Underground operation of the ICARUS T600 LAr-TPC: first results

Open questions are still present in fundamental Physics and Cosmology, like the nature of Dark Matter, the matter-antimatter asymmetry and the validity of the particle interaction Standard Model. Addressing these questions requires a new generation of massive particle detectors exploring the subatomic and astrophysical worlds. ICARUS T600 is the first large mass (760 ton) example of a novel detector generation able to combine the imaging capabilities of the old famous "bubble chamber" with an excellent energy measurement in huge electronic detectors. ICARUS T600 now operates at the Gran Sasso underground laboratory, studying cosmic rays, neutrino oscillation and proton decay. Physical potentialities of this novel telescope are presented through few examples of neutrino interactions reconstructed with unprecedented details. Detector design and early operation are also reported.Comment: 14 pages, 8 figures, 2 tables. Submitted to Jins

LKB1/KRAS mutant lung cancers constitute a genetic subset of NSCLC with increased sensitivity to MAPK and mTOR signalling inhibition

LKB1/STK11 is a multitasking tumour suppressor kinase. Germline inactivating mutations of the gene are responsible for the Peutz-Jeghers hereditary cancer syndrome. It is also somatically inactivated in approximately 30% of non-small-cell lung cancer (NSCLC). Here, we report that LKB1/KRAS mutant NSCLC cell lines are sensitive to the MEK inhibitor CI-1040 shown by a dose-dependent reduction in proliferation rate, whereas LKB1 and KRAS mutations alone do not confer similar sensitivity. We show that this subset of NSCLC is also sensitised to the mTOR inhibitor rapamycin. Importantly, the data suggest that LKB1/KRAS mutant NSCLCs are a genetically and functionally distinct subset and further suggest that this subset of lung cancers might afford an opportunity for exploitation of anti-MAPK/mTOR-targeted therapies

Complement c5a receptor facilitates cancer metastasis by altering t-cell responses in the metastatic niche

The impact of complement on cancer metastasis has not been well studied. In this report, we demonstrate in a preclinical mouse model of breast cancer that the complement anaphylatoxin C5a receptor (C5aR) facilitates metastasis by suppressing effector CD8(+) and CD4(+) T-cell responses in the lungs. Mechanisms of this suppression involve recruitment of immature myeloid cells to the lungs and regulation of TGF beta and IL10 production in these cells. TGF beta and IL10 favored generation of T regulatory cells (T-reg) and Th2-oriented responses that rendered CD8(+) T cells dysfunctional. Importantly, pharmacologic blockade of C5aR or its genetic ablation in C5aR-deficient mice were sufficient to reduce lung metastases. Depletion of CD8(+) T cells abolished this beneficial effect, suggesting that CD8(+) T cells were responsible for the effects of C5aR inhibition. In contrast to previous findings, we observed that C5aR signaling promoted T-reg generation and suppressed T-cell responses in organs where metastases arose. Overall, our findings indicated that the immunomodulatory functions of C5aR are highly context dependent. Furthermore, they offered proof-of-concept for complement-based immunotherapies to prevent or reduce cancer metastasis. (C) 2014 AACR

The tuberous sclerosis proteins regulate formation of the primary cilium via a rapamycin-insensitive and polycystin 1-independent pathway

Tuberous sclerosis complex (TSC) is a tumor suppressor gene syndrome in which severe renal cystic disease can occur. Many renal cystic diseases, including autosomal dominant polycystic kidney disease (ADPKD), are associated with absence or dysfunction of the primary cilium. We report here that hamartin (TSC1) localizes to the basal body of the primary cilium, and that Tsc1−/− and Tsc2−/− mouse embryonic fibroblasts (MEFs) are significantly more likely to contain a primary cilium than wild-type controls. In addition, the cilia of Tsc1−/− and Tsc2−/− MEFs are 17–27% longer than cilia from wild-type MEFs. These data suggest a novel type of ciliary disruption in TSC, associated with enhanced cilia development. The TSC1 and TSC2 proteins function as a heterodimer to inhibit the activity of the mammalian target of rapamycin complex 1 (TORC1). The enhanced ciliary formation in the Tsc1−/− and Tsc2−/− MEFs was not abrogated by rapamycin, which indicates a TORC1-independent mechanism. Polycystin 1 (PC1), the product of the PKD1 gene, has been found to interact with TSC2, but Pkd1−/− MEFs did not have enhanced ciliary formation. Furthermore, while activation of mTOR has been observed in renal cysts from ADPKD patients, Pkd1−/− MEFs did not have evidence of constitutive mTOR activation, thereby underscoring the independent functions of the TSC proteins and PC1 in regulation of primary cilia and mTOR. Our data link the TSC proteins with the primary cilium and reveal a novel phenotype of enhanced ciliary formation in a cyst-associated disease

Synergistic antitumour effects of rapamycin and oncolytic reovirus.

