The BeppoSAX HELLAS survey: on the nature of faint hard X-ray selected sources

The BeppoSAX 4.5-10 keV High Energy Large Area Survey has covered about 80 square degrees of sky down to a flux of F(5-10keV)~5E-14 cgs. Optical spectroscopic identification of about half of the sources in the sample (62) shows that many (~50%) are highly obscured AGN, in line with the predictions of AGN synthesis models for the hard X-ray background (XRB, see e.g. Comastri et al. 1995). The X-ray data, complemented by optical, near-IR and radio follow-up, indicate that the majority of these AGN are ``intermediate'' objects, i.e. type 1.8-1.9 AGN,`red' quasars, and even a few broad line, blue continuum quasars, obscured in X-rays by columns of the order of logNH=22.5-23.5 cm-2, but showing a wide dispersion in optical extinction. The optical and near-IR photometry of the obscured objects are dominated by galaxy starlight, indicating that a sizeable fraction of the accretion power in the Universe may actually have been missed in optical color surveys. This also implies that multicolor photometry techniques may be efficiently used to assess the redshift of the hard X-ray selected sources.Comment: 9 pages, Invited talk to appear in the Proceedings of the Conference X-ray Astronomy '999: Stellar Endpoints, AGNs and the Diffuse X-ray Background. (September 6-10 - 1999

Lenvatinib exhibits antineoplastic activity in anaplastic thyroid cancer in vitro and in vivo

Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor (TKI) of VEGFR1-VEGFR3, FGFR1-FGFR4, PDGFRα, RET and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) signaling networks involved in tumor angiogenesis. We have evaluated the antitumor activity of lenvatinib in primary anaplastic thyroid cancer (ATC) cells, in the human cell line 8305C (undifferentiated thyroid cancer) and in an ATC-cell line (AF). The AF cell line was obtained from the primary ATC cultures and was the one that grew over 50 passages. The effect of lenvatinib (1 and 100 nM; and 1, 10, 25 and 50 μM) was investigated in primary ATC, 8305C and AF cells as well as in AF cells in CD nu/nu mice. Lenvatinib significantly reduced ATC cell proliferation (P<0.01, ANOVA) and increased the percentage of apoptotic ATC cells (P<0.001, ANOVA). Furthermore, lenvatinib inhibited migration (P<0.01) and invasion (P<0.001) in ATC. In addition, lenvatinib inhibited EGFR, AKT and ERK1/2 phosphorylation and downregulated cyclin D1 in the ATC cells. Lenvatinib also significantly inhibited 8305C and AF cell proliferation, increasing apoptosis. AF cells were subcutaneously injected into CD nu/nu mice and tumor masses were observed 20 days later. Tumor growth was significantly inhibited by lenvatinib (25 mg/kg/day), as well as the expression of VEGF-A and microvessel density in the AF tumor tissues. In conclusion, the antitumor and antiangiogenic activities of lenvatinib may be promising for the treatment of anaplastic thyroid cancer, and may consist a basis for future clinical therapeutic applications

Vandetanib has antineoplastic activity in anaplastic thyroid cancer, in vitro and in vivo

The antitumor activity of vandetanib [a multiple signal transduction inhibitor including the RET tyrosine kinase, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) receptor (VEGFR), ERK and with antiangiogenic activity], in primary anaplastic thyroid cancer (ATC) cells, in the human cell line 8305C [undifferentiated thyroid cancer (TC)] and in an ATC-cell line (AF), was investigated in the present study. Vandetanib (1 and 100 nM; 1, 10, 25 and 50 μM) was tested by WST-1, apoptosis, migration and invasion assays: in primary ATC cells, in the 8305C continuous cell line, and in AF cells; and in 8305C cells in CD nu/nu mice. Vandetanib significantly reduced ATC cell proliferation (P<0.01, ANOVA), induced apoptosis dose-dependently (P<0.001, ANOVA), and inhibited migration (P<0.01) and invasion (P<0.001). Furthermore, vandetanib inhibited EGFR, AKT and ERK1/2 phosphorylation and downregulated cyclin D1 in ATC cells. In 8305C and AF cells, vandetanib significantly inhibited the proliferation, inducing also apoptosis. 8305C cells were injected subcutaneously in CD nu/nu mice and tumor masses became detectable after 30 days. Vandetanib (25 mg/kg/day) significantly inhibited tumor growth and VEGF-A expression and microvessel density in 8305C tumor tissues. In conclusion, the antitumor and antiangiogenic activity of vandetanib is very auspicious in ATC, opening the way to a future clinical evaluation

