy resistance. However, molecular epigenetic and transcriptional mechanisms enabling this are poorly understood. In this study, we aimed to identify novel mechanistic approaches to overcome or prevent resistance in PDAC.

DETAILS: Authors used in vitro and in vivo models of resistant PDAC and integrated epigenomic, transcriptomic, nascent RNA and chromatin topology data. They identified a JunD-driven subgroup of enhancers, called interactive hubs (iHUBs), which mediate transcriptional reprogramming and chemoresistance in PDAC. iHUBs display characteristics typical for active enhancers (H3K27ac enrichment) in both therapy sensitive and resistant states but exhibit increased interactions and production of enhancer RNA (eRNA) in the resistant state. Notably, deletion of individual iHUBs was sufficient to decrease transcription of target genes and sensitise resistant cells to chemotherapy. Overlapping motif analysis and transcriptional profiling identified the activator protein 1 (AP1) transcription factor JunD as a master transcription factor of these enhancers. JunD depletion decreased iHUB interaction frequency and transcription of target genes. Moreover, targeting either eRNA production or signaling pathways upstream of iHUB activation using clinically tested small molecule inhibitors decreased eRNA production and interaction frequency, and restored chemotherapy responsiveness in vitro and in vivo. Representative iHUB target genes were found to be more expressed in patients with poor response to chemotherapy compared with responsive patients.

Copyright © BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.

Source: Hamdan, F. H., Abdelrahman, A. M., Kutschat, A. P., et al. (2023). Interactive Enhancer Hubs (iHUBs) Mediate Transcriptional Reprogramming And Adaptive Resistance In Pancreatic Cancer. Gut. 2023; 72(6): 1174-1185. Published: June, 2023. DOI: 10.1136/gutjnl-2022-328154.

Lessons for the Adult Gastroenterologist

[Posted 18/Aug/2023]

AUDIENCE: Gastroenterology, Pediatric, Internal Medicine

KEY FINDINGS: The present review addresses the epidemiology, clinical features, diagnostic testing, treatment, prognosis, and transplant outcomes of 4 hallmark childhood cholestatic liver diseases: biliary atresia, Alagille syndrome, progressive familial intrahepatic cholestasis, and bile acid synthesis disorders.

BACKGROUND: Children with cholestatic liver diseases are increasingly living into adulthood, thanks to innovations in medical and surgical therapies. The excellent outcomes observed in pediatric liver transplantation for diseases, such as biliary atresia, have transformed the life trajectory of children born with once-fatal liver diseases.

DETAILS: The evolution of molecular genetic testing, has helped expedite the diagnosis of other cholestatic disorders, improving the clinical management, disease prognosis, and family planning for inherited disorders, such as progressive familial intrahepatic cholestasis and bile acid synthesis disorders. The expanding list of therapeutics, including bile acids and the newer ileal bile acid transport inhibitors, has also helped slow the progression of disease and improve the quality of life for certain diseases, like Alagille syndrome. More and more children with cholestatic disorders are expected to require care from adult providers familiar with the natural history and potential complications of these childhood diseases. The aim of this review is to bridge the gap between pediatric and adult care in children with cholestatic disorders.

Copyright © Wolters Kluwer Health, Inc. All rights reserved.

Source: Chan, A. P. and Venick, R. S. (2023). Childhood Cholestatic Liver Diseases that Persist Into Adulthood : Lessons for the Adult Gastroenterologist. Journal of Clinical Gastroenterology. 2023; 57(7): 686-693. Published: August, 2023. DOI: 10.1097/MCG.0000000000001850.

A Diet Intervention In Pre-Diabetes

[Posted 20/Jul/2023]

AUDIENCE: Gastroenterology, Internal Medicine

KEY FINDINGS: The findings support the role of gut microbiome in modulating the effects of dietary modifications on cardiometabolic outcomes, and advance the concept of precision nutrition strategies for reducing comorbidities in pre-diabetes.

BACKGROUND: Aim of the study is to explore the interplay between dietary modifications, microbiome composition and host metabolic responses in a dietary intervention setting of a personalised postprandial-targeting (PPT) diet versus a Mediterranean (MED) diet in pre-diabetes.

