Loss of Adenomatous polyposis coli function renders intestinal epithelial cells resistant to the cytokine IL-22

Interleukin-22 (IL-22) is a critical immune defence cytokine that maintains intestinal homeostasis and promotes wound healing and tissue regeneration, which can support the growth of colorectal tumours. Mutations in the adenomatous polyposis coli gene (Apc) are a major driver of familial colorectal cancers (CRCs). How IL-22 contributes to APC-mediated tumorigenesis is poorly understood. To investigate IL-22 signalling in wild-type (WT) and APC-mutant cells, we performed RNA sequencing (RNAseq) of IL-22-treated murine small intestinal epithelial organoids. In WT epithelia, antimicrobial defence and cellular stress response pathways were most strongly induced by IL-22. Surprisingly, although IL-22 activates signal transducer and activator of transcription 3 (STAT3) in APC-mutant cells, STAT3 target genes were not induced. Our analyses revealed that ApcMin/Min cells are resistant to IL-22 due to reduced expression of the IL-22 receptor, and increased expression of inhibitors of STAT3, particularly histone deacetylases (HDACs). We further show that IL-22 increases DNA damage and genomic instability, which can accelerate cellular transition from heterozygosity (ApcMin/+) to homozygosity (ApcMin/Min) to drive tumour formation. Our data reveal an unexpected role for IL-22 in promoting early tumorigenesis while excluding a function for IL-22 in transformed epithelial cells

How I report breast magnetic resonance imaging studies for breast cancer staging and screening

Magnetic resonance imaging (MRI) of the breast is the most sensitive imaging technique for the diagnosis and local staging of primary breast cancer and yet, despite the fact that it has been in use for 20 years, there is little evidence that its widespread uncritical adoption has had a positive impact on patient-related outcomes. This has been attributed previously to the low specificity that might be expected with such a sensitive modality, but with modern techniques and protocols, the specificity and positive predictive value for malignancy can exceed that of breast ultrasound and mammography. A more likely explanation is that historically, clinicians have acted on MRI findings and altered surgical plans without prior histological confirmation. Furthermore, modern adjuvant therapy for breast cancer has improved so much that it has become a very tall order to show a an improvement in outcomes such as local recurrence rates. In order to obtain clinically useful information, it is necessary to understand the strengths and weaknesses of the technique and the physiological processes reflected in breast MRI. An appropriate indication for the scan, proper patient preparation and good scan technique, with rigorous quality assurance, are all essential prerequisites for a diagnostically relevant study. The use of recognised descriptors from a standardised lexicon is helpful, since assessment can then dictate subsequent recommendations for management, as in the American College of Radiology BI-RADS (Breast Imaging Reporting and Data System) lexicon (Morris et al., ACR BI-RADS® Atlas, Breast Imaging Reporting and Data System, 2013). It also enables audit of the service. However, perhaps the most critical factor in the generation of a meaningful report is for the reporting radiologist to have a thorough understanding of the clinical question and of the findings that will influence management. This has never been more important than at present, when we are in the throes of a remarkable paradigm shift in the treatment of both early stage and locally advanced breast cancer. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40644-016-0078-0) contains supplementary material, which is available to authorized users

A Multicellular Model of Intestinal Crypt Buckling and Fission

Crypt fission is an in vivo tissue deformation process that is involved in both intestinal homeostasis and colorectal tumourigenesis. Despite its importance, the mechanics underlying crypt fission are currently poorly understood. Recent experimental development of organoids, organ-like buds cultured from crypt stem cells in vitro, has shown promise in shedding light on crypt fission. Drawing inspiration from observations of organoid growth and fission in vivo, we develop a computational model of a deformable epithelial tissue layer. Results from in silico experiments show the stiffness of cells and the proportions of cell subpopulations affect the nature of deformation in the epithelial layer. In particular, we find that increasing the proportion of stiffer cells in the layer increases the likelihood of crypt fission occurring. This is in agreement with and helps explain recent experimental work

Paneth cell - rich regions separated by a cluster of Lgr5+ cells initiate crypt fission in the intestinal stem cell niche

