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The promise of adaptive cancer immunotherapy in treating highly malignant tumors such as glioblastoma multiforme (GBM) can only be realized through expanding its benefits to more patients. Alleviating various modes of immune suppression has so far failed to achieve such expansion, but exploiting endogenous immune enhancers among mutated cancer genes could represent a more direct approach to immunotherapy improvement. We found that Isocitrate Dehydrogenase-1 (IDH1), which is commonly mutated in gliomas, enhances glioma vaccine efficacy in mice and discerns long from short survivors after vaccine therapy in GBM patients. Extracellular IDH1 directly enhanced T cell responses to multiple tumor antigens, and prolonged experimental glioma cell lysis. Moreover, IDH1 specifically bound to and exhibited sialidase activity against CD8. By contrast, mutant IDH1R132H lacked sialidase activity, delayed killing in glioma cells, and decreased host survival after immunotherapy. Overall, our findings identify IDH1 as an immunotherapeutic enhancer that mediates the known T cell-enhancing reaction of CD8 desialylation. This uncovers a new axis for immunotherapeutic improvement in GBM and other cancers, reveals novel physiological and molecular functions of IDH1, and hints at an unexpectedly direct link between lytic T cell function and metabolic activity in target cells.

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.

Supplementary Figure 1: spheroid growth in VersaGel using tumor cell lines. A) HepG2 hepatocarcinoma cell line; B) LN18 glioblastoma cell line. Scale bar = 1 millimeter. Supplementary Figure 2: VersaGel vs. BME (Matrigel) for Patient 4, Partial Responder (A) and Patient 5, Responder (B).

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.

Novel strategies for the management of soybean looper, Chrysodeixis includens (Walker) (Lepidoptera: Noctuidae), are needed due to its increasing importance, costs, and challenges of management in soybeans (Glycine max [L.] Merr.; Fabaceae) in the Americas. Pheromone-mediated mating disruption may be 1 such novel strategy, but an effective tool for estimating mating disruption success must be found. The technique of trapping male moths using pheromone baited traps is a common method for assessing mating disruption technology. This paper reports on the testing of 2 trap types and 3 commercially available lures containing (Z)-7-dodecenyl acetate as the major active component. Trapping was conducted at 5 locations in the southern USA in the summer of 2019. Universal moth traps and delta traps were tested in combination with the Alpha Scents, Bio Pseudoplusia, and Scentry brand lures along with unbaited traps. Overall, both trap types were effective at capturing C. includens male moths, with universal traps having a higher capture rate. The Alpha Scents and Bio Pseudoplusia lures both had a significantly higher capture rate than the Scentry lure regardless of trap design. The active components of the Scentry lure differed from the others with the inclusion of 2 known minor pheromone components (esters) of C. includens, (Z)-7-dodecenyl propionate and (Z)-7-dodecenyl butyrate. The amount of (Z)-7-dodecenyl acetate of the Scentry lure also was lower than the Alpha Scents and Bio Pseudoplusia lures. The additional esters or unidentified components (impurities) of the Scentry lures may have influenced C. includens captures. A large number of Ctenoplusia oxygramma (Geyer) (Lepidoptera: Noctuidae) were captured in traps at 3 of the locations, though not in those traps baited with the ester-containing Scentry lure. Taken together, the data provide insight into effective trapping methods for C. includens and elucidates the need for researchers to understand the effectiveness of trapping components available in a region and the need for researchers to plan for captures of non-target species in pheromone-related research.

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.

