delta16HER2 splice variant and its role in HER2-overexpressing breast cancer

Deep insight on delta16HER2 splice variant and its role in HER2-overexpressing breast cancer

A measurement of the solar and sidereal cosmic-ray anisotropy at E(0)similar to 10(14)eV

The results of the measurement of the cosmic-ray solar and sidereal anisotropies at primary energy E(0) approximate to 10(14) eV performed by the EAS-TOP Extensive Air Shower array (Campo Imperatore, National Gran Sasso Laboratories, 2005 m above sea level, latitude 42 degrees.5 N are presented. The measurement includes 4 years of data taking (1990, 1992, 1993, 1994) for a total of 1.3 x 10(9) events and is performed at two different mean primary energies: (E) over bar(0)(v) approximate to 1.5 x 10(14) eV and (E) over bar(0)(i) approximate to 2.5 x 10(14) eV. The two results are compatible (within 2 sigma) and can therefore be combined. The obtained amplitude and phase of the first harmonic in sidereal time are (in the equatorial plane) A(sid,delta=0c)((E) over bar(0) approximate to 2 x 10(14) eV) = (3.73 +/- 0.57) x 10(-4) and phi(sid) = 1.82 +/- 0.49 hr local sidereal time, with significance 6.5 sigma. The amplitude of the anisotropy exhibits the expected cos delta dependence. A first harmonic in solar time compatible with the expected Compton-Getting effect due to the motion of revolution of the Earth around the Sun is observed with significance 7.3 sigma. The corresponding measured amplitude and phase (also in the equatorial plane) are A(sol,delta=0o)=(4.06 +/- 0.55) x 10(-4) and phi(sol) = 4.92 +/- 0.53 hr, the expected values being 4.7 x 10(-4) and 6.0 hr. Different checks of stability of the detectors and consistency of the data are presented.4701150150

Search for gamma-ray bursts at photon energies E>=10 GeV and E>=80 TeV

The EAS-TOP extensive air shower array has been operating since 1992 in the search for gamma-ray bursts at primary energies E(1) greater than or equal to 10 GeV and E(2) greater than or equal to 80 TeV. The study is performed by searching for short transients in the cosmic-ray intensity in the single particle (E(1)) and extensive air shower (E(2)) counting rates at mountain altitude (2005 m above sea level). We discuss the method and the results obtained both in sky survey and in correlation with BATSE events. In both energy ranges, the observed fluctuations in the event rate obtained in the sky survey during similar to 800 days of live time are compatible with the statistical fluctuations of the cosmic-ray background. A single candidate of time duration Delta t similar to 2 s and energy fluence F(10 < E < 100 GeV) = 1.7 x 10(-4)/(cos theta)(10.5) ergs cm(-2) (where theta is the unknown zenith angle) has been observed on 1992 July 15 at 13:22:26 UT in the energy range E(1) greater than or equal to 10 GeV with significance 10.6 and 20.1 sigma in two measurement channels. In the analysis made in correlation with similar to 50 events detected by BATSE, no burst candidate was found in time coincidence or in the 2 hr interval, around the BATSE detection time. The following ranges of upper limits F-max to the energy fluence in the time interval Delta t(90) in which BATSE detected 90% of the counts are obtained: F-max = 2.3 x 10(-5)-7.4 x 10(-3) ergs cm(-2) (10 < E < 100 GeV) F-max = 1.6 x 10(-6)-3.3 x 10(-5) ergs cm(-2) (100 < E < 1000 TeV).4691130531

The shapes of the atmospheric Cherenkov light images from extensive air showers

Experimental results on the shapes of atmospheric Cherenkov light images from Extensive Air Showers at E(0) = 10(13)-10(14) eV are presented, The results are based on data obtained by the first element of the Cherenkov light array of the EAS-TOP experiment at Campo Imperatore (2005 m a.s.l., National Gran Sasso Laboratories, Italy), Images are obtained with pixel field of view omega = 1.5 x 10(-5) sr and full field of view Omega approximate to 10(-3) sr. The shapes of the images agree with the expectations and their fluctuations are large and significant, Experimental data on the dependence of the image shapes on the detection geometry are reported, The images are well reproduced by two independent side by side detectors, within measured accuracies, Such accuracies (approximate to 15% for large photoelectron content) define the level at which each pixel content is related to the shower structure, The presence of events characterized by patterns with multiple structures is proved, It is shown that such features are related to physical fluctuations of the shower structure.6214315

