Explore the vast range of titles available.

Glioblastoma multiforme (GBM) is the most common form of malignant glioma, characterized by genetic instability, intratumoral histopathological variability, and unpredictable clinical behavior. We investigated global gene expression in surgical samples of brain tumors. Gene expression profiling revealed large differences between normal brain samples and tumor tissues and between GBMs and lower-grade oligodendroglial tumors. Extensive differences in gene expression were found among GBMs, particularly in genes involved in angiogenesis, immune cell infiltration, and extracellular matrix remodeling. We found that the gene expression patterns in paired specimens from the same GBM invariably were more closely related to each other than to any other tumor, even when the paired specimens had strikingly divergent histologies. Survival analyses revealed a set of ≈70 genes more highly expressed in rapidly progressing tumors that stratified GBMs into two groups that differed by >4-fold in median duration of survival. We further investigated one gene from the group, FABP7, and confirmed its association with survival in two unrelated cohorts totaling 105 patients. Expression of FABP7 enhanced the motility of glioma-derived cells in vitro. Our analyses thus identify and validate a prognostic marker of both biologic and clinical significance and provide a series of putative markers for additional evaluation.

Computers might well be said to work “like magic.” Graphical User Interfaces (GUIs) allow computers to work predictably but inscrutably. Central to the design of GUIs are visual metaphors that help users understand the function of interface elements. In 1992, as GUIs were supplanting command-based interfaces, Snow Crash was published. In it, Neal Stephenson offers a new take on the SF/cyberpunk conceit of “cyberspace” with “the Metaverse,” a VR world Stephenson claims was inspired by real-world GUI design principles. Yet in Stephenson's 1999 essay “In the Beginning… was the Command Line,” the author rails against metaphor-based interfaces, claiming such software separates users from total control of their systems, control that can only be achieved by learning computer code. Similarly, in Snow Crash, programming code itself is cast as magical, an analog to a pre-Babelian speech that can control human minds as if they are computers. While Stephenson's novel does show that GUIs can constrain what users can do with their computers—as well as articulate ideas about what computers are for—it does something else. Despite its attack on GUIs, Snow Crash sees the appeal of cyberspace visions as rooted in a human desire to interact with computers in a human way. The real “magic” of making computers mean something on a human level occurs through metaphor-based mental operations which long predate computers.

BackgroundProcaspase-3 (PC-3) is overexpressed in multiple tumour types and procaspase-activating compound 1 (PAC-1) directly activates PC-3 and induces apoptosis in cancer cells. This report describes the first-in-human, phase I study of PAC-1 assessing maximum tolerated dose, safety, and pharmacokinetics.MethodsModified-Fibonacci dose-escalation 3 + 3 design was used. PAC-1 was administered orally at 7 dose levels (DL) on days 1–21 of a 28-day cycle. Dose-limiting toxicity (DLT) was assessed during the first two cycles of therapy, and pharmacokinetics analysis was conducted on days 1 and 21 of the first cycle. Neurologic and neurocognitive function (NNCF) tests were performed throughout the study.ResultsForty-eight patients were enrolled with 33 completing ≥2 cycles of therapy and evaluable for DLT. DL 7 (750 mg/day) was established as the recommended phase 2 dose, with grade 1 and 2 neurological adverse events noted, while NNCF testing showed stable neurologic and cognitive evaluations. PAC-1’s t1/2 was 28.5 h after multi-dosing, and systemic drug exposures achieved predicted therapeutic concentrations. PAC-1 clinical activity was observed in patients with neuroendocrine tumour (NET) with 2/5 patients achieving durable partial response.ConclusionsPAC-1 dose at 750 mg/day was recommended for phase 2 studies. Activity of PAC-1 in treatment-refractory NET warrants further investigation.Clinical trial registrationClinical Trials.gov: NCT02355535.

Radiation necrosis is a devastating complication following radiation to the central nervous system. The purpose of this study was to perform a comprehensive analysis of cases in the literature using bevacizumab, a monoclonal antibody against vascular endothelial growth factor, as treatment for radiation necrosis. A MEDLINE/PubMed search of articles about the use of bevacizumab for radionecrosis treatment yielded 16 studies published between 2007 and 2012. Data was summarized according to patient characteristics, treatment received and outcomes measured. A total of 71 unique cases were identified that met the inclusion criteria. The median age at the time of treatment with bevacizumab was 47 years. The most common tumors treated were glioblastoma (31 %), anaplastic glioma (14 %), and metastatic brain tumors (15 %). The median time from ending radiotherapy to starting treatment with bevacizumab was 11 months and the median follow up time after bevacizumab treatment was 8 months. The median number of cycles of bevacizumab was administered was 4, and the median dosage of bevacizumab was 7.5 mg/kg. The median time elapsed between cycles of bevacizumab was 2 weeks. Overall, pre and post treatment imaging revealed a median decrease in T1 contrast enhancement of 63 %, and a 59 % median decrease in T2/FLAIR signal abnormality. Treatment with bevacizumab resulted in a significant radiographic response for patients with radionecrosis. The median dosage of bevacizumab of 7.5 mg/kg for four cycles every 2 weeks should be considered as a treatment option in this patient population.

