Search

The δ 13 C profile of Globigerinoides ruber , measured in the GT90/3 shallow-water Ionian sea core and dated with high precision, is presented and analyzed using the Singular Spectrum Analysis and the Wavelet Transform. This time series covers the period 200–1979 AD, with a resolution of 3.87 years. The δ 13 C of foraminifera depends on the photosynthetic activity of the symbiontic algae living on the shells, strictly related to the illumination of the sea-surface. Both spectral methods, besides an 11-years oscillation in phase with the Schwabe cycle of the solar activity, show the presence of a centennial cycle that is in phase with the amplitude modulation of the sunspot number series in the last 300 years. Moreover, another climatic record, the tree ring δ 13 C of a Japanese cedar covering the time interval 125–1952 AD, shows a similar centennial oscillation and therefore suggests that this climatic variation is global and in phase with the solar activity.

Extensive Air Showers at large zenith angles θ > 70° (Horizontal Air Showers, HAS) are observed at the EAS-TOP array at Campo Imperatore (Gran Sasso Laboratories). The rate of these events exceeds the one due to primary cosmic rays (at this angles) and therefore these showers have to be generated by penetrating particles. Assuming that they are produced by atmospheric muons we derived the muon flux as Fμ(> 30 TeV) = 1.1 × 10−11cm−2s−1sr−1, in good agreement with the underground measurements. The upper limits for diffuse neutrino radiation from these measurements is Iν(> 105GeV) dI ν e (E 0 )/dE ν e −18 cm −2 s −1 sr −1 GeV −1 , for the resonant ( E 0 = m W 2 2m e = 6.4 × 10 6 GeV ) neutrinos.

The evolution of the cosmic ray primary composition in the energy range 10 6 –10 7 GeV (i.e. the “knee” region) is studied by means of the e.m. and muon data of the Extensive Air Shower EAS-TOP array (Campo Imperatore, National Gran Sasso Laboratories). The measurement is performed through: (a) the correlated muon number ( N μ ) and shower size ( N e ) spectra, and (b) the evolution of the average muon numbers and their distributions as a function of the shower size. From analysis (a) the dominance of helium primaries at the knee, and therefore the possibility that the knee itself is due to a break in their energy spectrum (at E k He =(3.5±0.3)×10 6 GeV) are deduced. Concerning analysis (b), the measurement accuracies allow the classification in terms of three mass groups: light (p,He), intermediate (CNO), and heavy (Fe). At primary energies E 0 ≈10 6 GeV the results are consistent with the extrapolations of the data from direct experiments. In the knee region the obtained evolution of the energy spectra leads to: (i) an average steep spectrum of the light mass group ( γ p,He >3.1), (ii) a spectrum of the intermediate mass group harder than the one of the light component ( γ CNO ≃2.75, possibly bending at E k CNO ≈(6–7)×10 6 GeV), (iii) a constant slope for the spectrum of the heavy primaries ( γ Fe ≃2.3–2.7) consistent with the direct measurements. In the investigated energy range, the average primary mass increases from 〈ln A 〉=1.6–1.9 at E 0 ≃1.5×10 6 GeV to 〈ln A 〉=2.8–3.1 at E 0 ≃1.5×10 7 GeV. The result supports the standard acceleration and propagation models of galactic cosmic rays that predict rigidity dependent cut-offs for the primary spectra of the different nuclei. The uncertainties connected to the hadronic interaction model (QGSJET in CORSIKA) used for the interpretation are discussed.

UHE cosmic rays are studied by means of the detectors of the different components of secondaries produced by their interactions in the atmosphere (EAS). We describe and discuss the reconstruction techniques and accuracies of the e.m. detector of EAS-TOP. They allow, besides independent high resolution measurements of UHE γ-ray astronomy, good correlation possibilities with the detectors of the different EAS components.

Images of atmospheric EAS Cherenkov light have been recorded in connection with the EAS-TOP experiment. We describe the technique (based on a multianode photomultiplier Philips XP4702) and present some preliminary data analysis.

The current role of chemotherapy in pancreatic carcinoma is limited, and progress in the treatment of this disease represents a significant challenge to medical oncology. The most promising drug under study is gemcitabine, a relatively new antimetabolite that represents an attractive candidate for combination chemotherapy because of its excellent side-effect profile and the absence of overlapping toxicities with other chemotherapeutic agents. Combined administration of gemcitabine and anthracyclines could result in the induction of DNA breaks that are not easily repaired by the cell's machinery, thus enhancing the apoptotic signals triggered by these lesions. Forty-four patients with locally advanced and/or metastatic pancreatic adenocarcinoma were enrolled in this multicenter study. Patients received Epirubicin 20 mg m−2 for 3 weeks followed by 1 week of rest (1 cycle) and gemcitabine 1000 mg m−2 after Epirubicin on the same day. All were assessable for toxicity and response, 11 patients responded to treatment with one complete response and 10 partial responses, for an overall response rate of 25%. Median survival was 10.9 months (range, 2–26 months). Therapy was well tolerated, with a low incidence of haematologic grade >2 toxicity. A total of 12 of 27 (44.4%) eligible patients attained a clinical benefit response. Our findings suggest that the gemcitabine-epirubicin schedule is active and well tolerated in patients with advanced pancreatic cancer. British Journal of Cancer (2002) 87, 497–501. doi:10.1038/sj.bjc.6600482 www.bjcancer.com © 2002 Cancer Research UK

On February 23, 1989, an excess of counts of > 100 TeV Extensive Air Showers has been recorded from the direction of the Crab Nebula by three independent detectors: Baksan (North Caucasus, USSR), KGF (India) and EAS-TOP (Gran Sasso, Italy). The chance probability of the combined detection is ~ 10-7. We discuss the EAS-TOP observations from the statistical point of view (chance probability ≤ 10-2) and present some phenomenological characteristics of the events.

