Reply to Comment of Gazdzicki and Heinz on Strangeness Enhancement in p+Ap+A and S+AS+A

The Comment of Gazdzicki and Heinz is flawed because their assumed baryon stopping power in $pA$ is inconsistent with data and because they ignored half the analysis based on the VENUS model. The Comment continues the misleading presentation of strangeness enhancement by focusing on ratios of integrated yields. Those ratios discard essential experimental information on the rapidity dependence of produced $\Lambda$ and obscure discrepancies between different data sets. Our conclusion remains that the NA35 minimum bias data on $p+S\rightarrow\Lambda +X$ indicate an anomalous enhancement of central rapidity strangeness in few nucleon reactions that points to non-equilibrium dynamics as responsible for strangeness enhancement in nuclear reactions.Comment: revtex file, 6 pages, submitted to Phys. Rev.

Establishment of Highly Tumorigenic Human Colorectal Cancer Cell Line (CR4) with Properties of Putative Cancer Stem Cells

BACKGROUND: Colorectal cancer (CRC) has the third highest mortality rates among the US population. According to the most recent concept of carcinogenesis, human tumors are organized hierarchically, and the top of it is occupied by malignant stem cells (cancer stem cells, CSCs, or cancer-initiating cells, CICs), which possess unlimited self-renewal and tumor-initiating capacities and high resistance to conventional therapies. To reflect the complexity and diversity of human tumors and to provide clinically and physiologically relevant cancer models, large banks of characterized patient-derived low-passage cell lines, and especially CIC-enriched cell lines, are urgently needed. PRINCIPAL FINDINGS: Here we report the establishment of a novel CIC-enriched, highly tumorigenic and clonogenic colon cancer cell line, CR4, derived from liver metastasis. This stable cell line was established by combining 3D culturing and 2D culturing in stem cell media, subcloning of cells with particular morphology, co-culture with carcinoma associated fibroblasts (CAFs) and serial transplantation to NOD/SCID mice. Using RNA-Seq complete transcriptome profiling of the tumorigenic fraction of the CR4 cells in comparison to the bulk tumor cells, we have identified about 360 differentially expressed transcripts, many of which represent stemness, pluripotency and resistance to treatment. Majority of the established CR4 cells express common markers of stemness, including CD133, CD44, CD166, EpCAM, CD24 and Lgr5. Using immunocytochemical, FACS and western blot analyses, we have shown that a significant ratio of the CR4 cells express key markers of pluripotency markers, including Sox-2, Oct3/4 and c-Myc. Constitutive overactivation of ABC transporters and NF-kB and absence of tumor suppressors p53 and p21 may partially explain exceptional drug resistance of the CR4 cells. CONCLUSIONS: The highly tumorigenic and clonogenic CIC-enriched CR4 cell line may provide an important new tool to support the discovery of novel diagnostic and/or prognostic biomarkers as well as the development of more effective therapeutic strategies

Prostate Cancer Stem Cell-Targeted Efficacy of a New-Generation Taxoid, SBT-1214 and Novel Polyenolic Zinc-Binding Curcuminoid, CMC2.24

Background Prostate cancer is the second leading cause of cancer death among men. Multiple evidence suggests that a population of tumor-initiating, or cancer stem cells (CSCs) is responsible for cancer development and exceptional drug resistance, representing a highly important therapeutic target. The present study evaluated CSC-specific alterations induced by new-generation taxoid SBT-1214 and a novel polyenolic zinc-binding curcuminoid, CMC2.24, in prostate CSCs. Principal Findings The CD133high/CD44high phenotype was isolated from spontaneously immortalized patient-derived PPT2 cells and highly metastatic PC3MM2 cells. Weekly treatment of the NOD/SCID mice bearing PPT2- and PC3MM3-induced tumors with the SBT-1214 led to dramatic suppression of tumor growth. Four of six PPT2 and 3 of 6 PC3MM2 tumors have shown the absence of viable cells in residual tumors. In vitro, SBT-1214 (100nM-1µM; for 72 hr) induced about 60% cell death in CD133high/CD44+/high cells cultured on collagen I in stem cell medium (in contrast, the same doses of paclitaxel increased proliferation of these cells). The cytotoxic effects were increased when SBT-1214 was combined with the CMC2.24. A stem cell-specific PCR array assay revealed that this drug combination mediated massive inhibition of multiple constitutively up-regulated stem cell-related genes, including key pluripotency transcription factors. Importantly, this drug combination induced expression of p21 and p53, which were absent in CD133high/CD44high cells. Viable cells that survived this treatment regimen were no longer able to induce secondary spheroids, exhibited significant morphological abnormalities and died in 2-5 days. Conclusions We report here that the SBT-1214 alone, or in combination with CMC2.24, possesses significant activity against prostate CD133high/CD44+/high tumor-initiating cells. This drug combination efficiently inhibits expression of the majority of stem cell-related genes and pluripotency transcription factors. In addition, it induces a previously absent expression of p21 and p53 (“gene wake-up”), which can potentially reverse drug resistance by increasing sensitivity to anti-cancer drugs

