Aryl hydantoin Ro 13-3978, a broad-spectrum antischistosomal

Objectives Praziquantel is the only drug available for the treatment of schistosomiasis and the state of the exhausted drug discovery pipeline is alarming. We restarted investigations on the abandoned antischistosomal Ro 13-3978, an aryl hydantoin discovered in the early 1980s by Hoffmann La-Roche. Methods Newly transformed schistosomula and adult Schistosoma mansoni were studied in the presence of Ro 13-3978 in vitro. The metabolic stability of Ro 13-3978 was determined in vitro using human and mouse liver S9 fractions. Dose-response relationship, stage specificity, hepatic shift and scanning electron microscopy studies were carried out in S. mansoni-infected mice. In addition, efficacy experiments were conducted in rodents infected with Echinostoma caproni and Fasciola hepatica as well as in S. mansoni-infected immunocompromised nude (Foxn1nu) mice. Results Ro 13-3978 showed minor in vitro activity and no damage to the tegument was found. No cytotoxicity was detected for Ro 13-3978. Ro 13-3978 was metabolically stable. ED50 values of 138.9 and 14.6 mg/kg were calculated for the treatment of juvenile and adult S. mansoni infections, respectively, with a single oral dose of Ro 13-3978. SEM studies revealed severe damage to the worms 48 h post-treatment of infected mice. A single oral dose of Ro 13-3978 (100 mg/kg) administered to S. mansoni-infected (Foxn1nu) mice reduced the worm burden by 88%. Ro 13-3978 was not active against E. caproni and F. hepatica in vivo. Conclusions Ro 13-3978 has excellent antischistosomal properties in vivo. Structure-activity relationship studies with the aryl hydantoins have been launched in order to elucidate active pharmacophores, further investigate the mechanism of action and to identify a derivative with minimal antiandrogenic effect

Deep learning to segment liver metastases on CT images: Impact on a radiomics method to predict response to chemotherapy

Predicting response to neo-adjuvant chemotherapy of liver metastases (mts) using CT images is of key importance to provide personalized treatments. However, manual segmentation of mts should be avoid to develop methods that could be integrated into the clinical practice. The aim of this study is to evaluate if and how much automatic segmentation can affect a radiomics-based method to predict response to neoadjuvant chemotherapy of individual liver mts. To this scope, we developed an automatic deep learning method to segment liver mts, based on the U-net architecture, and we compared the classification results of a classifier fed with manual and automatic masks. In the validation set composed of 39 liver mts, the automatic deeplearning algorithm was able to detect 82% of mts, with a median precision of 67%. Using manual and automatic masks, we obtained the same classification in 19/32 mts. In case of mts with largest diameter > 20 mm, the precision of the segmentation does not impact the classification results and we obtained the same classification with both masks. Conversely, with smaller mts, we showed that a Dice coefficient of at least 0.5 should be obtained to extract the same information from the two segmentations. This are very important results in the perspective of using radiomics-based approach to predict response to therapy into clinical practice. Indeed, either precisely manually segment all lesions or refine them after automatic segmentation is a time-consuming task that cannot be performed on a daily basis

Detection of Significant Prostate Cancer Using Target Saturation in Transperineal Magnetic Resonance Imaging/Transrectal Ultrasonography-fusion Biopsy

BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) and targeted biopsies (TBs) facilitate accurate detection of significant prostate cancer (sPC). However, it remains unclear how many cores should be applied per target. OBJECTIVE: To assess sPC detection rates of two different target-dependent magnetic resonance imaging (MRI)/transrectal ultrasonography (TRUS)-fusion biopsy approaches (TB and target saturation [TS]) compared with extended systematic biopsies (SBs). DESIGN, SETTING, AND PARTICIPANTS: Retrospective single-centre outcome of transperineal MRI/TRUS-fusion biopsies of 213 men was evaluated. All men underwent TB with a median of four cores per MRI lesion, followed by a median of 24 SBs, performed by experienced urologists. Cancer and sPC (International Society of Urological Pathology grade group ≥2) detection rates were analysed. TB was compared with SB and TS, with nine cores per target, calculated by the Ginsburg scheme and using individual cores of the lesion and its "penumbra". OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cancer detection rates were calculated for TS, TB, and SB at both lesion and patient level. Combination of SB + TB served as a reference. Statistical differences in prostate cancer (PC) detection between groups were calculated using McNemar's tests with confidence intervals. RESULTS AND LIMITATIONS: TS detected 99% of 134 sPC lesions, which was significantly higher than the detection by TB (87%, p = 0.001) and SB (82%, p < 0.001). SB detected significantly more of the 72 low-risk PC lesions than TB (99% vs 68%, p < 0.001) and 10% (p = 0.15) more than that detected by TS. At a per-patient level, 99% of men harbouring sPC were detected by TS. This was significantly higher than that by TB and SB (89%, p = 0.03 and 81%, p = 0.001, respectively). Limitations include limited generalisability, as a transperineal biopsy route was used. CONCLUSIONS: TS detected significantly more cases of sPC than TB and extended SB. Given that both 99% of sPC lesions and men harbouring sPC were identified by TS, the results suggest that this approach allows to omit SB cores without compromising sPC detection. PATIENT SUMMARY: Target saturation of magnetic resonance imaging-suspicious prostate lesions provides excellent cancer detection and finds fewer low-risk tumours than the current gold standard combination of targeted and systematic biopsies

Orally active antischistosomal early leads identified from the open access malaria box.