DETAILS: In a 6-month dietary intervention, adults with pre-diabetes were randomly assigned to follow an MED or PPT diet (based on a machine-learning algorithm for predicting postprandial glucose responses). Data collected at baseline and 6 months from 200 participants who completed the intervention included: dietary data from self-recorded logging using a smartphone application, gut microbiome data from shotgun metagenomics sequencing of faecal samples, and clinical data from continuous glucose monitoring, blood biomarkers and anthropometrics. PPT diet induced more prominent changes to the gut microbiome composition, compared with MED diet, consistent with overall greater dietary modifications observed. Particularly, microbiome alpha-diversity increased significantly in PPT (p=0.007) but not in MED arm (p=0.18). Post hoc analysis of changes in multiple dietary features, including food-categories, nutrients and PPT-adherence score across the cohort, demonstrated significant associations between specific dietary changes and species-level changes in microbiome composition. Furthermore, using causal mediation analysis we detect nine microbial species that partially mediate the association between specific dietary changes and clinical outcomes, including three species (from Bacteroidales, Lachnospiraceae, Oscillospirales orders) that mediate the association between PPT-adherence score and clinical outcomes of hemoglobin A1c (HbA1c), high-density lipoprotein cholesterol (HDL-C) and triglycerides. Finally, using machine-learning models trained on dietary changes and baseline clinical data, we predict personalised metabolic responses to dietary modifications and assess features importance for clinical improvement in cardiometabolic markers of blood lipids, glycaemic control and body weight.

Copyright © BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.

Source: Ben-Yacov, O., Godneva, A., Rein, M., et al. (2023). Gut Microbiome Modulates The Effects Of A Personalised Postprandial-Targeting (PPT) Diet On Cardiometabolic Markers: A Diet Intervention In Pre-Diabetes. Gut. 2023; 72(8): 1486-1496. Published: August, 2023.

[Posted 29/Jun/2023]

AUDIENCE: Gastroenterology, Cardiology, Internal Medicine

KEY FINDINGS: In vitro, in vivo, and early-phase trial data showed no significant effects of prucalopride on CV safety. Later-phase studies demonstrated a consistent CV safety profile in men and women, and a pooled analysis of long-term phase 3 data showed there was no increased risk associated with prucalopride vs PEG3350 for MACE or its individual components. These results were also consistently observed in populations of clinical interest. Long-term data were generally consistent with the primary data from these studies, suggesting no long-term CV risk in patients with CIC receiving prucalopride. Despite the innate limitations of literature reviews and the inclusion of post hoc or pooled analyses, this review provides robust evidence regarding the CV safety of prucalopride and its value as a treatment for patients with CIC who currently have limited therapeutic options.

BACKGROUND: Prokinetic agents, specifically 5-hydroxytryptamine type 4 (5-HT4) receptor agonists, have been shown to provide relief in chronic idiopathic constipation (CIC). The first-generation 5-HT4 agonists were initially withdrawn from use owing to associations with serious cardiovascular (CV) events.

DETAILS: This review summarizes CV safety data for prucalopride, a high-affinity 5-HT4 agonist approved in the United States in 2018 for adults with CIC. No significant effects of prucalopride on CV safety were observed in animal models or early-phase clinical studies, including a thorough QT study at therapeutic (2 mg) or supratherapeutic (10 mg) doses. Among 1,750 patients with CIC who received prucalopride (2-4 mg) in 5 phase 3 studies, no trends in CV adverse events, electrocardiogram parameters, or blood pressure were documented; <=1.0%-2.0% of patients had prolonged QT interval corrected for heart rate (HR) using Fridericia formula after placebo or prucalopride treatment, and low HR occurred in <=6.1% and <=3.3% of these patients, respectively. In two 24-month observational studies among 2,468 patients, changes in electrocardiogram parameters over time were minor, except at occasional time points when significant changes from baseline were reported for HR or QT interval. In a real-world European CV safety study among 35,087 patients (prucalopride, 5,715; polyethylene glycol 3350 [PEG3350], 29,372), results were consistent for no evidence of increased risk of major adverse CV events among patients treated with prucalopride vs PEG3350 (incidence rate ratio = 0.64; 95% confidence interval 0.36-1.14). Studies to date have not raised concerns regarding the impact of prucalopride treatment on CV parameters.

Copyright © The American College of Gastroenterology. All rights reserved.

Source: Tack, J., Derakhchan, K., Gabriel, A., et al. (2023). A Review of the Cardiovascular Safety of Prucalopride in Patients With Chronic Idiopathic Constipation. The American Journal of Gastroenterology. 2023; 118(6): 955-960. Published: June, 2023. DOI: 10.14309/ajg.0000000000002249.

[Posted 17/Apr/2023]

AUDIENCE: Gastroenterology, Oncology, Internal Medicine

KEY FINDINGS: In CRC, CD39 is strongly expressed on tumour infiltrating lymphocytes and its inhibition represents a promising therapeutic strategy for treating patients.

BACKGROUND: T cells are major effectors of the antitumoural immune response. Their activation by tumour-associated antigens can unleash their proliferation and cytotoxic functions, leading to tumour cell elimination. However, tumour-related immunosuppressive mechanisms including the overexpression of immune checkpoints like programmed cell death protein-1 (PD-1), are also engaged, promoting immune escape. Current immunotherapies targeting these pathways have demonstrated weak efficacy in colorectal cancer (CRC). It is thus crucial to find new targets for immunotherapy in this cancer type.

