Supplementary Tables 1-6, Figures 1-4 from Randomized Study of Paclitaxel and Tamoxifen Deposition into Human Brain Tumors: Implications for the Treatment of Metastatic Brain Tumors

If artists and art explore organization of the brain [Zeki, S., Lamb, M., 1994. The neurology of kinetic art. Brain 117, 607–636], then investigation of response to artistic performance holds promise as a window to perceptual and cognitive processes. A new instrument for recording real-time audience response – the portable Audience Response Facility (pARF) – is described. Twenty, hand-held, Personal Digital Assistants (PDAs) collect responses on customizable skin interfaces. The pARF server transmits the customizable options, synchronizes devices and collects data for export. We report two studies using the pARF that demonstrate respondent agreement of perceived emotion during particular sections of two dance works. Greater agreement was evident in continuous ratings of arousal than valence; arousal appears to be related to surface features of the dance work. Future applications of the pARF to studies of multi-modal perception and cognition are discussed.

BACKGROUND:The prognosis for patients with recurrent high-grade gliomas is poor and treatment options are limited. Current chemotherapeutic regimens can improve clinical outcomes, but extend survival by only a few months. Temozolomide is a methylating agent that is typically administered once daily. Because preclinical studies suggested that a twice-daily dosing schedule might be more effective, the safety and efficacy of twice-daily dosing of temozolomide were studied in patients with recurrent gliomas at their first, second, or third recurrence.METHODS:This multi-institutional trial enrolled 120 patients with recurrent glioblastoma multiforme (GBM), anaplastic astrocytoma (AA), or anaplastic oligodendroglioma (AO). An initial oral dose of 200 mg/m(2) of temozolomide was followed by 9 consecutive doses of 90-mg/m(2) every 12 hours. Treatment cycles were repeated every 28 days. Doses were escalated to 100 mg/m(2) twice daily in the absence of unacceptable toxicity or were reduced if unacceptable toxicity occurred.RESULTS:For GBM, AA, and AO patients, respectively, the median progression-free survival (PFS) was 4.2 months, 5.8 months, and 7.7 months, whereas the median overall survival (OS) was 8.8 months, 14.6 months, and 18 months. The overall response rate (partial and complete) for the GBM, AA, and AO patients was 31%, 46%, and 46%, respectively. Grade 3/4 toxicities included neutropenia (1.1%), thrombocytopenia (3.6%), and anemia (0.3%) (graded according to the World Health Organization grading system).CONCLUSIONS:Twice-daily dosing may enhance the efficacy of temozolomide in the treatment of recurrent gliomas without increasing toxicity. This regimen compares favorably with other dosing schedules of temozolomide reported in the literature.

This paper describes the Thinking-Talking Head; an interdisciplinary project that sits between and draws upon engineering/computer science and behavioural/cognitive science; research and performance; implementation and evaluation. The project involves collaboration between computer scientists, engineers, language technologists and cognitive scientists, and its aim is twofold (a) to create a 3-D computer animation of a human head that will interact in real time with human agents, and (b) to serve as a research platform to drive research in the contributing disciplines, and in talking head research in general. The thinkingtalking head will emulate elements of face-to-face conversation through speech (including intonation), gaze and gesture. So it must have an active sensorium that accurately reflects the properties of its immediate environment, and must be able to generate appropriate communicative signals to feedback to the interlocutor. Here we describe the current implementation and outline how we are tackling issues concerning both the outputs (synthetic voice, visual speech, facial expressiveness and naturalness) from and inputs (auditory-visual speech recognition, emotion recognition, auditory-visual speaker localization) to the head. We describe how these head functions will be tuned and evaluated using various paradigms, including an imitation paradigm.