Sporadic Alzheimer’s disease, the most common neurodegenerative disorder of aging, is characterized by cerebral plaques and neurofibrillary tangles. Experimental rodents develop plaques but neither tangles nor substantial neurodegeneration under conditions that guarantee Alzheimer’s in humans, suggesting rodents lack critical co-initiation factors. Accumulation of antigen-reactive memory CD8 T cells increases with aging, and was recently revealed as a hallmark of human Alzheimer’s. The impact of this process on disease initiation, however, has not been established because age-related T cell changes are muted in rodents. We developed a mouse model of human-like CD8 T cell aging that promotes antigen-reactive memory CD8 T cell accumulation. Here we show that these “hiT” mice develop all major hallmarks of Alzheimer’s with aging, including tangle-like inclusions and substantial neurodegeneration. Antigen-reactive CD8 T cells analogous to those in hiT mice increased in Alzheimer’s brain, but decreased earlier in blood, where their loss effectively distinguished the Alzheimer’s continuum from aging controls. Our findings establish a clinically relevant mouse model for sporadic Alzheimer’s and show that age-related immune dysfunction critically contributes to its initiation. They also identify useful immune-based targets to track and potentially treat human Alzheimer’s, while validating a model system to examine age-related disease immuno-biology more generally.

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.

Researchers studying income inequality, economic segregation, and other subjects must often rely on grouped data—that is, data in which thousands or millions of observations have been reduced to counts of units by specified income brackets. The distribution of households within the brackets is unknown, and highest incomes are often included in an open-ended top bracket, such as “$200,000 and above.” Common approaches to this estimation problem include calculating midpoint estimators with an assumed Pareto distribution in the top bracket and fitting a flexible multiple-parameter distribution to the data. The authors describe a new method, mean-constrained integration over brackets (MCIB), that is far more accurate than those methods using only the bracket counts and the overall mean of the data. On the basis of an analysis of 297 metropolitan areas, MCIB produces estimates of the standard deviation, Gini coefficient, and Theil index that are correlated at 0.997, 0.998, and 0.991, respectively, with the parameters calculated from the underlying individual record data. Similar levels of accuracy are obtained for percentiles of the distribution and the shares of income by quintiles of the distribution. The technique can easily be extended to other distributional parameters and inequality statistics.

Mitigating effects of aging on human health remains elusive because aging impacts multiple systems simultaneously, and because experimental animals exhibit critical aging differences relative to humans. Separation of aging into discrete processes may identify targetable drivers of pathology, particularly when applied to human-specific features. Gradual homeostatic expansion of CD8 T cells dominantly alters their function in aging humans but not in mice. Injecting T cells into athymic mice induces rapid homeostatic expansion, but its relevance to aging remains uncertain. We hypothesized that homeostatic expansion of T cells injected into T-deficient hosts models physiologically relevant CD8 T cell aging in young mice, and aimed to analyze age-related T cell phenotype and tissue pathology in such animals. Indeed, we found that such injection conferred uniform age-related phenotype, genotype, and function to mouse CD8 T cells, heightened age-associated tissue pathology in young athymic hosts, and humanized amyloidosis after brain injury in secondary wild-type recipients. This validates a model conferring a human-specific aging feature to mice that identifies targetable drivers of tissue pathology. Similar examination of independent aging features should promote systematic understanding of aging and identify additional targets to mitigate its effects on human health.

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.

A cell culture platform that enables

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.

In an aposematic system, the warning display (e.g., color, odor, or behavior) advertises the presence and potentially the strength of the chemical defense. A strong coupling between the indicator trait and the defensive trait is therefore integral to the evolution and maintenance of aposematism. An ostensibly conflicting theory predicts that a negative correlation between the indicator and defensive trait can exist, depending on the selective pressure on defenses and the presence of multiple aposematic signals. The aposematic ladybeetle, Hippodamia convergens, displays a variety of aposematic signals, the combined effects of which have been rigorously tested in predator stimulus–response experiments. Intraspecific variation of investment in these multimodal aposematic displays, however, has not been explored thoroughly. In this study, we examine multimodal signal theory from the perspective of the signaler, and identify significant correlations between warning coloration, warning odor, and toxicity. We show that the red coloration of H. convergens functions as an honest signal of alkaloid toxicity, while methoxypyrazine warning odors are negatively correlated with alkaloid content. However, there is no correlation between red coloration and methoxypyrazine content. Thus, the reddest females contained the highest concentrations of alkaloids and some of the lowest concentrations of methoxypyrazines. The reddest males, although producing less alkaloids than their red female counterparts, on average produced significantly more alkaloids and methoxypyrazines than orange females and orange males. Within each of these groups, the negative correlation between methoxypyrazines and alkaloid toxicity remains. The relationship between variations in these signals may be affected by the interactions of color and odor on avoidance learning in predators, as well as the supplemental aggregative function of the aposematic methoxypyrazine signal.