DETAILS: In a prospective cohort of patients with CRC, authors investigated the phenotype of tumour-related and non-tumour related intestinal T cells (n=44), particularly the adenosinergic pathway, correlating with clinical phenotype. An autologous coculture model was developed between patient-derived primary tumour spheroids and their autologous tumour-associated lymphocytes. We used this relevant model to assess the effects of CD39 blockade on the antitumour T cell response. Study shows the increased expression of CD39, and its co-expression with PD-1, on tumour infiltrating T cells compared with mucosal lymphocytes. CD39 expression was higher in the right colon and early-stage tumours, thus defining a subset of patients potentially responsive to CD39 blockade. Finally, authors demonstrate in autologous conditions that CD39 blockade triggers T cell infiltration and tumour spheroid destruction in cocultures.

Copyright © BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.

Source: Bonnereau, J., Courau, T., Asesio, N., et al. (2023). Autologous T Cell Responses To Primary Human Colorectal Cancer Spheroids Are Enhanced By Ectonucleotidase Inhibition. Gut. 2023; 72(4): 699-709. Published: March, 2023. DOI: 10.1136/gutjnl-2021-326553.

[Posted 24/Mar/2023]

AUDIENCE: Infectious Disease, Internal Medicine

KEY FINDINGS: C. auris case counts have increased for many reasons, including poor general infection prevention and control (IPC) practices in healthcare facilities. Case counts may also have increased because of enhanced efforts to detect cases, including increased colonization screening, a test to see if someone has the fungus somewhere on their body but does not have an infection or symptoms of infection. The timing of this increase and findings from public health investigations suggest C. auris spread may have worsened due to strain on healthcare and public health systems during the COVID-19 pandemic.

BACKGROUND: Candida auris (C. auris), an emerging fungus considered an urgent antimicrobial resistance (AR) threat, spread at an alarming rate in U.S. healthcare facilities in 2020-2021, according to data from the Centers for Disease Control and Prevention (CDC) published in the Annals of Internal Medicine. Equally concerning was a tripling in 2021 of the number of cases that were resistant to echinocandins, the antifungal medicine most recommended for treatment of C. auris infections. In general, C. auris is not a threat to healthy people. People who are very sick, have invasive medical devices, or have long or frequent stays in healthcare facilities are at increased risk for acquiring C. auris. CDC has deemed C. auris as an urgent AR threat, because it is often resistant to multiple antifungal drugs, spreads easily in healthcare facilities, and can cause severe infections with high death rates.

DETAILS: "The rapid rise and geographic spread of cases is concerning and emphasizes the need for continued surveillance, expanded lab capacity, quicker diagnostic tests, and adherence to proven infection prevention and control," said CDC epidemiologist Dr. Meghan Lyman, lead author of the paper.

As further explained in the article, C. auris has spread in the United States since it was first reported in 2016, with a total of 3,270 clinical cases (in which infection is present) and 7,413 screening cases (in which the fungus is detected but not causing infection) reported through December 31, 2021. Clinical cases have increased each year since 2016, with the most rapid rise occurring during 2020-2021. CDC has continued to see an increase in case counts for 2022. During 2019-2021, 17 states identified their first C. auris case ever. Nationwide, clinical cases rose from 476 in 2019 to 1,471 in 2021. Screening cases tripled from 2020 to 2021, for a total of 4,041. Screening is important to prevent spread by identifying patients carrying the fungus so that infection prevention controls can be used.

The CDC's Antimicrobial Resistance Laboratory Network, which provides nationwide lab capacity to rapidly detect antimicrobial resistance and inform local responses to prevent spread and protect people, provided some of the data for this report. CDC worked to significantly strengthen laboratory capacity, including in state, territorial, and local health departments, through supplemental funding supported by the American Rescue Plan Act. These efforts include increasing susceptibility testing capacity for C. auris from seven Regional Labs to more than 26 labs nationwide.

CDC continues to work with state, local, and territorial health departments and other partners to address this emerging threat to public health. Review more information on C. auris, the Antimicrobial Resistance Threats Report that identified C. auris as an urgent threat in the United States, or the WHO fungal priority pathogen list that identifies C. auris as a priority globally.

Copyright © CDC. All rights reserved.

Source: Increasing Threat of Spread of Antimicrobial-resistant Fungus in Healthcare Facilities. Centers for Disease Control and Prevention. 2023; 320. Published: March 20, 2023. https://www.cdc.gov/media/releases/2023/p0320-cauris.html.