This paper describes recent developments in our investigations into psychological reactions of audience members as they watch live performance, specifically contemporary dance. The first method, developed by Glass (5,6), is a new psychometric instrument - the Audience Response Tool (ART) - that records emotional and cognitive responses in the form of qualitative open-ended descriptions and quantitative ratings to live performance. The second method - the portable Audience Response Facility (pARF) - is a programmable, hand-held PC that samples one- or two-dimensional data continuously as a performance unfolds. A third method records eye movements of novice and expert observers as they watch a pre-recorded performance. The ART was developed in the context of an experimental design that investigated the effect of pre-performance information sessions (generic, specific, no information-control group) on cognitive and emotional responses to two new Australian dance works, Anna Smith's Red Rain and Sue Healey's Fine Line Terrain. The pARF has been used to record continuous responses from 19 audience members in the Playhouse Theatre in Canberra as they watched the Quantum Leap Youth Choreographic Ensemble perform Albert David's Silent Heartbeat. Judged emotional expression in the 30 minute work was captured in two orthogonal dimensions, valence and arousal (13). The pARF revealed an increase in arousal as the work progressed, explicable in terms of music and movement intensity and tempo. The eye movement experiment investigated effects of observer expertise on fixation duration and saccadic amplitude while four dance experts and four novices watched a five-minute dance film, Sue Healey's 13 and 32. Expert observers relative to novices recorded shorter fixations and larger saccades. This effect has been interpreted in light of organizational strategies and expectancies acquired by experts through experience with a particular art form. The qualitative and quantitative methods have wide application across the performing arts, film, and digital media.

BACKGROUND:P-glycoprotein (Pgp) mediates, in part, resistance to natural product chemotherapy drugs which constitute over half of the available drugs for cancer treatment. Tamoxifen (TAM) enhances intracellular deposition of natural product chemotherapy in human cell lines by inhibition of Pgp. Pgp is highly expressed in the choroid plexus and is thought to be a key component of the blood-cerebrospinal fluid barrier (BCSFB). We conducted a prospective, randomized study to assess if Pgp inhibition by TAM alters deposition of paclitaxel in cerebrospinal fluid (CSF).METHODS:Ten patients with either primary or metastatic brain tumors were randomized to: paclitaxel alone (175 mg/m2/IV) or a course of TAM (160 mg/m2 PO BID on Days 1-5) followed by paclitaxel (175 mg/m2/IV on Day 5). CSF and plasma samples were obtained following paclitaxel infusion; paclitaxel and TAM concentrations were measured by high-performance liquid chromatography assays.RESULTS:Paclitaxel was detected in the CSF of six of the 10 patients. Peak CSF paclitaxel concentrations of the paclitaxel and paclitaxel-TAM groups ranged between 3.5-57.4 and 2.3-24.6 nM, respectively. Though there was a 2.4-fold higher mean CSF paclitaxel concentration and a 3.7-fold higher median peak CSF:plasma paclitaxel ratio for those who received paclitaxel alone as compared to combined paclitaxel-TAM, it was not statistically significant (P = 0.22). In one patient enrolled to both arms, higher CSF concentrations of paclitaxel and higher paclitaxel CSF: plasma ratios were observed when given paclitaxel alone.CONCLUSIONS:The trend towards lower paclitaxel CSF concentrations when given with TAM is consistent with the published finding that Pgp's localization in the endothelial cells of the choroid plexus works in an opposite direction and keeps drugs in the CSF. Thus, agents which inhibit Pgp, such as TAM, may increase efflux of Pgp substrates out of the BCSFB and may paradoxically lower CSF concentrations of natural product chemotherapy drugs. Conceptually, this finding implies that the Pgp in the BBB and BCSFB keeps natural toxins such as paclitaxel, from entering the brain (BBB) and, if they do enter the brain, keeps them in the CSF (BCSFB) where they may be less harmful than if they re-entered the brain. Thus, our work supports this novel idea and adds to the understanding of the functions of the BCSFB.

Abstract Purpose: Drug resistance in brain tumors is partially mediated by the blood-brain barrier of which a key component is P-glycoprotein, which is highly expressed in cerebral capillaries. Tamoxifen is a nontoxic inhibitor of P-glycoprotein. This trial assessed, in primary and metastatic brain tumors, the differential deposition of paclitaxel and whether tamoxifen could increase paclitaxel deposition. Experimental Design: Patients for surgical resection of their primary or metastatic brain tumors were prospectively randomized to prior paclitaxel alone (175 mg/m2/i.v.) or tamoxifen for 5 days followed by paclitaxel. Central and peripheral tumor, surrounding normal brain and plasma, were analyzed for paclitaxel and tamoxifen. Results: Twenty-seven patients completed the study. Based on a multivariate linear regression model, no significant differences in paclitaxel concentrations between the two study arms were found after adjusting for treatment group (tamoxifen versus control). However, in analysis for tumor type, metastatic brain tumors had higher paclitaxel concentrations in the tumor center (1.93-fold, P = 0.10) and in the tumor periphery (2.46-fold, P = 0.039) compared with primary brain tumors. Pharmacokinetic analyses showed comparable paclitaxel areas under the serum concentration between treatment arms. Conclusions: Paclitaxel deposition was not increased with this tamoxifen schedule as the low plasma concentrations were likely secondary to concurrent use of P-450-inducing medications. However, the statistically higher paclitaxel deposition in the periphery of metastatic brain tumors provides functional evidence corroborating reports of decreased P-glycoprotein expression in metastatic versus primary brain tumors. This suggests that metastatic brain tumors may respond to paclitaxel if it has proven clinical efficacy for the primary tumor's histopathology.

