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Alcohol relapse is the treatment target for medications development for alcohol dependence. Aticaprant, a selective and short-acting kappa-opioid receptor (KOR) antagonist, has recently been under development for new clinical implications (depression or anhedonia). Recent studies have also found that aticaprant reduces alcohol intake and prevents stress- triggered alcohol seeking in rodents via a KOR-mediated mechanism. Here, we further investigated whether aticaprant alone or in combination with naltrexone (mu-opioid receptor [MOR] antagonist) altered alcohol relapse-like drinking using a mouse alcohol deprivation effect (ADE) paradigm to mimic the relapse episodes in human alcoholics. A long-acting and selective KOR antagonist nor-BNI was used as a reference compound for the effects of the KOR antagonism on the ADE. After 3-week intermittent-access alcohol drinking (two-bottle choice, 24-h access every other day), male and female mice displayed excessive alcohol intake and then pronounced ADE after 1-week abstinence. Aticaprant alone decreased alcohol ADE in a dose- dependent manner (1-3 mg/kg) in both males and females. Aticaprant at a lower dose (0.3 mg/kg) than the effective one (3 mg/kg) combined with a low dose of naltrexone (1 mg/kg) reduced the ADE in both sexes, and the combination was effective after a multi-dosing regimen (5 daily injections during the abstinence) without development of tolerance, suggesting synergistic effects of the combination. In contrast, nor-BNI alone or with naltrexone had no effect on the ADE in either sex. Our present study suggests that a combination of clinically developed, short-acting KOR antagonist aticaprant with low-dose naltrexone has therapeutic potential in alcohol "relapse" treatment.

To compare short-term and long-term efficacy after laparoscopic left hepatectomy(LLR) to open left hepatectomy(OLH) for primary left-sided hepatolithiasis.

Broad infrared emissions at 1131, 1107 and 1291 nm were observed in the bismuth doped aluminosilicate glasses under 532, 690 and 808 nm excitation respectively. The origin of the broadband infrared luminescence was investigated in the aluminosilicate glasses. Based on the energy matching conditions, it is suggested that the infrared luminescence centres might be Bi1+ ions and BiO molecules. The broadband infrared luminescent characteristics of the glasses indicate that they are promising for broadband optical fibre amplifiers and tunable lasers.

Optimization models play an important role in long-term hydroelectric resources planning. The effectiveness of an optimization model, however, depends on its capability of dealing with uncertainties. This study presents a multistage interval-stochastic programming model for long-term hydropower planning, in which uncertainties are reflected as randomness and intervals. The model is developed based on interval programming technique and recourse-based multistage stochastic programming and using the expected value of long-term hydroelectric profit as the objective function. A solution method of the developed model is also presented, which is based on a decomposition method by partitioning the multistage interval-stochastic program into two-stage stochastic programming sub-problems in each scenario-tree node. A hypothetical case study is used to demonstrate the developed model and its solution method. Modeling results demonstrates the computationally effectiveness of the solution method and reveal the applicability of the developed model for long term planning of hydroelectric resources.

We discuss the physics requirements of the ALICE PHOton Spectrometer (PHOS) and describe its main characteristics and structure. The beam test results of the PHOS show that PHOS is capable of detecting photons efficiently up to 100 GeV/c in ALICE.

The energy loss of heavy quarks in a quark-gluon plasma of finite size is studied within the light-cone integral approach. A simple analytical formulation of the radiative energy loss of heavy quarks is derived. This provides a convenient way to quantitatively estimate the quark energy loss. Our results show that if the energy of a heavy quark is much larger than its mass, the radiative energy loss approaches the radiative energy loss of light quarks., 4 pages, 2 figures. Accepted for publication in European Physical Journal A

We analyse the multifractal structure of moments Gq in terms of a new variable X on data of 197Au, 32S and 16O induced interactions with emulsion nuclei and Monte Carlo generated samples. The dynamical properties of the produced particles are mapped onto multifractal spectra. We compare ln G in experimental data of 197Au, 32S and 16O with pure statistical fluctuations. It is shown that the stochasticity plays an important role for the G-moments.

The complete charge distribution of products from Au nuclei fragmenting in nuclear emulsion at 10.7A GeV has been measured. Multiplicities of produced particles and particles associated with the target source are used to select peripheral and central events. A statistical analysis, based on event-by-event charge distributions, show that a population of subcritical, critical and supercritical events, i.e. a phase transition like behaviour, is observed among peripheral collisions.