We demonstrate the presence of solar flare as well as neutron capture effects in the isotopic composition of rare gases in the Fermo regolith breccia acquired on its parent body based on the measurements of tracks, rare gases and radionuclides. The track density along a 3.2 cm long core decreases by a factor of about 6 and by more than a factor of 13 within the meteorite, indicating small (2-9 cm) and asymmetrical ablation. Rare gases show a large trapped component; the isotopic ratios, particularly 20 Ne/ 22 Ne ≅ 11 and 20 Ne/ 36 Ar = 10 are indicative of a solar component. The galactic cosmic-ray exposure age is determined to be 8.8 Ma. Activities of a dozen radionuclides ranging in half-life from 16 day 48 V to 0.73 Ma 26 Al are consistent with their expected production rates. Track, rare gas and radionuclide data show that the meteoroid was a small body (≤ 120 kg) and had a simple, one-stage exposure history to cosmic rays in the interplanetary space. However, 82 Kr and 128 Xe show an excess due to neutron irradiation on the parent body of the meteorite. The presence of solar gases and the neutron capture effects indicate several stages of irradiation on the parent asteroid. The chemical composition of Fermo confirms that it belongs to the H group of ordinary chondrites with lithic clasts having varying compositions. δ 15 N is found to be 8.3 ± 1.2%0, close to the typical values observed in H chondrites.

A search for transient point sources of ultra-high-energy (UHE) γ-rays has been performed, based on the correlation of two extensive air shower arrays, BAKSAN (North Caucasus, 1700 m a.s.l., BAKSAN Neutrino Observatory, Russia) and EAS-TOP (Campo Imperatore, 2005 a.s.l., Laboratori Nazionali del Gran Sasso, Italy), which are located at very similar latitudes (φ≈43° N), and separated in longitude by Δλ≈33.7°. The search has been conducted at primary energy Eγ⩾5×1013 eV on the time scale of a daily source transit over the sky, observable in the northern hemisphere (19° The stability of the single detectors has been studied and verified up to high significance level. No coincident excess, not compatible with the expectations from statistical fluctuations, has been observed. The obtained upper limits to the rate of transient events, nγ, at 90% c.l., are • concerning the sky survey, in the declination band corresponding to the zenith, n γ /(Ωt) /(yr sr) with Φγ(Eγ>5×1013 eV)>2.0×10−11 cm −2 s−1 and duration Δt • concerning the candidate sources, e.g., for Markarian 421: nγ/t 5×1013 eV)>1.3×10−11 cm −2 s−1 and Δt A coincident episode from Markarian 421, observed on 15 January, 1994, with expected chance imitation rate nch= 0.01 is discussed.

The break observed in the electron shower size power law spectrum of Extensive Air Showers (EAS) at corresponding primary energy E-0 similar to (3 - 5)10(15) eV ("knee") is studied in different EAS components (electromagnetic and muonic) and at different atmospheric depths. A consistent description is obtained. The interpretation of data in terms of primary composition, and following the most accepted high energy interaction models, leads to an increasing average primary mass in this energy range. The study of such behaviour is expected to provide a crucial information for the understanding of the physical parameters that characterize the break for the different primaries.

The cross section for large p t jet production for transverse momentum 10≤ p t ≤20 GeV/c and rapidity 1.6≤ η ≤2.6 in p – N ( p –`air') interactions is studied from the analysis of multicore Extensive Air Showers recorded in the EAS–TOP calorimeter. The projectiles are the leading particles interacting at atmospheric depths between 250 and 480 cm −2 , the CMS energy of interaction being s ≈500 GeV. The slope of the p t distribution agrees with the expected one from the p – p collider data at the same CMS energy. The measured jet production cross section in p – N interactions with respect to p – p interactions is (dσ/dp t ) pN jet =(dσ/dp t ) p p jet ·A α with α =1.56±0.07 for A =14.7 (average mass number of `air' nuclei). Such value is compatible within the experimental uncertainties with the one obtained in p –nucleus accelerator measurements at s ≃30 GeV in the same range of transverse momentum and rapidity. No indication of increase of α with energy, i.e. of the entity of the `Cronin effect', is found.

The cosmic ray energy spectrum in the range E-o = 10(15)-10(16) eV (including the region of the steepening, "knee") is studied by means of the EAS-TOP array (Campo Imperatore, Gran Sasso Laboratories, atmospheric depth 820 g cm(-2)). Measurements of the electromagnetic size (N-e = total number of charged particles at the observation level) are performed as a function of zenith angle with statistical accuracies of a few percent. The change of slope of the spectrum is observed in each bin of zenith angle at size values decreasing with increasing atmospheric depth. Its attenuation is compatible with the one of shower particles (Lambda(e) = 219 +/- 3 g cm(-2)). This observation provides a consistency check, supporting a normal behaviour of showers at the break, that make plausible astrophysical interpretations based on an effect on primaries occurring at a given primary energy. The break has a "sharp" shape (i.e., within experimental errors is compatible with two intersecting power laws) that represents a constraint with which any interpretation has to match. The change of slope of the power law index reproducing the size spectrum is Delta gamma = 0.40 +/- 0.09. The derived all particle energy spectrum is in good agreement with the extrapolation of the direct measurements at low energies and with other EAS data at and above the knee. Power laws fits to the energy spectrum below and above the knee give tin units of m(-2) s(-1) sr(-1) TeV-1) S(E-o) = (3.48 +/- 0.06) x 10(-10) (E-o/2300)(-2.76+/-0.03) for 900 TeV < E-o < 2300 TeV and S(E-o) = (3.77 +/- 0.08) x 10(-11) (E-o/5000)(-3.19+/-0.06) for 5000 TeV < E-o < 10(4) TeV. The systematic uncertainties connected to the interaction model and the primary composition are discussed. (C) 1999 Elsevier Science B.V.

