Dysregulated KLF4 expression plays a pivotal role in the pathogenesis of pancreatic intraductal papillary mucinous neoplasms

Intraductal papillary mucinous neoplasms (IPMNs) carry a significant risk of progressing to invasive pancreatic cancer (PC), yet the lack of sensitive and specific biomarkers hampers accurate prognostication and clinical intervention. The prevalence of somatic KLF4 hotspot mutations, notably KLF4K409Q and KLF4S411Y, in over 50% of cases, predominantly in low-grade (LG) regions of IPMNs, suggests a potential role of KLF4 in IPMN pathogenesis. However, critical knowledge gaps persist regarding KLF4 expression in IPMNs, its causal role in pathogenesis and the impact of mutations on KLF4 function. In this study, we conducted an immunohistochemical analysis to characterise KLF4 expression in IPMNs and PC. We found elevated KLF4 levels in IPMNs but reduced expression in PC. Using an established Klf4 conditional transgenic mouse model, we demonstrated that KLF4 overexpression induced pancreatic IPMN-like cystic lesions under Kras mutant conditions. Gene transduction and functional assays revealed that the KLF4K409Q mutant protein maintains its DNA…

Read More

p53 mutation biases squamocolumnar junction progenitor cells towards dysplasia rather than metaplasia in Barretts oesophagus

Background
While p53 mutations occur early in Barrett’s oesophagus (BE) progression to oesophageal adenocarcinoma (EAC), their role in gastric cardia stem cells remains unclear.

Objective
This study investigates the impact of p53 mutation on the fate and function of cardia progenitor cells in BE to EAC progression, particularly under the duress of chronic injury.

Design
We used a BE mouse model (L2-IL1β) harbouring a Trp53 mutation (R172H) to study the effects of p53 on Cck2r+ cardia progenitor cells. We employed lineage tracing, pathological analysis, organoid cultures, single-cell RNA sequencing (scRNA-seq) and computational analyses to investigate changes in progenitor cell behaviour, differentiation patterns and tumour progression. Additionally, we performed orthotopic transplantation of sorted metaplastic and mutant progenitor cells to assess their tumourigenic potential in vivo.

Results
The p53 mutation acts as a switch to expand progenitor cells and inhibit their differentiation towards metaplasia, but only amidst chronic injury. In L2-IL1β mice, p53 mutation increased progenitors expansion and lineage-tracing with a shift from metaplasia to dysplasia. scRNA-seq revealed dysplastic cells arise directly from mutant progenitors rather than progressing through metaplasia. In vitro, p53 mutation enhanced BE progenitors’ organoid-forming efficiency, growth, DNA damage resistance and progression to aneuploidy. Sorted metaplastic cells grew poorly with no progression to dysplasia, while mutant progenitors gave rise to dysplasia in orthotopic transplantation. Computational analyses indicated that p53 mutation inhibited stem cell differentiation through Notch activation.

Conclusions
p53 mutation contributes to BE progression by increasing expansion and fitness of undifferentiated cardia progenitors and preventing their differentiation towards metaplasia.

Read More

Preferences of pregnant women and obstetric healthcare professionals on using noninvasive prenatal testing to predict adverse pregnancy outcomes: a discrete choice experiment

Objectives
Noninvasive prenatal testing (NIPT) to screen for fetal aneuploidies by analysing cell-free DNA in maternal plasma is available to pregnant women worldwide. In the future, the scope of NIPT could potentially be expanded to the prediction of adverse pregnancy outcomes. The objective of this study was to assess and compare the preferences of pregnant women and obstetric healthcare professionals on this new test purpose of NIPT.

Design
A discrete choice experiment was designed to assess participants’ preferences on the use of NIPT to predict adverse pregnancy outcomes regarding three attributes on test characteristics: test accuracy rate, unnecessary intervention rate and false reassurance rate. A questionnaire assessed general attitudes towards using noninvasive prenatal testing to predict adverse pregnancy outcomes.

Setting
Dutch prenatal healthcare system.

Participants
Pregnant women with singleton pregnancies and obstetric healthcare professionals.

Results
In total, 1580 pregnant women and 308 obstetric healthcare professionals participated in the discrete choice experiment. Higher test accuracy, fewer unnecessary interventions and less false reassurance all had a statistically significant (p

Read More