Search

Purpose There is an unmet need for biomarkers for identifying patients likely to benefit from anticancer treatments, selecting dose, and understanding mechanisms of resistance. Plasma vascular endothelial growth factor (VEGF) and soluble VEGF receptor 2 (sVEGFR-2) are known to be modulated by VEGF pathway inhibitors. It is unknown whether chemotherapy or VEGFR inhibitor/chemotherapy combinations induce changes in these or other cytokines and angiogenic factors (CAFs) and whether such changes could be markers of benefit. Methods Thirty-five plasma CAFs were analyzed using multiplexed bead arrays and enzyme-linked immunosorbent assays from 123 patients with non–small-cell lung cancer in a randomized phase II study who received vandetanib, a VEGFR and epidermal growth factor receptor inhibitor, monotherapy carboplatin and paclitaxel (CP), or the combination (VCP). Changes in CAFs at days 8, 22, and 43 from baseline were correlated with progression risk. Results VEGF increased and sVEGFR-2 decreased by day 43 in the vandetanib arm, whereas a distinct pattern was observed in the CP and VCP arms, with significant decreases in interleukin (IL) -12, IL-1 receptor antagonist, and matrix metalloproteinase 9 (MMP-9) and increased macrophage chemoattractant protein 1. In each treatment arm, changes in different markers were associated with progression risk. For example, increases in IL-8 with VCP, MMP-9 with CP, and VEGF with vandetanib monotherapy were associated with increased progression risk, and increase in intercellular adhesion molecule 1 with vandetanib was associated with decreased risk. Conclusion Vandetanib and chemotherapy treatment led to distinct patterns of CAF changes; the combination resembled chemotherapy alone. Changes in specific CAFs correlated with clinical outcome, but markers differed for each treatment arm. CAF profiling may provide insights into the biologic effects of treatment and identify drug-specific markers of activity and clinical benefit.

Background: We investigated cytokines and angiogenic factors (CAFs) in patients with metastatic renal cell carcinoma (mRCC) treated in a randomized phase II clinical trial of sorafenib versus sorafenib+ interferon-a (IFN-a) that yielded no differences in progression-free survival (PFS). We aimed to link the CAF profile to PFS and select candidate predictive and prognostic markers for further study. Methods: The concentrations of 52 plasma CAFs were measured pretreatment (n = 69), day 28, and day 56 using multiplex bead arrays and enzyme-linked immunosorbent assay. We investigated the association between baseline levels of CAFs with PFS and posttreatment changes. Results: Unsupervised CAF clustering analysis revealed two distinct mRCC patient groups with elevated proangiogenic or proinflammatory mediators. A six-marker baseline CAF signature [osteopontin, vascular endothelial growth factor (VEGF), carbonic anhydrase 9, collagen IV, VEGF receptor-2, and tumor necrosis factor-related apoptosis-inducing ligand] correlated with PFS benefit (hazard ratio 0.20 versus 2.25, signature negative versus positive, respectively; P = 0.0002). While changes in angiogenic factors were frequently attenuated by the sorafenib+ IFN combination, most key immunomodulatory mediators increased. Conclusions: Using CAF profiling, we identified two mRCC patient groups, a candidate plasma signature for predicting PFS benefit, and distinct marker changes occurring with each treatment. This platform may provide valuable insights into renal cell carcinoma biology and the molecular consequences of targeted therapies.

Basal stem rot (BSR) of oil palm (Elaeis guineensis) is caused by Ganoderma boninense, and, commercially, is one of the most devastating diseases in South East Asia. Losses of more than 80% of stands by the time they are halfway through their normal economic life have been reported. High incidence of BSR results in economic losses due to zero yields from dead palms and significantly reduced weight and number of fruit bunches in infected but living palms. Due to the importance of oil palm industry to Malaysia’s economy, the transfer of any materials that are related to Ganoderma is strictly prohibited from Peninsular Malaysia to Sabah and Sarawak. No basic identification method using molecular techniques for the identification of G. boninense exist in this study for G. boninense isolates from Sabah. The only report on this pathogens isolate in Sabah was based on their morphology and pathogencity. In conjunction with the morphological similarities among the different isolates, there are numerous opinions on the aggressiveness of the pathogen in Sabah. The isolates of G. boninense from Sabah were claimed to be less aggressive compared to those from Peninsular Malaysia. This may be due to lower incidence of BSR in Sabah and Sarawak compared to Peninsular Malaysia. Since the oil palm industry is a fast income-generating tool, data related to it may be highly sensitive. Researchers, plantation managers and entrepreneurs are not forthcoming with the information on oil palm genetic materials or isolates of G. boninense with others. The current speculations on the Sabah isolates need further investigation. In this study, we report the identity of isolates Ganoderma from Langkon Oil Palm Estate in Sabah, Malaysia. The identity of these isolates was confirmed using DNA sequence analysis after PCR amplification. The latter method shows that the Sabah isolates were very similar to aggressive G. boninense strains FA5017 or FA5035 from West Malaysia, with a maximum similarity of 98%.Key words: Aggressive, FA5017, FA5035, G1_5, isolate.