The amplitude and phase of the first harmonic of the sidereal anisotropy of cosmic rays at E 0 = 2·10 14 eV have been measured by the EAS-TOP experiment (Campo Imperatore, 2005 m a.s.l., LNGS, Italy) and are respectively (at the equatorial plane): A sid = (3.73±0.57)·10 −4 ; φ sid = 1.82±0.49 h lst, with significance 6.5 s.d. The result is supported by different consistency checks. From the comparison with lower energy data, it follows that the amplitude and the phase of the cosmic ray anisotropy are constant over the energy range 10 12 – 2·10 14 eV. This implies at these energies a constant influence of the local interstellar medium on the propagation of cosmic rays.

We have previously shown that the very low activity of the cosmogenic 44Ti in meteorites records the galactic cosmic ray (GCR) flux over a century time-scale (Bonino et al., 1995). The heliospheric magnetic field (HMF) variations are the principal source of the GCR modulation in the heliosphere. We present here new measurements which extend our investigation over the last two centuries. The 44Ti activity at the time of fall has been obtained on the basis of the recently revised value of its half-life of 59.2 years. We basically confirm our earlier findings (Bonino et al., 1997). The 44Ti profile, with the time of fall of the meteorites, shows variations in phase in agreement with those expected. The magnitude of oscillations is ∼ 4 times higher than expected (∼ 6%) on the basis of the GCR flux over the past centuries deduced from sunspot number since 1700 and by the neutron monitor and balloon measurements in the last decades. The higher 44Ti production rate during prolonged solar quiet periods (Gleissberg minima) may imply that during these minima the HMF was weaker than during the recent minima of the 11-year solar cycle.

In this paper we present the δ18O profile of Globigerinoides ruber measured in the GT90/3 shallow water Ionian sea core, dated with high precision. The δ18O profile covers the period 1200–1900 AD, with a resolution of 3.87 years. This long record of 700 years of δ18O allows us to identify the imprint of the solar cycle in a climatic record. In fact, the spectral analysis of the time series performed with different methods shows a dominant periodicity of about 11 years with an amplitude of ≈0.07‰. The signal is in opposition to the sunspot number cycle. This component is identified at a high significance level by Monte Carlo Singular Spectrum Analysis (MC-SSA).

We report on a measurement of the ${}^{44}\mathrm{Ti}$ half-life aimed at lowering existing systematic uncertainties in this value, which is important to astrophysics. The half-life was measured by following the decay of ${}^{44}\mathrm{Ti}$ relative to ${}^{60}\mathrm{Co}$ for about 5 yr and the measurements were performed independently in three laboratories---Argonne, Jerusalem, and Torino. We suggest to combine our result, $59.0\ifmmode\pm\else\textpm\fi{}0.6$ yr, with the one from the accompanying Letter by G\"orres et al., $60.3\ifmmode\pm\else\textpm\fi{}1.3$ yr, to obtain a current ``best value'' for the half-life of ${}^{44}\mathrm{Ti}$ of $59.2\ifmmode\pm\else\textpm\fi{}0.6$ yr ( $1\ensuremath{\sigma}$ error).

We tested the effects of daily melatonin treatment on the growth of the ascites hepatoma in rats, determining survival time, cell number and cell cycle phases at various stages of tumor development. Melatonin inhibited cellular proliferation, doubled mean life-time and increased survival. Thymidine incorporation in hepatoma cells from treated rats decreased significantly without changes in the apoptotic index. Flow cytometric analysis showed that melatonin slowed cell cycle progression by increasing the number of cells in phase G0G1. Thus, similar to in vitro models, melatonin's oncostatic action in vivo appears to be directed to specific cell cycle mechanisms, which remain to be elucidated.

Production of cosmogenic radioisotopes in meteorites depends on the galactic cosmic ray flux, which is controlled by the heliospheric magnetic field (HMF), which, in turn, depends on the solar activity. The radioisotopes can, therefore, serve as proxy records of the behaviour of the heliosphere in the past, in particular over prolonged solar quiet periods, such as during Gleissberg or Maunder minima, when the production rate of radioisotopes is expected to change significantly. For this purpose we have measured the 44 Ti (T 1/2 =66.6 yr) in ten stony meteorites, which fell between 1840–1992. The results indicate that the production of 44 Ti was significantly higher when the solar activity was persistently low, indicating that the HMF was weak during such periods, enabling higher flux of cosmic rays to enter the inner heliosphere.