The BeppoSAX High Energy Large Area Survey -V. The nature of the hard X-ray source populations and its evolution

We present optical spectroscopic identifications of hard X-ray (5-10 keV) selected sources belonging to the HELLAS sample obtained with BeppoSAX down to a 5-10 keV flux limit of f_{5-10 keV}~3x10^-14 erg cm^-2 s^-1. The sample consists of 118 sources. 25 sources have been identified trough correlations with catalogues of known sources. 49 have been searched for spectroscopic identification at the telescope. 13 fields resulted empty down to R=21. 37 sources have been identified with type 1 AGN and 9 with type 2 AGN. The remaining are: 5 narrow emission line galaxies, 6 Clusters, 2 BL Lac, 1 Radio Galaxy and 1 Star. Combining these objects with other hard X-ray selected AGNs from ASCA and HEAO1, we find that the local luminosity function of type 1 AGN in the 2-10 keV band is fairly well represented by a double-power-law-function. There is evidence for significant cosmological evolution according to a pure luminosity evolution (PLE) model L_X(z)~(1+z)^k, with k=2.12 and k=2.22 in a (Omega_m,Omega_lambda)=(1.0,0.0) and in a (Omega_m,Omega_lambda)=(0.3,0.7) cosmology, respectively. The data show an excess of faint high redshift type 1 AGN which is well modeled by a luminosity dependent density evolution (LDDE), similarly to what observed in the soft X-rays. However, in both cosmologies, the statistic is not significant enough to distinguish between the PLE and LDDE models. The fitted models imply a contribution of AGN1 to the 2-10 keV X-ray background from 35% up to 60%.Comment: 16 pages, 12 figures. Emulateapj version. To appear on ApJ, v570, May 1 200

Pyrazolopyrimidine Derivatives as Antineoplastic Agents: with a Special Focus on Thyroid Cancer

Tyrosine kinase inhibitors (TKIs) are molecules that compete with ATP on tyrosine kinase receptors (TKRs), blocking tyrosine kinase (TK) activation and then oncogenic pathways; they have been studied, and some of them are right approved for the treatment of many types of cancer. Among TKIs, one of the most explored chemical template is the pyrazolo[3,4-d]pyrimidine (PP) heterocyclic core, which proved to be a useful scaffold for the obtainment of effective compounds. Actually, derivatives belonging to this structural class show a large spectrum of activity, thus standing out as multi-target agents. Different PP compounds have been shown to act as: a) ABL inhibitors and antiproliferative agents against human leukemia cell lines; b) Src kinase inhibitors in neuroblastoma, medulloblastoma and osteosarcoma; c) Phospholipase D inhibitors in different neoplasias; d) Urokinase plasminogen activator inhibitors, in breast cancer. In thyroid cancer (TC), PP1 and PP2 (inhibitors of RET, Hck, lck, and fynT kinases, and a good inhibitor of c-Src and platelet-derived growth factor receptor) showed antineoplastic actvity in human papillary TC cell lines that carry spontaneous RET/PTC1 rearrangements. More recently, new derivatives, (R)-1-phenethyl-N-(1-phenylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4- amine, namely, CLM3 and CLM29, have been demonstrated to exert a multiple signal transduction inhibition (including the RET-TK, BRAF, EGFR, and with antiangiogenic activity), showing antineoplastic activity, in vitro and in vivo, in papillary dedifferentiated, medullary and anaplastic TC. These data have shown the antineoplastic activity of PP in different neoplasias, opening the way to a future clinical evaluation in human cancers