BCL-W is dispensable for the sustained survival of select Burkitt lymphoma and diffuse large B-cell lymphoma cell lines

Dysregulated expression of BCL-2 family proteins allows cancer cells to escape apoptosis. To counter this, BH3-mimetic drugs that target and inhibit select BCL-2 prosurvival proteins to induce apoptosis have been developed for cancer therapy. Venetoclax, which targets BCL-2, has been effective as therapy for patients with chronic lymphocytic leukemia, and MCL-1-targeting BH3-mimetic drugs have been extensively evaluated in preclinical studies for a range of blood cancers. Recently, BCL-W, a relatively understudied prosurvival member of the BCL-2 protein family, has been reported to be abnormally upregulated in Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), and Hodgkin lymphoma patient samples. Therefore, to determine if BCL-W would be a promising therapeutic target for B-cell lymphomas, we have examined the role of BCL-W in the sustained growth of human BL- and DLBCL-derived cell lines. We found that CRISPR/CAS9-mediated loss or short hairpin RNA-mediated knockdown of BCL-W expression in selected BL and DLBCL cell lines did not lead to spontaneous apoptosis and had no effect on their sensitivity to a range of BH3-mimetic drugs targeting other BCL-2 prosurvival proteins. Our results suggest that BCL-W is not universally required for the sustained growth and survival of human BL and DLBCL cell lines. Thus, targeting BCL-W in this subset of B-cell lymphomas may not be of broad therapeutic benefit

Prodrug Strategy for PSMA-targeted Delivery of TGX-221 to Prostate Cancer Cells

TGX-221 is a potent, selective, and cell membrane permeable inhibitor of the PI3K p110β catalytic subunit. Recent studies showed that TGX-221 has anti-proliferative activity against PTEN-deficient tumor cell lines including prostate cancers. The objective of this study was to develop an encapsulation system for parenterally delivering TGX-221 to the target tissue through a prostate-specific membrane aptamer (PSMAa10) with little or no side effects. In this study, PEG-PCL micelles were formulated to encapsulate the drug, and a prodrug strategy was pursued to improve the stability of the carrier system. Fluorescence imaging studies demonstrated that the cellular uptake of both drug and nanoparticles were significantly improved by targeted micelles in a PSMA positive cell line. The area under the plasma concentration time curve of the micelle formulation in nude mice was 2.27-fold greater than the naked drug, and the drug clearance rate was 17.5-fold slower. These findings suggest a novel formulation approach for improving site-specific drug delivery of a molecular-targeted prostate cancer treatment

Identified baryon and meson distributions at large transverse momenta from Au+Au collisions at sNN=200\sqrt{s_{_{NN}}} = 200 GeV

Transverse momentum spectra of $\pi^{\pm}$, $p$ and $\bar{p}$ up to 12 GeV/c at mid-rapidity in centrality selected Au+Au collisions at $\sqrt{s_{_{NN}}} = 200$ GeV are presented. In central Au+Au collisions, both $\pi^{\pm}$ and $p(\bar{p})$ show significant suppression with respect to binary scaling at $p_T >$ 4 GeV/c. Protons and anti-protons are less suppressed than $\pi^{\pm}$, in the range 1.5 $< p_{T} <$6 GeV/c. The $\pi^-/\pi^+$ and $\bar{p}/p$ ratios show at most a weak $p_T$ dependence and no significant centrality dependence. The $p/\pi$ ratios in central Au+Au collisions approach the values in p+p and d+Au collisions at $p_T >$ 5 GeV/c. The results at high $p_T$ indicate that the partonic sources of $\pi^{\pm}$, $p$ and $\bar{p}$ have similar energy loss when traversing the nuclear medium.Comment: 6 pages, 4 figure

Longitudinal double-spin asymmetry and cross section for inclusive jet production in polarized proton collisions at sqrt(s) = 200 GeV

