Thin Asphalt Concrete Pavement on Crushed Rock Base - Cass County, Construction Report, HR-2075, 1997

The road paving cost continues to increase and the backlog of projects waiting for funding is growing. Finding a more cost-effective way to use the available money to pave roads will result in more miles of road being paved with the same amount of money. This project is in Cass County on G35 between US 71 and Norway-Center. It consists of a thin layer of asphalt over a base designed to achieve stability while having some permeability. This project was paved in 1996. An asphalt cement concrete pavement was chosen for the project based on cost, convenience, and historic portland cement concrete problems in Cass County. The new pavement gives quicker access time to farms and residences.

Bonded, Thin-Lift, Non-Reinforced Portland Cement Concrete Resurfacing, MLR-77-2, 1977

A research project involving 2, 3, 4, and 5 in. (5.1, 7.6, 10.2, and 12.7 cm) of bonded portland cement concrete (PCC) overlay on a 1.3 mile (2.1 km) PCC pavement was conducted in Clayton County, Iowa, during September 1977, centering on the following objectives: (1) Determine the mixing and proportioning procedures required in using a conventional, central mix proportioning plant to produce a dense PCC mixture using standard mixes with super water reducing admixtures; (2) Determine the economics, longevity and maintenance performance of a bonded, thin-lift, non-reinforced PCC resurfacing course using conventional procedures, equipment and concrete paving mixtures both with and without super water reducing admixtures; and (3) Determine if an adequate bond between the existing pavement and an overlay of thin-lift, dense, non-reinforced PCC can be obtained with only special surface cleaning and no surface removal or grinding. The conclusions are as follows: (1) Normal mixing equipment and proportioning procedures could be used using a conventional central-mix proportioning plant. This was successful when used with super water reducing admixtures. Only minor changes need be made in procedures and timing. (2) The time has been too short since the completion of the project to determine how the new pavement will perform, however, initially it appears that the method is economical and no reason is seen at this time why the life of the pavement should not be comparable to an all new pavement. (3) The initial test results show that bond strength, regardless of which method of cleaning is used, scarifying, sand blasting or water blasting, far exceed what is considered the minimum bond strength of 200 psi (1379 kPa) except where the paint stripes were intentionally left, thus showing that the paint must be removed. (4) It appears that either cement and water grout or sand, cement and water grout may be used and still obtain the required bond.

A novel population of human melanoma-specific CD8 T cells recognizes Melan-AMART-1 immunodominant nonapeptide but not the corresponding decapeptide.

HLA-A2-restricted cytolytic T cells specific for the immunodominant human tumor Ag Melan-A(MART-1) can kill most HLA-matched melanoma cells, through recognition of two naturally occurring antigenic variants, i.e., Melan-A nonamer AAGIGILTV and decamer EAAGIGILTV peptides. Several previous studies have suggested a high degree of TCR cross-reactivity to the two peptides. In this study, we describe for the first time that some T cell clones are exclusively nonamer specific, because they are not labeled by A2/decamer-tetramers and do not recognize the decamer when presented endogenously. Functional assays with peptides gave misleading results, possibly because decamers were cleaved by exopeptidases. Interestingly, nonapeptide-specific T cell clones were rarely Valpha2.1 positive (only 1 of 19 clones), in contrast to the known strong bias for Valpha2.1-positive TCRs found in decamer-specific clones (59 of 69 clones). Molecular modeling revealed that nonapeptide-specific TCRs formed unfavorable interactions with the decapeptide, whereas decapeptide-specific TCRs productively created a hydrogen bond between CDR1alpha and glutamic acid (E) of the decapeptide. Ex vivo analysis of T cells from melanoma metastases demonstrated that both nonamer and decamer-specific T cells were enriched to substantial frequencies in vivo, and representative clones showed efficient tumor cell recognition and killing. We conclude that the two peptides should be regarded as distinct epitopes when analyzing tumor immunity and developing immunotherapy against melanoma.

PD-1 and Tim-3 regulate the expansion of tumor antigen-specific CD8⁺ T cells induced by melanoma vaccines.

Although melanoma vaccines stimulate tumor antigen-specific CD8(+) T cells, objective clinical responses are rarely observed. To investigate this discrepancy, we evaluated the character of vaccine-induced CD8(+) T cells with regard to the inhibitory T-cell coreceptors PD-1 and Tim-3 in patients with metastatic melanoma who were administered tumor vaccines. The vaccines included incomplete Freund's adjuvant, CpG oligodeoxynucleotide (CpG), and the HLA-A2-restricted analog peptide NY-ESO-1 157-165V, either by itself or in combination with the pan-DR epitope NY-ESO-1 119-143. Both vaccines stimulated rapid tumor antigen-specific CD8(+) T-cell responses detected ex vivo, however, tumor antigen-specific CD8(+) T cells produced more IFN-γ and exhibited higher lytic function upon immunization with MHC class I and class II epitopes. Notably, the vast majority of vaccine-induced CD8(+) T cells upregulated PD-1 and a minority also upregulated Tim-3. Levels of PD-1 and Tim-3 expression by vaccine-induced CD8(+) T cells at the time of vaccine administration correlated inversely with their expansion in vivo. Dual blockade of PD-1 and Tim-3 enhanced the expansion and cytokine production of vaccine-induced CD8(+) T cells in vitro. Collectively, our findings support the use of PD-1 and Tim-3 blockades with cancer vaccines to stimulate potent antitumor T-cell responses and increase the likelihood of clinical responses in patients with advanced melanoma.

