Epitope recognition of peptide-imprinted polymers for Regenerating protein 1 (REG1)

Molecularly imprinted polymers (MIPs) were developed to replace natural antibodies with a cost-effective and durable synthetic material. Molecular imprinting of proteins conventionally utilizes the whole protein as the template, which is complex (as many different epitopes may be imprinted) and expensive. In this work, seven peptides (13–18 amino acids) were synthesized and used as templates for the imprinting and recognition of Regenerating Protein 1 (REG1). REG1 is involved in the proliferation and differentiation of diverse cell types, and was recently described as a urinary biomarker for pancreatic ductal adenocarcinoma (PDAC). Peptide-imprinted poly(ethylene-co-vinyl alcohol)s (PIPs), containing four different mole fractions of ethylene were cast on screen-printed electrodes to find the optimum composition for both the sensing and the extraction of REG1 in an E. coli culture medium. Peptides with fewer than 16 amino acids and two or three aromatic and hydrophobic groups have a higher affinity for MIPs of poly(ethylene-co-vinyl alcohol) (EVAL) with 27 mol% of ethylene, while those with four aromatic and hydrophobic groups have a higher affinity for MIPs with EVALs that contain 32 mol% of ethylene. The peptide / EVAL combination that maximized both imprinting effectiveness and response to REG1B was the sequence NEDRETWVDADLY imprinted into 32 mol% EVAL. This EVAL composition and template peptide were then modified by incorporation of magnetic nanoparticles, thus extending applications for PIPs to include extraction of REG1 protein from E. coli culture medium

S100PBP (S100P binding protein)

Review on S100PBP (S100P binding protein), with data on DNA, on the protein encoded, and where the gene is implicated

Nutraceuticals as Supportive Therapeutic Agents in Diabetes and Pancreatic Ductal Adenocarcinoma: A Systematic Review

The correlation between pancreatic ductal adenocarcinoma (PDAC) and diabetes-related mechanisms support the hypothesis that early therapeutic strategies targeting diabetes can contribute to PDAC risk reduction and treatment improvement. A systematic review was conducted, using PubMed, Embase and Cochrane Library databases, to evaluate the current evidence from clinical studies qualitatively examining the efficacy of four natural products: Curcumin—Curcuma longa L.; Thymoquinone—Nigella sativa L.; Genistein—Glycine max L.; Ginkgo biloba L.; and a low-carbohydrate ketogenic diet in type 2 diabetes (T2D) and PDAC treatment. A total of 28 clinical studies were included, showing strong evidence of inter-study heterogeneity. Used as a monotherapy or in combination with chemo-radiotherapy, the studied substances did not significantly improve the treatment response of PDAC patients. However, pronounced therapeutic efficacy was confirmed in T2D. The natural products and low-carbohydrate ketogenic diet, combined with the standard drugs, have the potential to improve T2D treatment and thus potentially reduce the risk of cancer development and improve multiple biological parameters in PDAC patients

Non-Invasive Biomarkers for Earlier Detection of Pancreatic Cancer-A Comprehensive Review

SIMPLE SUMMARY: Pancreatic ductal adenocarcinoma (PDAC), which represents approximately 90% of all pancreatic cancers, is an extremely aggressive and lethal disease. It is considered a silent killer due to a largely asymptomatic course and late clinical presentation. Earlier detection of the disease would likely have a great impact on changing the currently poor survival figures for this malignancy. In this comprehensive review, we assessed over 4000 reports on non-invasive PDAC biomarkers in the last decade. Applying the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool, we selected and reviewed in more detail 49 relevant studies reporting on the most promising candidate biomarkers. In addition, we also highlight the present challenges and complexities of translating novel biomarkers into clinical use. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) carries a deadly diagnosis, due in large part to delayed presentation when the disease is already at an advanced stage. CA19-9 is currently the most commonly utilized biomarker for PDAC; however, it lacks the necessary accuracy to detect precursor lesions or stage I PDAC. Novel biomarkers that could detect this malignancy with improved sensitivity (SN) and specificity (SP) would likely result in more curative resections and more effective therapeutic interventions, changing thus the present dismal survival figures. The aim of this study was to systematically and comprehensively review the scientific literature on non-invasive biomarkers in biofluids such as blood, urine and saliva that were attempting earlier PDAC detection. The search performed covered a period of 10 years (January 2010—August 2020). Data were extracted using keywords search in the three databases: MEDLINE, Web of Science and Embase. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool was applied for study selection based on establishing the risk of bias and applicability concerns in Patient Selection, Index test (biomarker assay) and Reference Standard (standard-of-care diagnostic test). Out of initially over 4000 published reports, 49 relevant studies were selected and reviewed in more detail. In addition, we discuss the present challenges and complexities in the path of translating the discovered biomarkers into the clinical setting. Our systematic review highlighted several promising biomarkers that could, either alone or in combination with CA19-9, potentially improve earlier detection of PDAC. Overall, reviewed biomarker studies should aim to improve methodological and reporting quality, and novel candidate biomarkers should be investigated further in order to demonstrate their clinical usefulness. However, challenges and complexities in the path of translating the discovered biomarkers from the research laboratory to the clinical setting remain and would have to be addressed before a more realistic breakthrough in earlier detection of PDAC is achieved

