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High grade gliomas are associated with poor prognosis and high mortality. Conventional treatments and management of high grade gliomas have shown little improvement in 5-year overall survival. This phase I trial evaluated the safety, immunogenicity, and potential synergy of surgical resection with Gliadel Wafer implantation, followed by autologous tumor lysate-pulsed dendritic cell (DC) vaccine in patients with malignant glioma. Primary end points of this study were safety and surrogate markers of immunogenicity, overall survival, and progression free survival. Following surgical resection, Gliadel Wafers were placed along the resection cavity. Patients subsequently received intradermal injections of autologous tumor lysate-pulsed DC vaccines 3 times at 2 week intervals. Treatment response was evaluated clinically and through MRI at regular intervals. Twenty-eight patients received Gliadel Wafers and DC vaccination: 11 newly diagnosed (8 glioblastoma [GBM], 2 anaplastic astrocytoma [AA], and 1 anaplastic oligodendroglioma [AO]) and 17 recurrent (15 GBMs, 1 AA, and 1 AO) high grade gliomas. Immunogenicity data was collected for 20 of the 28 patients. Five of 20 patients showed elevated IFN-γ responses following vaccination. Median progression-free survival and overall survival for all GBM patients in the trial from the start of vaccination were 3.6 months and 16.9 months respectively. Comparisons between vaccine responders and non-vaccine responders were not statistically significant. Adjuvant autologous dendritic cells pulsed with tumor-lysate following resection and Gliadel Wafer placement is safe, elicits modest immunogenicity and shows similar clinical outcomes in patients who had DC vaccination in previous studies.

A cell culture platform that enables ex vivo tissue growth from patients or patient-derived xenograft (PDX) models and assesses sensitivity to approved therapies (e.g., temozolomide) in a clinically relevant time frame would be very useful in translational research and personalized medicine. Here, we present a novel three-dimensional (3D) ECM hydrogel system, VersaGel, for assaying ex vivo growth and therapeutic response with standard image microscopy. Specifically, multicellular spheroids deriving from either 5 patients with glioblastoma (GBM) or a renal cell carcinoma (RCC) PDX model were incorporated into VersaGel and treated with temozolomide and several other therapies, guided by the most recent advances in GBM treatment. RCC ex vivo tissue displayed invasive phenotypes in conditioned media. For the GBM patient tumor testing, all five clinical responses were predicted by the results of our 3D-temozolomide assay. In contrast, the MTT assay found no response to temozolomide regardless of the clinical outcome, and moreover, basement membrane extract failed to predict the 2 patient responders. Finally, 1 patient was tested with repurposed drugs currently being administered in GBM clinical trials. Interestingly, IC50s were lower than Cmax for crizotinib and chloroquine, but higher for sorafenib. In conclusion, a novel hydrogel platform, VersaGel, enables ex vivo tumor growth of patient and PDX tissue and offers insight into patient response to clinically relevant therapies. We propose a novel 3D hydrogel platform, VersaGel, to grow ex vivo tissue (patient and PDX) and assay therapeutic response using time-course image analysis.

Neurological disorders significantly impact the world’s economy due to their often chronic and life-threatening nature afflicting individuals which, in turn, creates a global disease burden. The Group of Twenty (G20) member nations, which represent the largest economies globally, should come together to formulate a plan on how to overcome this burden. The Neuroscience-20 (N20) initiative of the Society for Brain Mapping and Therapeutics (SBMT) is at the vanguard of this global collaboration to comprehensively raise awareness about brain, spine, and mental disorders worldwide. This paper aims to provide a comprehensive review of the various brain initiatives worldwide and highlight the need for cooperation and recommend ways to bring down costs associated with the discovery and treatment of neurological disorders. Our systematic search revealed that the cost of neurological and psychiatric disorders to the world economy by 2030 is roughly $16T. The cost to the economy of the United States is $1.5T annually and growing given the impact of COVID-19. We also discovered there is a shortfall of effective collaboration between nations and a lack of resources in developing countries. Current statistical analyses on the cost of neurological disorders to the world economy strongly suggest that there is a great need for investment in neurotechnology and innovation or fast-tracking therapeutics and diagnostics to curb these costs. During the current COVID-19 pandemic, SBMT, through this paper, intends to showcase the importance of worldwide collaborations to reduce the population’s economic and health burden, specifically regarding neurological/brain, spine, and mental disorders.

