Estrogen related receptor alpha in castration-resistant prostate cancer cells promotes tumor progression in bone

Bone metastases are one of the main complications of prostate cancer and they are incurable. We investigated whether and how estrogen receptor-related receptor alpha (ERRα) is involved in bone tumor progression associated with advanced prostate cancer. By meta-analysis, we first found that ERRα expression is correlated with castration-resistant prostate cancer (CRPC), the hallmark of progressive disease. We then analyzed tumor cell progression and the associated signaling pathways in gain-of-function/loss-of-function CRPC models in vivo and in vitro. Increased levels of ERRα in tumor cells led to rapid tumor progression, with both bone destruction and formation, and direct impacts on osteoclasts and osteoblasts. VEGF-A, WNT5A and TGFβ1 were upregulated by ERRα in tumor cells and all of these factors also significantly and positively correlated with ERRα expression in CRPC patient specimens. Finally, high levels of ERRα in tumor cells stimulated the pro-metastatic factor periostin expression in the stroma, suggesting that ERRα regulates the tumor stromal cell microenvironment to enhance tumor progression. Taken together, our data demonstrate that ERRα is a regulator of CRPC cell progression in bone. Therefore, inhibiting ERRα may constitute a new therapeutic strategy for prostate cancer skeletal-related events

ERRα promotes breast cancer cell dissemination to bone by increasing RANK expression in primary breast tumors

Bone is the most common metastatic site for breast cancer. Estrogen-related-receptor alpha (ERRα) has been implicated in cancer cell invasiveness. Here, we established that ERRα promotes spontaneous metastatic dissemination of breast cancer cells from primary mammary tumors to the skeleton. We carried out cohort studies, pharmacological inhibition, gain-of-function analyses in vivo and cellular and molecular studies in vitro to identify new biomarkers in breast cancer metastases. Meta-analysis of human primary breast tumors revealed that high ERRα expression levels were associated with bone but not lung metastases. ERRα expression was also detected in circulating tumor cells from metastatic breast cancer patients. ERRα overexpression in murine 4T1 breast cancer cells promoted spontaneous bone micro-metastases formation when tumor cells were inoculated orthotopically, whereas lung metastases occurred irrespective of ERRα expression level. In vivo, Rank was identified as a target for ERRα. That was confirmed in vitro in Rankl stimulated tumor cell invasion, in mTOR/pS6K phosphorylation, by transactivation assay, ChIP and bioinformatics analyses. Moreover, pharmacological inhibition of ERRα reduced primary tumor growth, bone micro-metastases formation and Rank expression in vitro and in vivo. Transcriptomic studies and meta-analysis confirmed a positive association between metastases and ERRα/RANK in breast cancer patients and also revealed a positive correlation between ERRα and BRCA1mut carriers. Taken together, our results reveal a novel ERRα/RANK axis by which ERRα in primary breast cancer promotes early dissemination of cancer cells to bone. These findings suggest that ERRα may be a useful therapeutic target to prevent bone metastases

Targeting the ERG oncogene with splice-switching oligonucleotides as a novel therapeutic strategy in prostate cancer

This is the author accepted manuscript. The final version is available from Springer Nature via the DOI in this recordBackground The ERG oncogene, a member of the ETS family of transcription factor encoding genes, is a genetic driver of prostate cancer. It is activated through a fusion with the androgen-responsive TMPRSS2 promoter in 50% of cases. There is therefore significant interest in developing novel therapeutic agents that target ERG. We have taken an antisense approach and designed morpholino-based oligonucleotides that target ERG by inducing skipping of its constitutive exon 4. Methods We designed antisense morpholino oligonucleotides (splice-switching oligonucleotides, SSOs) that target both the 5′ and 3′ splice sites of ERG’s exon 4. We tested their efficacy in terms of inducing exon 4 skipping in two ERG-positive cell lines, VCaP prostate cancer cells and MG63 osteosarcoma cells. We measured their effect on cell proliferation, migration and apoptosis. We also tested their effect on xenograft tumour growth in mice and on ERG protein expression in a human prostate cancer radical prostatectomy sample ex vivo. Results In VCaP cells, both SSOs were effective at inducing exon 4 skipping, which resulted in a reduction of overall ERG protein levels up to 96 h following a single transfection. SSO-induced ERG reduction decreased cell proliferation, cell migration and significantly increased apoptosis. We observed a concomitant reduction in protein levels for cyclin D1, c-Myc and the Wnt signalling pathway member β-catenin as well as a marker of activated Wnt signalling, p-LRP6. We tested the 3′ splice site SSO in MG63 xenografts in mice and observed a reduction in tumour growth. We also demonstrated that the 3′ splice site SSO caused a reduction in ERG expression in a patient-derived prostate tumour tissue cultured ex vivo. Conclusions We have successfully designed and tested morpholino-based SSOs that cause a marked reduction in ERG expression, resulting in decreased cell proliferation, a reduced migratory phenotype and increased apoptosis. Our initial tests on mouse xenografts and a human prostate cancer radical prostatectomy specimen indicate that SSOs can be effective for oncogene targeting in vivo. As such, this study encourages further in vivo therapeutic studies using SSOs targeting the ERG oncogene.Prostate Cancer U

The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Advanced Machine Learning Coupled with Heart-Inter-beat derivatives for Cardiac Arrhythmia Detection