Treatment with calcium antagonists has been shown to be beneficial in patients with primary and secondary Raynaud’s phenomenon. A double-blind placebo-controlled crossover trial was performed to assess the efficacy of amlodipine, a new long-acting calcium antagonist, in patients with Raynaud’s phenomenon without underlying disease. 20 of the 24 patients enrolled (20 women and 4 men, mean age 45 years) completed the trial. The number of episodes of Raynaud’s phenomenon per week and the severity of discomfort significantly improved during amlodipine (p < 0.0001 and p < 0.0004, respectively) but not placebo treatment. Perfusion-pressure index, evaluated with Doppler sonography using a postischaemia reactive hyperaemia test, significantly improved (p < 0.04) after treatment with amlodipine but not placebo. These results indicate that amlodipine is a useful treatment for primary and suspected secondary Raynaud’s phenomenon, at least in the short term.

We study sequences of times between successive arrivals of air showers detected in the EAS-TOP experiment (primary energy between 70 and 1000 TeV) in order to establish their nature, whether stochastic or chaotic.

We present the results of a search for Gamma Ray Bursts at energies Eγ ≥ 10 GeV and Eγ ≥ 100 TeV made by the EAS-TOP Air Shower Array in correlation with ∼ 50 events detected by BATSE in the last 3 years.

Different fluxes and spectra of galactic cosmic rays (GCR) and solar cosmic rays result in a wide variety of radioactive and stable-nuclides production rates. The records of cosmic-ray interactions, have been studied in terrestrial archives, in meteorites, cosmic dust and lunar samples. We present here some results obtained in our laboratory on the study of cosmogenic radionuclides produced in meteorites which fell in the last century. The laboratory is situated in the underground station of Monte dei Cappuccini, Torino, at a depth of 70 m water equivalent to reduce the cosmic-ray background level. To measure γ-activity in meteorites we have set up a highly efficient and selective Ge−NaI(Tl) γ-ray spectrometer surrounded by a passive shield. The solar modulation affects the intensity of GCR and therefore the isotopes production rates in meteorites. The 11 y solar cycle is well reproduced by the variations of22Na (T 1/2=2.6 y) in meteorites which fell during the past three solar cycles. The44Ti (T 1/2=66.6 y) activity measured in eight chondrites which fell in the last 110 y is qualitatively consistent with the century-scale solar-activity variation, called the Gleissberg cycle. The increase is roughly four times higher, than expected (about 5%) for a GCR flux calculated by a model in which the solar-activity modulation is determined solely by the sunspot number indexR. This result suggests a much weakened modulation of GCR during the prolonged Gleissberg minimum during which highly ordered magnetic fields set up in the heliosphere.

Purpose: Since metastatic renal cell carcinoma has a poor prognosis and treatment strategies, including hormone therapy, chemotherapy and immunotherapy, have little impact on the quality of life and global survival statistics, new interest has recently focused on the combination of immuno-chemotherapy using pyrimidine analogues, such as gemcitabine.Materials and Methods: In a phase II study 16 patients with metastatic renal cell carcinoma were treated with 1,000 mg./m.2 gemcitabine intravenously on days 1, 8, 15 and 28 for 6 months, 3 MU (1 MU = 1 × 106 IU) interferon (IFN)-α intramuscularly 3 times a week and 4.5 million IU interleukin (IL)-2 subcutaneously daily for 5 days a week for 2 consecutive weeks every month for 6 months. Responding and nonprogressing cases were maintained on immunotherapy consisting of IFN-α and IL-2 for further 6 months.Results: In 15 evaluable patients overall response rate (1 complete response plus 3 partial response) was 28% while stable disease was achieved in 7 (47...

We have measured the thermoluminescence (TL) profile of the Mediterranean Sea core CT85.5 at the same depths where the cosmogenic-isotope10Be production peak at 35 ky BP was found. Strong TL peaks are evident at 37.5 ky and 35.6 ky BP. The Fourier analysis of the TL time series running from 32.5 ky to 42.6 ky at 100 y sampling interval shows 2500 y and 500 y periodicities. We suggest that the Sun was «active» at the time of the10Be enhancement.

A number of marine as well as continental K/T sections in India, particularly around the Deccan volcanic regime, have been analyzed to obtain concentration profiles of some platinum group and other trace elements, specifically to search for anomalous levels of iridium. Except for the Um Sohryngkew River (USR) section in Meghalaya, where iridium is found to occur at an anomalously high level in the K/T boundary layer, all other sections show low levels in the range of 10 to ∼120 pg/g. The iridium profile in the USR section is characterized by a sharp peak of 12.1 ng/g in a 1.5 cm thick limonitic layer, superimposed on a broad band of ∼0.2 ng/g extending over a 50±20 cm thick section, beyond which Ir decreases to the base level of ∼0.02 ng/g, both in the Tertiary as well as in the Cretaceous. High Ir is accompanied by high Os but the Os/Ir ratio in the peak (0.37) is different from the Os/Ir ratio of ∼2 measured in the broad band. The Ir profile in the USR section seems to be consistent with fallout of cometary debris preceding and following the main impact. The measurements at other sites in the Deccan suggest that the iridium inventory of the Deccan is too low to account for the high iridium observed in the KTB layer all over the world, but may be sufficient to give rise to its enhancement adjacent to the KTB peak.

An accurate dating of recent Ionian Sea sediment cores has been performed by the210Pb radiometric method and by a detailed tephroanalysis. The markers of the historical volcanic eruptions which occurred in the Campanian area (Vesuvius, Phlegrean Fields, Ischia) during the last two millenia have been identified along the cores. Among the others, the famous Plinian Vesuvius eruption of 79 AD, which buried the Roman town of Pompei, has been recognized. Direct210Pb dating is limited to the last two centuries. The tephroanalysis demonstrates that the sedimentation rate estimated by the210Pb method is correct and it is constant, at least for the last 2 ky. The presence of the137Cs peak due to the intense activity of nuclear-weapon testing in the atmosphere in 1963–64 AD assures that the top of the core is present and not disturbed. The high precision of the core dating allows to transform the depth scale into a time scale with an accuracy of ∼1%. The analysis of several cores taken in the same area demonstrates that the results presented here are of general validity, at least in this region. The carbonatic mud deposited in the last millennia in the Gallipoli Terrace can be successfully utilized for investigating the environmental conditions in the recent past.