The incidence of autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD), which frequently co-occur, are both rising. The causes of ASD and ADHD remain elusive, even as both appear to involve perturbation of the gut-brain-immune axis. CD103 is an integrin and E-cadherin receptor most prominently expressed on CD8 T cells that reside in gut, brain, and other tissues. CD103 deficiency is well-known to impair gut immunity and resident T cell function, but it's impact on neurodevelopmental disorders has not been examined. We show here that CD8 T cells influence neural progenitor cell function, and that CD103 modulates this impact both directly and potentially by controlling CD8 levels in brain. CD103 knockout (CD103KO) mice exhibited a variety of behavioral abnormalities, including superior cognitive performance coupled with repetitive behavior, aversion to novelty and social impairment in females, with hyperactivity with delayed learning in males. Brain protein markers in female and male CD103KOs coincided with known aspects of ASD and ADHD in humans, respectively. Surprisingly, CD103 deficiency also decreased age-related cognitive decline in both sexes, albeit by distinct means. Together, our findings reveal a novel role for CD103 in brain developmental function, and identify it as a unique factor linking ASD and ADHD etiology. Our data also introduce a new animal model of combined ASD and ADHD with associated cognitive benefits, and reveal potential therapeutic targets for these disorders and age-related cognitive decline.

Community development theory provides a strong and robust theoretical basis for effective community development practice. However these theoretical constructs have broad implications beyond effective community development practice, they might also inform the lack of community development progress in certain contexts. This article engages community development theory to describe what factors block the advancement of community development in distressed city contexts. By examining the effects of structure, shared meaning, solidarity, agency, and poverty on community development in the case of the city of Camden, New Jersey, the article demonstrates how these social phenomena can potentially inhibit community development progress. The article concludes with a discussion of how these barriers might be overcome to facilitate successful community development.

The Geostationary Operational Environmental Satellite-R Series (GOES-R) is the next generation of Untied States geostationary weather satellites. The GOES-R series significantly improves the detection and observation of environmental phenomena that directly affect public safety, protection of property and the economic health and prosperity of the United States and all countries within the western hemisphere. Given the real-time or ''now-casting'' nature of the GOES science gathering mission, any data outage or interruption can reduce warning times or scientific fidelity for critical weather data. GOES-R mission level requirements limit key performance product outages to a total of six hours per year to maximize science data availability. Lower level requirement only allow for 120 minutes of disruption between the spacecraft bus interface to the instruments. This requirement is met using both design features of the satellite and ground system, in addition to operational strategies.

The cyclical movement of housing prices likely affects the supply of and demand for credit for home purchases, but little is known about how this process might influence differential access to credit between minority and non-minority borrowers. This paper uses data reported through the Home Mortgage Disclosure Act (HMDA) over the period 1990–2013 to estimate the relationship between annual metropolitan area-level house price inflation and the extent to which Black borrowers are denied relative to ‘comparable’ White borrowers on their loan applications. The results indicate that, on average, Black borrowers are denied more frequently than White borrowers, but this difference in denial rates decreases significantly as house prices rise more rapidly. Such results demonstrate the importance of considering local housing market conditions when using HMDA data to assess lender compliance with fair lending laws.

The dismal prognoses suffered by malignant primary brain tumor (glioma) patients remain unchanged over the past two decades despite significant improvements in the treatment of distinct tumors. Den...

DCVax-Brain (Northwest Biotherapeutics, Inc., Bethesda, MD, USA) is a personalized treatment for brain tumors. Its approach of administering autologous tumor antigen-bearing dendritic cells (DCs) has garnered hope for more effective and less toxic therapy for patients with malignant brain tumors including glioblastoma multiforme (GBM). DCVax-Brain composition and efficacy are not fully disclosed, although sponsors claim it is poised to critically test clinical DC vaccine efficacy in GBM patients.This review examines the efficacy of DC vaccine therapy in treating GBM patients. REVIEW QUESTION: To determine if the approach of DC vaccination followed by DCVax-Brain shows ample clinical promise in GBM patients.All published reports of DC vaccination for GBM and press releases regarding DCVax-Brain findings were evaluated. CRITICAL APPRAISAL OF REPORTS AND SUMMARY OF OUTCOMES: Published DC vaccine trials for high-grade glioma patients suggest favorable clinical outcomes not easily ascribed to non-treatment parameters. Evidence of possible selection bias exists in many reports, but efforts to account for this are evident in the most recent publications.DC vaccine trials provide evidence of low toxicity in GBM patients and effective induction of antitumor immunity in the latest publications correlate with clinical improvements. Preliminary reports on DCVax-Brain clinical outcomes seem to follow these trends.