The anomalous behavior of 2-dimensional factorial moment in nucleus-nucleus collisions is studied in some detail using both mini-bias and central collision data of ^{16}O-, ^{32}S- and ^{197}Au-Em interactions from EMU01 experiment. The correct value for the effective Hurst exponent in the analysis of higher-dimensional factorial moment is found to be greater than unity, showing clearly the existence of superposition effect in nucleus-nucleus collisions. The anomalous behavior of 2-dimensional factorial moment in nucleus-nucleus collisions is studied in some detail using both mini-bias and central collision data of ~{16}O-, ~{32}S- and ~{197}Au-Em interactions from EMU01 experiment. The correct value for the effective Hurst exponent in the analysis of higher-dimensional factorial moment is found to be greater than unity, showing clearly the existence of superposition effect in nucleus-nucleus collisions. The anomalous behavior of 2-dimensional factorial moment in nucleus-nucleus collisions is studied in some detail using both mini-bias and central collision data of ~{16}O-, ~{32}S- and ~{197}Au-Em interactions from EMU01 experiment. The correct value for the effective Hurst exponent in the analysis of higher-dimensional factorial moment is found to be greater than unity, showing clearly the existence of superposition effect in nucleus-nucleus collisions. The anomalous behavior of 2-dimensional factorial moment in nucleus-nucleus collisions is studied in some detail using both mini-bias and central collision data of ~{16}O-, ~{32}S- and ~{197}Au-Em interactions from EMU01 experiment. The correct value for the effective Hurst exponent in the analysis of higher-dimensional factorial moment is found to be greater than unity, showing clearly the existence of superposition effect in nucleus-nucleus collisions. The anomalous behavior of 2-dimensional factorial moment in nucleus-nucleus collisions is studied in some detail using both mini-bias and central collision data of ~{16}O-, ~{32}S- and ~{197}Au-Em interactions from EMU01 experiment. The correct value for the effective Hurst exponent in the analysis of higher-dimensional factorial moment is found to be greater than unity, showing clearly the existence of superposition effect in nucleus-nucleus collisions. The anomalous behavior of 2-dimensional factorial moment in nucleus-nucleus collisions is studied in some detail using both mini-bias and central collision data of ~{16}O-, ~{32}S- and ~{197}Au-Em interactions from EMU01 experiment. The correct value for the effective Hurst exponent in the analysis of higher-dimensional factorial moment is found to be greater than unity, showing clearly the existence of superposition effect in nucleus-nucleus collisions. The anomalous behavior of 2-dimensional factorial moment in nucleus-nucleus collisions is studied in some detail using both mini-bias and central collision data of ~{16}O-, ~{32}S- and ~{197}Au-Em interactions from EMU01 experiment. The correct value for the effective Hurst exponent in the analysis of higher-dimensional factorial moment is found to be greater than unity, showing clearly the existence of superposition effect in nucleus-nucleus collisions. The anomalous behavior of 2-dimensional factorial moment in nucleus-nucleus collisions is studied in some detail using both mini-bias and central collision data of ~{16}O-, ~{32}S- and ~{197}Au-Em interactions from EMU01 experiment. The correct value for the effective Hurst exponent in the analysis of higher-dimensional factorial moment is found to be greater than unity, showing clearly the existence of superposition effect in nucleus-nucleus collisions. The anomalous behavior of 2-dimensional factorial moment in nucleus-nucleus collisions is studied in some detail using both mini-bias and central collision data of ~{16}O-, ~{32}S- and ~{197}Au-Em interactions from EMU01 experiment. The correct value for the effective Hurst exponent in the analysis of higher-dimensional factorial moment is found to be greater than unity, showing clearly the existence of superposition effect in nucleus-nucleus collisions. The anomalous behavior of 2-dimensional factorial moment in nucleus-nucleus collisions is studied in some detail using both mini-bias and central collision data of ^{16}O-, ^{32}S- and ^{197}Au-Em interactions from EMU01 experiment. The correct value for the effective Hurst exponent in the analysis of higher-dimensional factorial moment is found to be greater than unity, showing clearly the existence of superposition effect in nucleus-nucleus collisions.

Recent results from the EMU-01/12 collaboration are presented for 10.7 GeV/nucleon gold nuclei interactions in emulsion. The distributions of "bound" charge ( Zbound ,Z b3), multiplicity distributions, fragment correlations and fluctua- tions are discussed. The data are compared to similar results obtained on the ALADIN setup at 600 MeV/nucleon. It is shown that multifragmentation of gold nuclei at high and in- termediate energies has common features. It is also obtained that the IMFs have reduced multiplicity at high energies. The data are analyzed within the scope of the statistical model of multifragmentation. This model requires the fol- lowing predetermined model ingredients: mass, charge and excitation energy of nuclear residuals. The simple estimation method of these characteristics is proposed in the framework of the Glauber approach. It is shown that the multifragmentation model reproduces qualitatively the present data. A dramatic discrepancy between the predicted and experimental yield of two charged fragments is found. The evolution of transverse momentum of fragments as a function of Zbound is presented. It is shown that the model greatly underpredicts the transverse momentum of fragments. It is interpreted as evidence of a strong radial flow of spectator fragments.

Results on charged particle multiplicities, densities and fluctuations from central Pb+Pb interactions at 158 A GeV are presented and discussed.

