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PDF file - 46K, Primers sequences used in this study

PDF file - 86K

PDF file - 68K, Example sequencing and genotyping output for rs10680577

SuPDF file - 232K, The linkage disequilibrium (LD) analyses of rs10680577 and relevant SNPs identified in GWAS using Haploview

PDF file - 146, Stratified analysis of rs10680577 genotypes associated with HCC susceptibility in Suzhou and Shanghai case control sets recruited during 2007-2010

PDF file - 158K, The genomic locations of rs10680577 and three adjacent genes (RAB4B, EGLN2 and RERT-lncRNA)

Genetic variants in the DPYD gene that are deleterious to dihydropyrimidine dehydrogenase (DPD) enzyme function have demonstrated clinical validity as predictive biomarkers for severe (i.e., CTCAE grade ≥3) and potentially lethal toxicity to fluorouracil (5-FU) and capecitabine chemotherapies. Variants within the coding region only explain 5-10% of 5-FU-related toxicities; and GWAS approaches have been unable to identify validated predictive biomarkers to date. Our previous studies demonstrated that DPD expression was controlled by multiple epigenetic processes; considerable variation was also noted in liver DPYD/DPD levels. Using CRISPR-interference (CRISPRi) and CRISPR-activation (CRISPRa), we identified functional enhancer regions within liver tissues and cells. Epigenetic status at these regions was shown to correlate with DPYD expression in cell models and human liver tissues. Chromosome conformation capture (3C) confirmed direct promoter-enhancer interactions. A multi-omics analysis of >1000 human liver specimens identified a proximal eQTL for DPYD expression within an enhancer, with a global minor allele frequency of 27%. This variant was subsequently shown to directly alter DPYD expression in knock-in cell line models. The variant disrupts transcription factor binding at the DPYD enhancer, leading to reduced enhancer-promoter interaction, reduced DPD expression, and increased cellular sensitivity to 5-FU. Collectively, our data suggest that the variant could represent a novel predictive biomarker for severe 5-FU toxicity. The evaluation of this marker in the clinical setting is currently underway. Citation Format: Ting Zhang, Alisa Ambrodji, Huixing Huang, Kelly Bouchonville, Amy Etheridge, Remington Schmidt, Jose Cardiel Nunez, Zoey Temesgen, Federico Innocenti, Robert Diasio, Carlo Largiadèr, Steven M. Offer. DPYD enhancer variant confers increased risk of severe toxicity in 5-FU chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5420.

The primary mechanism of action for the chemotherapeutic 5-fluorouracil (5-FU) is inhibition of thymidylate synthase (TS), which leads to nucleotide imbalance and subsequent cellular death. Expression of TS has been suggested to be determined by a variable number of tandem repeats located within the TS enhancer region (TSER). TSER genotype has been inconsistently linked to 5-FU-related adverse events, including severe grade ≥3 drug-related toxicity. Our recent studies demonstrated that the number of repeats within the TSER, as well as the presence or absence of a polymorphism within each repeat, was significantly associated with 5-FU toxicity in 629 patients. Our findings are consistent with a model in which the number of upstream stimulatory factor (USF1) transcription factor binding sites in the TSER, which is determined both by repeat status and genotype within each repeat, defines TYMS expression and contributions to 5-FU toxicity risk. We present an updated nomenclature that concisely and unambiguously identifies both the number of repeats and the number of USF1 binding sites. The difficulty in obtaining clear genotypes within this highly repetitive and variable region limits the ability to integrate this biomarker into predictive tests. We present methodologies for assigning TSER genotypes using conventional and high-throughput sequencing, including whole genome sequence data. Our results are expected to promote the improved study of TSER genotype in future clinical studies and the integration of TSER status into clinical predictive tests for severe 5-FU toxicity. Citation Format: Huixing Huang, Dominic Schaerer, Remington Schmidt, Ting Zhang, Tanja K Froehlich, Kelly Bouchonville, Robert B Diasio, Ursula Amstutz, Carlo Largiadèr, Steven M Offer. Novel approach to thymidylate synthase genotype determination and utility as a biomarker of severe toxicity to 5-FU chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5805.

The electronic conductivity enhanced has been extensively studied and reported in lithium iron phosph-ate (LiFePO4). However, only few existing literatures are available for researchers to enhance simultaneously the ion and electronic conductivity of LiFePO4. Herein, we disclose that the LiFePO4 is co-coated with novel GdPO4 and Carbon via a hydrothermal-assisted solid-phase method, contributing to particle size and dispersibility. What surprising is that the ionic and electronic conductivity of the material is significantly enhanced, and the interfacial side reaction is effectively inhibited between the materials and the electrolytes. The diverse proportions of the mixed coating (LiFePO4/C&xGdPO4 (x = 0, 1 wt%, 2 wt%, 3 wt%, 4 wt%)) are synthesized compared with bare LiFePO4. The experimental results suggest that LiFePO4/C&0.03GdPO4 exhibits the most excellent electrochemical performance. There is discharge capacity of 158, 148.8, 141.6, 134.9, 121.8, 104.9, and 86.7mAh/g at 0.1, 0.2, 0.5, 1, 2, 5, and 10 C rates, respectively.