Although the association between industrial agglomeration and productivity has been widely examined and documented, little work has explored the possibility that these `external' productivity shifts are the product of more advanced technologies. This paper offers a look at this hypothesis using data on individual-level computer usage across a sample of U.S. metropolitan areas over the years 1984, 1989, 1993, and 1997. The results indicate that, for a wide array of industries at the two-, three-, and four-digit SIC level, an industry's scale within a metropolitan area is positively associated with the frequency of computer use by its workers. However, in spite of these observable differences in workplace technology, I also find that estimated localization effects on wages are largely not explained by computer usage. Even after controlling for computer use, there remain significant own-industry scale effects in labor earnings.

While the productivity gains associated with the geographic concentration of industry (i.e., localisation) are by now well-documented, little work has considered how those gains are distributed across individual workers. This article offers evidence on the connection between total employment and the relative wage earnings of high- and low-skill workers (i.e., inequality) within two-digit manufacturing industries across the states, and a collection of metropolitan areas in the U.S. between 1970 and 1990. Using measures of overall, between-education-group and residual inequality, I find that wage dispersion falls significantly as industry employment expands.

A large body of research has established a positive connection between an industry's productivity and the magnitude of its presence within locally defined geographic areas. This paper examines the extent to which this relationship can be explained by a micro-level underpinning commonly associated with productivity: establishment scale. Looking at data on two-digit manufacturing across a sample of U.S. metropolitan areas, I find two primary results. First, average plant size - defined in terms of numbers of workers - increases substantially as an industry's employment in a metropolitan area rises. Second, results from a decomposition of localization effects on labor earnings into plant-size and plant-count components reveal that the widely observed, positive association between a worker's wage and the total employment in his or her own metropolitan area-industry derives predominantly from the former, not the latter. Localization economies, therefore, appear to be the product of plant-level organization rather than pure population effects.

While a sizable body of research has studied the relationship between aggregate productivity and geographic density, little work has considered how density influences the distribution of productivity across workers. This paper offers some descriptive evidence on the relationship between three measures of earnings inequality--unconditional percentile gaps, residual percentile gaps, between education-group gaps--and population density across a sample of US metropolitan areas between 1970 and 1990. On the whole, the findings reveal a significant and strikingly robust negative association between density and each measure. Copyright 2004, Oxford University Press.

The primary goal of this Phase I study was to assess the safety and bioactivity of tumor lysate-pulsed dendritic cell (DC) vaccination to treat patients with glioblastoma multiforme and anaplastic astrocytoma. Adverse events, survival, and cytotoxicity against autologous tumor and tumor-associated antigens were measured. Fourteen patients were thrice vaccinated 2 weeks apart with autologous DCs pulsed with tumor lysate. Peripheral blood mononuclear cells were differentiated into phenotypically and functionally confirmed DCs. Vaccination with tumor lysate-pulsed DCs was safe, and no evidence of autoimmune disease was noted. Ten patients were tested for the development of cytotoxicity through a quantitative PCR-based assay. Six of 10 patients demonstrated robust systemic cytotoxicity as demonstrated by IFN-γ expression by peripheral blood mononuclear cells in response to tumor lysate after vaccination. Using HLA-restricted tetramer staining, we identified a significant expansion in CD8+ antigen-specific T-cell clones against one or more of tumor-associated antigens MAGE-1, gp100, and HER-2 after DC vaccination in four of nine patients. A significant CD8+ T-cell infiltrate was noted intratumorally in three of six patients who underwent reoperation. The median survival for patients with recurrent glioblastoma multiforme in this study (n = 8) was 133 weeks. This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous tumor lysate-pulsed DC vaccine for patients with malignant glioma. We demonstrate for the first time the ability of an active immunotherapy strategy to generate antigen-specific cytotoxicity in brain tumor patients.