There are currently numerous oncolytic viruses undergoing clinical trial evaluation in cancer patients and one agent, Talimogene laherparepvec, has been approved for the treatment of malignant melanoma. This progress highlights the huge clinical potential of this treatment modality, and the focus is now combining these agents with conventional anticancer treatments or agents that enhance viral replication, and thereby oncolysis, in the tumour microenvironment. We evaluated the combination of reovirus with rapamycin in B16F10 cell, a murine model of malignant melanoma, based on potential mechanisms by which mTOR inhibitors might enhance viral oncolysis. Rapamycin was not immunomodulatory in that it had no effect on the generation of an antireovirus-neutralising antibody response in C57/black 6 mice. The cell cycle effects of reovirus (increase G0/G1 fraction) were unaffected by concomitant or sequential exposure of rapamycin. However, rapamycin attenuated viral replication if given prior or concomitantly with reovirus and similarly reduced reovirus-induced apoptotic cell death Annexin V/PI and caspase 3/7 activation studies. We found clear evidence of synergistic antitumour effects of the combination both in vitro and in vivo, which was sequence dependent only in the in vitro setting. In conclusion, we have demonstrated synergistic antitumour efficacy of reovirus and rapamycin combination

High Resolution Density Map as the Visualization of a Larger Time Scale Molecular Dynamics

A method of visualization of two-dimensional systems of particles in a large time scale molecular dynamics with application to the domain reorientation process in 2D Lennard-Jones system is presented. The described processing is general and can be used in comparing experimental results of atomic force microscopy with the results calculated using a computer as well as for predicting new phenomena. Domain reorientation process in 2D Lennard-Jones system approaching equilibrium is presented and confronted with the Fourier analysis of the data obtained for different initial parameters and at different states of aggregation. New border domain features accompanying this process are discussed

Interakcje pomiędzy ciekłymi żużlami, a grafitem w trakcie redukcji tlenków metalicznych

High global demand for metallic elements such as Fe, Cr, Ti, Mn leads to an intensive technological development of metal recovery. One of the ways is to recover metals from metallurgical slag. The sessile drop method was adopted in order to study the interactions between liquid slag and graphite. Steelmaking slag was used during this research. The slag used included converter slag and slag from chrome steel melting as well as their mixtures with other modifiers. The analysis covered six types of slag in the temperature ranging from 1100°C to 1600°C in the argon atmosphere. In the course of research mass spectrometry and scanning microscope were used. The following were set for the examined samples during the reduction process: liquidus temperature and the nature of interactions (wettability or its lack). It was observed that the volume of slag samples dynamically changed in the course of the reduction of metallic oxides.Duże zapotrzebowanie dzisiejszego Świata na pierwiastki metaliczne np. Fe, Cr, Ti, Mn, powoduje bardzo intensywny rozwój technologii ich odzysku m.in. z żużli metalurgicznych. Przy użyciu techniki leżącej kropli wykonano badania współoddziaływania ciekłych żużli z grafitem. Do badań wykorzystano żużle stalownicze: konwertorowy i z wytopu stali chromowych oraz ich mieszanin z innymi modyfikatorami, analizie poddano sześć żużli w zakresie temp 1100-1600°C w atmosferze argonu. W badaniach wykorzystano również spektrometr masowy oraz mikroskop skaningowy. Określono temperaturę liquidus dla analizowanych próbek, jak również charakter interakcji - zwilżanie lub jego brak - w trakcie trwania procesu redukcji. Zaobserwowano dynamiczne zmiany objętości próbek żużlowych w trakcie zachodzenia procesu redukcji tlenków metalicznych

Pienienie żużli zawierających Cr2O3 podczas produkcji stali nierdzewnych w piecu łukowym przy użyciu Steelcal(TM)

Foaming of EAF stainless steel slags with Cr2O3 using Steelcal has been examined in a 10 kg laboratory furnace at the AGH University of Science & Technology in Kraków, Poland. Steelcal (a modified grade of calcium nitrate) has been injected through a lance into the molten slag in a crucible electric arc furnace with one electrode. 22 tests have been performed changing such parameters as the slag composition, injection gas, pure Steelcal or mixed with C or FeSi. The slag height has been measured. Steel and slag analyses have been carried out. The results of the tests have been evaluated.Przeprowadzono badanie w warunkach laboratoryjnych zjawiska pienienia żużli zawierających Cr2O3, występujących podczas produkcji stali nierdzewnych w piecu łukowym. Zastosowano laboratoryjny jednoelektrodowy piec łukowy o pojemności 10 kg zainstalowany w Katedrze Metalurgii Stopów Żelaza Akademii Górniczo-Hutniczej. Jako materiał spieniający zastosowano SteelcalTM (zmodyfikowana postać azotanu wapnia). Materiał był wdmuchiwany do objętości ciekłego żużla. Wykonano 22 wytopy testowe przy zmiennych parametrach technologicznych, takich jak: skład chemiczny żużla, rodzaj gazu użytego do wdmuchiwania, ilość i rodzaj mieszanki spieniającej (tylko Steelcal lub zmieszany z węglem lub żelazokrzemem). Mierzono wysokość spienionego żużla jako parametru wyjściowego testów. Po przeprowadzeniu testów poddano analizie skład chemiczny żużla i metalu. Przedstawiono wyniki i wnioski z przeprowadzonych testów

