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Diffuse large B cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin lymphoma. While the initial treatment strategy is highly effective, relapse occurs in 40% of cases. Histone deacetylase inhibitors (HDACi) are a promising class of anti-cancer drugs but their single agent efficacy against relapsed DLBCL has been variable, ranging from few complete/partial responses to some stable disease. However, most patients showed no response to HDACi monotherapy for unknown reasons. Here we show that sensitivity and resistance to the hydroxamate HDACi, PXD101, can be modeled in DLBCL cell lines. Sensitivity is characterized by G2/M arrest and apoptosis and resistance by reversible G1 growth arrest. These responses to PXD101 are independent of several negative prognostic indicators such as DLBCL subtype, BCL2 and MYC co-expression, and p53 mutation, suggesting that HDACi might be used effectively against highly aggressive DLBCL tumors if they are combined with other therapeutics that overcome HDACi resistance. Our investigation of mechanisms underlying HDACi resistance showed that cyclin-dependent kinase inhibitors (CKIs), p21 and p27, are upregulated by PXD101 in a sustained fashion in resistant cell lines concomitant with decreased activity of the cyclin E/cdk2 complex and decreased Rb phosphorylation. PXD101 treatment results in increased association of CKI with the cyclin E/cdk2 complex in resistant cell lines but not in a sensitive line, indicating that the CKIs play a key role in G1 arrest. The results suggest several treatment strategies that might increase the efficacy of HDACi against aggressive DLBCL.

A general formalism is described for the treatment of Coulomb fission, within the framework of the semiquantal theory. We develop a model for the fission probabilities of levels excited in Coulomb excitation. This model contains penetration of the double-humped fission barrier, competition from gamma and neutron emission, and the spreading of the collective states into noncollective compound states. For ::dW+ii8U, the fission probability at B,"= 180" is increased by a factor of 3.9, 3.3, and 2.0 at E/E""=0.77, 0.85, and 0.935, respectively, compared to the simplified sharp cutoff model used in earlier model calculations. The enhancement Comes from barrier penetration. The damping of the fission probability due to spreading into noncollective compound states is small. Prompt Coulomb fission (near the distance of closest approach) is studied in a one-dimensional model. The results clearly imply that prompt fission is negligible. We have also studied the sudden approximation for collective rotational levels in connection with Coulomb fission. At high spins (I z 2 0 ) , it leads to significant errors. Contrary to the basic assumption of the sudden approximation that the nuclear symmetry axis remains fixed during the collision, it is shown that Coulomb excitation results in a strong alignment of the riuclear symmetry axis perpendicular to the beam axis at small intemuclear distances.neutron and y emission. Calculated d E p , B, . , .= 180').

Strong indirect evidence exists for the existence of attractive forces between nuclei making surface contact. Experimentally, the recent observations of spontaneous positron production in heavy-ion collisions can only be understood if nuclei stick together for times long compared to the collision time. We show that any such tendency for nuclei to attract implies the existence of nuclear molecules with entirely new kinds of collective modes. We present a simple model for these modes and apply it to 2 3 8~-2 3 8~.PACS numbers: 25.70.Jj, 21.30.+y There seems to be little doubt that spontaneous positrons have been observed in recent', * heavy-ion experiments. The theoretical ana~ysisl-~ of the data requires the nuclei to stick together for times T of order 10-l9 sec. Because the experiments are done at nominally sub-Coulomb energies, it was initially difficult to understand how the nuclei could get sufficiently close together for attractive nuclear forces to act. However, double-folding-model calculations4 have shown that the nuclear plus Coulomb interactions of strongly deformed nuclei show a dramatic dependence on nuclear orientation. These calculations predict the formation of potential barriers which are lower by 100 MeV when the nuclei approach with their symmetry axes collinear than in the least favorable case, in which they approach so that their equators touch. Although the foldingmodel predictions cannot be relied upon at shorter distances where there is significant overlap of nuclear densities, they suggest the very real possibility that a potential energy minimum exists in the nuclear surface-a "pocket, " depending on orientation, which can capture the nuclei. Improved potential models are under study, and preliminary calculations5 suggest the existence of pockets. The purpose of this Letter is to show that pockets of only a few megaelectronvolts in depth are needed to produce a rich spectroscopy of quasimolecular resonances, and to present a simple model for the structure of some of these states of heavy nuclear molecules.Quantum mechanically capture behind a barrier and the resultant delay time imply a resonance, of width related to delay time T according to The "sticking times" required correspond to 50-100 keV. A simple estimate can be made of the minimum depth D needed to produce a resonance this width. Consider the potential V sketched in Fig. l(a). A resonance is expected at the energy