Novel actions of next-generation taxanes benefit advanced stages of prostate cancer.

PURPOSE: To improve the outcomes of patients with castration-resistant prostate cancer (CRPC), there is an urgent need for more effective therapies and approaches that individualize specific treatments for patients with CRPC. These studies compared the novel taxane cabazitaxel with the previous generation docetaxel, and aimed to determine which tumors are most likely to respond. EXPERIMENTAL DESIGN: Cabazitaxel and docetaxel were compared via in vitro modeling to determine the molecular mechanism, biochemical and cell biologic impact, and cell proliferation, which was further assessed ex vivo in human tumor explants. Isogenic pairs of RB knockdown and control cells were interrogated in vitro and in xenograft tumors for cabazitaxel response. RESULTS: The data herein show that (i) cabazitaxel exerts stronger cytostatic and cytotoxic response compared with docetaxel, especially in CRPC; (ii) cabazitaxel induces aberrant mitosis, leading to pyknotic and multinucleated cells; (iii) taxanes do not act through the androgen receptor (AR); (iv) gene-expression profiling reveals distinct molecular actions for cabazitaxel; and (v) tumors that have progressed to castration resistance via loss of RB show enhanced sensitivity to cabazitaxel. CONCLUSIONS: Cabazitaxel not only induces improved cytostatic and cytotoxic effects, but also affects distinct molecular pathways, compared with docetaxel, which could underlie its efficacy after docetaxel treatment has failed in patients with CRPC. Finally, RB is identified as the first potential biomarker that could define the therapeutic response to taxanes in metastatic CRPC. This would suggest that loss of RB function induces sensitization to taxanes, which could benefit up to 50% of CRPC cases

On the fourth-order accurate compact ADI scheme for solving the unsteady Nonlinear Coupled Burgers' Equations

The two-dimensional unsteady coupled Burgers' equations with moderate to severe gradients, are solved numerically using higher-order accurate finite difference schemes; namely the fourth-order accurate compact ADI scheme, and the fourth-order accurate Du Fort Frankel scheme. The question of numerical stability and convergence are presented. Comparisons are made between the present schemes in terms of accuracy and computational efficiency for solving problems with severe internal and boundary gradients. The present study shows that the fourth-order compact ADI scheme is stable and efficient

The retinoblastoma tumor suppressor modulates DNA repair and radioresponsiveness.

PURPOSE: Perturbations in the retinoblastoma pathway are over-represented in advanced prostate cancer; retinoblastoma loss promotes bypass of first-line hormone therapy. Conversely, preliminary studies suggested that retinoblastoma-deficient tumors may become sensitized to a subset of DNA-damaging agents. Here, the molecular and in vivo consequence of retinoblastoma status was analyzed in models of clinical relevance. EXPERIMENTAL DESIGN: Experimental work was performed with multiple isogenic prostate cancer cell lines (hormone sensitive: LNCaP and LAPC4 cells and hormone resistant C42, 22Rv1 cells; stable knockdown of retinoblastoma using shRNA). Multiple mechanisms were interrogated including cell cycle, apoptosis, and DNA damage repair. Transcriptome analysis was performed, validated, and mechanisms discerned. Cell survival was measured using clonogenic cell survival assay and in vivo analysis was performed in nude mice with human derived tumor xenografts. RESULTS: Loss of retinoblastoma enhanced the radioresponsiveness of both hormone-sensitive and castrate-resistant prostate cancer. Hypersensitivity to ionizing radiation was not mediated by cell cycle or p53. Retinoblastoma loss led to alteration in DNA damage repair and activation of the NF-κB pathway and subsequent cellular apoptosis through PLK3. In vivo xenografts of retinoblastoma-deficient tumors exhibited diminished tumor mass, lower PSA kinetics, and decreased tumor growth after treatment with ionizing radiation (P \u3c 0.05). CONCLUSIONS: Loss of retinoblastoma confers increased radiosensitivity in prostate cancer. This hypersensitization was mediated by alterations in apoptotic signaling. Combined, these not only provide insight into the molecular consequence of retinoblastoma loss, but also credential retinoblastoma status as a putative biomarker for predicting response to radiotherapy