BACKGROUND: Worldwide hundreds of millions of schistosomiasis patients rely on treatment with a single drug, praziquantel. Therapeutic limitations and the threat of praziquantel resistance underline the need to discover and develop next generation drugs. METHODOLOGY: We studied the antischistosomal properties of the Medicines for Malaria Venture (MMV) malaria box containing 200 diverse drug-like and 200 probe-like compounds with confirmed in vitro activity against Plasmodium falciparum. Compounds were tested against schistosomula and adult Schistosoma mansoni in vitro. Based on in vitro performance, available pharmacokinetic profiles and toxicity data, selected compounds were investigated in vivo. PRINCIPAL FINDINGS: Promising antischistosomal activity (IC50: 1.4-9.5 µM) was observed for 34 compounds against schistosomula. Three compounds presented IC50 values between 0.8 and 1.3 µM against adult S. mansoni. Two promising early leads were identified, namely a N,N'-diarylurea and a 2,3-dianilinoquinoxaline. Treatment of S. mansoni infected mice with a single oral 400 mg/kg dose of these drugs resulted in significant worm burden reductions of 52.5% and 40.8%, respectively. CONCLUSIONS/SIGNIFICANCE: The two candidates identified by investigating the MMV malaria box are characterized by good pharmacokinetic profiles, low cytotoxic potential and easy chemistry and therefore offer an excellent starting point for antischistosomal drug discovery and development

Detection of the Water Reservoir in a Forming Planetary System

Icy bodies may have delivered the oceans to the early Earth, yet little is known about water in the ice-dominated regions of extra-solar planet-forming disks. The Heterodyne Instrument for the Far-Infrared on-board the Herschel Space Observatory has detected emission from both spin isomers of cold water vapor from the disk around the young star TW Hydrae. This water vapor likely originates from ice-coated solids near the disk surface hinting at a water ice reservoir equivalent to several thousand Earth Oceans in mass. The water's ortho-to-para ratio falls well below that of Solar System comets, suggesting that comets contain heterogeneous ice mixtures collected across the entire solar nebula during the early stages of planetary birth.Comment: 18 pages, 2 figures. Corrected typo in reported mass (in g) of detected water vapor reservoir. All conclusions are unchange

Water in Star-Forming Regions with the Herschel Space Observatory (WISH): Overview of key program and first results

`Water In Star-forming regions with Herschel' (WISH) is a key program on the Herschel Space Observatory designed to probe the physical and chemical structure of young stellar objects using water and related molecules and to follow the water abundance from collapsing clouds to planet-forming disks. About 80 sources are targeted covering a wide range of luminosities and evolutionary stages, from cold pre-stellar cores to warm protostellar envelopes and outflows to disks around young stars. Both the HIFI and PACS instruments are used to observe a variety of lines of H2O, H218O and chemically related species. An overview of the scientific motivation and observational strategy of the program is given together with the modeling approach and analysis tools that have been developed. Initial science results are presented. These include a lack of water in cold gas at abundances that are lower than most predictions, strong water emission from shocks in protostellar environments, the importance of UV radiation in heating the gas along outflow walls across the full range of luminosities, and surprisingly widespread detection of the chemically related hydrides OH+ and H2O+ in outflows and foreground gas. Quantitative estimates of the energy budget indicate that H2O is generally not the dominant coolant in the warm dense gas associated with protostars. Very deep limits on the cold gaseous water reservoir in the outer regions of protoplanetary disks are obtained which have profound implications for our understanding of grain growth and mixing in disks.Comment: 71 pages, 10 figures, PASP, in pres

Circumstellar discs: What will be next?

This prospective chapter gives our view on the evolution of the study of circumstellar discs within the next 20 years from both observational and theoretical sides. We first present the expected improvements in our knowledge of protoplanetary discs as for their masses, sizes, chemistry, the presence of planets as well as the evolutionary processes shaping these discs. We then explore the older debris disc stage and explain what will be learnt concerning their birth, the intrinsic links between these discs and planets, the hot dust and the gas detected around main sequence stars as well as discs around white dwarfs.Comment: invited review; comments welcome (32 pages

Sensitive limits on the abundance of cold water vapor in the DM Tau protoplanetary disk

We performed a sensitive search for the ground-state emission lines of ortho- and para-water vapor in the DM Tau protoplanetary disk using the Herschel/HIFI instrument. No strong lines are detected down to 3sigma levels in 0.5 km/s channels of 4.2 mK for the 1_{10}--1_{01} line and 12.6 mK for the 1_{11}--0_{00} line. We report a very tentative detection, however, of the 1_{10}--1_{01} line in the Wide Band Spectrometer, with a strength of T_{mb}=2.7 mK, a width of 5.6 km/s and an integrated intensity of 16.0 mK km/s. The latter constitutes a 6sigma detection. Regardless of the reality of this tentative detection, model calculations indicate that our sensitive limits on the line strengths preclude efficient desorption of water in the UV illuminated regions of the disk. We hypothesize that more than 95-99% of the water ice is locked up in coagulated grains that have settled to the midplane.Comment: 5 pages, 3 figures. Accepted for publication in the Herschel HIFI special issue of A&