Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma

PURPOSE: Hreceptor (VEGFR) and FGF receptor (FGFR) signaling pathways. EXPERIMENTAL DESIGN: Six different s.c. patient-derived HCC xenografts were implanted into mice. Tumor growth was evaluated in mice treated with brivanib compared with control. The effects of brivanib on apoptosis and cell proliferation were evaluated by immunohistochemistry. The SK-HEP1 and HepG2 cells were used to investigate the effects of brivanib on the VEGFR-2 and FGFR-1 signaling pathways in vitro. Western blotting was used to determine changes in proteins in these xenografts and cell lines. RESULTS: Brivanib significantly suppressed tumor growth in five of six xenograft lines. Furthermore, brivanib-induced growth inhibition was associated with a decrease in phosphorylated VEGFR-2 at Tyr(1054/1059), increased apoptosis, reduced microvessel density, inhibition of cell proliferation, and down-regulation of cell cycle regulators. The levels of FGFR-1 and FGFR-2 expression in these xenograft lines were positively correlated with its sensitivity to brivanib-induced growth inhibition. In VEGF-stimulated and basic FGF stimulated SK-HEP1 cells, brivanib significantly inhibited VEGFR-2, FGFR-1, extracellular signal-regulated kinase 1/2, and Akt phosphorylation. CONCLUSION: This study provides a strong rationale for clinical investigation of brivanib in patients with HCC.

Proteasome inhibitors trigger NOXA-mediated apoptosis in melanoma and myeloma cells

Patients with metastatic melanoma or multiple myeloma have a dismal prognosis because these aggressive malignancies resist conventional treatment. A promising new oncologic approach uses molecularly targeted therapeutics that overcomes apoptotic resistance and, at the same time, achieves tumor selectivity. The unexpected selectivity of proteasome inhibition for inducing apoptosis in cancer cells, but not in normal cells, prompted us to define the mechanism of action for this class of drugs, including Food and Drug Administration-approved bortezomib. In this report, five melanoma cell lines and a myeloma cell line are treated with three different proteasome inhibitors (MG-132, lactacystin, and bortezomib), and the mechanism underlying the apoptotic pathway is defined. Following exposure to proteasome inhibitors, effective killing of human melanoma and myeloma cells, but not of normal proliferating melanocytes, was shown to involve p53-independent induction of the BH3-only protein NOXA. Induction of NOXA at the protein level was preceded by enhanced transcription of NOXA mRNA. Engagement of mitochondrial-based apoptotic pathway involved release of cytochrome c, second mitochondria-derived activator of caspases, and apoptosis-inducing factor, accompanied by a proteolytic cascade with processing of caspases 9, 3, and 8 and poly(ADP)-ribose polymerase. Blocking NOXA induction using an antisense (but not control) oligonucleotide reduced the apoptotic response by 30% to 50%, indicating a NOXA-dependent component in the overall killing of melanoma cells. These results provide a novel mechanism for overcoming the apoptotic resistance of tumor cells, and validate agents triggering NOXA induction as potential selective cancer therapeutics for life-threatening malignancies such as melanoma and multiple myeloma.

FGFR2 mutations are rare across histologic subtypes of ovarian cancer

OBJECTIVE: Ovarian cancer is the leading cause of death from gynecologic malignancies in the Western world. Fibroblast growth factor receptor (FGFR) signaling has been implicated to play a role in ovarian tumorigenesis. Mutational activation of one member of this receptor family, FGFR2, is a frequent event in endometrioid endometrial cancer. Given the similarities in the histologic and molecular genetics of ovarian and endometrial cancers, we hypothesized that activating FGFR2 mutations may occur in a subset of endometrioid ovarian tumors, and possibly other histotypes. METHODS: Six FGFR2 exons were sequenced in 120 primary ovarian tumors representing the major histologic subtypes. RESULTS: FGFR2 mutation was detected at low frequency in endometrioid (1/46, 2.2%) and serous (1/41, 2.4%) ovarian cancer. No mutations were detected in clear cell, mucinous, or mixed histology tumors or in the ovarian cancer cell lines tested. Functional characterization of the FGFR2 mutations confirmed that the mutations detected in ovarian cancer result in receptor activation. CONCLUSIONS: Despite the low incidence of FGFR2 mutations in ovarian cancer, the two FGFR2 mutations identified in ovarian tumors (S252W, Y376C) overlap with the oncogenic mutations previously identified in endometrial tumors, suggesting activated FGFR2 may contribute to ovarian cancer pathogenesis in a small subset of ovarian tumors.

