Shan Bai

Risk of Type 1 Diabetes Progression in Islet Autoantibody-Positive Children Can Be Further Stratified Using Expression Patterns of Multiple Genes Implicated in Peripheral Blood Lymphocyte Activation and Function

There is tremendous scientific and clinical value to further improving the predictive power of autoantibodies because autoantibody-positive (AbP) children have heterogeneous rates of progression to clinical diabetes. This study explored the potential of gene expression profiles as biomarkers for risk stratification among 104 AbP subjects from the Diabetes Autoimmunity Study in the Young (DAISY) using a discovery data set based on microarray and a validation data set based on real-time RT-PCR. The microarray data identified 454 candidate genes with expression levels associated with various type 1 diabetes (T1D) progression rates. RT-PCR analyses of the top-27 candidate genes confirmed 5 genes (BACH2, IGLL3, EIF3A, CDC20, and TXNDC5) associated with differential progression and implicated in lymphocyte activation and function. Multivariate analyses of these five genes in the discovery and validation data sets identified and confirmed four multigene models (BI, ICE, BICE, and BITE, with each letter representing a gene) that consistently stratify high- and low-risk subsets of AbP subjects with hazard ratios >6 (P < 0.01). The results suggest that these genes may be involved in T1D pathogenesis and potentially serve as excellent gene expression biomarkers to predict the risk of progression to clinical diabetes for AbP subjects.

Identification of serum proteins and multivariate models for diagnosis and therapeutic monitoring of lung cancer

Lung cancer is one of the most prevalent cancers and has very poor treatment outcome. Biomarkers useful for screening and assessing early therapeutic response may significantly improve the therapeutic outcome but are still lacking. In this study, serum samples from 218 non-small cell lung cancer (NSCLC) patients, 34 small cell lung cancer (SCLC) patients and 171 matched healthy controls from China were analyzed for 11 proteins using the Luminex multiplex assay. Eight of the 11 proteins (OPN, SAA, CRP, CYFRA21.1, CEA, NSE, AGP and HGF) are significantly elevated in NSCLC and SCLC (p = 10−5−10−59). At the individual protein level, OPN has the best diagnostic value for NSCLC (AUC = 0.92), two acute phase proteins (SAA and CRP) have AUC near 0.83, while CEA and CYFRA21.1 also possess good AUC (0.81 and 0.77, respectively). More importantly, several three-protein combinations that contain OPN and CEA plus one of four proteins (CRP, SAA, CYFRA21.1 or NSE) have excellent diagnostic potential for NSCLC (AUC = 0.96). Four proteins (CYFRA21.1, CRP, SAA and NSE) are severely reduced and three proteins (OPN, MIF and NSE) are moderately decreased after platinum-based chemotherapy. Therapeutic response index (TRI) computed with 3–5 proteins suggests that approximately 25% of the NSCLC patients respond well to the therapy and TRI is significantly correlated with pre-treatment protein levels. Our data suggest that therapeutic response in NSCLC patients can be effectively measured but personalized biomarkers may be needed to monitor different subsets of patients.

IGF-Binding Proteins in Type-1 Diabetes Are More Severely Altered in the Presence of Complications.

Aims Reduced levels of free and total insulin-like growth factor 1 (IGF-I) have been observed in type-1 diabetes (T1D) patients. The bioavailability of IGF-I from the circulation to the target cells is controlled by multifunctional IGF-binding proteins (IGFBPs). The aim of this study was to profile serum IGFBPs in T1D and its complications. Design We measured the IGFBP levels in 3662 patient serum samples from our ongoing Phenome and Genome of Diabetes Autoimmunity (PAGODA) study. IGFBP levels of four different groups of T1D patients (with 0, 1, 2, and ≥3 complications) were compared with healthy controls. Results Three serum IGFBPs (IGFBP-1, -2, and -6) are significantly higher in T1D patients, and these alterations are greater in the presence of diabetic complications. IGFBP-3 is lower in patients with diabetic complications. Analyses using quintiles revealed that risk of T1D complications increases with increasing concentrations of IGFBP-2 (fifth quintile ORs: 18–60, p < 10−26), IGFBP-1 (fifth quintile ORs: 8–20, p < 10−15), and IGFBP-6 (fifth quintile ORs: 3–148, p < 10−3). IGFBP-3 has a negative association with T1D complications (fifth quintile ORs: 0.12–0.25, p < 10−5). Conclusion We found that elevated serum levels of IGFBP-1, -2, and -6 were associated with T1D, and its complications and IGFBP-3 level was found to be decreased in T1D with complications. Given the known role of these IGFBPs, the overall impact of these alterations suggests a negative effect on IGF signaling.

