Modeling Lung Carcinoids with Zebrafish Tumor Xenograft

Lung carcinoids are neuroendocrine tumors that comprise well-differentiated typical (TCs) and atypical carcinoids (ACs). Preclinical models are indispensable for cancer drug screening since current therapies for advanced carcinoids are not curative. We aimed to develop a novel in vivo model of lung carcinoids based on the xenograft of lung TC (NCI-H835, UMC-11, and NCI-H727) and AC (NCI-H720) cell lines and patient-derived cell cultures in Tg(fli1a:EGFP)^y1 zebrafish embryos. We exploited this platform to test the anti-tumor activity of sulfatinib. The tumorigenic potential of TC and AC implanted cells was evaluated by the quantification of tumor-induced angiogenesis and tumor cell migration as early as 24 h post-injection (hpi). The characterization of tumor-induced angiogenesis was performed in vivo and in real time, coupling the tumor xenograft with selective plane illumination microscopy on implanted zebrafish embryos. TC-implanted cells displayed a higher pro-angiogenic potential compared to AC cells, which inversely showed a relevant migratory behavior within 48 hpi. Sulfatinib inhibited tumor-induced angiogenesis, without affecting tumor cell spread in both TC and AC implanted embryos. In conclusion, zebrafish embryos implanted with TC and AC cells faithfully recapitulate the tumor behavior of human lung carcinoids and appear to be a promising platform for drug screening.     

Vandetanib versus Cabozantinib in Medullary Thyroid Carcinoma: A Focus on Anti-Angiogenic Effects in Zebrafish Model

Medullary thyroid carcinoma (MTC) is a tumor deriving from the thyroid C cells. Vandetanib (VAN) and cabozantinib (CAB) are two tyrosine kinase inhibitors targeting REarranged during Transfection (RET) and other kinase receptors and are approved for the treatment of advanced MTC. We aim to compare the in vitro and in vivo anti-tumor activity of VAN and CAB in MTC. The effects of VAN and CAB on viability, cell cycle, and apoptosis of TT and MZ-CRC-1 cells are evaluated in vitro using an MTT assay, DNA flow cytometry with propidium iodide, and Annexin V-FITC/propidium iodide staining, respectively. In vivo, the anti-angiogenic potential of VAN and CAB is evaluated in Tg(fli1a:EGFP)^y1 transgenic fluorescent zebrafish embryos by analyzing the effects on the physiological development of the sub-intestinal vein plexus and the tumor-induced angiogenesis after TT and MZ-CRC-1 xenotransplantation. VAN and CAB exert comparable effects on TT and MZ-CRC-1 viability inhibition and cell cycle perturbation, and stimulated apoptosis with a prominent effect by VAN in MZ-CRC-1 and CAB in TT cells. Regarding zebrafish, both drugs inhibit angiogenesis in a dose-dependent manner, in particular CAB shows a more potent anti-angiogenic activity than VAN. To conclude, although VAN and CAB show comparable antiproliferative effects in MTC, the anti-angiogenic activity of CAB appears to be more relevant.     

Stable tracer investigations in humans for assessing the biokinetics of ruthenium and zirconium radionuclides

The interest in the biokinetics of ruthenium and zirconium in humans is justified by the potential radiological risk represented by their radionuclides. Only a few data related to the biokinetics of ruthenium and zirconium in humans are available and, accordingly, the biokinetic models currently recommended by the ICRP for these elements are mainly based on data from animal experiments. The use of stable isotopes as tracers, coupled with a proper analytical technique (nuclear activation analysis with protons) for their determination in biological samples, represents an ethically acceptable methodology for biokinetic investigations, being free from any radiation risk for the volunteer subjects. In this work, the results obtained in eight biokinetic investigations for ruthenium, conducted on a total of three healthy volunteers, and six for zirconium, performed on a total of three subjects, are presented and compared to the predictions of the ICRP models.     

Non-destructive examination of the bonding interface in DEMO divertor fingers

Plasma facing components (PFCs) with tungsten (W) armor materials for DEMO divertor require a high heat flux removal capability (at least 10 MW/m² in steady-state conditions). The reference divertor PFC concept is a finger with a tungsten tile as a protection and sacrificial layer brazed to a thimble made of tungsten alloy W – 1% La₂O₃ (WL10). Defects may be located at the W thimble to W tile interface. As the number of fingers is considerable (>250,000), it is then a major issue to develop a reliable control procedure in order to control with a non-destructive examination the fabrication processes. The feasibility for detecting defect with infrared thermography SATIR test bed is presented. SATIR is based on the heat transient method and is used as an inspection tool in order to assess component heat transfer capability. SATIR tests were performed on fingers integrating or not the complex He cooling system (steel cartridge with jet holes). Millimeter size artificial defects were manufactured and their detectability was evaluated. Results of this study demonstrate that the SATIR method can be considered as a relevant non-destructive technique examination for the defect detection of DEMO divertor fingers.     

