Tracing oncogene-driven remodelling of the intestinal stem cell niche.

Interactions between tumour cells and the surrounding microenvironment contribute to tumour progression, metastasis and recurrence1-3. Although mosaic analyses in Drosophila have advanced our understanding of such interactions4,5, it has been difficult to engineer parallel approaches in vertebrates. Here we present an oncogene-associated, multicolour reporter mouse model-the Red2Onco system-that allows differential tracing of mutant and wild-type cells in the same tissue. By applying this system to the small intestine, we show that oncogene-expressing mutant crypts alter the cellular organization of neighbouring wild-type crypts, thereby driving accelerated clonal drift. Crypts that express oncogenic KRAS or PI3K secrete BMP ligands that suppress local stem cell activity, while changes in PDGFRloCD81+ stromal cells induced by crypts with oncogenic PI3K alter the WNT signalling environment. Together, these results show how oncogene-driven paracrine remodelling creates a niche environment that is detrimental to the maintenance of wild-type tissue, promoting field transformation dominated by oncogenic clones.Royal Societ

Defining the Identity and Dynamics of Adult Gastric Isthmus Stem Cells.

The gastric corpus epithelium is the thickest part of the gastrointestinal tract and is rapidly turned over. Several markers have been proposed for gastric corpus stem cells in both isthmus and base regions. However, the identity of isthmus stem cells (IsthSCs) and the interaction between distinct stem cell populations is still under debate. Here, based on unbiased genetic labeling and biophysical modeling, we show that corpus glands are compartmentalized into two independent zones, with slow-cycling stem cells maintaining the base and actively cycling stem cells maintaining the pit-isthmus-neck region through a process of "punctuated" neutral drift dynamics. Independent lineage tracing based on Stmn1 and Ki67 expression confirmed that rapidly cycling IsthSCs maintain the pit-isthmus-neck region. Finally, single-cell RNA sequencing (RNA-seq) analysis is used to define the molecular identity and lineage relationship of a single, cycling, IsthSC population. These observations define the identity and functional behavior of IsthSCs.Wellcome Trust Royal Societ

Tracing oncogene-driven remodelling of the intestinal stem cell niche

Interactions between tumour cells and the surrounding microenvironment contribute to tumour progression, metastasis and recurrence(1-3). Although mosaic analyses in Drosophila have advanced our understanding of such interactions(4,5), it has been difficult to engineer parallel approaches in vertebrates. Here we present an oncogene-associated, multicolour reporter mouse model-the Red2Onco system-that allows differential tracing of mutant and wild-type cells in the same tissue. By applying this system to the small intestine, we show that oncogene-expressing mutant crypts alter the cellular organization of neighbouring wild-type crypts, thereby driving accelerated clonal drift. Crypts that express oncogenic KRAS or PI3K secrete BMP ligands that suppress local stem cell activity, while changes in PDGFR(lo)CD81(+) stromal cells induced by crypts with oncogenic PI3K alter the WNT signalling environment. Together, these results show how oncogene-driven paracrine remodelling creates a niche environment that is detrimental to the maintenance of wild-type tissue, promoting field transformation dominated by oncogenic clones.1

Effect of statin on progression of symptomatic basilar artery stenosis and subsequent ischemic stroke

<div><p>Background and objective</p><p>Symptomatic basilar artery stenosis (BAS) is associated with high risk of ischemic stroke recurrence. We aimed to investigate whether statin therapy might prevent the progression of symptomatic BAS and stroke recurrence.</p><p>Methods</p><p>We retrospectively analyzed the data of patients with acute ischemia with symptomatic BAS, which was assessed using magnetic resonance angiogram (MRA) imaging on admission day, and 1 year later (or the day of the clinical event). The clinical endpoints were recurrent ischemic stroke and its composites, transient ischemic attack, coronary disease, and vascular death.</p><p>Results</p><p>Of the 153 patients with symptomatic BAS, 114 (74.5%) were treated with a statin after experiencing a stroke. Statin therapy significantly prevented the progression of symptomatic BAS (7.0% vs 28.2%) and induced regression (22.8% vs 15.4%) compared to non-statin users (p = 0.002). There were 31 ischemic stroke incidences and 38 composite vascular events. Statin users showed significantly lower stroke recurrence (14.9% vs 35.9%, p = 0.05) and composite vascular events (17.5% vs 46.2%; odds ratio [OR], 0.29; 95% confidence interval [CI], 0.13–0.64) than those not using statins did. Recurrent stroke in the basilar territory and composite vascular events were more common in patients with progression of BAS than they were in other patients (OR, 5.16; 95% CI, 1.63–16.25 vs OR, 4.2; 95% CI, 1.56–11.34).</p><p>Conclusion</p><p>Our study suggests that statin therapy may prevent the progression of symptomatic BAS and decrease the risk of subsequent ischemic stroke. Large randomized trials are needed to confirm this result.</p></div

Outcome of symptomatic basilar artery disease according to statin treatment.

<p>Outcome of symptomatic basilar artery disease according to statin treatment.</p

The change of basilar stenosis by lipid profile and clinical events.

<p>The change of basilar stenosis by lipid profile and clinical events.</p

Baseline and follow-up three-dimensional (3D) time-of-flight magnetic resonance angiogram (MRA) of intracranial stenosis.

<p>A) Stationary, (B) regression, and (C) progression.</p

Baseline characteristics of patients who were treated with statin and those who were not.

<p>Baseline characteristics of patients who were treated with statin and those who were not.</p