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ObjectiveTo discover and confirm blood-based colon cancer early-detection markers.DesignWe created a high-density antibody microarray to detect differences in protein levels in plasma from individuals diagnosed with colon cancer <3 years after blood was drawn (ie, prediagnostic) and cancer-free, matched controls. Potential markers were tested on plasma samples from people diagnosed with adenoma or cancer, compared with controls. Components of an optimal 5-marker panel were tested via immunoblotting using a third sample set, Luminex assay in a large fourth sample set and immunohistochemistry (IHC) on tissue microarrays.ResultsIn the prediagnostic samples, we found 78 significantly (t-test) increased proteins, 32 of which were confirmed in the diagnostic samples. From these 32, optimal 4-marker panels of BAG family molecular chaperone regulator 4 (BAG4), interleukin-6 receptor subunit beta (IL6ST), von Willebrand factor (VWF) and CD44 or epidermal growth factor receptor (EGFR) were established. Each panel member and the panels also showed increases in the diagnostic adenoma and cancer samples in independent third and fourth sample sets via immunoblot and Luminex, respectively. IHC results showed increased levels of BAG4, IL6ST and CD44 in adenoma and cancer tissues. Inclusion of EGFR and CD44 sialyl Lewis-A and Lewis-X content increased the panel performance. The protein/glycoprotein panel was statistically significantly higher in colon cancer samples, characterised by a range of area under the curves from 0.90 (95% CI 0.82 to 0.98) to 0.86 (95% CI 0.83 to 0.88), for the larger second and fourth sets, respectively.ConclusionsA panel including BAG4, IL6ST, VWF, EGFR and CD44 protein/glycomics performed well for detection of early stages of colon cancer and should be further examined in larger studies.

Abstract Rationale Screening for non–small cell lung cancer is associated with earlier diagnosis and reduced mortality but also increased harm caused by invasive follow-up of benign pulmonary nodules. Lung tumorigenesis activates the immune system, components of which could serve as tumor-specific biomarkers. Objectives To profile tumor-derived autoantibodies as peripheral biomarkers of malignant pulmonary nodules. Methods High-density protein arrays were used to define the specificity of autoantibodies isolated from B cells of 10 resected lung tumors. These tumor-derived autoantibodies were also examined as free or complexed to antigen in the plasma of the same 10 patients and matched benign nodule control subjects. Promising autoantibodies were further analyzed in an independent cohort of 250 nodule-positive patients. Measurements and Main Results Thirteen tumor B-cell–derived autoantibodies isolated ex vivo showed greater than or equal to 50% sensitivity and greater than or equal to 70% specificity for lung cancer. In plasma, 11 of 13 autoantibodies were present both complexed to and free from antigen. In the larger validation cohort, 5 of 13 tumor-derived autoantibodies remained significantly elevated in cancers. A combination of four of these autoantibodies could detect malignant nodules with an area under the curve of 0.74 and had an area under the curve of 0.78 in a subcohort of indeterminate (8–20 mm in the longest diameter) pulmonary nodules. Conclusions Our novel pipeline identifies tumor-derived autoantibodies that could effectively serve as blood biomarkers for malignant pulmonary nodule diagnosis. This approach has future implications for both a cost-effective and noninvasive approach to determine nodule malignancy for widespread low-dose computed tomography screening.

Harnessing the immune response to tumor antigens in the form of autoantibodies, which occurs early during tumor development, has relevance to the detection of cancer at early stages. We conducted an initial screen of antigens associated with an autoantibody response in serous ovarian cancer using recombinant protein arrays. The top 25 recombinants that exhibited increased reactivity with cases compared to controls revealed TP53 and MYC, which are ovarian cancer driver genes, as major network nodes. A mass spectrometry based independent analysis of circulating immunoglobulin (Ig)-bound proteins in ovarian cancer and of ovarian cancer cell surface MHC-II bound peptides also revealed a TP53–MYC related network of antigens. Our findings support the occurrence of a humoral immune response to antigens linked to ovarian cancer driver genes that may have utility for early detection applications.