Adjuvant chemotherapy of gastric cancer after curative resection is still subject to discussion. In this study 137 patients with gastric adenocarcinoma, all with positive nodes, were randomized after curative resection so that 69 received epidoxorubicin (EPI), leucovorin (LV) and 5-fluorouracil (5-FU) on days 1–3 every 3 weeks for 7 months, whereas the remaining 68 did not. After a follow-up period of 5 years, 21 of the 69 treated patients (30%) and nine controls (13%) were still alive; median survival time was 18 months for the controls and 31 months for the patients treated with adjuvant chemotherapy (P< 0.01). © 2001 Cancer Research Campaign http://www.bjcancer.com

The Large Volume Detector (LVD) in the Gran Sasso underground Laboratory is a multipurpose detector consisting of a large volume of liquid scintillator interleaved with limited streamer tubes. In this paper we discuss its power to study low-energy cosmic neutrinos. The results show that the first LVD tower (368 tons of liquid scintillator) is well suited to detect neutrinos from gravitational stellar collapses within all of our Galaxy over a wide range of burst duration (up to a few hundred seconds). No burst candidates have been observed in the first two months of data taking.

The EAS-TOP Extensive Air Shower array, on top of the under-ground Gran Sasso Laboratory, is fully operating as a γ-ray astronomy observatory since the beginning of 1989. After showing the measured angular resolution of the detector, we present the results obtained from the analysis of 280 days of measurements in 1989–1990, with the purpose of investigating possible emission (d.c. and sporadic) from the candidate sources in the Northern hemisphere at an energy, >200 TeV.

We study the total carbonate profiles of three coastal cores extracted from the continental shelf in the Ionian Sea and of two deep-sea cores extracted from the Tyrrhenian abissal plane. An overall similarity between the two deep-sea profiles and among the three coastal profiles is observed, indicating the complete reproductibility of this type of experimental measurements. In the case of the coastal cores, a constant sedimentation rates=(0.0646±0.0007) cm/y has been determined by radiometric methods and by tephroanalysis. For the deep-sea cores, the spectra of the upper and lower halves of the carbonate depth profiles display the same periodic components, suggesting that the sedimentation rate is nearly the same along the entire deep cores as well. The use of a careful tephroanalysis, the recognition of the Ignimbrite layers of Campanian origin at the expected depths and the similarity between the upper part (5000y) of the carbonate profile of the deep-sea core with that of the coastal cores provide the indication that, on the average, 1 cm of sediment is deposited in about 100 y. We show that the trend of the carbonate record in the deep-sea core is well approximated by a signal obtained by linearly superposing the obliquity and the precession parameters of the Earth rotation axis. Since these astronomical factors contribute to the temporal variations of the Earth insolation, and since the CaCO3 content of the sediment is presumably affected by climatic factors, this result supports the evidence of astronomical control on the Earth's climate, as already pointed out by several authors who analysed the power spectra of δ18O, δD and CO2 temporal series from sediment and ice cores. After removal of the «astronomical» trend, the carbonate record displays a dominant periodicity at approximately 12000 y. The 12000 y wave, taken with the opposite sign, corresponds to the trend of the radiocarbon record in tree-rings. This result becomes particularly relevant in view of the existence of common periodicities of about 200 y waves (Suess wiggles) which have already been detected in the carbonate profiles of the coastal cores and in tree-ring radiocarbon data.

First results on the lateral and temporal structures of EAS obtained from the EAS-TOP array are presented. A correlation between the slope of the lateral distribution function and the time delay of EAS particles with respect to the shower front at fixed core distance is found and discussed.

A study was performed in Yoshida hepatoma-bearing rats to confirm in vivo, in an experimental model, the preliminary data on the potentiation by lonidamine of the antitumor activity of adriamycin. Lonidamine alone, administered orally with food, did not reduce tumor cell proliferation, but in combination with adriamycin (5 mg/kg intraperitoneally 6 days after tumor transplant), it produced a remarkable increase in adriamycin's hepatoma cell toxicity (44% vs controls, P P

A large-volume HPGe gamma-ray spectrometer in a NaI(Tl) well has been set up underground at 70 m.w.e. depth for whole body counting of cosmogenic radionuclides in meteorites. The detectors are housed in a 20 cm thick lead shield with a lining of cadmium and OFHC copper. The scintillator is simultaneously operated in anticoincidence as well as in coincidence in selected energy channels to achieve low background levels (in the range of counts per day) and high specificity. In this way a large number of radionuclides such as26Al,44Ti,60Co,22Na,54Mn, and shorter-lived nuclides produced in extraterrestrial materials like meteorites and lunar rocks can be analysed. Results on Bouvante and Bereba achondrites and Dhajala and Torino chondrites are presented.