The convergent lady beetle (Hippodamia convergens) forms large overwintering aggregations at revisited montane microsites far removed from their summer foraging grounds. Although orientation responses to visual and altitudinal features of habitat can explain the arrival of migrants at the general overwintering macrosite, the role that pheromones play in the accumulation of individuals in inconspicuous hibernacula microsites is not fully understood. Through two-choice bioassays and gas chromatography and mass spectrometry, we found that H. convergens orient towards hydrocarbons previously deposited on their walking surfaces by conspecifics. n-Tricosane (C23) is primarily responsible for this chemically-mediated orientation. Footprint extracts, as well as C23 alone, induce the eventual accumulation in the field of migrant H. convergens at artificial hibernacula, confirming their probable role as aggregation signals. Aggregations persisted over many days when footprint extracts were applied in conjunction with the previously identified 2-isobutyl-3-methoxypyrazine (IBMP) aggregation pheromone. The C23 hydrocarbon functions as a pheromone that interacts with responses to methoxypyrazines to effectively mediate formation of persistent aggregations of diapausing conspecifics at specific microsites. Also discussed is the potential effect that C23 has as a persistent scent marker in establishing the traditional use of hibernacula.

Household income inequality is increasing in the US, both nationally and within metropolitan areas. Depending on how the housing stock is distributed and how households sort into neighborhoods, metropolitan income inequality translates into unequal neighborhoods. Inequality between neighborhoods causes concentration of poverty and leads to vastly different developmental contexts for children growing up in poor, middle-class, and affluent neighborhoods. This paper examines neighborhood inequality using new measures that highlight the separate contributions of income inequality, on the one hand, and economic segregation on the other. While both matter, we find that economic segregation is the driving force behind the variation between metropolitan areas in the degree of neighborhood inequality and that changes in economic segregation are more important in driving the changes in inequality from one decade to the next. We also examine case studies of metropolitan areas with large and small changes in economic segregation between 1970 and 2010, and examine the role of demographic and housing market changes that underlie these changes.

Dicyano-ferriprotoporphyrin supported on Pt microelectrodes was investigated as a possible electrocatalytic material capable of selectively oxidizing the gasotransmitter H 2 S over interfering gasotransmitters CO and NO. The modified microelectrodes were able to detect H 2 S concentrations as low as 50 nM at a potential of 0.15 V vs . Ag/AgCl and demonstrated a 100–1000× higher sensitivity toward H 2 S than CO and NO, respectively. However, H 2 S detection was affected by the presence of CO and NO due, at least in part, to imperfect coverage of the underlying Pt microelectrode by the electrocatalyst. Incomplete CN − coordination and questionable stability of the porphyrin layer are also discussed as possible causes of CO and NO interference. Work is on-going to alleviate these limitations in order to fully develop the material into a practical electrocatalyst capable of selective H 2 S oxidation.

After articulating 12 concepts for the reasoning component of citizen-level science literacy and restating these as assessable student learning outcomes (SLOs), we developed a valid and reliable assessment instrument for addressing the outcomes with a brief 25-item science literacy concept inventory (SLCI). In this paper, we report the results that we obtained from assessing the citizen-level science literacy of 17,382 undergraduate students, 149 graduate students, and 181 professors. We address only findings at or above the 99.9% confidence level. We found that general education (GE) science courses do not significantly advance understanding of science as a way of knowing. However, the understanding of science’s way of knowing does increase through academic ranks, indicating that the extended overall academic experience better accounts for increasing such thinking capacity than do science courses alone. Higher mean institutional SLCI scores correlate closely with increased institutional selectivity, as measured by the institutions’ higher mean SAT and ACT scores. Socioeconomic factors of a) first-generation student, b) English as a native language, and c) interest in commitment to a science major are unequally distributed across ethnic groups. These factors proved powerful in accounting for the variations in SLCI scores across ethnicities and genders.

