Phase I Study Of The Poly(ADP-Ribose) Polymerase Inhibitor, AG014699, In Combination With Temozolomide in Patients with Advanced Solid Tumors

Purpose: One mechanism of tumor resistance to cytotoxic therapy is repair of damaged DNA. Poly(ADP-ribose) polymerase (PARP)-1 is a nuclear enzyme involved in base excision repair, one of the five major repair pathways. PARP inhibitors are emerging as a new class of agents that can potentiate chemotherapy and radiotherapy. The article reports safety, efficacy, pharmacokinetic, and pharmacodynamic results of the first-in-class trial of a PARP inhibitor, AG014699, combined with temozolomide in adults with advanced malignancy.

Experimental Design: Initially, patients with solid tumors received escalating doses of AG014699 with 100 mg/m2/d temozolomide × 5 every 28 days to establish the PARP inhibitory dose (PID). Subsequently, AG014699 dose was fixed at PID and temozolomide escalated to maximum tolerated dose or 200 mg/m2 in metastatic melanoma patients whose tumors were biopsied. AG014699 and temozolomide pharmacokinetics, PARP activity, DNA strand single-strand breaks, response, and toxicity were evaluated.

Results: Thirty-three patients were enrolled. PARP inhibition was seen at all doses; PID was 12 mg/m2 based on 74% to 97% inhibition of peripheral blood lymphocyte PARP activity. Recommended doses were 12 mg/m2 AG014699 and 200 mg/m2 temozolomide. Mean tumor PARP inhibition at 5 h was 92% (range, 46-97%). No toxicity attributable to AG014699 alone was observed. AG014699 showed linear pharmacokinetics with no interaction with temozolomide. All patients treated at PID showed increases in DNA single-strand breaks and encouraging evidence of activity was seen.

Conclusions: The combination of AG014699 and temozolomide is well tolerated, pharmacodynamic assessments showing proof of principle of the mode of action of this new class of agents.

A phase I study of the p-glycoprotein antagonist Tarquidar in combination with Vinorelbine.

P-glycoprotein (Pgp) antagonists have had unpredictable pharmacokinetic interactions requiring reductions of chemotherapy. We report a phase I study using tariquidar (XR9576), a potent Pgp antagonist, in combination with vinorelbine. EXPERIMENTAL DESIGN: Patients first received tariquidar alone to assess effects on the accumulation of (99m)Tc-sestamibi in tumor and normal organs and rhodamine efflux from CD56+ mononuclear cells. In the first cycle, vinorelbine pharmacokinetics was monitored after the day 1 and 8 doses without or with tariquidar. In subsequent cycles, vinorelbine was administered with tariquidar. Tariquidar pharmacokinetics was studied alone and with vinorelbine. RESULTS: Twenty-six patients were enrolled. Vinorelbine 20 mg/m(2) on day 1 and 8 was identified as the maximum tolerated dose (neutropenia). Nonhematologic grade 3/4 toxicities in 77 cycles included the following: abdominal pain (4 cycles), anorexia (2), constipation (2), fatigue (3), myalgia (2), pain (4) and dehydration, depression, diarrhea, ileus, nausea, and vomiting, (all once). A 150-mg dose of tariquidar: (1) reduced liver (99m)Tc-sestamibi clearance consistent with inhibition of liver Pgp; (2) increased (99m)Tc-sestamibi retention in a majority of tumor masses visible by (99m)Tc-sestamibi; and (3) blocked Pgp-mediated rhodamine efflux from CD56+ cells over the 48 hours examined. Tariquidar had no effects on vinorelbine pharmacokinetics. Vinorelbine had no effect on tariquidar pharmacokinetics. One patient with breast cancer had a minor response, and one with renal carcinoma had a partial remission. CONCLUSIONS: Tariquidar is a potent Pgp antagonist, without significant side effects and much less pharmacokinetic interaction than previous Pgp antagonists. Tariquidar offers the potential to increase drug exposure in drug-resistant cancers.

The Combination of Multiple Classifiers Using an Evidential Reasoning Approach

In many domains when we have several competing classifiers available we want to synthesize them or some of them to get a more accurate classifier by a combination function. In this paper we propose a ‘class-indifferent’ method for combining classifier decisions represented by evidential structures called triplet and quartet, using Dempster's rule of combination. This method is unique in that it distinguishes important elements from the trivial ones in representing classifier decisions, makes use of more information than others in calculating the support for class labels and provides a practical way to apply the theoretically appealing Dempster–Shafer theory of evidence to the problem of ensemble learning. We present a formalism for modelling classifier decisions as triplet mass functions and we establish a range of formulae for combining these mass functions in order to arrive at a consensus decision. In addition we carry out a comparative study with the alternatives of simplet and dichotomous structure and also compare two combination methods, Dempster's rule and majority voting, over the UCI benchmark data, to demonstrate the advantage our approach offers. (A continuation of the work in this area that was published in IEEE Trans on KDE, and conferences)

Re-investigating Dempster's idea on evidence combination.

In this paper, we investigate the problem encountered by Dempster's combination rule in view of Dempster's original combination framework. We first show that the root of Dempster's combination rule (defined and named by Shafer) is Dempster's original idea on evidence combination. We then argue that Dempster's original idea on evidence combination is, in fact, richer than what has been formulated in the rule. We conclude that, by strictly following what Dempster has suggested, there should be no counterintuitive results when combining evidence.

A 4500-year proxy climate record from peatlands in the North of Ireland: the identification of widespread summer ‘drought phases’?

Mid-to-late Holocene high-resolution testate amoebae-derived water table reconstructions from two peatlands in the North of Ireland are presented. The proxy climate records are dated and correlated using a combination of AMS 14C dating, spheroidal carbonaceous particles and tephrochronology. The reconstructions start prior to the Hekla 4 tephra isochron (2395–2279 BC) and thus span the last ~4500 years. The records are compiled by the process of tuning within chronological errors, standardisation and stacking. Comparisons are made to existing palaeoclimate records from peatlands in Northern Britain and Ireland and the compiled lake-level record for mid-latitude Europe. Four coherent dry phases are identified in the records at ca 1150–800 BC, 320 BC–AD 150, AD 250–470 and AD 1850–2000. Recent research has shown that peat-derived water table reconstructions reflect summer water deficit and therefore the dry phases are interpreted as periods with a higher frequency and/or greater magnitudes of summer drought. These ‘drought phases’ occur during periods of relatively low 14C production, which may add support to the hypothesis of persistent solar forcing of climate change during the Holocene. Any relationship with the North Atlantic stacked drift ice record is less clear. © 2009 Elsevier Ltd. All rights reserved.

Coherent X-ray production via pulse reflection from laser-driven dense electron sheets

A scheme to obtain brilliant x-ray sources by coherent reflection of a counter-propagating pulse from laser-driven dense electron sheets is theoretically and numerically investigated in a self-consistent manner. A radiation pressure acceleration model for the dynamics of the electron sheets blown out from laser-irradiated ultrathin foils is developed and verified by PIC simulations. The first multidimensional and integral demonstration of the scheme by 2D PIC simulations is presented. It is found that the reflected pulse undergoes Doppler-upshift by a factor 4?z2, where ?z = (1- vz2/c2)-1/2 is the effective Lorentz factor of the electron sheet al ong its normal direction. Meanwhile the pulse electric field is intensified by a factor depending on the electron density of the sheet in its moving frame ne/?, where ? is the full Lorentz factor.