NA49 results on hadron production: indications of the onset of deconfinement ?

The NA49 experiment at the CERN SPS measured the energy and system size dependence of particle production in A+A collisions. A change of the energy dependence of several hadron production properties at low SPS energies is observed which suggests a scenario requiring the onset of deconfinement.Comment: XXXV International Symposium on Multiparticle Dynamics 200

Bose-Einstein correlations of pion pairs in central Pb+Pb collisions at CERN SPS energies

Measurements of Bose-Einstein correlations of pion pairs in central Pb+Pb collisions were performed with the NA49 detector at the CERN SPS for beam energies of 20A, 30A, 40A, 80A, and 158A GeV. Correlation functions were measured in the longitudinally co-moving ``out-side-long'' reference frame as a function of rapidity and transverse momentum in the forward hemisphere of the reaction. Radius and correlation strength parameters were obtained from fits of a Gaussian parametrization. The results show a decrease of the radius parameters with increasing transverse momentum characteristic of strong radial flow in the pion source. No striking dependence on pion-pair rapidity or beam energy is observed. Static and dynamic properties of the pion source are obtained from simultaneous fits with a blast-wave model to radius parameters and midrapidity transverse momentum spectra. Predictions of hydrodynamic and microscopic models of Pb+Pb collisions are discussed.Comment: 22 pages, 23 figure

Multiplicity fluctuations in nuclear collisions at 158 A GeV

System size dependence of multiplicity fluctuations of charged particles produced in nuclear collisions at 158 A GeV was studied in the NA49 CERN experiment. Results indicate a non-monotonic dependence of the scaled variance of the multiplicity distribution with a maximum for semi-peripheral Pb+Pb interactions with number of projectile participants of about 35. This effect is not observed in a string-hadronic model of nuclear collision HIJING.Comment: Presented at "Focus on Multiplicity", 17-19 of June, Bari, Ital

Transverse Momentum Fluctuations in Nuclear Collisions at 158 AGeV

Results are presented on event-by-event fluctuations in transverse momentum of charged particles, produced at forward rapidities in p+p, C+C, Si+Si and Pb+Pb collisions at 158 AGeV. Three different characteristics are discussed: the average transverse momentum of the event, the Phi_pT fluctuation measure and two-particle transverse momentum correlations. In the kinematic region explored, the dynamical fluctuations are found to be small. However, a significant system size dependence of Phi_pT is observed, with the largest value measured in peripheral Pb+Pb interactions. The data are compared with predictions of several models.Comment: will be submitted to Phys. Rev.

Semi-Inclusive Lambda and Kshort Production in p-Au Collisions at 17.5 GeV/c

The first detailed measurements of the centrality dependence of strangeness production in p-A collisions are presented. Lambda and Kshort dn/dy distributions from 17.5 GeV/c p-Au collisions are shown as a function of "grey" track multiplicity and the estimated number of collisions, nu, made by the proton. The nu dependence of the Lambda yield deviates from a scaling of p-p data by the number of participants, increasing faster than this scaling for nu<=5 and saturating for larger nu. A slower growth in Kshort multiplicity with nu is observed, consistent with a weaker nu dependence of K-Kbar production than Y-K production.Comment: 5 pages, 3 figures, formatted with RevTex, current version has enlarged figure catpion