Lonidamine (LND) is a new drug that interferes with mitochondrial functions, thereby inhibiting cellular oxygen consumption and energy metabolism in both normal and neoplastic cells. These metabolic actions of LND seem to increase the cytotoxic effect of antitumor agents such as doxorubicin (Dx). Dx is a widely used antitumor agent, but the specific cardiac toxicity which develops at a critical cumulative dose is the major limiting factor in its long term use. So far, nothing is known about a possible synergic action of LND and Dx on the metabolism of cardiac cells. The purpose of this study was to verify in an experimental model in vivo, whether LND could increase the toxicity of Dx on rat heart. Groups each consisting of 10 female Wistar rats (weighing 100-150 g) were injected ip with a single dose of Dx (10 mg/kg), LDN (50 mg/kg), or Dx plus LND and dimethylsulfoxide (DMSO) (ratio LND:DMSO = 1/10). After 24 h, oxygen uptake (QO2) and intracellular concentrations of ATP and GTP indices of cardiac metabolic impairment, were measured on heart slices in Warburg apparatus and by high-pressure liquid chromatography. Dx, significantly (p less than 0.01), reduced QO2 (34%) and intracellular concentration of ATP and GTP (32-57%). LND alone only partially reduced cardiac QO2 (23%) and intracellular ATP-GTP concentration (16-31%). By contrast, the combination of the two agents did not enhance Dx-related metabolic cardiac toxicity.

The premise of this study is that mitochondrial lesions caused by anthracyclines lead directly to cardiotoxicity. We compared several biochemical parameters, including endogenous cellular respiration, adenosine and guanosine triphosphate levels, and 14C-amino acid incorporation, of rat hearts treated with doxorubicin and some of its derivatives, recent products of pharmacological research aimed at selecting less toxic antiblastic agents. In rats treated in vivo, we further examined the ultrastructural changes induced by anthracycline antibiotics in order to elucidate which biochemical parameters were consistent with the morphological lesions. Our data indicate that mitochondria are the target of the anthracycline effects and that oxygen uptake and nucleotide levels may be regarded as markers of the toxicity when evaluating new drugs before their clinical use. The lack of cytoplasmatic or endoplasmatic reticulum alterations may account for the failure of anthracyclines to affect amino acid incorporation. In any event, the rate of protein synthesis cannot serve as a marker of cardiac toxicity. In this context, epidoxorubicin and iododoxorubicin are two derivatives characterized by less cardiotoxic potential than doxorubicin and thus appear to be promising antiblastic agents.

In the energy region 10 - 100 TeV both the c.r. composition from direct measurements and the cross section for high energy secondary production in the very forward region for p-air interactions are rather uncertain. Contemporaneous measurements of the total energy and of the threshold energy/nucleon of the primary particle can be provided by the atmospheric Cherenkov light and high energy muons. These measurements are performed by the combined operation of the Cherenkov array of the EAS-TOP experiment on the surface (810 gcm(2) atmospheric depth) and of the LVD experiment in the underground Gran Sasso Laboratories (3300 m w.e.; E-mu(th) = 1.3 TeV) leading to the measurement of < N-mu > (E-mu > 1.3 TeV, E-o) in the given energy range. The combined operation of the experiments and preliminary results are reported.

The attenuation length of proton primaries and the proton-air inelastic cross section are studied at energies E 0 ≈ 10 15 eV by using the EAS-TOP array data. Proton initiated Extensive Air Showers, in the energy range (2 ÷ 4) 10 15 eV and near maximum development, are selected from their N μ ( E μ > 1 GeV) and N e sizes. The experimental attenuation length A obs is compared with those obtained from simulations, including the full detector response. based on different interaction models (HDPM, VENUS, DPMJET, QGSJET and SIBYLL) in the frame of CORSIKA code. The proton-air inelastic cross section is also inferred by using the factor k = Λ obs sim /λ p —air sim obtained from each interaction model.

Horizontal Air Showers, i.e. events observed at “quasi” horizontal incidence, are studied from EAS-TOP at Campo Imperatore (National Gran Sasso Laboratories). The “reality” of such events as due to deeply penetrating particles is discussed from the experimental point of view. We deduce: • -the measurement of the HE muon flux at E μ = 20 TeV : F μ (> 20 TeV ) = (1.3 ± 0.4) × 10 −11 cm −2 s −1 sr −1 , • -the upper limit to the extraterrestrial HE neutrino flux: I ν (> 10 5 GeV ) −9 cm −2 s −1 sr −1 . • The possibility to develop the technique for UHE ν detection is discussed.

The authors confirm and extend the results previously reported on the carbonate profile of the GT14 Ionian Sea core (Cini Castagnoli et al., 1990). A second, much longer core (2.81 meters) named GT89/3, has been taken about 1 km apart from the previous one. The carbonate profiles of the two cores are impressively similar; the details of the CaCO{sub 3} variations in the two sediments match on the scale of the sampling interval {Delta}d = 2.5 mm used for both cores. The authors show that {Delta}d corresponds to the mud deposited in a time interval {Delta}t = 3.87 {plus minus} 0.04 years, a value which is constant throughout the entire length of the cores. This precision is achieved by the tephroanalysis of the two cores. In this approach the markers of well-known historical eruptions in the Vesuvius area are recognized (Pompei, AD 79, Pollena, AD 472, Ischia, AD 1301), providing a precise dating which accurately tunes that obtained by the radiometric method. The correlation between the carbonate profile of the GT14 core and the tree-ring radiocarbon record has been discussed in (Cini Castagnoli et al., 1990); here the authors extend these results and show that the same correlation holds atmore » least up to 1690 BC. Due to the longer length of the GT89/3 time series, they also show that three periodic components at about 206 yr, 228 yr and 179 yr may now be resolved in the carbonate series, in close agreement with the results already found for the radiocarbon record.« less