The hadron calorimeter of EAS-TOP: operation, calibration and resolution

We describe and discuss the operation, calibration and stability of the EAS-TOP calorimeter (Campo Imperatore, National Gran Sasso Laboratories), a large area hadron and muon detector devoted to cosmic-ray physics. It consists of iron slabs (for a total thickness of 818 g cm(-2)) and Iarocci tubes as sensitive layers, operating in the streamer mode and the "quasi proportional" regime. Using a model describing the operation of the "quasi proportional" chambers, we derive a calibration curve in the energy range 50-5000 GeV, whose reliability has been indirectly checked through on-site measurements, by means of an accelerator beam run (up to similar or equal to 600-700 GeV) and by comparing the model predictions on hadron shower transition curves with the data. (C) 1999 Elsevier Science B.V. All rights reserved.4204167111713

Activated d16HER2 Homodimers and SRC Kinase Mediate Optimal Efficacy for Trastuzumab.

A splice isoform of the HER2 receptor that lacks exon 16 (d16HER2) is expressed in many HER2-positive breast tumors, where it has been linked with resistance to the HER2-targeting antibody trastuzumab, but the impact of d16HER2 on tumor pathobiology and therapeutic response remains uncertain. Here, we provide genetic evidence in transgenic mice that expression of d16HER2 is sufficient to accelerate mammary tumorigenesis and improve the response to trastuzumab. A comparative analysis of effector signaling pathways activated by d16HER2 and wild-type HER2 revealed that d16HER2 was optimally functional through a link to SRC activation (pSRC). Clinically, HER2-positive breast cancers from patients who received trastuzumab exhibited a positive correlation in d16HER2 and pSRC abundance, consistent with the mouse genetic results. Moreover, patients expressing high pSRC or an activated "d16HER2 metagene" were found to derive the greatest benefit from trastuzumab treatment. Overall, our results establish the d16HER2 signaling axis as a signature for decreased risk of relapse after trastuzumab treatment

Phenethyl isothiocyanate hampers growth and progression of HER2-positive breast and ovarian carcinoma by targeting their stem cell compartment

© 2019, International Society for Cellular Oncology. Purpose: Isothiocyanates elicit anticancer effects by targeting cancer stem cells (CSCs). Here, we tested the antitumor activity of phenethyl-isothiocyanate (PEITC), either alone or in combination with trastuzumab, in HER2-positive tumor models. Methods: We assessed the in vitro anticancer activity of PEITC, alone or combined with trastuzumab, in HER2-positive BT474, SKBR3, HCC1954 and SKOV3 cancer cells by measuring their sphere forming efficiency (SFE). The expression of the human/rodent CSC biomarkers aldehyde-dehydrogenase (ALDH) and CD29High/CD24+/Sca1Low was evaluated by cytofluorimetric analysis. The expression of wild type HER2 (WTHER2), its splice variant d16HER2 and NOTCH was analysed by quantitative RT-PCR and Western blotting. The in vivo activity of PEITC and trastuzumab was evaluated in mice orthotopically implanted with MI6 tumor cells transgenic for the human d16HER2 splice isoform. Magnetic resonance imaging/spectroscopy and immunohistochemistry were used to assess morpho-functional and metabolic profiles of treated versus untreated mice. Results: We found that PEITC significantly impaired the SFE of HER2-positive human cancer cells by decreasing their ALDH-positive compartments. The anti-CSC activity of PEITC was demonstrated by a reduced expression/activation of established cancer-stemness biomarkers. Similar results were obtained with MI6 cells, where PEITC, alone or in combination with trastuzumab, significantly inhibited their SFE. We also found that PEITC hampered the in vivo growth of MI6 nodules by inducing hemorrhagic and necrotic intra-tumor areas and, in combination with trastuzumab, by significantly reducing spontaneous tumor development in d16HER2 transgenic mice. Conclusions: Our results indicate that PEITC targets HER2-positive CSCs and that its combination with trastuzumab may pave the way for a novel therapeutic strategy for HER2-positive tumors