In this paper we present a new binary-programming formulation for the Steiner problem in graphs (SPG), which is well known to be NP-hard. We use this formulation to generate test problems with known optimal solutions. The technique uses the KKT optimality conditions on the corresponding quadratically constrained optimization problem.

Consider a set P of points in a normed space whose unit sphere is a d-dimensional symmetric polytope with 2d extreme points. This paper proves that there always exists a Steiner minimum tree whose Steiner points are located only at points whose coordinates appear in points of P. This generalizes a recent result of Snyder on d-dimensional rectilinear space, which itself extends Hanan’s well-known and much quoted result on the rectilinear plane. Furthermore, the proof in this paper is much simpler than Snyder’s proof, even considerably shorter than Hanan’s proof. A consequence of this result is that the Steiner problem for P in such a space is reduced to a Steiner problem on graphs and is solvable by any existing Steiner graph algorithms. The paper also conjectures that such a reduction is impossible if the polytope has more than $2d$ extreme points and provides partial support for the conjecture.

Let P be a set of n points on the euclidean plane. Let Ls(P) and Lm(P) denote the lengths of the Steiner minimum tree and the minimum spanning tree on P, respectively. In 1968, Gilbert and Pollak conjectured that for any P, Ls(P) >/= (radical3/2)Lm(P). We provide an abridged proof for their conjecture in this paper.

5114 Background: SR, an oral inhibitor of Raf kinase, RET-receptor (R), VEGFR-1, 2, and 3, PDGFR-β, FLT-3, and c-KIT tyrosine kinases, has been shown to prolong progression-free survival (PFS) in mRCC after cytokine failure. In a phase II trial, mRCC pts were randomized to first line treatment with SR vs. SR plus interferon (IFN) to assess whether combination therapy improved PFS. Both treatment arms showed similar outcomes (Tannir et al, ASCO. 2008). Here we investigated predictive and prognostic biomarkers in plasma. Methods: Pts received SR 400 mg PO BID or same dose SR plus IFN 0.5 MU SC BID. Plasma was collected from 69 pts at baseline (BL; SR 34, SR+IFN 35), 59 on day (D) 28, and 57 pts on D56. We used multiplex bead suspension arrays to measure concentrations of 54 CAFs, including VEGF, PDGFbb, EGF, HGF, MMP-9, and multiple chemokines and interleukins (IL). Osteopontin (OPN), soluble carbonic anhydrase 9 (sCA9), placental growth factor (PlGF), collagen type IV (ColIV) and sVEGFR-2 were measured by ELISA. The primary objective of this analysis was to establish a CAF signature based on a set of individual markers at BL with a significant and differential impact on the association between treatment arm and PFS. Results: Among 52 CAFs available at BL, higher than median EGF concentrations associated with poor outcome independently of treatment arm, whereas low IL-2 had the opposite effect (p = 0.003 for both). Only OPN showed a significant treatment by factor interaction at BL (p < 0.01), suggesting that OPN has a differential effect on PFS in the two arms. Pts with high OPN benefitted more from single agent SR (7.74 vs. 3.93 mos for the combination; p = 0.007), but no differences were found for those with low OPN. Lower than median on-treatment increases in sCA9 (D28, p = 0.01) and GRO-alpha (D56, p = 0.04) on SR only were also associated with a better outcome. A 6-marker CAF signature at BL containing OPN, sCA9, VEGF, sVEGFR-2, ColIV, and TRAIL demonstrated predictive value on PFS. Conclusions: A CAF signature showed potential value in predicting differential benefit from single agent SR vs. SR+IFN in mRCC. Broad-based screening of circulating CAFs may identify predictive and prognostic biomarkers in the context of clinical trials. [Table: see text]