T-lymphocytes have been previously implicated in protecting dopaminergic neurons in the substantianigra from induced cell death. However, the role of T-cells in neurodegenerative models such as Parkinson's disease (PD) has not been fully elucidated. To examine the role of T-lymphocytes on motor behavior in the 6-hydroxydopamine (6-OHDA) unilateral striatal partial lesion PD rat model, we assessed progression of hemi-parkinsonian lesions in the substantia nigra, induced by 6-OHDA striatal injections, in athymic rats (RNU-/-, T-lymphocyte-deficient) as compared to RNU-/+ rats (phenotypically normal). Motor skills were determined by the cylinder and D-amphetamine sulfate-induced rotational behavioral tests. Cylinder behavioral test showed no significant difference between unilaterally lesioned RNU-/- and RNU-/+ rats. However both unilaterally lesioned RNU-/- and RNU-/+ rats favored the use of the limb ipsilateral to lesion. Additionally, amphetamine-induced rotational test revealed greater rotational asymmetry in RNU-/- rats compared to RNU-/+ rats at two- and six-week post-lesion. Quantitative immunohistochemistry confirmed loss of striatal TH-immunopositive fibers in RNU-/- and RNU-/+ rat, as well as blood-brain-barrier changes associated with PD that may influence passage of immune cells into the central nervous system in RNU-/- brains. Specifically, GFAP immunopositive cells were decreased, as were astrocytic end-feet (AQP4) contacting blood vessels (laminin) in the lesioned relative to contralateral striatum. Flow cytometric analysis in 6-OHDA lesioned RNU-/+rats revealed increased CD4+ and decreased CD8+ T cells specifically within lesioned brain. These results suggest that both major T cell subpopulations are significantly and reciprocally altered following 6-OHDA-lesioning, and that global T cell deficiency exacerbates motor behavioral defects in this rat model of PD.

SUMMARY Glioblastoma multiforme (GBM) is a malignant neoplasm of the CNS with almost uniform lethality. Even with standard-of-care treatments, the prognosis for patients remains dismal. GBM, as with other malignancies, often acquires treatment resistance after an initial response to therapy. Treatment resistance may come about through the adaptive evolution of tumors in response to selection pressures from treatment interventions and the microenvironment. This review discusses how adaptive evolution might potentially be exploited as a new paradigm in GBM treatment.

The availability of reliable, cost effective power and temperature control is critical to all facets of oil and gas operations around the globe. Dropping of global oil prices has had significant effects on long-term liquefied natural gas contracts. Oil and gas producers have experienced a decline in profits, and unprecedented pressure has been put on these companies to remain viable. Many marginal operators have experienced freezing of exploration budgets, delays on future planned expansions and the wind down of non-essential operations. Herein are four case studies from the oil and gas industry, which highlight several business solutions that assisted companies to stabilise their profits by starting production early, reducing operational down time and assisting process efficiencies.

According to the United States Air Force (USAF) Personnel Center, over the next several years, the USAF intends on hiring up to 20,000 new civilians to its workforce, including 3,000 new hires by the end of 2010.1 Stemming the outsourcing of critical functions to private contractors, 10,000 of these new authorizations will replace the work of contractors, while the remaining positions will increase the approved civilian authorization end strength numbers. Though most of these positions will be in acquisition career fields, the other positions will increase civilian authorizations across the spectrum of base operations, including civilian engineering, logistics and security. In 2011, these increases will bring the Air Force up from 148,000 to 168,000 in civilian employment.

School clusters in Thailand represent a management strategy for improving primary school quality. This chapter examines the way school clusters carry out these responsibilities through an indepth case study of one school cluster (with references to a pilot study of a second cluster). The cluster studied indepth focused more on accountability than capacity-building policies, an emphasis which is probably typical of most clusters. School cluster influence was found to vary by school, depending on the degree of receptivity to change by the school and especially its principal. The chapter concludes by examining a number of changes which could improve the efficiency of school clusters and school receptivity to cluster influence.

Cancer vaccine trials have failed to yield robust immune-correlated clinical improvements as observed in animal models, fueling controversy over the utility of human cancer vaccines. Therapeutic vaccination represents an intriguing additional therapy for glioblastoma multiforme (GBM; grade 4 glioma), which has a dismal prognosis and treatment response, but only early phase I vaccine trial results have been reported. Immune and clinical responses from a phase II GBM vaccine trial are reported here. IFN-γ responsiveness was quantified in peripheral blood of 32 GBM patients given therapeutic dendritic cell vaccines. Posttreatment times to tumor progression (TTP) and survival (TTS) were compared in vaccine responders and nonresponders and were correlated with immune response magnitudes. GBM patients (53%) exhibited ≥1.5-fold vaccine-enhanced cytokine responses. Endogenous antitumor responses of similar magnitude occurred in 22% of GBM patients before vaccination. Vaccine responders exhibited significantly longer TTS and TTP relative to nonresponders. Immune enhancement in vaccine responders correlated logarithmically with TTS and TTP spanning postvaccine chemotherapy, but not with initial TTP spanning vaccination alone. This is the first report of a progressive correlation between cancer clinical outcome and T-cell responsiveness after therapeutic vaccination in humans and the first tracing of such correlation to therapeutically exploitable tumor alteration. As such, our findings offer unique opportunities to identify cellular and molecular components of clinically meaningful antitumor immunity in humans. [Cancer Res 2008;68(14):5955–64]