The wide discrepancies in the frequency of ‘positive’ samples for multidrug resistance (MDR) phenotype within the same type of tumor observed in the literature justified the need for the definition of consensus recommendations. To define standard techniques of MDR phenotype measurement, we ran a large multicentric evaluation of the different methods available. Thirty-six French centers participated in the study, and 742 samples of 2–10 × 106 viable cells were sent by overnight express mail between December 1993 and February 1996. The same batches of MRK16, 4E3 and UIC2 were used. Nineteen samples of leukemia (12 AML, 1 ALL, 6 lymphoproliferative syndromes) and six leukemic cell lines with different levels of MDR expression were tested. Five meetings reached agreement concerning the guidelines for each technique, except immunocytochemistry. The 19 fresh samples were tested by each center using one to four techniques among cytofluorometry, immunocytochemistry, functional tests and RT-PCR. Five samples were diagnosed as ‘negative’ according to local criteria, with few discordant results (0 to 16% of ‘positive’ results). For all the 14 remaining samples, large discrepancies were observed from center to center, and from one technique to another. No correlations could be found between techniques. Flow cytometric analysis of cells already exposed to MRK16 or control IgG2A, fixed in paraformaldehyde and sent to centers did not reduce the discrepancies between centers in two of the four samples with moderate expression, emphasizing the role of histogram interpretation. The use of alternative monoclonal antibodies (4E3 and UIC2) did not reduce the discrepancies observed. In a second step, the K562 parental cell line, a low resistant subline (K562/HHT100, ×7 resistance index to DNR) and a high resistant subline (K562/HHT300, ×125 resistance index to DNR) were sent blindly three times, with an increasing level of recommendations for flow cytometry. Dramatic improvements were observed in cytometric results when the result was expressed as the ratio of arithmetic mean of fluorescence of antibody (10 μg of MRK16)/arithmetic mean of fluorescence of control (10 μ g IgG2A): the proportion of expected results increased from 61 to 100% for K562, and from 37 to 85% for K562/HHT100. For uptake and drug efflux measurements, the use of 1 h uptake of 0.1μ M of rhodamine, followed by 1 h efflux ±10 μ M of verapamil, permitted an increased reproducibility of the technique from 71 to 100% for K562 and K562/HHT100. Whatever the technique used, concordant results were obtained for K562/HHT300. The immunocytochemistry, using several antibodies (MRK16, JSB1 and C219) gave many non-interpretable results (44%), due to a frequent high background and discordant results between antibodies in the same centers, and discordant conclusions between centers. The group does not recommend this technique for circulating tumoral cells.

A possible universal description of rapidity dependence of multiplicity distributions in high energye+e−, μp, hh, hA and AA collisions is proposed based on a cluster mechanism, local charged compensation and its violation. It appears that there exist a statistical connection between multiplicity distribution in a full longitudinal phase space and that in a selected rapidity window with limited size.

The mechanism for producing slow, target associated particles in high energy heavy ion collisions is investigated. It is shown that the same mechanism which was proposed for hadron induced interactions is likely to appear also for heavy-ion reactions. The results indicate however a much weaker correlation between impact parameter and yield of slow particles.

The fragmentation topology of28Si at 3.7A GeV and 14.6A GeV and32S at 200A GeV in reactions with emulsion nuclei is presented. The fragmentation cross sections are very similar at all three energies. A statistical percolation model can qualitatively describe the data forZ≥ 6. The He production is underestimated and the 3 ≤Z ≤ 5 fragments overestimated by this model.

In this talk we will present some of the recent results from the experiments E863 and EMU12 using the BNL AGS Au-beam at 11.6 A GeV/c and the CERN SPS Pb-beam at 158 A GeV, respectively. Aspects on the particle production and on the target break-up will be discussed. The results are compared with model expectations. The lead data is here shown for the first time.

Charged particle pseudorapidity density distributions in Au induced reactions in nuclear emulsion at 10.7 A GeV have been measured. In peripheral events the shower particle distribution exhibits a two peak structure while in central collisions it has a Gaussian shape. The spectator protons appear in the second peak in the pseudorapidity spectra and exhibits a broader momentum distribution than expected from Fermi motion. The produced particle yield in central collisions is not substantially different from phenomenological descriptions based on data from O and S induced reactions.

Angular distributions of projectile-associated He fragments from Au induced reactions in nuclear emulsions at 10.7 A GeV have been measured with a precision of ±0.1 mrad. Two emission components are indubitably appearing, one representing fragmentation of a fermionic system while the other one exhibits large transverse momentum transfer. Possible explanations for the latter component are discussed.

The first rapidity density distributions from relativistic collisions between truly heavy nuclei are presented. The distributions are compared with expectations from a linear extrapolation of results obtained from collisions with lighter nuclei. Fluctuations are essentially described by a simple scenario with stochastic emission.

We use scaled factorial cumulant moments to analyze pseudorapidity fluctuations in nucleus-nucleus collisions. This approach is similar to the method of scaled factorial moments except that it removes the effects of lower-order correlations upon a given moment. Significant second-order cumulants and cumulant indices (slopes with respect to bin size) are found for all of the interactions studied. These indices are found to have an inverse dependence upon average pseudorapidity particle density.

