Erratum to 'Core Biopsies from Prostate Cancer Patients in Active Surveillance Protocols Harbor PTEN and MYC Alterations'[European Urology Oncology 2 (2019) 277-285].

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The efficacy of imatinib mesylate in patients with FIP1L1-PDGFRα-positive hypereosinophilic syndrome. Results of a multicenter prospective study

BACKGROUND AND OBJECTIVES: The hypereosinophilic syndrome (HES) may be associated with the fusion of the platelet derived growth factor receptor a (PDGFRalpha) gene with the FIP1L1 gene in chromosome 4 coding for a constitutively activated PDGFRalpha tyrosine kinase. These cases with FIP1L1-PDGFRalpha rearrangement have been reported to be very sensitive to the tyrosine kinase inhibitor imatinib mesylate. DESIGN AND METHODS: A prospective multicenter study of idiopathic or primary HES was established in 2001 (Study Protocol Registration no. NCT 0027 6929). One hundred and ninety-six patients were screened, of whom 72 where identified as having idiopathic or primary HES and 63 were treated with imatinib 100 to 400 mg daily. RESULTS: Twenty-seven male patients carried the FIP1L1-PDGFRalpha rearrangement. All 27 achieved a complete hematologic remission (CHR) and became negative for the fusion transcripts according to reverse transcriptase polymerase chain reaction (RT-PCR) analysis. With a median follow-up of 25 months (15-60 months) all 27 patients remain in CHR and RT-PCR negative, and continue treatment at a dose of 100 to 400 mg daily. In three patients imatinib treatment was discontinued for few months, the fusion transcript became rapidly detectable, and then again undetectable upon treatment reassumption. Thirty-six patients did not carry the rearrangement; of these, five (14%) achieved a CHR, which was lost in all cases after 1 to 15 months. INTERPRETATION AND CONCLUSIONS: All patients meeting the criteria for idiopathic or primary HES should be screened for the FIP1L1-PDGFRalpha rearrangement. For all patients with this rearrangement, chronic imatinib treatment at doses as low as 100 mg daily ensures complete and durable responses

Impact assessment support study for the review of the Community guidelines on State aid for railway undertakings

In the wake of stagnant modal share of the European rail freight sector, this support study provides market information for the revision of the Guidelines on State aid for railway undertakings. It addresses four areas of interest: status of rail infrastructure; accessibility and costs pertaining to rolling stock; profitability and demand elasticity of rail freight ser- vices; and effectiveness of State support measures. A novel dataset of costs and revenues of rail freight across Europe, compiled using both publicly available data and input from extensive stakeholder consultation was built for that purpose. The findings are as follows. The inadequacy of intermodal terminals, congested rail networks, and costliness of private sidings all restrict the capacity of European rail infrastructure. Access to rolling stock is characterised by high costs and a lack of technical standardisation across Member States. We find that rail freight sectors in many countries are loss-making, with some segments being profitable. Efficient transshipment and transport of high freight volumes over long distances improves profitability of intermodal operations. The study shows that price sen- sitivity of rail freight services differs depending on the level of competition faced by road transport. The study also highlights to what extent higher thresholds for proportionate State aid and improved flexibility of schemes could be considered

A Deep Learning Approach Validates Genetic Risk Factors for Late Toxicity After Prostate Cancer Radiotherapy in a REQUITE Multi-National Cohort.

Background: REQUITE (validating pREdictive models and biomarkers of radiotherapy toxicity to reduce side effects and improve QUalITy of lifE in cancer survivors) is an international prospective cohort study. The purpose of this project was to analyse a cohort of patients recruited into REQUITE using a deep learning algorithm to identify patient-specific features associated with the development of toxicity, and test the approach by attempting to validate previously published genetic risk factors. Methods: The study involved REQUITE prostate cancer patients treated with external beam radiotherapy who had complete 2-year follow-up. We used five separate late toxicity endpoints: ≥grade 1 late rectal bleeding, ≥grade 2 urinary frequency, ≥grade 1 haematuria, ≥ grade 2 nocturia, ≥ grade 1 decreased urinary stream. Forty-three single nucleotide polymorphisms (SNPs) already reported in the literature to be associated with the toxicity endpoints were included in the analysis. No SNP had been studied before in the REQUITE cohort. Deep Sparse AutoEncoders (DSAE) were trained to recognize features (SNPs) identifying patients with no toxicity and tested on a different independent mixed population including patients without and with toxicity. Results: One thousand, four hundred and one patients were included, and toxicity rates were: rectal bleeding 11.7%, urinary frequency 4%, haematuria 5.5%, nocturia 7.8%, decreased urinary stream 17.1%. Twenty-four of the 43 SNPs that were associated with the toxicity endpoints were validated as identifying patients with toxicity. Twenty of the 24 SNPs were associated with the same toxicity endpoint as reported in the literature: 9 SNPs for urinary symptoms and 11 SNPs for overall toxicity. The other 4 SNPs were associated with a different endpoint. Conclusion: Deep learning algorithms can validate SNPs associated with toxicity after radiotherapy for prostate cancer. The method should be studied further to identify polygenic SNP risk signatures for radiotherapy toxicity. The signatures could then be included in integrated normal tissue complication probability models and tested for their ability to personalize radiotherapy treatment planning

Electrophysiological correlates of non-conscious face processing. A systematic review.