Cisplatin-cyclophosphamide-mitomycin combination chemotherapy with supportive care versus supportive care alone for treatment of metastatic non-small-cell lung cancer

BACKGROUND: Patients with TNM stage IV non-small-cell lung cancer have short survival times. Previous controlled studies comparing chemotherapy and supportive care for the treatment of this type of cancer have not given consistent results, have included patients with different disease stages, and have rarely reported drug dose intensity. PURPOSE: The present trial was designed to assess the safety and the effect on survival of supportive care alone versus chemotherapy with cisplatin, cyclophosphamide, and mitomycin combined with appropriate supportive care in patients with stage IV non-small-cell lung cancer. METHODS: Patients (n = 102) with stage IV non-small-cell lung cancer were randomly assigned to one of two treatment regimens. The combined modality group (52 patients) received supportive care along with cisplatin (75 mg/m2), cyclophosphamide (400 mg/m2), and mitomycin (10 mg/m2) given intravenously at 3-week intervals. The supportive care group (50 patients) received supportive care alone. Randomization was stratified on the basis of histology (squamous versus nonsquamous cell carcinoma), performance status (Karnofsky), and weight loss (during the 6 months preceding randomization). The two groups were well matched for age and sex. Survival analysis was performed after the last patient died. RESULTS: The median number of chemotherapy cycles was 3.5 per patient. Mean weekly delivered doses of drugs were as follows: cisplatin, 22.1 mg/m2; cyclophosphamide, 118 mg/m2; and mitomycin, 2.9 mg/m2. Toxic effects due to chemotherapy were generally mild, but peripheral neuropathy and hematologic and renal toxic effects were observed. In the supportive care group, mean survival was 6.1 months (median, 4.0 months); six patients lived at least 12 months and two lived at least 18 months. In the combined modality group, mean survival was 11.3 months (median, 8.5 months); 20 patients lived at least 12 months, 13 lived at least 18 months, and five lived at least 24 months. Difference in survival was statistically significant (P < .0001). Survival was directly related to initial performance status in both groups (P < .01) and was significantly (P < .01) longer for patients with squamous cell carcinoma than for those with nonsquamous cell carcinoma. CONCLUSIONS: The combination of supportive care and cisplatin-cyclophosphamide-mitomycin therapy offers a survival advantage over supportive care alone in patients with advanced non-small-cell lung cancer. IMPLICATIONS: Metastatic non-small-cell lung cancer, generally considered to be unresponsive or marginally responsive to chemotherapy, can be treated with chemotherapy, with an expectation of prolonging patient survival. Although the results of the present study are encouraging, clinical research should continue to be directed toward developing more effective treatments for this disease.     

The use of alpha-Al2O3:C in Risø OSL single grains attachment system for assessing the spatial dose rate distribution due to incorporation of 90Sr in human teeth

The possibility of using a single grain OSL attachment system developed by the Ris? National Laboratory (Roskilde, Denmark) for assessing the spatial distribution of radionuclides incorporated in human tissues was investigated. Detectors containing arrays of single grains of alpha-Al2O3)C powder (Landauer Inc., USA) were prepared using aluminium discs (diameter 9.7 mm), which can accommodate 100 single grains in 0.3 mm holes positioned in a 10 x 10 grid. The luminescence and dosimetric properties of each grain were investigated by exposing the detectors to uniform photon radiation fields. After the characterisation of the detectors, the systems were tested to assess the spatial dose rate distribution because of 90Sr incorporated in a tooth sample extracted from an inhabitant of the Techa River region.     

Modelling urinary excretion of molybdenum after oral and intravenous administration of stable tracers

An extensive study using stable isotopes of molybdenum as tracers was undertaken to investigate intestinal uptake, systemic kinetics and urinary excretion of molybdenum in healthy human volunteers. In total 63 experiments with 17 volunteers were performed administering the tracers in different chemical forms and measuring their concentrations in blood plasma and urine samples by means of activation analysis and mass spectrometry. Molybdenum was eliminated very rapidly from the circulation. The amount eliminated via the renal pathway was observed to be dependent on several factors, such as form and modality of administration and also the total amount of circulating molybdenum. The fact that the urinary excretion patterns diverged significantly from the current predictions of the International Commission on Radiological Protection model might be relevant when using the model for retrospective intake assessments in case of an accident. On the basis of the experimental data, a more realistic compartmental structure has been presented.     

Decision procedures for elementary sublanguages of set theory: X. Multilevel syllogistic extended by the singleton and powerset operators

The class of unquantified formulae of set theory involving Boolean operators, the powerset and singleton operators, and the equality and membership predicates is shown to have a solvable satisfiability problem.It is shown that whenever a formula in the above class is satisfiable there exists a hereditarily finite model of , whose rank is bounded by a doubly exponential expression in the number of variables occurring in .This paper was written while the author was a Visiting Professor at Courant Institute of Mathematical Sciences, New York University, U.S.A.     

Estimating the number of remaining links in traceability recovery

Although very important in software engineering, establishing traceability links between software artifacts is extremely tedious, error-prone, and it requires significant effort. Even when approaches for automated traceability recovery exist, these provide the requirements analyst with a, usually very long, ranked list of candidate links that needs to be manually inspected. In this paper we introduce an approach called Estimation of the Number of Remaining Links (ENRL) which aims at estimating, via Machine Learning (ML) classifiers, the number of remaining positive links in a ranked list of candidate traceability links produced by a Natural Language Processing techniques-based recovery approach. We have evaluated the accuracy of the ENRL approach by considering several ML classifiers and NLP techniques on three datasets from industry and academia, and concerning traceability links among different kinds of software artifacts including requirements, use cases, design documents, source code, and test cases. Results from our study indicate that: (i) specific estimation models are able to provide accurate estimates of the number of remaining positive links; (ii) the estimation accuracy depends on the choice of the NLP technique, and (iii) univariate estimation models outperform multivariate ones.