This paper presents data on the emission of helium fragments due to break up of 200 A GeV 32S ions in collision with emulsion nuclei. A total of 499 minimum bias events have been studied in an emulsion stack and 97 events in emulsion chambers. Emission angles of He fragments have been measured with high precision. This data has been compared with data of breakup of heavier as well as lighter projectiles and we observe that the value of the momentum spread, σ(p), increases with increasing projectile mass. The bulk part of the helium emission is consistent with a single source for helium fragments with an average excitation energy of (9.1±0.9) MeV. A tail of a few (

Non-statistical fluctuations are used to probe the dynamical behaviour of multi-particle production in heavy-ion interactions at ultra-relativistic energies. In a one-dimensional analysis a 1〈ϱ〉-scaling is established and it is furthermore found that effects from higher-order particle correlations are small. In a two-dimensional analysis it is shown that a small background of particle pairs with a narrow opening angle can distort the observed signal. As an example we estimate the influence of γ-conversion and find that in our experiment γ-conversion alone gives results consistent with the experimental observations from a two-dimensional analysis. Whereas a two-dimensional analysis filters events where two particles are extremely close in phase space, the one-dimensional analysis picks out events with particles clustered in pseudorapidity, which are at the same time diluted in the azimuthal plane.

The energy and centrality dependence of local particle pseudorapidity densities as well as validity of various parametrizations of the distributions are examined. The dispersion, σ, of the rapidity density distribution of produced particles varies slowly with centrality and is 0.80, 0.98, 1.21 and 1.41 for central interactions at 3.7, 14.6, 60 and 200A GeV incident energy, respectively, σ is found to be independent of the size of the interacting system at fixed energy. A novel way of representing the window dependence of the multiplicity as normalized variance versus inverse average multiplicity is outlined.

The mass, energy, and centrality dependence of rapidity density distributions of relativistic, charged particles, produced in heavy-ion interactions in the energy range 4A–200A GeV, are investigated. The results indicate that the rapidity density distributions show systematic variations, which are used to predict distributions for Au+Au and Pb+Pb interactions in a model-independent way.

The EMU01 Collaboration has employed emulsion chamber and pellicle detectors to accumulate a large database of heavy nucleus interactions. Samples include both minimum bias and central collisions, analyzed in a uniform manner to extract multiplicities and angular distributions of charged particles and nuclear fragments. We find that the main features of these distribution are well represented by geometrical superposition models. A unique feature of EMU01 is the use of emulsion chambers with thin foil targets to observe produced particle angular distributions with exceptionally high precision, permitting extension of fluctuations and correlations analyses beyond the resolution limits imposed by other experimental techniques. The data are generally well reproduced by interaction simulations such as FRITIOF (the Lund monte carlo for nuclear collisons) which include only conventional physics effects. However, the analysis of fluctuations and correlations via factorial moment and cumulant techniques yields some suggestive results which require further investigation, both by continued analysis of existing data and from Au and Pb beam exposures scheduled for the next few years.

The scaling behaviour in the fragmentation regions is investigated for16O-Em interactions from 3.7 to 200A GeV. It is found that in both the projectile- and the target-fragmentation regions, the multiplicity and pseudo-rapidity distributions as well as the two-particle pseudo-rapidity correlations are independent of incident energy. The intermittency indices at 14.6, 60 and 200A GeV are the same within the experimental errors, indicating that the limiting fragmentation hypothesis works with regard to dynamical as well as statistical fluctuations.

M.I. Adamovich a, M.M. Aggarwal b, Y.A. Alexandrov a, N.P. Andreeva c, Z.V. Anson c, R. Arora b, F.A. Avetyan d, S.K. Badyal e, E. Basova f, K.B. Bhalla g, A. Bhasin e, V.S. Bhatia b, V.G. Bogdanov h, V.I. Bubnov c, T.H. Burnett i, X. Cai J, I.Y. Chasnikov c, L.P. Chernova k, M.M. Chernyavski a, B. Dressel ~, G.Z. Eligbaeva c, L.E. Eremenko ~, E.M. Friedlander m, A.S. Gaitinov ~, E.R. Ganssauge ~, S. Garpman ", S.G. Gerassimov a, j. Grote i, K.G. Gulamov k, S.K. Gupta g, V. Gupta e, H.H. Heckrnan ~, H. Huang J, B. Jakobsson ", B. Judek o, S. Kachroo e, F.G. Kadyrov k, G.S. Kalyachkina c, E.K. Kanygina ~, M. Karabova P, G.L. Kaul e, M. Kaur b, S.P. Kharlamov a, T. Koss i, S.A. Krasnov P, V. Kumar g, P. Lal g, V.G. Larionova a, V.N. Lepetan ~, P.J. Lindstrom m, L.S. Liu J, S. Lokanathan g, J. Lord i, N.S. Lukicheva k, S.B. Luo q, L.K. Mangotra e, N.A. Marutyan d, N.V. Maslennikova ", I.S. Mittra b, S. Mookerjee g, C. Mueller ~, H. Nasrulaeva f, S.H. Nasyrov f, V.S. Navotny k, G.I. Orlova a, I. Otterlund n, H.S. Palsania g, N.G. Peresadko a, N.V. Petrov f, V.A. Plyushchev h, W.Y. Qian J, R. Raniwala g, S. Raniwala g, N.K. Rao ~, V.M. Rappoport a, J.T. Rhee ~, N. Saidkhanov k, N.A. Salmanova ~, L.G. Sarkisova d, V.R. Sarkisyan d, W. Schulz ~, G.S. Shabratova P, T.I. Shakhova ~, B. Singh b, D. Skelding i, K. SSderstrSm ", Z.I. Solovjeva h, E. Stenlund n, S.C. Strausz i, J.F. Sun r, L.N. Svechnikova k, K.D. Tolstov P, M.I. Tretyakova a, T.P. Trofimova r, U. Tuleeva r, S. Vokal P, H.Q. Wang J, Z.Q. Weng r, R.J. Wilkes i, G.F. Xu s, D.H. Zhang q, P.Y. Zheng s, S.I. Zhochova k, D.C. Zhou J and J.C. Zhou J

