RSPO3 expands intestinal stem cell and niche compartments and drives tumorigenesis

Objective The gross majority of colorectal cancer cases results from aberrant Wnt/ß-catenin signalling through adenomatous polyposis coli (APC) or CTNNB1 mutations. However, a subset of human colon tumours harbour, mutually exclusive with APC and CTNNB1 mutations, gene fusions in RSPO2 or RSPO3, leading to enhanced expression of these R-spondin genes. This suggested that RSPO activation can substitute for the most common mutations as an alternative driver for intestinal cancer. Involvement of RSPO3 in tumour growth was recently shown in RSPO3-fusion-positive xenograft models. The current study determines the extent into which solely a gain in RSPO3 actually functions as a driver of intestinal cancer in a direct, causal fashion, and addresses the in vivo activities of RSPO3 in parallel. Design We generated a conditional Rspo3 transgenic mouse model in which the Rspo3 transgene is expressed upon Cre activity. Cre is provided by cross-breeding with Lgr5-GFP-CreERT2 mice. Results Upon in vivo Rspo3 expression, mice rapidly developed extensive hyperplastic, adenomatous and adenocarcinomatous lesions throughout the intestine. RSPO3 induced the expansion of Lgr5+ stem cells, Paneth cells, non-Paneth cell label-retaining cells and Lgr4+ cells, thus promoting both intestinal stem cell and niche compartments. Wnt/ß-catenin signalling was modestly increased upon Rspo3 expression and mutant Kras synergised with Rspo3 in hyperplastic growth. Conclusions We provide in vivo evidence that RSPO3 stimulates the crypt stem cell and niche compartments and drives rapid intestinal tumorigenesis. This establishes RSPO3 as a potent driver of intestinal cancer and proposes RSPO3 as a candidate target for therapy in patients with colorectal cancer harbouring RSPO3 fusions

Еволюція топоформанта -щина в слов’янських мовах та його рефлекси в реґіональній історичній ойконімії

У статті автор на широкому географічно-історичному тлі простежує еволюцію топоформанта -щина в слов'янській топонімії детально аналізує рефлекси цього суфікса в реґіональній історичній ойконімії на прикладі дев'яти назв (і 12-ти мікроойконімних варіантів) населених пунктів Галицької та Львівської земель Руського воєводства із подальшим встановленням їхньої етимологи.В статье автор на широком географическо-историческом фоне прослеживает эволюцию топонимического форманта -щина в славянской топонимии детально анализирует рефлексы этого суффикса в региональной исторической ойконимии на примере девяти названий (с 12-ю микроойконимными вариантами) населенных пунктов Галицкой и Львовской земель Русского воеводства с последующим установлением их этимологии.The author traces the evolution of topoformant -schyna on the basis of historical and geographical studies in Slavic Toponymy. Reflexes of the suffix are analyzed in regional historical oykonymy in 12 toponyms (and their 12 microokonymic variants) of villages and towns of Halych and Lviv Lands of Ruske Woyewodstwo. Their etymology is also analysed

Intraoperative Assessment of the Resection Specimen Facilitates Achievement of Adequate Margins in Oral Carcinoma

Background: Inadequate resection margins in oral cavity squamous cell carcinoma have an adverse effect on patient outcome. Intraoperative assessment provides immediate feedback enabling the surgeon to achieve adequate resection margins. The goal of this study was to evaluate the value of specimen-driven intraoperative assessment by comparing the margin status in the period before and the period after the introduction of specimen-driven assessment as a standard of care (period 2010–2012 vs period 2013–2017). Methods: A cohort of patients surgically treated for oral squamous cell carcinoma at the Erasmus MC Cancer Institute, Rotterdam, between 2010–2012 was studied retrospectively and compared to results of a prospectively collected cohort between 2013–2017. The frequency, type and results of intraoperative assessment of resection margins were analyzed. Results: One hundred seventy-four patients were included from 2010–2012, 241 patients were included from 2013–2017. An increase in the frequency of specimen-driven assessment was seen between the two periods, from 5% in 2010–2012 to 34% in 2013–2017. When performing specimen-driven assessment, 16% tumor-positive resection margins were found in 2013–2017, compared to 43% tumor-positive resection margins overall in 2010–2012. We found a significant reduction of inadequate resection margins for specimen-driven intraoperative assessment (p < 0.001). Also, tumor recurrence significantly decreased, and dise

Genetic loci influencing kidney function and chronic kidney disease

Using genome-wide association, we identify common variants at 2p12-p13, 6q26, 17q23 and 19q13 associated with serum creatinine, a marker of kidney function (P = 10 10 to 10 15). Of these, rs10206899 (near NAT8, 2p12-p13) and rs4805834 (near SLC7A9, 19q13) were also associated with chronic kidney disease (P = 5.0 × 10 5 and P = 3.6 × 10 4, respectively). Our findings provide insight into metabolic, solute and drug-transport pathways underlying susceptibility to chronic kidney disease

Colorectal liver metastases: Surgery versus thermal ablation (COLLISION) - a phase III single-blind prospective randomized controlled trial

