Wars2 is a determinant of angiogenesis.

Coronary flow (CF) measured ex vivo is largely determined by capillary density that reflects angiogenic vessel formation in the heart in vivo. Here we exploit this relationship and show that CF in the rat is influenced by a locus on rat chromosome 2 that is also associated with cardiac capillary density. Mitochondrial tryptophanyl-tRNA synthetase (Wars2), encoding an L53F protein variant within the ATP-binding motif, is prioritized as the candidate at the locus by integrating genomic data sets. WARS2(L53F) has low enzyme activity and inhibition of WARS2 in endothelial cells reduces angiogenesis. In the zebrafish, inhibition of wars2 results in trunk vessel deficiencies, disordered endocardial-myocardial contact and impaired heart function. Inhibition of Wars2 in the rat causes cardiac angiogenesis defects and diminished cardiac capillary density. Our data demonstrate a pro-angiogenic function for Wars2 both within and outside the heart that may have translational relevance given the association of WARS2 with common human diseases

Author Correction: WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Odours of cancerous mouse congeners: detection and attractiveness

International audienceABSTRACT Chemical communication plays a major role in social interactions. Cancer, by inducing changes in body odours, may alter interactions between individuals. In the framework of research targeting non-invasive methods to detect early stages of cancer development, this study asked whether untrained mice could detect odour changes in cancerous congeners. If yes, were they able to detect cancer at an early developmental stage? Did it influence female preference? Did variations in volatile organic components of the odour source paralleled mice behavioural responses? We used transgenic mice strains developing or not lung cancer upon antibiotic ingestion. We sampled soiled bedding of cancerous mice (CC) and not cancerous mice (NC), at three experimental conditions: before (T0), early stage (T2) and late stage (T12) of cancer development. Habituation/generalisation and two-way preference tests were performed where soiled beddings of CC and NC mice were presented to wild-derived mice. The composition and relative concentration of volatile organic components (VOC) in the two stimuli types were analysed. Females did not show directional preference at any of the experimental conditions, suggesting that cancer did not influence their choice behaviour. Males did not discriminate between CC and NC stimuli at T0 but did so at T2 and T12, indicating that wild-derived mice could detect cancer at an early stage of development. Finally, although the VOC bouquet differed between CC and NC it did not seem to parallel the observed behavioural response suggesting that other types of odorant components might be involved in behavioural discrimination between CC and NC mice

Detection of Volatile Organic Compounds from Preclinical Lung Cancer Mouse Models

International audienceVolatile organic compounds (VOCs) may help detect cancer tumour. This study addressed this question, as well as two methodological issues: 1) repeatability, comparing VOCs profiles obtained with two Solid Phase Micro Extraction (SPME) fibers used simultaneously; 2) detectability of cancer VOCs biomarkers, comparing profiles obtained following 1h versus 24h exposure of SPME fibers. We analyzed VOCs composition of soiled bedding obtained from a lung adenocarcinoma mouse model in which cancer was induced by doxycycline ingestion. We compared the VOCs profile of soiled bedding of cancerous (CC) and non-cancerous (NC) mice, before (T0), after two-weeks (T2) and after twelve weeks (T12) doxycycline ingestion. The results indicate: 1) qualitative and quantitative consistency in VOCs detection by two distinct SPME fibers ; 2) although more VOCs were detected following a 24h compared to 1h SPME exposure, none of the former molecules were related to cancer; 3) doxycycline impacted VOCs emissions in both CC and NC mice; 4) cancer impacted four VOCs at T12 only: the benzaldehyde which showed higher levels in CC mice and the hexan-1-ol and two mice pheromones, the 2 sec -butyl-4,5-dihydrothiazole and the 3,4-dehydro- exo -brevicomine, which showed lower levels in CC mice. Our study points out that the use of two SPME fibers and an extraction duration of 1h may be considered a good compromise allowing detection of cancer biomarkers while easing bench constraints

Urinary VOCs as biomarkers of early stage lung tumour development in mice

Background: Lung cancer is the primary cause of cancer-induced death. In addition to prevention and improved treatment, it has increasingly been established that early detection is critical to successful remission. Objective: The aim of this study was to identify volatile organic compounds (VOCs) in urine that could help diagnose mouse lung cancer at an early stage of its development. Methods: We analysed the VOC composition of urine in a genetically engineered lung adenocarcinoma mouse model with oncogenic EGFR doxycycline-inducible lung-specific expression. We compared the urinary VOCs of 10 cancerous mice and 10 healthy mice (controls) before and after doxycycline induction, every two weeks for 12 weeks, until full-blown carcinomas appeared. We used SPME fibres and gas chromatographymass spectrometry to detect variations in cancer-related urinary VOCs over time. Results: This study allowed us to identify eight diagnostic biomarkers that help discriminate early stages of cancer tumour development (i.e., before MRI imaging techniques could identify it). Conclusion: The analysis of mice urinary VOCs have shown that cancer can induce changes in odour profiles at an early stage of cancer development, opening a promising avenue for early diagnosis of lung cancer in other models

Solutions analytiques aux équations de Saint-Venant pour les études environnementales et hydrauliques

Correction of the list of authorsCompilation of analytic solutions (in 1d and 2d) for free surface flo

Author Correction: WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Porocarcinomas with <i>PAK1/2/3</i> fusions: a series of 12 cases

International audienceAims: Porocarcinoma is a malignant sweat gland tumour differentiated toward the upper part of the sweat duct and may arise from the transformation of a preexisting benign poroma. In 2019, Sekine et al. demonstrated the presence of YAP1::MAML2 and YAP1::NUTM1 fusions in most poromas and porocarcinomas. Recently, our group identified PAK2‐ fusions in a subset of benign poromas. Herein we report a series of 12 porocarcinoma cases harbouring PAK1/2/3 fusions. Methods and Results: Five patients were male and the median age was 79 years (ranges: 59–95). Tumours were located on the trunk ( n = 7), on the thigh ( n = 3), neck ( n = 1), or groin area ( n = 1). Four patients developed distant metastases. Microscopically, seven cases harboured a benign poroma component and a malignant invasive part. Ductal formations were observed in all, while infundibular/horn cysts and cells with vacuolated cytoplasm were detected in seven and six tumours, respectively. In three cases, the invasive component consisted of a proliferation of elongated cells, some of which formed pseudovascular spaces, whereas the others harboured a predominant solid or trabecular growth pattern. Immunohistochemical staining for CEA and EMA confirmed the presence of ducts. Focal androgen receptor expression was detected in three specimens. Whole RNA sequencing evidenced LAMTOR1::PAK1 ( n = 2), ZDHHC5::PAK1 ( n = 2), DLG1::PAK2 , CTDSP1::PAK1 , CTNND1::PAK1 , SSR1::PAK3 , CTNNA1::PAK2 , RNF13::PAK2 , ROBO1::PAK2, and CD47::PAK2 . Activating mutation of HRAS (G13V, n = 3, G13R, n = 1, Q61L, n = 2) was present in six cases. Conclusion: Our study suggests that PAK1/2/3 fusions is the oncogenic driver of a subset of porocarcinomas lacking YAP1 rearrangement