The slow, target associated particles produced in ultrarelativistic heavy-ion interactions are a quantitative probe of the cascading processes in the spectator parts of the target nucleus. These processes are directly influenced by the proper timescale for the formation of hadronic matter. In this letter we show experimental data on singly and multiply charged particles, with velocities smaller than 0.7 c , produced in ultrarelativistic heavy-ion interactions in nuclear emulsion.

In this letter we show that most of the fluctuations in particle densities observed in relativistic heavy-ion collisions are consistent with stochastic emission, i.e., most of the correlations between produced particles are washed out due to the vast number of particles in the environment. We further explore the general trends by investigating different systems, energies and centrality cuts. Comparisons with the Fritiof model show that string fragmentation gives results similar to the data.

In the present letter we discuss the general features of the multiplicity distributions in relativistic heavy ion collisions. It is shown that from simple statistical considerations it is possible to predict the dependence of the dispersions of multiplicity distributions on the average multiplicities in any given rapidty wwindow. The applicability of the negative binomial distribution to multiplicity distributions from collisions with heavy ions is discussed.

The average multiplicities of singly charged relativistic particles in oxygen-induced interactions with a nuclear emulsion target are studied over the energy range 2.1–200 A GeV. A similar energy dependence as for proton-induced interactions is observed. Both the number of participating nucleons and the number of binary collisions are shown to be of importance for the particle production.

The multiplicity distributions of low-energetic target-associated particles from 200 A GeV oxygen-induced interactions with emulsion nuclei are presented. The experimental distributions are compared with distributions obtained using the Ranft and Fritiof simulation codes. It is found that the intra-nuclear cascade plays an important role in ion-induced interactions, similar to what is the case for hadron-induced interactions.

We report on recent results obtained by the EMUO1 collaboration from studies of 16O + emulsion, at 14.6, 60 and 200 A GeV, and 32S + emulsion and 32S + Au interactions at 200 A GeV. Shower-particle production in oxygen-induced interactions are studied over the energy range 2.1-200 A GeV. Scaling and limiting fragmentation are observed. Multiplicity and angular distributions of low energy target-associated particles are presented and compared with distributions obtained using the Ranft and the Fritiof simulation codes.

It’s important to well analyze ship motions’ mechanism accurately. The deterministic differential equations can well describe ship motions with small amplitudes in regular waves, but can hardly describe ship motions with large amplitudes at rough sea because of the complicated nonlinear characteristics. With help of some collected time series samples of ship model roll, this paper studied the nonlinear characteristics of ship’s large amplitude roll with zero speed at irregular beam waves synthetically based on several methods, including the power spectrum analysis (PSA) method, the primary component analysis (PCA) method, and the largest Lyapunov exponent (LLE) analysis method. The result is useful for ship roll’s nonlinear mechanism study.