BACKGROUND: Dendritic cell vaccines are a promising treatment for glioblastoma. The glioblastoma stem-like cell subpopulation is refractory to standard chemotherapy and radiation treatment, but may be susceptible to immunotherapeutic targeting. METHODS: This single-institution phase I trial is designed to assess the safety, tolerability, and potential efficacy of an autologous dendritic cell vaccine pulsed with lysate derived from a glioblastoma stem-like cell line. Patients with newly diagnosed glioblastoma (Cohort A) receive standard radiation and temozolomide in addition to vaccine. Patients with up to third glioblastoma recurrence (Cohort B) receive vaccine alone, although patients previously treated with bevacizumab are allowed to continue bevacizumab on study. Prior to enrollment, patients must undergo a qualifying gross total or near-gross total resection. Treatment consists of a Vaccine Induction Phase (weekly vaccines x 4 – for Cohort A, given upon completion of radiation), followed by a Vaccine Maintenance Phase (vaccine every 8 weeks until supply depleted). Imaging is performed during Week 4 of the Induction phase and every 8 weeks thereafter until progression. The primary objective of safety and tolerability includes adverse event grading per NCI CTC. Clinical assessment includes progression-free survival at 6 months and overall survival. Immunological testing to assess cytotoxic T-lymphocyte response will be performed at predetermined intervals. Goal enrollment is 20 patients in each cohort. Stopping rules for safety and efficacy using Bayesian sequential design will be followed. RESULTS: To date, 18 patients (7 new GBM, 11 recurrent GBM) have enrolled in this trial. No adverse events related to vaccine have been noted. CONCLUSION: This single-institution phase I dendritic cell vaccine trial builds upon our previous research efforts by specifically targeting the glioblastoma stem-like cell subpopulation that is resistant to standard radiation and chemotherapy. Accrual is proceeding rapidly, and results will be published when available.

Human capital tends to have significant external effects within local markets, increasing the average income of individuals within the same metropolitan area. However, evidence on both human capital spillovers and peer effects in neighborhoods suggests that these effects may be confined to relatively small areas. Hence, the distribution of income gains from average levels of human capital should depend on how that human capital is distributed throughout a city. This paper explores this issue by documenting the extent to which college graduates are residentially segregated across more than 165000 block groups in 359 U.S. metropolitan areas over the period 1980-2000. Using three different metrics, we find that the segregation of college graduates rose between 1980 and 2000. We also find that cities which experienced larger increases in their levels of segregation also experienced larger increases in income inequality, although our results suggest that inequality and segregation likely influence each other.

This paper offers a descriptive empirical analysis of the geographic pattern of income inequality within a sample of 359 US metropolitan areas between 1980 and 2000. Specifically, we decompose the variance of metropolitan area-level household income into two parts: one associated with the degree of variation among household incomes within neighborhoods - defined by block groups and tracts - and the other associated with the extent of variation among households in different neighborhoods. Consistent with previous work, the results reveal that the vast majority of a city's overall income inequality - at least three quarters - is driven by within-neighborhood variation rather than between-neighborhood variation, although we find that the latter rose significantly during the 1980s, especially between block groups. We then identify a number of metropolitan area-level characteristics that are associated with both levels of and changes in the degree of each type of residential income inequality.

Existing research has found an inverse relationship between urban density and the degree of income inequality within metropolitan areas, suggesting that, as cities spread out, they become increasingly segregated by income. This paper examines this hypothesis using data covering more than 160000 block groups within 359 US metropolitan areas over the years 1980, 1990, and 2000. The findings indicate that income inequality - defined by the variance of the log household income distribution - does indeed rise significantly as urban density declines. This increase, however, is associated with rising inequality within block groups as cities spread out. The extent of income variation exhibited between different block groups, by contrast, shows virtually no association with population density. There is, accordingly, little evidence that sprawl is systematically associated with greater residential segregation of households by income.