The calcium carbonate (CaCO{sub 3}) profile of a recent sediment core, drilled in the Ionian Sea in 1979, is studied. The CaCO{sub 3} content of the sediment has been measured at regularly spaced intervals of {Delta}d=0.25 cm corresponding to {Delta}t=3.87 yr from AD 170 to the present. The CaCO{sub 3} profile of the core closely resembles the radiocarbon time series as deduced from tree ring data. The two records have a correlation coefficient of about 0.8 and show strikingly similar long-term variations. This result presumably follows from the fact that both systems take part in the carbon cycle. The spectral analysis of the CaCO{sub 3} time series reveals the presence of the well known periodicity with period ca: 200 years, characteristic of the {Delta}{sup 14}C record. Since the CaCO{sub 3} content of sea sediments is governed by biological, physical and chemical processes in surface sea waters, which in turn are strongly influenced by climatic conditions, and since the {approx}200 yr {Delta}{sup 14}C wave is known to be governed by solar modulation of galactic cosmic rays, the tuning of these two records on the same frequencies suggests a strong Sun-climate relationship.

EAS-TOP is a detector of the extensive air showers that very high-energy cosmic rays (E 0≥1014eV) produce in the atmosphere. The array is located on top of the underground Gran Sasso Laboratory in central Italy; a subarray (11 modules of the e.m. detector) has been operating since the end of 1987. From such data the stability of the detector, and the accuracies in the determination of the arrival directions and in the reconstruction of the electron lateral distribution and of the shower size are derived. The results obtained on VHE-UHE γ-ray sources in the first months of operation are presented.

The cosmic ray primary composition in the energy range between 10(15) and 10(16) eV, i.e., around the "knee" of the primary spectrum, has been studied through the combined measurements of the EAS-TOP air shower array (2005 m a. s.l., 10(5) m(2) collecting area) and the MACRO underground detector (963 m.a.s.l., 3100 m w.e. of minimum rock overburden, 920 m(2) effective area) at the National Gran Sasso Laboratories. The used observables are the air shower size (N-c) measured by EAS-TOP and the muon number (N-mu) recorded by MACRO. The two detectors are separated on average by 1200 m of rock, and located at a respective zenith angle of about 30degrees. The energy threshold at the surface for muons reaching the MACRO depth is approximately 1.3 TeV. Such muons are produced in the early stages of the shower development and in a kinematic region quite different from the one relevant for the usual N-mu - N-e studies. The measurement leads to a primary composition becoming heavier at the knee of the primary spectrum, the knee itself resulting from the steepening of the spectrum of a primary light component (p, He) of Deltay = 0.7 +/- 0.4 at E-0 similar to 4 x 10(15) eV. The result confirms the ones reported from the observation of the low energy muons at the surface (typically in the GeV energy range), showing that the conclusions do not depend on the production region kinematics. Thus, the hadronic interaction model used (CORSIKA/QGSJET) provides consistent composition results from data related to secondaries produced in a rapidity region exceeding the central one. Such an evolution of the composition in the knee region supports the "standard" galactic acceleration/propagation models that imply rigidity dependent breaks of the different components.. and therefore breaks occurring at lower energies in the spectra of the light nuclei. (C) 2003 Elsevier B.V. All rights reserved.

The heliospheric magnetic field (HMF) is controlled by solar activity, as established by measurements over the last few decades, but its characteristics when the sun was quiet for prolonged periods, such as during Gleissberg or Maunder minima, are not known. Titanium-44, produced in meteorites, provides a monitor of the galactic cosmic ray (GCR) flux and allows estimation of the modulation effect of the sun for the period 1883 to 1992. The titanium-44 activity is consistent with the expected value, but the increase, due to the last Gleissberg minimum, is four times greater than expected for a GCR modulation based solely on sunspot numbers. This result implies that the HMF was weaker than at present and as a result the GCR flux (for energy greater than 1 gigaelectron volt) was higher between 2.2 to 3.6 protons per square centimeter per second per 4π steradians at 1 to 3 astronomical units in solar cycles 12 to 15.

Combination chemotherapy with newer, more active drugs in patients with advanced and/or metastatic bladder cancer might show improved response rate and survival. Gemcitabine (GEM) and Epidoxorubicin (EPI) have demonstrated activity in this disease. In addition, experimental studies in vitro have shown that the two agents have additive-synergistic effects when used in combination. Our prior phase I dose-finding study in previously untreated patients with advanced or metastatic bladder cancer defined recommended doses for further trials of GEM 1000 mg/m2 and EPI 25 mg/m2 on days 1, 8 and 15 every 28 days. A phase II trial at this dose level was initiated in previously untreated patients to assess efficacy and toxicity. Eligible patients had measurable disease; Karnofsky performance status (PS) of40; no prior chemotherapy; and adequate bone marrow reserve, cardiac, hepatic and renal function. Thirty- one patients (22 males, 9 females) with median age of 64 (range 44-75) and median PS of 80 were accrued, and all were eligible. Twelve patients had T4N1-2 M0, 8 had lymph node only metastases, while 11 had visceral metastases (liver, bone, lung). A total of 181 cycles was administered (range 3-7 per patient). Major toxicities (WHO gradeor = 3) were: neutropenia in 5 patients, thrombocytopenia in 2 patients, and anemia in 2 patients. Three patients had febrile neutropenic episodes and only 3 patients required dose reduction. Grade 1-2 non-hematological toxicities included nausea/vomiting, stomatitis and alopecia. No cardiac toxicity was observed. Of the 30 response evaluable patients, 17 (57%) demonstrated a major response (3 complete and 14 partial) (95% CI: 39%-75%), 7 had stable disease (23%) and 6 progressed (20%). These preliminary results confirm the phase I observation that the combination of GEM--EPI is highly active in the treatment of advanced and metastatic bladder cancer with a favourable toxicity profile.