The up-regulation of cellular retinoic acid binding protein-II (CRABP-II) has been invoked as an important mechanism of clinically acquired resistance to all-trans retinoic acid (RA) therapy in acute promyelocytic leukemia (APL). To test this hypothesis, we used quantitative reverse transcription-PCR and fast performance liquid chromatography procedures to examine the levels of CRABP-II mRNA and RA binding activity in APL patient samples. We found that CRABP-II mRNA in APL cells from pretreatment patients (n = 36) was constitutively expressed at relatively high levels (median, 0.92; range, 0.16-4.13) relative to the level in CRABP-H protein-expressing NB4 cells (arbitrarily set at 1.0 unit). Consistent with this finding, the RA binding activity of CRABP in APL cells from three pretreatment cases (range, 27.2-53.2 fmol/mg protein) was similar to that of NB4 cells (22.6 +/- 5.4 fmol/mg protein). Furthermore, in the pretreatment samples, there was no association between CRABP-H mRNA expression level and APL cellular sensitivity to RA-induced differentiation in vitro. After 45 days of remission induction therapy on Eastern Cooperative Oncology Group protocol E2491, CRABP-II mRNA was modestly increased from day 0 values in patients treated with either RA (median increase, 0.41) or chemotherapy (median increase, 0.56), and there was no significant difference between the two treatment groups (P = 0.91). In patients studied after relapse from RA therapy (n = 7), there was a significant decline in APL cell sensitivity to RA-induced differentiation in vitro compared with patients after relapse from chemotherapy (n = 5; P = 0.015-0.055 at three RA concentrations tested), but in the RA relapse cases, there was no change from pretreatment levels of CRABP-II mRNA (median, 0.98) or, in three relapse cases studied, of RA protein binding activity (range, 22.1-70.7 fmol/mg protein). Taken together, our data strongly imply that variations in CRABP-II expression and RA binding activity are not causally related to the development of clinically acquired APL cellular RA resistance, but rather, they suggest that constitutive expression of CRABP-II could have a facilitative role in the response of APL cells to RA.

Thirty-six French centres are involved in an evaluation of the techniques used for MDR phenotype measurement. Until now, 14 samples of various kinds of leukemia (mainly acute myelogenous leukemia) and three cell lines with different levels of resistance were sent by one centre and tested. MRK16 antibody was used for flow cytometry and immunocytochemistry, RNA was measured by RT-PCR, rhodamine or anthracyclin efflux were tested for functional assay. Wide discrepancies were observed in the results, mainly with flow cytometry, specially for the samples with a probable low level of MDR1 expression. The importance of histogram interpretation was documented by the comparative analysis of results obtained on cells already marked with MRK16, fixed and sent to all centers. The use of the ratio of the mean of fluorescence, instead of percentage, should help for standardization. The use of only one control RNA (used at different dilutions) for standardisation of RT-PCR could help in decreasing the discrepancies observed. The mean of fluorescence should also be used for expressing the rhodamine cell content.

To investigate the mechanism of resistance to an antineoplastic natural product homoharringtonine (HHT) in leukemic cells, we have established 5 sub-lines of human myeloid leukemia K562 cells, designated as K-H30, K-H100, K-H200, K-H300 and K-H400, which showed progressive resistance to different concentrations of HHT. These sub-lines were cross-resistant to daunorubicin, vincristine, etoposide and mitoxantrone, but not to melphalan. Immunofluorescence with monoclonal anti-Pgp antibody MRK16 and Northern-blot analysis demonstrated that resistance to HHT is related to the sequential emergence of MRP- and MDR1-gene over-expression. In the low-level-resistant K-H30 sub-line, the MDR1 gene was not over-expressed, but the MRP gene was over-expressed 2.1-fold. In the intermediate-level-resistant K-H100 and K-H200 sublines, both the MRP and the MDR1 genes were over-expressed. However, in the high-level-resistant K-H300 and K-H400 sublines, MDR1-gene over-expression predominated (20- and 21-fold respectively). On the other hand, GST pi-gene expression was decreased in all 5 sub-lines. Southern-blot analysis revealed no MRP-gene amplification in any of the 5 sub-lines, whereas the MDR1 gene was amplified in the high-level-resistant K-H300 and K-H400 sub-lines. The most interesting observation is a homogeneously staining region (HSR) found in chromosome 2 of the K-H300 and K-H400 sub-lines. Chromosome painting and in situ hybridization demonstrated that this HSR was translocated from chromosome 7 and consisted of the amplified MDR1 gene, suggesting that there is a relationship between MDR1-gene, translocation and MDR1-gene amplification.

Homoharringtonine (HHT) is a cytotoxic alkaloid isolated from the evergreen tree cephalotaxus harringtonia native to the southern provinces of China. The principal mechanism of action of HHT is the inhibition of protein synthesis in a dose- and time-dependent manner by acting on the ribosomes of cancer cells. It blocks the progression of cells from G1 phase into S phase and from G2 phase into M phase. It is synergestic or additive in vitro with AraC, amsacrine, actinomycin D and dexamethasone. Clinical studies have indicated that HHT is effective in treating acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and myelodysplastic syndrome (MDS), but not acute lymphoblastic leukemia (ALL) and solid tumors. The dose limiting toxicities are hypotention and myelosuppression. Homoharringtonine has relatively mild extramedullary toxicities and no anthracycline-like cardiac toxicity, which make it a suitable candidate for the treatment of aged patients. Pharmacological studies indicate that HHT belongs to the category of multidrug resistance (MDR)-related drugs. The cells resistant to HHT are cross-resistant to anthracycline, vinca alkaloids, mitoxantrone, but not cis-platine and AraC. Multiple mechanisms, including the sequential emergence of overexpression of multidrug resistance-associated protein (MRP) and MDR1 genes, are involved in the cross-resistance of tumor cells to HHT.