A transport protocol for real-time applications in wireless networked control systems

A Networked Control System (NCS) is a feedback-driven control system wherein the control loops are closed through a real-time network. Control and feedback signals in an NCS are exchanged among the system’s components in the form of information packets via the network. Nowadays, wireless technologies such as IEEE802.11 are being introduced to modern NCSs as they offer better scalability, larger bandwidth and lower costs. However, this type of network is not designed for NCSs because it introduces a large amount of dropped data, and unpredictable and long transmission latencies due to the characteristics of wireless channels, which are not acceptable for real-time control systems. Real-time control is a class of time-critical application which requires lossless data transmission, small and deterministic delays and jitter. For a real-time control system, network-introduced problems may degrade the system’s performance significantly or even cause system instability. It is therefore important to develop solutions to satisfy real-time requirements in terms of delays, jitter and data losses, and guarantee high levels of performance for time-critical communications in Wireless Networked Control Systems (WNCSs). To improve or even guarantee real-time performance in wireless control systems, this thesis presents several network layout strategies and a new transport layer protocol. Firstly, real-time performances in regard to data transmission delays and reliability of IEEE 802.11b-based UDP/IP NCSs are evaluated through simulations. After analysis of the simulation results, some network layout strategies are presented to achieve relatively small and deterministic network-introduced latencies and reduce data loss rates. These are effective in providing better network performance without performance degradation of other services. After the investigation into the layout strategies, the thesis presents a new transport protocol which is more effcient than UDP and TCP for guaranteeing reliable and time-critical communications in WNCSs. From the networking perspective, introducing appropriate communication schemes, modifying existing network protocols and devising new protocols, have been the most effective and popular ways to improve or even guarantee real-time performance to a certain extent. Most previously proposed schemes and protocols were designed for real-time multimedia communication and they are not suitable for real-time control systems. Therefore, devising a new network protocol that is able to satisfy real-time requirements in WNCSs is the main objective of this research project. The Conditional Retransmission Enabled Transport Protocol (CRETP) is a new network protocol presented in this thesis. Retransmitting unacknowledged data packets is effective in compensating for data losses. However, every data packet in realtime control systems has a deadline and data is assumed invalid or even harmful when its deadline expires. CRETP performs data retransmission only in the case that data is still valid, which guarantees data timeliness and saves memory and network resources. A trade-off between delivery reliability, transmission latency and network resources can be achieved by the conditional retransmission mechanism. Evaluation of protocol performance was conducted through extensive simulations. Comparative studies between CRETP, UDP and TCP were also performed. These results showed that CRETP significantly: 1). improved reliability of communication, 2). guaranteed validity of received data, 3). reduced transmission latency to an acceptable value, and 4). made delays relatively deterministic and predictable. Furthermore, CRETP achieved the best overall performance in comparative studies which makes it the most suitable transport protocol among the three for real-time communications in a WNCS.

Dynamics of attacker–defender dyads in Association Football : parameters influencing decision-making

Previous work on pattern-forming dynamics of team sports has investigated sub-phases of basketball and rugby union by focussing on one-versus-one (1v1) attacker-defender dyads. This body of work has identified the role of candidate control parameters, interpersonal distance and relative velocity, in predicting the outcomes of team player interactions. These two control parameters have been described as functioning in a nested relationship where relative velocity between players comes to the fore within a critical range of interpersonal distance. The critical influence of constraints on the intentionality of player behaviour has also been identified through the study of 1v1 attacker-defender dyads. This thesis draws from previous work adopting an ecological dynamics approach, which encompasses both Dynamical Systems Theory and Ecological Psychology concepts, to describe attacker-defender interactions in 1v1 dyads in association football. Twelve male youth association football players (average age 15.3 ± 0.5 yrs) performed as both attackers and defenders in 1v1 dyads in three field positions in an experimental manipulation of the proximity to goal and the role of players. Player and ball motion was tracked using TACTO 8.0 software (Fernandes & Caixinha, 2003) to produce two-dimensional (2D) trajectories of players and the ball on the ground. Significant differences were found for player-to-ball interactions depending on proximity to goal manipulations, indicating how key reference points in the environment such as the location of the goal may act as a constraint that shapes decision-making behaviour. Results also revealed that interpersonal distance and relative velocity alone were insufficient for accurately predicting the outcome of a dyad in association football. Instead, combined values of interpersonal distance, ball-to-defender distance, attacker-to-ball distance, attacker-to-ball relative velocity and relative angles were found to indicate the state of dyad outcomes.