Bonded, Thin-Lift, Non-Reinforced Portland Cement Concrete Resurfacing, HR-191, 1980

A Research Project involving two, three, four and five inches of bonded Portland Cement Concrete Overlay on a 1.3 mile Portland Cement Concrete pavement was conducted in Clayton County, Iowa, during September, 1977, centering on the following objectives: 1. Determine the mixing and proportioning procedures required in using a conventional, central mix proportioning plant to produce a dense Portland Cement Concrete mixture using standard mixes with super-water reducing admixtures; 2. Determine the economics, longevity and maintenance performance of a bonded, thin-lift, non-reinforced Portland Cement Concrete resurfacing course using conventional procedures, equipment and concrete paving mixtures both with and without super-water reducing admixtures; 3. Determine if an adequate bond between the existing pavement and an overlay of thin-lift, dense, non-reinforced Portland Cement Concrete can be obtained with only special surface cleaning and no surface removal or grinding.

Thin Bonded Concrete Overlay with Fast Track Concrete, Final Report, HR-531, 1990

Pavements have been overlaid with thin bonded portland cement concrete (PCC) for several years. These projects have had traffic detoured for a period of 5-10 days. These detours are unacceptable to the traveling public and result in severe criticism. The use of thin bonded fast track overlay was promoted to allow a thin bonded PCC overlay with minimal disruption of local traffic. This project demonstrated the concept of using one lane of the roadway to maintain traffic while the overlay was placed on the other and then with the rapid strength gain of the fast track concrete, the construction and local traffic is maintained on the newly placed, thin bonded overlay. The goals of this project were: 1. Traffic usage immediately after placement and finishing. 2. Reduce traffic disruption on a single lane to less than 5 hours. 3. Reduce traffic disruption on a given section of two-lane roadway to less than 2 days. 4. The procedure must be economically viable and competitive with existing alternatives. 5. Design life for new construction equivalent to or in excess of conventional pavements. 6. A 20 year minimum design life for rehabilitated pavements.

Thin Bonded Concrete Resurfacing U.S. 34 West Burlington, Iowa, HR-34

The Experimental Project was designated as Research Project No. HR-34, sponsored by the Iowa Highway Research Board and constructed by the Iowa Highway Commission. Construction was supervised cooperatively by Engineers of the Iowa Highway Commission and the Portland Cement Association. The objective of the experiment is to study the behavior of relatively thin portland cement concrete resurfacing courses placed with bond on old concrete pavements. The phase of the problem being studied now, involves only pavements in which the old concrete is structurally sound.

Phenotyping of 60 cultured human gliomas and 34 other neuroectodermal tumors by means of monoclonal antibodies against glioma, melanoma and HLA-DR antigens.

The reactivity spectrum of three monoclonal antibodies (Mabs) to human malignant glioma, five Mabs to melanomas and one Mab anti-HLA-DR was investigated by an indirect antibody binding radioimmunoassay on a panel of cells derived from 60 glioma lines, including 47 malignant astrocytomas, 11 low-grade astrocytomas and two malignant ependymomas as well on cells from 12 melanoma, three neuroblastoma, three medulloblastoma, two schwannoma, two retinoblastoma, two choroïd plexus papilloma, ten meningioma and 12 unrelated tumor lines. The anti-glioma Mabs BF7 and GE2 reacted preferentially with gliomas, while the anti-glioma Mab CG12 reacted with gliomas, melanomas, neuroblastomas and medulloblastomas. The five anti-melanoma Mabs reacted with gliomas, neuroblastomas and medulloblastomas. The anti-HLA-DR Mab D1-12 reacted with gliomas, melanomas and some meningiomas. On the basis of the data presented, we describe three different antigenic systems; the first one is glioma-associated, the second one is related to differentiation antigens expressed on cells derived from the neuroectoderm and the third is represented by HLA-DR antigens which are expressed not only on B-lymphoblastoid cells but also on melanomas and gliomas.

Treatment implications of the emerging molecular classification system for melanoma.

Melanoma is an aggressive disease with few standard treatment options. The conventional classification system for this disease is based on histological growth patterns, with division into four subtypes: superficial spreading, lentigo maligna, nodular, and acral lentiginous. Major limitations of this classification system are absence of prognostic importance and little correlation with treatment outcomes. Recent preclinical and clinical findings support the notion that melanoma is not one malignant disorder but rather a family of distinct molecular diseases. Incorporation of genetic signatures into the conventional histopathological classification of melanoma has great implications for development of new and effective treatments. Genes of the mitogen-associated protein kinase (MAPK) pathway harbour alterations sometimes identified in people with melanoma. The mutation Val600Glu in the BRAF oncogene (designated BRAF(V600E)) has been associated with sensitivity in vitro and in vivo to agents that inhibit BRAF(V600E) or MEK (a kinase in the MAPK pathway). Melanomas arising from mucosal, acral, chronically sun-damaged surfaces sometimes have oncogenic mutations in KIT, against which several inhibitors have shown clinical efficacy. Some uveal melanomas have activating mutations in GNAQ and GNA11, rendering them potentially susceptible to MEK inhibition. These findings suggest that prospective genotyping of patients with melanoma should be used increasingly as we work to develop new and effective treatments for this disease.