The frequency, prognostic value and interrelation of MRP and MDR1 gene expressions were investigated by quantitative reverse transcription polymerase chain reaction (RT-PCR) in 91 cases of de novo acute myeloid leukemia (AML), of which 51 were newly diagnosed, 21 were relapsed, and 19 were refractory patients. As compared with normal bone marrow cells and peripheral granulocytes, an overexpression of MRP gene was found in 24% (22 of 91) cases of de novo AML. The incidence of MRP gene overexpression tended to be higher in relapsed patients than in newly diagnosed patients (38 vs 18%, P = 0.063). In 52 evaluable newly diagnosed and relapsed patients treated with MDR-related drugs, both MRP and MDR1 gene overexpressions correlated to a higher rate of emergence of clinical drug resistance (83 vs 22%, P = 0.005; and 67 vs 24%, P = 0.045, respectively). A positive correlation was found between MRP and MDR1 gene overexpressions (R = 0.53, P0.001). Analysis of 46 evaluable MDR1-negative cases revealed a trend for higher resistant disease rate in MRP-positive patients as compared with MRP-negative patients (100 vs 20%, P = 0.053). These data suggest that MRP, like MDR1, may have an important negative impact on the outcome of chemotherapy, and that there may be a common mechanism of induction for the overexpression of these two genes.

Homoharringtonine (HHT) is a new drug with antileukemic activity which is currently tested for treatment of acute and chronic leukemias, either alone or in combination with other agents. Since HHT showed a low efficacy in refractory and relapsed acute leukemia and in the blastic phase of chronic myeloid leukemia (CML) which are frequently characterized by an overexpresion of the multidrug resistance (MDR)-related P170-glycoprotein, we postulated a relationship between the poor antileukemic effect of HHT in these leukemias and the expression of P170-glycoprotein. For this reason, sensitive (LOVO109 and CEM) and MDR (LOVO DX and CEM VLB) cell lines were exposed to HHT with or without some MDR modifiers, namely, Cyclosporine A (CyA), the Cyclosporine derivative SDZ PSC 833 (PSC), and the D-isomer of Verapamil (DVRP). It was found that MDR cells were about 15 times more resistant to HHT than non-MDR cells, and that resistance to HHT was significantly decreased by all the MDR modifiers that were tested. This in vitro study showed that HHT belongs to the category of MDR-related drugs, like anthracyclines, vinca alkaloids, epipodophylline derivatives, and taxol.

The phenomenon of multidrug resistance (MDR) is frequently encountered in clinical situations, and could contribute to the failure of chemotherapy in acute leukemia. Preliminary studies have suggested that MDR1 gene expression in normal hematopoietic stem cells might be downregulated during differentiation. In the present study, we induced a multidrug-resistant promyelocytic leukemia cell line, HL60/DNR, to myeloid differentiation by exposure to all-trans retinoid acid and dimethyl sulfoxide (DMSO). We found that HL60/DNR cells retained the ability to respond to the differentiation stimulus. However, although MTT assays revealed a slight decrease of IC50 in differentiated cells, neither efflux of daunorubicin (DNR), nor expression of P-glycoprotein (P-gp), nor quantity of MDR1 mRNA has been downregulated in differentiated cells. We can conclude, therefore, that MDR1 gene expression in this multidrug-resistant myeloid cell line is not modified by induction of its differentiation.

The recent status of the EMU01 experiment where nuclear emulsions are used as both target/detector material for horizontally exposed stacks and as detector for vertically exposed chamber plates is discussed. An investigation of the behaviour in the number of produced particles per participating nucleon reveal weak nonlinear effects for the most central collisions. Intermittency index can be obtained from the density distributions for S+Au and S+Ag interactions which corresponds to fractal dimensions somewhat smaller than unity.

We study the rapidity losses in central heavy-ion collisions from AGS to RHIC energies with the mean rapidity determined from the projectile net-baryon distribution after collisions. The projectile net-baryon distribution in the full rapidity range was obtained by removing the target contribution phenomenologically at forward rapidity region from the experimental net-baryon measurements and taking into account the projectile contribution at backward rapidity region. Based on the full projectile net-baryon distributions, calculation results show that the rapidity loss stops increasing from the SPS top energy to RHIC energies, indicating that baryon transport does not depend strongly on energy at high energies., 7 pages, 4 figures

