Increased Single-Lift Thicknesses for Unbound Aggregate Base Courses

A study was conducted to evaluate the feasibility of compacting unbound aggregate base courses in thicker lifts than currently permitted by state departments of transportation (DOTs). At present, the majority of states allow a maximum lift thickness of 8 inches or less. This project constructed and tested full-scale test sections using a variety of material types. Two test pads were constructed in an aggregate quarry in Texas utilizing crushed limestone. Three crushed granite test sections were built as part of a road widening project in Georgia, and two test pads were constructed of uncrushed and partially crushed gravel with loess fines at a gravel production facility near Memphis, Tennessee. Single-lift thicknesses varied from 6 inches to 21 inches. Moisture contents and densities were evaluated using the Nuclear Density Gauge (NDG). Nondestructive seismic testing, using the Spectral-Analysis-of-Surface-Waves (SASW) technique, was used to evaluate stiffness profiles within the compacted lifts. Cyclic plate load tests were accomplished by means of the Rolling Dynamic Deflectometer (RDD), modified for this static application. Results showed that compaction targets could be attained for lifts up to 21 inches thick. Density and stiffness results for 13-inch thick lifts in the Georgia tests were equal to, or better than, the results for the base placed in two lifts, a 7-inch lift followed by a 6-inch lift. Higher moisture contents during compaction yielded lower shear wave velocity and Young’s modulus values. Seismic results show that the upper 3 inches of the final test pads had lower stiffness values, presumably from lower effective stresses near the surface and possibly from some disturbance caused by the compaction equipment. This zone of lower stiffness and slightly less compaction is less evident in the density measurements.Aggregates Foundation for Technology, Research, and Education (AFTRE)Civil, Architectural, and Environmental Engineerin

Defining the Critical Hurdles in Cancer Immunotherapy

ABSTRACT: Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators, others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet be overcome to improve outcomes of patients with cancer

Defining the critical hurdles in cancer immunotherapy

Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer

Emerging concepts in biomarker discovery; The US-Japan workshop on immunological molecular markers in oncology

Supported by the Office of International Affairs, National Cancer Institute (NCI), the "US-Japan Workshop on Immunological Biomarkers in Oncology" was held in March 2009. The workshop was related to a task force launched by the International Society for the Biological Therapy of Cancer (iSBTc) and the United States Food and Drug Administration (FDA) to identify strategies for biomarker discovery and validation in the field of biotherapy. The effort will culminate on October 28th 2009 in the "iSBTc-FDA-NCI Workshop on Prognostic and Predictive Immunologic Biomarkers in Cancer", which will be held in Washington DC in association with the Annual Meeting. The purposes of the US-Japan workshop were a) to discuss novel approaches to enhance the discovery of predictive and/or prognostic markers in cancer immunotherapy; b) to define the state of the science in biomarker discovery and validation. The participation of Japanese and US scientists provided the opportunity to identify shared or discordant themes across the distinct immune genetic background and the diverse prevalence of disease between the two Nations

Classification of current anticancer immunotherapies

During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into “passive” and “active” based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Hypervelocity impact analysis of International Space Station Whipple and Enhanced Stuffed Whipple Shields

The International Space Station (ISS) must be able to withstand the hypervelocity impacts of micrometeoroids and orbital debris that strike its many surfaces. In order to design and implement shielding which will prevent hull penetration or other operational losses, NASA must first model the orbital debris and micrometeoroid environment. Based upon this environment, special multi-stage shields called Whipple and Enhanced Stuffed Whipple Shields are developed and implemented to protect ISS surfaces. Ballistic limit curves that establish shield failure criteria are determined via ground testing. These curves are functions of material strength, shield spacing, projectile size, shape and density, as well as a number of other variables. The combination of debris model and ballistic limit equations allows NASA to model risk to ISS using a hydro-code called BUMPER. This thesis modifies and refines existing ballistic limit equations for U.S. Laboratory Module shields to account for the effects of projectile (debris/ micro-meteoroid) densities. Using these refined ballistic limit equations this thesis also examines alternative shielding materials and configurations to optimize shield design for minimum mass and maximum stopping potential, proposing alternate shield designs for future NASA ground testing. A final goal of this thesis is to provide the Department of Defense a background in satellite shield theory and design in order to improve protection against micrometeoroid and orbital debris impacts on future spacebased national systems.http://archive.org/details/hypervelocityimp109451233Lieutenant, United States NavyApproved for public release; distribution is unlimited

Soil mechanics lab manual

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Determination of in situ Vs and Gmax using surface wave measurements in cased and uncased boreholes

The Spectral-Analysis-of-Surface-Waves (SASW) method is a technique in which surface waves are used to determine variations in small-strain shear modulus (G [subscript max]) with depth in layered systems. The SASW method has traditionally been applied to flat systems where the surface is readily accessible, such as soil profiles and pavement systems. However, the research presented herein shows the applicability of the SASW method to characterize materials around cased and uncased boreholes in soil and rock by propagating surface waves along the borehole wall. In cased boreholes, surface wave measurements can be used to determine G [subscript max] of the casing. In many instances, surface wave measurements can be used to determine G [subscript max] of the surrounding material and the quality of the bond between the material and the casing. In these instances, success is limited by the thickness of the casing and the stiffness contrast between the casing and the surrounding material. In uncased boreholes, surface wave measurements were used to identify and delineate zones of disturbance and cracking around cylindrical drilled shafts in rock. In addition, surface wave measurements were used to delineate the extent of affected soil in a large-diameter (42-in. (1.1-m)) borehole treated with a lime slurry. In both cased and uncased boreholes, it was found experimentally that the cylindrical geometry of the borehole significantly affected the dispersive characteristics of the surface wave energy. Furthermore, this geometry-induced dispersion was completely different when propagating in the axial and circumferential directions. Appropriate numerical formulations developed on companion projects were incorporated into the results presented herein to accurately model the experimental surface wave data. The focus of this research was the development of a borehole SASW tool to determine the in situ relationship between G [subscript max] and state of stress in uncased pressurized boreholes in soil. In situ relationships were successfully determined using the borehole SASW tool in unsaturated cohesive and cohesionless soils. These relationships compared favorably to relationships determined from laboratory resonant column testing. At this time, minimization of soil disturbance around the borehole is the single most important issue in advancing this technology, although many other opportunities exist for future researchCivil, Architectural, and Environmental Engineerin

Measurements of intact and cracked concrete structural elements by the SASW method

Research was conducted to apply the Spectral-Analysis-of-Surface-Waves (SASW) method to the identification of internal cracking in concrete structural elements such as beams and columns. The SASW method is a nondestructive technique which involves the propagation of surface stress waves along the exposed face of a structural element. By yielding the relationship between wave velocity and wavelength of the surface wave energy, the SASW method provides information about how the stiffness of a material varies with depth. SASW measurements were made on intact and cracked concrete structural elements. Surface waves propagated through cracked concrete at consistently lower velocities. These velocity reductions corresponded to the presence of visibly detectable cracking and, in some cases, occurred in the absence of visible cracking. This result demonstrated the ability of the SASW method to detect otherwise hidden damage. When the cracks were reclosed by the application of a compressive load, the surface waves propagated at velocities comparable to those of uncracked concrete. In addition to performing velocity measurements, material damping measurements were made on intact and cracked concrete structural elements. These measurements revealed that the presence of cracking can be qualitatively assessed through an increase in observed surface wave material damping, with material damping ratios ranging from less than 1% in undamaged concrete to around 3% in damaged concreteCivil, Architectural, and Environmental Engineerin