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Search Results: 1 - 10 of 31082 matches for " Thomas Kieber-Emmons "
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Carbohydrate Mimetic Peptides for Pan Anti-Tumor Responses
Thomas Kieber-Emmons,Ramachandran Murali
Frontiers in Immunology , 2014, DOI: 10.3389/fimmu.2014.00308
Abstract: Molecular mimicry is fundamental to biology which transcends to many disciplines ranging from immune pathology to drug design. Structural characterization of molecular partners has provided insight into the origins and relative importance of complementarity in mimicry. Chemical complementarity is easy to understand; amino acid sequence similarity between peptides, for example, can lead to cross-reactivity triggering similar reactivity from their cognate receptors. However, conformational complementarity is difficult to decipher. Molecular mimicry of carbohydrates by peptides is often considered one of those. Extensive studies of innate and adaptive immune responses suggests the existence of carbohydrate mimicry, but the structural basis for this mimicry yields confounding details; peptides mimicking carbohydrates in some cases fail to exhibit both chemical and conformational mimicry. Deconvolution of these two types of complementarity in mimicry and its relationship to biological function can nevertheless lead to new therapeutics. Here, we discuss our experience in bringing a tumor-associated carbohydrate mimetic peptide to the clinic. Emphasis is placed on the rationale, the lessons learned from the methodologies to identify mimics, a perspective on the limitations of structural analysis, the biological consequences of mimicking tumor associated carbohydrate antigens and the notion of reverse engineering to develop carbohydrate mimetic peptides in vaccine design strategies to induce responses to pan-glycan antigens expressed on cancer cells.
Tumor-Associated Glycans and Immune Surveillance
Behjatolah Monzavi-Karbassi,Anastas Pashov,Thomas Kieber-Emmons
Vaccines , 2013, DOI: 10.3390/vaccines1020174
Abstract: Changes in cell surface glycosylation are a hallmark of the transition from normal to inflamed and neoplastic tissue. Tumor-associated carbohydrate antigens (TACAs) challenge our understanding of immune tolerance, while functioning as immune targets that bridge innate immune surveillance and adaptive antitumor immunity in clinical applications. T-cells, being a part of the adaptive immune response, are the most popular component of the immune system considered for targeting tumor cells. However, for TACAs, T-cells take a back seat to antibodies and natural killer cells as first-line innate defense mechanisms. Here, we briefly highlight the rationale associated with the relative importance of the immune surveillance machinery that might be applicable for developing therapeutics.
The promise of the anti-idiotype concept
Thomas Kieber-Emmons,Anastas Pashov,Somdutta Saha,Ramachandran Murali
Frontiers in Oncology , 2012, DOI: 10.3389/fonc.2012.00196
Abstract: A basic tenet of antibody-based immunity is their specificity to antigenic determinates from foreign pathogen products to abnormal cellular components such as in cancer. However, an antibody has the potential to bind to more than one determinate, be it an antigen or another antibody. These observations led to the idiotype network theory (INT) to explain immune regulation, which has wax and waned in enthusiasm over the years. A truer measure of the impact of the INT is in terms of the ideas that now form the mainstay of immunological research and whose roots are spawned from the promise of the anti-idiotype concept. Among the applications of the INT is understanding the structural implications of the antibody-mediated network that has the potential for innovation in terms of rational design of reagents with biological, chemical, and pharmaceutical applications that underlies concepts of reverse immunology which is highlighted herein.
Bridging Innate and Adaptive Antitumor Immunity Targeting Glycans
Anastas Pashov,Bejatolah Monzavi-Karbassi,Gajendra P. S. Raghava,Thomas Kieber-Emmons
Journal of Biomedicine and Biotechnology , 2010, DOI: 10.1155/2010/354068
Abstract: Effective immunotherapy for cancer depends on cellular responses to tumor antigens. The role of major histocompatibility complex (MHC) in T-cell recognition and T-cell receptor repertoire selection has become a central tenet in immunology. Structurally, this does not contradict earlier findings that T-cells can differentiate between small hapten structures like simple glycans. Understanding T-cell recognition of antigens as defined genetically by MHC and combinatorially by T cell receptors led to the “altered self” hypothesis. This notion reflects a more fundamental principle underlying immune surveillance and integrating evolutionarily and mechanistically diverse elements of the immune system. Danger associated molecular patterns, including those generated by glycan remodeling, represent an instance of altered self. A prominent example is the modification of the tumor-associated antigen MUC1. Similar examples emphasize glycan reactivity patterns of antigen receptors as a phenomenon bridging innate and adaptive but also humoral and cellular immunity and providing templates for immunotherapies.