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). Methods TAA epitopes included HER2, TRP-2, gp100, MAGE-1, IL13Rα2, and AIM-2. HLA-A1- and/or HLA-A2-positive patients with glioblastoma (GBM) were eligible. Mononuclear cells from leukapheresis were differentiated into dendritic cells, pulsed with TAA peptides, and administered intradermally three times at two-week intervals. Results Twenty-one patients were enrolled with 17 newly diagnosed (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 from fresh-frozen tumor samples showed all patient tumors expressed at least three TAA, with 75 % expressing all six. Correlations of increased PFS and OS with quantitative expression of MAGE1 and AIM-2 were observed, and a trend for longer survival was observed with gp100 and HER2 antigens. Target antigens gp100, HER1, and IL13Rα2 were downregulated in recurrent tumors from 4 HLA-A2+ patients. A decrease in or absence of CD133 expression was seen in five patients who underwent a second resection. At a median follow-up of 40.1 months, six of 16 ND-GBM patients showed no evidence of tumor recurrence. Median PFS in newly diagnosed patients was 16.9 months, and median OS was 38.4 months. 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 tumors.

Electrodeposited Fe(III) meso-Tetra(4-carboxyphenyl) porphyrin with cyanide ligands coordinated to the central iron ion is being investigated as a possible material capable of selectively oxidizing H2S in the presence of CO and NO in physiologically relevant solutions. Preliminary results suggest this to be a very attractive material as it oxidizes H2S at low potentials while exhibiting minimal activity towards both CO and NO. However certain results suggest that the Fe may not be completely coordinated with cyanide ligands. This may explain the limitations of the material at elevated H2S concentrations and imperfect selectivity over the interfering gases. Additionally, a cathodic-post run treatment is suggested in order to maintain the electrochemical activity of the porphyrin-modified electrode surface by stripping any S0 that deposits on the electrode surface during the H2S oxidation.

The completion of the Human Genome Project resulted in discovery of many unknown novel genes. This feat paved the way for the future development of novel therapeutics for the treatment of human disease based on novel biological functions and pathways. Towards this aim, we undertook a bioinformatics analysis of in-house microarray data derived from purified hematopoietic stem cell populations. This effort led to the discovery of HSS1 (Hematopoietic Signal peptide-containing Secreted 1) and its splice variant HSM1 (Hematopoietic Signal peptide-containing Membrane domain-containing 1). HSS1 gene is evolutionarily conserved across species, phyla and even kingdoms, including mammals, invertebrates and plants. Structural analysis showed no homology between HSS1 and known proteins or known protein domains, indicating that it was a truly novel protein. Interestingly, the human HSS1 (hHSS1) gene is located at chromosome 19q13.33, a genomic region implicated in various cancers, including malignant glioma. Stable expression of hHSS1 in glioma-derived A172 and U87 cell lines greatly reduced their proliferation rates compared to mock-transfected cells. hHSS1 expression significantly affected the malignant phenotype of U87 cells both in vitro and in vivo. Further, preliminary immunohistochemical analysis revealed an increase in hHSS1/HSM1 immunoreactivity in two out of four high-grade astrocytomas (glioblastoma multiforme, WHO IV) as compared to low expression in all four low-grade diffuse astrocytomas (WHO grade II). High-expression of hHSS1 in high-grade gliomas was further supported by microarray data, which indicated that mesenchymal subclass gliomas exclusively up-regulated hHSS1. Our data reveal that HSS1 is a truly novel protein defining a new class of secreted factors, and that it may have an important role in cancer, particularly glioma.