Innovative solutions in the technology for manufacturing large-size forgings from ultra-clean steels for power equipment

Przedstawiono trzy innowacyjne rozwiązania – rafinacji ciekłej stali we wlewnicy po odlaniu stali z zastosowaniem izotermicznej pokrywy i rafinacyjnej zasypki, syfonowego odlewania stali przez kształtkę kierunkową w kanale wlotowym do wlewnicy, służące zmniejszeniu lub wyeliminowaniu egzogenicznych wtrąceń niemetalicznych, pochodzących z procesu odlewania stali oraz odlewanie wlewków w komorze próżniowej z kadzi z zamknięciem suwakowym. Dzięki zastosowaniu tych rozwiązań znacznej poprawie uległa czystość stali, osiągając poziom wynoszący 0,06% mierzony udziałem powierzchniowym wtrąceń niemetalicznych, wielkość wtrąceń – mierzoną średnicą równoważną – mniejszą niż 4 μm oraz wskaźnik K4, mniejszy niż 10. Stworzyły one realne szanse produkcji ciężkich odkuwek na wały turbin wiatrowych, wodnych i parowych o coraz większej mocy dla nowoczesnej energetyki.Three innovative solutions are presented: refining of liquid steel in an ingot mould after casting of steel using an isothermal cover and refining casting powder; uphill casting of steel through a swirl blade in inlet channel to a mould directional brick, which is used for reduction or elimination of exogenous non-metallic inclusions from the steel casting process; and casting of ingots in a vacuum chamber from a ladle with slide gate. The use of these solutions has resulted in significant improvement of steel purity, reaching the level of 0.06% as measured by surface fraction of nonmetallic inclusions, size of inclusions – as measured by equivalent diameter – less than 4 μm, and K4 coefficient – less than 10. They have provided real chances of manufacturing heavy forgings for wind, water and steam turbine shafts with higher and higher power for the modern power industry

Innovative technology solutions for manufacturing heavy ultra-clean steel forgings for the oil and power industries to operate under extreme conditions

Przedstawiono szereg innowacyjnych rozwiązań w metalurgii stali przeznaczonej na wlewki do kucia o dużej masie. Obejmują one: rafinację ciekłej stali we wlewnicy po odlaniu stali z zastosowaniem izotermicznej pokrywy i rafinacyjnej zasypki; syfonowe odlewanie stali przez kształtkę kierunkową w kanale wlotowym do wlewnicy; antyerozyjną powłokę materiałów ogniotrwałych syfonowego układu odlewania stali, odlewanie wlewków ciężkich w komorze próżniowej z kadzi z zamknięciem suwakowym oraz odlewanie wlewków do kucia o różnej masie i geometrii do jednej uniwersalnej wlewnicy. Rozwiązania te są unikalne w skali światowej i służą zmniejszeniu ilości i wielkości wtrąceń niemetalicznych w stali, wyeliminowaniu egzogenicznych wtrąceń niemetalicznych, pochodzących z procesu odlewania stali oraz optymalizacji procesu przeróbki plastycznej wlewków dla wyeliminowania rzadzizn. Dzięki zastosowaniu tych rozwiązań znacznej poprawie uległa czystość stali, spełniając wymagania odbiorców odkuwek o dużej masie dla przemysłu energetycznego (wały turbin wiatrowych, gazowych i wodnych, itp.) oraz wydobywczego ropy naftowej i gazu ziemnego (łączniki rurociągów i inne akcesoria), przeznaczonych do pracy w ekstremalnych warunkach niskich temperatur i dużych głębokości. Średnia wartość wskaźnika K4 (S+O) dla odkuwek z wlewków odlanych z zastosowaniem innowacyjnych rozwiązań wyniosła 3,9 przy wymaganej przez odbiorców odkuwek średniej wartości K4 (S+O) < 10. Praca przedstawia wyniki trzech projektów realizowanych w ramach konkursów Initech i Innotech.A number of innovative solutions in metallurgy of steel for heavy forging ingots are presented. They include: refining of liquid steel in an ingot mould after casting of steel using an isothermal cover and refining casting powder; uphill casting of steel through a directional brick in inlet channel to a mould; erosion-proof coating on refractory materials of the system for uphill casting of steel; casting of heavy ingots in a vacuum chamber from a ladle with slide gate; and casting of forging ingots with different weights and geometries into a single universal mould. These are worldwide unique solutions used to reduce the amount and size of non-metallic inclusions in steel, eliminate exogenous non-metallic inclusions from the steel casting process and optimise the plastic working of ingots to eliminate microshrinkages. With these solutions, the purity of steel has been signifi cantly improved, thus meeting the requirements of buyers of heavy forgings for the power industry (shafts of wind, gas and water turbines, etc.) and the oil and natural gas extraction industry (pipeline connectors and other accessories) to be operated under extreme low-temperature and high-depth conditions. The average value of K4 (S+O) index for forgings from ingots cast using the innovative solutions was 3.9, while the average value of K4 (S+O) required by forging buyers is < 10. This paper presents the results of three projects carried out under Initech and Innotech competitions