The crypts of the intestinal epithelium house the stem cells that ensure the continual renewal of the epithelial cells that line the intestinal tract. Crypt number increases by a process called crypt fission, the division of a single crypt into two daughter crypts. Fission drives normal tissue growth and maintenance. Correspondingly, it becomes less frequent in adulthood. Importantly, fission is reactivated to drive adenoma growth. The mechanisms governing fission are poorly understood. However, only by knowing how normal fission operates can cancer-associated changes be elucidated. We studied normal fission in tissue in three dimensions using high-resolution imaging and used intestinal organoids to identify underlying mechanisms. We discovered that both the number and relative position of Paneth cells and Lgr5+ cells are important for fission. Furthermore, the higher stiffness and increased adhesion of Paneth cells are involved in determining the site of fission. Formation of a cluster of Lgr5+ cells between at least two Paneth-cell-rich domains establishes the site for the upward invagination that initiates fission

First demonstration of ionization cooling by the muon ionization cooling experiment

High-brightness muon beams of energy comparable to those produced by state-of-the-art electron, proton and ion accelerators have yet to be realised. Such beams have the potential to carry the search for new phenomena in lepton-antilepton collisions to extremely high energy and also to provide uniquely well-characterised neutrino beams. A muon beam may be created through the decay of pions produced in the interaction of a proton beam with a target. To produce a high-brightness beam from such a source requires that the phase space volume occupied by the muons be reduced (cooled). Ionization cooling is the novel technique by which it is proposed to cool the beam. The Muon Ionization Cooling Experiment collaboration has constructed a section of an ionization cooling cell and used it to provide the first demonstration of ionization cooling. We present these ground-breaking measurements

Multiple Coulomb scattering of muons in lithium hydride

Copyright © 2022 the author(s). Multiple Coulomb scattering (MCS) is a well-known phenomenon occurring when charged particles traverse materials. Measurements of muons traversing low Z materials made in the MuScat experiment showed that theoretical models and simulation codes, such as GEANT4 (v7.0), over-estimated the scattering. The Muon Ionization Cooling Experiment (MICE) measured the cooling of a muon beam traversing a liquid hydrogen or lithium hydride (LiH) energy absorber as part of a programme to develop muon accelerator facilities, such as a neutrino factory or a muon collider. The energy loss and MCS that occur in the absorber material are competing effects that alter the performance of the cooling channel. Therefore measurements of MCS are required in order to validate the simulations used to predict the cooling performance in future accelerator facilities. We report measurements made in the MICE apparatus of MCS using a LiH absorber and muons within the momentum range 160 to 245 MeV=c. The measured RMS scattering width is about 9% smaller than that predicted by the approximate formula proposed by the Particle Data Group, but within the latter’s stated uncertainty. Data at 172, 200 and 240 MeV=c are compared to the GEANT4 (v9.6) default scattering model. These measurements show agreement with this more recent GEANT4 (v9.6) version over the range of incident muon momenta.SCOAP

Lattice design and expected performance of the Muon Ionization Cooling Experiment demonstration of ionization cooling

Muon beams of low emittance provide the basis for the intense, well-characterized neutrino beams necessary to elucidate the physics of flavor at a neutrino factory and to provide lepton-antilepton collisions at energies of up to several TeV at a muon collider. The international Muon Ionization Cooling Experiment (MICE) aims to demonstrate ionization cooling, the technique by which it is proposed to reduce the phase-space volume occupied by the muon beam at such facilities. In an ionization-cooling channel, the muon beam passes through a material in which it loses energy. The energy lost is then replaced using rf cavities. The combined effect of energy loss and reacceleration is to reduce the transverse emittance of the beam (transverse cooling). A major revision of the scope of the project was carried out over the summer of 2014. The revised experiment can deliver a demonstration of ionization cooling. The design of the cooling demonstration experiment will be described together with its predicted cooling performance.The work described here was made possible by grants from the Science and Technology Facilities Council (UK), the Department of Energy and National Science Foundation (USA), the Instituto Nazionale di Fisica Nucleare (Italy), the Bulgarian Academy of Sciences, the Chinese Academy of Sciences, the Dutch National Science Foundation, the Ministry of Education, Science and Technological Development of the Republic of Serbia, the European Community under the European Commission Framework Programme 7 (AIDA project, Grant Agreement No. 262025, TIARA project, Grant Agreement No. 261905, and EuCARD), the Japan Society for the Promotion of Science and the Swiss National Science Foundation in the framework of the SCOPES programme. We gratefully acknowledge all sources of support. We are grateful to the support given to us by the staff of the STFC Rutherford Appleton and Daresbury Laboratories