International audienceThis paper presents a novel strategy based on derivatives time series and advanced machine learning for medical decision-support especially for cardiac arrhythmia diagnosis. Most of recent technologies (smartphones, smart watches, etc.) are focusing on a unique source of information extracted from electrocardiography/photoplethysmography (i.e. heat inter-beat (RR) interval time series) coupled with classical pattern recognition methods to build efficient data-driven models. Herein, we demonstrate that the second derivative time series coupled with principal component analysis (PCA) and relevance vector machine (RVM) allow detection of abnormal rhythm. To achieve this aim, four features were extracted from one minute RR time series as well as from their derivatives and were subjected to PCA and RVM. PCA, as explanatory method, has shown that detection of AF arrhythmia became straightforward by targeting the second derivative time series. RVM was optimized through four kernel functions and the best model has reached 99.83% success rate to diagnosis AF and normal rhythm. The proposed approach outperformed several recent studies dealing with automatic AF diagnosis. Therefore, this method, which can be easily embedded in personal monitoring devices for real time cardiac arrhythmia detection, could be adapted for various medical decision-support involving time series recordings

Survenue de symptômes tardifs après un test de provocation par la méthacholine

International audienceThere are few prospective studies available on the development of delayed symptoms following challenge tests with methacholine (MCT) at the currently recommended doses. The objective of this study was to describe the nature and frequency of respiratory symptoms suggestive of bronchospasm developing within 24 hours after a MCT. The study was offered to adult patients who underwent MCT seen consecutively between June and October 2015. Following the test, a questionnaire adapted from the GINA asthma control questionnaire bearing on diurnal and nocturnal symptoms (cough, dyspnoea, wheeze and tightness), was delivered to the patient and the replies collected by telephone 24 hours later. Of the 101 patients included (initial FEV1 2.82 ± 0.79 L), 46 (46 %) were MCT+ and 55 (54 %) MCT−. Among the MCT−, 4 (7 %) presented with immediate symptoms (S+) and 4 (7 %) with delayed symptoms. Among the MCT+ patients, 36 (78 %) presented with immediate symptoms (P < 0.001 compared with the MCT− patients), and 39 (85 %) with delayed symptoms (P < 0.001 compared with the MCT− patients). Delayed symptoms developed with a mean of 5 h 30 after the provocation test. Immediate and delayed symptoms were more frequent in subjects having significant non-specific bronchial hyper-reactivity. Informing patients of the risk of developing delayed symptoms seems useful and allows optimization of their management after a MCT.Peu d’études prospectives sur la survenue de symptômes tardifs (ST) aux doses actuellement recommandées pour les tests de provocation par la méthacholine (TPM) sont disponibles. L’objectif a été de décrire la nature et la fréquence des symptômes respiratoires évocateurs d’un bronchospasme 24 heures après un TPM. L’étude était proposée aux patients adultes adressés consécutivement de juin à octobre 2015 et ayant effectué un TPM. En post-test, un questionnaire, adapté de celui du contrôle de l’asthme du GINA visant au recueil des symptômes diurnes et nocturnes (toux, dyspnée, sibilant, oppression) était remis et les réponses recueillies par téléphone 24 heures après. Sur 101 patients inclus (VEMS initial 2,82 ± 0,79 L), 46 (46 %) étaient TPM+ et 55 (54 %) TPM−. Parmi les TPM−, 4 (7 %) ont présenté des symptômes immédiats (S+) et 4 (7 %) ont présenté des symptômes tardifs (ST+). Parmi les patients TPM+, 36 (78 %) ont présenté des symptômes immédiats (p < 0,001 contre les sujets TPM−) et 39 (85 %) ont présenté des symptômes tardifs (p < 0,001 contre les sujets TPM−). Les symptômes tardifs survenaient en moyenne 5 h 30 après le test de provocation. Les symptômes immédiats et tardifs étaient plus fréquents chez les sujets ayant une hyperréactivité bronchique non spécifique importante. Informer les patients sur le risque de survenue de symptômes respiratoires tardifs apparaît utile et permettra d’optimiser leur prise en charge après un TPM

Fin swimming improves respiratory gas exchange.

International audienceData in the literature suggest that compared to dry-land exercise fin swimming might delay the activation of the anaerobic metabolism. To verify this hypothesis, we explored indirect indices such as the oxygen pulse (VO(2)/HR), carbon dioxide production (VCO(2)), and ventilatory threshold, comparing fin swimming exercise to dry-land cycling. Thirteen participants, experienced or inexperienced in fin swimming, completed an incremental fin swimming exercise and a maximal exercise on a cycloergometer with breath-by-breath measurements of heart rate (HR), ventilation (VE), tidal volume (VT), VO(2), VCO(2), and VO(2)/HR and determination of the ventilatory threshold and maximal oxygen uptake (VO(2)max). Compared to dry-land cycling exercise, fin swimming resulted in elevated or absent ventilatory threshold. Although VO(2)max did not differ in either condition, in fin swimming the maximal HR value was lower (-18%, p=0.0072), maximal VO(2)/HR higher (+20%, p=0.0325), and maximal VCO(2) lower (-17%, p=0.0071). We also measured significant reduction of VE, VT, and HR variations for the same VO(2) increase. This study suggests that the anaerobic muscle metabolism might be delayed in fin swimming. An attenuated chemoreflex drive to the heart and respiratory centres exerted by muscle metabolites might explain the depressed cardiopulmonary response to fin swimming