Non-hormonal systemic therapy in men with hormone-refractory prostate cancer and metastases: a systematic review from the Cancer Care Ontario Program in Evidence-based Care's Genitourinary Cancer Disease Site Group

BACKGROUND: Prostate cancer that has recurred after local therapy or disseminated distantly is usually treated with androgen deprivation therapy; however, most men will eventually experience disease progression within 12 to 20 months. New data emerging from randomized controlled trials (RCTs) of chemotherapy provided the impetus for a systematic review addressing the following question: which non-hormonal systemic therapies are most beneficial for the treatment of men with hormone-refractory prostate cancer (HRPC) and clinical evidence of metastases? METHODS: A systematic review was performed to identify RCTs or meta-analyses examining first-line non-hormonal systemic (cytotoxic and non-cytotoxic) therapy in patients with HRPC and metastases that reported at least one of the following endpoints: overall survival, disease control, palliative response, quality of life, and toxicity. Excluded were RCTs of second-line hormonal therapies, bisphosphonates or radiopharmaceuticals, or randomized fewer than 50 patients per trial arm. MEDLINE, EMBASE, the Cochrane Library, and the conference proceedings of the American Society of Clinical Oncology were searched for relevant trials. Citations were screened for eligibility by four reviewers and discrepancies were handled by consensus. RESULTS: Of the 80 RCTs identified, 27 met the eligibility criteria. Two recent, large trials reported improved overall survival with docetaxel-based chemotherapy compared to mitoxantrone-prednisone. Improved progression-free survival and rates of palliative and objective response were also observed. Compared with mitoxantrone, docetaxel treatment was associated with more frequent mild toxicities, similar rates of serious toxicities, and better quality of life. More frequent serious toxicities were observed when docetaxel was combined with estramustine. Three trials reported improved time-to-disease progression, palliative response, and/or quality of life with mitoxatrone plus corticosteroid compared with corticosteroid alone. Single trials reported improved disease control with estramustine-vinblastine, vinorelbine-hydrocortisone, and suramin-hydrocortisone compared to controls. Trials of non-cytotoxic agents have reported equivocal results. CONCLUSION: Docetaxel-based chemotherapy modestly improves survival and provides palliation for men with HRPC and metastases. Other than androgen deprivation therapy, this is the only other therapy to have demonstrated improved overall survival in prostate cancer in RCTs. Further investigations to identify more effective therapies for HRPC including the use of systemic therapies earlier in the natural history of prostate cancer are warranted

Oceanic corrosion test of bare and zinc-protected aluminum alloys for seawater heat exchangers

Bare 3004 tubes, 7072 Alclad 3004 tubes, and bare and zinc diffusion treated 3003 extrusions from a brazed aluminum, plate-fin heat exchanger were exposed to 1.8 m/sec flowing seawater aboard an open ocean test facility moored 3.4 km off the southeast coast of Puerto Rico. After six months exposure, the average corrosion rates for most varieties of aluminum materials converged to a low value of 0.015 mm/yr (0.6 mils/yr). Pitting did not occur in bare 3003 and 3004 samples during the six month test. Pitting did occur to varying degrees in the Alclad and zinc diffusion treated material, but did not penetrate to the base metal. Biofouling countermeasures (intermittent chlorination and brushing) did not affect the corrosion rates to any significant extent. Intermittent chlorination at a level of 0.5 ppm for 28 minutes daily controlled microbiofouling of the samples but did not prevent the development of a macrobiofouling community in areas of the plumbing with low flow

