Faculty Bibliography

In recent years, nanomaterials and nanotechnology have emerged as vital factors in the medical field with a unique contribution to cancer medicine. Given the increasing number of cancer patients, it is necessarily required to develop innovative strategies and therapeutic modalities to tackle hypoxia, which forms a hallmark and great barrier in treating solid tumors. The present review details the challenges in nanotechnology-based hypoxia, targeting the strategies and solutions for better therapeutic performances. The interaction between hypoxia and tumor is firstly introduced. Then, we review the recently developed engineered nanomaterials towards multimodal hypoxia tumor therapies, including chemotherapy, radiotherapy, and sonodynamic treatment. In the next part, we summarize the nanotechnology-based strategies for overcoming hypoxia problems. Finally, current challenges and future directions are proposed for successfully overcoming the hypoxia tumor problems.

In many eukaryotes, Argonaute proteins, guided by short RNA sequences, defend cells against transposons and viruses. In the eubacterium Thermus thermophilus, the DNA-guided Argonaute TtAgo defends against transformation by DNA plasmids. Here, we report that TtAgo also participates in DNA replication. In vivo, TtAgo binds 15- to 18-nt DNA guides derived from the chromosomal region where replication terminates and associates with proteins known to act in DNA replication. When gyrase, the sole T. thermophilus type II topoisomerase, is inhibited, TtAgo allows the bacterium to finish replicating its circular genome. In contrast, loss of gyrase and TtAgo activity slows growth and produces long sausage-like filaments in which the individual bacteria are linked by DNA. Finally, wild-type T. thermophilus outcompetes an otherwise isogenic strain lacking TtAgo. We propose that the primary role of TtAgo is to help T. thermophilus disentangle the catenated circular chromosomes generated by DNA replication.

Registry-based epidemiologic studies suggest associations between chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma (PDAC). As genetic susceptibility contributes to a large proportion of chronic inflammatory intestinal diseases, we hypothesize that the genomic regions surrounding established genome-wide associated variants for these chronic inflammatory diseases are associated with PDAC. We examined the association between PDAC and genomic regions (+/- 500 kb) surrounding established common susceptibility variants for ulcerative colitis, Crohn's disease, inflammatory bowel disease, celiac disease, chronic pancreatitis, and primary sclerosing cholangitis. We analyzed summary statistics from genome-wide association studies data for 8,384 cases and 11,955 controls of European descent from two large consortium studies using the summary data-based adaptive rank truncated product method to examine the overall association of combined genomic regions for each inflammatory disease group. Combined genomic susceptibility regions for ulcerative colitis, Crohn's disease, inflammatory bowel disease, and chronic pancreatitis were associated with PDAC at P-values < 0.05 (0.0040, 0.0057, 0.011, and 3.4 × 10-6, respectively). After excluding the 20 PDAC susceptibility regions (+/- 500 kb) previously identified by GWAS, the genomic regions for ulcerative colitis, Crohn's disease, and inflammatory bowel disease remained associated with PDAC (P-values = 0.0029, 0.0057, and 0.0098, respectively). Genomic regions for celiac disease (P-value = 0.22) and primary sclerosing cholangitis (P-value = 0.078) were not associated with PDAC. Our results support the hypothesis that genomic regions surrounding variants associated with inflammatory intestinal diseases, particularly, ulcerative colitis, Crohn's disease, inflammatory bowel disease, and chronic pancreatitis are associated with PDAC.

In this study, a novel MgO-biochar composite was generated for nutrient recovery from biogas slurry using magnesium chloride (MgCl₂) and ammonia hydroxide (NH₃·H₂O). Biochar properties, including pH, CEC, pHpzc, magnesium content, surface area, and total pore volume (V_total), were evaluated. Moreover, the removal of NH₄⁺ and PO₄^3- in both single and bi-solute system were investigated. Results indicated that NH₃·H₂O pretreatment and MgO-coating enhanced biochar pH, CEC, and pHpzc. Additionally, there were generally higher surface area and V_total in MgAWS₅₅₀. The maximum adsorption capacities for NH₄⁺ and PO₄^3-, respectively, increased as WS₅₅₀ (0.555 and 1.57 mg g^-1) < MgWS₅₅₀ (15.4 and 21.8 mg g^-1) < MgAWS₅₅₀ (17.5 and 31.3 mg g^-1). Moreover, higher removal efficiencies were achieved in the bi-solute system, and over 25% and 90% of NH₄⁺ and PO₄^3-, respectively, was removed from biogas slurry by MgASW₅₅₀. Mechanically, NH₄⁺ removal was mainly attributed to ionic exchange, while PO₄^3- adsorption on MgO-coated biochars was due to electrostatic attraction and precipitation. Furthermore, the formation of struvite (MgNH₄PO₄·6H₂O) further enhanced N and P in the bi-solute system.

Background/UNASSIGNED:Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes. Methods/UNASSIGNED:We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided. Results/UNASSIGNED:We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets. Conclusion/UNASSIGNED:Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.