The failed liberalisation of Algeria and the international context: a legacy of stable authoritarianism

The paper attempts to challenge the somewhat marginal role of international factors in the study of transitions to democracy. Theoretical and practical difficulties in proving causal mechanisms between international variables and domestic outcomes can be overcome by defining the international dimension in terms of Western dominance of world politics and by identifying Western actions towards democratising countries. The paper focuses on the case of Algeria, where international factors are key in explaining the initial process of democratisation and its following demise. In particular, the paper argues that direct Western policies, the pressures of the international system and external shocks influence the internal distribution of power and resources, which underpins the different strategies of all domestic actors. The paper concludes that analysis based purely on domestic factors cannot explain the process of democratisation and that international variables must be taken into more serious account and much more detailed

AMRA: An Adaptive Mesh Refinement Hydrodynamic Code for Astrophysics

Implementation details and test cases of a newly developed hydrodynamic code, AMRA, are presented. The numerical scheme exploits the adaptive mesh refinement technique coupled to modern high-resolution schemes which are suitable for relativistic and non-relativistic flows. Various physical processes are incorporated using the operator splitting approach, and include self-gravity, nuclear burning, physical viscosity, implicit and explicit schemes for conductive transport, simplified photoionization, and radiative losses from an optically thin plasma. Several aspects related to the accuracy and stability of the scheme are discussed in the context of hydrodynamic and astrophysical flows.Comment: 41 pages, 21 figures (9 low-resolution), LaTeX, requires elsart.cls, submitted to Comp. Phys. Comm.; additional documentation and high-resolution figures available from http://www.camk.edu.pl/~tomek/AMRA/index.htm

Should an Institution That Has Commercial Rights in a New Drug or Device Be Allowed to Evaluate the Technology?

Background to the debate: In the United States, the passage of the Bayh–Dole Act in 1980 encouraged universities to license inventions for commercial development. Although this financial incentive can stimulate academic researchers to discover new drugs and devices, there is concern that the possibility of monetary reward could distort investigators' objectivity

Monoclonal antibodies made to chick mesencephalic neural crest cells and to ciliary ganglion neurons identify a common antigen on the neurons and a neural crest subpopulation

We previously reported the production of monoclonal antibodies (Mabs) that identified cell surface components of cultured chick and quail ciliary ganglion (CG) neurons and of a subpopulation of neural crest (NC) cells from 31-hr chick embryos (stage 9). Here we demonstrate that another Mab, CG-14, which was prepared to nitrocellulose-immobilized, lightly fixed (0.125% paraformaldehyde) mesencephalic NC cells from 31-hr (stage 9) chick embryos, labels the same antigen(s) recognized by CG-1 and CG-4 on both the CG neurons and the subpopulation of NC cells. All three Mabs label a polypeptide of 75 kD on Western blots of one-dimensional SDS-polyacrylamide gels. CG-14 blocked the binding of CG-1 and/or CG-4 to the 75 kD band on Western blots and blocked the binding of CG-1 and CG-4 to CG and NC cells. CG-1 and/or CG-4 antibodies, in turn, blocked the binding of CG-14 to Western blots, as well as NC and CG cells. We had previously shown that antibodies CG-1 and CG-4 were synergistically cytotoxic for the majority (95%) of cultured CG neurons in vitro in the presence of guinea pig complement. Here we show that the antibodies, which are both of the Γ2a subclass, are also cytotoxic for the NC cells that they label in vitro. After the cells are ablated in culture, no other cells bearing the antigen(s) recognized by any of the three Mabs appear over a 2.5-week period. CG-14, however, is not cytotoxic for either the CG or NC cell populations alone or in combinations with CG-1 or CG-4. These results confirm our original observation that cultured CG neurons and NC cells share cell-surface antigen(s). The antigen recognized by all three Mabs appears to be the same whether the immunogen used to produce the antibodies was CG neurons or NC cells. This finding encourages us to continue tests of the hypothesis that the subpopulation of mesencephalic neural crest cells contributes to the formation of the ciliary ganglion in the embryo. Further characterization of the antigen appears in the accompanying paper.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50219/1/490210204_ftp.pd