One of the most robust findings emerging from studies of industrial agglomeration is the rise in productivity that tends to accompany it. What most studies have not addressed, however, is the potential role played by human capital externalities in driving this relationship. This paper seeks to do so using data from the 1980, 1990, and 2000 US Census covering a collection of 77 (primarily) three-digit manufacturing industries across a sample of more than 200 metropolitan areas. The analysis generates two primary results. First, a variety of education- and experience-based measures of average human capital rise significantly as an industry’s employment in a metropolitan area increases. Hence, clusters of industry do tend to be characterized by larger stocks of human capital. However, second, even after accounting for the level of human capital in a worker’s own industry, the overall size of the industry remains strongly associated with wages. Such results cast some doubt on the notion that localization economies emanate from education- or experience-based knowledge spillovers.

Through their influence on the cross-sectional distribution of productivity across firms and workers, job creation and destruction likely have an impact on the rate at which aggregate productivity changes over time. However, the nature of this effect is not, a priori, clear. While a broad consensus has emerged suggesting that job destruction enhances productivity by eliminating inefficient production units, theories disagree with regard to the effect of job creation. In particular, 'vintage-capital' theories of creative destruction suggest a positive influence since job flows are conjectured to represent the reallocation of labor from low- to high-productivity positions. Others suggest that job creation may, instead, represent the expansion of employment primarily along a lowskill (or low 'match-quality') dimension. In such a case, job creation would serve to lower aggregate productivity. This paper estimates the influence of job creation and destruction on total factor productivity (TFP) growth using annual data on 389 4- digit U.S. manufacturing industries over the period 1974-1993. As expected, the results reveal a positive association between job destruction and changes in TFP. Yet, they also indicate that, contrary to the creative-destruction view, job creation tends to have a negative effect on productivity growth.

Purpose: Although the development of immune-based therapies for various cancers including malignant glioma has been heralded with much hope and optimism, objective clinical improvements in most vaccinated cancer patients have not been realized. To broaden the search for vaccine-induced benefits, we examined synergy of vaccines with conventional chemotherapy.Experimental Design: Survival and progression times were analyzed retrospectively in 25 vaccinated (13 with and 12 without subsequent chemotherapy) and 13 nonvaccinated de novo glioblastoma (GBM) patients receiving chemotherapy. Immune responsiveness and T-cell receptor excision circle (TREC) content within CD8+ T cells (CD8+ TRECs) was determined in vaccinated patients.Results: Vaccinated patients receiving subsequent chemotherapy exhibited significantly longer times to tumor recurrence after chemotherapy relative to their own previous recurrence times, as well as significantly longer postchemotherapy recurrence times and survival relative to patients receiving isolated vaccination or chemotherapy. Patients exhibiting objective (>50%) tumor regression, extremely rare in de novo GBM, were also confined to the vaccine + chemotherapy group. Prior tumor behavior, demographic factors, other treatment variables, distribution of vaccine responders, and patients with high CD8+ TRECs all failed to account for these differences in clinical outcome. Within all GBM patients receiving post-vaccine chemotherapy, however, CD8+ TRECs predicted significantly longer chemotherapeutic responses, revealing a strong link between the predominant T-cell effectors in GBM and tumor chemosensitivity.Conclusions: We propose that therapeutic vaccination synergizes with subsequent chemotherapy to elicit tangible clinical benefits for GBM patients.

While the productivity gains associated with the geographic concentration of industry (i.e. localization) are by now well-documented, little work has considered how those gains are distributed across individual workers. This paper offers evidence on the connection between total employment and the relative wage earnings of high- and low-skill workers (i.e. inequality) within two-digit manufacturing industries across the states and a collection of metropolitan areas in the U.S. between 1970 and 1990. Using two different measures - 90-10 percentile gaps in both overall and residual wages - I find that wage dispersion falls substantially as industry employment expands. Results from a simple decomposition of this relationship into average plant-size and plant-count components indicate overwhelmingly that average plant size is the primary driving mechanism. Although not necessarily inconsistent with theories appealing to intermediate inputs or technological spillovers, such findings are particularly supportive of Marshall's (1920) labor market pooling explanation for localization.