Deconvoluting kinase inhibitor induced cardiotoxicity

Many drugs designed to inhibit kinases have their clinical utility limited by cardiotoxicity-related label warnings or prescribing restrictions. While this liability is widely recognized, designing safer kinase inhibitors (KI) requires knowledge of the causative kinase(s). Efforts to unravel the kinases have encountered pharmacology with nearly prohibitive complexity. At therapeutically relevant concentrations, KIs show promiscuity distributed across the kinome. Here, to overcome this complexity, 65 KIs with known kinome-scale polypharmacology profiles were assessed for effects on cardiomyocyte (CM) beating. Changes in human iPSC-CM beat rate and amplitude were measured using label-free cellular impedance. Correlations between beat effects and kinase inhibition profiles were mined by computation analysis (Matthews Correlation Coefficient) to identify associated kinases. Thirty kinases met criteria of having (1) pharmacological inhibition correlated with CM beat changes, (2) expression in both human-induced pluripotent stem cell-derived cardiomyocytes and adult heart tissue, and (3) effects on CM beating following single gene knockdown. A subset of these 30 kinases were selected for mechanistic follow up. Examples of kinases regulating processes spanning the excitation–contraction cascade were identified, including calcium flux (RPS6KA3, IKBKE) and action potential duration (MAP4K2). Finally, a simple model was created to predict functional cardiotoxicity whereby inactivity at three sentinel kinases (RPS6KB1, FAK, STK35) showed exceptional accuracy in vitro and translated to clinical KI safety data. For drug discovery, identifying causative kinases and introducing a predictive model should transform the ability to design safer KI medicines. For cardiovascular biology, discovering kinases previously unrecognized as influencing cardiovascular biology should stimulate investigation of underappreciated signaling pathways

Aggregation and Representation in the European Parliament Party Groups

While members of the European Parliament are elected in national constituencies, their votes are determined by the aggregation of MEPs in multinational party groups. The uncoordinated aggregation of national party programmes in multinational EP party groups challenges theories of representation based on national parties and parliaments. This article provides a theoretical means of understanding representation by linking the aggregation of dozens of national party programmes in different EP party groups to the aggregation of groups to produce the parliamentary majority needed to enact policies. Drawing on an original data source of national party programmes, the EU Profiler, the article shows that the EP majorities created by aggregating MEP votes in party groups are best explained by cartel theories. These give priority to strengthening the EP’s collective capacity to enact policies rather than voting in accord with the programmes they were nationally elected to represent

General-relativistic Model of Magnetically Driven Jet

The general scheme for the construction of the general-relativistic model of the magnetically driven jet is suggested. The method is based on the usage of the 3+1 MHD formalism. It is shown that the critical points of the flow and the explicit radial behavior of the physical variables may be derived through the jet ``profile function."Comment: 12 pages, LaTex, no figure

Nonlinear Circuits

Contains reports on four research projects

Miscellaneous Problems

Contains reports on five research projects

Measurement of the eta-Meson Mass using psi(2S) --> eta J/psi

We measure the mass of the eta meson using psi(2S) --> eta J/psi events acquired with the CLEO-c detector operating at the CESR e+e- collider. Using the four decay modes eta --> gamma gamma, 3pi0, pi+pi-pi0, and pi+pi-gamma, we find M(eta)=547.785 +- 0.017 +- 0.057 MeV, in which the first uncertainty is statistical and the second systematic. This result has an uncertainty comparable to the two most precise previous measurements and is consistent with that of NA48, but is inconsistent at the level of 6.5sigma with the much smaller mass obtained by GEM.Comment: 10 pages postscript,also available through http://www.lns.cornell.edu/public/CLNS/2007/, Submitted to PR

Suppressed Decays of D_s^+ Mesons to Two Pseudoscalar Mesons

Using data collected near the Ds*+ Ds- peak production energy Ecm = 4170 MeV by the CLEO-c detector, we study the decays of Ds+ mesons to two pseudoscalar mesons. We report on searches for the singly-Cabibbo-suppressed Ds+ decay modes K+ eta, K+ eta', pi+ K0S, K+ pi0, and the isospin-forbidden decay mode Ds+ to pi+ pi0. We normalize with respect to the Cabibbo-favored Ds+ modes pi+ eta, pi+ eta', and K+ K0S, and obtain ratios of branching fractions: Ds+ to K+ eta / Ds+ to pi+ eta = (8.9 +- 1.5 +- 0.4)%, Ds+ to K+ eta' / Ds+ to pi+ eta' = (4.2 +- 1.3 +- 0.3)%, Ds+ to pi+ K0S / Ds+ to K+ K0S = (8.2 +- 0.9 +- 0.2)%, Ds+ to K+ pi0 / Ds+ to K+ K0S = (5.0 +- 1.2 +- 0.6)%, and Ds+ to pi+ pi0 / Ds+ to K+ K0S < 4.1% at 90% CL, where the uncertainties are statistical and systematic, respectively.Comment: 9 pages postscript,also available through http://www.lns.cornell.edu/public/CLNS/2007/, Submitted to PR