Regularized gene selection in cancer microarray meta-analysis

<p>Abstract</p> <p>Background</p> <p>In cancer studies, it is common that multiple microarray experiments are conducted to measure the same clinical outcome and expressions of the same set of genes. An important goal of such experiments is to identify a subset of genes that can potentially serve as predictive markers for cancer development and progression. Analyses of individual experiments may lead to unreliable gene selection results because of the small sample sizes. Meta analysis can be used to pool multiple experiments, increase statistical power, and achieve more reliable gene selection. The meta analysis of cancer microarray data is challenging because of the high dimensionality of gene expressions and the differences in experimental settings amongst different experiments.</p> <p>Results</p> <p>We propose a Meta Threshold Gradient Descent Regularization (MTGDR) approach for gene selection in the meta analysis of cancer microarray data. The MTGDR has many advantages over existing approaches. It allows different experiments to have different experimental settings. It can account for the joint effects of multiple genes on cancer, and it can select the same set of cancer-associated genes across multiple experiments. Simulation studies and analyses of multiple pancreatic and liver cancer experiments demonstrate the superior performance of the MTGDR.</p> <p>Conclusion</p> <p>The MTGDR provides an effective way of analyzing multiple cancer microarray studies and selecting reliable cancer-associated genes.</p

AGR2, a unique tumor-associated antigen, is a promising candidate for antibody targeting.

Anterior gradient 2 (AGR2), a protein disulfide isomerase, shows two subcellular localizations: intracellular (iAGR2) and extracellular (eAGR2). In healthy cells that express AGR2, the predominant form is iAGR2, which resides in the endoplasmic reticulum. In contrast, cancer cells secrete and express eAGR2 on the cell surface. We wanted to test if AGR2 is a cancer-specific tumor-associated antigen. We utilized two AGR2 antibodies, P3A5 and P1G4, for in vivo tumor localization and tumor growth inhibition. The monoclonal antibodies recognized both human AGR2 and mouse Agr2. Biodistribution experiments using a syngeneic mouse model showed high uptake of P3A5 AGR2 antibody in xenografted eAgr2+ pancreatic tumors, with limited uptake in normal tissues. In implanted human patient-derived eAGR2+ pancreatic cancer xenografts, tumor growth inhibition was evaluated with antibodies and Gemcitabine (Gem). Inhibition was more potent by P1G4 + Gem combination than Gem alone or P3A5 + Gem. We converted these two antibodies to human:mouse chimeric forms: the constructed P3A5 and P1G4 chimeric mVLhCκ and mVHhCγ (γ1, γ2, γ4) genes were inserted in a single mammalian expression plasmid vector, and transfected into human 293F cells. Expressed human:mouse chimeric IgG1, IgG2 and IgG4 antibodies retained AGR2 binding. Increase in IgG yield by transfected cells could be obtained with serial transfection of vectors with different drug resistance. These chimeric antibodies, when incubated with human blood, effectively lysed eAGR2+ PC3 prostate cancer cells. We have, thus, produced humanized anti-AGR2 antibodies that, after further testing, might be suitable for treatment against a variety of eAGR2+ solid tumors.University of Washington CoMotion FundNCI-EDRN Biomarker Developmental Lab grant U01CA111244, and DoD W81XWH-16-1-0614