Carbohydrate Mimetic Peptides Augment Carbohydrate-Reactive Immune Responses in the Absence of Immune Pathology
Leah Hennings,Cecile Artaud,Fariba Jousheghany,Behjatolah Monzavi-Karbassi,Anastas Pashov,Thomas Kieber-Emmons
Cancers , 2011, DOI: 10.3390/cancers3044151
Abstract: Among the most challenging of clinical targets for cancer immunotherapy are Tumor Associated Carbohydrate Antigens (TACAs). To augment immune responses to TACA we are developing carbohydrate mimetic peptides (CMPs) that are sufficiently potent to activate broad-spectrum anti-tumor reactivity. However, the activation of immune responses against terminal mono- and disaccharide constituents of TACA raises concerns regarding the balance between “tumor destruction” and “tissue damage”, as mono- and disaccharides are also expressed on normal tissue. To support the development of CMPs for clinical trial testing, we demonstrate in preclinical safety assessment studies in mice that vaccination with CMPs can enhance responses to TACAs without mediating tissue damage to normal cells expressing TACA. BALB/c mice were immunized with CMPs that mimic TACAs reactive with Griffonia simplicifolia lectin 1 (GS-I), and tissue reactivity of serum antibodies were compared with the tissue staining profile of GS-I. Tissues from CMP immunized mice were analyzed using hematoxylin and eosin stain, and Luxol-fast blue staining for myelination. Western blots of membranes from murine mammary 4T1 cells, syngeneic with BALB/c mice, were also compared using GS-I, immunized serum antibodies, and naive serum antibodies. CMP immunization enhanced glycan reactivities with no evidence of pathological autoimmunity in any immunized mice demonstrating that tissue damage is not an inevitable consequence of TACA reactive responses.
Expression analysis of carbohydrate antigens in ductal carcinoma in situ of the breast by lectin histochemistry
Soheila Korourian, Eric Siegel, Thomas Kieber-Emmons, Behjatolah Monzavi-Karbassi
BMC Cancer , 2008, DOI: 10.1186/1471-2407-8-136
Abstract: For detection of TACA expression, specimens were stained with Griffonia simplicifolia lectin-I (GS-I) and Vicia vilosa agglutinin (VVA). We studied associations of lectin reactivity with established prognostic factors, such as tumor size, tumor nuclear grade, and expression of Her-2/neu, p53 mutant and estrogen and progesterone receptors.We observed that both lectins showed significant associations with nuclear grade of DCIS. DCIS specimens with nuclear grades II and III showed significantly more intense reactivity than DCIS cases with nuclear grade I to GS-1 (Mean-score chi-square = 17.60, DF = 2; P = 0.0002) and VVA (Mean-score chi-square = 15.72, DF = 2; P = 0.0004).The results suggest that the expression of VVA- and GS-I-reactive carbohydrate antigens may contribute to forming higher grade DCIS and increase the recurrence risk.Breast carcinoma is the most common malignancy and currently the second leading cause of cancer death in women in the United States. An increasing number of women choose more sensitive screening with digital mammograms and magnetic resonance imaging, which has ultimately resulted in dramatic increase in the diagnosis of ductal carcinoma in situ (DCIS) during recent years [1-4]. The majority of invasive breast cancers likely develop over extended periods of time from pre-invasive lesions such as DCIS and culminating in metastatic disease [5-9]. Untreated DCIS lesions develop into invasive breast cancer with an average progression rate of 43% as estimated by using the results of 8 different independent studies performed with a wide range of follow-up time [3].An increased risk of a recurrence as DCIS or invasive cancer was associated with initial DCIS lesions that were larger than 10 mm or were of high or intermediate nuclear grade [10-14]. High nuclear grade of initial lesions and cancer recurrence were significantly associated with increased rates of metastasis and breast cancer death [15,16]. Therefore, nuclear grade is used as a major de
Chondroitin sulfates play a major role in breast cancer metastasis: a role for CSPG4 and CHST11 gene expression in forming surface P-selectin ligands in aggressive breast cancer cells
Craig A Cooney, Fariba Jousheghany, Aiwei Yao-Borengasser, Bounleut Phanavanh, Tina Gomes, Ann Kieber-Emmons, Eric R Siegel, Larry J Suva, Soldano Ferrone, Thomas Kieber-Emmons, Behjatolah Monzavi-Karbassi
Breast Cancer Research , 2011, DOI: 10.1186/bcr2895
Abstract: Quantitative real-time PCR (qRT-PCR) and flow cytometry assays were used to detect the expression of genes involved in the sulfation and presentation of chondroitin in several human breast cancer cell lines. Transient transfection of the human breast cancer cell line MDA-MB-231 with the siRNAs for carbohydrate (chondroitin 4) sulfotransferase-11 (CHST11) and chondroitin sulfate proteoglycan 4 (CSPG4 ) was used to investigate the involvement of these genes in expression of surface P-selectin ligands. The expression of CSPG4 and CHST11 in 15 primary invasive breast cancer clinical specimens was assessed by qRT-PCR. The role of CS-GAGs in metastasis was tested using the 4T1 murine mammary cell line (10 mice per group).The CHST11 gene was highly expressed in aggressive breast cancer cells but significantly less so in less aggressive breast cancer cell lines. A positive correlation was observed between the expression levels of CHST11 and P-selectin binding to cells (P < 0.0001). Blocking the expression of CHST11 with siRNA inhibited CS-A expression and P-selectin binding to MDA-MB-231 cells. The carrier proteoglycan CSPG4 was highly expressed on the aggressive breast cancer cell lines and contributed to the P-selectin binding and CS-A expression. In addition, CSPG4 and CHST11 were over-expressed in tumor-containing clinical tissue specimens compared with normal tissues. Enzymatic removal of tumor-cell surface CS-GAGs significantly inhibited lung colonization of the 4T1 murine mammary cell line (P = 0.0002).Cell surface P-selectin binding depends on CHST11 gene expression. CSPG4 serves as a P-selectin ligand through its CS chain and participates in P-selectin binding to the highly metastatic breast cancer cells. Removal of CS-GAGs greatly reduces metastatic lung colonization by 4T1 cells. The data strongly indicate that CS-GAGs and their biosynthetic pathways are promising targets for the development of anti-metastatic therapies.Tumor-associated glycans play a significant