Triple-negative breast cancer is a particularly aggressive and lethal breast cancer subtype that is more likely to be interval-detected rather than screen-detected. The purpose of this study is to discover and initially validate novel early detection biomarkers for triple-negative breast cancer using preclinical samples. Plasma samples collected up to 17 months before diagnosis from 28 triple-negative cases and 28 matched controls from the Women’s Health Initiative Observational Study were equally divided into a training set and a test set and interrogated by a customized antibody array. Data were available on 889 antibodies; in the training set, statistically significant differences in case versus control signals were observed for 93 (10.5 %) antibodies at p  < 0.05. Of these 93 candidates, 29 were confirmed in the test set at p  < 0.05. Areas under the curve for these candidates ranged from 0.58 to 0.79. With specificity set at 98 %, sensitivity ranged from 4 to 68 % with 20 candidates having a sensitivity ≥20 % and 6 having a sensitivity ≥40 %. In an analysis of KEGG gene sets, the pyrimidine metabolism gene set was upregulated in cases compared to controls ( p  = 0.004 in the testing set) and the JAK/Stat signaling pathway gene set was downregulated ( p  = 0.003 in the testing set). Numerous potential early detection biomarkers specific to triple-negative breast cancer in multiple pathways were identified. Further research is required to followup on promising candidates in larger sample sizes and to better understand their potential biologic importance as our understanding of the etiology of triple-negative breast cancer continues to grow.

This body of work focuses on improving the sensitivity and specificity of surface plasmon resonance (SPR) sensor surfaces through modification of surface chemistries and assays and increasing the throughput of the sensors by developing array-based detection formats. Improvements in sensor sensitivity were studied by altering the attachment chemistries for biorecognition elements on the surface. Using DNA-directed immobilization, proteins are immobilized in an area of interest through the high specificity of DNA hybridization. The DNA also provides a tether to distance the biorecognition clement from the denaturing effects of the sensor surface, thus improving the sensing element's performance. The lowest detectable concentration of human Chorionic Gonadotropin (hCG) was improved by a factor of 10 over a more conventional biotin-based immobilization. The use of a DNA surface and site-specific immobilization also enables array detections of both oligonucleotides and protein analytes on the same chip. Using a SPR imaging sensor and limiting the site-directed protein immobilization to a small number of array spots, DNA sequences on the surface are still available to detect the presence of oligonucleotides in a sample of interest. This hybrid may has applications in many areas, including the biomedical field and food safety, where detection of both proteomic and genetic markers are important. Array-based detection of cancer biomarker candidates is also demonstrated with a SPR imaging sensor. Activated leukocyte cell adhesion molecule/CD 166 (ALCAM) and transgelin-2 (TAGLN2) are detected without the need of secondary antibody binding at concentrations relevant to levels observed in serum samples. A second area of sensor research this work strives to improve is the detection of samples in complex matrices. Novel nonfouling materials based on zwitterionic polymers are developed and studied for use in human serum and plasma based diagnostics. These polymers show an improved resistance to non-specific adsorption over conventional ethylene glycol-based surfaces and have the potential to be used as sensor backgrounds for real-world samples. Assays in real-world samples applicable to the biomedical and food safety fields are also demonstrated. Increased levels of autoantibodies to carcinoembryonic antigen (a known ovarian cancer biomarker) were detected without the need of secondary antibody labeling in clinical serum samples. Detections of botulinum neurotoxins in honey demonstrate the applicability of SPR sensors to food safety.

The emerald ash borer, Agrilus planipennis Fairmaire (Coleoptera: Buprestidae), is a serious pest of ash (Fraxinus spp.) (Oleaceae) in North America. Control of emerald ash borer is difficult in natural forest settings; therefore, a classical biological control programme is the most feasible management option for this invasive, nonnative insect. Here, we report the first Canadian release and establishment of parasitoids Tetrastichus planipennisi Yang (Hymeoptera: Eulophinae), Oobius agrili Zhang and Huang (Hymenoptera: Encyrtidae), and Spathius galinae Belokobylskij and Strazanac (Hymenoptera: Braconidae) in natural forests in Ontario, Quebec, and New Brunswick, Canada for the control of emerald ash borer. Releases of T. planipennisi were made from 2013 to 2019, O. agrili from 2015 to 2019, and S. galinae from 2017 to 2019. Trees from release sites were destructively sampled to rear out adult emerald ash borers and parasitoids 1–3 years after parasitoid release. Recoveries of T. planipennisi were made at 81% of release sites (13 of 16) 1–2 years after release, and O. agili were recovered from 29% of release sites (4 of 14) 1–3 years after release. Spathius galinae was not recovered. These data provide important information for the development and deployment of a successful biological control programme for the management of emerald ash borer in Canada.