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Normative values for esophageal functional lumen imaging probe measurements: A meta-analysis

Background: The functional lumen imaging probe (Endoflip™) is increasingly used for evaluation of patients with esophageal symptoms. To improve the interpretation of Endoflip™ in clinical practice, normative values with appropriate cut-off values are required. Methods: Original clinical studies describing Endoflip™ use for measurements of esophageal motility in healthy adults were considered. Meta-analysis was performed based on published values. Results: A total of 17 articles were included in the systematic review, 15 of which were included in the meta-analysis, representing 154 unique subjects. At 40 ml distention, the 5th–95th and 10th–90th percentiles for esophagogastric junction distensibility index (EGJ-DI) were 1.96–10.95 mm2/mmHg and 2.36–8.95 mm2/mmHg, respectively. An EGJ-DI below 2 mm2/mmHg was found in 5.4%, and below 3 mm2/mmHg in 20.1% of healthy subjects. At 50 ml distention, the 5th–95th and 10th–90th percentiles for EGJ-DI are 2.86–10.66 mm2/mmHg and 3.28–9.12 mm2/mmHg, respectively (below 2 mm2/mmHg: 0.6%, 3 mm2/mmHg: 6.3%). The 5th–95th and 10th–90th percentiles for EGJ-DI at 60 ml distention were 3.06–8.14 mm2/mmHg and 3.33–7.18 mm2/mmHg, respectively (below 2 mm2/mmHg: 0.0%, 3 mm2/mmHg: 7%). A clear cut-off for lower values was identified while a large spread in values was observed for upper limits of normal for EGJ-DI for all filling volumes. Conclusions: Given these observations, we recommend using a cut-off of 2 mm2/mmHg for clinical practice, values below can be considered abnormal. Given that 5.4% of the healthy subjects will have an EGJ-DI below 2 mm2/mmHg at 40 ml, we recommend using the 50 and 60 ml distention volumes. The clinical use of an upper limit for normality of EGJ-DI seems questionable

Prediction of late radiotherapy toxicity in prostate cancer patients via joint analysis of SNPs sequences

Negli ultimi decenni, la ricerca oncologica e le tecniche di radioterapia hanno visto miglioramenti sostanziali. Tuttavia, molti dei trattamenti utilizzati soffrono al momento di effetti collaterali blandi e severi. Concentrandoci sul caso della radioterapia per pazienti con cancro alla prostata, indaghiamo la possibilità, già suggerita da ricerche precedenti, di predire la radiotossicità tardiva attraverso fattori genetici. Quindi, costruiamo e validiamo un indicatore di radiosensibilità basato sull’analisi di sequenze di SNPs (Single Nucleotide Polimorphism). Diversamente da altri lavori in letteratura, teniamo esplicitamente conto di possibili interazioni tra SNPs e forniamo uno score finale facilmente incorporabile in modelli con predittori aggiuntivi.Over the past few decades, oncological research and radiotherapy techniques have experienced massive improvements. However, many treatments that are currently used suffer from mild to severe side-effects. Focusing on the case of radiotherapy for prostate cancer patients, we assess the already suggested possibility of predicting long-term radiotoxicity through genomic factors. We construct and validate a radiosensitivity indicator that is based on the analysis of SNPs (Single Nucleotide Polimorphism) sequences. Differently from previous works, we directly account for interactions among SNPs and provide a final score that can be easily incorporated into larger models that allow for additional predictors

N2FXm, a method for joint nuclear and cytoplasmic volume measurements, unravels the osmo-mechanical regulation of nuclear volume in mammalian cells

Abstract In eukaryotes, cytoplasmic and nuclear volumes are tightly regulated to ensure proper cell homeostasis. However, current methods to measure cytoplasmic and nuclear volumes, including confocal 3D reconstruction, have limitations, such as relying on two-dimensional projections or poor vertical resolution. Here, to overcome these limitations, we describe a method, N2FXm, to jointly measure cytoplasmic and nuclear volumes in single cultured adhering human cells, in real time, and across cell cycles. We find that this method accurately provides joint size over dynamic measurements and at different time resolutions. Moreover, by combining several experimental perturbations and analyzing a mathematical model including osmotic effects and tension, we show that N2FXm can give relevant insights on how mechanical forces exerted by the cytoskeleton on the nuclear envelope can affect the growth of nucleus volume by biasing nuclear import. Our method, by allowing for accurate joint nuclear and cytoplasmic volume dynamic measurements at different time resolutions, highlights the non-constancy of the nucleus/cytoplasm ratio along the cell cycle