We report a measurement of the longitudinal double-spin asymmetry A_LL and the differential cross section for inclusive midrapidity jet production in polarized proton collisions at sqrt(s)=200 GeV. The cross section data cover transverse momenta 5 < pT < 50 GeV/c and agree with next-to-leading order perturbative QCD evaluations. The A_LL data cover 5 < pT < 17 GeV/c and disfavor at 98% C.L. maximal positive gluon polarization in the polarized nucleon.Comment: 6 pages, 3 figures. Minor changes from review process in Phys. Rev. Lett. Plain text tables of data in STAR publications may be found at http://www.star.bnl.gov/central/publications

Neutral Kaon Interferometry in Au+Au collisions at sqrt(s_NN) = 200 GeV

We present the first statistically meaningful results from two-K0s interferometry in heavy-ion collisions. A model that takes the effect of the strong interaction into account has been used to fit the measured correlation function. The effects of single and coupled channel were explored. At the mean transverse mass m_T = 1.07 GeV, we obtain the values R = 4.09 +/- 0.46 (stat.) +/- 0.31 (sys) fm and lambda = 0.92 +/- 0.23 (stat) +/- 0.13 (sys), where R and lambda are the invariant radius and chaoticity parameters respectively. The results are qualitatively consistent with m_T systematics established with pions in a scenario characterized by a strong collective flow.Comment: 11 pages, 10 figure

Minijet deformation and charge-independent angular correlations on momentum subspace (η,ϕ)(\eta,\phi) in Au-Au collisions at sNN\sqrt{s_{NN}} = 130 GeV

First measurements of charge-independent correlations on angular difference variables $\eta_1 - \eta_2$ (pseudorapidity) and $\phi_1 - \phi_2$ (azimuth) are presented for primary charged hadrons with transverse momentum $0.15 \leq p_t \leq 2$ GeV/$c$ and $|\eta| \leq 1.3$ from Au-Au collisions at $\sqrt{s_{NN}} = 130$ GeV. Strong charge-independent angular correlations are observed associated with jet-like structures and elliptic flow. The width of the jet-like peak on $\eta_1 - \eta_2$ increases by a factor 2.3 from peripheral to central collisions, suggesting strong coupling of semi-hard scattered partons to a longitudinally-expanding medium. New methods of jet analysis introduced here provide evidence for nonperturbative QCD medium effects in heavy ion collisions.Comment: 8 pages, 4 figure

The energy dependence of ptp_t angular correlations inferred from mean-ptp_{t} fluctuation scale dependence in heavy ion collisions at the SPS and RHIC

We present the first study of the energy dependence of $p_t$ angular correlations inferred from event-wise mean transverse momentum fluctuations in heavy ion collisions. We compare our large-acceptance measurements at CM energies $\sqrt{s_{NN}} =$ 19.6, 62.4, 130 and 200 GeV to SPS measurements at 12.3 and 17.3 GeV. $p_t$ angular correlation structure suggests that the principal source of $p_t$ correlations and fluctuations is minijets (minimum-bias parton fragments). We observe a dramatic increase in correlations and fluctuations from SPS to RHIC energies, increasing linearly with $\ln \sqrt{s_{NN}}$ from the onset of observable jet-related fluctuations near 10 GeV.Comment: 10 pages, 4 figure

Plasma Wakefield Acceleration with a Modulated Proton Bunch

The plasma wakefield amplitudes which could be achieved via the modulation of a long proton bunch are investigated. We find that in the limit of long bunches compared to the plasma wavelength, the strength of the accelerating fields is directly proportional to the number of particles in the drive bunch and inversely proportional to the square of the transverse bunch size. The scaling laws were tested and verified in detailed simulations using parameters of existing proton accelerators, and large electric fields were achieved, reaching 1 GV/m for LHC bunches. Energy gains for test electrons beyond 6 TeV were found in this case.Comment: 9 pages, 7 figure

A Comprehensive Association Analysis of Homocysteine Metabolic Pathway Genes in Singaporean Chinese with Ischemic Stroke

10.1371/journal.pone.0024757PLoS ONE69