In this paper, nano-scale LiFePO4/C composite was prepared by adding monocarboxylic acid (benzoic acid), dicarboxylic acid (oxalic acid) and tricarboxylic acid (citric acid) as additives in ethylene glycol. A systematic description of the impacts from the number of carboxyl groups on the morphology and electrochemical properties of LiFePO4/C composite in the ethylene glycol system was provided. And the significantly size reduction and similar morphology to uniform rice grain were observed after the surface grafting reaction of ethylene glycol with carboxylic acids on the LiFePO4/C particle surface. Furthermore, the experiments indicated regular changes in the dispersibility and electrochemical properties. The sample in which citric acid was added performed best in terms of dispersibility with the particle size of about 800 nm, and also good regarding electrochemical property with first discharge capacity of 148.13 mAh/g and coulombic efficiency of 97.97%.

A number of activated carbon fibers (ACF) were prepared by activation with steam, Phosphoric acid, or Zinc Chloride. Their reduction-adsorption behavior for Pt(IV) was studied using scanning electron microscopy, X-ray diffraction (XRD) and X-ray photoelectron spectroscopy. The results show that Pt ions in solution can be adsorbed by ACFs and reduced to metallic platinum. The reduction–adsorption capacity of ACF for Pt could be greater than 200 mg/g. Generally, higher specific surface area or lower electrode potential produces a higher capacity. Most of the adsorbed platinum ions were reduced into metallic platinum, and about 25% of platinum atoms remained as Pt(II) or Pt(IV). XRD examination showed that the Pt particles on the ACF surface were crystallized when heated to 673 K.

Hepatocellular carcinoma (HCC) is among the commonest kind of malignant tumors, which accounts for more than 500,000 cases of newly diagnosed cancer annually. Many microarray studies for identifying differentially expressed genes (DEGs) in HCC have been conducted, but results have varied across different studies. Here, we performed a meta-analysis of publicly available microarray Gene Expression Omnibus datasets, which covers five independent studies, containing 753 HCC samples and 638 non-tumor liver samples. We identified 192 DEGs that were consistently up-regulated in HCC vs. normal liver tissue. For the 192 up-regulated genes, we performed Kyoto Encyclopedia of Genes and Genomes pathway analysis. To our surprise, besides several cell growth-related pathways, spliceosome pathway was also up-regulated in HCC. For further exploring the relationship between spliceosome pathway and HCC, we investigated the expression data of spliceosome pathway genes in 15 independent studies in Nextbio database ( https://www.nextbio.com/b/nextbioCorp.nb ). It was found that many genes of spliceosome pathway such as HSPA1A, SNRPE, SF3B2, SF3B4 and TRA2A genes which we identified to be up-regulated in our meta-analysis were generally overexpressed in HCC. At last, using real-time PCR, we also found that BUD31, SF3B2, SF3B4, SNRPE, SPINK1, TPA2A and HSPA1A genes are significantly up-regulated in clinical HCC samples when compared to the corresponding non-tumorous liver tissues. Our study for the first time indicates that many genes of spliceosome pathway are up-regulated in HCC. This finding might put new insights for people's understanding about the relationship of spliceosome pathway and HCC.

The removal of NO X at high temperature by Chelatococcus daeguensis TAD1 in a biotrickling filter was studied. Media components of the recycling liquid were screened using Plackett–Burman design and then were optimized using response surface methodology, which enhanced the efficiency of nitrate removal by TAD1. The optimal medium was used to perform long-term experiments of NO X removal in a biotrickling filter under high concentrations of O 2 and NO in simulated flue gas. Results showed that the biotrickling filter was able to consistently remove 80.2–92.3% NO X when the inlet NO concentration was 600 ppm under the conditions of oxygen concentration ranging between 2% and 20% and empty bed residence time (EBRT) being 112.5 s. Analyses by polymerase chain reaction and denaturing gradient gel electrophoresis (PCR–DGGE) indicated that TAD1 was always predominant in the biofilm under a flue gas environment. Overall, the present study demonstrated that utilizing a biotrickling filter inoculated with the aerobic denitrifier TAD1 to remove NO X at high temperature was practically feasible.