Obesity promotes 7,12-dimethylbenz(a)anthracene-induced mammary tumor development in female zucker rats
Reza Hakkak, Andy W Holley, Stewart L MacLeod, Pippa M Simpson, George J Fuchs, Chan Jo, Thomas Kieber-Emmons, Soheila Korourian
Breast Cancer Research , 2005, DOI: 10.1186/bcr1263
Abstract: Fifty-day-old female obese (n = 25) and lean (n = 28) Zucker rats were orally gavaged with 65 mg/kg DMBA. Rats were weighed and palpated twice weekly for detection of mammary tumors. Rats were killed 139 days after DMBA treatment.The first mammary tumor was detected in the obese group at 49 days after DMBA treatment, as compared with 86 days in the lean group (P < 0.001). The median tumor-free time was significantly lower in the obese group (P < 0.001). Using the days after DMBA treatment at which 25% of the rats had developed mammary tumors as the marker of tumor latency, the obese group had a significantly shorter latency period (66 days) than did the lean group (118 days). At the end of the study, obese rats had developed a significantly (P < 0.001) greater mammary tumor incidence (68% versus 32%) compared with the lean group. The tumor histology of the mammary tumors revealed that obesity was associated with a significant (P < 0.05) increase in the number of rats with at least one invasive ductal and lobular carcinoma compared with lean rats.Our results indicate that obesity increases the susceptibility of female Zucker rats to DMBA-induced mammary tumors, further supporting the hypothesis that obesity and some of its mediators play a significant role in carcinogenesis.Obesity has been identified as an epidemic in the USA for more than two decades, yet the proportion of overweight and obese adults in the population continues to grow. The most recent data from the 1999–2000 National Health and Nutrition Examination Survey (NHANES) [1] showed that almost 65% of adults in the USA are overweight, defined as having a body mass index (BMI) greater than 25 kg/m2. This is a significant increase from the 56% for adults reported as overweight in NHANES III, which was conducted between 1988 and 1994. The prevalence of obesity, defined as a BMI of 30 kg/m2 or greater, also increased dramatically from 23% to 31% during the same period. It is estimated that the prevalence of
Fluorescence blinking statistics from single CdSe nanorods
Siying Wang,Claudia Querner,Thomas Emmons,Marija Drndic,Catherine H. Crouch
Physics , 2006,
Abstract: We report fluorescence blinking statistics measured from single CdSe nanorods (NRs) of seven different sizes with aspect ratio ranging from 3 to 11. This study included core/shell CdSe/ZnSe NRs and core NRs with two different surface ligands producing different degrees of surface passivation. We compare the findings for NRs to our measurements of blinking statistics from spherical CdSe core and CdSe/ZnS core/shell nanocrystals (NCs). We find that for both NRs and spherical NCs, the off-time probability distributions are well described by a power law, while the on-time probability distributions are best described by a truncated power law. The measured crossover time is indistinguishable within experimental uncertainty for core and core/shell NRs, and for core NRs with different ligands, indicating that surface passivation does not affect the blinking statistics significantly. We find that at fixed excitation intensity, the inverse crossover time increases approximately linearly with increasing NR aspect ratio; for a given sample, the inverse crossover time increases very gradually with increasing excitation intensity. The measured per-particle absorption cross section for all samples indicates that the change in NR absorption cross-section with sample size can account for some but not all of the differences in crossover time. This suggests that the degree of quantum confinement may be partially responsible for the aspect ratio dependence of the crossover time.
Common MicroRNA Signatures in Cardiac Hypertrophic and Atrophic Remodeling Induced by Changes in Hemodynamic Load
Ali El-Armouche,Alexander Peter Schwoerer,Christiane Neuber,Julius Emmons,Daniel Biermann,Thomas Christalla,Adam Grundhoff,Thomas Eschenhagen,Wolfram Hubertus Zimmermann,Heimo Ehmke
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0014263
Abstract: Mechanical overload leads to cardiac hypertrophy and mechanical unloading to cardiac atrophy. Both conditions produce similar transcriptional changes including a re-expression of fetal genes, despite obvious differences in phenotype. MicroRNAs (miRNAs) are discussed as superordinate regulators of global gene networks acting mainly at the translational level. Here, we hypothesized that defined sets of miRNAs may determine the direction of cardiomyocyte plasticity responses.
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