2087 Background: This study evaluated the safety and immune responses to an autologous dendritic cell vaccine pulsed with class I peptides from tumor associated antigens (TAA) expressed on gliomas and overexpressed in their cancer stem cell population (ICT-107). These TAA epitodes AIM-2. TRP-2, HER2 and AIM-2, are also overexpressed on glioblastoma multiforme (GBM) cancer stem cells. Methods: TAA epitopes included HER2, TRP-2, gp100, MAGE-1, IL13Rα2, and AIM-2. HLA-A1 and/or HLA-A2 positive glioblastoma (GBM) patients with gross total resection were eligible. Mononuclear cells from leukapheresis were differentiated into dendritic cells, pulsed with TAA peptides, and administered intradermally three times at two-week intervals in the axilla region after a standard treatment with concurrent temozolomide (TMZ) and radiation therapy for newly diagnosed (ND-GBM). Results: Twenty-one patients were enrolled with 17 ND-GBM and three recurrent GBM patients and one brainstem glioma. Immune response data on 15 newly diagnosed patients showed 33% responders. TAA expression by qRT-PCR showed all patient tumors expressed at least three TAA with 75% expressing all six. Correlations of increased PFS and quantitative expression of MAGE1, AIM-2, gp100 and HER2 were observed. A decrease or absence of CD133 expression was seen in five patients who underwent a second resection. As of February 1, 2012, six of 16 ND-GBM patients showed no evidence of tumor recurrence (44-63 months). Median progressive free survival (PFS) in newly diagnosed patients was 16.9 months with a two-year PFS rate was 43.8% (95%CI,19.8-66.0 ). The median overall survival rate (OS) was 38.4 months and a two-year OS was 80.3% (95%CI,58.6-96.7). Conclusions: Expression of four ICT-107 targeted antigens in the pre-vaccine tumors correlated with prolonged overall survival and PFS in ND-GBM patients. The goal of targeting tumor antigens highly expressed on glioblastoma cancer stem cells is supported by the observation of decreased or absent CD133 expression in the recurrent areas of gadolinium-enhanced tumor.

2084 Background: Our prior immunotherapy trials demonstrated efficacy in generating a tumor specific immune response in malignant glioma and the potential for high tumor-specific toxicity and sustained tumoricidal activity. Immunotherapy may synergize with chemotherapy and biodegradable carmustine (BCNU) wafers and have a modest impact to extend overall survival. We exploited this synergistic effect to maintain a cytotoxic environment around the tumor milieu, and this is a presentation of the final results of our clinical trial. Methods: Patients with glioblastoma were eligible after maximal resection with biodegradable carmustine (BCNU) wafer placement. Screening leukapheresis was used to isolate mononuclear cells which were differentiated into dendritic cells, pulsed with tumor lysate, and then 3 intradermal vaccines administered at 2-week intervals. Patients continued systemic chemotherapy after vaccine or at progression. Results: Twenty three patient with glioblastoma received therapy including 8 with newly diagnosed disease (35%) and 15 with recurrent disease (65%) were evaluable. Immune response data is available for 20/23 patients although survival data is present for all. One grade 3 SAE of fever and chills was noted otherwise therapy was well tolerated. Within the newly diagnosed GBM cohort the median overall survival (OS) was 25.5 months (15,31+), and within the recurrent GBM cohort, the median OS was 16 months (8,23+). Among the recurrent GBM an increase of >1.5 X baseline interferon gamma production post vaccination was associated with a prolonged median OS 22 months (8,40) in 4/12 patients versus 17 months (9,27) in 8/12 patients. Conclusions: We were able to generate an immune response in 25% of patients which is lower than what we have seen in previous trials and suggests a limited synergy with local control. However, within the recurrent GBM cohort we did find prolonged survival in both groups with an increased survival noted in immune responders demonstrating the potential for this therapy.

2042 Background: Active immunotherapy offers the potential for high tumor-specific toxicity and sustained tumoricidal activity. We developed a dendritic cell (DC) immunotherapy to target specific g...

2097 Background: Active immunotherapy offers the potential for high tumor-specific toxicity and sustained tumoricidal activity. We therefore have developed this protocol to exploit the most current...