The recent data on the EAS size spectrum, and on the rate of ‘Horizontal Air Showers’ (HAS), as detected by the EAST-TOP experiment at Campo Imperatore (LNGS), are presented. Their implications for the interpretation of underground muon data, and for UHE neutrino astronomy are discussed.

We present measurements and data analysis of the oarbon stable isotopes (delta^13C) in the planktonic Globigerinoides ruber extracted from the GT9O/3 shallow water lonian sea core, dated with high precision. It is commonly accepted that delta^13C variations in symbiontic foraminifera mainly record the effects of productivity and of photosynthetic activity, varying with the ambient light level. Therefore from this time series we can deduce information on the sea surface illumination at the time of the planktonic foraminifera growth. The profile (359 points) covers the period 590-1979 AD, with a resolution of 3.87 years and it is an extension of the time series (215 points) previously published in this journal. The spectral analysis of the longer time series confirms the presence of the 11 y signal, with amplitude —0.08 per mille (peak-to-trough), found in the shorter time series in phase with the sunspot solar cycle; furthermore it shows the presence of two centennial cycles of 100 and 200 years, with amplitude 0.08 per mille and 0.02 per mille respectively. These components are identified at high significance level by Monte Carlo singular spectrum analysis (MC-SSA). A comparison between the delta^13C profile and the historical aurorae series (600-1500 AD) shows that the long-term delta^13C variations are at least partially generated by the solar activity modulation and in phase with the solar output, as represented by the solar wind interaction with the magnetosphere.

Combined measurements of extensive air showers at the surface and high-energy muons deep underground have been initiated at the Gran Sasso Laboratory. The underground detector is the first supermodule of MACRO (area = 140 ${\mathrm{m}}^{2}$, depth = 3100 m of water equivalent, ${E}_{\ensuremath{\mu}}g1.3$ TeV) and the surface detector is the EAS-TOP array (altitude 2000 m above sea level, total enclosed area $A\ensuremath{\sim}{10}^{5}$ ${\mathrm{m}}^{2}$). We discuss the correlation technique, the comparison between the shower parameters as determined by the two detectors, and some of the characteristics of the reconstructed events.

The neuroendocrine system modulates the immune response through neuropeptides and neurohormones, findings which point to the existence of a neuro-endocrine-immune system regulatory axis. At the same time, there is growing evidence that the pineal gland has anti-neoplastic properties, which include the action of its principal hormone, melatonin (MLT), on the immune system through the release of cytokines by activated T-cells and monocytes. The present study was carried out on 31 patients (19 males and 12 females, age range 46-73 years) with advanced solid tumors (7 gastric, 9 enteric, 8 renal, 5 bladder, 2 prostate) who either failed to respond to chemotherapy and radiotherapy or showed insignificant responses and were therefore shifted to MLT therapy (10 mg/die orally for 3 months). We obtained blood samples just before the start of MLT administration and after 30 days of therapy. Plasma was collected in EDTA tubes on ice, immediately centrifuged at 4 degrees C and stored frozen at -80 degrees C; samples were measured by immunoradiometric assays (Medgenix-Fleurus, Belgium) for tumor necrosis factor alpha (TNF), interleukin-1, 2 and 6 (IL-1, IL-2, IL-6) and interferon gamma (IFN). We used Student's paired t-test to compare each patient's cytokine circulating levels before and after MLT administration and found a significant differences (p0.05). After 3 months of therapy, none of our patients displayed adverse reactions to MLT or had to discontinue treatment. Nineteen patients (61%) showed disease progression. The other 12 (39%), however, achieved disease stabilization with no further growth of either the primary tumor or of secondaries; moreover, they experienced an improvement in their general well-being, in terms of Tchekmedyian's criteria, associated with a significative decrease of IL-6 circulating levels. These findings are consistent with the hypothesis that MLT modulates immune function in cancer patients by activating the cytokine system which exerts growth-inhibitory properties over a wide range of tumor cell types. Furthermore, by stimulating the cytotoxic activity of macrophages and monocytes, MLT plays a critical role in host defence against the progression of neoplasia.

After curative resection for gastric adenocarcinoma, 103 patients, all with positive nodes, were randomised so that 48 received adjuvant chemotherapy of epidoxorubicin (EPI) 75 mg m-2 on day 1, leucovorin (LV) 200 mg m-2 on days 1-3 and 5-fluorouracil (5-FU) 450 mg m-2 on days 1-3, every 21 days for 7 months, whereas the remaining 55 did not. During the first year of observation, 21 control patients (38%) and five treated patients had recurrences. After a follow-up period of 36 months, 12 of the treated patients (25%) and only seven controls (13%) were still alive. At that point, the median survival was 13.6 months for the 55 untreated patients and 20.4 months for the 48 treated patients, a significant difference. We found a survival advantage for patients treated with the EPI-LV-5-FU regimen and a consistent delay in the appearance of recurrent or metastatic cancer. Acute toxicity was mild and treatment was well accepted by all patients. There was no long-term toxicity or any cardiac toxicity. We conclude that this particular chemotherapy, administered shortly after gastric resection, improves survival rate in node-positive gastric cancer patients, even although final assessment of this particular adjuvant approach must await completion of the trial.