Molecular hydrogen diffusion in nanostructured amorphous silicon thin films

We study hydrogen stability and its evolution during thermal annealing in nanostructured amorphous silicon thin films. From the simultaneous measurement of heat and hydrogen desorption, we obtain the experimental evidence of molecular diffusion in these materials. In addition, we introduce a simple diffusion model which shows good agreement with the experimental data

In vivo expression of natural killer cell inhibitory receptors by human melanoma-specific cytolytic T lymphocytes.

Natural killer (NK) receptor signaling can lead to reduced cytotoxicity by NK cells and cytolytic T lymphocytes (CTLs) in vitro. Whether T cells are inhibited in vivo remains unknown, since peptide antigen-specific CD8(+) T cells have so far not been found to express NK receptors in vivo. Here we demonstrate that melanoma patients may bear tumor-specific CTLs expressing NK receptors. The lysis of melanoma cells by patient-derived CTLs was inhibited by the NK receptor CD94/NKG2A. Thus, tumor-specific CTL activity may be decreased through NK receptor triggering in vivo.

Final antigenic Melan-A peptides produced directly by the proteasomes are preferentially selected for presentation by HLA-A*0201 in melanoma cells.

The melanoma-associated protein Melan-A contains the immunodominant CTL epitope Melan-A(26/27-35)/HLA-A*0201 against which a high frequency of T lymphocytes has been detected in many melanoma patients. In this study we show that the in vitro degradation of a polypeptide encompassing Melan-A(26/27-35) by proteasomes produces both the final antigenic peptide and N-terminally extended intermediates. When human melanoma cells expressing the corresponding fragments were exposed to specific CTL, those expressing the minimal antigenic sequence were recognized more efficiently than those expressing the N-terminally extended intermediates. Using a tumor-reactive CTL clone, we confirmed that the recognition of melanoma cells expressing an N-terminally extended intermediate of Melan-A is inefficient. We demonstrated that the inefficient cytosolic trimming of N-terminally extended intermediates could offer a selective advantage for the preferred presentation of Melan-A peptides directly produced by the proteasomes. These results imply that both the proteasomes and postproteasomal peptidases limit the availability of antigenic peptides and that the efficiency of presentation may be affected by conditions that alter the ratio between fully and partially processed proteasomal products.

The human T cell response to melanoma antigens.

The cornerstone of the concept of immunosurveillance in cancer should be the experimental demonstration of immune responses able to alter the course of in vivo spontaneous tumor progression. Elegant genetic manipulation of the mouse immune system has proved this tenet. In parallel, progress in understanding human T cell mediated immunity has allowed to document the existence in cancer patients of naturally acquired T cell responses to molecularly defined tumor antigens. Various attributes of cutaneous melanoma tumors, notably their adaptability to in vitro tissue culture conditions, have contributed to convert this tumor in the prototype for studies of human antitumor immune responses. As a consequence, the first human cytolytic T lymphocyte (CTL)-defined tumor antigen and numerous others have been identified using lymphocyte material from patients bearing this tumor, detailed analyses of specific T cell responses have been reported and a relatively large number of clinical trials of vaccination have been performed in the last 15 years. Thus, the "melanoma model" continues to provide valuable insights to guide the development of clinically effective cancer therapies based on the recruitment of the immune system. This chapter reviews recent knowledge on human CD8 and CD4 T cell responses to melanoma antigens.

CD28-negative cytolytic effector T cells frequently express NK receptors and are present at variable proportions in circulating lymphocytes from healthy donors and melanoma patients.

In humans, NK receptors are expressed by natural killer cells and some T cells, the latter of which are preferentially alphabetaTCR+ CD8+ cytolytic T lymphocytes (CTL). In this study we analyzed the expression of nine NK receptors (p58.1, p58.2, p70, p140, ILT2, NKRP1A, ZIN176, CD94 and CD94/NKG2A) in PBL from both healthy donors and melanoma patients. The percentages of NK receptor-positive T cells (NKT cells) varied strongly, and this variation was more important between individual patients than between individual healthy donors. In all the individuals, the NKT cells were preferentially CD28-, and a significant correlation was found between the percentage of CD28- T cells and the percentage of NK receptor+ T cells. Based on these data and the known activated phenotype of CD28- T cells, we propose that the CD28- CD8+ T cell pool represents or contains the currently active CTL population, and that the frequent expression of NK receptors reflects regulatory mechanisms modulating the extent of CTL effector function. Preliminary results indicate that some tumor antigen-specific T cells may indeed be CD28- and express NK receptors in vivo.