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.

This paper examines the determinants of employment growth in metro areas. To obtain growth rates, we use a Markov-switching model that separates a city’s growth path into two distinct phases (high and low), each with its own growth rate. The simple average growth rate over some period is, therefore, the weighted average of the high-phase and low-phase growth rates, with the weight being the frequency of the two phases. We estimate the effects of a variety of factors separately for the high-phase and low-phase growth rates, along with the frequency of the low phase. We find that growth in the high phase is related to human capital, industry mix, and average firm size. In contrast, we find that growth in the low phase is mostly related to industry mix, specifically, the relative importance of manufacturing. Finally, the frequency of the low phase appears to be related to the level of non-education human capital, but to none of the other variables. Overall, our results strongly reject the notion that city-level characteristics influence employment growth equally across the phases of the business cycle.

In the karstic lower Flint River Basin, limestone fracturing, jointing, and subsequent dissolution have resulted in the development of extensive secondary permeability and created a system of major conduits that facilitate the exchange of water between the Upper Floridan aquifer and Flint River. Historical streamflow data from U.S. Geological Survey gaging stations located in Albany and Newton, Georgia, were used to quantify ground-water and surface-water exchanges within a 55.3 km section of the Flint River. Using data from 2001, we compared estimates of ground-water flux using a time adjustment method to a water balance equation and found that these independent approaches yielded similar results. The associated error was relatively large during high streamflow when unsteady conditions prevail, but much lower during droughts. Flow reversals were identified by negative streamflow differences and verified with in situ data from temperature sensors placed inside large spring conduits. Long-term (13 years) analysis showed negative streamflow differentials (i.e., a losing stream condition) coincided with high river stages and indicated that streamflow intrusion into the aquifer could potentially exceed 150 m 3 /s. Although frequent negative flow differentials were evident, the Flint River was typically a gaining stream and showed a large net increase in flow between the two gages when examined over the period 1989-2003. Ground-water contributions to this stream section averaged 2-42 m 3 /s with a mean of 13 m 3 /s. The highest rate of ground-water discharge to the Flint River occurred during the spring when regional ground-water levels peaked following heavy winter and spring rains and corresponding rates of evapo-transpiration were low. During periods of extreme drought, ground-water contributions to the Flint River declined.

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.

It has recently been demonstrated that malignant glioma cells express certain known tumor-associated antigens, such as HER-2, gp100, and MAGE-1. To further determine the possible utilization of these antigens for glioma immunotherapy and as surrogate markers for specific tumor antigen cytotoxicity, we characterized the presence of mRNA and protein expression in 43 primary glioblastoma multiforme (GBM) cell lines and 7 established human GBM cell lines. HER-2, gp100, and MAGE-1 mRNA expression was detected in 81.4%, 46.5%, and 39.5% of the GBM primary cell lines, respectively. Using immunoreactive staining analysis by flow cytometry, HER-2, gp100, and MAGE-1 protein expression was detected in 76%, 45%, and 38% of the GBM primary cell lines, respectively. HLA-A1-restricted epitope specific for MAGE-1 peptide (EADPTGHSY) CTL clone B07 and HLA-A2-restricted epitope specific for HER-2 peptide (KIFGSLAFL) CTL clone A05 and gp100 peptide (ITDQVPFSV) CTL clone CK3H6 were used in this study. The specificity of CTL clone was verified by HLA/peptide tetramer staining. Three CTL clones could efficiently recognize GBM tumor cells in an antigen-specific and MHC class I-restricted manner. IFN-γ treatment can dramatically increase MHC class I expression of GBM tumor cells and significantly increase CTL recognition of tumor cells. Treatment with the DNA hypomethylating agent 5-aza-2′-deoxycytidine induced and up-regulated the mRNA expression of MAGE-1 and epitope presentation by autologous MHC. These data indicate that HER-2, gp100, and MAGE-1 could be used as tumor antigen targets for surrogate assays for antigen-specific CTLs or to develop antigen-specific active immunotherapy strategies for glioma patients.

