Browsing by Author "Campa, Michael J"
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Item Open Access A Therapeutic Antibody for Cancer, Derived from Single Human B Cells.(Cell Rep, 2016-05-17) Bushey, Ryan T; Moody, M Anthony; Nicely, Nathan L; Haynes, Barton F; Alam, S Munir; Keir, Stephen T; Bentley, Rex C; Roy Choudhury, Kingshuk; Gottlin, Elizabeth B; Campa, Michael J; Liao, Hua-Xin; Patz, Edward FSome patients with cancer never develop metastasis, and their host response might provide cues for innovative treatment strategies. We previously reported an association between autoantibodies against complement factor H (CFH) and early-stage lung cancer. CFH prevents complement-mediated cytotoxicity (CDC) by inhibiting formation of cell-lytic membrane attack complexes on self-surfaces. In an effort to translate these findings into a biologic therapy for cancer, we isolated and expressed DNA sequences encoding high-affinity human CFH antibodies directly from single, sorted B cells obtained from patients with the antibody. The co-crystal structure of a CFH antibody-target complex shows a conformational change in the target relative to the native structure. This recombinant CFH antibody causes complement activation and release of anaphylatoxins, promotes CDC of tumor cell lines, and inhibits tumor growth in vivo. The isolation of anti-tumor antibodies derived from single human B cells represents an alternative paradigm in antibody drug discovery.Item Open Access Behavioral patterns of Djungarian hamsters: An adaptive profile(Animal Learning & Behavior, 1984-09) Sawrey, D Kim; Baumgardner, Denis J; Campa, Michael J; Ferguson, Bruce; Hodges, Alan W; Dewsbury, Donald AItem Open Access Biomarkers to help guide management of patients with pulmonary nodules.(Am J Respir Crit Care Med, 2013-08-15) Patz, Edward F; Campa, Michael J; Gottlin, Elizabeth B; Trotter, Priscilla R; Herndon, James E; Kafader, Don; Grant, Russell P; Eisenberg, MarciaRATIONALE: Indeterminate pulmonary nodules are a common radiographic finding and require further evaluation because of the concern for lung cancer. OBJECTIVES: We developed an algorithm to assign patients to a low- or high-risk category for lung cancer, based on a combination of serum biomarker levels and nodule size. METHODS: For the serum biomarker assay, we determined levels of carcinoembryonic antigen, α1-antitrypsin, and squamous cell carcinoma antigen. Serum data and nodule size from a training set of 509 patients with (n = 298) and without (n = 211) lung cancer were subjected to classification and regression tree and logistic regression analyses. Multiple models were developed and tested in an independent, masked validation set for their ability to categorize patients with (n = 203) or without (n = 196) lung cancer as being low- or high-risk for lung cancer. MEASUREMENTS AND MAIN RESULTS: In all models, a large percentage of individuals in the validation study with small nodules (<1 cm) were assigned to the low-risk group, and a large percentage of individuals with large nodules (≥3 cm) were assigned to the high-risk group. In the validation study, the classification and regression tree algorithm had overall sensitivity, specificity, and positive and negative predictive values for determining lung cancer of 88%, 82%, 84%, and 87%, respectively. The logistic regression model had overall sensitivity, specificity, and positive and negative predictive values of 80%, 89%, 89%, and 81%, respectively. CONCLUSION: Integration of biomarkers with lung nodule size has the potential to help guide the management of patients with indeterminate pulmonary nodules.Item Open Access Characterising phase variations in MALDI-TOF data and correcting them by peak alignment.(Cancer Inform, 2005) Lin, Simon M; Haney, Richard P; Campa, Michael J; Fitzgerald, Michael C; Patz, Edward FThe use of MALDI-TOF mass spectrometry as a means of analyzing the proteome has been evaluated extensively in recent years. One of the limitations of this technique that has impeded the development of robust data analysis algorithms is the variability in the location of protein ion signals along the x-axis. We studied technical variations of MALDI-TOF measurements in the context of proteomics profiling. By acquiring a benchmark data set with five replicates, we estimated 76% to 85% of the total variance is due to phase variation. We devised a lobster plot, so named because of the resemblance to a lobster claw, to help detect the phase variation in replicates. We also investigated a peak alignment algorithm to remove the phase variation. This operation is analogous to the normalization step in microarray data analysis. Only after this critical step can features of