In an attempt to determine the incidence and clinical relevance of mdr1 gene expression in acute myeloid leukemia (AML), we examined 126 specimens obtained from adult patients with de novo AML by slot blot and immunocytochemistry. We found a high incidence of mdr1 gene expression in newly diagnosed patients (27% by immunocytochemistry and 43% by slot blot). No difference was observed between newly diagnosed patients and relapsed patients. However, patients with resistant disease showed statistically higher incidence of mdr1 gene expression compared to the untreated and relapsing patients (60% versus 27% by immunocytochemistry, p 0.005; and 73% versus 45% by slot blot, p less than 0.05). The expression of mdr1 gene correlated significantly with clinical drug resistance: 62% of patients positive for mdr1-mRNA and 68% of patients positive for P-glycoprotein (P-gp) eventually developed resistance to chemotherapy, while this was the case for a lower percentage of patients who did not express mdr1 gene (only 23% by slot blot analysis, p = 0.0052, or 24% by immunocytochemistry, p = 0.0009). A combined parameter, mdr1-mRNA/P-gp, had a very high prognostic value in terms of specificity and sensitivity. All nine patients (100%) who were mdr1-mRNA+/P-gp+ progressed to clinical drug resistance afterward, whereas 11 of 13 (85%) patients who were mdr1-mRNA-1 P-gp- entered complete remission and only two patients later developed drug resistance (p = 0.0005). It could thus be used as a reliable parameter in clinical settings.

Based on Conesa del Valle et al (2008 Phys. Lett. B 663 202), we present the results for the nuclear modification factors RAA and RCP of the high transverse momentum (5 < pt < 60 GeV/c) distribution of muons in Pb–Pb collisions at LHC energies, in which two pseudo-rapidity ranges covered by the LHC experiments, |η| < 2.5 and 2.5 < η < 4, are investigated. Heavy-quark energy loss is taken into account by mass-dependent BDMPS quenching weights. Muons from semi-leptonic decays of heavy quarks (c and b) and from leptonic decays of weak gauge bosons (W and Z) are the main contributions to the muon pt distribution above a few GeV/c. The muons from W and Z, that dominates the high pt, can be used as a medium-blind reference to observe the medium-induced suppression of beauty quarks.

In this study we analyzed the induction of NK and LAK cell functions by TNF alpha, alone or combined with IL-2, in 4 days in vitro culture of PBMC from patients treated with alpha IFN + IL-2. Although the MN cell recovery after 4 days culture was very similar with TNF alpha alone or with IL-2 alone, TNF alpha did not maintain nor induce LAK or NK activities of in vivo preactivated PBMC. When compared to preculture values, TNF alpha alone induced a preferential outgrowth of CD4+ T cells together with a decrease of CD8+ T cells, NK cells and IL-2R (p55)-expressing cells. The combination of TNF alpha (100 ng) and high dose IL-2 (9,000 IUg/ml) did not improve the MN cell recovery after 4 days culture; but increased IL-2-induced NK activities in PBMC from 6/7 patients, and IL-2-induced LAK activities in 4/7 patients. However, these variations were not significant. The combination of TNF alpha and lower doses of IL-2, ranging from 150 IU/ml to 30 IU/ml, did not modify MN cell recovery in culture nor IL-2-induced NK and LAK cell activities. When compared to paired samples cultured with IL-2 alone, the combination of TNF alpha with all doses of IL-2 did not modify the distribution of T and NK cells, but increased the expression of CD8 on NK cells. Furthermore, the combination of TNF alpha and IL-2 increased the expression of IL-2R (p55) on PBMC but the expression of this receptor was restricted to CD4+ T cells and did not appear on NK cells.

The effect of human IL-4, used as a single agent or in combination with low or high dose IL-2, upon LAK-cell proliferation and activation has been tested on PBMC from patients treated with alpha 2-IFN and IL-2. Four days in vitro culture with IL-4 did not induce any LAK-cell activation; IL-4 induced the proliferation of CD3+ CD4+ T-cells, but decreased the percentage of NK cells in culture samples. When combined with high dose IL-2, IL-4 improved the recovery of MN cell without modification of T-cell subsets; however, IL-4 had no major effect on IL-2-induced NK or LAK cell activity. The combination of IL-4 and low dose IL-2 still significantly improved the total MN cell recovery but did not modify the distribution of T and NK lymphocytes; IL-4 inhibited low dose IL-2-induced NK and LAK cell activity, and increased the BL-esterase activity induced by high or low dose IL-2. The combination of IL-4 and IL-2 did not induce any large variation in the percentage of IL-2R (p55) expressing cells. In all tested conditions, IL-2R (p55) was mainly expressed on CD4+ T cells; less than 2% of the cells coexpressed the NK cell marker CD56 and IL-2R (p55). The effect of IL-4 upon IL-2-induced LAK cell expansion is thus very different on PBMC pre-activated in vivo by alpha IFN + IL-2 therapy than on PBMC pre-treated in vitro with IL-2.(ABSTRACT TRUNCATED AT 250 WORDS)

S+Au interactions at 200{ital A} GeV were observed using emulsion chambers, permitting measurement of pseudorapidities in the central region with precision {similar to}0.01 unit. Scaled-factorial-moment analyses are extended to bin sizes smaller than those accessible to other fixed-target experimental techniques. For a sample of 151 central collisions, moments are calculated using both horizontal'' and vertical'' analysis techniques. While the moments are found to rise (in a log-log plot) with decreasing pseudorapidity bin size {delta}{eta}, their slopes roll off to approximately zero for {delta}{eta}{lt}0.1.