Familiarity with the updated results in genetic screening and work-up presented here is essential to early diagnosis and possible cure. In the metastatic setting, we most frequently begin with the GTX regimen, consisting of Gemcitabine, Taxotere, and Xeloda. The regimen is based on our laboratory data demonstrating a synergistic increase in cell killing of pancreatic cancer cell lines. The combination takes advantage of the selective cell cycle effects of each of the three drugs. In our initial experience, we have seen a response rate of 40% at metastatic sites and 31% at the primary site after nine cycles of GTX. We are now conducting a formal phase II protocol to confirm these results. The median survival of this group of patients (at least 10.4 months) is as long as, or longer than other currently used regimens. In those patients who do not tolerate GTX or progress despite the regimen, we have found that a regimen of the same three drugs, administered on a different schedule, can produce responses. In the neoadjuvant (unresectable) setting, we treat with GTX initially and then follow with radiation; gemcitabine is used as a radiosensitizer during this treatment. An aggressive surgical approach with a team of surgeons were able to resect for cure 12 of the 16 patients who were initially unresectable; one year survival of these 12 was 100%; 2 year survival was 50%. Future work in this disease should focus on targeted agents such as bevacizumab.

Discovering Internet topology is important for analyzing routing protocols and Internet robustness and resilience. Recent research results dealing with Internet topology, such as the discovery of power-laws and the application of normalized Laplacian analysis to Internet topology data, have increased the need for more complete datasets and their more rigorous interpretations. In this paper, we examine datasets from two sources: Route Views and RIPE. We show that each dataset may have a geographical bias and, consequently, consist of distinct routes. Furthermore, by employing normalized Laplacian analysis, we identify distinct cluster characteristics that could not be inferred by directly examining the collected data.

Object embedded stereo panoramic images have received increasing attention recently due to their numerous applications in computer vision. This article explores an approach to embed object images, both dynamic and static, into background panoramas. The approach involves three steps; namely, image acquisition, postacquisition, and image visualization. A GUI tool is developed for image registering, merging, and pose recovering. A panoramic player is also developed for visualizing the resultant anaglyphic panorama.

Two novel cyclic tetrapeptides: cyclo[Lys-Tyr-Lys-Ahx-] 7a and cyclo[Lys-Trp-Lys-Ahx-] 7b were synthesized by coupling protected amino acid in solution and the subsequent cyclization effected by the pentafluorophenyl ester method as described in previous papers. These cyclic peptides were designed and synthesized to study their interaction with DNA, based on previous reports that linear peptides Lys-Tyr-Lys and Lys-Trp-Lys could bind to various forms of DNA and cleaved supercoiled DNA at apurinic sites. Ethidium bromide displacement assay showed that the apparent DNA binding constant of linear Lys-Tyr-Lys and cyclic peptide 7a are far below 1 x 10(3) M(-1), whereas those of cyclic peptide 7b and linear Lys-Trp-Lys are 1.9 x 10(4) M(-1) and 9.5 x 10(3) M(-1), respectively. Kinetic studies using agarose gel electrophoresis showed that cyclic peptide 7b and Lys-Trp-Lys possessed DNA nicking activity on natural supercoiled phi X174 DNA with nicking rate of 50.7 and 75.6 pM min(-1) at 65 degrees C, respectively, whereas cyclic peptide 7a and linear Lys-Tyr-Lys were devoid of the corresponding activity. The DNA nicking rate increased significantly with increase in reaction temperature. At reaction temperatures lower than 65 degrees C, the DNA nicking rate of cyclic peptide 7b exceeded that of linear Lys-Trp-Lys. The addition of 1 microM ferrous ion did not give significant enhancement effect on the DNA nicking rate by the peptides. UV irradiation gave a marked rate enhancement on the DNA nicking rate of linear Lys-Trp-Lys and a moderate enhancement on the DNA nicking rate of cyclic peptide 7b.