Diagnostic and prognostic biomarker potential of kallikrein family genes in different cancer types

Purpose The aim of this study was to compare and contrast the expression of all members of the Kallikrein (KLK) family of genes across 15 cancer types and to evaluate their utility as diagnostic and prognostic biomarkers. Results Severe alterations were found in the expression of different Kallikrein genes across various cancers. Interestingly, renal clear cell and papillary carcinomas have similar kallikrein expression profiles, whereas, chromophobe renal cell carcinoma has a unique expression profile. Several KLK genes have excellent biomarker potential (AUC > 0.90) for chromophobe renal cell carcinoma (KLK2, KLK3, KLK4, KLK7, KLK15), renal papillary carcinoma (KLK1, KLK6, KLK7), clear cell renal cell carcinoma (KLK1, KLK6), thyroid carcinoma (KLK2, KLK4, KLK13, KLK15) and colon adenocarcinoma (KLK6, KLK7, KLK8, KLK10). Several KLK genes were significantly associated with mortality in clear cell renal cell carcinoma (KLK2: HR = 1.69; KLK4: HR = 1.63; KLK8: HR = 1.71; KLK10: HR = 2.12; KLK11: HR = 1.76; KLK14: HR = 1.86), papillary renal cell carcinoma (KLK6: HR = 3.38, KLK7: HR = 2.50), urothelial bladder carcinoma (KLK5: HR = 1.89, KLK6: HR = 1.71, KLK8: HR = 1.60), and hepatocellular carcinoma (KLK13: HR = 1.75). Methods The RNA-seq gene expression data were downloaded from The Cancer Genome Atlas (TCGA). Statistical analyses, including differential expression analysis, receiver operating characteristic curves and survival analysis (Cox proportional-hazards regression models) were performed. Conclusions A comprehensive analysis revealed the changes in the expression of different KLK genes associated with specific cancers and highlighted their potential as a diagnostic and prognostic tool.

Proteomic alterations in aqueous humor from patients with primary open angle glaucoma

Purpose Primary open angle glaucoma (POAG) is the most prevalent form of glaucoma, accounting for approximately 90% of all cases. The aqueous humor (AH), a biological fluid in the anterior and posterior chambers of the eye, is involved in a multitude of functions including the maintenance of IOP and ocular homeostasis. This fluid is very close to the pathologic site and is also known to have a significant role in glaucoma pathogenesis. The purpose of this study was to identify proteomic alterations in AH from patients with POAG. Methods AH samples were extracted from 47 patients undergoing cataract surgery (controls: n = 32; POAG: n = 15). Proteomic analysis of the digested samples was accomplished by liquid-chromatography-mass spectrometry. The identified proteins were evaluated using a variety of statistical and bioinformatics methods. Results A total of 33 proteins were significantly altered in POAG subjects compared with the controls. The most abundant proteins in POAG subjects are IGKC (13.56-fold), ITIH4 (4.1-fold), APOC3 (3.36-fold), IDH3A (3.11-fold), LOC105369216 (2.98-fold). SERPINF2 (2.94-fold), NPC2 (2.88-fold), SUCLG2 (2.70-fold), KIAA0100 (2.29-fold), CNOT4 (2.23-fold), AQP4 (2.11-fold), COL18A1 (2.08-fold), NWD1 (2.07-fold), and TMEM120B (2.06-fold). A significant increasing trend in the odds ratios of having POAG was observed with increased levels of these proteins. Conclusion Proteins identified in this study are implicated in signaling, glycosylation, immune response, molecular transport, and lipid metabolism. The identified candidate proteins may be potential biomarkers associated with POAG development and may lead to more insight in understanding the mechanisms underlying the pathogenesis of this disease.

Proteins of TNF-α and IL6 Pathways Are Elevated in Serum of Type-1 Diabetes Patients with Microalbuminuria

Soluble cytokine receptors may play an important role in development of microalbuminuria (MA) in type-1 diabetes (T1D). In this study, we measured 12 soluble receptors and ligands from TNF-α/IL6/IL2 pathways in T1D patients with MA (n = 89) and T1D patients without MA (n = 483) participating in the PAGODA study. Twelve proteins in the sera from T1D patients with and without MA were measured using multiplex Luminex assays. Ten serum proteins (sTNFR1, sTNFR2, sIL2Rα, MMP2, sgp130, sVCAM1, sIL6R, SAA, CRP, and sICAM1) were significantly elevated in T1D patients with MA. After adjusting for age, duration of diabetes, and sex in logistic regression, association remained significant for seven proteins. MA is associated with increasing concentrations of all 10 proteins, with the strongest associations observed for sTNFR1 (OR = 108.3, P < 10−32) and sTNFR2 (OR = 65.5, P < 10−37), followed by sIL2Rα (OR = 12.9, P < 10−13), MMP2 (OR = 5.5, P < 10−6), sgp130 (OR = 5.2, P < 10−3), sIL6R (OR = 4.6, P < 10−4), and sVCAM1 (OR = 3.3, P < 10−4). We developed a risk score system based on the combined odds ratios associated with each quintile for each protein. The risk scores cluster MA patients into three subsets, each associated with distinct risk for MA attributable to proteins in the TNF-α/IL6 pathway (mean OR = 1, 13.5, and 126.3 for the three subsets, respectively). Our results suggest that the TNF-α/IL6 pathway is overactive in approximately 40% of the MA patients and moderately elevated in the middle 40% of the MA patients. Our results suggest the existence of distinct subsets of MA patients identifiable by their serum protein profiles.