Although many theories of urban growth have broad implications regarding the dynamics of wage inequality, little empirical work has explored the issue. This paper studies the relationship between the growth of three measures of economic activity—population, employment, and per capita income—and a variety of wage-dispersion measures across a sample of US metropolitan areas between 1970 and 1990. Overall, the results indicate a negative association between the two: cities experiencing more rapid growth also tend to witness smaller increases (or larger decreases) in their inequality. Such findings offer some support to theories stressing growth-mechanisms which equalize productivity across workers.

Introduction: T cell presence in TIL, and the ratio of CD8+ and CD4+ T cell subsets in particular, can correlate with tumor prognosis in some tumors, although the significance of such infiltration into glioma is controversial. However, gliomas represent a lower extreme in their extent of T cell infiltration, and are thus useful in assessing factors that can decrease T cell presence within tumor tissue. Fas ligand, a pro-apoptotic cell surface protein, may play a key role in reduction of T cells in tumor tissue. Objective: To assess the level of FasL expression on brain tumor endothelium and to correlate this with relative levels of CD4+ and CD8+ T cell subsets in TIL from brain tumors. Methods: CD3+, CD4+, and CD8+ cells were quantified in fresh TIL by flow cytometry. Paraffin embedded sections of tumors, including meningiomas and gliomas as well as extracranial malignancies, underwent immunohistochemical staining for FasL and Von-Willebrand’s factor (Factor VIII) to determine expression levels of endothelial FasL. Results: FasL expression was high in aggressive intracranial malignancies compared to more indolent neoplasms, and correlated inversely with CD8+/CD4+ TIL ratios in all tumor classes combined (ANOVA,p

Conventional urban economic analysis suggests that a local economy's size is closely related to a number of features, including levels of human capital and the availability of specialized inputs, which are likely to influence positively the rate at which it accumulates further economic activity. At the same time, urban theory also suggests that once cities reach a certain level of size, these agglomeration benefits begin to peter out, while diseconomies rise rapidly. Consequently, we should see an ‘inverted U-shaped’ pattern of growth with respect to economic size—rates of growth first rise, then fall as size increases. This paper shows that, while such a pattern is largely absent from recent data on growth in metropolitan area population and employment, it emerges strikingly in county-level data. Copyright © 2002 John Wiley & Sons, Ltd.

Background Human Hematopoietic Signal peptide-containing Secreted 1 (hHSS1) is a truly novel protein, defining a new class of secreted factors. We have previously reported that ectopic overexpression of hHSS1 has a negative modulatory effect on cell proliferation and tumorigenesis in glioblastoma model systems. Here we have used microarray analysis, screened glioblastoma samples in The Cancer Genome Atlas (TCGA), and studied the effects of hHSS1 on glioma-derived cells and endothelial cells to elucidate the molecular mechanisms underlying the anti-tumorigenic effects of hHSS1. Methods Gene expression profiling of human glioma U87 and A172 cells overexpressing hHSS1 was performed. Ingenuity® iReport™ and Ingenuity Pathway Analysis (IPA) were used to analyze the gene expression in the glioma cells. DNA content and cell cycle analysis were performed by FACS, while cell migration, cell invasion, and effects of hHSS1 on HUVEC tube formation were determined by transwell and matrigel assays. Correlation was made between hHSS1 expression and specific genes in glioblastoma samples in the TCGA database. Results We have clarified the signaling and metabolic pathways (i.e. role of BRCA1 in DNA damage response), networks (i.e. cell cycle) and biological processes (i.e. cell division process of chromosomes) that result from hHSS1effects upon glioblastoma growth. U87-overexpressing hHSS1 significantly decreased the number of cells in the G0/G1 cell cycle phase, and significantly increased cells in the S and G2/M phases (P