Glioblastoma multiforme (GBM) is the most aggressive of the infiltrating gliomas. Standards of care for treatment continue to evolve. In many westernized countries standard treatment of GBM at diagnosis includes surgery, radiotherapy and chemotherapy. In other parts of the world, chemotherapy that is considered beneficial by many is excluded from standard therapy, in large part due to issues of cost; treatment may be completely palliative, even limited to corticosteroid treatment alone. This review will focus on the current standard of care in the USA for newly diagnosed GBM, focusing on the evidence supporting that care.

Malignant gliomas are invasive tumors with the potential to progress through current available therapies. These tumors are characterized by a number of abnormalities in molecular signaling that play roles in tumorigenesis, spread, and survival. These pathways are being actively investigated in both the pre-clinical and clinical settings as potential targets in the treatment of malignant gliomas. We will review many of the therapies that target the cancer cell, including the epidermal growth factor receptor, mammalian target of rapamycin, histone deacetylase, and farnesyl transferase. In addition, we will discuss strategies that target the extracellular matrix in which these cells reside as well as angiogenesis, a process emerging as central to tumor development and growth. Finally, we will briefly touch on the role of neural stem cells as both potential targets as well as delivery vectors for other therapies. Interdependence between these varied pathways, both in maintaining health and in causing disease, is clear. Thus, attempts to easily classify some targeted therapies are problematic.

Summary Background : Cilengitide (EMD121974) is a cyclized pentapeptide that is a potent and selective integrin antagonist which has shown activity in malignant gliomas. In all previous studies, cilengitide has been administered in an intermittent fashion. However, cilengitide has a short half-life of 3–5 h with no evidence of drug accumulation. These data prompted the initiation of this phase I study of continuous infusion cilengitide. Methods : Cilengitide was administered as a continuous infusion without break in 4-week cycles. Plasma samples for pharmacokinetic studies were obtained weekly in cycle 1 immediately prior to and 2 h after infusion bag change. Results : Thirty-five patients were treated (median age 56; 23 males) at dose levels of 1, 2, 4, 8, 12, 18, 27, and 40 mg/h. Toxicities were limited to grade ≤2 and showed no relation to dose. Fatigue was most common (17%), while all other toxicities were reported in <10% of patients. No dose-limiting toxicities were observed, and therefore the maximum tolerated dose was not reached. Pharmacokinetic analysis showed that values for clearance and volume of distribution were comparable across dose levels, and the steady-state concentration increased proportionally with dose. Conclusions : Cilengitide can be safely administered as a continuous infusion at doses up to at least 40 mg/h, which represents the maximum feasible dose due to drug solubility and delivery limitations. The pharmacokinetics of continuous infusion cilengitide are linear and consistent with the results obtained using a twice weekly infusion.

Chemotherapeutic regimens in present use for recurrent glioma have substantial toxicity. Activity against recurrent gliomas has been reported for both tamoxifen and interferon alpha, agents that have more acceptable toxicity profiles and that can be administered in an outpatient setting. We tested the efficacy and toxicity of the combination of high-dose tamoxifen and interferon alpha in adults with recurrent glioma in a phase II trial. Eligible patients had radiographically measurable recurrent gliomas of any grade after initial radiation therapy. Interferon-alpha [6 x 10(6) U subcutaneously three times per week] and tamoxifen (240 mg/m2/day orally) were administered continuously. Treatment response was assessed at 6 week intervals using clinical and radiographic criteria. Eighteen patients (11 males and 7 females) were enrolled. Median age was 41 years (range 23-61 years). All patients had gliomas that progressed after radiation therapy and nitrosourea chemotherapy. The histologic diagnosis of the original tumor was glioblastoma multiforme in 8 patients, anaplastic astrocytoma in 5 patients, astrocytoma in 4 patients and mixed malignant glioma in 1 patient. Reversible moderate to severe neurological toxicity manifested by dizziness and unsteady gait was seen at tamoxifen doses of 240 mg/m2/day. Although the initial tamoxifen dose was reduced to 120 mg/m2/day, moderate neurotoxicity was noted at this dose as well and the trial was closed early. The combination of oral tamoxifen (120 to 240 mg/m2/day) and subcutaneous interferon-alpha [6 x 10(6) U three times per week] was associated with significant neurotoxicity in this group of recurrent glioma patients, resulting in early study closure. Of 16 evaluable patients, 12 had progressive disease after one cycle of treatment, 3 had stable disease, and there was one minor response. Gradual dose escalation may be required if similar patients are to be treated with high dose tamoxifen in conjunction with interferon.

\"The Freedom of Information Hacked: Console Cowboys, Computer Wizards, and Personal Freedom in the Digital Age\" examines depictions of computer hackers in fiction, the media, and popular culture, assessing how such depictions both influence and reflect popular conceptions of hackers and what they do. In doing so, the dissertation demonstrates the central concerns of hacker stories - concerns about digital security, privacy, and the value of information - have become the concerns of digital culture as a whole, hackers laying bare collective hopes and fears regarding digital networks.