biological interest be clearly revealed. With the help of principal component analysis, we demonstrated that after peak alignment, the differences among replicates are reduced. We compared this approach to peak alignment with a model-based calibration approach in which there was known information about peaks in common among all spectra. Finally, we examined the potential value at each point in an analysis pipeline of having a set of methods available that includes parametric, semiparametric and nonparametric methods; among such methods are those that benefit from the use of prior information.Item Open Access Interrogation of individual intratumoral B lymphocytes from lung cancer patients for molecular target discovery.(Cancer Immunol Immunother, 2016-02) Campa, Michael J; Moody, M Anthony; Zhang, Ruijun; Liao, Hua-Xin; Gottlin, Elizabeth B; Patz, Edward FIntratumoral B lymphocytes are an integral part of the lung tumor microenvironment. Interrogation of the antibodies they express may improve our understanding of the host response to cancer and could be useful in elucidating novel molecular targets. We used two strategies to explore the repertoire of intratumoral B cell antibodies. First, we cloned VH and VL genes from single intratumoral B lymphocytes isolated from one lung tumor, expressed the genes as recombinant mAbs, and used the mAbs to identify the cognate tumor antigens. The Igs derived from intratumoral B cells demonstrated class switching, with a mean VH mutation frequency of 4%. Although there was no evidence for clonal expansion, these data are consistent with antigen-driven somatic hypermutation. Individual recombinant antibodies were polyreactive, although one clone demonstrated preferential immunoreactivity with tropomyosin 4 (TPM4). We found that higher levels of TPM4 antibodies were more common in cancer patients, but measurement of TPM4 antibody levels was not a sensitive test for detecting cancer. Second, in an effort to focus our recombinant antibody expression efforts on those B cells that displayed evidence of clonal expansion driven by antigen stimulation, we performed deep sequencing of the Ig genes of B cells collected from seven different tumors. Deep sequencing demonstrated somatic hypermutation but no dominant clones. These strategies may be useful for the study of B cell antibody expression, although identification of a dominant clone and unique therapeutic targets may require extensive investigation.Item Open Access Prognostic significance of a complement factor H autoantibody in early stage NSCLC.(Cancer biomarkers : section A of Disease markers, 2022-01-14) Gottlin, Elizabeth B; Campa, Michael J; Gandhi, Rikesh; Bushey, Ryan T; Herndon Nd, James E; Patz, Edward FBiomarkers that predict which patients with early stage NSCLC will develop recurrent disease would be of clinical value. We previously discovered that an autoantibody to a complement regulatory protein, complement factor H (CFH), is associated with early stage, non-recurrent NSCLC, and hypothesized that the anti-CFH antibody inhibits metastasis. The primary objective of this study was to evaluate the anti-CFH antibody as a prognostic marker for recurrence in stage I NSCLC. A secondary objective was to determine if changes in antibody serum level one year after resection were associated with recurrence. Anti-CFH antibody was measured in the sera of 157 stage I NSCLC patients designated as a prognostic cohort: 61% whose cancers did not recur, and 39% whose cancers recurred following resection. Impact of anti-CFH antibody positivity on time to recurrence was assessed using a competing risk analysis. Anti-CFH antibody levels were measured before resection and one year after resection in an independent temporal cohort of 47 antibody-positive stage I NSCLC patients: 60% whose cancers did not recur and 40% whose cancers recurred following resection. The non-recurrent and recurrent groups were compared with respect to the one-year percent change in antibody level. In the prognostic cohort, the 60-month cumulative incidence of recurrence was 40% and 22% among antibody negative and positive patients, respectively; this difference was significant (Gray's test, P= 0.0425). In the temporal cohort, the antibody persisted in the serum at one year post-tumor resection. The change in antibody levels over the one year period was not statistically different between the non-recurrent and recurrent groups (Wilcoxon two-sample test, P= 0.4670). The anti-CFH autoantibody may be a useful prognostic marker signifying non-recurrence in early stage NSCLC patients. However, change in the level of this antibody in antibody-positive patients one year after resection had no association with recurrence.