Circadian disruption has been linked to carcinogenesis in animal models, but the evidence in humans is inconclusive. Genetic variation in circadian rhythm genes provides a tool to investigate such associations. We examined associations of genetic variation in nine core circadian rhythm genes and six melatonin pathway genes with risk of colorectal, lung, ovarian and prostate cancers using data from the Genetic Associations and Mechanisms in Oncology (GAME-ON) network. The major results for prostate cancer were replicated in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, and for colorectal cancer in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). The total number of cancer cases and controls was 15,838/18,159 for colorectal, 14,818/14,227 for prostate, 12,537/17,285 for lung and 4,369/9,123 for ovary. For each cancer site, we conducted gene-based and pathway-based analyses by applying the summary-based Adaptive Rank Truncated Product method (sARTP) on the summary association statistics for each SNP within the candidate gene regions. Aggregate genetic variation in circadian rhythm and melatonin pathways were significantly associated with the risk of prostate cancer in data combining GAME-ON and PLCO, after Bonferroni correction (Ppathway <0.00625). The two most significant genes were NPAS2 (Pgene =0.0062) and AANAT (Pgene =0.00078); the latter being significant after Bonferroni correction. For colorectal cancer, we observed a suggestive association with the circadian rhythm pathway in GAME-ON (Ppathway =0.021); this association was not confirmed in GECCO (Ppathway =0.76) or the combined data (Ppathway =0.17). No association was observed for ovarian and lung cancer. These findings support a potential role for circadian rhythm and melatonin pathways in prostate carcinogenesis. Further functional studies are needed to better understand the underlying biologic mechanisms

With the rapid development of high throughput technologies such as array and next generation sequencing (NGS), genome-wide, nucleotide-resolution epigenomic data are increasingly available. In recent years, there has been particular interest in data on DNA methylation and 3-dimensional (3D) chromosomal organization, which are believed to hold keys to understand biological mechanisms, such as transcription regulation, that are closely linked to human health and diseases. However, small sample size, complicated correlation structure, substantial noise, biases, and uncertainties, all present difficulties for performing statistical inference. In this review, we present an overview of the new technologies that are frequently utilized in studying DNA methylation and 3D chromosomal organization. We focus on reviewing recent developments in statistical methodologies designed for better interrogating epigenomic data, pointing out statistical challenges facing the field whenever appropriate.

OBJECTIVE: Vascular endothelial cell injury contributes to the pathogenesis of viral encephalitis. This study was designed to investigate the roles of vascular endothelial growth factor (VEGF) and vascular cell adhesion molecule-1(VCAM-1) in cerebral spinal fluid (CSF) in the pathogenesis of viral encephalitis and in the evaluation of the severity and the prognosis of viral encephalitis in children. METHODS: CSF VEGF and VCAM-1 levels were measured using ELISA in 65 children with viral encephalitis and 20 age-matched controls (10 cases of epilepsy and 10 cases of congenital abnormality). RESULTS: CSF levels of VEGF and VCAM-1 in the viral encephalitis group in the acute phase were significantly elevated compared with those in the congenital abnormality (P<0.01) and the epilepsy groups (P<0.05). CSF levels of VEGF and VCAM-1 in the viral encephalitis group in the recovery phase decreased significantly and were similar to the levels of the epilepsy group, but remained higher than those in the congenital abnormality group (P<0.05). There was a positive correlation between CSF levels of VEGF and VCAM-1 in the viral encephalitis group in the acute and recovery phases. CSF levels of VEGF and VCAM-1 were positively correlated to CSF protein contents and the degree of MRI abnormality in the viral encephalitis group. CONCLUSIONS: VEGF and VCAM-1 may participate in the pathogenesis of viral encephalitis. Detection of the two parameters may be helpful to the evaluation of the severity and prognosis of viral encephalitis.

During the previous cloning of the fibrillin gene (FBN1), we isolated a partial cDNA coding for a fibrillin-like peptide and mapped the corresponding gene (FBN2) to human chromosome 5. (Lee, B., M. Godfrey, E. Vitale, H. Hori, M. G. Mattei, M. Sarfarazi, P. Tsipouras, F. Ramirez, and D. W. Hollister. 1991. Nature [Lond.]. 352:330-334). The study left, however, unresolved whether or not the FBN2 gene product is an extracellular component structurally related to fibrillin. Work presented in this report clarifies this important point. Determination of the entire primary structure of the FBN2 gene product demonstrated that this polypeptide is highly homologous to fibrillin. Immunoelectron microscopy localized both fibrillin proteins to elastin-associated extracellular microfibrils. Finally, immunohistochemistry revealed that the fibrillins co-distribute in elastic and non-elastic connective tissues of the developing embryo, with preferential accumulation of the FBN2 gene product in elastic fiber-rich matrices. These results support the original hypothesis that the fibrillins may have distinct but related functions in the formation and maintenance of extracellular microfibrils. Accordingly, we propose to classify the FBN1 and FBN2 gene products as a new family of extracellular proteins and to name its members fibrillin-1 and fibrillin-2, respectively.