7593 Background: VAN (ZD6474) is an oral inhibitor of VEGFR, EGFR and RET. In a phase II trial, 181 patients with advanced NSCLC were randomized to 1st-line treatment with VAN, CP or VAN + CP. Progression free survival (PFS) was prolonged for VAN + CP vs CP (Heymach et al, submitted for ASCO 2007). Exploratory subgroup analyses suggest gender differences in PFS benefit for VAN + CP vs CP (HR 0.47 in females vs 1.05 in males). We performed exploratory analyses of plasma levels of 35 C/AFs to investigate gender differences and potential prognostic or predictive markers. Methods: Plasma was collected at baseline (n = 123; VAN 55, CP 32, VAN + CP 36), day (D) 8 (n = 104), D22 (n = 95), and D43 (n = 83). We used multiplex bead assays to measure 33 plasma C/AFs, including VEGF, basic FGF, EGF, HGF, E-selectin, ICAM-1, MMP-9, multiple chemokines and interleukins (IL). Osteopontin and sVEGFR-2 were measured by ELISA. Cox models were applied on PFS to identify prognostic/predictive markers after rank transformation and adjusted for covariates. Results: Significant gender differences in baseline C/AF levels were seen for IL-15, IL-1RA, IL-2R, MIG, and MIP-1A (all higher in females, all p = 0.022). Controlling for gender and treatment, high baseline E-selectin (p = .01), IL-6 (p = 0.018), and IL-2R (p = 0.008) were adverse prognostic indicators for PFS. Controlling for gender, the tests for treatment by factor interactions (to assess whether treatment effect was different in patients with low and high C/AF levels) were significant for baseline HGF (p = 0.04) and IL-2R (p = 0.008). For both HGF and IL- 2R, low levels were associated with prolonged PFS in the VAN arm, but were not associated with differences in the CP or VAN + CP arms. Significant changes in VEGF (rise) and sVEGFR-2 (decrease) occurred with treatment in the VAN arm; IL12, IL-1RA, MMP-9 and MCP-1 changed in the CP and VAN + CP arms. Conclusions: There are gender differences in PFS benefit from VAN and in plasma C/AF profile. Several C/AFs were of prognostic value, whereas low HGF and IL-2R were predictive of benefit in the VAN but not CP and VAN + CP arms. These gender differences and markers warrant further investigation. [Table: see text]

We give a sufficient condition for one regular series parallel channel graph to be superior to another with the same number of stages. The main mathematical tools used for doing this are the recently developed results on majorization over a partial order.

We show that the Steiner minimal tree for a set of points on a circle is the shortest path connecting them if at most one distance between two consecutive points is "large". We prove this by making an interesting use of the Steiner ratio ρ \rho which has been well studied in the literature.

Channel graphs are often used to describe the connecting paths between a pair of terminals in a link system. Series-parallel (SP) channel graphs and Takagi graphs are special classes of channel graphs heavily studied in the literature. In this paper, we give a noninductive definition of SP channel graphs which we prove to be equivalent to the usual inductive definition. We then use this new definition to characterize SP Takagi graphs and regular SP channel graphs.

We consider the problem of finding the repetitive structure of a given fixed string y. A factor u of y is a cover of y, if every letter of y falls within some occurrence of u in y. A factor v of y is a seed of y, if it is a cover of a superstring of y. There exist linear-time algorithms for solving the minimal cover problem. The minimal seed problem is of much higher algorithmic difficulty, and no linear-time algorithm is known. In this article, we solve one of its variants - computing the minimal and maximal right-seed array of a given string. A right seed of y is the shortest suffix of y that it is a cover of a superstring of y. An integer array RS is the minimal right-seed (resp. maximal right-seed) array of y, if RS[i] is the minimal (resp. maximal) length of right seeds of y[0 . . i]. We present an O(n log n) time algorithm that computes the minimal right-seed array of a given string, and a linear-time solution to compute the maximal right-seed array by detecting border-free prefixes of the given string.

In this paper we address the problem of estimating the number of stations in a wireless network. Under the assumption that each station can detect collisions, we show that it is possible to estimate the number stations in the network within a factor 2 from the correct value in time O(log n log log n). We further show that if no station can detect collisions, the same task can be accomplished within a factor of 3 in time O(log2n) and maximum energy O(log n) per node, with high probability. Finally, we present an algorithm that computes the minimum value held by the stations in the wireless network in time O(log2n).

We study network load games, a class of routing games in networks which generalize selfish routing games on networks consisting of parallel links. In these games, each user aims to route some traffic from a source to a destination so that the maximum load she experiences in the links of the network she occupies is minimum given the routing decisions of other users. We present results related to the existence, complexity, and price of anarchy of Pure Nash Equilibria for several network load games. As corollaries, we present interesting new statements related to the complexity of computing equilibria for selfish routing games in networks of restricted parallel links.

This paper is a survey of feedback set problems (FSP). FSP originated from applications in combinatorial circuit design, but have found their way into numerous other applications, such as deadlock prevention in operating systems, constraint satisfaction and Bayesian inference in artificial intelligence, and graph theory. Directed and undirected feedback vertex set problems are considered, including polynomially solvable cases, approximation algorithms, exact algorithms, and practical heuristics. The relationship between the feedback vertex set and feedback arc set problems is examined and the state of the art of feedback arc set problems is surveyed. Applications of feedback set problems are described. Finally, future directions in feedback set problem research are mapped out.