2033 Background: Our prior immunotherapy trials demonstrated efficacy in generating a tumor specific immune response in malignant glioma and the potential for high tumor-specific toxicity and sustained tumoricidal activity. Immunotherapy may synergize with chemotherapy and biodegradable carmustine (BCNU) wafers extend overall survival from 11.6 to 13.9 months. Methods: We exploited this synergistic effect to maintain a cytotoxic environment around the tumor milieu. Patients with high-grade glioma were eligible after maximal resection with biodegradable carmustine (BCNU) wafer placement. Screening leukapheresis is used to isolate mononuclear cells which are differentiated into dendritic cells, pulsed with tumor lysate, and then 3 intradermal vaccines are administered at 2-week intervals. Patients continued systemic chemotherapy after vaccine or at progression. Results: Eighteen patients have been enrolled (7 Male, 11 Female) between April 2007 and February 2009 with one screen failure and two patients with clinical progression prior to vaccination. The median patient age was 57 years (26 to 74 ) and median Karnofsky performance status was 90% (80–100). The histology included 3 newly diagnosed glioblastoma multiforme (GBM), 8 recurrent GBM, 2 newly diagnosed anaplastic astrocytoma (AA), and 2 recurrent AA. 15 patients were successfully treated by vaccine injections with 12 patients receiving vaccine every 2 weeks x 3 followed by adjuvant chemotherapy. Our preliminary data on 15 patients and 39 courses of Dendritic Cell vaccines demonstrate one grade 3 toxicity of fever/chest pain. A stable disease interval of 13 to 90 weeks was observed for patients who received vaccine. The 3 newly diagnosed GBM patients have stable disease (18 to 71 weeks). In the recurrent GBM cohort 7/8 patients had progression within 6 months from the post-vaccination MRI. Conclusions: This phase I study demonstrates the safety, feasibility of dendritic cell vaccination with biodegradable carmustine (BCNU) wafers with one grade 3 AE. Immunological data is pending to determine potential synergy of dendritic cell vaccination with intracranial chemotherapy. No significant financial relationships to disclose.

2032 Background: Previous immunotherapy trials for malignant glioma (Yu, J.,et al, Cancer Res. 2001;61:842–7 and 2004;64;4973–9) have demonstrated efficacy in generating a tumor specific immune response. Here we set out to determine feasibility and immunogenecity of dendritic vaccination with specific glioma-associated antigens. Methods: The goal of this study is to use tumor associated antigens (TAA) known to be expressed on gliomas and pulse dendritic cells with these antigens in an MHC compatible fashion using epitopes of HER-2, TRP-2, gp100, MAGE-1, IL13R alpha, and AIM-3. In this phase I trial, HLA-A1 and/or HLA-A2-positive patients with newly diagnosed or recurrent glioblastoma were eligible. Leukapheresis was used to isolate mononuclear cells which were differentiated into dendritic cells in culture, pulsed with tumor peptide, and then administered intradermally three times at 2-week intervals. Results: Twenty patients, 15 males and five females, were enrolled between November 2006 and December 2008 with one screen failure. The median patient age was 47 years (range: 26–65) and patients had a median Karnofsky performance status of 90% (range: 90–100). There were 16 newly diagnosed and three recurrent glioblastoma multiforme (GBM) patients, who underwent surgery prior to vaccination. Our data on 19 patients and 54 courses of dendritic cell vaccines demonstrate zero grade 3 /4 toxicities that were attributable to the vaccination. Thirteen patients continue to have stable disease (ranging from 15 to 115 weeks), six patients have demonstrated tumor progression. Median survival from surgery was 60 weeks (ranging from 26 to 115 weeks). Of 15 patients tested to date, six patients demonstrated an antigen-specific cytotoxic T-cell response to at least one antigen after vaccination. Only 17% of CTL responders (1/6) demonstrated tumor progression compared to 56% (5/9) of nonresponders to date. Conclusions: This phase I study demonstrated the feasibility, safety, and bioactivity of a TAA-pulsed dendritic cell vaccine for patients with glioblastoma progression free survival correlated with CTL response. [Table: see text]

3060 Background: Therapeutic vaccination represents a novel therapy for glioblastoma multiforme (grade IV glioma; GBM), which has a dismal prognosis and treatment response, but only early phase I v...

The dismal prognoses suffered by malignant primary brain tumor (glioma) patients remain unchanged over the past two decades despite significant improvements in the treatment of distinct tumors. Immunotherapy, and vaccine therapy in particular, represents a promising experimental approach to treat malignant gliomas, but major challenges still remain to render vaccination clinically effective. These challenges include diminishing the risk of pathologic autoimmunity, and identifying the cellular basis of clinical vaccine benefits. Addressing such challenges should eventually help increase the proportion of patients experiencing clinical vaccine benefits. Recent studies in glioma patients have characterized tumor antigens on human gliomas, identified some of the immune cells involved in beneficial anti-glioma immunity, and examined how gliomas may be altered by sub-lethal immune influences. This has provided a glimpse of the strength to which immunity influences glioma clinical outcome, and resurrects hope that clinically effective vaccines to treat these tumors is within reach. Insight into the complex dynamics of immune-tumor interactions promises to extend this reach by delineating mechanisms of immune synergy with other forms of treatment.