Background: Radiofrequency ablation (RFA) and microwave ablation (MWA) are widely accepted techniques to eliminate small unresectable colorectal liver metastases (CRLM). Although previous studies labelled thermal ablation inferior to surgical resection, the apparent selection bias when comparing patients with unresectable disease to surgical candidates, the superior safety profile, and the competitive overall survival results for the more recent reports mandate the setup of a randomized controlled trial. The objective of the COLLISION trial is to prove non-inferiority of thermal ablation compared to hepatic resection in patients with at least one resectable and ablatable CRLM and no extrahepatic disease. Methods: In this two-arm, single-blind multi-center phase-III clinical trial, six hundred and eighteen patients with at least one CRLM (≤3cm) will be included to undergo either surgical resection or thermal ablation of appointed target lesion(s) (≤3cm). Primary endpoint is OS (overall survival, intention-to-treat analysis). Main secondary endpoints are overall disease-free survival (DFS), time to progression (TTP), time to local progression (TTLP), primary and assisted technique efficacy (PTE, ATE), procedural morbidity and mortality, length of hospital stay, assessment of pain and quality of life (QoL), cost-effectiveness ratio (ICER) and quality-adjusted life years (QALY). Discussion: If thermal ablation proves to be non-inferior in treating lesions ≤3cm, a switch in treatment-method may lead to a reduction of the post-procedural morbidity and mortality, length of hospital stay and incremental costs without compromising oncological outcome for patients with CRLM. Trial registration:NCT03088150 , January 11th 2017

Ground-penetrating radar profiling on embanked floodplains

Management of the Dutch embanked floodplains is of crucial interest in the light of a likely increase of extreme floods. One of the issues is a gradual decrease of floodwater accommodation space as a result of overbank deposition of mud and sand during floods. To address this issue, sediment deposits of an undisturbed embanked floodplain near Winssen along the river Waal were studied using ground-penetrating radar (GPR). A number of radar facies units were recognized. Boreholes were used to relate radar facies units to sedimentary facies and to determine radar velocity. The GPR groundwave is affected by differences in moisture and texture of the top layer and probably interferes with the first subsurface reflector. The architectural elements recognized in the GPR transects confirm earlier reported insights on human-influenced river behaviour. This is testified in the development of sand bars during flood regimes that are probably more widespread than previously established

Ground-penetrating radar profiling on embanked floodplains

Management of the Dutch embanked floodplains is of crucial interest in the light of a likely increase of extreme floods. One of the issues is a gradual decrease of floodwater accommodation space as a result of overbank deposition of mud and sand during floods. To address this issue, sediment deposits of an undisturbed embanked floodplain near Winssen along the river Waal were studied using ground-penetrating radar (GPR). A number of radar facies units were recognized. Boreholes were used to relate radar facies units to sedimentary facies and to determine radar velocity. The GPR groundwave is affected by differences in moisture and texture of the top layer and probably interferes with the first subsurface reflector. The architectural elements recognized in the GPR transects confirm earlier reported insights on human-influenced river behaviour. This is testified in the development of sand bars during flood regimes that are probably more widespread than previously established

The missing link: Predicting connectomes from noisy and partially observed tract tracing data

Contains fulltext : 166548.pdf (publisher's version ) (Open Access)Our understanding of the wiring map of the brain, known as the connectome, has increased greatly in the last decade, mostly due to technological advancements in neuroimaging techniques and improvements in computational tools to interpret the vast amount of available data. Despite this, with the exception of the C. elegans roundworm, no definitive connectome has been established for any species. In order to obtain this, tracer studies are particularly appealing, as these have proven highly reliable. The downside of tract tracing is that it is costly to perform, and can only be applied ex vivo. In this paper, we suggest that instead of probing all possible connections, hitherto unknown connections may be predicted from the data that is already available. Our approach uses a ‘latent space model’ that embeds the connectivity in an abstract physical space. Regions that are close in the latent space have a high chance of being connected, while regions far apart are most likely disconnected in the connectome. After learning the latent embedding from the connections that we did observe, the latent space allows us to predict connections that have not been probed previously. We apply the methodology to two connectivity data sets of the macaque, where we demonstrate that the latent space model is successful in predicting unobserved connectivity, outperforming two baselines and an alternative model in nearly all cases. Furthermore, we show how the latent spatial embedding may be used to integrate multimodal observations (i.e. anterograde and retrograde tracers) for the mouse neocortex. Finally, our probabilistic approach enables us to make explicit which connections are easy to predict and which prove difficult, allowing for informed follow-up studies. Author summary: Tract tracing is a highly accurate procedure for identifying animal brain connectivity. However, the technique is labor intensive and requires the sacrifice of animal subjects. In our work, we describe a computational method that is able to predict the presence or absence of unobserved connections, without having to probe these connections physically. The model works by learning for each of the nodes in the connectome its position in a latent space. Nodes that are connected according to the available data are placed close to one another, while disconnected nodes are positioned far apart. Unobserved connections may now be inferred by looking at the corresponding distance in the latent space. We apply the procedure to two data sets of the macaque brain and show that the latent space model is able to predict the strength of unknown connections. Furthermore, we use the model to integrate anterograde and retrograde data for the mouse connectome. Because the model is probabilistic, it allows us to quantify how certain we are about our predictions. This enables future research to determine which connections can confidently predicted, and which connections require further data acquisition.22 p