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The tumour suppressor APC is the most commonly mutated gene in colorectal cancer. Loss of Apc in intestinal stem cells drives the formation of adenomas in mice via increased WNT signalling.sup.1, but reduced secretion of WNT ligands increases the ability of Apc-mutant intestinal stem cells to colonize a crypt (known as fixation).sup.2. Here we investigated how Apc-mutant cells gain a clonal advantage over wild-type counterparts to achieve fixation. We found that Apc-mutant cells are enriched for transcripts that encode several secreted WNT antagonists, with Notum being the most highly expressed. Conditioned medium from Apc-mutant cells suppressed the growth of wild-type organoids in a NOTUM-dependent manner. Furthermore, NOTUM-secreting Apc-mutant clones actively inhibited the proliferation of surrounding wild-type crypt cells and drove their differentiation, thereby outcompeting crypt cells from the niche. Genetic or pharmacological inhibition of NOTUM abrogated the ability of Apc-mutant cells to expand and form intestinal adenomas. We identify NOTUM as a key mediator during the early stages of mutation fixation that can be targeted to restore wild-type cell competitiveness and provide preventative strategies for people at a high risk of developing colorectal cancer. NOTUM from Apc-mutant cells acts as a key mediator during the early stages of mutation fixation and drives the formation of intestinal adenomas., Author(s): Dustin J. Flanagan [sup.1] , Nalle Pentinmikko [sup.2] [sup.3] , Kalle Luopajärvi [sup.2] [sup.3] , Nicky J. Willis [sup.4] , Kathryn Gilroy [sup.1] [sup.5] , Alexander P. Raven [sup.1] [...]

Background: Nursing, as a profession, is a facet where job satisfaction and performance matter. In the changing landscape of nursing practice in the Philippines and the aftermath of the COVID-19 pandemic, it is imperative to revisit and to perform an empirical investigation of the current state of nurses' job satisfaction and performance in the hospital setting. This study aimed to describe the job satisfaction and performance among staff nurses in private and government hospitals in Baguio City. Design: Using a quantitative descriptive cross-sectional survey design, a sample of 313 randomly selected staff nurses working in two private and two government hospitals in Baguio City were surveyed from March to April 2023, using a questionnaire. This study's protocol was approved by two ethics committees, namely the Saint Louis University Research Ethics Committee and the BGHMC REC. Nominal data was analyzed using the SPSS trial version employing frequencies, percentages, and the Chi-square test. Findings: There are more staff nurses in both private and government hospitals who reported satisfactory job satisfaction levels (276 nurses, 87.9%) and had good job performance (303 nurses, 96.5%) in all domains. However, results show that there are more nurses (209 nurses, 90.7% ) in government hospitals who are satisfied with their jobs than in private hospital nurses (67 nurses, 80.1%) in the domains Intra-practice Partnership/Collegiality (p=0.010); Challenge/Autonomy (p=0.001); Professional, Social and Community Interaction (p=0.010); Professional Growth (p=0.036); Time (p=0.009); and Benefits (p=0.045). In terms of job performance, more government nurses at 97.3% (224 nurses) rated a higher self-appraisal of job performance. In comparison, only 94.8% (79 nurses) of private staff nurses appraised themselves as having good performance. No significant differences were found in the domains of job performance, namely leadership, teaching, planning, communications, and professional development, except in critical care. In "Critical care," which showed significance, the results suggest that more nurses in government hospitals perceive higher job performance, revealing a significant difference (p=0.011) in the "critical care" domain, indicating that a higher proportion of nurses in government hospitals demonstrate superior performance in this area. Conclusion: Through this study, it was learned that nurses in both private and government hospitals generally experience high job satisfaction and performance, reflecting a fulfilled workforce and indicating commendable competency among the staff nurses. However, more nurses in government hospitals report high satisfaction and perceived performance in critical care compared to those in private hospitals. Thus, the findings of this study can contribute to and serve as a rationale for policy-making regarding creating a positive work environment, proper management and leadership, creation of training and skill development for critical care, providing opportunities for professional growth, and conducting regular evaluation and feedback----- all geared towards a satisfied and productive workforce. [ABSTRACT FROM AUTHOR]

Author(s): Alexander Raven; Wei-Yu Lu; Tak Yung Man; Sofia Ferreira-Gonzalez; Eoghan ODuibhir; Benjamin J. Dwyer; John P. Thomson; Richard R. Meehan; Roman Bogorad; Victor Koteliansky; Yuri Kotelevtsev; Charles ffrench-Constant; Luke [...]

The prognosis of cholangiocarcinoma (CC) is dismal. Notch has been identified as a potential driver; forced exogenous overexpression of Notch1 in hepatocytes results in the formation of biliary tumors. In human disease, however, it is unknown which components of the endogenously signaling pathway are required for tumorigenesis, how these orchestrate cancer, and how they can be targeted for therapy. Here we characterize Notch in human-resected CC, a toxindriven model in rats, and a transgenic mouse model in which p53 deletion is targeted to biliary epithelia and CC induced using the hepatocarcinogen thioacetamide. We find that across species, the atypical receptor NOTCH3 is differentially overexpressed; it is progressively up-regulated with disease development and promotes tumor cell survival via activation of PI3k-Akt. We use genetic KO studies to show that tumor growth significantly attenuates after Notch3 deletion and demonstrate signaling occurs via a noncanonical pathway independent of themediator of classical Notch, Recombinant Signal Binding Protein for Immunoglobulin Kappa J Region (RBPJ). These data present an opportunity in this aggressive cancer to selectively target Notch, bypassing toxicities known to be RBPJ dependent. [ABSTRACT FROM AUTHOR]

The article presents a study that explores the Lef1 restricts ectopic crypt formation and tumor cell growth in intestinal adenomas. It mentions that how ectopic Lef1 expression suppresses intestinal tumorigenesis by restricting adenoma cell dedifferentiation to a crypt-progenitor phenotype and by reducing the formation of cancer stem cell niches.